PREPARATION OF SOME ORGANOZINC COMPOUNDS
AND THEIR ENANTIOSELECTIVE ADDITION TO
ALDEHYDES
THESIS
SUBMITTED TO THE
UNIVERSITY OF PUNE
FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
IN
CHEMISTRY
BY
Mr. RAVINDRA SUBHASH JAGTAP
DR. N. N. JOSHI
(RESEARCH SUPERVISOR)
DIVISION OF ORGANIC CHEMISTRY
NATIONAL CHEMICAL LABORATORY
PUNE 411 008, INDIA
Dedicated to my beloved parents
CERTIFICATE
The research work presented in thesis entitled “Preparation of some
organozinc compounds and their enantioselective addition to aldehydes” has
been carried out under my supervision and is a bonafide work of Mr. Ravindra
Subhash Jagtap. This work is original and has not been submitted for any other
degree or diploma of this or any other university.
March, 2012
Dr. N. N. Joshi
(Research Supervisor)
National Chemical Laboratory, Pune (India)
DECLARATION
I hereby declare that the thesis entitled “Preparation of some organozinc
compounds and their enantioselective addition to aldehydes” submitted for Ph.
D. degree to the University of Pune has been carried out at National Chemical
Laboratory, under the supervision of Dr. N. N. Joshi. This work is original and has
not been submitted in part or full by me for any degree or diploma to this or any
other university.
March, 2012
Ravindra S. Jagtap
Acknowledgements
First of all I wish to express my deep sense of gratitude and profound thanks to my
teacher and research supervisor Dr. N. N. Joshi for introducing me in the fascinating field of
asymmetric synthesis. I am indebted to him for his personal care and his enthusiastic
encouragement in the progress of my research work. His wide knowledge and logical way of
thinking have been of great value for me. My interaction with him have improved my quality of
research and developing me a critical research attitude. I will be always obliged to him for
teaching me the finest skill and giving excellent training required for the research as well as for
his constant effort to instill us with several essential habits, like group meeting, monthly report
and daily planning of work. His systematic working style, discipline and humanitarianism is an
attribute that I wish to take forward with me along with the chemistry that I learnt from him.
My sincere regards and respect are for him forever.
I would like to thank Dr. S. P. Chavan and prof. D. D. Dhawale for their valuable
suggestions and scientific discussion during assessment of my Ph.D. work.
I would like to thank the Council of Scientific and Industrial Research (CSIR), New
Delhi for the award of fellowship. I am thankful to Dr. G. P. Pandey, Head of organic chemistry
division and Dr. Sivram (ex. Director, NCL), Dr. Sourav Pal, Director, NCL who gave me an
opportunity to work in this prestigious research institute and providing all necessary
infrastructure and facilities.
My sincere thanks to Dr. M. S. Shasidhar, Dr. C. V. Ramana, Dr. U. R. Kalkote, Dr.
N. P. Argade, Dr. H. B. Borate, Dr. P. K. Tripathi, Dr. B. G. Hazara, Dr. H. V. Thulasiram,
Dr. D. Dethe, Dr. G. Sanjayan, Dr. Gumaste, Dr. (Mrs) A. P. Likhithe, Dr. (Mrs) S. P.
Maybhate, Dr. Gajbhiye, Dr. Muthukrishnan, Dr. M. K. Dongare, Dr. P. P. Wadgaonkar, Dr.
B. Idage Dr. (Mrs). Idage, Dr. (Mrs) Umbharkar and to other scientist of NCL.
I take this opportunity to express my great sense of gratitude to thank my teachers; Prof.
R. A. Mane, Prof. M. S. Shingare, Prof. B. R. Arbad, Prof. T. K. Chondekar, Dr. Lande (M. Sc.,
Dr. B. A. M. university, Aurangabad), Dr. Nalawade, Mrs. Nalawade madam, Dr. Mahadik,
Dr. Dhumure, Dr. Ghodke, Mungare sir, Fulsagar sir, Thorat sir (B. Sc., R. P. College
Osmanabad), Bhosale Sir and Mahadik Sir (I. T. I. Osmanabad), late Sarang Sir, Bangar Sir,
Naikawadi Sir, Padwal Sir, Raut Sir, Shinde Sir, Salunke Guruji, Sheikh Guruji, Nimbalkar Sir
(School teachers) for their support and constant encouragement.
Help from spectroscopy, microanalysis and X-ray crystallographic groups is greatfully
acknowledged. I sincerely thanks to Dr. Rajmohan, Dr. (Mrs) Phalgune, Mr. Sathe for NMR,
Mrs. S. P. Kunte for recording chiral HPLC, Mr. Kalal, Dr. Borikar for GC analysis, Dr. P. L.
Joshi for microanalysis. Help from IR and mass facility is also acknowledged. I express my
thanks to the office staff, Library members and administrative staff for their timely help.
It gives me immense pleasure to express my sincere thanks to my senior colleagues; Dr.
Kartick Bhoumick, Dr. Anamitra Chatterjee, Dr. M. Sasikumar for their friendly nature, giving
excellent training, valuable discussion and support. I am very thankful my senior colleague Dr.
Mannamth Patil for helpful scientific discussion, moral support and being a good fried.
I also would like to mention special thanks to Dr. (Mrs) B. N. Joshi and Rohit Joshi for
rendering pleasant association during my research period.
I feel very fortunate to have friends like Kishor, Rahul, Ramchandra and seema. I have
no word to express my emotions for their love, care and support in a tough time of my stay. I
thank them and their family for everything that they gave.
Special thanks to dear friends; Amol, Goroba (samya), Sunil, Tirupati, Dr. Sanjay,
Kiran, Jayant, Nana, Praveen, Ajit, Madhav, Kalyan, Appa, Ravi, Sanjay Chavan, Rajkanya,
Shubhangi, Deepali, Meera, Dr. Sachin Navle, Prashant Mangshetti, Sunil sontakke, Tanaji
gapat, Gurunath, Laxman, Sanjay, and Sakharam, Sambhaji, Sachin, Sandeep, Amar.
Help from my seniors, Dr. Bapu Shingate, Dr. Bhaskar Sathe, Dr. Rajiv Sawant and
Dr. Sandeep Udawant is greatfully and sincerely appreciated.
It is a pleasure to thank all my friend at NCL, Scientist apartment and GJ hostel for
their cheerfull company, which made my stay at NCL memorable one, especially Nilesh, Lalit,
Dhanlaxmi, Namrata, Satish biradar, Ganesh Gogdand, Dr. Sudhir bavikar, Dr. Kondekar, Dr.
Giri, Dr. Sharad, Amrut, Deepak, Ganesh, Ankush, Prakash, Bhausaheb, Dr. Bhange, Dhanu,
Kiran, Pankaj, Abhijeet, Dayanand, dattatraya, Dr. Aabasaheb, Dr. Suleman, Sumantho,
Prakash, Pradeep, kailash, Harshali, Balaji selukar, Pitambar, Dr. Sunil Pandey, Sachin, Dr.
Vikhe, Dr. Pushpesh, Dr. Abhishek, Krishanu, Sangmash, Gopi, Dhiraj, Dr. Pandurang, Dr.
Amol, Dr. Shriram, Dr. Deepak, Dr. Murli, Dr. Ajay kale, Dr. Shafi, Dr. Manish Shimpi, Dr.
Kalpesh Rana, Dr. Haval, Dr. Umesh, Dr. Ramesh, Dr. Prasad, Mandeep, Tukaram, Sangram,
Vijaykumar, Prasana, Swaroop, Priyanka, Ravindra, Debashish, Sridhar, Mahesh, Rohan,
Ganesh, Nitin, Prakash sultane, Sachin mali, Jaman, Eknath, Anand (bapu), Kedar, Vinay, Dr.
Omprakash bande, Dr. Viswas, Amit, Mahendra, Balaji Bhosale.
My special thanks to Madhuri patil, Dr. Rajendra, Bharat, Shobhana, Alson, Richa, and
Majid for their support, help and cheerful atmosphere during my thesis writing.
There are no words to acknowledge my parents (Baba and Aai) for their blessing, love,
care and continuous encouragement throughout all my life. Whatever I am and whatever I will
be in future is because of their commitment to my ambitions, their patience and selfless sacrifices.
I also express my heartfelt gratitude to my elder brother (Aaba) and my sister-in-law (Archana),
younger brother Manojkumar, Sharad and sister in law (Laxmi), late Grandfather and
grandmother for their moral support, love and blessing. Thanks to little members of my family
Amar (dada) and Amruta (didi), for giving happiness to all of us.
I also express my heartfelt gratitude to my dear wife Bhakti for her constant support and
love and my dear son Atharva for giving happiness and love.
I also express my heartfelt gratitude to late dada, Aai, Bhau, Nani, Bapu, Appa, Tatya,
Babasaheb, Vahini, Mama, Mami, Kaka, Mavsi for their support and love.
Finally I thank God for giving me strength to carry out this work.
Ravi
CONTENTS
Page No.
Chapter 1:
Abbreviations
i
General remarks
iv
Abstract
v
Preparation and applications of organozinc compounds:
A literature survey
Chapter 2:
Introduction
1
Organozinc halides
2
Organozincates
42
Summary and Outlook
54
References
55
Present work on organozinc compounds
Introduction
62
Section 2A:
Preparation of alkylzinc halides and alkylzinc acetates
63
Section 2B:
Enantioselective addition of RZnX to benzaldehyde
72
Section 2C:
Organozincates and their enantioselective addition to
Chapter 3:
benzaldehyde
84
Conclusions
91
Experimental section
92
References
102
Spectra
109
Potential chiral ligands
Introduction
Section 3A:
Section 3B:
117
Synthesis and resolution of cis- and trans-2,3-diphenyl
Morpholines
118
Attempted resolution of 2,3-diphenylbuatane-2,3-diol
146
Conclusions
159
Experimental section
160
References
172
Spectra
179
i
ABBREVIATIONS
Ac
Acetyl
AcOH
Acetic acid
Ar
Aryl
aq
Aqueous
acac
acetylacetone
BINOL
2,2’-Dihydroxy-1,1’-binaphthol
BINAP
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
Bn
Benzyl
i-Bu
Iso-butyl
n-Bu
n-butyl
n-BuLi
n-butyllithium
t-Bu
tertiary butyl
Cat.
Catalytic
o
Temperature in degrees Centigrade
C
Config.
Configuration
DCM
Dichloromethane
DEPT
Distortionless Enhancement by Polarization
Transfer
DIBAL-H
Diisobutylaluminium hydride
DIEA
Diisopropylethyl amine
DMA
N,N-dimethylacetamide
DMAP
4-Dimethylaminopyridine
DME
Dimethoxy ethane
DMF
N,N-Dimethylformamide
DMI
1,3-dimethyl-2-imidazolidinone
DMPU
N,N-dimethylpropyleneurea
DMSO
Dimethyl sulfoxide
Dpp
Diphenylphosphino
Dppf
(diphenylphosphino)ferrocene
de
Diastereomeric excess
ee
Enantiomeric excess
ii
eq
Equation
equiv.
Equivalent
Et
Ethyl
ET
electron transfer
Et3N
Triethyl amine
EtOAc
Ethyl acetate
EtOH
Ethyl alcohol
EWG
Electron withdrawing group
FG
Functional group
g
Gram(s)
GC
Gas Chromatography
h
Hour(s)
HMPA
Hexamethylphosphoramide
HPLC
High Performance Liquid Chromatography
Hz
Hertz
IR
Infrared
M
Molar
Me
Methyl
MeOH
Methanol
min.
Minute(s)
mL
Milliliter(s)
mmol
Millimole
mp
Melting point
Ms
Mesyl
MS
Mass spectroscopy
MsCl
Methanesulfonyl chloride
MTBE
Methyl tert-butyl ether
NaH
Sodium hydride
NMP
N-methyl-2-pyrrolidone
NMR
Nuclear magnetic resonance
ORTEP
Oak Ridge Thermal Ellipsoid Plot
Oct
Octyl
PE
Pet ether
Ph
Phenyl
iii
Piv
Pivaloyl
i-Pr
Isopropyl
PTSA
para-Toluene sulfonic acid
Py
Pyridyl
Red-Al
bis(2-methoxyethoxy)aluminumhydride
RT
Room temperature
TADDOL
α,α,α´,α´-Tetraaryl-1,3-dioxolan-4,5-
dimethanol
TBAB
Tetrabutylammonium bromide
TBAF
Tetrabutylammonium fluoride
TBAI
Tetrabutylammonium Iodide
TEEDA
N,N,N,N-Tetraethylethylenediamine
TFA
Trifluoroacetic acid
THF
Tetrahydrofuran
TLC
Thin Layer Chromatography
TMEDA
N,N,N,N-tetramethylethylenediamine
TMSCl
Trimethylsilyl chloride
TMU
1,1,3,3-tetramethyl urea
Tr
Triphenylmethyl
Ts
Tosyl
iv
GENERAL REMARKS
•
Independent compound numbering, scheme numbers and reference numbers
have been employed for abstract, as well as each chapter (Chapter 1-3).
•
All the solvents and reagents were purified and dried according to procedures
given in D. D. Perin’s “Purification of Laboratory Reagents.” All reactions were
carried out under argon atmosphere using freshly distilled solvents, unless
otherwise specified. Yields refer to isolated product unless otherwise mentioned.
Column chromatographic separations were carried out by gradient elution using
silica gel (100-200 mesh / 230-400 mesh) using light petroleum ether-ethyl
acetate as the eluent, unless otherwise mentioned. Petroleum ether used in the
experiments was of 60-80 °C boiling range.
•
TLC was performed on E-Merck pre-coated silica gel 60 F254 plates and the spots
were rendered visible by exposing to UV light, iodine, charring or staining with
ninhydrin, p-anisaldehyde or phosphomolybdic acid solutions in ethanol.
•
All the melting points reported are uncorrected and were recorded using Buchi
melting point B-540 apparatus.
•
IR spectra were recorded on Shimadzu FTIR instrument, for solid in chloroform
and neat in case of liquid compounds and are measured in cm-1.
•
1
H NMR spectra were recorded on Bruker ACF 200 MHz, AV200 MHz, AV 400
MHz, DRX 500 MHz spectrometers using tetramethylsilane (TMS) as an internal
standard in CDCl3. Chemical shifts have been expressed in parts per million
(ppm) on δ scale downfield from TMS. The abbreviations s, bs, d, t, dd, dt, td
and m refer to the singlet, broad singlet, doublet, triplet, doublet of doublet,
doublet of triplet, triplet of doublet and multiplet respectively. Coupling
constants whenever mentioned have been given in MHz.
•
13
C NMR spectra were recorded at 50 MHz and 75 MHz with CDCl3 (δ = 77
ppm) as the reference.
•
Microanalytical data were obtained using a Carlo-Erba CHNS-O EA 1108
Elemental Analyzer.
•
Optical rotations were obtained on Bellingham & Stanley ADP-220 Polarimeter.
Specific rotations, [α]D are reported in deg, and the concentration (c) is given in
g/100 mL in the specific solvent.
v
ABSTRACT
Introduction
Enantioselective addition of organometallic reagents to aldehydes is one of the most
important contemporary reactions. Such asymmetric reaction allows the preparation
of enantioriched secondary alcohols, which are building blocks for the synthesis of
natural products and pharmaceuticals. Enantioselctive addition of alkyllithium and
Grignard reagents is a straightforward approach to synthesize optically active
alcohols. However the method is of limited use due to the need of stoichiometric
amount of valuable chiral ligand to achieve high enantioselectivity. Use of less
reactive organozinc reagents has emerged as the solution to overcome above
difficulties. Organozinc reagents are very attractive owing to their mild reactivity
and
excellent
chemoselectivity.
Amongst
different
approaches,
catalytic
enantioselective addition of dialkylzincs to aldehydes is the most studied reaction.
However lack of wide commercial availability of dialkylzincs, high cost and their
pyrophoric nature demands an easy in situ preparation of these reagents. The
reagents of type RZnX (X = Cl, Br, I) which are easily accessible, represent the best
choice in this context. However, these reagents are not much explored in asymmetric
catalysis. The present work deals with the preparation of RZnX (X = Cl, Br, I, OAc)
and the corresponding organozincates and their applications in enantioselective
alkylation of aldehydes. The thesis entitled “Preparation of some organozinc
compounds and their enantioselective addition to aldehydes” is divided into three
chapters.
Chapter 1: Preparation and applications of organozinc compounds: A literature
survey
This chapter is a review of the literature on preparation of RZnX (X = Cl, Br, I,
OAc) and organozincates and their applications in various asymmetric reactions.
Chapter 2: Present work on organozinc compounds
This chapter is divided into three sections. Section 2A describes the preparation of
RZnX (X=Cl, Br, I) by oxidative insertion and preparation of RZnX (X = Cl, OAc)
by transmetallation or ligand exchange method. Section 2B deals with a detailed
vi
study on reactivity and enantioselective addition of RZnX to benzaldehyde. Section
2C describes the preparation, reactivity and enantioselective addition of
organozincates to benzaldehyde.
Section 2A: Preparation of alkylzinc halides and alkylzinc acetates
1. Preparation of RZnX (R= alkyl, allyl, benzyl, X= Cl, Br, I) by oxidative
insertion
Apart from the preparation of organozinc halides using highly reactive Rieke Zinc,
which is tedious, there are very few methods for the preparation of alkylzinc
bromides from commercial zinc and unactivated alkyl bromides. The two reliable
methods known in the literature require use of polar solvents like N,N-dimethyl
acetamide (DMA) or use of 1,2-dibromoethane as activator. However DMA is not
suitable for large scale preparation, whereas dibromoethane has limitations due to its
carcinogenic toxicity. Our aim was to develop easier preparative method for
alkylzinc halides in solvent like tetrahydrofuran which is more convenient and easy
to handle.
In our initial effort, the reaction of zinc dust and BuBr was carried out to
explore the reactivity pattern (Table 1).
Table 1. Oxidative insertion of zinc dust into butyl halides
Zn
(1 equiv.)
Entry
RX
1
2
3
4
5
6
BuI
BuI
BuBr
BuBr
BuBr
BuBr
+
RX
(1.1 equiv.)
THF, additives
RZnX
o
50-55 C
Additives (equiv.)
none
LiCl (1.1)
LiCl (1.1)
5 mol% I2
LiCl (1.1) + 5 mol% I2
LiCl (1.1) + 2 mol% I2 + 5
mol% TMSCl
7
BuBr LiCl (1.1) + 10 mol% LiI
8
BuBr LiCl (1.1) + 10 mol%
TBAI
9
BuCl LiCl (1.1) + 5 mol% I2 + 5
mol% TMSCl
a
Determined by iodometric titration.
Time (h)
RZnX, yield a
(%)
Zn consumed
(%)
24
2
48
48
18
48
60
70
65
52
>95
quantitative
20
28
quantitative
>95
24
26
62
62
quantitative
quantitative
48
-
25
vii
It was found that butyl iodide reacts with zinc without any additive (entry 1).
However the use of LiCl dramatically increase the rate of the reaction (entry 2). As
expected, BuBr was much less reactive and required 1.1 equivalent LiCl along with
5 mol % I2 for complete dissolution of zinc (entry 5). Use of other activators like LiI
or TBAI also gave complete conversion (entry 7 and 8). Butyl chloride was found to
be unreactive under these reaction conditions (entry 9). Reaction does not proceed
even in polar solvents like EtOAc and DMA. In the course of our study, we have
observed the formation of small amount of butyl iodide when I2 / LiI / TBAI was
used. This could explain the increased reactivity for BuBr.
Several other alkylzinc bromides were prepared using excess zinc under the
optimized reaction conditions in good yields (Scheme 1). Due to steric bulk around
bromide, reaction of isobutyl and isopropyl bromide was slow and incomplete even
after 48 h. Reaction of tert-butyl bromide lead to complete dissolution of zinc in 24
h, although with only 40% yield of the zinc reagent. Allylzinc chloride and
benzylzinc chloride were also prepared in good yield from the corresponding
chlorides. To confirm the reagent formation, some of these reagents were further
reacted with electrophiles like benzoyl chloride and benzaldhyde.
RX
(1 equiv.)
+
Zn
5 mol% I2
LiCl (1.1 equiv.)
(1.5 equiv.)
THF, 50-55 oC
RZnX.LiCl
RX= EtBr (75%), BuBr (74%), HexBr (74%), OctBr (72%), Ethyl-4-bromobutyrate (73%)
i
BuBr (42%), iPrBr (25%),
t
BuBr (40%), allyl chloride (68%), benzyl chloride (75%).
Scheme 1. Preparation of RZnX using Zn, LiCl and catalytic iodine
2. Preparation of RZnX by transmetallation or ligand exchange
Organozinc halides also can be prepared by transmetallation that is, reaction
of RLi or RMgX with zinc halide. We have prepared RZnCl by stoichiometric
reaction of RMgBr (R = alkyl) with ZnCl2 (eqn.1). We extended this method for the
preparation of RZnOAc. Thus reaction of RMgBr (R = alkyl) with Zn(OAc)2 gives
RZnOAc with more than 95% yield (eqn.2). Using this method, there is always
formation of magnesium salts in stoichiometric amount along with the zinc reagent.
viii
Salt-free RZnX (X = Cl, Br, I, OAc) can be prepared by reaction of R2Zn and ZnX2,
so called ligand exchange. Thus ethylzinc chloride and ethylzinc acetate were
RMgBr
+ ZnCl2
RMgBr
+ Zn(OAc)2
Et2Zn
+ ZnCl2
THF
0 to 25 oC, 1h
THF
RZnOAc.Mg(OAc)Br
0 to 25 oC, 1h
THF:Hexane
+ Zn(OAc)2
(1)
(2)
2 EtZnCl
(3)
2 EtZnOAc
(4)
25 oC, 1h
THF:Hexane
Et2Zn
RZnCl.Mg(Br)Cl
o
25 C, 1h
obtained by the reaction of diethylzinc with ZnCl2 and Zn(OAc)2 respectively (eqn. 3
& 4). All these reagents can be stored for several days as THF solution under inert
atmosphere.
Section 2B: Enantioselective addition of RZnX to benzaldehyde
Alkylzinc halides (RZnX) are known to be weakly active nucleophiles. It should be
possible to enhance the reactivity of these reagents by (i) reagent activation with
Lewis base catalyst, and (ii) substrate activation with Lewis acid. Initially we
examined the reactivity of salt free RZnX (prepared by ligand exchange method, R =
Et, X = Cl, OAc) with benzaldehyde in the presence of various chelating
agent/catalysts. It was thought that a bidentate chelating agent can coordinate with
zinc centre and forms reactive tetrahedral complex (fig.1).
X
R
Y
Zn
X
( reactive tetrahedral complex)
Figure 1
However the strategy did not prove fruitful. We also examined reactivity of
RZnX.LiX (prepared by insertion method) in the presence of various catalysts
(Scheme 2).
ix
RZnX.LiCl
OH
catalyst (10 mol%)
+ PhCHO
THF, 0 to 25oC, 24 h
R = Me, Et
(X= Br, I)
catalysts:
Ph
R
trace
Ph Ph
O
OMgBr
O
O
N
Me
Ph
O
OiPr
Ph
O
Me
N
Ts
MgBr
OMgBr
Ph Ph
Me
N
Ti
(-)
(-)
OiPr
(-)
Scheme 2. Addition of RZnX.LiCl to benzaldehyde
Only trace amount of expected product was observed in all the cases. As we found
MgX2 has role on the reactivity of RZnX, we prepared EtZnX (X= Cl, OAc) by
transmetallation method in which stoichiometric amount of MgX2 is present. Initially
EtZnCl.Mg(Br)Cl was reacted with PhCHO in the presence of various chelating
agents/catalysts (Scheme 3). Metal dialkoxides were prepared by the reaction of
corresponding diol with 2 equivalent of BuLi/EtMgBr. In our initial experiment, the
reaction of EtZnCl.Mg(Br)Cl with PhCHO without any additive gave only 11%
alkylated product in 4 h at 25 oC. To obtain enantioselectivity we tried chiral
chelating agent like (2R,3S)-(−)-4-methyl-2,3-diphenyl morpholine (1) and
lithium/magnesium dialkoxides (2), (3) and (5) derived from corresponding chiral
diols. One equivalent of 1, 4-dioxane was added to reduce the Lewis acidic effect of
Mg(Br)Cl. Although good yields were obtained, negligible enantioselectivity was
realized in all the cases.
OH
catalyst (10 mol%)
EtZnCl.Mg(Br)Cl + PhCHO
THF, 0 oC
(62-66%), <1% ee
catalysts:
Ph
Ph
Ph
O
N
Me
(-)-(1)
Ph
OM
Ph
OM
(-)
M = Li
(2)
= MgBr (3)
Ph Ph
O
OM
O
(-)
OMgBr
OMgBr
OM
Ph Ph
M = Li
(4)
= MgBr (5)
Scheme 3. Addition of EtZnCl.Mg(Br)Cl to benzaldehyde
(+)-(6)
x
We then examined the reactivity of EtZnOAc.Mg(OAc)Br (prepared by
transmetallation method) with benzaldehyde in the presence of various additives
(Table 2). Without any additive, the reaction was slow at 0 oC, alkylated product was
obtained with 29% yield in 4h at 25 oC. Use of chiral morpholine (−)-(1) gave
racemic product with 18% yield in 8h at 0 oC. Interestingly the reaction with
benzaldehyde in the presence of 10 mol% lithium-dialkoxide (−)-(4) derived from
(−)-TADDOL gave 31% yield of the product with 13% ee (entry 3). The
corresponding Mg-dialkoxide (−)-(5) provided 28% ee (entry 4). Efforts to reduce
the Lewis acidic effect of Mg(OAc)Br by addition of one equivalent of 1,4-dioxane
or TMEDA did not help (entry 5&6). We observed increase in yield as well as
enantioselectivity by changing solvent from THF to MTBE. Under similar reaction
conditions product was obtained in 44% yield with 50% ee (entry 7). When the
reaction was carried out at room temperature, yield increased up to 60% with
decrease in ee (entry 8). Similar results were obtained when diethyl ether was used
as solvent (entry 9). Other Mg-dialkoxide (−)-(3) and (+)-(6) proved inferior to
TADDOL (entry 10 and 11).
Table 2. Enantioselective addition of EtZnOAc.Mg(OAc)Br(a) to benzaldehyde
OH
catalyst (10 mol%)
EtZnOAc.Mg(OAc)Br
+ PhCHO
Ph
(S)
Entry
Catalyst
Solvent
Temp (oC),
Time (h)
Product,
Yield (%)
ee
1
2
3
4
5
6
7
8
9
10
11
none
(−)-(1)
(−)-(4)
(−)-(5)
(−)-(5)
(−)-(5)
(−)-(5)
(−)-(5)
(−)-(5)
(−)-(3)
(+)-(6)
THF
THF
THF
THF
THF
THF
MTBE
MTBE
Et2O
MTBE
MTBE
0 to 25, 4
0, 8
0, 8
0, 8
0, 8
0, 8
0, 8
25, 24
25, 24
25, 24
25, 24
29
18
31
34
37
22
44
60
54
45
49
13
28
18
21
50
39
38
<5
<1
xi
To avoid heterogeneous reaction conditions in solvent like MTBE and diethyl ether,
we decided to use THF. After extensive optimization it was found that by adding
Grignard reagent to a suspension of Zn(OAc)2 and (−)-TADDOL in THF, gave a
homogenous solution at 0 oC (Scheme 4). Under these conditions, up to 50%
enantiselectivity was obtained with moderate yields. We also found that rate of the
reaction as well as enantioselectivity vary with the stoichiometry of RMgBr with
respect to Zn(OAc)2. Best results were obtained with 1:1 ratio. In the study of halide
effect in RMgX, bromide and iodide were found better as compared to chloride.
Other Grignard reagents like butyl and isobutyl magnesium bromide gave 13% and
16% ee with lower yields. In the case of tBuMgCl, no reaction took place.
RMgX + Zn(OAc)2
(1.7)
(1.5)
+ (-)-TADDOL
ii) PhCHO (1.0), 0 oC,
(0.1)
R = Et, Bu, Bui, But
X = Cl, Br, I
Scheme
4.
Enantioselective
OH
i) THF, 0 oC, 1h
Ph
R
(-)
up to 50% ee
addition
of
and
their
various
RZnOAc.Mg(OAc)X
to
benzaldehyde
Section
2C:
Organozincates
enantioselective
addition
to
benzaldehyde
Addition of organozinc reagents to various organic electrophiles has become
one of the most common method to construct carbon-carbon bond. Pure dialkylzinc
reagents react sluggishly with aldehydes and ketones. However, their reactivity can
be enhanced by Lewis acid like MgX2 and chelating agent or metal alkoxide derived
from aminoalcohols. The preparation of dialkylzincs and organozincates is well
documented in the literature. In the present work, ethylzinc reagents were prepared
by the reaction of ZnX2 (X = Cl, OAc) with n equivalent of EtMgBr (n = 2, 3), eqn.5
and 6. In our initial experiment, the reaction of Et2Zn.2Mg(X)Br (X = Cl, OAc) with
0.9 equivalent benzaldehyde proceeds quantitatively in 1h at 0 oC. Next, the reagent
prepared from two equivalent of EtMgBr with ZnCl2/Zn(OAc)2 was then reacted
with 1.9 equivalent benzaldehyde. After 1h GC analysis showed formation of 73%
product in both the cases. These results indicate that more than one equivalent of
alkyl group transfer takes place. When the mixture of ZnX2 (X= Cl, OAc) and
xii
2EtMgBr was equilibrated for longer time (16 h) at room temperature, approximately
50% yield of the product was obtained in both cases. This difference in the
2 EtMgBr
+
ZnX2
3 EtMgBr
+
ZnX2
THF
Et2Zn.2Mg(X)Br
(5)
[Et3Zn]MgBr
(6)
THF
X= Cl, OAc
reactivity can be attributed to the formation of the ate complexes I and II depicted in
eqn.7 and 8 respectively. After longer stirring the ate complex decomposes to give
Et2Zn, which can transfer only one alkyl group.
2 EtMgBr + ZnCl2
THF
Et
0 oC
Et
Cl
Zn
25 oC
Mg
Br
overnight
Et2Zn + 2Mg(Br)Cl
(7)
Et2Zn + 2Mg(OAc)Br
(8)
ate complex-I
Et
2 EtMgBr+Zn(OAc)2
THF
0 oC
O
Et Zn
Br
25 oC
overnight
O
Mg
ate complex-II
Et
THF
ZnX2
+
Et
3 EtMgBr
0 oC
Zn
Mg Br
+ 2Mg(X)Br
(9)
Et
X= Cl, OAc
ate complex-III
Next we studied the reactivity of trialkylzincates with benzaldehyde. In the present
study, the zincate III was prepared by reacting ZnX2 (X = Cl, OAc) with three
equivalents of EtMgBr at 0 oC (eqn. 9). The reaction of III with 2.9 equivalent
PhCHO gave 78% and 86% yield of the product in case of ZnCl2 and Zn(OAc)2
respectively. These results indicate that more than two equivalents of alkyl group
transfer in both cases. From the above results it can be concluded that zincate species
generated from ZnX2 and RMgBr can transfer all the three alkyl groups to
benzaldehyde. Based upon these findings we planned to use optically active diols as
chirality source for the preparation of chiral zincates.
xiii
Enantioselective addition of organozincates to benzaldehyde
The reaction of chiral diol is known to form zinc alkoxide (Scheme 5), which on
treatment with stoichiometric Grignard reagent would give chiral zincate complexIV. This chiral zincate complex can react with aldehyde to give enantioselective
product.
OH
*
+ Et2Zn
OH
Chiral diol
O
Toluene
*
o
80 C, 30 min.
-2 Ethane
Zn
RMgX
*
O
Zn
R MgX
O
O
Chiral zincate complex- IV
Scheme 5: Preparation of chiral zincates
Various chiral diols were examined for enantioselective addition to benzaldehyde
under different reaction conditions. Up to 50% enantioselectivity was obtained using
(−)-TADDOL. The use of EtMgBr.LiCl (a structurally different Grignard reagent)
did not help. Poor ee was realized in case of hydrobenzoin and BINOL as diols.
Moderate ee may be due to background reaction of free Grignard reagent with
PhCHO.
Chapter 3: Potential chiral ligands
Section 3A: Synthesis and resolution of cis and trans-2,3-diphenyl morpholines
Synthesis of the title compounds 7 and 8 was reported by Stefanovsky and coworkers in low overall yields starting from optically active aminoalcohol 10 and 15
respectively. We have synthesized cis and trans-2,3-diphenyl morpholines with
excellent overall yields after optimizing the reported procedure.
Ph
O
Ph
O
Ph
N
H
Ph
N
H
7
8
1. Synthesis of cis-(±)-2,3-diphenyl morpholine (7)
Synthesis of reacmic 7 starts from commercially available α-benzoin oxime
9. The benzoin oxime 9 was hydrogenated to cis-amino alcohol 10 in 80% yield
(Scheme 6). Reaction of 10 with chloroacetyl chloride in the presence of NaHCO3
gave hydroxy amide 11 as single product. Without further purification, compound 11
xiv
was cyclized to the lactam 12 using potassium hydroxide in EtOH. Relative
stereochemistry of phenyl rings in 12 was confirmed by single X-ray crystal
structure. The crude compound 12 was reduced with LiAlH4 to obtain 7 in overall
59% yield from 10.
Ph
OH
Ph
N
OH
a
Ph
OH
Ph
NH2
b
10
9
c
Ph
O
Ph
N
H
Ph
OH
Ph
N
11
d
H
Cl
O
(±)-7
O
12
Scheme 6. (a) H2-Pd/C, MeOH, rt, 6 h, 80% (b) Chloroacetyl chloride, NaHCO3,
MeOH, -10 oC to rt, 24 h; (c) KOH, EtOH, Reflux, 1.5 h; (d) LiAlH4, THF, reflux,
16 h, 59% (over three steps).
2. Synthesis of trans-(±)-2,3-diphenyl morpholine (8)
Similar reaction sequence was used for the preparation of trans-(±)-8 (Scheme 7).
The trans-amino alcohol 15 was obtained following the literature procedure. Further,
trans-amide 16 was prepared by N-Acylation of 15 using chloroacetyl chloride. Then
16 was further cyclized to trans-lactam 17 followed by LiAlH4 reduction give trans(±)-8 in 56% overall yield starting from 15.
Ph
OH
Ph
NH2
a
Ph
OH
Ph
NH3Cl
b
Ph
OH
Ph
N
H
c
Ph
OH
Ph
NH2
O
10
d
13
Ph
OH
Ph
N
Cl
Ph
Ph
O
16
15
14
e
H
H
O
N
H
f
(±)-8
O
17
Scheme 7. (a) conc. HCl, MeOH, 50 oC, 1.5 h 98%; (b) HCONH2, 150 oC, 15 min.;
(c) (i) SOCl2, 0 oC to rt; (ii) H2O, reflux, 77% (over two steps); (d) Chloroacetyl
chloride, NaHCO3, MeOH:THF, -10 oC to rt, 24 h; (e) KOH, EtOH, Reflux, 1.5 h;
(f) LiAlH4, THF, reflux, 16 h, 56% (over three steps).
xv
3. Resolution of cis and trans-2,3-diphenyl morpholines
The most practical method for the resolution of racemic amines is the
preparation of diastereomeric salt with optically active acid, and then separation
through crystallization. In the present work, resolution of 7 was accomplished
through sequential use of L and D-tartaric acid (Scheme 8). Both the enantiomers
were obtained in good yield and high enantiomeric purity. Optical purity of both the
enantiomer was found to be ≥ 99% by chiral HPLC.
i) Recrystallization
(2R, 3S)-(-)-7
Solid salt
ii) aq. NaOH, DCM
Ph
O
i) L-(+)-Tartaric acid
(0.25 equiv.)
Ph
N
H
ii) Et2 O
(±)-7
Filtrate
i) D-(-)-Tartaric acid
ii) Recrystallization
iii) aq. NaOH, DCM
36%, 99% ee
(2S, 3R)-(+)-7
43%, > 99% ee
Scheme 8. Resolution of cis-2,3-diphenyl morpholine 7.
However L-tartaric acid failed to resolve the racemic trans-2,3-diphenyl morpholine
8. Success was achieved by using (−)-mandelic acid as resolving agent (Scheme 9).
Ph
O
+
Ph
R-(-)-mandelic acid
N
H
(±)-8
(DS)
PPT
MeOH
Diastereomeric salt
(DS)
aq. NaHCO3, DCM
(2S, 3S)-(-)-8
39%, 92% ee
Preferential
precipitation
2-propanol
i) Recrystallization
Filtrate
ii) aq. NaHCO3, DCM
(2R, 3R)-(+)-8
44%, > 99% ee
Scheme 9. Resolution of trans-2,3-diphenyl morpholine 8.
xvi
4. Application of 2,3-diphenyl morpholines in enantioselective diethylzinc
addition
Previously our research group had reported conceptually different and
efficient catalytic system viz zinc-amide, derived from oxazolidines in which both
zinc centres are tri-coordinate. We anticipated that morpholine based catalytic
system would be more efficient due to formation of tetra coordinate zinc centre. The
reaction of PhCHO with Et2Zn was carried out using 10 mol% of the ligand (Table
3). In case of 7 although good yields were obtained, only moderate enantioselectivity
was realized. Use of the corresponding lithium amide did not help (Table 3, entry 3).
Trans isomer (−)-8 proved inferior to cis. At this stage we are unable to provide
reason for low ee. Further optimization of reaction conditions and modification of
ligand structure is underway.
Table 3. Enantioselective addition of Et2Zn to benzaldehyde
O
Ph
OH
Et2Zn (1.5 equiv.)
H
Ligand (10 mol%)
Ph
(s)
Entry
Ligand
Temp. (oC)
Time (h)
1
0
8
(−)-7
2
25
4
(−)-7
3
25
2
(−)-7/BuLi
4
25
24
(−)-8
a
Isolated yield. b Determined by chiral GC analysis
Yielda (%)
68
86
85
73
eeb (%)
40
36
29
12
Section 3B: Attempted resolution of 2,3-diphenylbuatane-2,3-diol
C2-Symmetric chiral diols have found numerous applications in asymmetric
synthesis as chiral auxiliaries, chiral ligands as well as chiral building blocks. We
wanted to explore sterically demanding chiral tertiary diol like 2,3-diphenyl-butane2,3-diol 18 in asymmetric synthesis. Although synthesis of enantiopure 18 was
reported by Cram et. al. resolution of this diol is not known in the literature. The
resolution of diols could be accomplished through diasereomeric esters or ketals, and
also through borate esters.
We have prepared dl-18 by pinacol coupling of acetophenone according to
the literature procedure, with excellent diastereoselectivity, equation 10.
xvii
THF
O
+
Mn*
25 oC, 2h
Me
Ph
Me
Ph
Me
Ph
Mn* = highly reactive manganese
OH
(10)
OH
dl-18
49%, >99% de
1. Attempted resolution of dl-18 through addition complex
This method is based on formation of diastereomeric addition complex
between diol and resolving agent through hydrogen bonding. We examined various
resolving
agent
like
trans-(−)-1,2-diamino
cyclohexane,
trans-(−)-1,2-
diphenylethane-1,2-diamine, (+)-cinchonine, and (−)-cinchonidine using various
solvents. However no addition compound could be isolated.
2. Resolution of dl-18 through chiral borate complex
This method involves formation of well defined covalent borate complex
between boric acid, diol and a resolving agent. We examined (−)-α-methyl benzyl
amine and (−)-phenyl glycinol as resolving agents. Only partial resolution of 18
could be realized using (S)-Proline as resolving agent (Scheme 10).
+
N
H
COOH
B(OH)3
(i) Toluene, Reflux, 12 h
PPT-1+ Filtrate
(ii) dl-18, Toluene
reflux, 12 h
(S)-Proline
Aq. 3N HCl:THF
PPT-2
(-)-18
RT, 4h
29%, 30% ee
THF, RT, 24h
PPT-1
Filtrate
Scheme 10. Resolution of 18 by (S)-Proline and boric acid
CHAPTER-1
Preparation and applications of organozinc compounds: A
literature survey
1
Introduction
Enantioselective addition of organometallic reagents to aldehydes is one of
the fundamental asymmetric reactions and it is a powerful tool for the construction of
chiral carbon-carbon bond. This method provides enantiorich secondary alcohols,
which are building blocks for the synthesis of natural products and pharmaceuticals.1
Asymmetric addition of alkyllithium and Grignard reagents is a straightforward
approach for the synthesis of optically active alcohols. Although several examples
involving organolithium and Grignard reagents have been reported, these usually
require stoichiometric amounts of valuable chiral ligands.2 Due to the high
background reactivity of these reagents, catalytic version remained unexplored until
the recent report of Harada and co-workers.3 Furthermore, these reagents preclude
the presence of many functional groups due to their high reactivity which reduces
their attractiveness in organic synthesis. In contrast, organozinc reagents show very
mild reactivity and excellent chemoselectivity.4 In addition to the Reformatsky
reaction5 and the Simmons−Smith6 reaction, a number of carbon-carbon bond
forming reactions using organozinc reagents have been reported.4 Organozinc
reagents can be classified as four types,
(I) Organozinc halides (R-Zn-X, X = Cl, Br, I)
(II) Diorganozincs (R-Zn-R)
(III) Organozincates R3ZnM (M= MgX, Li) or R4ZnLi2
OZnX
(IV) Reformatsky reagent
OR
Despite their discovery in 1849 by Frankland,7 organozinc reagents were
unexplored in asymmetric synthesis for a long period of time due to their poor
reactivity. After the report of Oguni and Omi in 1984,8a the enantioselective addition
of diorganozinc reagents to carbonyl compounds emerged as one of the attractive
tools for the preparation of optically active alcohols.1c,8 However lack of wide
commercial availability, high cost and pyrophoric nature limits their use to only
lower homologues.9 Therefore a search for the other alternatives is desirable. The
reagents of type RZnX (X = Cl, Br, I) which are easily accessible, are good
2
alternatives to diorganozincs. Organozinc halides have very less reactivity towards
most class of organic electrophiles due to high covalent character of carbon-zinc
bond and less Lewis acidity of Zn(II) metal centre. However, transmetallation with
transition metals such as Pd, Ni, Cu etc. generates reactive complex which shows
excellent reactivity.4b Their use has been mainly in Ni and Pd-catalyzed crosscoupling reactions.10
Organozincates11 is another class of organozinc compounds which are more
reactive as compared to organozinc halides and diorganozincs. These reagents were
found to be attractive by synthetic organic chemists due to their unique reactivity and
excellent chemoselectivity.4a Organozincates have shown their usefulness in many
chemoselective organic transformations.4a,11c,d,g As compared to diorganozinc
reagents, reagent of type I and III are not much explored in asymmetric synthesis.
The present chapter will focus on reviewing the literature on preparation and
applications of organozinc halides and triorganozincates in asymmetric synthesis.
1. Preparation of organozinc halides
There are three general methods for the preparation of organozinc halides;
(i) Oxidative insertion (direct insertion of metallic zinc into carbon-halogen bond)
(ii) Transmetallation (the reaction of RM (M = Li or MgX) with zinc salt) and
(iii) Ligand exchange (the exchange of ligands between R2Zn and zinc salt)
1.1. Preparation of organozinc halides by oxidative insertion
The oxidative insertion is the most general and attractive protocol for the
preparation of organozinc halides. This method shows very broad scope and it is
applicable to the preparation of a number of simple as well as functionalized
organozinc reagents. In 1942 Hunsdiecker12a reported the preparation of number of
functionalized alkylzinc iodides 1 by the reaction of zinc with corresponding alkyl
iodide in ethyl acetate (Scheme 1).
RO2C(CH2)nI + Zn
n>5
EtOAc
reflux
RO2C(CH2)nZnI
1
Scheme 1. Oxidative insertion of zinc into alkyl iodide in EtOAc
3
After this report, various other procedures have been reported. Some of the
important ones are described below.
In 1962, Gaudemar et al.12b reported that the primary alkyl iodide reacts with
zinc foil in THF at 50 oC in few hours to give corresponding alkylzinc iodide
whereas secondary iodide reacts at ambient temperature (Scheme 2).
THF, 25−50 oC
RI
+
Zn
RZnI
RI = primary or secondary alkyl iodide
Scheme 2. Preparation of alkylzinc iodides in THF
In 1964 Paleeva et al.12c reported the preparation of ethylzinc iodide by the
reaction of zinc-copper couple13 (8% copper) with ethyl iodide under reflux
condition (Scheme 3).
EtI + Zn-Cu
reflux
EtZnI
68%
Scheme 3. Preparation of ethylzinc iodide using Zn-Cu couple
In 1988 Knochel et al.14a observed fast reaction rates when zinc was
activated successively with a catalytic amount of 1,2-dibromoethane and TMSCl.
Thus, in the case of primary alkyl iodides insertion is complete in 2−3 h in THF at 40
o
C, whereas secondary iodides react at room temperature. Under the optimized
conditions, various simple as well as functionalized alkylzinc iodides (RZnI) were
prepared in good yield (Scheme 4).
(CH2Br)2 (4 mol%)
TMSCl (3 mol%)
RI
+
RZnI
Zn
o
THF, 25−40 C
Up to 90% yield
R = alkyl, FG-alkyl; FG = CN, CO2R'
Scheme 4. Preparation of alkylzinc iodides using in situ activated zinc
4
In the same year Knochel′s group observed that the presence of cyano group
at β-carbon greatly accelerates the rate of the insertion reaction.14b The reaction of 2cyano iodides 2 with in situ activated zinc14c (cut foil or dust) in THF provided
corresponding zinc reagents 3 in good yield14d (Scheme 5).
R
THF
I
CN
+ Zn
5−30 oC, 3−5 h
R
IZn
CN
3
2
R = H, Pr
80-90% yield
Scheme 5. Preparation of 2-cyanozinc iodides
Knochel et al. also observed the presence of oxygen at α-carbon accelerates
the rate of the insertion reaction.15a,b For example, treatment of iodomethyl pivalate 4
with activated zinc foil14c in THF at 12 oC furnished PivOCH2ZnI 5 in excellent
yield15a (Scheme 6).
O
THF, 12 oC, 1 h
O
I
PivOCH2ZnI
+ Zn
5
4
>85% yield
Scheme 6. Preparation of iodomethylzinc pivalate 5
Later in 2004 Kimura and Seki15c reported the preparation of alkylzinc iodide
7 by the treatment of zinc dust (activated with bromine) with corresponding alkyl
iodide 6 in excellent yield (Scheme 7). In comparison with other activators such as
TMSCl or 1,2-dibromoethane, use of bromine proved better for the large scale
preparation.
I + Zn
EtO2C
6
Br2 (0.5 equiv)
THF:toluene
50-60 oC, 1 h
Scheme 7. Preparation of ethyl iodovalerate
ZnI
EtO2C
7
94% yield
5
Simple alkyl bromides and chlorides usually cannot be converted to the
corresponding organozinc compounds in THF under the normal reaction conditions.
In 1990 Knochel et al.15d reported that the presence of phosphate group
considerably accelerates the rate of formation of organozinc bromides. Thus, the
treatment of primary bromophosphonates 8a with activated zinc dust14c in THF at 30
o
C for 12 h gave the corresponding alkylzinc bromide 9a in excellent yield.
Secondary bromophosphonates 8b-d requires only 0.5 h for completion of the
reaction (Scheme 8).
R2O
R2O
Br
O
P
THF, 25−30 oC
R1
+ Zn
0.5−12 h
R2O
R2O
O
P
ZnBr
R1
9a-d
8a = R1 = H, R2 = Et
8b = R1 = Me, R2 = Me
8c = R1 = Pr, R2 = Me
8d = R1 = Pr, R2 = Et
upto 90% yield
Scheme 8. Oxidative insertion of zinc into bromophosphonates 8a-d
In the same year, Knochel et al. reported that the presence of sulfur allows
smooth insertion of zinc into carbon-chlorine bond.15e,f Thus, the reaction of αchloroalkyl phenyl sulfides 10a-e with activated zinc dust14c in THF at room
temperature for 2 h provided corresponding organozinc chlorides 11a-e in good
yield15e (Scheme 9).
R
PhS
10a
10b
10c
10d
10e
R
THF, 25 oC, 2 h
Cl
+ Zn
R=H
R = CH3
R = Pr
R = CH2CN
R = (CH2)2CO2Et
PhS
ZnCl
11a-e
>85% yield
Scheme 9. Oxidative insertion of zinc into α-chloroalkyl phenyl sulfide 10a-e
6
In 1992 Knochel et al.16a reported that the use of polar solvents such as N,Ndimethylacetamide (DMA) or N,N-dimethylpropyleneurea (DMPU) allows the
preparation of functionalized alkylzinc bromides 13 by the reaction of activated zinc
dust14c with corresponding primary alkyl bromides 12 using catalytic amount of
alkali iodide (Scheme 10). The insertion is reported to be complete in few hours at
70−80 oC.
FG
Br
n
+ Zn
MI (0.2 equiv)
DMA or DMPU
70−80 oC, 2.5 h
12
FG
ZnBr
n
13
n = 3, 4
M = Li or Cs
FG = Cl, CO2Et
Scheme 10. Preparation of alkylzinc bromides in polar solvent
This reaction was extended for the preparation of functionalized alkylzinc
chlorides, tosylates, mesylates and diphenylphosphates using additional equivalent of
LiBr (or NaBr) (Scheme 11).
FG
X
n
MI (0.2 equiv)
MBr (1.0 equiv)
FG
+ Zn
DMA or DMPU
40−80 oC, 6−12 h
ZnX
n
n = 3 to 8
FG = Cl, CO2R
X = Cl, OMs, OTs, OP(O)(OPh)2
M = Li, Na, Cs
Scheme 11. Preparation of RZnX (X = Cl, OMs, OTs, OP(O)(OPh)2)
Later in 2003 Huo et al.16b reported a very efficient method for the
preparation of alkylzinc bromides in DMA. The treatment of zinc metal (activated by
5 mol % iodine) with primary alkyl bromide 14a in polar solvent such as DMA at 80
o
C afforded the corresponding alkylzinc bromide 15a in excellent yield (Scheme 12).
Number of simple as well as functionalized alkyl bromides 14b-i (Figure 1) were
reacted with zinc under the optimized conditions to obtain corresponding zinc
reagent in >90% yield. However, the reaction of secondary alkyl bromides was
sluggish whereas, tertiary alkyl bromide did not even require iodine for activation.
7
On the other hand, no zinc reagent was formed when less polar solvents such as
diethyl ether, THF, dioxane, DME and acetonitrile were used.
I2 (5 mol%)
n-OctBr + Zn
n-OctZnBr
DMA, 80 oC, 3 h
15a
14a
Scheme 12. Preparation of n-Octylzinc bromide in DMA
O
Br
NC
EtO
4
14b
3
O
Br
14g
Br
5
14d
14c
Br
14f
O
Br
Cl
Br
6
14e
Br
Br
14h
14i
Figure 1
Use of other polar solvents such as DMF, DMSO, DMPU or NMP, and also
the various forms of zinc metal provided comparable results (Table 1).
8
Table 1. Direct insertion of zinc into n-Octyl bromide under various conditions
cat. I2
n-Oct-Br + Zn
n-OctZnBr
80 oC
14a
15a
Entry
Zn
I2 (mol %)
Solvent
Time (h)
Conversion (%)
1
dust
5
DMA
3
>99
2
dust
1
DMA
9
>98
3
dust
5
DMF
4.5
>99
4
dust
5
DMSO
3
>99
5
dust
5
DMPU
3
>99
6
dust
5
NMP
6
>98
7
powder
5
DMA
3
>99
8
granule
5
DMA
3
>98
9
shot
5
DMA
12
>98
Using this methodology alkylzinc chlorides 17a,b were also prepared from
the corresponding alkyl chlorides 16a,b in very good yield. The presence of
stoichiometric amount of salts like LiBr or R4NBr is required to achieve efficient
conversion (Scheme 13).
I2 (5 mol%)
LiBr or Bu4NBr (1 equiv)
RCl + Zn
DMA, 80 oC, 12 h
16a,b
RZnCl
17a,b
O
Cl
RCl =
7
16a
Cl
EtO
3
16b
Scheme 13. Preparation of alkylzinc chlorides in DMA
Later in 2006 Knochel et al.16c described LiCl-accelerated preparation of
alkylzinc bromides in THF. This method allows the preparation of alkylzinc
bromides from simple as well as functionalized alkyl bromides. Thus, the treatment
of zinc powder in situ activated by catalytic 1,2-dibromoethane and TMSCl, with
9
primary or secondary alkyl bromides (14a-c and 14j-o) in the presence of
stoichiometric amount of LiCl furnished the corresponding alkylzinc bromides in
excellent yield (Scheme 14). Author proposed that LiCl rapidly removes the formed
organozinc reagent from the metal surface by generating highly soluble RZnX⋅LiCl
complex, and freshly activated metal surface gets exposed to further insertion
process.
LiCl, THF
RBr + Zn
RZnBr LiCl
50 oC, 1−50 h
14a-c, 14j-o
Br
Cl
5
14j
>92% yield
Br
O
Br
4
O
14l
14k
Br
Br
Br
5
14m
14n
14o
Scheme 14. LiCl-accelerated preparation of alkylzinc bromides
Unlike alkyl iodides, vinyl or aryl iodides do not undergo insertion in THF
under normal conditions and requires higher temperature or polar solvents such as
DMF, DMA.
In 1990 Knochel et al.17a reported the preparation of arylzinc iodides by the
reaction of commercial zinc with aryl iodides. The treatment of aryl iodides 18 with
zinc dust (in situ activated using 1,2-dibrmoethane) in DMF or DMA at 25 to 55 oC
afforded the corresponding arylzinc iodides 19 in good yield (Scheme 15). It was
observed that the substituent on the aromatic ring strongly influence the rate of the
zinc insertion. For example, iodobenzene requires 22 h at 55 oC for 80% conversion
whereas 2-iodobenzonitrile undergoes complete insertion within 2 h at 35 oC. A
comparison between the zinc insertion rates of o-, m- and p-iodobenzonitrile
indicated that o-iodobenzonitrile reacts significantly faster.
10
I
ZnI
DMF or DMA
+ Zn
25−55 oC, 2−22 h
FG
FG
18
19
FG = CN, Cl, COR, CO2Et
65-85% yield
Scheme 15. Preparation of arylzinc iodides in polar solvent
Author has also reported the preparation of alkenylzinc iodide 20 under these
conditions. The (E)-1-iodo-1-octene reacts with zinc in 14 h at 70 oC (Scheme 16).
Hex
Hex
DMF
H
I
+ Zn
H
70 oC, 14 h
ZnI
20
E :Z
(1:1 to 1 :1.5)
Scheme 16. Preparation of alkenylzinc iodide
In 1993 Takagi et al.17b reported the ultrasound-promoted insertion of zinc
into functionalized aryl iodides. Various functionalized aryl iodides were reacted
under different reaction conditions to obtain the corresponding arylzinc iodides in
good yield. One representative example is described below. Under ultrasoundirradiation, the reaction of methyl 2-iodobenzoate with zinc powder in TMU (1,1,3,3tetramethyl urea) at 30 oC for 5 h gave arylzinc iodide 21 in good yield (Scheme 17).
Same reaction without irradiation of ultrasound requires 15 h for the completion.
I
+ Zn
ZnI
TMU, 30 oC
CO2Me
CO2Me
21
ultrasound-irradiation
without ultrasound-irradiation
5h
15 h
87% yield
Scheme 17. Ultrasound-promoted preparation of arylzinc iodide
11
Later in 2003 the same author17c reported the preparation of functionalized
arylzinc iodides in ethereal solvents such as THF, diglyme or triglyme. The reaction
of zinc powder with functionalized aryl iodides 18 provided corresponding arylzinc
iodides 19 in good yield (Scheme 18).
I
ZnI
TMSCl (3 mol%)
+ Zn
THF or diglyme
or triglyme
70−180 oC
FG
18
FG
19
Up to 95% yield
FG = H, CN, Cl, Br, CO2R', CH3, OCH3
Scheme 18. Preparation of arylzinc iodides in ethereal solvents
It was observed that the aryl iodides containing EWG at the ortho-position
smoothly reacts in THF at 70 oC (Table 2), whereas those containing EWG at the
meta- and para-position or electron-rich aryl iodides were less reactive and requires
elevated temperature as well as solvents such as diglyme or triglyme.
Table 2. Preparation of various arylzinc iodides in etheral solvents
I
ZnI
TMSCl (3 mol%)
+ Zn
24 h
FG
FG
18
a
19
Entry
R
Solvent
Temp (oC)
Yield (%)
1
o-CO2Me
THF
70
87
2
m-CO2Me
THF
70
20
3
m-CO2Me
diglyme
100
84
4
p-CO2Me
diglyme
100
89
5
p-CH3
diglyme
130
87
6a
p-CH3
triglyme
180
83
The reaction time was 1.5 h.
12
In the same year Gosmini et al.18a reported a new method for the preparation
of arylzinc bromides and iodides. In this method the treatment of aryl halide 22a-c
with zinc dust in the presence of catalytic amounts of PhBr, CoBr2, ZnBr2 and TFA
in acetonitrile furnished corresponding arylzinc halide 23 in moderate to excellent
yield (Scheme 19). In their initial study, they observed the formation of byproducts
such as reduction product (ArH) and the homocoupling product Ar-Ar. The addition
of catalytic amount of phenyl bromide prior to the addition of aryl halide (the
substrate) allows this side reaction to proceed on PhBr rather than on aryl halide
which results in increased yield of the desired product. Number of simple as well as
functionalized aryl and hetero arylzinc halides were prepared under mild reaction
conditions in good yield. The role of TFA was to activate the zinc metal. Author
proposed that the activated zinc reduces the Co(II) to Co(I) species which initiates
the insertion process.
TFA (cat.)
PhBr (0.1 equiv.)
CoBr2 (0.1 equiv.)
ArZnX
ArX + Zn
ZnBr2 (0.1 equiv.)
Acetonitrile, RT, 30 min.
22a-c
23
Up to 100% yield
Br
X
ArX =
FG
S
Br
S
22a
22b
22c
X = Br, I
FG = H, Cl, CN, OCH3, NR2, OCOR,
COR, SO2Me
Scheme 19. CoBr2 catalyzed preparation of arylzinc halides
Aromatic chlorides are generally inexpensive and readily available substrates
as compared to the corresponding bromides and iodides. Later in 2005 the same
group18b extended the above reaction for the preparation of functionalized aryl and
hetero arylzinc chlorides using optimized reaction conditions.18c In this protocol the
reaction of aryl chlorides 24a-c with zinc dust in the presence of catalytic amount of
TFA, CoBr2, allyl chloride and use of pyridine as co-solvent furnished the
corresponding arylzinc chlorides 25 in moderate to excellent yield (Scheme 20).
13
TFA (cat.)
allyl chloride (0.33 equiv.)
CoBr2 (0.33 equiv.)
ArCl + Zn
ArZnCl
Acetonitrile:Pyridine
RT, 2−31 h
24a-c
25
45-95% yield
Cl
Cl
ArCl =
FG
24a
S
Cl
24b
S
24c
FG = H, CN, CF3, COMe, SO2Me
Scheme 20. CoBr2 catalyzed insertion of zinc into aryl chlorides
In 2006 Knochel et al.16c reported LiCl-accelerated preparation of arylzinc
iodides from activated zinc powder and corresponding aryl iodides in THF. Various
simple as well as functionalized aryl iodides 18 were converted to the corresponding
zinc reagent in excellent yield (Scheme 21).
I
ZnI LiCl
LiCl, THF
+ Zn
50 oC, 1−90 h
FG
18
FG
Up to 98% yield
FG = H, CF3, CN, OMe, CHO, COR, CO2Et, CONR2
Scheme 21. LiCl-accelerated insertion of zinc into aryl iodides
This method was successfully extended for the preparation of vinyl and
arylzinc bromides. The treatment of aryl bromide 26a,c or vinyl bromide 26b
(containing electron withdrawing substituent) with activated zinc powder furnished
corresponding organozinc bromides 27 in very good yield (Scheme 22).
14
LiCl, THF
ArZnBr LiCl
ArBr + Zn
25 oC, 24 h
26a-c
ArBr =
27
>90% yield
CO2Et
Br
Br
EtO2C
EtO2C
26a
26b
O
Br
26c
Scheme 22. LiCl-accelerated insertion of zinc into activated aryl bromides
In contrast to alkyl and aryl halides, allyl and benzyl halides are highly
reactive towards oxidative insertion of zinc. In 1962 Gaudemar et al.12b reported the
preparation of allylic and benzyliczinc bromides. The reaction of cinnamyl bromide
with zinc in THF at −15 to −5 oC gave corresponding zinc reagent in good yield
(Scheme 23). Benzyl bromide was also reacted under the similar reaction conditions
to obtain benzylzinc bromide.
Ph
Br
THF, −15 to −5 oC
+ Zn
Ph
ZnBr
Scheme 23. Preparation of cinnamylzinc bromide
Later in 1978 Bellassoued and Frangin19a reported the preparation of allylzinc
bromide by the reaction of allyl bromide and zinc in THF at ambient temperature
(Scheme 24).
Br + Zn
THF, 20 oC, 1 h
Scheme 24. Preparation of allylzinc bromide
ZnBr
15
The zinc insertion to substituted allylic halides is less satisfactory due to the
formation of substantial amount of homocoupling product. Knochel et al.19b in 2007
described the preparation of substituted allyliczinc chlorides 29 by the reaction of
allylic chloride 28a-d with zinc dust in the presence of LiCl in THF with moderate to
good yield (Scheme 25).
LiCl, THF
R
Cl + Zn
R
ZnCl
0 oC to RT
28a-d
29
55-84% yield
R
Cl =
Cl
Cl
Cl
Cl
Ph
Me
28a
28b
28c
28d
Scheme 25. Preparation of substituted allyliczinc chlorides
In 1988 Knochel et al.20a reported the preparation of various benzyliczinc
bromides. The reaction of benzylic halides 30 with zinc foil activated with 1,2dibromoethane in THF at 5 oC for 2−3 h gave corresponding benzylzinc bromides 31
in >90% yield along with the formation of homocoupling product in <5% yield
(Scheme 26). In the case of secondary benzyl bromides addition was done at −15 oC
to obtain good yield while corresponding chloride requires higher temperature (30
o
C) for smooth conversion.
Br
R + Zn
ZnBr
(CH2Br)2 (cat.)
R
THF, 5 oC, 2−3 h
FG
30
R = H, CH3
FG = Cl, I, CN, OMe, COR', OAc
Scheme 26. Preparation of benzyliczinc bromides
FG
31
> 90% yield
16
Recently, Knochel et al.20b reported excellent method for the preparation of
benzyliczinc chlorides. Various functionalized benzylic chlorides 32 were converted
to the corresponding zinc organometallics 33 at room temperature in excellent yields
using activated zinc dust14c and stoichiometric amount of LiCl (Scheme 27). In the
absence of LiCl the reaction was incomplete and proceeds at slow rate.
Cl
R + Zn
FG
ZnCl LiCl
LiCl
R
THF, 25 oC, 3 h
32
FG
32a R = H
32b R = Me
33
Up to 99% yield
FG = Cl, Br, I, F, CN, COR', CO2R'.
Scheme 27. Preparation of various benzyliczinc chlorides
1.1.1. Preparation of organozinc halide using highly reactive zinc (Zn*)
In 1973 Rieke et al.21a reported that the metallic zinc can be generated in situ
by the reduction of zinc halide with alkali metals. The zinc prepared by the reduction
of ZnCl2 with alkali metals such as Li, Na or K using electron carriers like
naphthalene shows higher reactivity than the commercial zinc powder and reacts
with unreactive alkyl as well as aryl bromides in less polar solvents like THF to give
corresponding organozinc bromides in excellent yield21b-f (Scheme 28).
THF or DME
ZnCl2 + 2 Li +
Zn* +
2 LiCl
RT
(cat.)
THF or DME
RX + Zn*
RZnX
RT to reflux
Zn* = Highly reactive zinc
RX = 1o, 2o or 3o alkyl bromides, simple or functionalized
aryl bromides and iodides
Scheme 28. Preparation of RZnX (R = alkyl, aryl, X= Br, I) using Rieke zinc (Zn*)
17
However alkyl chlorides are unreactive under these conditions and requires
Zn* prepared by the reduction of Zn(CN)2 with lithium using catalytic amount of
naphthalene.21g The zinc obtained by this method smoothly reacts with alkyl
chlorides 16a,c-f in THF at room temperature to provide corresponding alkylzinc
chlorides in good yield (Scheme 29).
THF
Zn(CN)2 + 2 Li +
Zn* + 2 Li(CN)2
RT, 5 h
(cat.)
THF
RZnCl
RCl + Zn*
RT, 12 h
16a, c-f
O
RCl =
Cl
Cl
7
NC
5
16a
16c
Cl
4
16d
Cl
6
NC
Cl
N
N
16f
16e
Scheme 29. Preparation of alkylzinc chlorides using Rieke zinc
Later in 1999 Rieke's group21h has done a detailed study on oxidative addition
of highly reactive zinc to organic bromides. On the basis of kinetic and linear free
energy relationship studies (LFERs) they have suggested a mechanism in which the
insertion reaction proceeds through electron transfer (ET) and it is the rate
determining step. It was observed that the rate of insertion of zinc into organic
bromides follows the order allyl > benzyl > 3o alkyl > 2o alkyl > 1o alkyl > aryl >
vinyl. Authors proposed that zinc transfers the electron to alkyl halide and reaction
proceeds through intermediate I which upon transfer of second electron gives
alkylzinc halide (Scheme 30).
Zn + Br-R
Zn
δ
Br R
ET
Zn-Br
R
ET
RZnBr
I
Scheme 30. Proposed mechanism for the oxidative insertion of zinc into R-Br
18
1.2. Preparation of organozinc halides by transmetallation
The second method for the preparation of organozinc halides is
transmetallation that is the reaction of highly reactive organometallics like RLi or
RMgX with zinc halide (Scheme 31). In this method, there is always formation of
lithium / magnesium salts in stoichiometric amount along with the zinc reagent. Due
to the high reactivity of alkyl lithium and Grignard reagent, this method cannot be
applied for the preparation of functionalized organozinc halides. There are several
reports on preparation of organozinc halides by transmetallation method.22,23 Few
important reports where the preparation and characterization of organozinc halides
have been done are described below.
RMX
+
ZnX2
Transmetallation
RZnX MX2
R = Alkyl, Aryl, benzyl etc
M = Li, MgX
X = Cl, Br, I
Scheme 31. Preparation of organozinc halides by transmetallation
In 2009, Marder and Aiwen23e reported the preparation of PhZnCl⋅MgCl2 34
by the stoichiometric reaction of PhMgCl with ZnCl2 in THF (Scheme 32). The
complex was shown by single crystal X-ray analysis to be the novel dichloro-bridged
Zn/Mg complex (Figure 2).
THF
PhMgCl + ZnCl2
PhZnCl MgCl2
0 oC to RT, 2 h
34
Scheme 32. Preparation of phenylzinc chloride
Cl
Ph
Zn
Cl
THF
THF
Mg
Cl
THF
THF
Figure 2
19
Recently, Hevia et al.23f reported the preparation of complex t-BuZnCl⋅MgCl2
35 by the stoichiometric reaction of t-BuMgCl with ZnCl2 in THF (Scheme 33).
t
THF
BuMgCl + ZnCl2
t
BuZnCl MgCl2 4THF
35
Scheme 33. Preparation of tbutylzinc chloride complex
The complex 35 was characterized by X-ray crystallography. The structure of
the complex is depicted in figure 3, where zinc and magnesium are connected
through two chlorine bridges. Zinc forms distorted tetrahedral geometry whereas
magnesium achieves distorted octahedral geometry through bonding with four THF
molecules.
Cl
But
Zn
Cl
THF
THF
Mg
Cl
THF
THF
Figure 3
1.3. Preparation of organozinc halides by ligand exchange
The third method is ligand exchange,24 that is the exchange of ligands
between diorganozinc reagent and zinc halide. The reaction of R2Zn with ZnX2 gives
corresponding RZnX (Scheme 34). This method provides organozinc halides which
are free of magnesium or lithium salts.
R2Zn
+ ZnX2
2 RZnX
R = alkyl, aryl etc.
X = Cl, Br, I
Scheme 34. Preparation of organozinc halides by ligand exchange
Important contributions made by different research groups for the preparation
of organozinc halides by ligand exchange method are described below.
20
In 1966, Boersma and Noltes24a prepared EtZnX (X = Cl, Br, I) by heating
the ZnX2 with diethylzinc at 70 oC (Scheme 35). These compounds were found to be
colorless, crystalline solids.
70 oC, 10-20 min.
2 EtZnX
Et2Zn + ZnX2
X = Cl, Br, I
Scheme 35. Preparation of salt-free ethylzinc halide
On the basis of cryoscopic molecular weight determination it was suggested
that ethylzinc chloride and bromide forms tetramer in benzene and have cubic
arrangement of Zn and halogen (Figure 4).
Et
X
Et
Zn
Zn
X
Zn
X
X = Cl, Br
X
Et
Zn
Et
Figure 4
Later in 1973, Shearer et al.24b crystallized EtZnI from ethyl iodide solution.
The X-ray crystallographic studies showed that ethylzinc iodide forms polymeric
structure which is consistent with the results obtained by Boersma and Noltes.24a
In 2006 Bochmann et al.24d prepared EtZnCl by heating the mixture of
diethylzinc and ZnCl2 in toluene for 72 h (Scheme 36). The X-ray crystallographic
studies showed that ethylzinc chloride forms infinite sheets [EtZnCl]∞ in which each
zinc atom is tetrahedrally coordinated to one ethyl and three chloride ligands.
Et2Zn + ZnCl2
toluene
2 EtZnCl
70 oC, 72 h
Scheme 36. Preparation of salt-free ethylzinc chloride
21
In 2007 Woodward et al.24e reported the preparation of ethylzinc chloride in
THF by the treatment of diethylzinc with ZnCl2 at ambient temperature (Scheme 37).
Et2Zn + ZnCl2
THF
2 EtZnCl
25 oC, 1 h
Scheme 37. Preparation of salt-free ethylzinc chloride
1.4. Miscellaneous methods
1.4.1. From diethylzinc and alkyl iodide
Higher homologues of alkylzinc halides can be prepared from Et2Zn and
alkyl halide in the presence of transition metal catalyst such as palladium or nickel.
In 1993 Knochel et al.25a reported the preparation of higher alkylzinc halides
for e.g. n-octylzinc iodide by the treatment of 1-iodooctane with Et2Zn in the
presence of catalytic PdCl2(dppf)2 in THF with good yield (Scheme 38).
n-OctI + 2 Et2Zn
PdCl2(dppf)2 (1.5 mol%)
n-OctZnI
o
THF, 25 C, 1.5 h
78% yield
Scheme 38. Preparation of salt-free octylzinc iodide
A tentative mechanism25b was proposed for the above transformation. The in
situ generated L2Pd (L2 = dppf) inserts into OctI to give Pd(II) intermediate, which
undergoes transmetallation with Et2Zn to give OctZnI and L2Pd(Et)2 complex. This
complex rapidly decomposes to ethylene and ethane regenerating Pd(0) catalyst.
In 1994 Knochel and Cahiez25c reported Mn/Cu catalyzed preparation of
alkylzinc bromides using alkyl bromide and Et2Zn. The treatment of n-octyl bromide
14a with Et2Zn in the presence of MnBr2 (5 mol %) and CuCl (3 mol %) in DMPU
under mild reaction conditions provided n-octylzinc bromide 15a in good yield
(Scheme 39). Other functionalized alkylzinc halides were also prepared in good
yield.
22
MnBr2 (5 mol%)
CuCl (3 mol%)
n-OctBr +
Et2Zn
14a
n-OctZnBr
DMPU, 25 oC, 4−10 h
-(CH2=CH2, H3C-CH3)
15a
80-90% yield
Scheme 39. Preparation of alkylzinc bromide from RBr and Et2Zn
Later in 1996, the same author25d reported Ni-catalyzed preparation of
alkylzinc halides from diethylzinc and alkyl halide without use of solvent. The
reaction of primary alkyl bromide or chloride (14a or 16a) with Et2Zn in the
presence of catalytic Ni(acac)2 afforded the corresponding alkylzinc halide in 7080% yield along with protonated
product RH (~10%) and elimination product
(~10%) (Scheme 40).
RX +
Et2Zn
14a or 16a
Ni(acac)2 (5 mol%)
neat, 50−60 oC
RZnX
70-80% yield
X = Cl, Br
Scheme 40. Ni-catalyzed preparation of alkylzinc halides from Et2Zn and RX
Author proposed the mechanism in which the in situ formed Ni(0) from
Ni(acac)2 and Et2Zn undergoes insertion reaction with alkyl halide to form RNiXLn
complex. This complex on transmetallation with Et2Zn gives RZnX and diethyl
nickel complex, which decomposes to give Ni(0), ethylene and ethane.
In 2008 Knochel et al.26a reported one pot procedure for the preparation of
benzyliczinc chlorides by using magnesium, ZnCl2 and LiCl. In this method
magnesium metal was reacted with benzylic chlorides 32a,b in the presence of ZnCl2
and LiCl in THF at room temperature to provide corresponding benzyliczinc
chlorides in excellent yield (Scheme 41). The formation of homocoupling product
was observed in <5% amount.
23
ZnCl
Cl
R + Mg + ZnCl2 + LiCl
THF
25 oC, 2 h
FG
R
FG
32
32a R = H
32b R = Me
FG = Cl, F, CN, CF3, CO2Et, OMe, SMe
Scheme 41. One pot preparation of benzyliczinc chlorides using Mg, ZnCl2 and LiCl
Later, using this methodology various alkylzinc bromides, arylzinc chlorides,
bromides and iodides were prepared from corresponding halides in excellent yield
under the mild reaction conditions.26b-d Various functional groups like cyano, esters,
amides etc. were tolerated.
24
2. Applications of organozinc halides
2.1. Enantioselective 1,2-addition
In 2007 Woodward et al.27a reported the Me3Al promoted addition of arylzinc
bromides and iodides to aromatic aldehydes. In this protocol PhZnBr was first
converted to PhZnMe by stoichiometric amount of Me3Al.
13
C NMR studies of the
mixture indicated rapid ligand exchange takes place between zinc and aluminum. In
situ formed PhZnMe was then treated with the 4-chlorobenzaldehyde in the presence
of catalytic amount of chiral β-aminoalcohols 36a-d, 37 and 38 (Scheme 42).
PhZnX
+
AlMe3
PhZnMe
O
+
Me2AlX
AlMe3
36- 38 (10 mol%)
H +
OH
PhZnX
THF:Toluene
RT, 16 h
Cl
S
Ph
Cl
63% yield
up to 83 % ee
Ph
OH
Ph
OH
Ph
OH
Ph
OH
Me
NMe2
Me
NBu2
Me
N
Me
N
Ph
Ph
36a
36b
Ph
OH
Ph
NBu2
37
36c
36d
Ph
Ph
OH
Ph
N
38
Scheme 42. Me3Al promoted addition of PhZnBr to 4-chloro benzaldehyde
The ligand 36b was found to be the most efficient ligand and therefore used
for the addition of ArZnX to various aldehydes (Table 3). Authors proposed that the
addition of Ph group takes place from Si face as shown in Figure 5.
25
Table 3. Enantioselective addition of ArZnMe to aromatic aldehydes using 36b
Entry
Aldehyde
ArZnX
Yield (%) ee (%) Config.
1
4-ClC6H4CHO
PhZnBr
67
83
S
2
4-ClC6H4CHO
PhZnI
50
89
S
3
4-FC6H4CHO
PhZnBr
76
90
S
4
4-MeC6H4CHO
PhZnBr
61
89
S
5
4-MeOC6H4CHO
PhZnBr
70
86
S
6
3-MeC6H4CHO
PhZnBr
58
91
S
7
2-MeC6H4CHO
PhZnBr
51
86
S
8
C6H5CHO
4-MeOC6H4ZnI
73
84
R
Ph
Me
Me
O
Bu2N
Ph
Si
Ar
Zn
O
Al
Me
X
H
Figure 5. Proposed transition state
Later in 2010, the same research group27b studied the scope of the above
reaction in detail. They have examined number of other promoters such as ZnR2 (R =
Me, Et, Bu), AlR3 (R = Et, i-Bu), methylaluminooxane (MAO) and BR3 (R = Et,
OMe, F). However Me3Al proved to be the best. Under optimized conditions, the
addition of ArZnBr to various aromatic as well as aliphatic aldehydes afforded good
to excellent enantioselectivities. Few important examples of aliphatic aldehydes are
given in (Table 4).
26
Table 4. Enantioselective addition of ArZnMe to aliphatic aldehydes
AlMe3
36b (10 mol%)
O
R
+
H
OH
ArZnBr
Ar
R
CH3CN:Toluene
RT, 16 h
Entry
Aldehyde
Ar
Yield (%)
ee (%)
1
n-BuCHO
4-MeOC6H4
87
82
2
t-BuCHO
4-MeOC6H4
96
93
3
t-BuCHO
4-EtO2CC6H4
76
96
4
i-PrCHO
4-EtO2CC6H4
48
93
5
c-C6H11CHO
4-EtO2CC6H4
53
97
In 2009 Walsh et al.27c used EtZnCl for the preparation of mixed
phenylethylzinc (PhZnEt) by treatment with PhLi in methyl tert-butyl ether (MTBE).
This reagent was then reacted with 2-benzofurancarbaldehyde 39 in the presence of
isoborneol based ligand (−)-MIB 40 (5 mol %) to obtain arylated product 41 in 92%
yield with 90% ee (Scheme 43). The role of N,N,N,N-tertaethylethylenediamine
(TEEDA) was to reduce the Lewis acidic effect of lithium halide generated during
the preparation of PhZnEt. In the absence of TEEDA poor enantioselectivity was
realized.
The
alcohol
41
was
further
converted
to
(S)-1-(benzofuran-3-
yl(phenyl)methyl)-1H-imidazole, a potential anticancer compound.
iii) TEEDA (0.8 equiv)
toluene, 0 oC
i) n-BuLi (2 equiv)
MTBE
2 PhBr
HO
PhZnEt
ii) EtZnCl (2 equiv)
−78 oC
O
iv) 40 (5 mol%)
v) 39, 0 oC, 12 h
H
O
N
O
39
OH
40
Scheme 43. Enantioselective addition of PhZnEt to aldehyde
O
41
92% yield
90% ee
Ph
27
2.2. Diastereoselective 1,2-addition
2.2.1. Diastereoselective addition to keto esters
In 1991 Basavaiah et al.28a described cyclohexyl based chiral auxiliary
mediated preparation of various optically active α-hydroxy acids by the
diastereoselective
addition
of
RZnCl
to
(1R,2S)-2-phenylcyclohex-1-yl
phenylglyoxalate 42. The treatment of 42 with alkylzinc chlorides, prepared from
RMgBr and ZnCl2, afforded corresponding α-hydroxy ester 43 which on hydrolysis
gave the desired α-hydroxy acid 44 in moderate to good yield with high optical
purity (Scheme 44).
O
Ph
Ph
+ RZnCl
O
O
O
Ph
ether
Ph
O
−78 to 0 oC
MeOH
HOOC
KOH
HO
HO R
42
43
Ph
R
(R)
44
R = Et, n-Bu, n-Hex
i-Pr, i-Bu
50- 80% yield
84- 99% ee
Scheme 44. Diastereoselective addition of RZnCl to α-keto esters
Encouraged by these result, the same group28b,c later examined various
cyclohexyl based chiral auxiliaries 45a-d (Figure 6) to study the steric effect. The
result showed that introduction of more bulky group on cyclohexyl ring does not
have significant variation on the diastereoselectivity.
t
Ph
Bu
O
OH
45a
ONO2
O
O
OH
OH
45b
45c
Figure 6
OH
45d
28
Later in 2002, Monteux et al.28d used the protected isomannide and isosorbide
as chiral auxiliaries in diastereoselective addition of various alkylzinc halides to
corresponding glyoxalate. The outcome of study was described below with one
representative example. Treatment of phenyl glyoxylate 46a (Figure 7) with i-PrZnX
(prepared from i-PrMgX and ZnCl2) in the presence of stoichiometric amount of
ZnCl2 gave corresponding α-hydroxy ester 47a in 78% yield with 88% de (Table 5,
entry 1). On the basis of outcome of the stereoselectivity, it was suggested that the
addition takes place in accordance with Whitesell′s model.28e However dramatic
decrease in selectivity was observed by interchanging the positions of α-ketoester
and protecting group. Thus, addition of i-PrZnX to 46b furnished the desired αhydroxy ester 47b with only 12% de whereas 46c afforded the ester 47c with >99%
de (Table 5, entry 2 and 3). In the case of 46c conformational arrangement allows the
л-stacking between the dicarbonyl moiety and phenyl ring of protecting group, which
is responsible for high stereoselectivity. Lack of such interactions in the case of 46b
explains the low selectivity. Saponification of 47a provided the corresponding αhydroxy acid with good enantioselectivity.
Ph
O
BnO
O
O
O
O
O
H
O
H
H
O
H
O
46a
BnO
H
Ph
O
O
O
H
O
OBn
46b
Figure 7
Ph
O
O
46c
29
Table 5. Diastereoselective addition of RZnX to 46a-c
BnO
H
i) ZnCl2
O
O
KOH
46a-c
ii) RZnX
OH
O
H
47a-c
O
*
MeOH/H2O
Ph
R
Ph *
OH
R OH
82% ee
O
Entry
Substrate
R
47, Yield (%)
de (%)
1
46a
i-Pr
78
88
2
46b
i-Pr
51
12
3
46c
i-Pr
53
>99
In 2006 Gaertner et al.28f reported the diastereoselective addition of RZnX to
α-ketoesters containing chiral m-hydrobenzoin auxiliaries. This reaction was studied
in solution as well as on solid support. Addition of alkylzinc chlorides to αketoesters 48 afforded corresponding α-hydroxy esters 50a-c with moderate to
excellent diastereoselectivity (Table 6, entries 1−3). The larger nucleophiles like nBuZnCl and i-PrZnCl gave excellent diastereoselectivity, whereas the reaction with
small nucleophile like MeZnCl resulted in only moderate diastereoselectivity. Under
similar reaction conditions the keto ester 49 containing polymer supported chiral
auxiliary showed similar results affording the hydroxyl esters 51a-c (Table 6, entries
4−6). Author proposed that chelation of Zn2+ cation forces the two carbonyls of the
keto carboxylic ester into syn-conformation29 which effectively shields one face of
the elcetrophile (Figure 8). This methodology was employed for the preparation of
frontalin which is an aggregation pheromone of a pine beetle population in the
Dendroctonus family.
30
Table 6. Diastereoselective addition of RZnCl to 48 and 49
O
Ph
O
O
R
RZnCl
OR'
Ph
THF, -78 to -20 oC
Ph
OH
O
O
OR'
Ph
50a-c
48 R' =
O
49 R' =
O
51a-c
= Wang resin
Up to 98% yield
30-98% de
Entry
Substrate
R
Product
de (%)
1
48
n-Bu
50a
>98
2
48
i-Pr
50b
94
3
48
Me
50c
45
4
49
n-Bu
51a
90
5
49
i-Pr
51b
84
6
49
Me
51c
30
H
H
Ph
R'
O
O
O
Ph
Ph
O
O
Zn
Nu
re-attack
X
Figure 8. Proposed model for the diastereoselective addition
2.2.2. Diastereoselective addition to imino esters
The reaction of α-imino esters with organometallic reagents is an interesting
and potentially useful reaction for the synthesis of optically active amino acids and
amino alcohols.
In 1988 Yamamoto et al.30a reported the diastereoselective addition of
benzylzinc bromide to imino esters. The reaction of iminoester 52 with PhCH2ZnBr
in THF gave the desired product 53 (C-alkylation at imino carbon) in moderate yield
31
with 48% de (Scheme 45). Other organometallic reagents such as RMgX, R3Al,
RTi(O-i-Pr)3 provide the N-alkylated product.
H
Ph
Ph
R CO Bu
2
CO2Bu
THF
N
+ PhCH2ZnBr
RT, overnight
Me
Ph S N
+
H
Ph
S CO2Bu
Ph S N
Me
52
H
Me
53a (major)
53b (minor)
50% yield
48% de
Scheme 45. Diastereoselective addition of PhCH2ZnBr to 52
Later in 2002, Roland et al.30b studied this reaction in detail. In their
preliminary investigation they found that the presence of a chelating atom such as
oxygen in amine part or chiral alcohol in ester moiety and use of ZnBr2 is necessary
to achieve excellent diastereoselectivity in the addition of t-BuZnBr to α-imino ester.
Under the optimized conditions various organozinc bromides were reacted with αimino ester 54 to obtain desired product 55 in moderate to good yield with good
diastereoselectivity (Scheme 46).
OEt
Ph
N
O
Me
i) ZnBr2, Et2O
ii) RZnBr, 0 oC to RT
R
OEt
NH
O
Ph
O
iii) NH4Cl
54
R = t-Bu, sec-Bu, c-Hex, Bn
O
Me
55
Up to 68% yield
Up to 92% de
Scheme 46. Diastereoselective addition of RZnBr to 54
The stereochemical outcome of the reaction was explained by the proposed
chelate models A and B (Figure 9). Both the models lead to (R)-product. In chelate
A, ZnBr2 coordinates to imine nitrogen and two oxygen atoms (from the ester and
OMe) to form rigid five-membered rings and the zinc reagent attacks from less
hindered re face. In chelate B, zinc reagent may coordinate with oxygen atom of
methoxy group leading to preferential attack from re face.
32
re face
re face
Ph
OEt
Ph
N
H
O
Br O
O Zn Zn
X
Br
ZnBr2
O
N
H
OEt
R
chelate A
chelate B
Figure 9
Very recently Ellman et al.30c reported highly diastereoselective addition of
benzylzinc reagents to N-tert-butanesulfinyl aldimines. The treatment of benzylzinc
chloride with imine 56a gave the corresponding addition product 57a in good yield
and diastereoselectivity (Scheme 47). Under the optimized conditions, various
benzyliczinc chlorides were reacted with number of substituted imines. Few
representative examples are given in table 7.
t
Bu
N
S
t
O
THF, RT
H
+ Ph
MeO
HN
S
O
ZnCl
Ph
MeO
56a
Bu
57a
70% yield
86% de
Scheme 47. Diastereoselective addition of PhCH2ZnCl to imine 56a
33
Table 7. Diastereoselective addition of benzyliczinc chlorides to various imines
t
Bu
t
Bu
S
N
HN
O
ZnCl
+
R
H
S
O
THF, RT
R
X
56
57
X
Entry
R
X
Yield (%)
de (%)
1
4-CO2MeC6H4
H
86
84
2
4-ClC6H4
H
87
84
3
3-ClC6H4
H
86
84
4
2-ClC6H4
H
79
>98
5
3-Py
H
98
92
6
4-CO2MeC6H4
4-OMe
69
88
7
4-CO2MeC6H4
4-F
86
88
8
t-Bu
4-F
77
52
2.3. Enantioselective 1,4-addition
In 2004 Hayashi et al.31a reported Rh-catalyzed enantioselective 1,4addition31b,c of arylzinc chlorides to protected 2,3-dihydro-4-pyridone to prepare
synthetically useful 2-aryl-4-piperidones 60a-f. In their initial study, they found that
PhZnCl was superior to other organometallics such as PhB(OH)2 or PhTi(O-i-Pr)3.
The addition of Phenylzinc chloride to 2,3-dihydro-4-pyridone 58 in the presence of
catalytic amount of [RhCl((R)-BINAP)]2 in THF afforded the desired product 60a in
excellent yield with high enantioselectivity (Scheme 48). This reaction showed broad
scope and the addition of various functionalized arylzinc reagents afforded excellent
enantioselectivities (Table 8). The methodology was successfully applied in the
preparation of a key intermediate for tachykinin antagonists B.
34
O
+ ArZnCl
N
CO2Bn
58
O
3 mol%
[RhCl ((R)-BINAP)]2
THF, 20 oC, 2 h
Ar
N
CO2Bn
60a Ar = Ph
(R)-BINAP =
95% yield
> 99.5% ee
PPh2
PPh2
59
Scheme 48. Enantioselective 1,4-addition of PhZnCl to 58
Table 8. Enantioselective 1,4-addition of various ArZnCl to 58
Entry
Ar
Product
Yield (%)
ee (%)
1
4-PhC6H4
60b
97
>99.5
2
4-MeOC6H4
60c
90
99
3
4-FC6H4
60d
91
>99.5
4
3,5-Me2C6H3
60e
87
99
5
2-MeC6H4
60f
100
99
The same author in 200531d described the preparation of 2-aryl-2,3-dihydro-4quinolones which are antimitotic antitumor agents. Initially the treatment of PhZnCl
with 4-quinolone 61 under the above reported conditions31a resulted in very low
yield. However, the addition of TMSCl (as a Lewis acid) gave smooth conversion
under mild conditions and expected product 62 was obtained with excellent
enantioselectivity (Scheme 49). The outcome of the stereoselectivity in Rh/(R)BINAP catalyzed 1,4-addition was rationalized by the re face approach of the
substrate to avoid the steric repulsion between the phenyl ring on the phosphorus
atom of (R)-BINAP and fused benzene ring of the substrate.
35
O
O
[RhCl (C2H4)2]2 (7.5 mol% Rh)
59 (8.2 mol%)
+ PhZnCl
TMSCl
THF, 20 oC, 20 h
then 10% aq. HCl
N
CO2Bn
N
Ph
CO2Bn
61
62
88% yield
98% ee
Scheme 49. Enantioselective 1,4-addition of PhZnCl to 61
In the same year Hayashi′s group31e reported the use of above methodology35d
in enantioselective 1,4-addition of phenylzinc chloride to α,β-unsaturated ketones
catalyzed by [Rh((1R,5R)-Ph-cod)((R)-1,1′-binaphthyl-2,2′-diamine)] 64. Treatment
of α,β-unsaturated ketones or esters 63a-d with phenylzinc chloride in the presence
of catalytic amount of 64 provided the expected product 65a-d in excellent yield with
high enantioselectivity (Scheme 50). The reaction was very fast and completes in 20
minutes at 0 oC.
O
X
O
TMSCl (1.5 equiv)
64 (3 mol%)
THF, 0 oC, 20 min.
X = CH2, O
63a-d
O
Ph
(R)-65a-d
86-99% yield
90-98% ee
O
O
O
63a
X
+ PhZnCl
63b
O
O
63c
63d
Ph
H H
N
Rh
N
H H
Ph
64
BF4
Scheme 50. Enantioselective 1,4-addition of PhZnCl to 63
Later in 2006, Hayashi et al.31f described the enantioselective 1,4-addition of
arylzinc halides to α,β-unsaturated aldehydes. The reaction of various (E)-3arylpropenal 66 with ArZnCl in the presence of TMSCl and catalytic amount of
36
Rhodium catalyst (coordinated with (R)-BINAP 59) in THF at 20 oC furnished
corresponding 3,3-diarylpropanal 67 with excellent enantioselectivity (Scheme 51).
Ar
1
[RhCl((R)-BINAP)]2
(3 mol% of Rh)
H + ArZnCl
Ar1
MeOH/H2O
RT, 1 h
TMSCl, THF
20 oC 1 h
O
K2CO3
H
Ar
O
67
66
Ar1 = 4-MeOC6H4, 2-MeOC6H4, 2-FC6H4, C6H5
55-80% yield
98-99% ee
Ar = C6H5, 4-MeOC6H4, 3-MeOC6H4, 3,5-Me2C6H3
2-naphthyl, 4-ClC6H4, 3-ClC6H4
Scheme 51. Rh-catalyzed enantioselective 1,4-addition to enal 66
In 2008 Frost et al.31g reported the enantioselective 1,4-addition of substituted
thienylzinc and 2-furanylzinc bromides to α,β-unsaturated ketones and esters using
catalyst prepared from [Rh(C2H4)2Cl]2 and chiral phosphorous ligand. Initial
investigations showed (R,R)-Me-DUPHOS 69 gave excellent results as compared to
other phosphorus ligands. Excellent enantioselectivities were obtained in 1,4addition of 68a and 68b to α,β-unsaturated ketones (63a and 63b) and ester 63c
using catalytic amount of 69 (Scheme 52).
[Rh(C2H4)2Cl]2 (cat.)
O
69 (cat.)
X
X
+ 68a,b
TMSCl, THF, 20 oC
X = CH2, O
Y = O, S
R1
63a-c
S
68a
ZnBr
O
ZnBr
(R,R)-Me-DUPHOS
O
(R)
Y
R1
P
P
69
38-91% yield
Up to 98% ee
68b
R1 = Br, Me,
Scheme 52. Enantioselective 1,4-addition to 63 using ligand 69
In 2009 Martin et al.31h reported Rhodium-catalyzed enantioselective 1,4addition of 2-heteroarylzinc chlorides to cyclic enones, unsaturated lactones, and
unsaturated lactams using (R)-MeO-BIPHEP ligand 71. The addition of benzofuran-
37
2-ylzinc chloride 70a or benzothiophene-2-ylzinc chloride 70b to Michael acceptors
63a-e in the presence of TMSCl and catalytic amount of 71 afforded the
corresponding 1,4-addition product in moderate to good yield with high
enantioselectivity (Scheme 53).
[Rh(cod)acac] (cat.)
71 (cat.)
63a-e +
Ar1ZnCl
O
(R)-MeO-BIPHEP
X
TMSCl, THF
−78 to 0 oC
70a,b
Ar1
47-93% yield
91- 98% ee
O
N
Me
MeO
MeO
P(Ph)2
P(Ph)2
71
Ar1 =
S
63e
70a
O
70b
Scheme 53. Enantioselective 1,4-addition of 70 using ligand 71
2.4. Asymmetric cross-coupling reactions
In 1983 Kumada et al.32a reported Pd-catalyzed cross-coupling of organozinc
halides with vinyl bromide. The reaction of secondary alkylzinc halides 72 with vinyl
bromide in the presence of Palladium catalyst 73 afforded olefin 74a-c in good yield
with up to 86% enantioselectivity (Scheme 54).
Ar
ZnX + CH2=CHBr
R
72
73 (cat.)
Ar
THF, -78 to 0 oC
R
H
H
(s)
74a-c
X = Cl, Br, I
72a Ar = Ph, R = Me
72b Ar = p-Tol, R = Me
72c Ar = Ph, R = Et
Fe
NMe2
Cl
Pd
P
Cl
Ph
2
73 PdCl2[(R)-(S)-PPFA]
Scheme 54. Pd-catalyzed enantioselective cross-coupling
Later in 1989, Hayashi and Ito32b reported Pd-catalyzed enantioselective
cross-coupling of l-phenylethylzinc chloride 72a with vinyl bromide using catalytic
amount of ferrocenylphosphine ligand 75. The expected product was obtained in
quantitative yield with excellent enantioselectivity (Scheme 55).
38
Me
Ph
ZnCl + CH2=CHBr
Me
Ph
75 (0.5 mol%)
NMe2
H
H
Me
(R)
74a
THF, 0 oC
72a
Ph2
P
PdCl2
P
Ph2
Fe
H
93% ee
NMe2
Me
75
Scheme 55. Pd-catalyzed enantioselective cross-coupling catalyzed by 75
In 2005 Fu et al.33a reported first example of Ni-catalyzed asymmetric
Negishi cross-coupling33b of alkylzinc bromides with secondary α-bromo amides.
The treatment of various secondary α-bromo amides 76 with simple as well as
functionalized
alkylzinc
bromides
in
DMI/THF
(DMI
=
1,3-dimethyl-2-
imidazolidinone) using catalytic amount of NiCl2⋅glyme and (R)-i-Pr-Pybox ligand
77 provided desired product 78 in moderate to good yield with excellent
enantioselectivity (Scheme 56).
O
Bn
N
Ph
R
+ R1ZnBr
Br
NiCl2.glyme (10 mol%)
ligand 77(13 mol%)
O
Bn
DMI/THF, 0 oC
R
N
Ph
R1
78
76
(Recemic)
O
R = Me, Et, n-Bu, i-Bu
R1 = alkyl, functionalized alkyl
Pr
O
N
N
N
i
51-90% yield
87 to >98% ee
77
i
Pr
(R)-i-Pr-Pybox
Scheme 56. Nickel-catalyzed asymmetric Negishi coupling of R1ZnBr with 76
The same year Fu′s group33c described Ni-catalyzed cross-coupling of
alkylzinc bromides with secondary benzylic halides. Thus, the reaction of 1-bromo or
1-chloro indanes 79 with various alkylzinc bromides in the presence of NiBr2⋅glyme
and (R)-i-Pr-Pybox ligand 77 in DMA gave desired product 80 in moderate to good
yield with moderate to excellent enantioselectivity (Scheme 57). Author
39
demonstrated that this methodology can be used in the synthesis of bioactive
molecules such as LG 121071.
X
+ R1ZnBr
R2
R1
NiBr2.glyme (10 mol%)
ligand 77 (13 mol%)
R2
o
DMA, 0 C, 24 h
80
79
(Racemic)
41-89% yield
75-99% ee
X = Cl, Br
R1 = alkyl, functionalized alkyl
R2 = Cl, CN, Me, OMe
Scheme 57. Nickel-catalyzed asymmetric Negishi coupling of R1ZnBr with 79
Later in 2008, the same author33d reported the Ni-catalyzed asymmetric crosscoupling of allylic chlorides with various alkylzinc bromides. The reaction of various
symmetrical as well as unsymmetrical allylic chlorides 81 with alkylzinc bromides in
the presence of excess NaCl and catalytic amount of (S)-BnCH2-Pybox ligand 82
gave the corresponding coupling product 83 in good yield with excellent
enantioselectivity (Scheme 58). In the case of unsymmetrical allylic chlorides the
cross-coupling preferentially occurs at less hindered carbon with the regioselectivity
>20:1. The addition of NaCl accelerates the rate of cross-coupling, but has little
effect on ee. Author applied this methodology for the formal synthesis of
fluvirucinine A1.
Cl
R3 + R1ZnBr
R2
81
NiCl2.glyme (5 mol%)
ligand 82 (5.5 mol%)
NaCl (4 equiv)
R1
R2
DMA/DMF, −10 oC, 24 h
R1 = alkyl, functionalized alkyl
R2 = n-Bu, i-Pr, t-Bu, COOEt, CONEt2,
CON(OMe)Me, PO(OEt)2
R3 = Me, n-Pr, i-Pr
O
83
Up to 95% yield
Up to 98% ee
O
N
N
Bn
R3
N
82
Bn
(S)-BnCH2-Pybox
Scheme 58. Nickel-catalyzed asymmetric Negishi coupling of R1ZnBr with 81
40
In 2009 Fu et al.33e reported the asymmetric cross-coupling of arylzinc
iodides with α-bromoketones. After extensive optimization of the reaction
conditions, they found that this reaction proceeds smoothly in the presence of
NiCl2⋅glyme (5 mol%), Pybox ligand 85 (6.5 mol%) in glyme/THF. Under optimized
conditions, treatment of α-bromoketones 84 with various arylzinc iodides provided
corresponding cross coupled product in good yield and good enantioselectivity
(Scheme 59). Decreased yield as well as ee was observed when Ar1 and R were the
bulky substituent.
NiCl2.glyme (5 mol%)
ligand 85(6.5 mol%)
O
Ar1
R
O
glyme/THF, −30 oC
Br
84
(Recemic)
R
Ar1
+ ArZnI
Ar
O
Ph
N
Up to 93 % yield
Up to 96 % ee
O
N
85
OMe
N
Ph
MeO
Ar = Ph, 2-MeOC6H4, 3-MeOC6H4, 4-MeOC6H4, 4-FC6H4,
4-Me2NC6H4, 4-MeSC6H4.
Ar1 = Ph, 2-FC6H4, 3-EtC6H4, 4-MeOC6H4, 4-F3CC6H4, 2-thienyl
Scheme 59. Nickel-catalyzed asymmetric Negishi coupling of ArZnI with 84
2.5. Miscellaneous reactions
In 1997 Knochel et al.34a reported the preparation of various chiral ferrocenes
by the reaction of ferrocenyl acetate with various organozinc reagents. The treatment
of chiral ferrocenyl acetate 86 with RZnX in the presence of BF3⋅OEt2 provided the
expected product 87 in good yield with >95% retention of stereochemistry (Scheme
60).
OAc
R
1
R
Fe
+ RZnX
THF
-78 oC to RT, 1.5 h
R1
Fe
86
X = Br, I
R = i-Pr, (E)-PhCH=CH, allyl, 3-MeC6H4CH2
R1 = Me, Ph
87
64-98% yield
95-98% ee
Scheme 60. Substitution of ferrocenyl acetate 86 with RZnX
41
Later in 2003, Xue et al.34b reported the preparation of C-Glycosides by
addition of organozinc halides to glycal epoxide 88. Treatment of 88 (prepared by
Danishefsky′s protocol35) with organozinc halides, prepared from RLi and ZnCl2,
provided
α-glycoside
89a
as
major
product
(Table
9).
However,
low
diastereoselectivity was observed when RZnX was prepared from RMgX and ZnCl2.
Table 9. Addition of various RZnX to epoxide 88
O
BnO
O + RZnX
BnO
Et2O
O
BnO
0 oC to RT
R
O
BnO
R
+
BnO
OH
BnO
OH
OBn
OBn
OBn
89a
88
89b
Entry
RZnXa
Yield (%)
89a:89b
1
n-BuZnCl
69
>95:5
2
PhZnCl
78
>95:5
3
O
72
>95:5
ZnCl
4
Ph-C
C-ZnCl
86
100:0
5
C3H7 -
C-ZnCl
80
100:0
41
66:34
n-BuZnClb
6
a
prepared from RLi and ZnCl2. b Prepared from RMgX and ZnCl2.
In 2004 Ready et al.36 found that alkylzinc chlorides prepared from Grignard
reagent and ZnCl2 undergo efficient cross-coupling with α-halo ketones in the
presence of copper catalyst. Using this methodology optically pure α-chloroketone
90 was reacted with iso-propylzinc chloride to obtain desired product 91 in good
enantioselectivity with 100% inversion of stereochemistry (Scheme 61).
O
O
CH3
Cl
i-PrZnCl MgCl2
Cu(acac)2 (5 mol%)
Et2O/THF, 25 oC, 14 h
90
95% ee
Scheme 61. Cu-catalyzed coupling of α-haloketones
CH3
Me
Me
91
77% yield
95% ee
42
3. Preparation of organozincates
The organometallic reagent having Lewis acidic metal centre possess ability
to react with anionic fragment. Due to the presence of vacant orbitals on the metal
centre these reagents when reacted with Lewis base, form a new organometallic
species which is termed as an ‘ate’ complex.11c,37 The outer shell of zinc atom in
dialkylzinc (e. g. Me2Zn) is filled with 14 electrons and there are two empty orbitals
which can occupy two pairs of electrons. Therefore it can react with one or two
Lewis basic reagent (e.g. MeLi) which results in the formation of organozincate
complex Me3ZnLi or Me3ZnLi2 respectively. Organozincates are further classified
into two classes: i) Triorganozincates [R3Zn]M and ii) Tetraorganozincates
[R4Zn]M2. We were particularly interested in the chemistry of triorganozincates. The
following literature survey therefore is mainly focused on preparation and
applications of triorganozincates in asymmetric reactions.
Triorganozincates are generally prepared by the reaction of zinc halide with
three equivalents of alkyllithium or Grignard reagent or from stoichiometric reaction
of organolithium or Grignard reagent with diorganozinc4a (Scheme 62).
ZnX2 + 3 RM
[R3Zn]M
ZnR2 + RM
[R3Zn]M
M = Li, MgX
Schemer 62. Methods for the preparation of triorganozincates
These reagents have very old history and are known since the report of
Wanklyn in 1858.38 Author prepared [Et3Zn]M (M = Na, K) from the reaction of
Et2Zn and alkali metals (Na or K). However very little information was known about
such complexes at that time. There are several reports on the preparation of
triorganozincates. Some of the important methods are discussed below.
On the basis of spectroscopic evidence, Waack and Doran39a reported in 1963
that the 1:1 mixture of Et2Zn and 1,1-diphenyl-n-hexyllithium forms triorganozincate
species (Scheme 63).
43
[Et2ZnR]Li
Et2Zn + RLi
R = 1,1-diphenyl-n-hexyllithium
Scheme 63. Preparation of lithium triorganozincate
In 1986 Kjonaas et al.39b reported the preparation of magnesium
trialkylzincate [R3Zn]MgBr by the reaction of ZnCl2⋅TMEDA complex with 3
equivalent of Grignard reagent in THF (Scheme 64). Authors have observed that this
complex reacts chemoselectively with α,β-unsaturated ketones to give 1,4-addition
as the major product.
THF
ZnCl2 TMEDA + 3 RMgX
[R3Zn]MgX
R = alkyl, aryl
X = Cl, Br, I
Scheme 64. Preparation of magnesium triorganozincates
In 1991 Richey Jr. et al.40 reported the preparation of heteroleptic
triorganozincate 92. The reaction of stoichiometric amount of diethylzinc with
potassium tert-butoxide in toluene provided the zincate 92 (Scheme 65). NMR
spectroscopy and X-ray crystallographic studies showed that the complex exists in
dimeric form.
toluene
Et2Zn + t-BuOK
[Et2ZnO-t-Bu]K
92
Scheme 65. Preparation of potassium triorganozincates
In 1992 Purdy et al.41 prepared the trialkylzincates 93a-c using the method of
Wanklyn (Scheme 66). These complexes were characterized using NMR
spectroscopy and X-ray crystallography. The alkyl groups on zinc adopt trigonalplanar geometry.
44
benzene, RT, 24 h
3 R2Zn + 2 M
2 [ZnR3]M
93a-c
93a M = Na, R = CH2CMe3
93b M = K, R = CH2CMe3
93c M = K, R = CH2SiMe3
Scheme 66. Preparation of trialkylzincates 93 from R2Zn and alkali metals
In 1993 Weiss et al.11b reported the crystal structure of potassium
trimethylzincate 94 in which methyl groups exhibit trigonal-planar coordination
(Figure 10). No details of preparation method were reported.
Me
Me
Zn
K
Me
94
Figure 10
In 1994 Purdy et al.42 reported the preparation of tri-tert-butoxyzincates 95a
and 95b by the reaction of ZnCl2 with 3 equivalent of t-BuOM (M = Na, K) in THF
or ether (Scheme 67). These complexes were purified by sublimation under reduced
pressure. Spectroscopic and X-ray crystallographic studies showed that both the
complex exists in dimeric form.
ZnCl2 + 3 t-BuOM
THF or Et2O
4 days
[(t-BuO)3Zn]M
95a M = Na
95b M = K
Scheme 67. Preparation of tri-tert-butoxyzincates 95
Later in 1996, Uchiyama et al.43a prepared Lithium trimethylzincate
(Me3ZnLi) and dilithium tetramethylzincate (Me4ZnLi2) by the reaction of ZnCl2
with 3 and 4 equivalent of MeLi in THF respectively (Scheme 68). The 1H NMR
studies clearly indicated the upfield shift of methyl protons in Me3ZnLi and
45
Me4ZnLi2 compared to that of Me2Zn (Table 10), which indicates more anionic
character of the zincates.
THF
ZnCl2 + 3 MeLi
[Me3Zn]Li
THF
ZnCl2 + 4 MeLi
[Me4Zn]Li2
Scheme 68. Lithium tri- and tetraorganozincates
Table 10. 1H NMR of zincates in THF
Entry
Reagent
δMe (ppm)a
1
MeLi
−1.96
2
Me2Zn
−0.84
3
Me3ZnLi
−1.08
4
Me4ZnLi2
−1.44
a
The δ values are relative to β methylene proton (1.85 ppm) of THF.
In 1998 Krieger et al.43b isolated the magnesium triphenylzincate
[Mg2Br3(THF)6][ZnPh3] 96 from the reaction of phosphoraneiminato complex
[ZnBr(NPMe3)]4 with excess PhMgBr (Scheme 69). The structure of the complex
was established by X-ray crystallographic studies.
THF
[ZnBr(NPMe3)]4 + PhMgBr
excess
Ph
Ph
Ph
Br
THF
THF
Zn
THF
[MgBr(NPMe3)]4 + 96
Mg
Br
Br
THF
Mg
THF
THF
96
Scheme 69. Preparation of magnesium triphenylzincate 96
46
Recently in 2010, Hevia et al.23f reported the preparation of magnesium tritert-butylzincate [t-Bu3Zn][Mg2Cl3⋅(THF)6] 97 by the reaction of ZnCl2 with 3
equivalent of t-BuMgCl in THF (Scheme 70).
ZnCl2 + 3 t-BuMgCl
THF
[t-Bu3Zn][Mg2Cl3(THF)6]
97
Scheme 70. Preparation of tri-(tert-butyl)zincate complex
X-ray crystallographic studies of 97 showed that in the anionic moiety, the
zinc centre is bonded to three tert-butyl groups with trigonal planar geometry
whereas cationic moiety consists of two distorted octahedral magnesium atoms
sharing three chlorines and with three molecules of THF completing the coordination
sphere of magnesium (Figure 11).
t
Bu
Bu
t
THF
Zn
t
Bu
Cl
THF
Mg
THF
Figure 11
Cl
Cl
THF
Mg
THF
THF
47
4. Applications of organozincates
Triorganozincates have been used in many organic reactions such as 1,2addition to carbonyl compounds,44 1,4-conjugated addition to α,β-unsaturated
carbonyl compounds,39b,45 addition to imines,44d,46 metalation of aromatic
halides,11c,43a,47 epoxide opening43a and Pd-catalyzed cross coupling23f,47b, (Fig. 12).
OH
R1 R2
R
R2
Ar-R
Pd
(II)
O
O
R
O
R1
ArI
[R3Zn]M
N
R1
O
R
R1
R1
ArI
OH
R3
R2
HN
R3
R1 R2
R
[R2ZnAr]M
Figure 12
However, these reagents have been used in a only few asymmetric reactions
such as addition to carbonyl compounds, imines and α,β-unsaturated ketones.
4.1. Asymmetric 1,2-addition
In 1979 Seebach et al.48a reported the enantioselective addition of lithium
tributylzincate (prepared from ZnCl2 and 3 equivalent of BuLi) to benzaldehyde
using (+)-DBB 98 as a chiral cosolvent (Scheme 71). Although good yield was
obtained, the enantioselectivities was very low.
48
OH
Et2O:(+)-DBB
[Bu3Zn]Li + PhCHO
Ph
OMe
Bu
85% yield
15% ee
NMe2
Me2N
(R)
OMe
(+)-DBB 98
Scheme 71. Asymmetric addition of lithium tributylzincate to benzaldehyde
Later in 2007, Gosselin et al.48b reported the enantioselective addition of
chiral organozincate 99 to Ethyl 2,2,2-trifluoropyruvate 100. Initial investigation
showed that (R)-BINOL was superior to other chiral modifiers. The chiral zincate 99
was prepared in situ by first treatment of the (R)-BINOL with stoichiometric amount
of Et2Zn followed by addition of Grignard reagent. The reaction of resulting chiralzincate complex with keto ester 100 in 1,2-dichloroethane:THF followed by
hydrolysis provided enantiomerically enriched α-hydroxy acids 101 with moderate to
good enantioselectivities (Table 11). Later in 2010, the same author48c used this
methodology in the preparation of biologically important 5-lipoxygenase inhibitor
MK-0633.
Table 11. Enantioselective addition of chiral-organozincates to 100
i)
Et2Zn
DCE:THF
−40 oC to RT
(R)-BINOL
ii) RMgCl
−40 oC to RT
O
i) CF
3
OEt
O
[(R1O)2Zn(R)]MgCl
100
o
99
-40 C, 18 h
R1 = (R)-BINOL-ate ii) KOH, H2O
O
R
OH
HO CF3
101
Up to 74% yield
Up to 83% ee
Entry
1
2
3
4
5
6
7
R
Me
Et
Bu
vinyl
phenyl
allyl
benzyl
Yield (%)
29
74
35
29
38
37
36
ee (%)
50
74
83
13
69
4
<5
49
4.2. Asymmetric 1,4-addition
In 1979 Seebach et al.49a reported the enantioselective addition of lithium
tributylzincate to 2-cyclohexenone using (+)-DBB 98 as chiral cosolvent. Moderate
yield of expected product was realized with poor enantioselectivity (Scheme 72).
Other Michael acceptors such as 2-cyclpentenone, crotonaldehyde and 1-nitro-1propene gave similar results.
O
O
Et2O:(+)-DBB
+ [Bu3Zn]Li
*
−78 oC
Bu
62% yield
16% ee
Scheme 72. Asymmetric 1,4-addition of lithium tributylzincate
In 1988 Feringa et al.49b found that the use of alkoxide as non-transferable
ligand in 1,4-addition of triorganozincates to 2-cyclohexenone. Encouraged by these
results, they examined chiral menthoxide as non-transferable ligand. Thus, chiral
zincate complex 102 was prepared in situ by the treatment of ZnCl2⋅TMEDA
complex with one equivalent of 1-menthyloxymagnesium bromide followed by the
addition of 2 equivalent of i-PrMgBr in THF. The reaction of resulting zincate
complex with 2-cyclohexenone provided the desired product with only 9% ee
(Scheme 73). Examination of triorganozincates obtained from chiral TMEDA⋅ZnCl2
analogue 103 provided similar results.
O
O
TMEDA [(iPr)2Zn(OR*)]MgBr
*
THF, 0 oC
102
OR* = menthyloxy
i
Pr
80% yield
9% ee
H
H
N
N
Zn
Cl
Cl
103
Scheme 73. Enantioselective 1,4-addition of chiral-zincate 102
50
In further study, Feringa′s group found that catalytic amount of ClZnOR can
be used in 1,4-addition.49c Later in 1990, they examined chiral-zinc alkoxides 104a
and 104b in enantioselective addition of Grignard reagent to 2-cyclohexenone.49d
The chiral zinc-alkoxide (prepared by the reaction of ZnCl2 with lithium alkoxides
derived from corresponding aminoalcohols) was first reacted with Grignard reagent
to form chiral organozincate species which on further treatment with to 2cyclohexenone afforded desired product in excellent yield with moderate
enantioselectivity (Scheme 74). Authors examined a library of various type of
ligands for this reaction but couldn’t achieve better results.
O
O
i-PrMgBr
+ R*OZnCl
5 mol%
THF, −90 oC, 15 min
Me
N
Me
Me
Zn
Cl
O
Pr
Up to 92% yield
Up to 33% ee
R*OZnCl
N
i
Ph
104a
Me
N
N
Me
Zn
Cl
O
104b
Scheme 74. Catalytic enantioselective 1,4-addition of triorganozincates
4.3. Diastereoselective addition to imines
In
1997
Savoia
et
al.50a
reported
diastereoselective
addition
of
triorganozincates to imines. Initial study showed that valine-derived imine 105 was
better as compared to other imines. The reaction of imine 105 with various lithium
and magnesium triorganozincates provided corresponding amines 106a-h in
moderate to excellent diastereoselectivity (Table 12). It was also found that the
zincates derived from Grignard reagents were more effective than the corresponding
lithium zincates. In the case of mixed organozincates [R′2ZnR]M (R′ = Me),
selective transfer of R group was observed rather than R′. The diastereoselectivity
was slightly affected by the nature of R group and decreased in the order vinyl > i-Pr,
n-Bu > Me > Bn > allyl > t-Bu.
51
Table 12. Diastereoselective addition of triorganozincates to imine 105
R
N
THF, −78 oC
COOEt + [R'2ZnR]M
N
N
105
(S)
N
COOEt
(S)
H
106a-h
M = Li, MgX
R' = Me, t-Bu
R = alkyl, vinyl, allyl, benzyl
Up to 90% yield
Up to 98% de
Entry
[R'2ZnR]M
Yield (%)
Product
de (%)
1
[Me3Zn]MgCl
50
106a
84
2
[Me3Zn]Li
50
106b
54
3
[Me2Zn-n-Bu]MgCl
86
106c
88
4
[Me2Zn-i-Pr]MgCl
90
106d
90
5
[Me2Zn-t-Bu]MgCl
80
106e
14
6
[Me2ZnBn]MgCl
88
106f
76
7
[Me2Zn(allyl)]MgBr
91
106g
46
8
[Me2Zn(vinyl)]MgBr
95
106h
98
On the basis of these results, the outcome of stereoselectivity was explained
through the formation of six-membered cyclic transition state (Figure 13).
N
X Mg Me
Zn Me
N
EtO2C
R
H
i
Pr
Figure 13
In 2008 Guijarro and Yus50b prepared various mixed trialkylzincates by the
treatment of Me2Zn with Grignard reagent. The reaction of these zincates with (R)-N(tert-butanesulfinyl)benzaldimine 107 furnished corresponding chiral amines 108
with moderate to good diastereoselectivity (Scheme 75).
52
O
N
Ph
S
O
t
H
THF, −78 oC
Bu
+ [Me2ZnR]MgBr
1−3 h
107
HN
Ph
S
t
Bu
R
(Rs,R)-108
R = Et, i-Pr, n-C5H11, vinyl
85-93% yield
88-96% de
Scheme 75. Diastereoselective addition of triorganozincates to 107
Later in 2009, the same author50c reported the catalytic version of the above
method. After extensive study they found that the use of 0.15 equivalent of Me2Zn
gave optimum results. Under the optimized conditions various Grignard reagents
were reacted with imine 107 to obtain corresponding chiral amine 108 with excellent
diastereoselectivity (Scheme 76). Author proposed that the reaction of RMgX with
Me2Zn generates triorganozincate [Me2ZnR]MgX, which transfers the R group
selectively to the imine and Me2Zn gets recycled to continue the reaction. This
methodology was later used for the preparation of various optically active α- and βamino acids.50d,e
O
N
Ph
S
H
O
t
THF, −78 oC
Bu
HN
S
+ Me2Zn + RMgBr
(cat.)
107
R = Et, i-Pr, n-C5H11, vinyl
Ph
t
Bu
R
(Rs,R)-108
83-99% yield
86-96% de
Scheme 76. Catalytic diastereoselective addition of triorganozincates to 107
53
4.4. Miscellaneous reactions
4.4.1. Diastereoselective addition to vinylic sulfoxides
In 1997 Houpis and Molina51a reported the addition of triphenylzincates
[Ph3Zn]M (M = Li, MgBr) to optically active vinyl sulfoxide 109. Treatment of
[Ph3Zn]M (M = Li or MgBr) with 109 in the presence of catalytic amount of
Ni(acac)2 gave the sulfoxide 110 in good yield. Compound 110 upon desulfurization
provided the phosphodiesterase IV inhibitor 111 with good enantioselectivity
(Scheme 77).
O
O
N
S
CpO
N
N
[Ph3Zn]M
S
tolyl Ni(acac) (cat.)
2
THF, −25 oC CpO
MeO
tolyl
Ph
MeO
109
M = Li, MgBr
Cp = cyclopentyl
Zn
THF:AcOH CpO
23 oC
MeO
Ph
111
70-75% yield
82-92% ee
110
>90% yield
Scheme 77. Diastereoselective addition of triphenylzincates to sulfoxide 109
4.4.2. Enantiospecific cross-coupling
In 2008 Briet et al.51b reported ZnCl2-catalyzed enantiospecific cross
coupling of α-hydroxy ester triflates 112 with Grignard reagents. Under optimized
conditions, various RMgX (X = Cl, Br) provided the coupling product 113 in good
yield with 100% transfer of chirality (Scheme 78). In the absence of ZnCl2, low yield
of expected product was observed.
O
ButO
R1
112 OTf
ZnCl2 (5 mol%)
RMgX
O
ButO
THF, 0 oC
(97 to >99% ee)
R1 = Me, n-Bu, i-Bu, i-Pr, Bn, CH2OR,
CH2COR
R = Me, Et, n-Bu, i-Bu, i-Pr, Oct, Bn, lauryl
R1
R
113
72 to >99% yield
97 to >99% ee
Scheme 78. Zn-catalyzed cross-coupling of Grignard reagents with 112
This
methodology
was
later
used
for
the
synthesis
of
(Oligo)deoxypropionates which are common motifs in a large number of biologically
54
relevant natural products of polyketide origin. In this report, the author proposed a
catalytic cycle (originally postulated by Ishihara et al.44d) as shown in figure 14. The
addition of RMgX to zinc chloride generates diorganozinc species (R2Zn) which then
reacts with a third molecule of Grignard reagent to give a triorganozincate species
(R3ZnMgX). Lewis acid activation of the triflate with magnesium ion followed by
SN2 attack of triorganozincate gives the expected product with very high
stereoselectivity.51c
cat. ZnCl2 + 2 RMgX
Product
(R2Zn)
RMgX
[R3Zn]MgX
ZnR3
Zn(II)-ate complex
R1
ButO
O
O
SO2CF3
112
Mg
X
Figure 14. Proposed catalytic cycle
Summary and Outlook
It is evident from the above account that efficient methodologies now exist
for the preparation of organozinc halides.12-26 However, there is still need to develop
simple methods for their preparation, for example using zinc dust in THF as solvent.
Moreover, less reactive alkyl chlorides and aryl bromides are still useless substrates
for the reaction with zinc. These reagents have found applications mainly in Pd- or
Ni-catalyzed enantioselective cross coupling and Rh-catalyzed 1,4-additions. Unlike
diorganozincs, organozinc halides could not gain popularity for the enantioselective
addition to carbonyl group.
Organozincates are reactive species and have proved their utility in
asymmetric synthesis. However there are no catalytic protocols for their use in
enantioselective transformations.
To sum up, the oldest organometallic reagent still remains significantly
unexplored, and promises rich dividend for researchers.
55
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61
CHAPTER-2
Present work on organozinc compounds
62
Introduction
As discussed in the Ist chapter, organozinc reagents are important
organometallics in asymmetric synthesis. Amongst these, dialkylzincs have proved to
be excellent nucleophiles in asymmetric addition to carbonyl compounds mainly
because of well established methods and use of simple ligands.1 However, lack of
wide commercial availability, high cost and their pyrophoric nature demands an easy
in situ preparation of these reagents. Significant efforts have been made by various
research groups to circumvent these difficulties,2 which includes preparation of
diorganozincs by boron-zinc3 or iodine-zinc4 exchange and transmetallation of
alkyllithium or Grignard reagents with zinc salts.5 One of the major drawbacks in the
case of in situ preparation of diorganozinc reagents from alkyllithium or Grignard
reagent and ZnX2, is the formation of lithium and magnesium salts which affect
enantioselectivity.5c,e To overcome this difficulty, additional tasks like centrifugation
/ filtration5a-c or the use of complexing agent like TMEDA have been explored.5d,e
Therefore search for other alternatives is desirable. We have been interested in the
reagents of type RZnX6 (X = Cl, Br, I) which are easily accessible and represent the
best choice in this context. Organozinc halides have been used as nucleophiles in few
asymmetric reactions like catalytic enantioselective 1,4-addition7 and asymmetric
Negishi coupling.8 Only few examples of the use of organozinc halides in catalytic
enantioselective addition to aldehyde are known.9 Similar to organozinc halides,
triorganozincate reagents are also less explored in asymmetric synthesis.10-13
Development of new methods for their application in asymmetric synthesis would
lead these reagents as a valuable organometallics.
The present chapter describes the preparation of RZnX (X = Cl, Br, I, OAc)
and the corresponding organozincates and their applications in enantioselective
alkylation of aldehyde. It has been divided into three sections.
Section 2A:
Preparation of alkylzinc halides and alkylzinc acetates
Section 2B:
Enantioselective addition of RZnX to benzaldehyde
Section 2C:
Organozincates and their enantioselective addition
to benzaldehyde
63
Section 2A
Preparation of alkylzinc halides and alkylzinc acetates
1. Preparation of RZnX by oxidative insertion
It is evident from the literature that the oxidative insertion of zinc into organic
halides is the most studied reaction. The oxidative insertion is most general and
attractive protocol for the preparation of organozinc halides. After the discovery of
first oxidative addition of zinc into a carbon-halogen bond in 1849 by Frankland,14
numerous procedures have been developed for the activation of zinc15 to achieve
efficient conversion. The heterogeneous reaction conditions and the nature of zinc
often pose a problem of reproducibility in the oxidative insertion. After longer
expose to air, the surface of metallic zinc gets coated with a layer of zinc oxide that
creates the difficulty in initiating the insertion reaction. Therefore the oxide layer
must be removed before the zinc metal gets engaged in insertion process with
organic halide. The most common initial step for the activation of zinc metal
involves washing of the commercial zinc with aqueous HCl.16 Further activation can
be done by making alloys with Cu,17 Ag,18 Hg.19 Another methods for in situ
activation of zinc metal includes treatment of the zinc metal with activators such as
1,2-dibromoethane,20 TMSCl,21 Bromine,22 Iodine,23 DIBALH24 and
ultrasound
25
irriadiation.
The rate of oxidative insertion of zinc depends on various factors such as,
nature of organic moiety in the substrate, the halide, method for activation of zinc
and reaction parameters such as temperature, concentration and the solvent. Apart
from the preparation of organozinc halides using highly reactive Rieke Zinc,26 which
is tedious, there are very few methods for the preparation of alkylzinc bromides from
commercial zinc and unactivated alkyl bromides. The two reliable methods known in
the literature require use of polar solvents like N,N-dimethyl acetamide23c or use of
1,2-dibromoethane27 as activator. However DMA is not suitable for large scale
preparation, whereas 1,2-dibromoethane has limitations due to its carcinogenic
toxicity.28 Our aim was to develop a easier preparative method for alkylzinc halides
in solvent like tetrahydrofuran which is more convenient and easy to handle.
We examined various additives / activators for the preparation of alkylzinc
bromides by oxidative insertion and the results obtained are discussed below.
64
Results and discussion
The efficiency of oxidative insertion into carbon-halogen bond can be
increased in number of ways like activation of zinc and use of additives which can
form soluble complex with zinc reagent to give freshly active metallic surface for
further reaction.
We examined various additives / activators for the reaction of primary alkyl
bromides with zinc dust in THF at 50 to 55 oC (Table 1). Initially we have reacted
zinc dust with RBr (R = Et, n-Bu) using catalytic amount of zinc activators like MeI,
Br2, and HCl (in Et2O). Most of the zinc was unreacted in all the cases (Table 1,
entries 1−3). Similar kind of results were obtained in the case of radical initiator such
as CuI, CeCl3 and InCl3 (entries 4−6). The examination of iodide salts such as LiI
and TBAI, which can convert alkyl bromide into more reactive iodide, also failed to
give the zinc reagent (entries 7 and 8). We also examined the complexing agents like
TBAB and ethane-1,2-dimethyl thioether in stoichiometric amount. But in both the
cases most of the zinc was unreacted (entries 9 and 10).
65
Table 1. Reaction of alkyl bromides with zinc
THF
RBr + Zn
50-55 oC
RZnBr
R = Et, n-Bu
Entry
RBr
Additives (equiv)
Time (h)
Result
1
EtBr
MeI (0.1)
24
2
BuBr
Br2 (0.2)
24
3
BuBr
HCl in Et2O (0.2)
24
4
EtBr
CuI (0.05)
40
Most of
5
EtBr
CeCl3 (0.1)
48
the zinc
6
EtBr
InCl3 (0.1)
48
was
7
EtBr
LiI (0.1)
48
unreacted
8
EtBr
TBAI (0.1)
48
9
BuBr
Bu4NBr (1.0)
24
10
BuBr
MeSCH2CH2SMe (1.0)
24
We therefore decided to investigate the reaction systematically using n-BuX
(X = Cl, Br, I). Without the use of any additive, more than 95% zinc was consumed
in the reaction of butyl iodide (1.1 equiv) with zinc dust (1 equiv) in THF at 50−55
o
C in 24 h (Table 2, entry 1). However iodometric titration29 revealed yield of 60%.
When 1.1 equivalent of LiCl was used, the rate of the reaction was dramatically
increased and the reaction was completed in only 2 h under similar reaction
conditions (entry 2). However, butyl bromide was found to be unreactive under these
reaction conditions (entry 3). We then employed activators like TMSCl, 1,2dibromoethane and iodine in catalytic amount. Most of the zinc was unreacted in all
the cases (entries 4−6). Use of catalytic amount of TMSCl in combination with
stoichiometric LiCl gave only 8% yield of the butylzinc bromide after 48 h (entry 7),
whereas 1,2-dibromoethane did not initiate the reaction (entry 8). Interestingly, in the
presence of 5 mol% I2 and 1.1 equivalents of LiCl, butylzinc bromide was obtained
in 65% yield (entry 9). The reaction was completed in 18 h with high reproducibility.
The presence of both LiCl and iodine is necessary for the complete conversion
66
(comparison between entries 3, 6 and 9). Encouraged by these results, we examined
other activators such as LiI and TBAI. Comparable results were obtained in both the
Table 2. Reaction of butyl halides with zinc
50-55 oC
BuX + Zn
Entry
BuX
Solvent
1
2
3
4
5
6
7
BuI
BuI
BuBr
BuBr
BuBr
BuBr
BuBr
THF
THF
THF
THF
THF
THF
THF
RZnX
Additives
none
1.1 equiv. LiCl
1.1 equiv. LiCl
10 mol% TMSCl
10 mol% (CH2Br)2
5 mol% I2
1.1 equiv. LiCl
5 mol% TMSCl
8
BuBr
THF
1.1 equiv. LiCl
10 mol% (CH2Br)2
9
BuBr
THF
1.1 equiv. LiCl
5 mol% I2
10
BuBr
THF
1.1 equiv. LiCl
10 mol% LiI
11
BuBr
THF
1.1 equiv. LiCl
10 mol% TBAI
12
BuBr
THF
1.1 equiv. LiCl
2 mol% I2
5 mol% TMSCl
13
BuBr
THF
1.1 equiv. LiCl
5 mol% LiI
5 mol% TMSCl
14
BuCl
THF
1.1 equiv. LiCl
5 mol% I2
5 mol% TMSCl
15
BuCl
EtOAc
1.1 equiv. LiCl
5 mol% I2
5 mol% TMSCl
16
BuCl
DMA
5 mol% I2
5 mol% TMSCl
a
Yields were determined by iodometric titration.
Time
(h)
Yield a
(%)
24
2
48
48
48
48
48
60
70
−
−
−
−
8
Zn
consumed
(%)
>95
quantitative
16
20
20
28
24
48
−
26
18
65
quantitative
24
62
quantitative
26
62
quantitative
48
52
>95
48
48
>95
48
−
25
48
−
24
48
−
31
67
cases with slight longer reaction time (entries 10 and 11). We also studied the effect
of iodine loading on the reaction rate. When iodine loading was reduced to 2 mol %,
the reaction proceeds much slowly (entry 12). Similar results were observed in the
case of LiI (entry 13). Next, less reactive butyl chloride was subjected to the
oxidative insertion in the presence of LiCl and catalytic amount of iodine and
TMSCl. However most of the zinc was unreacted even after 48 h (entry 14). Use of
polar solvents such as EtOAc and DMA also did not help (entries 15 and 16).
The mechanism of zinc insertion is well studied by Rieke et al.26h In the
course of our study, GC-MS analysis of the hydrolyzed reaction mixture (entries 9,
10 and 11, Table 2) showed the formation of a small amount of butyl iodide. On the
basis of these results, we proposed the possible mechanism as shown in scheme 1.
The formation of butyl iodide could be explained by the nucleophilic displacement of
bromide of BuBr by I¯ generated from the reaction of zinc and I2. This more reactive
butyl iodide reacts with zinc in the presence of LiCl to form the complex A. The
complex A exchanges30 the iodide with butyl bromide to give complex B and BuI is
recycled back in the insertion process.
BuBr + I
BuI + Zn
BuI + Br
LiCl
BuZnI LiCl
(A)
BuZnI LiCl
(A)
BuBr
BuZnBr LiCl + BuI
(B)
(recycled)
Scheme 1. Proposed mechanism for the oxidative insertion
Since iodides provided good results, we further examined these reaction
conditions for the preparation of various alkylzinc bromides. Under optimized
reaction conditions, various alkyl bromides were reacted with zinc dust (Table 3).
Thus, the reaction of ethyl bromide with zinc dust (1.5 equiv) in the presence of LiCl
(1.1 equiv) and 5 mol% iodine provided EtZnBr·LiCl in 75% yield (entry 1). Other
68
Table 3. Preparation of RZnX (X = Br, Cl) using LiCl and catalytic I2
RX + Zn + LiCl
(1.0)
(1.5)
5 mol% I2
RZnX LiCl
THF, 50-55 oC
(1.1)
Entry
RX
Time (h)
Yielda (%)
1
Ethyl bromide
14
75
2
n-Butyl bromide
18
74
3
n-Hexyl bromide
20
74
4
n-Octyl bromide
24
72
5
Ethyl-4-bromo-butyrate
10
73
6
iso-Butyl bromide
48
42
7
iso-Propyl bromide
48
25
8
tert-Butyl bromide
24
40
9
Allyl chloride
10
68
10
Benzyl chloride
5
75
a
Yields were determined by iodometric titration.
bromides like n-butyl, n-hexyl and n-octyl bromide were also converted to the
corresponding zinc reagent in good yield (entries 2–4). Functionalized alkyl bromide
like ethyl 4-bromo-butyrate provided corresponding zinc reagent in 73% yield (entry
5). Due to the steric bulk around bromide, the reaction of iso-butyl and iso-propyl
bromide was slow and incomplete after 48 h (entries 6 and 7). In the case of tertbutyl bromide only 40% yield of the product was obtained although zinc was used
quantitatively. To find out the reason for this abnormal result, we performed the
above reaction without LiCl under similar reaction conditions (eq 1). In this case,
5 mol% I2, THF
t-BuBr + Zn
t-BuZnBr
50-55 oC, 24 h
Zinc consumed 84%
Yield
0%
(1)
69
iodometric titration of the reaction mixture did not show the presence of zinc reagent
although 84% zinc was reacted. The GC-MS analysis of reaction mixture showed
two major peaks at (m/z 168) and (m/z 226) which corresponds to the probable
structures of 1 and 2 respectively (Figure 1). The above results clearly indicates that
LiCl stabilizes the zinc reagent by forming the complex t-BuZnBr⋅LiCl and also
explain the reason for low yield.
1
2
Figure 1
At this stage, the mechanism for the formation of 1 and 2 is not clear.
However, it can be explained by assuming the formation of tert-butyl radical (I)
(Scheme 2), which can decompose to give 2-methyl-1-propene (II). The intermediate
II can generate radical at allylic positions (path-a) and consequent coupling with I
gives hydrocarbon 1. The formation of 2 can be explained by generation of radical
III by coupling of I with II at vinylic position (path-b), which on homocoupling
gives hydrocarbon 2.
2
path-a
1
ZnBr
path-b
(I)
(II)
homocoupling
2
(III)
Scheme 2. Proposed mechanism for the formation of hydrocarbon 1 and 2
Allyl chloride and benzyl chloride were also reacted under the above
optimized conditions. Corresponding zinc reagents were obtained in good yield
(Table 3, entries 9 and 10).
70
To confirm the formation of the above described reagents, some of these were
reacted with carbonyl electrophiles. Thus, the reaction of BuZnBr⋅LiCl with benzoyl
chloride in the presence of CuCN⋅2LiCl20d provided 1-phenyl-1-pentanone (3) in
86% isolated yield (eq 2). Also the treatment of benzylzinc chloride with
benzaldehyde gave expected product 4 in good yield (eq 3).
O
O
CuCN 2LiCl
Cl
+ BuZnBr LiCl
THF
−10 to 0 oC, 6 h
(2)
Bu
3
86% yield
O
OH
THF
H + PhCH2ZnCl LiCl
Ph
o
(3)
0 C to RT, 6 h
4
85% yield
2. Preparation of RZnX by transmetallation or ligand exchange
Organozinc halides also can be prepared by transmetallation31,32 that is,
reaction of RLi or RMgX with zinc halide. We have prepared EtZnCl⋅Mg(Br)Cl (5)
by stoichiometric reaction of RMgBr (R = alkyl) with ZnCl2 (eq 4). To study the
ligand effect in RZnX, we extended this method for the preparation of RZnOAc.
Thus, the reaction of EtMgBr with Zn(OAc)2 gave EtZnOAc⋅Mg(OAc)Br (6) with
more than 95% yield (eq 5). The yield was determined by iodometric titration. Using
this method, there is always formation of magnesium salts in stoichiometric amount
EtMgBr + ZnCl2
EtMgBr + Zn(OAc)2
Et2Zn
+ ZnCl2
Et2Zn
+ Zn(OAc)2
THF
0 to 25 oC, 1 h
THF
0 to 25 oC, 1 h
THF:hexane
25 oC, 1 h
THF:hexane
o
25 C, 1 h
EtZnCl Mg(Br)Cl
5
(4)
EtZnOAc Mg(OAc)Br
6
(5)
2 EtZnCl
7
(6)
2 EtZnOAc
8
(7)
71
along with zinc reagent. To study the magnesium / lithium salt effect on the
reactivity of RZnX, we also prepared salt-free alkylzinc halides. The salt-free RZnX
(X = Cl, Br, I, OAc) can be prepared by reaction of R2Zn and ZnX2, the so called
“ligand exchange.”33 Thus ethylzinc chloride (7) and ethylzinc acetate (8) were
obtained by the reaction of diethylzinc with ZnCl233c and Zn(OAc)233d respectively
(eq 6 and 7) according to the literature procedures. All these reagents can be stored
for several days as a THF solution under inert atmosphere.
72
Section 2B
Enantioselective addition of RZnX to benzaldehyde
Enantioselective addition of diorganozinc reagents to carbonyl compounds
emerged as one of the powerful tools for the preparation of optically active alcohols.
Introduction of chiral heteroatom containing ligands to the zinc complex allows
facial differentiation in the addition of the alkyl group to carbonyl substrate. After
the first report of Oguni and Omi34 and pioneering work of Noyori and Soai,
numbers of ligand accelerated methods have been developed for the catalytic
enantioselective addition of dialkylzinc reagents to aldehyde. A majority of the
catalyst for this reaction were based on chiral β-amino alcohols.1 Our interest in this
field led us to study the reagent of type RZnX (X = Cl, Br, I, OCOR′) which have
been rarely studied. High covalent character and less Lewis acidity of zinc centre are
responsible for the poor reactivity of these reagents. The reactivity of these reagents
towards carbonyl substrates can be enhanced by, (i) substrate activation with Lewis
acid (Figure 2a), (ii) Reagent activation with Lewis base catalyst (Figure 2b). Lewis
acid coordinates with carbonyl oxygen resulting in increased electrophilicity of
carbonyl carbon. Organozinc halides (RZnX) have bent structure and differ
fundamentally from diorganozinc compounds (RZnR) which occur as monomers
with sp-hybridized linear geometry.35a Due to the presence of electronegative atom,
accepter character of zinc in RZnX is enhanced. This leads to association of
molecules and hence such compounds are always exists as dimers or higher
associates.35b Addition of nitrogen/oxygen containing ligand can break this
unreactive oligomeric association and provide reactive organozinc halides
monomeric species.
Lewis acid
O
R'
R'
R''
R-Zn-X
(a)
O
R''
R-Zn-X
Lewis Base
(b)
Figure 2
Y
X
R
Zn
X
(tetrahedral complex)
(c)
73
We presumed that a bidentate chelating agent can coordinate with zinc centre
and forms tetrahedral complex33a,36 (Figure 2c), resulting in enhanced metal-alkyl
bond polarity and hence increased nucleophilicity of the alkyl group. We have done a
systematic study on the reactivity of alkylzinc halides towards aldehyde by
examining various catalysts / chelating agent derived from N-Me ephedrine and
simple diols. These results are discussed below.
Results and discussion
For our present study, we chose simple chiral ligands (9−14) as shown in
figure 3.
Ph
OH
Ph
OH
Ph
O
Me
NMe2
Me
NHTs
Ph
N
Me
(1R,2S)-(−)-9
Ph
Ph
OH
OH
(1S,2S)-(−)-12
(1R,2S)-(−)-10
Ph Ph
O
OH
O
OH
Ph Ph
(4R,5R)-(−)-13
(2R,3S)-(−)-11
OH
OH
(R)-(+)-14
Figure 3
Preparation of catalysts
Several catalysts 15−24 (Figure 4) were prepared by the treatment of chiral
ligand with organometallic reagent. The change in the metal center (aluminum,
titanium, zinc, magnesium, lithium) provides change in Lewis acidities and also the
coordinating ability of nitrogen/oxygen atoms.
74
Ph Ph
O
O
O
O
Ph Ph
Ph
O
Me
N
Ph
O
Me
N
Ts
M
Al Cl
Ph
OM
Ph
OM
M = Li
20
= MgBr 21
O
Me
N
Ts
Ph
O
OiPr
Ti
Zn
M = Li
= 16
M = MgBr = 17
15
Ph
18
OiPr
19
Ph
OM
OMgBr
OMgBr
OM
O
Ph Ph
M = Li
22
= MgBr 23
24
Figure 4
Aluminum alkoxide 15 was prepared by the reaction of (−)-13 with Et2AlCl
(Scheme 3).
Ph Ph
O
OH
O
OH
Ph Ph
Et2AlCl
toluene, RT, 1 h
− 2 EtH
Ph Ph
O
O
O
O
Ph Ph
Al Cl
15
(−)-13
Scheme 3. Preparation of catalyst 15
N-Me ephedrine derived alkoxides 16 and 17 were prepared by treatment of
(−)-9 with BuLi/EtMgBr (Scheme 4).
Ph
O
Me
N
n-BuLi, THF
Ph
Li
16
0 oC to RT, 15 min. Me
Ph
O
0 oC to RT, 15 min. Me
NMe2
N
OH
(-)-9
Scheme 4. Preparation of catalyst 16 and 17
EtMgBr, THF
MgBr
17
75
Catalysts 18 and 19 were prepared by the treatment of (−)-10 with diethylzinc
and Ti(OiPr)4 respectively (Scheme 5).
Ph
O
Zn
Me
Ph
Et2Zn, toluene
8 0 oC, 30 min.
N
Ts
OH
Me
18
Ti(OiPr)4, toluene
Ph
O
0 oC to RT, 1 h
Me
N
Ts
NHTs
OiPr
Ti
OiPr
19
(-)-10
Scheme 5. Preparation of catalyst 18 and 19
Magnesium-dialkoxides 21, 23 and 24 were prepared by the treatment of
corresponding diols (12, 13 and 14) with 2 equivalent of EtMgBr (Scheme 6).
OH
OMgBr
2 EtMgBr, THF
*
0 oC to RT, 15 min.
*
OH
OMgBr
12−14
21, 23, 24
Scheme 6. Preparation of magnesium-dialkoxides
Lithium-dialkoxides 20 and 22 were prepared by the treatment of n-BuLi
with corresponding diols (−)-12 and (−)-13 respectively (Scheme 7).
Ph
OH
or
Ph
OH
(−)-12
Ph Ph
O
OH
O
OH
Ph Ph
n-BuLi, THF
0 oC to RT, 15 min.
20 or 22
(−)-13
Scheme 7. Preparation of lithium-dialkoxides
We then evaluated these catalysts for the addition of RZnX to benzaldehyde.
Alkylzinc halides (RZnX) are known to be weakly active nucleophiles.6b,37 Initially
we examined the reactivity of salt free RZnX 7 and 8 (prepared by ligand exchange
method, R = Et, X = Cl, OAc) with benzaldehyde in the presence of various
76
catalysts/chelating agent (Table 4). Without any additive, both the reagents 7 and 8
do not react with benzaldehyde (Table 4, entry 1). Similar kind of reactivity was
observed in the case of catalytic amount of Lewis acid catalyst 15 (entry 2). We then
examined N-Me ephedrine derived bifunctional catalysts 16 and 18. These catalysts
can play a dual role by acting as Lewis acids to activate the carbonyl substrate and
also as Lewis base to activate the zinc reagent38 (Figure 5). However the strategy did
not prove fruitful (entries 3 and 4).
R2
N
R1
O
X
M
O
Zn
Et
H
Ph
Figure 5
We decided to examine next bidentate chelating agents. First we used
chelating agent like N-Me morpholine. But these reagents did not reacted with
benzaldehyde in the presence of catalytic or stoichiometric amount of N-Me
morpholine (entries 5 and 6). We then employed metal dialkoxides39 20 and 23
which are stronger chelating agent. Only starting material was recovered in both the
cases (entries 7 and 8). When the reaction of EtZnCl 7 was carried out in the
presence of one equivalent of MgCl2, alkylated product (25) was obtained in 31%
yield along with the formation of propiophenone (26) and benzyl alcohol (27) (entry
9). Origin of byproducts can be explained by Oppenauer oxidation40 of intermediate
zinc-alkoxide I (Scheme 8). The zinc reagent 8 also gave similar kind of results in
the presence of Mg(OAc)Br (entry 10). However other Lewis acids such as ZnCl2
and LiCl failed to provide the alkylated product (entries 11 and 12).
77
Table 4. Addition of EtZnX (X = Cl, OAc) to benzaldehyde
EtZnX
+
PhCHO
Et
Ph
o
0 C to RT, 24 h
Salt free
O
OH
THF:Hexane
+
Ph
25
Et + Ph
26
OH
27
(X= Cl, OAc)
Entry
RZnXa
Catalyst (equiv)
1
none
Productb (%)
25
26
27
EtZnCl or EtZnOAc
<1
-
-
2
15
(0.1)
EtZnOAc
<1
-
-
3
16
(0.1)
EtZnOAc
<1
-
-
4
18
(0.1)
EtZnCl
<1
-
-
5
N-Me morpholine (0.1)
EtZnCl or EtZnOAc
<1
-
-
6
N-Me morpholine (1.0)
EtZnCl or EtZnOAc
<1
7
20
(0.2)
EtZnOAc
<1
-
-
8
23
(0.1)
EtZnOAc
<1
-
-
9
MgCl2
(1.0)
EtZnCl
31
19
20
10
Mg(OAc)Br
(1.0)
EtZnOAc
28
15
28
11
ZnCl2
(1.0)
EtZnCl or EtZnOAc
1
-
-
12
LiCl
(1.0)
EtZnCl or EtZnOAc
<1
-
-
a
Prepared from Et2Zn and ZnX2, (X= Cl , OAc). b Yields by GC analysis; remaining
unreacted benzaldehyde.
OZnX
PhCHO + EtZnX
Ph
PhCHO
O
Ph
(I)
X
H
H
Zn
O
Ph
O
+
Ph
Ph
26
Scheme 8. Proposed mechanism for the formation of byproducts 26 and 27
OH
27
78
Above results suggest that the reaction is not a Lewis catalyzed one. Instead,
MgX2 in stoichiometric amount forms addition complex32f (Figure 6), which is
responsible for the reaction.
S
Cl
R
Zn
S
R
S
O
Zn
Mg
X
S
X
Ac
O
O
Mg
S = solvent molecule
X
Figure 6
We also examined reactivity of RZnX⋅LiX (prepared by insertion method) in
the presence of various catalysts (Scheme 9). Only trace amount of expected product
was observed in all the cases.
RZnX LiCl + PhCHO
THF, 0 oC to RT, 24 h
R = Me, Et
(X= Br, I)
OH
catalyst (10 mol%)
Ph
R
trace
Catalysts
O
Ph
O
Ph
O
Me
N
Ts
MgBr
N
Me
Me
N
17
Ti
OiPr
Ph Ph
O
OMgBr
OiPr
O
19
OMgBr
Ph Ph
23
Scheme 9. Reaction of RZnX⋅LiCl with benzaldehyde
Since MgX2 has role on the reactivity of RZnX, we next examined the
reactivity of the zinc reagents 5 and 6 in which stoichiometric amount of MgX2 is
present. In our initial experiment, the reaction of reagent 5 with PhCHO without any
additive gave only 11% 1-phenyl-1-propanol (25) in 4 h at 25 oC (Table 5, entry 1).
This suggested that the effect of MgX2 is not very pronounced.
79
Table 5. Addition of EtZnCl⋅Mg(Br)Cl to benzaldehyde
EtZnCl Mg(Br)Cl + PhCHO
catalyst (10 mol%)
OH
Ph
THF
a
Entry
Catalyst
Temp (oC)
Time (h)
Yield a (%)
ee
1
none
0 to 25
4
11
-
2
11
0 to 25
16
63
<1
3
20
0
8
66
<1
4
21
0
8
62
<1
5
23
0
8
64
<1
Isolated yields; remaining was PhCOCH2CH3, PhCH2OH and unreacted PhCHO.
We therefore proceeded to evaluate various dicordinating ligands for the
reaction. These were, chiral chelating agent like (2R,3S)-(−)-4-methyl-2,3-diphenyl
morpholine (11) and lithium/magnesium dialkoxides 20, 21 and 23. One equivalent
of 1,4-dioxane was added to reduce the Lewis acidic effect of Mg(Br)Cl. Although
good yields were obtained, negligible enantioselectivity was realized in all the cases.
One of the difficulties in handling the zinc halides is their hygroscopic nature.
We decided to use zinc acetate which is non-hygroscopic and can be a good
alternative to zinc halides. The zinc reagent EtZnOAc⋅Mg(OAc)Br (6), prepared by
the transmetallation of EtMgBr with zinc acetate, was reacted with benzaldehyde
without any additive. It revealed reactivity pattern similar to that of reagent 5. In the
presence of chiral chelating agent 11, expected product 25 was obtained in 18% yield
as a racemate (Table 6, entry 2). Interestingly, the reaction of 6 in the presence of
lithium-dialkoxide 22 provided 31% yield with 13% ee (entry 3). The corresponding
magnesium-dialkoxide 23 furnished 34% yield with 28% ee (entry 4). Our attempts
to isolate the reagent 6 were unsuccessful. To verify the formation of EtZnOAc from
EtMgBr and Zn(OAc)2, salt free zinc reagent 8 was reacted with benzaldehyde in the
presence of stoichiometric amount of Mg(OAc)Br (prepared by stoichiometric
reaction of EtMgBr with AcOH) (eq 8).
80
i) Mg(OAc)Br (1 equiv)
8
ii) 23 (10 mol%)
iii) PhCHO, THF
OH
(8)
Ph
(S)
33% yield, 25% ee
These results obtained were comparable to the results with the reagent 6. Also
the comparison of reactivity difference between the reagent 8 (Table 4, entry 8) and
reagent 6 (Table 6, entry 4) revealed that the presence of MgX2 was crucial. One of
the reasons for moderate selectivity was attributed to MgX2-promoted background
reaction.41 To overcome this problem, we added complexing agents like 1,4-dioxane
or TMEDA. However, this modification proved inconsequential (entries 5 and 6). By
changing the solvent from THF to methyl tert-butyl ether (MTBE), enantioselectivity
increased to 50% (entry 7). Enantiomeric excess was determined by chiral HPLC.
When the reaction was carried out at room temperature, the product was isolated in
60% yield but the enantioselectivity was dropped to 39% (entry 8). Similar results
were obtained when diethyl ether was used as the solvent (entry 9). Other
magnesium-dialkoxides 21 and 24 proved inferior to 23 (entries 10 and 11).
81
Table 6. Enantioselective addition of EtZnOAc⋅Mg(OAc)Br to benzaldehyde
OH
catalyst (10 mol%)
EtZnOAc Mg(OAc)Br
+ PhCHO
Entry
Catalyst
Solventa
1
none
THF
0
2
11
THF
3
22
4
Ph
Temp (oC) Time (h)
(S)
Yield b (%)
eec
4
29
-
0
8
18
-
THF
0
8
31
13
23
THF
0
8
34
28
d
23
THF
0
8
37
18
6e
23
THF
0
8
22
21
7
23
MTBE
0
8
44
50
8
23
MTBE
25
24
60
39
9
23
Et2O
25
24
54
38
10
21
MTBE
25
24
45
<5
11
24
MTBE
25
24
49
<1
5
a
The reactions were carried out at 0.4-0.5 molar concentrations. b Isolated yields of
the desired product. c Determined by comparison of optical rotation with known
literature value or chiral GC / HPLC analysis. d One equivalent of 1,4-dioxane was
added. e One equivalent of TMEDA was added.
Heterogeneous reaction mixtures result during the use of solvents other than
THF. After extensive optimization, it was found that by adding the Grignard reagent
to a suspension of zinc acetate and (−)-13 in THF, homogenous solution was
obtained at 0 oC. This reagent was then reacted with benzaldehyde to obtain 30%
yield of the product with 40% ee (Table 7, entry 1). We also studied the effect of
stoichiometry of Grignard reagent with respect to zinc acetate. It was found that the
rate of the reaction as well as enantioselectivity varied with the change in
stoichiometry. Best results were obtained when the ratio was 1:1 (entries 1, 2 and 3).
In the case of 1.2 equivalent EtMgBr (Table 7, entry 3), the excess Grignard reagent
can generate diethylzinc by reacting with preformed EtZnOAc. This hypothesis was
supported by addition of commercial diethylzinc to benzaldehyde, which gave
82
comparable results (eq 9). In terms of halide effect in RMgX, bromide and iodide
were found to be better than chloride (entries 4, 5 and 6). We also examined other
Grignard reagents under these conditions. n-Butyl and iso-butyl magnesium bromide
provided 13% and 16% enantioselectivity respectively (entries 5 and 7). In the case
of t-BuMgCl, no reaction took place at all.
Table 7. Enantioselective addition of various RZnOAc⋅Mg(OAc)X to benzaldehyde
Ph Ph
O
OH
RMgX + Zn(OAc)2 +
O
OH
PhCHO, THF
Ph
OH
Ph Ph
25, R = Et
28, R = Bu
29, R = i-Bu
(−)-13
Entry RMgXa
(S) R
Temp. (oC) Time (h) Product Yieldb (%) eec (%)
1
EtMgBr
0
8
25
30
40
2d
EtMgBr
0
24
25
18
36
3e
EtMgBr
0
4
25
60
8
4
BuMgCl
0
8
28
5
0
5
BuMgBr
0
4
28
17
13
6f
BuMgI
0
4
28
41
50
7
i-BuMgBr
0
8
29
5
16
8
t-BuMgCl
0−25
24
-
g
-
a
The stoichiometric ratio of RMgX:Zn(OAc)2:(−)-13:PhCHO was 1.7:1.5:0.1:1.0
respectively unless otherwise noted. b Isolated yields of the desired product. c ee Was
determined by chiral GC or HPLC analysis. d 0.8 equiv. EtMgBr was added with
respect to Zn(OAc)2. e 1.2 equiv. EtMgBr was added with respect to Zn(OAc)2. f The
reaction was carried out in THF:Et2O. g The starting material was recovered.
O
OH
23 (10 mol%)
H + Et2Zn
THF:Hexane
0 oC, 2 h
Ph
(9)
(S)
76% yield
14% ee
83
Mechanism:
The difference in the selectivity showed by ligand (−)-13 compared to other
diols was attributed to the rigid backbone and the steric bulk due to phenyl rings
present in the molecule. At this stage a precise model which explains the outcome of
stereoselectivity using reagent 6 is not clear. However we presume that the oxygen
atoms of the metal alkoxide 23, EtZnOAc, BrMg(OAc), and PhCHO bind as
depicted in figure 7a. The resulting cyclic transition state could be responsible for
stereoselection. This would also explain the lack of enantioselectivity with the
reagent 5, which proceeds through MgX2-catalyzed acyclic pathway (Figure 7b).
Ph
Ph
O
O
M
O
Br
O
Zn
O
Ph
O
Ph M
Mg OAc
Et H
M
O
Cl
Zn
O
(cyclic-TS)
(a)
Ph
Ph
O
O
Ph
Ph
M = MgX
O
Ph M
Mg(Br)Cl
O
R H
Ph
(acyclic-TS)
(b)
Figure 7. Proposed mechanism for enantioselective alkylation
84
Section 2C
Organozincates and their enantioselective addition to
benzaldehyde
Addition of organozinc reagents to various organic electrophiles has become
one of the common methods to construct carbon-carbon bond. The preparation of
dialkylzincs2,31 and organozincates6a,32f,42 is well documented in the literature.
Diorganozinc reagents have sp-hybridized linear geometry (Figure 8a). Pure
dialkylzinc reagents react sluggishly with aldehydes and ketones. However, their
reactivity can be enhanced by incorporation by a third substituent like alkyl or
heteroatom containing ligand on zinc centre (Figure 8b). Richey et al.42f reported that
the treatment of alkali metal alkoxide with diethylzinc produces triorganozincates
species (R2ZnOR)M, which reacts rapidly with aldehyde and ketones. We envisaged
that introduction of two chiral alkoxides would form chiral-zincate species (Figure
8c) which can react enantioselectively with aldehyde. In this context, optically active
diols would be ideal ligands.
R
R-Zn-R
R
R
Zn
Zn
R'
*RO
OR*
R' = alkyl, OR''
(less reactive)
(reactive)
R* = chiral alkyl group
(a)
(b)
(c)
Figure 8
We have prepared various chiral-zincates using optically active diols. The present
section deals with the results obtained in this study.
Results and discussion
In our initial study, we examined the reactivity pattern of alkylzincates
prepared from ZnX2 and RMgX. In the present work, alkylzinc reagents were
prepared by the reaction of ZnX2 (X = Cl, OAc) with n equivalent of EtMgBr (n = 2
and 3) (eq 10, 11 and 12).
85
2 EtMgBr + ZnCl2
2 EtMgBr + Zn(OAc)2
3 EtMgBr + ZnX2
THF
Et2Zn 2Mg(Br)Cl
(10)
Et2Zn 2Mg(OAc)Br
(11)
[Et3Zn]MgBr
(12)
THF
THF
X= Cl, OAc
The reaction of Et2Zn⋅2Mg(X)Br (X = Cl, OAc) with 0.9 equivalent
benzaldehyde proceeds quantitatively in 1 h at 0 oC (Table 8, entries 1 and 2). This
indicates the presence of magnesium salt (Mg(X)Br (X = Cl, OAc)) increases the
reactivity of diethylzinc reagent. In addition to this, we observed that there is
dramatic decrease in reactivity when Mg(X)Br is replaced by less Lewis acidic
Mg(OAc)2. It was done by the reaction of Zn(OAc)2 with two equivalent of EtMgBr
in the presence of excess NaOAc (Scheme 10). The treatment of in situ formed
reagent with benzaldehyde provided only 49% yield of the product.
i)
THF
0 oC to RT, 4 h
2 EtMgBr + Zn(OAc)2 + 2.5 NaOAc
ii) PhCHO (0.9 equiv)
0 oC to RT, 24 h
OH
Ph
49% yield
Scheme 10
Next, the reagent prepared from two equivalent of EtMgBr with ZnCl2/Zn(OAc)2
was reacted with 1.9 equivalent benzaldehyde. After 1 h GC analysis revealed
formation of 73% product in both the cases (entries 3 and 4). These results indicate
that more than one equivalent32c,41 of alkyl group gets transferred, which can be
explained by scheme 11. When the mixture of ZnX2 (X = Cl, OAc) and 2EtMgBr
was equilibrated for longer time (16 h) at room temperature, approximately 50%
yield of the product was obtained in both the cases (entries 5 and 6). This difference
in the reactivity can be attributed to the formation of ate complexes I and II depicted
in eq 13 and 14 respectively. After longer stirring ate complex decomposes to give
Et2Zn, which can transfer only one alkyl group.
86
2 EtMgBr + ZnCl2
THF
Et
0 oC
Et
Cl
25 oC
Zn
Mg
Br
overnight
Et2Zn + 2Mg(Br)Cl
(13)
Et2Zn + 2Mg(OAc)Br
(14)
ate complex-I
Et
2 EtMgBr+Zn(OAc)2
THF
0 oC
O
25 oC
Et Zn
overnight
O
Br
Mg
ate complex-II
Et
THF
3 EtMgBr + ZnX2
Et
Zn
0 oC
Mg Br
+ 2Mg(X)Br
(15)
Et
X = Cl, OAc
ate complex-III
Table 8. Addition of ethylzincates to benzaldehyde
n EtMgBr + ZnX2
+
PhCHO
THF
0 oC, 1 h
OH
Ph
X = Cl, OAc
Entry n EtMgBr + ZnX2
[Temp (oC), Time (h)]a
PhCHO
Productb (%)
(equiv.)
1
2 EtMgBr + ZnCl2
0−25, 1 h
0.9
94
2
2 EtMgBr + Zn(OAc)2
0−25, 1 h
0.9
quantitative
3
2 EtMgBr + ZnCl2
0, 0.5
1.9
73
4
2 EtMgBr + Zn(OAc)2
0, 0.5
1.9
73
5
2 EtMgBr + ZnCl2
0−25, 16 h
1.9
58
6
2 EtMgBr + Zn(OAc)2
0−25, 16 h
1.9
48
7
3 EtMgBr + ZnCl2
0, 0.5
2.9
78
8
3 EtMgBr + Zn(OAc)2
0, 0.5
2.9
86
a
The mixture of EtMgBr and ZnX2 was stirred at mentioned temperature and time
before the addition of aldehyde. bYields by GC analysis; remaining propiophenone
benzyl alcohol and unreacted benzaldehyde.
We also studied the reactivity of trialkylzincates with benzaldehyde. In the
present study, the triethylzincate III was prepared by reacting ZnX2 (X = Cl, OAc)
87
with three equivalents of EtMgBr at 0 oC (eq 15). The reaction of III with 2.9
equivalent PhCHO gave 78% and 86% yield of the product in case of ZnCl2 and
Zn(OAc)2 respectively. These results indicate that more than two equivalents of alkyl
group can transfer in both cases. The possible explanation for the above results can
be that the ate complex III first reacts with one equivalent of PhCHO via a sixmembered42g TS-1 (Scheme 11) to give the expected product and Et2Zn. The
resulting ate complex I / II further react with 2nd equivalent of PhCHO via TS-2 and
gives product and EtZnX, (X = Cl or OAc). Finally EtZnX then reacts with 3rd
equivalent of PhCHO in the presence of Mg(X)Br via TS-3. From the above results it
can be concluded that the zincate species generated from ZnX2 and RMgBr can
transfer all the three alkyl groups to benzaldehyde. Based upon these findings we
planned to prepare optically active triorganozincates10b to achieve enantioselective
version.
Et
Et
Zn
1st PhCHO
Et
Mg Br
Et
Et Zn
Et
ate complex-III
Mg(X)Br
Br
O
Mg
H
OMgBr
+ Et2Zn
Ph
Ph
TS-1
I (or II)
X
2nd PhCHO
Et
Et Zn
ate complex
Br
O
Mg
H
Ph
TS-2
3rd PhCHO
OMgBr
Ph
+ EtZnX
Mg(X)Br
X
Zn
Et
H
X
Mg
O
Br
OH
Ph
Ph
TS-3
Scheme 11. Possible mechanism for the transfer of all three alkyl group.
88
Enantioselective addition of organozincates to benzaldehyde
We anticipated that simple C2-symmetric chiral diols43 would serve as non
transferrable ligand and effective chiral inducer for this transformation. We chose
simple chiral diols such as (−)-12, (−)-13 and (+)-14 as chiral source. Diols are
known39f to form alkoxide 30 when reacted with diethylzinc at 80 oC (Scheme 12,
path-a). Alkoxide 30 also can be prepared from sodium/magnesium dialkoxide and
ZnCl2 (path-b and path-c respectively). The alkoxide 30 on treatment with
stoichiometric Grignard reagent would give chiral zincate complex-IV, which can
react with aldehyde enantioselectively.
OH
2 NaH
ONa
ZnCl2
*
*
THF
OH
ONa
Chiral diol
Path-b
OH
+ Et2Zn
*
OH
Toluene
80 oC, 30 min.
−2 EtH
Chiral diol
O
*
RMgX
Zn
O
*
THF
30
O
R MgX
Zn
O
Chiral zincate complex- IV
Path-a
OMgX
ZnCl2
*
*
THF
OH
2 RMgX
OMgX
Path-c
OH
Chiral diol
Scheme 12
In our initial study, zincate complex prepared from diol (−)-13 via path-b (or
path-c) on reaction with benzaldehyde gave desired product in low enantioselectivity
(Scheme 13). Increased enantioselectivity was realized when the chiral zincatecomplex was prepared using path-a. Therefore we prepared chiral zinc-alkoxides
30a, 30b and 30c (Figure 9) by heating the equimolar quantity of diethylzinc and
corresponding diols at 80 oC according to path-a in scheme 12.
89
OH
(-)-13
Ph (S)
OH
i) 2 EtMgBr, THF
i) 2 NaH, THF
ii) EtMgBr, 0 oC
iii) PhCHO, 0 oC, 2 h
ii) EtMgBr, 0 oC
iii) PhCHO, 0 oC, 2 h
Ph (S)
44% yield
6% ee
71% yield
16% ee
Scheme 13
Ph
O
Ph
O
Ph
O
Zn
O
O
Zn
O
Ph
Ph Ph
30a
Zn
O
O
30b
30c
Figure 9
We then examined these in situ generated zinc-alkoxides (30a-c) in
enantioselective addition to benzaldehyde under different reaction conditions (Table
9). First we examined the zinc-alkoxide 30a. One equivalent of EtMgBr was added
to a suspension of 30a in toluene at oC. The resulting zincate complex was then
treated with benzaldehyde at 0 oC (Condition A). The product was isolated in 66%
yield with 24% ee (Table 9, entry 1). Low enantioselectivity was observed when
addition sequence of Grignard reagent and aldehyde was reversed (Condition B)
(entry 2). The enantioselectivity was increased substantially (to 50%) when the
addition was done simultaneously (Condition C) (entry 3). Lowering the temperature
from 0 to −78 oC diminished the enantioselectivity (entry 4). Less solubility of 30a at
low temperature promotes the direct addition of Grignard regent to aldehyde, which
could be the reason for lower enantioselectivity. The use of EtMgBr⋅LiCl (a
structurally
different
Grignard
reagent44)
did
not
help
(entry
5).
Poor
enantioselectivity was realized in the case of zinc-alkoxides 30b and 30c (entries 6
and 7).
90
Table 9. Enantioselective addition of chiral-zincates to benzaldehyde
O
*
Zn
EtMgBr
THF:Toluene
OH
Ph
PhCHO
O
(S)
30a-c
Entry Alkoxidea Conditionb Temp (oC), Time (h) Yieldc (%)
a
eed
1
30a
A
0
2
66
24
2
30a
B
0
2
72
9
3
30a
C
0
2
59
50
4
30a
C
−78 to 0
2
64
2
5e
30a
C
0
2
67
5
6
30b
C
0
2
74
<1
7
30c
C
0
2
69
6
The ratio of zinc-alkoxide:RMgX:PhCHO was 1:1:1 respectively. b Condition A:
Grignard reagent was added to zinc-alkoxide and after 15 minutes benzaldehyde was
added; Condition B: Benzaldehyde was added before the addition of Grignard
reagent; Condition C: Grignard reagent and aldehyde were added simultaneously.
c
Isolated yields of the desired product. d Determined by comparison of optical
rotation with known literature value. eEtMgBr⋅LiCl complex was added instead of
EtMgBr.
91
Conclusions
¾ We have found a simple procedure for the preparation of alkylzinc bromides
in THF by the use of LiCl as additive and I2 as activator. Using optimized
conditions, various alkylzinc bromides were prepared in good yields. We
have also prepared successfully alkylzinc acetates by transmetallation
method.
¾ Salt-free RZnX exhibit poor reactivity towards benzaldehyde. Moderate
enantioselectivity was achieved in the case of TADDOL-magnesium
dialkoxide using RZnOAc as alkylating agent.
¾ We have also observed that ate complex formed by the reaction of ZnX2 and
RMgX can transfer all alkyl groups to benzaldehyde. Moderate
enantioselectivity was realized in the case of TADDOL-zincate.
92
Experimental Section
General
All the solvents and reagents were purified and dried according to procedures
given in D. D. Perrin’s purification of Laboratory chemicals.45 Zinc dust (325 mesh)
was purchased from Sisco Research Laboratories, India. Diethylzinc was purchased
from Sigma-Aldrich chemical company. Benzaldehyde was freshly distilled before
use. THF was freshly distilled over sodium benzophenone ketyl. Anhydrous zinc
acetate was obtained by heating Zn(OAc)2.2H2O at 90 oC for 4 h under the reduced
pressure. All the reactions were performed in oven dried (120 oC) glasswares under
an argon atmosphere. Ligand 10 was prepared by reacting (1R,2S)-(-)-norephedrine
and p-toluenesulfonyl chloride following literature procedure.46a Diol 13 was
prepared according to the literature procedure.46b GC analysis was carried out using
HP-5 (30m x 0.25 m x 0.25 μ) column.
Preparation of organozinc halides by oxidative insertion using LiCl as additive
and I2 as catalyst.
The following procedure for preparation of n-BuZnBr⋅LiCl is representative (entry 2
in table-3)
To a 25 mL two-necked round bottom flask equipped with a stir bar and a
reflux condenser was added zinc dust (0.490 g, 7.5 mmol) and LiCl (0.233 g, 5.5
mmol). The mixture was heated at 150 oC for 1 h under high vacuum and cooled to
room temperature under argon. Anhydrous THF (5 mL) and I2 (0.063 g, 0.25 mmol)
were introduced in the flask and the mixture was stirred at room temperature for 15
minutes (red color of I2 disappears completely). n-Butyl bromide (0.53 mL, 5 mmol)
was then added and the reaction mixture was stirred at 50−55 oC for 18 h. The flask
was cooled to room temperature and mixture was allowed to settle for 1 h. The yield
of the zinc reagent was determined by iodometric titration.
Iodometric titration:
One mL of supernatant aliquot from the reaction mixture was transferred to
10 mL round bottom flask under argon atmosphere. To this, I2 (0.5 M solution in
benzene or THF) was added dropwise at 0 oC until solution becomes brown. The
93
amount of I2 consumed corresponds to one equivalent of alkylzinc halide.29
Calculation for total volume indicated 74% yield of the n-butylzinc bromide.
Reaction of butylzinc bromide with benzoyl chloride
A 50 ml two neck round bottom flask was charged n-BuZnBr⋅LiCl (6 mmol,
8.1 mL of 0.74 M solution in THF) and cooled to −10 oC. CuCN⋅2LiCl (6 mmol, 6
mL of 1 M solution in THF) was added to the solution. The resulting faint green
colored solution was stirred for 15 minutes. Then benzoyl chloride (0.58 mL, 5
mmol) was added dropwise over 5 minutes and the reaction mixture was allowed to
warm to 0 oC and stirred for 6 h. The reaction mixture was quenched cautiously by 2
mL saturated aqueous NH4Cl, acidified with 1N HCl and extracted with diethyl ether
(3 x 20 mL). The combined extract was washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified by “flash
chromatography” on silica gel (230-400 mesh) using ethyl acetate: petroleum ether
as the eluent to obtain 3 as oily liquid.
O
3
Yield
: 0.70 g (86%)
IR (neat)
: 3063, 2958, 1681, 1450 cm-1
1
: δ 0.96 (t, J = 7.20 Hz, 3H), 1.31−1.52 (m, 2H),
H NMR (CDCl3)
1.64−1.83 (m, 2H), 2.97 (t, J = 7.58 Hz, 2H),
7.38−7.62 (m, 3H, ArH), 7.90−8.04 (m, 2H, ArH)
Reaction of benzylzinc chloride with benzaldehyde
The same procedure (described for n-BuZnBr⋅LiCl) was followed for the preparation
of PhCH2ZnCl⋅LiCl.
A 25 ml two neck round bottom flask was charged with PhCH2ZnCl⋅LiCl (6
mmol, 8 mL of 0.75 M solution in THF) and the solution was cooled to 0 oC.
Benzaldehyde (0.5 mL, 5 mmol) was added dropwise over 5 minutes and the reaction
mixture was allowed to warm to room temperature and stirred for 6 h. The mixture
94
was then quenched cautiously by 1 mL MeOH at 0 oC. Saturated aqueous NH4Cl (20
mL) was added and the mixture was extracted with ethyl acetate (3 x 20 mL). The
combined extract was washed with brine, dried over Na2SO4 and concentrated under
reduced pressure. The crude compound was purified by “flash chromatography” on
silica gel using ethyl acetate: petroleum ether as the eluent to obtain 4 as a white
solid.
OH
Ph
4
Yield
: 0.84 g (85%)
Melting point
: 64–66 oC (Lit.47 67−67.5 oC )
IR (CHCl3)
: 3599, 3016, 2920, 1454 cm-1
1
: δ 1.95 (d, J = 2.9 Hz, 1H, OH), 2.95−3.06 (m,
H NMR (CDCl3)
2H), 4.84−4.96 (m, 1H), 7.15−7.43 (m, 10H, ArH)
Preparation of (2R,3S)-(–)-4-methyl-2,3-diphenylmorpholine (11)
A 10 mL round bottom flask was charged with (2R,3S)-(–)-2,3diphenylmorpholine48 (0.239 g, 1 mmol), formic acid (2 mL) and formaldehyde (2
mL). The reaction mixture was then refluxed for 1.5 h and cooled to room
temperature. Unreacted formic acid and formaldehyde were removed on rotary
evaporator. The residue was treated with 10 mL water followed by 5 mL of 2N
aqueous NaOH and extracted with DCM (3 x 10 mL). The combined extract was
washed with water (10 mL) followed by brine, dried over Na2SO4 and concentrated
under reduced pressure. The crude compound was treated with HCl in MeOH. The
resulting hydrochloride was washed with ether, and basified using aqueous NaOH to
obtain 11 as a white solid.
Ph
O
Ph
N
Me
11
95
Yield
: 0.232 g (92%)
TLC data
: Rf (EtOAc): 0.46
Melting point
: 54−56 oC
: −126.4 (c 1.06, CHCl3)
[α]25
D
IR (CHCl3)
: 3018, 2860, 1492, 1450 cm-1
1
: δ 2.16 (s, 3H,), 2.47 (brd, J = 11.28 Hz, 1H),
H NMR (CDCl3)
2.95 (td, J = 12.11 Hz and 3.85 Hz, 1H), 3.9 (d, J =
3.02 Hz, 1H), 4.05 (td, J = 11.55 Hz and 3.30 Hz,1H),
4.31 (brdd, J = 11.28 Hz and 3.3 Hz, 1H), 5.10 (d, J =
3.02 Hz, 1H), 7.0−7.37 (m, 10H, ArH)
13
C NMR (CDCl3)
: δ 139.4, 134.2, 131.2, 127.6, 127.2, 126.9, 126.5,
125.8, 81.2, 68.1, 67.6, 47.6, 43.1
Analysis for
: C17H19NO
Calculated (%)
: C, 80.60; H, 7.56; N, 5.53
Found (%)
: C, 80.20; H, 7.62; N, 5.12
Preparation of EtZnCl·Mg(Br)Cl (5)
In a 25 mL two neck round bottom flask, anhydrous zinc chloride (0.654 g,
4.8 mmol) was dissolved in anhydrous THF (3.4 mL). The solution was cooled to 0
o
C, treated with EtMgBr (4.8 mmol, 6.15 mL of 0.78 M solution in THF) dropwise
over 10 minutes. The resulting solution was stirred at 0 oC for 1 h. Ice bath was then
removed and reaction mixture was stirred for 1 h at room temperature to provide 0.5
M solution (by iodometric titration) of 5.
Preparation of EtZnOAc·Mg(OAc)Br (6)
To the suspension of anhydrous Zn(OAc)2 (2.75 g, 15 mmol) in anhydrous
THF (13.3 mL) was added EtMgBr (15 mmol, 16.66 mL of 0.9 M solution in THF)
dropwise at 0 oC over 10 minutes. Zinc acetate was dissolved within 10–15 min. and
solution became clear. Resulting solution was stirred at 0 oC for 1 h and then at room
temperature for 1 h to obtain 0.5 M solution (by iodometric titration) of 6.
96
Preparation of reagent (7) and (8)
To a solution of ZnCl2 (or Zn(OAc)2) (5 mmol) in 16.5 mL THF was added
diethylzinc (5 mmol, 3.44 mL of 1.45 M solution in hexane) dropwise at room
temperature over 5 minutes. The resulting clear solution was then stirred for 1 h to
obtain 0.5 M solution (by iodometric titration) of 7 or 8.
General procedure for the preparation of magnesium-dialkoxides (21, 23 and
24)
In a 10 mL round bottom flask containing magnetic stir bar and rubber
septum, the diol ((−)-12 or (−)-13 or (+)-14) (0.4 mmol) was dissolved in 2 mL
anhydrous THF. The solution was cooled to 0 oC and treated with EtMgBr (0.8
mmol, 0.84 mL of 0.95 M solution in THF). After 15 minutes ice bath was removed
and the mixture was stirred at room temperature for 15 minutes. The resulting
solution of magnesium-dialkoxides (21, 23 and 24 respectively) was used as it is for
alkylation step.
General procedure for the preparation of lithium-dialkoxides (20 and 22)
In a 10 mL round bottom flask containing magnetic stir bar and rubber
septum, the diol ((−)-12 or (−)-13) (0.22 mmol) was dissolved in 1.5 mL anhydrous
THF. The solution was cooled to 0 oC and treated with n-BuLi (0.44 mmol, 0.27 mL
of 1.6 M solution in cyclohexane). After 15 minutes ice bath was removed and
stirring was continued at room temperature for 15 minutes to obtain lithiumdialkoxides 20 and 22 respectively.
Magnesium-dialkoxide
catalyzed
addition
of
EtZnCl·Mg(Br)Cl
(5)
to
benzaldehyde
The following procedure for the addition of EtZnCl·Mg(Br)Cl to benzaldehyde
catalyzed by 23 is representative (entry 5 in table-5).
To a 50 mL two necked round bottom flask was added EtZnCl·Mg(Br)Cl (5)
(4.8 mmol, 9.6 mL of 0.5 M solution in THF) followed by 1,4-dioxane (0.41 mL, 4.8
mmol) at 0 oC. After 15 minutes, the catalyst 23 (0.4 mmol, solution in THF) was
added. The resulting heterogeneous reaction mixture was stirred for next 10 minutes
and was treated with benzaldehyde (0.4 mL, 4 mmol). After 8 h at 0 oC, the mixture
was cautiously quenched with MeOH (1 mL), diluted with EtOAc (20 mL), washed
97
with saturated NH4Cl solution and dried over anhydrous Na2SO4. Evaporation of the
solvent followed by Kugelrohr distillation (150 oC, 0 torr) provided the product
contaminated with benzyl alcohol and unreacted benzaldehyde. The crude compound
was then purified by flash chromatography on silica gel (230-400 mesh) using ethyl
acetate: petroleum ether as the eluent to obtain 25 as an oil.
OH
25
Yield
: 0.348 g (64%)
[α]25
D
:0
ee
:0
1
: δ 0.91 (t, J = 7.45 Hz, 3H), 1.68−1.90 (m, 3H, CH2
H NMR (CDCl3)
and OH), 4.59 (t, J = 6.57 Hz, 1H), 7.22−7.37 (m, 5 H,
ArH).
Addition
of
EtZnOAc·Mg(OAc)Br
(6)
to
benzaldehyde
catalyzed
by
magnesium-dialkoxide (23)
The following procedure for the addition of EtZnOAc·Mg(OAc)Br to benzaldehyde
catalyzed by 23 is representative (entry 7 in table-6). The catalyst 23 was prepared in
MTBE by following the same procedure as described for THF.
To the catalyst 23 (0.2 mmol) in MTBE was added EtZnOAc·Mg(OAc)Br
(2.4 mmol, 0.5 M solution in MTBE) at 0 oC under argon atmosphere. The
heterogeneous reaction mixture was stirred vigorously for next 5 minutes and treated
with benzaldehyde (0.2 mL, 2 mmol). After 8 h at 0 oC the reaction was cautiously
quenched with MeOH (1 mL). Usual work-up and purification provided desired
product (S)-25.
Yield
: 0.12 g (44%)
[α]25
D
: –25.5 (c 5.0, CHCl3) [lit.49a ─ 46.7 (c 5.1, CHCl3)]
ee
: 50% (by HPLC)
98
: Chiralcel OD-H column, i-PrOH:n-Hexane (2:98),
HPLC
flow rate 0.5 mL/min., detection at 254 nm., tR =
24.375 min, tR = 31.333 min.
One pot procedure for enantioselective addition of RZnOAc⋅Mg(OAc)Br to
benzaldehyde
The following procedure for the addition of RZnOAc·Mg(OAc)Br to benzaldehyde is
representative (Table-7).
In a 50 mL two neck round bottom flask anhydrous Zn(OAc)2 (1.1 g, 6
mmol) and (−)-13 (0.186 g, 0.4 mmol) were suspended in anhydrous THF (5 mL).
The mixture was cooled to 0 oC and treated dropwise with RMgBr (6.8 mmol, 6.8
mL of 1 M solution in THF) under argon atmosphere. The reaction mixture was
stirred for next 1 h resulting in a clear solution. Benzaldehyde (0.4 mL, 4 mmol) was
then added and the mixture was stirred for the time indicated in table-7. The reaction
was cautiously quenched with MeOH (1 mL). Usual work-up and purification
provided pure alcohol.
(S)-1-phenylpropan-1-ol (25)
Yield
: 0.163 g (30%)
[α]25
D
: −19.3 (c 5.18, CHCl3) [lit.49a ─ 46.7 (c 5.1, CHCl3)]
ee
: 40% (by chiral GC)
Chiral GC
: CP-Cyclodextrin-B-2,3,6-M-19 capillary column, at
100 oC (1 min.), 20 deg./min., 110 oC (40 min.), 20
deg/min, 230 deg (5 min.) tR = 33.261 min., tR =
34.370 min.
(S)-1-phenylpentan-1-ol (28)
OH
28
99
Yield
: 0.11 g (17%)
[α]26
D
: −5.0 (c 3.2, C6H6) [lit.49b −39.9 (c 3.08, C6H6)]
ee
: 13% (by HPLC)
HPLC
: Chiralcel OD-H column, i-PrOH:n-Hexane (10:90),
flow rate 0.5 mL/min., detection at 254 nm., tR =
12.350 min, tR = 13.200 min.
1
H NMR (CDCl3)
: 0.88 (t, J = 6.69 Hz, 3H), 1.16−1.45 (m, 4H), 1.65−
1.85 (m, 3H, CH2 and OH), 4.61−4.71 (m, 1H),
7.22−7.40 (m, 5 H, ArH).
(S)-3-methyl-1-phenylbutan-1-ol (29)
OH
29
Yield
: 0.032 g (5%)
[α]28
D
: −8.33 (c 3.2, n-heptane) [lit.49c −32.3 (c 16.7, nheptane)]
ee
: 16% (by chiral GC)
Chiral GC
: CP-Cyclodextrin-B-2,3,6-M-19 capillary column, at
122 oC (50 min.), 20 deg./min., 230 oC (1 min.), tR =
36.519 min., tR = 37.742 min.
1
H NMR (CDCl3)
: δ 0.95 (d, J = 6.06 Hz, 6H), 1.44−1.56 (m, 1H),
1.65−1.85 (m, 3H, CH2 and OH), 4.68−4.81 (m, 1H),
7.27−7.38 (m, 5 H, ArH).
Addition of diethylzinc to benzaldehyde catalyzed by 23 (as described in eq 9)
To a solution of diethylzinc (3.6 mmol, 2.48 mL of 1.45 M solution in
hexane) was added 0.3 mmol of catalyst 23 (solution in THF) followed by
benzaldehyde (0.3 mL, 3 mmol) at 0 oC. After 2 h at 0 oC TLC indicated
100
benzaldehyde was consumed completely. Thereafter the reaction mixture was
quenched with 1 mL MeOH. Usual work-up and purification provided desired
product (S)-25.
Yield
: 0.31 g (76%)
[α]25
D
: –6.66 (c 5.4, CHCl3) [lit.49a ─ 46.7 (c 5.1, CHCl3)]
ee
: 14%
Addition of ethylzinc reagents prepared from ZnX2 and n EtMgBr (entries 3−6
in table-8)
The following procedure for the addition of ethylzinc reagent (prepared from two
equivalent of EtMgBr and ZnX2) to benzaldehyde is representative.
A solution of ZnCl2 (or Zn(OAc)2) (1 mmol) in 1 mL THF was cooled to 0
o
C. EtMgBr (2 mmol, 2.44 mL of 0.82 M solution in THF) was then added dropwise
over 5 minutes. The reaction mixture was then stirred at mentioned temperature and
time indicated in table-8 (entries 3−6). The mixture was then treated with PhCHO
(0.19 mL, 1.9 mmol) at 0 oC. After 1 h the reaction mixture was analyzed by GC.
Addition of triethylzincates to benzaldehyde (entries 7 and 8 in table-8)
A solution of ZnCl2 (or Zn(OAc)2) (2 mmol) in 2 mL THF was cooled to 0 oC
and treated with EtMgBr (6 mmol, 6 mL of 1 M solution in THF) dropwise over 10
minutes. The reaction mixture was stirred at 0 oC for 30 minutes. PhCHO (0.58 mL,
5.8 mmol) was then added and after 1 h the reaction mixture was analyzed by GC.
General procedure for the preparation of zinc-alkoxides (30a-c)
To a 50 mL two neck round bottom flask with a stir bar and a reflux
condenser was added the diol ((−)-13 or (−)-12 or (+)-14) (3 mmol) in 5 mL
anhydrous toluene. The mixture was heated at 80 oC to dissolve the diol completely
and diethylzinc (3 mmol, 2.06 mL of 1.45 M solution in hexane) was added dropwise
at the same temperature. Immediate evolution of ethane was observed. The reaction
mixture was stirred at 80 oC for 0.5 h. A viscous solution of zinc alkoxide (30a or
30b or 30c respectively) was obtained, which was utilized as such for alkylation step.
101
Addition of chiral-zincate catalyzed by zinc-alkoxide (30a-c)
The following procedure for the addition of chiral-zincate to benzaldehyde using zinc
alkoxide 30a is representative (Condition C, entry 3 in table-9).
The suspension of zinc-alkoxide 30a (3 mmol) was cooled to 0 oC and treated
with EtMgBr (3 mmol, 3 mL of 1 M solution in THF) and benzaldehyde (3 mmol,
0.3 mL in 2 mL toluene) simultaneously over 10 minutes. As addition proceeds,
zinc-alkoxide dissolves completely and solution becomes clear. Reaction mixture
was stirred for 2 h at 0 oC and cautiously quenched by 1 mL MeOH. Usual work-up
and purification provided the desired product (S)-25.
Yield
: 0.24 g (59%)
[α]25
D
: –23.15 (c 4.96, CHCl3) [lit.49a ─ 46.7 (c 5.1,
CHCl3)]
ee
: 50%
102
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108
NMR Spectra and Chiral HPLC / GC Chromatogram
109
1
H-NMR of compound 3 (CDCl3, 200MHz)
2.00
0.00
3.01
2.97
2.93
1.93 2.94
1.80
1.77
1.73
1.69
1.65
1.47
1.43
1.39
1.36
0.99
0.96
0.92
7.98
7.95
7.60
7.56
7.55
7.52
7.49
7.46
7.42
TMS
O
Ph
3
9.5
1
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.09
2.5
2.0
1.5
2.99
1.0
0.5
0.0
-0.5
H-NMR of compound 4 (CDCl3, 200MHz)
0.00
1.00
1.96
1.95
4.94
4.93
4.91
4.90
4.89
4.87
4.86
10.29
3.04
3.03
3.01
2.99
7.37
7.35
7.31
7.30
7.28
7.23
7.22
7.21
TMS
OH
4
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
1.91
4.5
4.0
3.5
3.0
0.96
2.5
2.0
1.5
1.0
0.5
0.0
-1.0
110
1
H-NMR of compound 11 (CDCl3, 200MHz)
Ph
N
Me
11
1.05
1.07
4.0
3.5
10.22
9.5
13
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
1.05
3.0
1.00
5.0
2.5
1.07
4.5
4.0
0.00
5.11
5.10
4.32
4.29
4.08
4.07
4.06
4.05
4.03
3.91
3.90
2.98
2.97
2.95
2.95
2.93
2.92
2.48
2.45
2.16
1.071.04
2.48
2.45
O
2.98
2.97
2.95
2.95
2.93
2.92
Ph
4.32
4.32
4.30
4.29
4.07
4.06
4.05
4.03
3.91
3.90
7.36
7.34
7.22
7.21
7.16
7.14
7.12
7.11
7.04
TMS
1.07
3.5
3.0
3.19
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
C-NMR of compound 11 (CDCl3, 50.32MHz)
47.65
43.19
68.19
67.61
125.86
N
Me
126.58
Ph
127.23
126.96
O
127.62
Ph
81.22
77.00
139.43
134.27
131.21
127.62
127.23
126.96
126.58
125.86
Chloroform-d
11
128.0 127.5 127.0 126.5 126.0 125.5
200
190
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
111
Ph
N
Me
47.63
43.19
O
68.18
67.61
Ph
81.21
131.20
127.61
127.23
126.96
126.57
125.84
DEPT NMR of compound 11
11
200
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
H-NMR of compound 25 (CDCl3, 200MHz)
0.95
0.00
4.98
1.87
1.84
1.80
1.77
1.74
1.70
0.95
0.91
0.88
4.63
4.59
4.56
TMS
7.36
7.33
7.31
7.29
7.29
7.26
7.26
1
190
OH
25
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
3.27
4.0
3.5
3.0
2.5
2.0
3.00
1.5
1.0
0.5
0.0
-0.5
-1.0
112
1
H-NMR of compound 28 (CDCl3, 200MHz)
1.84
1.78
1.76
1.73
1.37
1.35
1.33
1.32
1.29
1.27
0.92
0.88
0.85
0.00
4.69
4.66
4.63
7.36
7.34
7.32
7.31
7.29
7.28
7.26
7.24
TMS
OH
28
4.87
10.0
9.0
8.5
8.0
7.5
0.91
7.0
6.5
6.0
5.5
5.0
3.17 4.05 3.00
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
H-NMR of compound 29 (CDCl3, 200MHz)
0.00
0.97
0.94
1.81
1.78
1.74
1.73
1.73
1.70
1.67
1.60
1.50
1.81
1.78
1.75
1.74
1.73
1.73
1.70
1.67
1.55
1.53
1.50
1.48
OH
4.78
4.75
4.74
4.71
TMS
7.36
7.36
7.34
7.32
7.31
7.29
7.26
7.26
1
9.5
29
2.98
1.8
1.00
1.7
1.6
1.5
1.4
5.02
9.5
9.0
8.5
8.0
7.5
0.96
7.0
6.5
6.0
5.5
5.0
2.98
4.5
4.0
3.5
3.0
2.5
2.0
6.00
1.5
1.0
0.5
0.0
113
Determination of enantiomeric excess for RZnOAc⋅Mg(OAc)Br addition
product
OH
(±)-25
OH
(−)-25
50% ee, Chiralcel OD-H column; i-PrOH:n-Hexane (2:98); 0.5 mL/min.; 254 nm.
Retention time: tR = 24.375 min, tR = 31.333 min.
114
OH
(±)-28
OH
(−)-28
13% ee, Chiralcel OD-H column; i-PrOH:n-Hexane (10:90); 0.5 mL/min.; 254 nm.
Retention time: tR = 12.35 min, tR = 13.20 min.
115
OH
(±)-29
OH
(−)-29
16% ee; GC analysis (CP-Cyclodextrin-B-2,3,6-M-19 capillary column), at 122 oC
(50 min.), 20 deg./min., 230 oC (1 min.), Retention time: tR = 36.519 min., tR =
37.742 min.
116
CHAPTER-3
Potential chiral ligands
117
Introduction
Asymmetric catalysis is a topic of increasing interest and is one of the most
important focal areas in organic synthesis.1 Asymmetric catalysis with enzymes,
chiral metal complexes and chiral organic molecules has emerged as powerful tools
for the synthesis of optically active compounds. Most asymmetric catalysts that have
been developed so far are metal complexes with chiral organic ligands.2 The chiral
ligand plays a crucial role and modifies the reactivity and selectivity of the metal
center in such a way that one of two possible enantiomeric products is formed
preferentially. Therefore, the design of new chiral ligands aimed at asymmetric
catalysis is of increasing importance in organic synthesis.3 The main requirement of a
chiral ligands is the presence of at least two hetero atoms capable of the formation of
a structurally well defined metal complex which can differentiate between
enantiotopic faces of the electrophile. The two hetero atoms allow flexibility as one
or both can be bound to Lewis acidic metal centre. Significant work has been done
for the development of chiral catalysts using various chiral ligands such as
phosphorus containing ligands,2c-e,j,4 oxygen containing ligands5 and nitrogen
containing ligands.6 As compared to phosphorous ligands, the nitrogen containing
ligands offer many advantages, such as the ease of preparation, high stability and
easy separation. C2-symmetric chiral diols are also excellent chirality inducers and
have been used in different types of asymmetric transformations.7
Amongst different approaches, ligand-accelerated enantioselective addition of
organozinc reagents to carbonyl compounds has emerged as one of the powerful
tools for the construction of chiral carbon stereocentre.8 Our interest in this area led
us to explore morpholine based ligands and sterically also demanding C2-symmetric
diols.
The chapter is divided into two sections.
Section 3A:
Synthesis and resolution of cis- and trans-2,3-diphenyl morpholines
Section 3B:
Attempted resolution of 2,3-diphenylbuatane-2,3-diol
118
Section 3A
Synthesis and resolution of cis- and trans-2,3-diphenyl
morpholines
Introduction
Substituted morpholines constitute an important class of heterocyclic
compounds found in many naturally occurring as well as synthetically important
organic molecules that exhibit interesting biological and pharmacological properties.9
This class of compounds has found important applications as antitumors,10
antimicrobials,11 antidepressants,12 antioxidants,13 other biological activity14 and in
agricultural use.15 Morpholine derivative such as reboxetine is a potent
antidepressant drug, which selectively inhibits the norepinephrine reuptake and is
widely studied for its pharmacological properties.16 These compounds have gained
much interest in recent years as a result of the pronounced biological activities and
their applications in asymmetric synthesis.17,18
Various methods are known in the literature for the synthesis of morpholine
derivatives.9,19-21 In most cases morpholine ring has been constructed by the reaction
of 1,2-amino alcohols with various electrophiles, such as chloroacetyl chloride,22
epoxides,14a,23 activated alkenes24 and others.18a,25 Some of the important literature
methods for the preparation of chiral morpholine derivatives are described below.
1. Synthesis of chiral morpholine derivatives: A literature review
1.1 From β-amino alcohol and chloroacetyl chloride
In 1985 Brown et al.22a described the preparation of morpholine derivative 4
(Scheme 1). Commercially available (R) or (S)-serine 1 was converted to N-benzyl
serine 2 by reductive amination. Compound 2 was reacted with chloroacetyl chloride
in the presence of sodium hydroxide to obtain morpholinone 3. Reduction of 3 using
borane-dimethyl sulphide complex provided optically pure morpholine 4 with good
optical purity.
119
OH
HO2C
*
NH2
OH
a
O
b
HO2C
*
NH
CH2Ph
HO2C
*
O
N
CH2Ph
O
c
HOH2C
(R) or (S)
*
N
CH2Ph
(R) or (S)
>90% ee
1
2
3
4
Scheme 1. Reagents and conditions: (a) PhCHO, NaBH4, 6−10 oC; (b) (i)
ClCH2COCl, NaOH, 0 oC; (ii) 30% aq. NaOH, 30−33 oC; (c) BH3⋅SMe2, THF, 0 oC.
The same author in 1987 prepared racemic morpholines 5a and 5b starting
from the corresponding racemic amino alcohols using above methodology.22b The
morpholine derivatives (5a and 5b) were resolved into corresponding enantiomers
using dibenzoyl tartaric acid in good yield with high enantiomeric purity (Scheme 2).
p-R-C6H4
O
i) (+)-dibenzoyl tartaric acid
N
H
ii) (−)-dibenzoyl tartaric acid
(+)-5a or (+)-5b + (−)-5a or (−)-5b
O
(±)-5a,b
5a = R = H
5b = R = F
> 98% ee
(+)-5a, 39%
(−)-5a, 28%
(+)-5b, 32%
(−)-5b, 35%
Scheme 2. Resolution of 5a and 5b.
In 2005 Tamagnan et al.22f reported the preparation of morpholine 9 from
commercially available (S)-3-amino-1,2-propanediol 6 (Scheme 3). Treatment of 6
with chloroacetyl chloride in the presence of Et3N provided amide 7, which was
cyclized to lactam 8 using potassium tert-butoxide. Compound 8 was reduced with
Red-Al to furnish morpholine (S)-9 in good yield. The morpholine 9 was further
converted to (S,S)-Reboxetine which is known to be a potent selective
norepinephrine reuptake inhibitor.
120
OH
OH
OH
OH
OH
a
O
b
N H
NH2
N
H
Cl
O
6
7
OH
c
O
O
N
H
(S)-9
8
Scheme 3. Reagents and conditions: (a) ClCH2COCl, Et3N, CH3CN/MeOH −10 to 0
o
C, 94%; (b) t-BuOK, t-AmOH, RT, 92%; (c) Red-Al, THF, 0 oC to RT, 85%.
1.2 From β-amino alcohol and epoxide
In 1998 Servi et al.14a reported the preparation of morpholine 13 starting from
chiral epoxide 10 (Scheme 4). The epoxide 10 was reacted with ethanolamine
sulphate 11 at 40 oC in the presence of sodium hydroxide to give intermediate 12,
which was converted in situ to morpholine 13 by heating the reaction mixture at 65
o
C.
O
Ph
10
+
H2N
OSO3Na
11
a
Ph
OH OSO3Na
b
Ph
O
N
H
N
H
12
13
Scheme 4. Reagents and conditions: (a) NaOH, MeOH, 40 oC; (b) NaOH, 65 oC,
66%.
In 1999 Quirion et al.23a reported the preparation of 2,5-disubstituted
morpholine 20 starting from chiral epoxide 15 (Scheme 5). The O-protected amino
alcohol 14 was reacted with epoxide 15 in methanol at 40 °C to furnish amino
alcohol 16. Subsequent condensation of 16 with chloroacetyl chloride gave amide 17
which on cyclization using sodium hydride followed by deprotection of silyl group
provided lactam 18. Next, the amide enolate of compound 18 was generated by
treatment with sec-BuLi in the presence of HMPA which on treatment with MeI
provided alkylated product 19 with >95% diastereoselectivity. Compound 19 was
converted to morpholine 20 by reduction with LiAlH4 followed by removal of chiral
121
auxiliary under hydrogenation. This methodology was also applied for the
preparation of other chiral morpholines derivative by using various enantiopure
epoxides.
Ph
OTBDMS
O
+
Ph
NH2
a
R
14
NH
R
OTBDMS
R
R
O
16
17
20
c, d
Ph
f
Me
Cl
OH
R = Ph, PhCH2OCH2
H
N
O
N
OH
15
OTBDMS
Ph
b
R
N
OH
O
O
Me
19
Ph
N
e
R
OH
O
O
18
Scheme 5. Reagents and conditions: (a) MeOH, 40 oC, 78%; (b) ClCH2COCl, 50%
aq. NaOH, THF, 76%; (c) NaH, THF, 90%; (d) TBAF, THF, 0 oC to RT, 96%; (e)
sec-BuLi, HMPA, THF, −78 oC then MeI, 74%; (f) (i) LiAlH4, THF; (ii) H2, Pd/C,
MeOH, 50%.
In 2004 Myers et al.23b described the preparation of trans 2,5-disubstituted
morpholine. Treatment of epoxide (S)-21 with excess of D-alaninol 22 in n-propanol
provided exclusively monoalkylated product 23 (Scheme 6). Compound 23 on
treatment with p-toluenesulfonyl chloride gave N-tosyl diol 24, which was cyclized
to 25 using sodium hydride and p-toluenesulfonyl imidazole. Deprotection of N-tosyl
group using sodium in ethanolic ammonia provided desired morpholine derivative 26
in excellent yield.
122
TBSO
TBSO
a
3H
21
N
3 OH
O
+
H
b
TBSO
3 OH
CH3
OH
NH2
N
24
Ts
CH3
OH
23
c
HO
CH3
22
H
N
TBSO
3
O
26
CH3
Ts
N
d
TBSO
3
CH3
O
25
Scheme 6. Reagents and conditions: (a) n-PrOH, 97 oC, 99%; (b) p-TsCl, Et3N,
DCM, 77%; (c) NaH, TsIm, THF, 99%; (d) Na, NH3, EtOH, 100%.
In 2007 Bruening et al.23c reported one pot procedure for the preparation of
various optically active morpholine derivatives by the reaction of chiral β-amino
alcohols with optically pure epichlorohydrin. Initial investigation showed that
LiClO4 as Lewis acid and NaOMe as Lewis base proved better as compared to other
reagents. Thus, the reaction of chiral β-amino alcohol 27 with (S)-epichlorohydrin 28
furnished desired morpholine derivative 29 in moderate to good yield with excellent
stereoselectivity (Table 1).
123
Table 1. LiClO4 mediated one-pot preparation of morpholine derivatives
LiClO4, toluene
20−50 oC
OH
R2
Cl
+
NH
R
R1
OH
R
then
NaOMe, MeOH
20−50 oC
O
27a-f
O
2
R1
N
R
29a-f
28
Entry
27
R
R1
R2
Yield of 29
ee/de
1
a
Bn
H
H
59
94
2
b
Bn
i-Pr
H
63
>97
3
c
Bn
t-Bu
H
60
>97
4
d
Bn
H
Ph
77
>97
5
e
Bn
Me
H
57
97
6
f
Me
H
H
61
>97
1.3 From β-amino alcohol and alkenes
In 1993 Hayashi et al.24b reported Pd-BINAP catalyzed preparation of vinyl
morpholines. Initial screening of the phosphorous ligand showed that BINAP 32 was
proved the best ligand. Under the optimized conditions, treatment of protected
ethanol amine 30 with activated alkene 31 in the presence of chiral Pd-BINAP
catalyst
provided
optically
enantioselectivity (Scheme 7).
active
vinyl
morpholine
33
with
moderate
124
X
OH
O *
Pd(0)/L*, THF
+
NH
R
40 oC, 24 h
N
R
X
33a-b
31
30
30a = R = CH2Ph
30b = R = SO2C6H4-p-CH3
32-64% yield
50-61% ee
31a = X = OCOCH3
31b = X = OCO2CH3
31c = X = OCO2tBu
PPh2
L* =
PPh2
(R)-BINAP (32)
Scheme 7. Pd-catalyzed enantioselective synthesis of 33
In 2000 Nishi et al.24c prepared morpholine derivative (R)-38, which is key
intermediate for tachykinin receptor antagonist, starting from alkene 35. In this
protocol, excess N-Boc-aminoethanol 34 was reacted with styrene derivative 35 in
the presence of N-iodosuccinimide in acetonitrile to obtain iodide 36 (Scheme 8).
Treatment of 36 with sodium hydride furnished N-Boc morpholine 37, which on
deprotection of both the triphenylmethyl (Tr) and Boc group by treatment with 4N
HCl provided racemic 38 in good yield. Morpholine 38 was resolved using D-(−)tartaric acid to obtain (R)-38 with high optical purity.
HO
34
Boc
O
+
Cl
NHBoc
I
NHBoc
a
Cl
OTr
Cl
OTr
b
O
Cl
OTr
Cl
37
36
c
Cl
35
H
Cl
N
H
N
d
O
OH
Cl
Cl
N
O
OH
Cl
(R)-38, >99% ee
(±)-38
Scheme 8. Reagents and conditions: (a) NIS, CH3CN, 70 oC, 72%; (b) NaH, DMF,
70 oC, 77%; (c) 4N HCl, dioxane/EtOH, 79%; (d) D-(−)-tartaric acid.
125
In 2008 Aggarwal et al.24e described one pot procedure for the construction of
morpholine unit starting from vinyl sulfonium salt 40. The salt 40 was prepared from
2-bromoethyl trifluoromethanesulfonate 39 (Scheme 9). Treatment of 40 with Ntosyl amino alcohol 41a-c in the presence of Et3N provided desired morpholine
derivative 42 in excellent yield (Scheme 10). The possible explanation for the
formation of 42 involves the base assisted conjugate addition of nitrogen atom of 41
to 40 followed by cyclization at oxygen gives desired morpholine derivative.
OTf
a
OTf
Br
Br
SPh2
b
OTf
SPh2
39
40
Scheme 9. Reagents and conditions: (a) Ph2S, toluene, reflux, 81%; (b) KHCO3,
THF/H2O, RT, 96%.
R1
OH
R2
NH
Ts
40, Et3N, CH2Cl2
0 oC−RT
41a-c
R1
O
R2
N
Ts
42a-c
96-98% yield
OH
OH
NH
Ts
41a
MeO2C
NH
Ts
41b
Ph
OH
NH
Ts
41c
Scheme 10. One-pot preparation of morpholines 42a-c using vinyl sulfonium salt 40
Recently Bagnoli et al.24g reported the use of vinyl selenones as Michael
acceptors for the synthesis of morpholine derivatives. Enantiopure N-protected
amino alcohols 27d and 41b,d were treated with selenones 43a-c in the presence of
sodium hydride in THF to obtain corresponding morpholine derivatives in good yield
(Scheme 11). In the case of substituted selenones 43b and 43c, the reaction was not
126
selective and the formation of a diastereomeric mixture of morpholine derivative was
observed.
OH
SeO2Ph
+
R1
R2
N
R1
0 oC to reflux
R2
NH
O
NaH, THF
R
R
43a = R2 = H
43b = R2 = Ph
43c = R2 = C6H13
27d = R1 = Ph,
R = Bn
41b = R1 = CO2Me, R = Ts
41d = R1 = Ph,
R = Ts
71-88% yield
Scheme 11. One-pot preparation of morpholine derivatives using selenones 43a-c
It was suggested that the reaction of aminoalcohol with 43 in the presence of
sodium hydride initially gives the carbanion 44 by the attack of oxygen atom of the
aminoalcohol at the β-carbon of the selenones (Scheme 12). Subsequent proton
transfer gives the nitrogen anion 45, which upon intramolecular displacement of
PhSeO2 group gives morpholine derivative.
R2
OH
+
R1
NH
O
NaH
SeO2Ph
R1
R
NH
R
R2
SeO2Ph
R2
O
R1
SeO2Ph
N
R
44
45
O
R1
N
R
Scheme 12. Proposed mechanism
R2
127
1.4. From β-amino alcohol and other electrophiles
Otto et al.25a in 1956 reported the preparation of morpholine 48 using
chloroethanol as electrophile. L-Ephedrine 46 was reacted with chloroethanol to give
diol 47, which upon treatment with concentrated sulfuric acid provided trans-3,4dimethyl-2-phenyl morpholine 48 (Scheme 13).
Ph
NH
Me
46
+
OH
Me
Cl
OH
toluene
Ph
OH
130 oC
Me
N
Me
47
OH
conc. H2SO4
Ph
O
Me
N
Me
48
Scheme 13. Synthesis of morpholine 48
In 2004 Sasaki et al.25c reported preparation of chiral trans-3,5-disubstituted
morpholines. The reaction of N-Boc protected amino alcohol 49, derived from Lserine, with (R)-2,3-O-isopropylideneglycerol triflate 50 in the presence of sodium
hydride gave compound 51 (Scheme 14). Acid hydrolysis of compound 51 provided
diol 52, which upon regioselective protection of the primary hydroxyl with
TBDPSCl provided alcohol 53. Compound 53 on O-mesylation gave 54, which upon
deprotection of Boc-group followed by base mediated cyclization furnished desired
enantiopure morpholine 55.
128
OH
O
TBDPSO
NH
Boc
49
a
O
TBDPSO
NH
Boc
+
O
TfO
O
OH
O
b
O
TBDPSO
NH
Boc
51
52
c
50
OH
OSO2CH3
O
TBDPSO
OH
OTBDPS
NH
Boc
O
d
TBDPSO
NH
Boc
OTBDPS
53
54
e
O
TBDPSO
OTBDPS
N
H
55
Scheme 14. Reagents and conditions: (a) NaH, THF, 83%; (b) 80% aq. AcOH, RT,
86%; (c) TBDPSCl, Imidazole, DMF, 87%; (d) MsCl, Et3N, DMAP, DCM, 93%; (e)
(i) CF3COOH, DCM; (ii) Et3N, DIEA, MeOH, reflux, 89%.
The same author in 2006 reported the preparation of morpholine 60 by using
tert-butyl bromoacetate as electrophile.18a Treatment 49 with tert-butyl bromoacetate
in the presence of 30% aq. NaOH and catalytic TBAI in toluene gave ester 56
(Scheme 15). The ester 56 was first reduced with DIBAL-H and the resulting crude
aldehyde was further reduced to 57 with LiBH4. O-mesylation of 57 provided
compound 58, which was converted to morpholine derivative 59 by removal of the
Boc-group followed by base-mediated cyclization. Compound 59 was converted to
desired morpholine 60 by removal of silyl group using TBAF.
129
O
49
+
O
Br
O
a
TBDPSO
OtBu
b
OtBu
NH
Boc
TBDPSO
56
O
NH
Boc
OH
57
c
O
HO
N
H
e
TBDPSO
60
O
d
O
N
H
TBDPSO
NH
Boc
59
OMs
58
Scheme 15. Reagents and conditions: (a) 30% aq. NaOH, TBAI, toluene, 87%; (b)
(i) DIBAL-H, DCM; (ii) LiBH4, Et2O, 85%; (c) MsCl, Et3N, DCM, 93%; (d) (i)
TFA, DCM; (ii) DIEA, DCM, reflux, 83%; (e) TBAF, THF, 87%.
In 2009 Wolfe et al.25e described the preparation of morpholine derivatives 64
using allyl bromide as electrophile. In this protocol, the treatment of enantiopure NBoc protected amino alcohol 61 with allyl bromide in the presence of sodium hydride
gave allyl ether 62 (Scheme 16). Deprotection of Boc-group followed by Pdcatalyzed N-arylation of the resulting amine trifluoroacetate salt furnished N-aryl
derivative 63. Compound 63 was cyclized to desired cis-3,5-disubstituted morpholine
64 using catalytic amount of Pd(OAc)2 under the optimized conditions in moderate
yield with >90% de. This methodology was also applied for the preparation of
various bicyclic morpholine derivatives.
130
OH
R
O
a
NH
Boc
R
61
O
b
R
NH
Boc
NH
62
O
c
R
Ar
N
Ar
63
64
R1
> 90% de
R = Me, Bn, (CH2)2SMe,
CH2OBn, CH2[(N-Bn)-3-indolyl]
Ar = Ph, p-MeO-Ph, p-Cl-Ph, m-CN-Ph
R1 = Ph, p-MeO-Ph, o-MeO-Ph,
p-Me-Ph, p-tBu-Ph, PhCH2=CH
Scheme 16. Reagents and conditions: (a) (i) NaH, DMF; (ii) allyl bromide; (b) (i)
TFA, DCM; (ii) ArBr, t-BuONa, 1 mol% Pd2(dba)3, 2 mol % (±)–BINAP or 8 mol %
P(tBu)3⋅HBF4, toluene, 40−80 oC ; (c) R1Br, 2 mol% Pd(OAc)2, 8 mol% P(2-furyl)3,
t-BuONa, toluene, 105 oC, 21-58%.
1.5. Preparation of morpholine derivatives from aziridine
In 2009 Ghorai et al.19b described highly regio- and stereoselective one pot
procedure for the preparation of chiral morpholines. This protocol involves Cu(OTf)2
catalyzed ring opening of chiral N-tosyl aziridine 65a in the presence of
chloroethanol followed by potassium hydroxide mediated intramolecular cyclization
to give corresponding morpholine 66a in excellent yield with good enantioselectivity
(Scheme 17). When R was alkyl (65b-d) the reaction was not regioselective and the
formation of mixture of regioisomeric product was observed. The above strategy was
successfully demonstrated for the preparation of 2,3-disubstituted morpholines from
enantiopure 2,3-disubstituted aziridines with excellent diastereoselectivity.
Ts
N
+
Cl
R
OH
Cu(OTf)2
O
R
Cl
NHTs
O
KOH
R
65
65a = R = Ph
65b = R = Bn
65c = R = i-Pr
65d = R = i-Bu
Scheme 17. One-pot preparation of chiral morpholines from aziridine 65
N
Ts
66a
R = Ph
131
1.6. Preparation of morpholine derivatives from aldehydes
In 2010 Waghmode et al.20a reported the proline catalyzed asymmetric αaminoxylation and reductive amination as key steps for the preparation of chiral
morpholine (R)-9 (Scheme 18). In this protocol, aldehyde 67 was treated with
nitrosobenzene in the presence of D-proline in acetonitrile followed by in situ
reduction with NaBH4 to give aminoxy alcohol, which upon treatment with catalytic
amount of CuSO4 provided diol 68. Selective tosylation of primary hydroxyl group
followed by treatment with sodium azide in DMF provided azido alcohol 69.
Treatment of 69 with allyl bromide using sodium hydride gave azido allyl ether 70,
which on potassium osmate mediated dihydroxylation and subsequent oxidative
cleavage of the resulting diol using NaIO4 furnished azido aldehyde 71.
Simultaneous
Pd-catalyzed
intramolecular reductive amination and benzyl
deprotection of 71 provided desired morpholine (R)-9 in good yield.
BnO
H
OH
a
b
BnO
OH
BnO
O
OH
67
N3
69
68
c
HO
O
N
H
(R)-9
e
BnO
O
N3
71
d
O
BnO
O
N3
70
Scheme 18. Reagents and conditions: (a) (i) PhNO, 25 mol% D-proline, CH3CN,
−20 oC, then NaBH4, MeOH; (ii) 30 mol% CuSO4, MeOH, 0 oC, 66%; (b) (i) 2 mol%
Bu2SnO, p-TsCl, Et3N, DCM, 0 oC to RT; (ii) NaN3, DMF, 70 oC, 89%; (c) NaH,
allyl bromide, DMF, 0 oC, 97%; (d) (i) 2 mol% K2OsO4⋅H2O, NMO, acetone/H2O,
RT; (ii) NaIO4, acetone/H2O, RT; (e) H2, Pd/C, MeOH, RT.
In the same year Rutjes et al.20b described chemoenzymatic synthesis of cisand trans-2,5-disubstituted morpholine derivatives starting from benzaldehyde.
Treatment of benzaldehyde with HCN in the presence of Hydroxynitrile lyases
(HNL) using citrate buffer furnished cyanohydrin 72 (Scheme 19). Subsequent MIP
protection of 72 provided compound 73 in excellent yield with high enantiomeric
excess. MIP protection was mandatory to prevent racemization of 72. Compound 73
132
was converted to ester 74 using three step-one-pot protocol. Treatment of 73 with
excess DIBAL-H followed by subsequent transimination with glycine methyl ester in
the presence of Et3N gave intermediate secondary imine, which on reduction with
NaBH4 furnished ester 74. LiAlH4 reduction of 74 gave amino alcohol 75, which was
treated with p-toluenesulfonyl chloride to give N-tosyl derivative 76. Deprotection of
MIP group using aqueous hydrochloric acid followed by cyclization of resulting diol
using p-toluenesulfonyl imidazole and sodium hydride provided N-Ts morpholine
derivative 77. Finally, samarium iodide mediated deprotection of tosyl group
furnished desired morpholine derivative 78 in good yield. This methodology was
also used for the preparation of enantiopure cis- and trans-2,5-disubstituted
morpholines using (R) and (S)-selective HNL and various chiral amino acid methyl
esters.
O
Ph
OH
a
H
Ph
OMIP
b
CN
Ph
c
Ph
CN
OMIP
H
N
>99% ee
73
72
CO2Me
74
d
Ph
O
N
H
78
g
Ph
O
N
Ts
77
OMIP
f
Ph
Ts
N
e
Ph
OMIP
H
N
OH
OH
76
75
Scheme 19. Reagents and conditions: (a) (R)-HNL, MTBE/H2O, PH = 5; (b) 2methoxy propene, cat. POCl3, then Et3N, RT; (c) (i) DIBAL-H, Et2O; (ii)
H2NCH2COOMe, Et3N; (iii) NaBH4, MeOH, −78 oC; (d) LiAlH4, THF, 0 oC; (e) pTsCl, Et3N, DCM, 0 oC to RT, 82%; (f) (i) aq. HCl, THF; (ii) TsIm, NaH, THF 0 oC
to RT, 83%; (g) SmI2, pyrrolidine, H2O/THF.
As evident from foregoing account, the chiral morpholine derivatives are
easily accessible from simple and easily available starting material.
Over the course of our work on enantioselective addition of organozinc
reagents to aldehydes,26 we wanted to use morpholine ligands 79 and 80 (Figure 1).
We anticipated that a six-membered heterocyclic ring containing heteroatom such as
oxygen allow extra coordination site in the catalyst which may influence its ligand
133
catalytic properties. The present section describes the optimized synthesis and
resolution of morpholine ligands 79 and 80.
Ph
O
Ph
O
Ph
N
H
Ph
N
H
79
80
Figure 1
In 1969 Stefanovsky et al.27a reported the synthesis of morpholines 79 and 80
starting from corresponding amino alcohols 81 and 82 respectively. The reaction of
racemic 81 (or 82) with chloroacetyl chloride in the presence of Et3N gave Nchloroacetyl derivative 83 (or 84) (Scheme 20). Intramolecular cyclization of
compound 83 (or 84) using sodium hydroxide furnished lactam 85 (or 86). Lithium
aluminum hydride reduction of 85 (or 86) provided corresponding racemic cis- and
trans-2,3-diphenyl derivatives 79 and 80 respectively. Similar strategy was used for
the synthesis of morpholines (−)-79 and (+)-80 starting from corresponding chiral
amino alcohols.
Ph
Ph
OH
NH2
a
Ph
OH
Ph
O
Ph
N
H
c
b
Ph
N
O
H
Cl
O
81, 82
erythro-(±)-(81)
erythro-(−)-(81)
threo-(±)-(82)
threo-(+)-(82)
Ph
O
Ph
N
H
79, 80
erythro-(±)-(83)
erythro-(−)-(83)
threo-(±)-(84)
threo-(+)-(84)
cis-(±)-(85)
cis-(−)-(85)
trans-(±)-(86)
trans-(+)-(86)
cis-(±)-(79)
cis-(−)-(79)
trans-(±)-(80)
trans-(+)-(80)
(11%)
(14%)
(22%)
(23%)
Scheme 20. Reagents and conditions: (a) ClCH2COCl, Et3N, 0 oC to RT; (b) NaOH,
EtOH, 40 oC; (c) LiAlH4, THF or Et2O, RT.
Although the preparation of the two stereoisomers of these molecules is
known (viz. (−)-79 and (+)-80), we found the procedure unsatisfactory in terms of
yield. Also, the reported rotations were incorrect. We describe here an optimized
preparation of (±)-79 and (±)-80 which were then efficiently resolved into
134
corresponding enantiomers in good yield with high enantiomeric purity. The results
are discussed below.
Present work
Results and discussion
1. Preparation of (±)-cis-2,3-diphenyl morpholine (79)
Both the cis- and trans-2,3-diphenyl morpholines can be accessed from a
common intermediate that is, erythro-2-amino-1,2-diphenylethanol 81. The amino
alcohol 8128 was prepared by hydrogenation of α-benzoin oxime 87 (Scheme 21).
The racemic amino alcohol 81 was converted to its threo-isomer 82 according to the
literature procedure.28a In this procedure, the amino alcohol 81 was treated with conc.
hydrochloric acid to obtain hydrochloride salt, which was reacted with excess
formamide to obtain N-formyl derivative 88. Subsequent treatment with thionyl
chloride
followed
by
hydrolysis
provided
racemic
threo-2-amino-1,2-
diphenylethanol 82 in good yield.
Ph
OH
Ph
N
OH
87
a
Ph
OH
Ph
NH2
81
b
Ph
OH
Ph
NH
CHO
c
88
Ph
OH
Ph
NH2
82
Scheme 21. Reagents and conditions: (a) H2, Pd/C, MeOH, RT, 80%; (b) (i) conc.
HCl, MeOH, 50 oC, 98%; (ii) HCONH2, 150 oC, 88%; (c) (i) SOCl2, 0 oC to RT; (ii)
H2O, reflux, 88%.
With both the starting material in hand, our next job was to construct
morpholine ring. Initially we tried one step protocol29 for the preparation of cismorpholine 79. In the case of reaction of erythro amino alcohol 81 with 1,2-dibromo
ethane using potassium hydroxide in DMSO, starting material was recovered
(Scheme 22). We then examined ethylene-di-p-toluenesulfonate as electrophile.
Treatment of racemic 81 with ethylene-di-p-toluenesulfonate in THF using Et3N
gave complex reaction mixture. Similar kind of results were realized when the
reaction was carried out in N,N-dimethyl formamide as solvent.
135
Br
Br
KOH, DMSO, RT
TsO
X
Ph
O
Ph
N
H
OTs
complex reaction mixture
81
THF, Et3N, reflux
TsO
OTs
complex reaction mixture
DMF, Et3N, 100 oC
Scheme 22
We then changed strategy to two step protocol. It was thought that cis-5,6diphenylmorpholin-3-one 85 could be directly obtained in single step using method
of Clarke et al.30 Therefore the amino alcohol 81 was reacted with ethyl
chloroacetate using sodium hydride in THF under reflux to obtain 85 (Scheme 23).
However, we did not observe expected product, instead racemic erythro-2(chloroacetylamino)-1,2-diphenylethanol 83 was isolated in low yield. The structure
of the compound was confirmed by IR, 1H NMR and microanalysis.
NaH, THF, reflux
X
81
O
Cl
Ph
O
Ph
N
H
OEt
Ph
OH
O
O
Cl
N
H
unexpected
Ph
83, (5%) yield
Scheme 23
As mentioned previously, Stefanovsky et al. reported the synthesis of (–)-79 and (+)80 in 14% and 23% overall yields starting from homochiral aminoalcohols (–)-81
and (+)-82 respectively.27a In asymmetric synthesis, it is always desirable to
introduce the chirality at last possible step. We therefore decided to redesign the
136
reported procedure for 79 and 80. To improve the yield, erythro amino alcohol 81
was reacted with chloroacetyl chloride in the presence of NaHCO3 using methanol as
the solvent at −10 oC. Amide 83 was obtained as sole product in 98% yield (Scheme
24). Due to competitive O-acylation, low yield was observed when the reaction was
carried out in THF solvent using pyridine as base. The crude compound 83 was
cyclized to lactam 85 in 97% yield using potassium hydroxide in ethanol under
reflux. 1H NMR of the unpurified 85 was clean and showed no isomerization at
stereocenters under the reflux conditions.
Ph
OH
Ph
NH2
81
a
Ph
OH
b
O
Ph
N
H
83
Cl
Ph
O
Ph
N
H
c
(±)-79
O
85
Scheme 24. Reagents and conditions: (a) ClCH2COCl, NaHCO3, MeOH, −10 oC to
RT, 98%; (b) KOH, EtOH, reflux, 97%; (c) LiAlH4, THF, reflux, 62%.
The structure of compound cis-(±)-85 was confirmed by IR, NMR,
microanalysis. The cis- stereochemistry of two phenyl group in 85 was confirmed by
single crystal X-ray analysis. The ORTEP diagram for compound 85 is shown in
figure 2.
Figure 2. ORTEP diagram for (±)-85
137
Cyclization of 83 to 85 also can be carried out using other bases. First we tried to
cyclize amide 83 using weak base like pyridine or potassium carbonate. However,
complex TLC pattern was observed in both the cases (Table 2, entries 1 and 2). Use
of sodium hydride gave complete conversion in THF as well as DMF solvent (entries
Table 2. Intramolecular cyclization of 83 to 85
Ph
OH
Reagent
O
Ph
N
H
Cl
Ph
O
Ph
N
H
83
a
O
85
Entry
Reagent
Solvent
Temp, (oC)
Time, (h)
Crude yield, (%)
1
Pyridine
DMF
100
10
a
2
K2CO3
DMF
100
12
a
3
NaH
THF
25
7
99
4
NaH
DMF
25
1.5
99
5
t-BuOK
THF
25
24
a
6
t-BuOK
t-BuOH
25
4.5
100
Complex reaction mixture was observed.
3 and 4). We observed complex reaction mixture, when potassium tert-butoxide was
used in THF solvent (entry 5). However, clean conversion was observed when the
reaction was carried out in tert-butanol (entry 6). Due to easy handling and cheap
reagents, we carried forward the synthesis with potassium hydroxide in ethanol.
Next, the reduction of 85 to 79 using Red-Al resulted in low yield (42%). We were
able to obtain good yield when 85 was reduced with LiAlH4 in THF under reflux for
16 h (Scheme 24). Racemic cis-2,3-diphenyl morpholine 79 was obtained in overall
59% yield from 81 without the need for chromatographic purification. We preferred
purification of 79 through preparation of its salt with acid rather than tedious column
chromatography. We observed that the oxalate salt of 79 has very low solubility in
ethanol. Therefore the purification of 79 was better achieved through oxalate salt
rather than reported hydrochloride method. After usual work up, the crude compound
was treated with oxalic acid (0.5 equiv) to obtain oxalate salt, which was
138
subsequently recrystallized from ethanol and basified with aqueous NaOH to give
(±)-79 in 62% yield. The structure of 79 was confirmed by IR, NMR, microanalysis.
Our attempts to obtain X-ray quality crystal of compound 79 failed. We therefore
converted racemic morpholine 79 to its N-acetate derivative 89 by treatment with
acetic anhydride using sodium bicarbonate (eq 1). In the IR spectrum of 89,
disappearance of peak due to N-H stretching and appearance of peak at 1635 cm-1
Ph
O
Ph
N
H
(±)-79
Ac2O, NaHCO3
THF:H2O, 0 oC, 45 min.
Ph
O
Ph
N
O
(1)
CH3
(±)-89, 68% yield
shows the formation of N-acetate derivative. However, due to the restricted rotation
of C-N amide bond,31 the 1H NMR spectrum of compound 89 in CDCl3 showed
complex pattern. We tried to obtain clean NMR by changing the solvent to DMSO-d6
or increase the temperature. But similar kind of NMR spectrum pattern was observed
in both the cases. Crystallization of compound 89 from ethanol provided X-ray
quality crystal. The single crystal X-ray analysis of 89 revealed that two phenyl rings
in the molecule are cis- to each other. The ORTEP diagram for compound 89 is
shown in figure 3.
Figure 3. ORTEP diagram for (±)-89
139
2. Preparation of (±)-trans-2,3-diphenyl morpholine (80)
After successful optimization of the reaction conditions, we used this protocol
for the preparation of racemic trans-2,3-diphenylmorpholine 80 (Scheme 25). The
reaction of racemic threo-2-amino-1,2-diphenylethanol 82 with chloroacetyl chloride
furnished threo-amide 84 in 95% yield. Treatment of 84 with potassium hydroxide
gave trans-lactam 86, which upon reduction with LiAlH4 provided (±)-80 in 56%
overall yield.
Ph
OH
Ph
NH2
a
Ph
Ph
82
OH
b
O
N
H
Cl
84
Ph
Ph
O
N
H
c
(±)-80
O
86
Scheme 25. Reagents and conditions: (a) ClCH2COCl, NaHCO3, MeOH:THF, −10
o
C to RT, 95%; (b) KOH, EtOH, reflux, 93%; (c) LiAlH4, THF, reflux, 64%.
3. Resolution of 79 and 80
Introduction
Optical resolution is a process of separation of a racemate into its enantiomer
constituents.32 In resolution method, the point of departure is a racemate, therefore
the maximum yield of each enantiomer is 50%. Several techniques for the resolution
of racemate are available which includes,
a) Resolution by direct crystallization
b) Resolution through formation and separation of diastereomers
c) Resolution through equilibrium asymmetric transformation
Among these methods, resolution through the formation of diastereomers is
most popular technique and is applicable to wide range of compounds. In this
method, the essence of resolution is the differential interaction of the components of
a racemic mixture with the single enantiomer of a chiral compound (the resolving
agent) to form a pair of diastereomeric complex. The nature of diastereomeric
complex could be covalent, ionic, or inclusion type, which have then to be separated
by achiral methods such as preferential crystallization, column chromatographic
separation etc.32b Finally the pure diastereomers have to be decomposed to obtain the
pure enantiomers.
The most practical method for the resolution of racemic amines is the
preparation of diastereomeric salt with optically active acid, and then separation
140
through crystallization.33 To the best of our knowledge, the optical resolution of 79
and 80 is not known in the literature. We have resolved both the molecules through
corresponding diastereomeric salt as described below.
Results and discussion
3.1. Resolution of (±)-79
Initially we examined various resolving agents like (−)-menthoxyacetic acid,
(−)-mandelic acid, (−)-glutamic acid, (1R)-(−)-camphorsulphonic acid, (−)Pyroglutamic acid and (+)-O-acetyl mandelic acid for the resolution of cis-2,3diphenyl morpholine. The salt obtained from (−)-menthoxyacetic acid, (−)-mandelic
acid and (−)-glutamic acid failed to crystallize due to gummy nature. (−)Pyroglutamic acid or (+)-O-acetyl mandelic acid provided resolution, but needed
multiple crystallizations which resulted in low yield (Table 3, entries 1 and 2).
Finally the resolution of (±)-79 was accomplished through sequential use of L- and
D-tartaric acid. It was observed that stoichiometry of the resolving agent affects the
yield as well as enantiomeric excess. A ratio of 1:1 did not provide any resolution at
all (Table 3, entry 3). When (±)-79 and L-(+)-tartaric acid were used in 1:0.5 ratio,
(−)-79 and (+)-79 were isolated in 39% and 42% yields with 94% and 72% ee
respectively (entry 4). Best results were obtained with the ratio 1:0.25 (entry 5). This
proportion separates (−)-79 as salt leaving (+)-79 in solution. Optically enriched and
free amine (+)-79 was then purified through the salt of D-(−)-tartaric acid.
141
Table 3. Resolution of 79 by using various chiral acids.
Ph
O
Resolving agent
(−)-79
Ph
+
(+)-79
N
H
(±)-79
Entry
a
Resolving agent
equiv.
(+)-79
(−)-79
Yield
ee
Yield
ee
(%)
(%)
(%)
(%)
1
(−)-pyroglutamic acid
1
19
>99
-
-
2
(+)-O-Acetyl mandelic acid
1
33
>99
-
-
3
L-(+)-tartaric acid
1
-
a
-
a
4
L-(+)-tartaric acid
0.5
39
94
42
72
5
L-(+)-tartaric acid
0.25
36
99
-
-
6
D-(−)-tartaric acid
0.25
-
-
43
>99
Racemic 79 was obtained.
In an optimized protocol, (±)-79 and L-(+)-tartaric acid (0.25 equiv) were
mixed in ethanol and stirred overnight (Scheme 26). Evaporation of the solvent
followed by addition of diethyl ether and filtration gave tartarate salt.
Recrystallization of crude salt from ethanol provided pure L-tartarate salt in 36%
yield [mp 181-184 oC, [α]25
D ─19.0 (c 0.42, MeOH)]. Basification of the salt using
aqueous NaOH gave (−)-79 ([α]25
D −77.2 (c 2.59, CHCl3)). The (+)- enantiomer was
obtained from mother liquor by similar treatment with D-(−)-tartaric acid. The
obtained crude salt after recrystallization from ethanol provided D-tartarate salt in
43% yield [mp 182-185 oC, [α]25
D +19.7 (c 0.44, MeOH)], which on basification
provided (+)-79 ([α]25
D +76.4 (c 2.59, CHCl3)). Both the enantiomers were obtained
in good yields and high enantiomeric purity after single crystallization of the
corresponding tartarate salts. Optical purity of both the enantiomers was found to be
≥99% by chiral HPLC. Solvent played crucial role in the resolution process as
revealed by the fact that racemic 79 was obtained when the salt was prepared in
methanol.
142
1. recrystallization
solid salt
Ph
O
1. L-(+)-Tartaric acid
(0.25 equiv.)
EtOH
Ph
N
H
2. Et2O
(2R, 3S)-(−)-79
2. aq. NaOH, DCM
1. D-(-)-Tartaric acid
2. recrystallization
(±)-79
filtrate
3. aq. NaOH, DCM
36%, 99% ee
(2S, 3R)-(+)-79
43%, >99% ee
Scheme 26. Resolution of cis-2,3-diphenyl morpholine 79
3.2. Resolution of (±)-80
To resolve the corresponding racemic trans-2,3-diphenyl morpholine 80, first
we examined L-(+)-tartaric acid. However, we could isolate only one enantiomer in
very low yield with 95% enantiomeric excess. Success was achieved using (−)mandelic acid as the resolving agent (Scheme 27). The diastereomeric salt was
prepared by mixing the acid and racemic 80 in methanol. However we could not
Ph
O
+
Ph
(R)-(−)-mandelic acid
N
H
(±)-80
precipitate
MeOH
diastereomeric salt
(DS)
aq. NaHCO3, DCM
39%, 92% ee
preferential
precipitation
(DS)
(2S, 3S)-(−)-80
iso-propanol
1.recrystallization
filtrate
2. aq. NaHCO3, DCM
(2R, 3R)-(+)-80
44%, >99% ee
Scheme 27. Resolution of trans-2,3-diphenyl morpholine 80
separate the diastereomeric salts by crystallization. Gratifyingly, the preferential
precipitation26c method resulted in clean separation. The resulting solid was dissolved
in boiling isopropanol and then stirred at room temperature for 2 h followed by
filtration gave solid salt in 39% yield [mp 175-177 oC, [α]25
D −116 (c 1, MeOH)]. The
purified salt after basification gave (−)-80 (39% yield, [α]25
D −100 (c 2, CHCl3)). The
143
mother liquor from the aforementioned resolution process was evaporated to dryness
and the solid was crystallized from ethyl acetate [44% yield, mp 150-151 oC, [α]25
D
+32 (c 1, MeOH)]. The basification of the salt provided (+)-80 (44% yield, [α]25
D
+102 (c 2, CHCl3)). Enantiomeric purity was determined by chiral HPLC. We
observed higher specific rotation for cis- as well as trans-isomers as compared to the
known values reported in literature27a (see experimental section for details).
4. Application of 2,3-diphenyl morpholines in enantioselective diethylzinc
addition
The enantioselective addition of Et2Zn to aldehydes is one of the most
intensely investigated carbon-carbon bond forming reactions and serves as a test for
new ligands. A variety of ligands such as chiral amino alcohols, amino thiols, amino
disulfides, amino diselenides, diamines and diols, for the asymmetric diethylzinc
addition reactions have been reported.8 Among these chiral β-amino alcohols are
most used ligands. Previously our research group26a had reported conceptually
different and efficient catalytic system viz zinc-amide, derived from oxazolidines
(Scheme 28). In this method, catalyst 91, prepared from oxazolidine ligand 90,
efficiently catalyzed the addition of diethylzinc to benzaldehyde to give (S)-1phenyl-1-propanol 92 with high enantioselectivity.
Ph
Ph
O
Ph
Et2Zn, Toluene
80 oC, 30 min.
N
H
90
(10 mol%)
Ph
O
N
ZnEt
91
Et2Zn, PhCHO
toluene, 0 oC
OH
Ph
(S)-92
85% yield
> 99% ee
Scheme 28. Enantioselective diethylzinc addition catalyzed by chiral zinc-amide
In the proposed mechanism, zinc atom in 91 activates the aldehyde. Due to
steric bulk around oxygen atom, the diethylzinc molecule coordinates to the nitrogen
atom of the catalyst 91 and both the zinc centre becomes tri-coordinate as shown in
figure 4. Transfer of ethyl group from diethylzinc molecule gives enantiopure
alcohol.
144
We anticipated that morpholine based catalytic system would be more
efficient due chelation of both heteroatoms to zinc centre. Both the heteroatoms
(oxygen and nitrogen) in morpholine ligand can co-ordinate with diethylzinc and
forms a tetra-coordinate zinc centre, which could have enhanced nucleophilicity as
compared to tri-coordinate zinc (Figure 5).
Ph
Ph
Ph
Ph
O
N
N
EtZn
O
Zn
EtZn
Et
Et
H
O
Et
Et
O
H
Ph
Ph
(tri-coordinate zinc centre)
Zn
(tetra-coordinate zinc centre)
Figure 4
Figure 5
We examined both the ligands 79 and 80 for the addition of diethylzinc to
benzaldehyde. The results obtained are described below.
Present work
Results and discussion
Chiral zinc-amide was prepared in situ by heating the mixture of diethylzinc
and chiral morpholine ligand [(−)-79 or (−)-80] at 80 oC for 30 minutes according to
the literature procedure.26a Treatment of diethylzinc with benzaldehyde in the
presence of above prepared catalyst (10 mol%) provided alcohol (S)-92. In the case
of (−)-(79), although good yields were obtained only moderate enantioselectivity was
realized (Table 4, entries 1 and 2).
145
Table 4. Enantioselective addition of Et2Zn to benzaldehyde
Ph
O
Ph
N
H
i) Et2Zn, Toluene
80 oC, 30 min.
Ph
O
Ph
N
ZnEt
OH
PHCHO
Ph
toluene:Hexane
(S)-92
(−)-79 or (−)-80
Entry
Ligand
Temp. (oC)
Time (h) Yielda (%)
eeb (%)
(10 mol%)
a
1
(−)-79
0
8
68
40
2
(−)-79
25
4
86
36
3
93
25
2
85
29
4
(−)-80
25
24
73
12
Isolated yield. b Determined by chiral GC analysis.
We have also examined lithium amide 93. Catalyst 93 was prepared by the reaction
of (−)-(79) with BuLi (eq 2). However this modification did not help (entry 3) either.
Trans isomer (−)-80 proved inferior to corresponding cis-isomer.
Ph
O
Ph
N
H
n-BuLi
toluene-hexane
0 oC to RT, 15 min.
Ph
O
Ph
N
Li
(−)-79
(2)
93
At this stage we are unable to provide reason for low enantioselectivity.
However, one of the reasons for moderate results can be explained by intramolecular
coordination of zinc centre to the oxygen atom (Figure 6), which results in the
reduced reactivity of the catalyst.
Ph
N
Ph
Zn
O
Et
Figure 6
146
Section 3B
Attempted resolution of 2,3-diphenylbuatane-2,3-diol
Introduction
Chiral diols are an important class of organic compounds in asymmetric
synthesis because of their applications in various asymmetric transformations. A
variety of chiral 1,2-, 1,3-, and 1,4-diols have been used as chiral auxiliaries, chiral
ligands as well as chiral building blocks in asymmetric synthesis.7 Presence of C2
symmetry axis within the chiral auxiliary / ligand is advantageous, serving the very
important function of reducing the number of possible diastereomeric transition
states to achieve high level of asymmetric induction.7a Consequently synthesis of C2
symmetric chiral diols has been of deep interest. In continuation of our work on
asymmetric catalysis,26 we wanted to explore sterically more demanding C2
symmetric chiral diol such as 2,3-diphenylbuatane-2,3-diol 94 (Figure 7) in
asymmetric synthesis. As described in section-2 of the chapter-2, moderate
enantioselectivity was realized for the enantioselective addition of RZnOAc to
benzaldehyde. We anticipated that use of bulky diol such as 94 will be more effective
for the above transformation.
Me
Ph
Me
Ph
OH
OH
94
Figure 7
Various methods are available in the literature for the synthesis of C2symmetric
chiral
diols.
These
methods
include
resolution,
asymmetric
dihydroxylation, asymmetric reduction, enantioselective Pinacol coupling and other
synthetic transformations.7a
In 1959 Cram et. al.34 reported the synthesis of enantiopure (−)-94 (eq 3). In
this method, the treatment of chiral ketone (−)-95 with methylmagnesium iodide at 0
o
C gives mixture of (−)-94 and corresponding meso-isomer, which upon repeated
crystallization provided enantiopure (−)-94 in 20% yield.
147
OH
Ph
Me
O
MeMgI, Et2O
0 oC, 5 h
Ph
(−)-95
Ph
Me
Ph
Me
OH
(3)
OH
(−)-94
20% yield
To the best of our knowledge, the resolution of 94 is not known in the
literature. The chiral resolution method is advantageous because it provides both the
enantiomers in a single step. The resolution of diols could be accomplished through
diastereomeric esters, or ketals, borate esters and inclusion complexes.7a,35 Tertiary
diols are sensitive to strong acidic as well as basic conditions. Therefore, last two
methods would be more suitable for the resolution of 94 because of the mild reaction
conditions. We examined various resolving agents for the resolution 94. The results
obtained are described below.
1. Attempted resolution of dl-94 through addition complex
The resolution of diol through formation of diastereomeric addition complex
(also called inclusion complex) is a very simple and preferred method. In this
method, the formation of diastereomeric addition complex between diol and the
resolving agent through hydrogen bonding favors the resolution. During 1980’s Toda
et al. have done pioneering work in this area and variety of inclusion complexes of
diols (host compounds) with various organic guest compounds such as alcohols,
ketone, amine, amides, xylene, benzene, CCl4, CHCl3 etc. were reported.36 The X-ray
crystal analysis of these complexes showed that the host and guest molecules are
associated with each other through hydrogen bond formation and van der Wall’s
interactions.37
Some important literature reports for the resolution of diol through addition
complex are described below.
In 1975 Cripps et al.38 reported the resolution of prefluoro(2,3diphenylbuatane-2,3-diol 96 using (−)-cinchonidine 97 as the resolving agent.
Treatment of diol 96 with 97 in CHCl3:hexane gave 1:1 adduct (Scheme 29).
Repeated crystallization of residue followed by treatment with aqueous hydrochloric
acid provided (+)-96. While (−)-96 was obtained from mother liquor. No details for
the yield and optical purity are mentioned.
148
H
C6F5
F3C
HO
OH
C6F5
N
CHCl3:hexane
RT, 3 days
+
OH
F3C
(+)-96
+
(−)-96
N
(±)-96
(−)-97
cinchonidine
Scheme 29. Resolution of diol 96 using cinchonidine
In 1988 Toda et al.39a reported the resolution of BINOL 98 using (+)-2,3dimethoxy-N,N,N',N'-tetramethylsuccinamide 99 as the resolving agent (Scheme 30).
In this procedure, racemic 98 was treated with (+)-99 in benzene:hexane solvent to
give mixture of diastereomeric addition complex. Precipitated complex on
recrystallization
furnished
pure
complex
of
(−)-98
with
(+)-99.
X-ray
crystallographic analysis39b of this complex showed presence of hydrogen bonds
between carbonyl oxygen of 99 and OH-hydrogen of 98. The silica gel column
chromatography of this complex provided (−)-98 with high optical purity. While (+)98 was obtained from filtrate. Using similar strategy, diols 100 and 101 (Figure 8)
were resolved using resolving agents 102 and 103 respectively. Later in 2004 Zhou
et al.39c reported the X-ray crystal structure obtained from (+)-101 and 103.
i) crystallization
ii) silica gel
chromatography
(−)-98
precipitate
OH
(±)-98
36% yield
100% ee
OH
benzene:hexane
+
RT, 12 h
i) silica gel
chromatography
ii) (−)-99
OMe O
Me2N
NMe2
O
OMe
(+)-98
filtrate
(+)-99
Scheme 30. Resolution of 98 using (+)-99
iii) crystallization
iv) silica gel
chromatography
29.5% yield
100% ee
149
O
OH
OH
O
CONMe2
O
CONMe2
(+)-102
OH
O
OMe O
(C6H11)2N
N(C6H11)2
OH
O
(±)-100
(±)-101
OMe
(+)-103
Figure 8
In 1990 Kawashima et al.40a reported the resolution of 98 using (1R,2S)-(−)1,2-diamino cyclohexane 104. In this method, heating the mixture of racemic 98 and
(–)-104 in benzene forms diastereomeric addition complex (Scheme 31). Separation
of these complexes by filtration and recrystallization from benzene followed by
treatment with aqueous hydrochloric acid provided both the enantiomers of 98 in
good yield with high enantiomeric excess.
i) crystallization
ii) aq. HCl
(+)-98
precipitate
NH2
(±)-98 +
NH2
43% yield
94% ee
benzene:hexane
heat
i) crystallization
ii) aq. HCl
(1R,2R)-(−)-104
filtrate
(−)-98
42% yield
96% ee
Scheme 31. Resolution of 98 using (−)-104
In 1991 the same author40b extended the above methodology for the
resolution of various aliphatic 1,2-diols. Racemic trans-cyclohexane-1,2-diol 105
was resolved in moderate ee by using (−)-104 as the resolving agent (Scheme 32).
150
OH
+
(−)-104
i) benzene, heat
ii) filtration followed by
silica gel chromatography
OH
OH
OH
trans-(±)-105
(-)-105
36.4% yield
67% ee
Scheme 32. Resolution of aliphatic diol using (−)-104
Using this method, diols 106, 107, 108 (Figure 9) were also resolved with
good enantiomeric excess.
OH
OH
Ph
OH
OH
OH
Ph
OH
trans-(±)-106
threo-(±)-108
threo-(±)-107
Figure 9
In 1993 Toda et al.41a reported the use of cihchonidium halide salt 109
(Figure 10) as the resolving agent for the resolution of diols. In this protocol, the
H
HO
N
N
R
X
109
109a = R = PhCH2, X = Cl
109b = R = n-Bu, X = Br
Figure 10
mixture of racemic 98 and N-benzyl cinchonidium chloride 109a at room
temperature gave diastereomeric complex (Scheme 33). The X-ray analysis study of
resulting diastereomeric complex showed hydrogen bonding between chloride anion
of 109a and OH-hydrogen of 98 (O-H---Cl, bond distance 3.1−3.2 Ao).41b
151
i) aq. HCl
ii) crystallization
(+)-98
precipitate
MeOH, RT
(±)-98 + 109a
30% yield
100% ee
Diastereomeric
complexes
aq. HCl
filtrate
(−)-98
62% yield
42% ee
Scheme 33. Resolution of 98 using 109a
(+)-Enantiomer of 98 was obtained in good yield with very high enantiomeric purity
by usual separation method. However, corresponding (−)-isomer was obtained from
mother liquor with moderate ee. Author also resolved diol 100 with high optical
purity using 109b as the resolving agent.
One of the disadvantage of the above method was only one enantiomer was
obtained with high enantiomeric purity. Later in 1995 Cai et al.41c described
improved procedure for the resolution of 98. The key success in this method was
selection of suitable solvent. In the modified procedure, heating the mixture of
racemic 98 and 109a (0.55−0.6 equiv) in acetonitrile under reflux gives complex-I
and (−)-98 (Scheme 34). Treatment of complex-I with aqueous hydrochloric acid
provided (+)-98 with >99% ee, whereas (−)-98 was obtained from mother liquor in
good yield with high enantiomeric purity.
109a (0.55−0.6 equiv)
(±)-98
(+)-98 109a
CH3CN, reflux
complex-I
+
(−)-98
>99% ee
aq. HCl
(+)-98
>99% ee
Scheme 34. Modified procedure for the resolution of 98 using 109a
152
Present work
Results and discussion
Various methods are available in the literature for the preparation of diol 94.
42-44
We have prepared dl-94 by manganese mediated pinacol coupling of
acetophenone (Scheme 35), according to the method of Rieke et al.44a Treatment of
anhydrous MnCl2 with lithium metal in the presence of catalytic amount of
naphthalene gave black slurry of highly reactive manganese (Mn*). The reaction of
in situ prepared Mn* with acetophenone gave mixture of dl- and meso isomers in the
ratio of (70:30) in 95% yield. The ratio was determined by 1H NMR by comparison
of the δ value of methyl protons with the literature.44g Recrystallization of the
mixture from ethyl acetate / petroleum ether provided pure dl-94 in 49% yield with
>99% diastereomeric excess.
O
Ph
THF
MnCl2 + Li + Naphthalene
RT, 3 h
Mn*
(cat.)
Highly reactive
manganese
Me
OH
Ph
49% yield
>99% de Me
OH
Ph
dl-94
Me
Me
Ph
Me
Ph
dl
OH
+
OH
Me
Ph
Ph
Me
OH
OH
meso
70:30
(95% yield)
recrystallization
Scheme 35. Preparation of dl-94
Next, we examined various resolving agents for the resolution of 94 (Table
5). Initially we tried (−)-104 as resolving agent. The 1:1 complex of racemic 94 and
(−)-104 was prepared by boiling the mixture in benzene (or toluene). We tried
various solvent for the separation of the addition complex (Table 5, entry 1). For
example, in the case of benzene and cyclohexane, the complex did not crystallize /
precipitate. In petroleum ether formation of gummy mass was observed. We then
tried mixture of pet ether:diethyl ether as the solvent. In this case the complex
became soluble and did not crystallize / precipitate at all. We could not isolate the
addition compound in any of the case. Changing the ratio of diol and (−)-104 from
153
1:1 to 2:1 did not help, racemic diol was recovered (entry 2). Similar kind of results
were obtained in the case of other resolving agents such as (1S,2S)-(−)-1,2diphenylethane-1,2-diamine 110 (Figure 11), (−)-cinchonidine 97 and (+)-cinchonine
111.
Table 5. Attempted resolution of 94 using various resolving agents
Me
Ph
Me
Ph
OH
Resolving agent
OH
x
(+)-94 +
(−)-94
dl-94
Entry
1
2
3
4
Resolving
agent
(−)-104
(−)-104
(−)-110
(−)-110
Ratio
Solvent
1:1
Benzene
cyclohexane
or Complex was highly soluble.
Pet ether
Gummy mass formation
which does not crystallizes.
Per ether:Et2O
2:1
Toluene
Complex was soluble at RT,
no crystallization at −10 oC.
Complex was highly soluble.
1:1
Pet ether
Toluene
Racemic diol was obtained.
Complex was highly soluble.
2:1
Pet ether or Et2O or Racemic diol crystallize out.
PE:Et2O
Toluene
Complex was highly soluble.
5
(−)-97
1:1
6
(+)-111
1:1
a
Result
Toluene:PE
Racemic diol precipitates out.
Toluene or THF or Cinchonidine precipitates out.
CHCl3:PE
or
CHCl3:CH3CN
Toluene or THF or Mixture was not soluble even
CHCl3
at boiling condition
EtOH
Ratio of (±)-94 with resolving agent.
Cinchonine precipitates out.
154
H
Ph
NH2
Ph
NH2
N
HO
N
(−)-110
(+)-111
cinchonine
Figure 11
The reason for the unexpected results was attributed to the formation of weak
hydrogen bonding between diol and the resolving agents. We thought that formation
well defined covalent complex between diol and the resolving agent would provide
the resolution. For this purpose we planned the resolution through formation of
borate complex.
2. Resolution of dl-94 through chiral borate complex
The resolution through borate ester is an attractive method for the preparation
of enantiomerically pure diols due to easy formation or cleavage of boron-oxygen
bond.
In 1996 Shan et al.45a reported the resolution of 98 using quinine 113 as the
resolving agent. In this method, the reaction of racemic 98 with borane-dimethyl
sulfide complex in diethyl ether gave binaphthol borane 112 which upon treatment
with 113 gave diastereomeric borate esters. Hydrolysis of these esters furnished (−)98 and (+)-98 in good yield with high enantiomeric purity (Scheme 36).
155
precipitate
H3B.SMe2
O
Et2O
(−)-98
41% yield
100% ee
113
B H
(±)-98
aq. HCl
O
THF
filtrate
112
aq. HCl
(+)-98
39% yield
100% ee
N
HO
MeO
N
Quinine 113
Scheme 36. Resolution of 98 through borate ester using 113
The same author45b in 1998 described resolution of 98 using boric acid and
(S)-proline (Scheme 37). In this protocol, the mixture of racemic 98 and boric acid
was refluxed for several hours with simultaneous azeotropic removal of water to
obtain binaphthol boric anhydride 114. It was then treated with excess (S)-proline in
THF under reflux to give binaphtholboric acid-(S)-proline complex 115a and 115b,
which upon treatment with sodium hydroxide followed by aqueous hydrochloric acid
provided (+)-98 and (−)-98 respectively in good yield with high enantiomeric purity.
Toluene
O
2 (±)-98 + 2 B(OH)3
azeotropic
distillation
B O B
O
O
O
114
(S)-proline
THF, reflux
i) aq. NaOH
ii) aq. HCl
(+)-98
37% yield
100% ee
H
N
B
O O
O
115a
+
O
H
N
B
O O
i) aq. NaOH
ii) aq. HCl
O
115b
Scheme 37. Resolution of 98 using boric acid and (S)-proline
(−)-98
O
39.5% yield
100% ee
156
In 1999 Periasamy et al.46a described the resolution of 98 using boric acid and
(+)-1-phenylethyl amine 116 (Scheme 38). In this method, the mixture of diol 98,
boric acid and amine (+)-116 was refluxed in acetonitrile to give diastereomeric
borate complex. Author observed that the precipitated and mother liquor borate
complex have different solubilities in acetonitrile and THF, which helped in the
separation of both the enantiomers of 98 with high optical purity.
i) CH3CN,
reflux
precipitate
(−)-98
ii) aq. HCl
Me
(±)-98 + B(OH)3 +
Ph
35% yield
>99% ee
CH3CN
NH2
Reflux
(R)-(+)-116
(1 equiv) (0.5 equiv)
(1.5 equiv)
i) THF,
reflux
filtrate
ii) aq. HCl
(+)-98
26% yield
>99% ee
Scheme 38. Resolution of 98 using boric acid and (+)-116
X-ray crystallographic analysis of the borate complex obtained from mother liquor
revealed that it was a Bronsted acid-amine complex 117 (Figure 12).
O
O
B
O
O
Me
Ph
NH3
117
Figure 12
Later in 2001 the same author46b described the resolution of aliphatic diol
using boric acid and (S)-proline (Scheme 39). In this protocol, first mixture of (S)proline and boric acid was refluxed in benzene (or toluene) for 12 h to give complex,
which on treatment with racemic 2,3-diphenylbutane-1,4-diol 118 under reflux for 12
h furnished diastereomeric borate esters. Precipitated borate complex gave (+)-118 in
157
moderate yield with excellent enantiomeric purity. While borate ester obtained from
filtrate gave (−)-118 with moderate ee.
i) THF, aq. HCl
precipitate
(+)-118
ii) crystallization
12-18% yield
Up to 98% ee
i) toluene or benzene
reflux, 12 h
N
H
COOH
+
B(OH)3
ii) then,
Ph
Ph
OH
OH
(±)-118
reflux, 12 h
i) THF, aq. HCl
filtrate
ii) column
chromatography
(−)-118
26-30% yield
Up to 57% ee
Scheme 39. Resolution of 118 using boric acid and (S)-proline
Present work
Results and discussion
Initially we tried the resolution of dl-94 by using chiral amine (+)-116 and
boric acid. In this experiment, the mixture of dl-94 (2 equiv), boric acid (1 equiv) and
(+)-116 (3 equiv) in acetonitrile was refluxed for 12 h with simultaneous removal of
water by azeotropic distillation (Table 6, entry 1). But the complex formed was
highly soluble
Table 6. Resolution of dl-94 through borate complex
Entry
Resolving agent
Solvent
Result
1
(+)-116
Acetonitrile
no resolution
2
(−)-phenyl glycinol
Toluene
no resolution
3
(S)-proline
Toluene
(−)-94, 29% yield
30% ee
in acetonitrile and did not precipitated / crystallized at all. We then examined (−)phenyl glycinol as the resolving agent. In this case first mixture of diol and boric acid
in toluene was refluxed for 3 h with simultaneous azeotropic removal of water.
Complete dissolution of boric acid indicated the formation of borate complex. The
158
resulting complex was then treated with phenyl glycinol under reflux for 3 h to give
diastereomeric borate complex. We tried various solvent for the separation of this
mixture. For example, in toluene and THF or mixture of solvents like THF:hexane or
hexane:ethyl acetate, the diastereomeric mixture was highly soluble. In the case of
hexane, formation of gummy mass was observed, which does not crystallized.
Finally, we could achieve partial resolution of dl-94 by using (S)-proline as the
resolving agent (Scheme 40).
+
N
H
COOH
B(OH)3
(i) Toluene, Reflux, 12 h
(ii) dl-94, toluene
reflux, 12 h
(S)-Proline
precipitate-1+ filtrate
3N aq. HCl:THF
precipitate-2
(−)-94
RT, 4 h
29%, 30% ee
THF, RT, 24h
precipitate-1
filtrate
Scheme 40. Resolution of 94 using (S)-Proline and boric acid
First, the mixture of boric acid and (S)-proline was refluxed in anhydrous toluene for
12 h with simultaneous azeotropic removal of water. TLC of the reaction mixture
showed that proline has reacted completely. The resulting complex was then treated
with dl-94 under reflux for 12 h. Filtration of the reaction mixture gave precipitate-1,
which was washed with THF to obtain borate ester (precipitate-2) in 37% yield [mp
263−268 oC (dec.), [α]26
D −8 (c 0.5, EtOH)]. Treatment of precipitate-2 with 3N
hydrochloric acid followed by column chromatographic purification provided (−)-94
in 29% yield with 30% ee.
159
Summary:
¾ We have synthesized and resolved all the four stereoisomers of 2,3-diphenyl
morpholine in good yields and high optical purity using tartaric acid and
mandelic acid.
¾ These ligands were examined for enantioselective addition of diethylzinc to
aldehyde and moderate enantioselectivity was realized.
¾ Partial resolution of 2,3-diphenylbutane-2,3-diol could be accomplished
through a chiral borate complex.
160
Experimental Section
General
All the solvents and reagents were purified and dried according to procedures
given in D. D. Perrin’s purification of Laboratory chemicals.47 Diethylzinc was
purchased from Sigma-Aldrich chemical company. Benzaldehyde was freshly
distilled before use. All the reactions were performed in oven dried (120 oC)
glasswares. The reactions were monitored by TLC using silica gel 60 F254 pre-coated
plates. The products were purified by column chromatography on silica gel (100−200
or 230−400 mesh). All melting points were recorded on a Büchi B-540 electro
thermal melting point apparatus and are uncorrected. Optical rotations were
measured on Bellimheam+Standley ADP220 digital polarimeter. IR spectra were
recorded on a Shimadzu FTIR-8400 spectrophotometer. 1H spectra were recorded at
200 MHz with TMS as internal standard. 13C NMR spectra were recorded at 50 MHz
with CDCl3 (δ = 77) as the reference. Micro analytical data were obtained using a
Carlo-Erba CHNS-0 EA 1108 elemental analyzer. Ligand (−)-10448a and (−)-phenyl
glycinol48b were prepared according to the literature procedures. GC analysis was
carried using HP-5 (30m x 0.25 m x 0.25 μ) column. Chiral HPLC was performed
using Kromasil-5-Amycoat column (250 x 4.6 mm).
(±)-Erythro-2-amino-1,2-diphenylethanol (81)
Ph
OH
Ph
NH2
(±)-81
A solution of racemic α-benzoin oxime 87 (11.36 g, 50 mmol) in methanol
(130 mL) was hydrogenated at room temperature and at 50 psi pressure using 10%
Pd/C (0.5 g) for 6 h. Usual work-up28b provided crude solid 10.13 g (95%).
Recrystallization of the solid from methanol gave racemic erythro-2-amino-1,2diphenylethanol 81 as white crystals.
Yield
: 8.53 g (80%)
TLC data
: Rf (20% MeOH/EtOAc): 0.3
Melting point
: 163−165 oC (lit.28a 163 oC).
161
(±)-Erythro-2-(chloroacetylamino)-1,2-diphenylethanol (83)
Ph
OH
Ph
N
H
O
Cl
(±)-83
A two liter round bottom flask equipped with a magnetic stir bar and addition
funnel was charged with 81 (10.67 g, 50 mmol), NaHCO3 (12.6 g, 150 mmol) and
methanol (700 mL). The assembly was cooled to −10
o
C. Freshly distilled
chloroacetyl chloride (4.4 mL, 55 mmol) was added dropwise through addition
funnel over 1 h and the mixture was gradually allowed to warm to room temperature
and stirred for further 2 h. The procedure was repeated by the addition of additional
chloroacetyl chloride (5.6 mL, 70 mmol) in three portions. The reaction mixture was
stirred at room temperature for 24 h. Methanol was then removed on a rotary
evaporator. The residue was suspended in water (300 mL) and stirred for 15 min.
The reaction mixture was then filtered and dried to obtain 83 as a white solid, which
was used for the next step without any purification.
Yield
: 14.18 g (98%)
TLC data
: Rf (30% EtOAc/PE): 0.26
Melting point
: 193-194 oC (lit.27a 187−188 oC)
IR (CHCl3)
: 3321, 3020, 2939, 1647 cm-1
1
: δ 2.43 (d, J = 4.29 Hz, 1 H, OH), 4.06 (ABq, J =
H NMR (CDCl3)
15.28 Hz, 2 H), 5.12 (t, J = 4.29 Hz, 1H), 5.28 (dd, J =
8.46, 4.17 Hz, 1 H), 6.97−7.35 (m, 10 H, ArH), 7.42
(bs, 1H, NH) ppm
Analysis for
: C16H16ClNO2
Calculated (%)
: C, 66.32; H, 5.57; N, 4.83
Found (%)
: 66.61; H, 5.55; N, 4.86
162
(±)-cis-5,6-diphenylmorpholin-3-one (85)
Ph
O
Ph
N
H
O
(±)-85
A two liter round bottom flask equipped with a magnetic stir bar and a reflux
condenser was charged with crude 83 (28.97 g, 100 mmol), KOH (8.41 g, 150 mmol)
and ethanol (700 mL). The reaction mixture was stirred under reflux. After 1.5 h the
mixture was allowed to cool to room temperature. Ethanol was then removed on a
rotary evaporator. To the residue 0.5N aqueous HCl (200 mL) was added and the
mixture was extracted with dichloromethane (1 x 300 mL, 2 x 150 mL). The
combined extracts were washed with brine, dried over Na2SO4 and concentration
under reduced pressure gave 85 as a white solid, which was used for the next step
without any purification.
Yield
: 24.54 g (97%)
TLC data
: Rf (50% EtOAc/PE): 0.29
Melting point
: 181-182 oC (lit.27a 177−179 oC)
IR (CHCl3)
: 3394, 3020, 2885, 1678 cm-1
1
: δ 4.40−4.73 (m, 3 H), 5.15 (d, J = 3.28 Hz, 1 H), 6.70
H NMR (CDCl3)
(bs, 1H, NH), 6.80−7.21 (m, 10 H, ArH) ppm
13
C NMR (CDCl3)
: δ 60.7, 68.4, 78.3, 125.9, 127.6, 127.7, 127.8, 128.2,
136.3, 136.6, 168.8 ppm
Analysis for
: C16H15NO2
Calculated (%)
: C, 75.87; H, 5.97; N, 5.53
Found (%)
: C, 75.71; H, 6.01; N, 5.29
163
(±)-cis-2,3-diphenylmorpholine (79)
O
Ph
Ph
N
H
(±)-79
An oven dried one liter round bottom flask with side arm equipped with a stir
bar, addition funnel and a reflux condenser, was charged with LiAlH4 (8.47 g, 223
mmol). The flask was cooled to 0 oC in an ice bath and 50 mL freshly distilled
anhydrous THF was added under argon atmosphere. To the resulting suspension a
solution of 85 (20.42 g, 80.61 mmol) in 600 mL THF was added dropwise over a
period of 2.5 h. After the addition ice bath was removed and the mixture was heated
at reflux for 16 h. The reaction mixture was cooled to 0 oC, diluted with diethyl ether
(200 mL) and quenched cautiously by dropwise addition of 1 N NaOH (50 mL). The
white solid was removed by filtration. The filtrate was dried over Na2SO4 and
concentrated under reduced pressure to obtain crude sticky mass (14.06 g), which
was then dissolved in ethanol (400 mL) and treated with oxalic acid.2H2O (3.7 g, 0.5
equiv.) and filtered. The resulting oxalate salt after recrystallization from ethanol
followed by basification with aqueous NaOH gave (±)-79 as a white solid.
Yield
: 12 g (62%)
TLC data
: Rf (EtOAc): 0.22
Melting point
: 82-84 oC (lit.27b 82−84 oC)
IR (CHCl3)
: 3325, 3014, 2858, 1490, 1450 cm-1
1
: δ 1.89 (bs, 1 H, NH), 2.72 (dt, J = 12.13, 2.78 Hz, 1
H NMR (CDCl3)
H), 3.16−3.38 (m, 1 H), 3.97 (td, J = 10.73, 2.9 Hz,
1H), 4.16−4.34 (m, 2 H), 5.13 (d, J = 3.29 Hz, 1 H),
7.0−7.50 (m, 10 H, ArH) ppm
13
C NMR (CDCl3)
: δ 40.2, 60.6, 67.7, 79.9, 126.0, 126.6, 126.7, 127.7,
127.8, 129.3, 139.5, 139.8 ppm
Analysis for
: C16H17NO
Calculated (%)
: C, 80.30; H, 7.16; N, 5.85
Found (%)
: C, 80.41; H, 7.38; N, 5.95
164
(±)-cis-1-(2,3-diphenylmorpholino)ethanone (89)
Ph
O
Ph
N
O
CH3
(±)-89
To a mixture of (±)-79 (0.478 g, 2 mmol) and NaHCO3 (0.336 g, 4 mmol) in
10 mL THF:water (1:1) was added freshly distilled acetic anhydride (0.23 ml, 2.5
mmol) dropwise at 0 oC and stirring was continued for 45 minutes. The reaction
mixture was diluted with ethyl acetate (10 mL). The organic layer was separated and
the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined
extracts were washed with water, brine, dried over Na2SO4 and concentrated under
reduced pressure. Recrystallization of the residue from ethyl acetate provided the
white crystals of (±)-89 suitable for single crystal X-ray analysis.
Yield
: 0.38 g (68%)
TLC data
: Rf (50% EtOAc/PE): 0.3
Melting point
: 153−155 oC
IR (CHCl3)
: 3014, 2860, 1635, 1419 cm-1
1
: δ 2.07−2.23 (m, 3 H), 3.35−3.75 (m, 2 H), 3.81−3.98
H NMR (CDCl3)
(m, 1 H), 4.26−4.51 (m, 1 H), 4.83−5.0 (m, 1 H), 6.05
(d, J = 3.53 Hz, 1 H) 7.05−7.56 (m, 10 H, ArH) ppm
Analysis for
: C18H19NO2
Calculated (%)
: C, 76.84; H, 6.81; N, 4.98
Found (%)
: C, 76.62; H, 6.77; N, 4.66
Resolution of (±)-cis-2,3-diphenylmorpholine (79)
To a solution of L-(+)-tartaric acid (1.5 g, 10 mmol) in ethanol (30 mL) was
added a solution of (±)-79 (9.57 g, 40 mmol) in ethanol (160 mL) and the resulting
mixture was stirred overnight at room temperature. Ethanol was then removed on a
rotary evaporator at 40 oC. To the residue diethyl ether (150 mL) was added and the
mixture was stirred for 1 h. Filtration of the reaction mixture provided the tartarate
165
salt (6.52 g), which was recrystallized from ethanol (90 mL) to obtain white crystals
4.53 g (36%), mp 181-184 oC; [α]25
D ─19.0 (c 0.42, MeOH).
The second isomer of morpholine was isolated from mother liquor. After
evaporation of the solvent, the residue was basified with aqueous NaOH and
resulting morpholine was mixed with etherial filtrate of the first step. Combined free
morpholine (6.18 g, 25.82 mmol) was then treated with D-(−)-tartaric acid (1.91 g,
12.72 mmol) in ethanol as described above. The resulting tartarate salt after
recrystallization from ethanol provided white crystals 5.4 g (43%), mp 182-185 oC,
[α]25
D +19.7 (c 0.44, MeOH). Basification of the salt was carried out using aqueous
NaOH to provide the corresponding optically pure morpholines in quantitative yield.
(−)-79 Isomer of morpholine was obtained from (−)-tartarate salt while (+)-79 isomer
was obtained from (+)-tartarate salt.
Yield of (−)-79 isomer
: 3.44 g (36%)
Nature
: White solid
Melting point
: 73−75 oC
[α]25
D
: −77.2 (c 2.59, CHCl3) [lit.27a ─28.3 (c 2.6, CHCl3)]
Ee
: 99% (Kromasil-5-Amycoat column; iPrOH:PE:TFA)
Absolute configuration
: 2R, 3S
Yield of (+)-79 isomer
: 4.11 g (43%)
Nature
: White solid
Melting point
: 73−75 oC
[α]25
D
: +76.4 (c 2.59, CHCl3)
Ee
: >99% ee (Kromasil-5-Amycoat column; iPrOH:PE:TFA)
Absolute configuration
: 2S, 3R
166
(±)-Threo-2-(chloroacetylamino)-1,2-diphenylethanol (84)
Ph
OH
Ph
N
H
O
Cl
(±)-84
The procedure described above for compound 83 was followed for 82 (14.78
g, 69.30 mmol), NaHCO3 (17.44 g, 207.6 mmol), chloroacetyl chloride (12.5 mL,
156 mmol) and THF:MeOH (250 mL).
Yield
: 19.04 g (95%)
Nature
: White solid
TLC data
: Rf (30% EtOAc/PE): 0.28
Melting point
: 149−150 oC (lit.27a 147−148 oC)
IR (CHCl3)
: 3325, 3020, 2950, 1645 cm-1
1
: δ 2.39 (d, J = 3.53 Hz, 1 H, OH), 3.96 (ABq, J =
H NMR (CDCl3)
15.28 Hz, 2 H), 5.06 (t, J = 3.41 Hz, 1H), 5.20 (dd, J =
8.21, 3.54 Hz, 1 H), 7.20−7.42 (m, 10 H, ArH), 7.51
(bs, 1H, NH) ppm
Analysis for
: C16H16ClNO2
Calculated (%)
: C, 66.32; H, 5.57; N, 4.83
Found (%)
: C, 66.33; H, 5.57; N, 4.62
(±)-Trans-5,6-diphenylmorpholin-3-one (86)
Ph
O
Ph
N
H
O
(±)-86
The procedure described above for compound 85 was followed for 84 (21.34
g, 73.64 mmol), KOH (6.2 g, 110.5 mmol), EtOH (443 mL).
167
Yield
: 17.37 g (93%)
Nature
: White solid
TLC data
: Rf (50% EtOAc/PE): 0.44
Melting point
: 185−187 oC (lit.27a 185−186 oC)
IR (CHCl3)
: 3390, 3020, 2897, 1674 cm-1
1
: δ 4.36−4.74 (m, 4 H), 6.30 (bs, 1H, NH), 6.95−7.33
H NMR (CDCl3)
(m, 10 H, ArH) ppm
13
C NMR (CDCl3)
: δ 63.2, 67.9, 82.5, 127.1, 127.4, 128.0, 128.5, 128.6,
136.2, 136.6, 168.7 ppm
Analysis for
: C16H15NO2
Calculated (%)
: C, 75.87; H, 5.97; N, 5.53
Found (%)
: C, 75.65; H, 5.69; N, 5.11
(±)-Trans-2,3-diphenylmorpholine (80)
Ph
Ph
O
N
H
(±)-80
The same procedure described above for compound 79 was followed for 86
(3.6 g, 14.2 mmol), LiAlH4 (1.34 g, 35.3 mmol) and THF (160 mL).
Yield
: 2.17 g (64%)
Nature
: White solid
TLC data
: Rf (EtOAc): 0.38
Melting point
: 85−87 oC
IR (CHCl3)
: 3328, 3018, 2862, 1492, 1450 cm-1
1
: δ 1.83 (bs, 1 H, NH), 3.0−3.13 (m, 1 H), 3.27 (td, J =
H NMR (CDCl3)
11.5, 3.41 Hz, 1 H), 3.77 (d, J = 8.84 Hz, 1H), 3.93 (td,
J = 11.24, 2.65 Hz, 1 H), 4.05−4.16 (m, 1 H), 4.36 (d, J
= 8.84 Hz, 1H) 6.95−7.20 (m, 10 H, ArH) ppm
13
C NMR (CDCl3)
: δ 46.5, 67.4, 67.9, 85.2, 127.3, 127.4, 127.5, 127.6,
127.8, 128.0, 139.0, 140.1 ppm
Analysis for
: C16H17NO
168
Calculated (%)
: C, 80.30; H, 7.16; N, 5.85
Found (%)
: C, 80.29; H, 7.46; N, 5.90
Resolution of (±)-trans-2,3-diphenylmorpholine (80)
To a solution of (±)-80 (7.42 g, 31.03 mmol) in MeOH (120 mL) was added
(R)-(−)-mandelic acid (4.73 g, 31.03 mmol) and the reaction mixture was stirred at
room temperature for 1 h. Methanol was then evaporated on a rotary evaporator. The
resulting salt was dissolved in boiling isopropanol (160 mL). The mixture was then
allowed to cool to room temperature, stirred for 2 h and filtered. The residue was
washed with hot ethyl acetate to obtain one of the diastereomeric salt as a white
precipitate 4.74 g (39%), mp 175-177 oC, [α]25
D −116 (c 1, MeOH). The second
isomer of the salt was obtained from mother liquor by evaporation followed by
recrystallization from ethyl acetate 5.36 g (44%), mp 150-151 oC, [α]25
D +32 (c 1,
MeOH). Basification of the salt was carried out using aqueous NaHCO3 to provide
the corresponding optically pure morpholines in quantitative yield. (−)-80 Isomer of
the morpholine was obtained from the precipitated salt while (+)-80 was obtained
from the salt left in the filtrate.
Yield of (−)-80 isomer
: 2.89 g (39%)
Nature
: White solid
Melting point
: 74−76 oC
[α]25
D
: −100 (c 2, CHCl3)
Ee
: 92% (Kromasil-5-Amycoat column; i-PrOH:PE:TFA)
Absolute configuration
: 2S, 3S
Yield of (+)-80 isomer
: 3.26 g (44%)
Nature
: White solid
Melting point
: 74−76 oC
[α]25
D
: +102 (c 2, CHCl3) [lit.27a +92.7 (c 2.2, CHCl3)]
Ee
: >99% ee (Kromasil-5-Amycoat column; iPrOH:PE:TFA)
Absolute configuration
: 2R, 3R
169
General procedure for the enantioselective addition of Et2Zn to benzaldehyde
To a solution of ligand (−)-79 (0.071 g, 0.3 mmol) in toluene (2 mL) was
added diethylzinc (4.5 mmol, 3.1 mL of 1.45 M solution in hexane) and the reaction
mixture was stirred at 80 oC for 30 min. The resulting solution was cooled to 0 °C,
and was treated with benzaldehyde (0.3 mL, 3 mmol). The reaction mixture was
stirred at room temperature for 4 h, TLC indicated complete absence of
benzaldehyde. The reaction mixture was then cautiously quenched with MeOH (1
mL) followed by 1 N HCl (15 mL) and the mixture was extracted with EtOAc (3 x
10 mL). The combined organic extracts were washed with water followed by brine
and dried over anhydrous Na2SO4. The residue obtained after evaporation of the
solvent was purified by flash column chromatography followed by Kugelrohr
distillation to obtain pure (S)-(−)-1-phenyl-1-propanol.
OH
(−)-92
Yield
: 0.35 g, (86%)
[α]25
D
: − 19.2 (c 5 CHCl3) [lit.26a −46.7 (c 5.1, CHCl3)]
Ee
: 36% (by Chiral GC)
Chiral GC
: CP-Cyclodextrin-B-2,3,6-M-19 capillary column, at
100 oC (1 min.), 20 deg./min., 110 oC (40 min.), 20
deg/min, 230 deg (5 min.) tR = 33.261 min., tR =
34.370 min.
Preparation of (dl)-2,3-diphenylbutane-2,3-diol (94)
Me
OH
Ph
Me
OH
Ph
dl-94
An oven dried three necked one liter round bottom flask was charged with
MnCl2 (25.16 g, 200 mmol), naphthalene (8.09 g, 62.8 mmol) and lithium wire (2.84
g, 410 mmol). The flask was kept in water bath and was added anhydrous THF (500
170
mL), the reaction mixture was then stirred vigorously at room temperature. After 3 h,
black slurry of manganese was obtained. To this mixture acetophenone (11.66 mL,
100 mmol) was added dropwise over 10 minutes and stirred at room temperature for
2 h. The reaction mixture was then cooled to 0 oC and quenched cautiously with 2N
HCl (400 mL). After 30 minutes at room temperature the reaction mixture was
extracted with ethyl acetate (1 x 250 mL, 2 x 150 mL). The combined organic layers
were washed with brine, dried over Na2SO4 and concentrated under reduced pressure.
Naphthalene was separated by filtration column chromatography using pet
ether/ethyl acetate as eluent to give 11.5 g (95%) mixture of dl- and meso- isomers in
the ratio of 70:30 respectively (by 1H NMR). Crystallization of the mixture from
EtOAc/PE (1:9) provided pure dl-94 as a white solid.
Yield
: 5.9 g (49%)
TLC data
: Rf (20% EtOAc/PE): 0.48
Melting point
: 121−123 oC (lit.34 122−124 oC)
IR (CHCl3)
: 3452, 3016, 2935, 1492, 1446 cm-1
1
: δ 1.51 (s, 6 H), 2.59 (s, 2 H, OH), 7.15−7.30 (m,
H NMR (CDCl3)
10H, ArH) ppm
Resolution of dl-94 using (S)-proline
To a 250 mL three neck round bottom flak was added (S)-proline (0.63 g, 5.5
mmol), boric acid (0.34 g, 5.5 mmol) and anhydrous toluene (40 mL). The reaction
mixture was refluxed for 12 h. The liberated water was removed by simultaneous
azeotropic distillation using 4 Ao molecular sieves. During reflux the solid
disappeared completely and the formation of gummy mass was observed. To this
reaction mixture was added dl-94 (1.21 g, 5 mmol, solution in 20 mL toluene). The
reaction mixture was then refluxed for 12 h and filtered to give white solid. The solid
was suspended in anhydrous THF (10 mL) and stirring at room temperature for 24 h
followed by filtration gave borate ester as a white solid in 37% yield (0.67 g, mp
263−268 dec., [α]26
D −8 (c 0.5, EtOH)). Borate ester was suspended in 1:1 mixture
THF:3N aq. HCl and stirred at room temperature for 3 h. The reaction mixture was
then extracted with ethyl acetate. The combined organic organic layer was washed
with brine, dried over Na2SO4 and concentrated on rotary evaporator to give crude
171
diol (0.42 g). Column chromatographic purification of the crude compound using pet
ether/ethyl acetate as eluent provided (−)-94 as a white solid.
Yield
: 0.356 g (29%)
Melting point
: 110−115 oC (for (−)-isomer lit.34 104−105 oC)
[α]25
D
: − 10.3 (c 2.7 EtOH) [lit.34 −34.4 (c 2.7, EtOH)]
Ee
: 30%
Absolute configuration
: 2S,3S
172
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178
NMR Spectra and Chiral HPLC / GC Chromatogram
179
1
H-NMR of compound 83 (CDCl3, 200MHz)
Ph
OH
Ph
N
H
0.00
Cl
1.00
5.30
0.99
5.25
5.20
10.01
1
2.44
2.42
O
83
9.5
4.15
4.07
4.06
3.98
5.31
5.29
5.27
5.25
5.14
5.12
5.10
7.45
7.42
7.27
7.26
7.24
7.06
7.05
7.04
TMS
9.0
8.5
8.0
7.5
7.0
5.15
5.10
1.00
6.5
6.0
5.5
2.08
5.0
4.5
4.0
0.96
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
H-NMR of compound 85 (CDCl3, 200MHz)
Ph
O
Ph
N
H
0.00
5.16
5.15
4.71
4.65
4.63
4.62
4.52
4.43
7.20
7.19
7.13
7.08
6.92
6.91
6.89
6.88
6.85
6.84
TMS
O
85
10.03 0.90
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
1.00
6.0
5.5
5.0
3.09
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
-1.0
180
13
C-NMR of compound 85 (CDCl3, 50.32MHz)
Ph
O
Ph
N
H
60.71
68.48
78.38
77.00
136.64
136.32
128.21
127.82
127.60
125.97
168.84
Chloroform-d
O
85
210
200
190
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
20
10
Ph
N
H
60.71
68.48
O
125.97
O
128.22
127.83
127.75
127.61
Ph
78.39
128.22
127.83
127.61
125.97
DEPT NMR of compound 85
85
129
190
180
170
160
150
140
130
120
128
110
127
100
126
125
90
80
70
60
50
40
30
0
200
9.0
190
180
8.5
Ph
O
Ph
N
H
79
170
8.0
7.5
160
7.0
150
6.5
140
6.0
130
120
1.04
4.0
3.5
10.19
1.00
5.5
5.0
110
2.12
4.5
140
100
1.04
4.0
90
3.5
80
1.03
3.0
2.5
135
70
60
40.21
9.5
1.09
60.61
2.12
129.30
127.80
127.73
126.73
126.63
126.05
N
H
79
67.73
Ph
79.97
77.00
O
139.86
139.55
13
Ph
4.30
4.29
4.26
4.22
4.20
4.02
3.98
3.96
3.92
3.35
3.33
3.29
3.29
3.28
3.27
3.23
3.22
2.76
2.75
2.74
2.69
2.0
130
50
0.00
1.89
5.14
5.13
4.30
4.29
4.26
4.22
4.20
4.19
4.02
3.98
3.96
3.29
3.29
3.27
2.76
2.75
2.74
2.69
1
139.86
139.55
129.30
127.80
127.73
126.63
126.05
7.43
7.42
7.29
7.18
7.17
7.16
7.15
7.14
7.13
7.04
181
H-NMR of compound 79 (CDCl3, 200MHz)
TMS
1.03
3.0
1.39
1.5
1.0
40
0.5
30
0.0
20
-0.5
C-NMR of compound 79 (CDCl3, 50.32MHz)
Chloroform-d
125
10
182
200
1
Ph
O
Ph
N
H
79
190
180
170
160
150
140
130
120
110
100
90
80
70
40.21
60.61
67.75
79.97
129.31
127.82
127.75
126.75
126.06
DEPT NMR of compound 79
60
50
40
30
20
10
0
H-NMR of compound 89 (CDCl3, 200MHz)
Ph
O
Ph
N
O
0.00
2.21
2.17
2.11
4.96
4.95
4.93
4.35
4.30
4.29
3.97
3.95
3.91
3.89
3.85
3.67
3.65
3.55
3.53
3.38
7.50
7.50
7.30
7.26
7.20
7.15
7.14
7.12
7.11
7.10
6.06
6.05
TMS
CH3
89
10.04
10.0
9.5
9.0
8.5
8.0
7.5
7.0
0.68
6.5
6.0
5.5
1.27
1.26 0.991.71
5.0
4.5
4.0
3.5
3.00
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
-1.0
183
1
H-NMR of compound 84 (CDCl3, 200MHz)
Ph
OH
Ph
N
H
0.00
2.40
2.39
4.05
3.97
3.96
3.88
5.23
5.21
5.19
5.17
5.07
5.06
5.04
7.55
7.51
7.36
7.33
TMS
Cl
5.07
5.06
5.04
5.23
5.21
5.19
5.17
O
84
1.00
5.2
9.80
10.0
9.0
8.5
8.0
5.0
1.00
7.5
7.0
6.5
6.0
5.5
5.0
2.05
4.5
4.0
1.02
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
-1.0
-0.5
-1.0
H-NMR of compound 86 (CDCl3, 200MHz)
Ph
O
Ph
N
H
0.00
1.72
4.68
4.64
4.59
4.51
4.48
4.47
4.43
4.38
7.03
7.02
7.02
6.98
6.30
TMS
7.27
7.26
7.25
7.24
7.21
1
9.5
1.00
5.1
O
(±)-86
10.06
9.5
9.0
8.5
8.0
7.5
7.0
0.83
6.5
4.00
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
184
13
C-NMR of compound 86 (CDCl3, 50.32MHz)
190
180
127.14
127.49
63.28
67.97
77.00
82.57
O
(±)-86
200
128.09
N
H
128.64
128.54
Ph
136.26
O
136.61
Ph
136.61
136.26
128.64
128.54
128.09
127.49
127.14
168.78
Chloroform-d
170
136.5
160
150
140
130
120
110
136.0
100
90
129.0
80
70
60
128.5
50
128.0
40
127.5
30
127.0
20
10
67.97
63.28
127.15
N
H
127.50
Ph
128.10
O
128.65
128.55
Ph
82.58
128.55
128.10
127.50
127.15
DEPT NMR of compound 86
O
(±)-86
129.0
190
180
170
160
150
140
130
120
110
100
90
80
70
60
50
128.5
40
128.0
30
127.5
127.0
20
126.5
10
0
185
1
H-NMR of compound 80 (CDCl3, 200MHz)
1.00
1.02
1.04
1.02
10.05
13
0.00
1.03
4.0
9.5
1.83
3.34
3.32
3.28
3.27
3.23
3.21
3.11
3.10
3.10
3.09
N
H
(±)-80
4.12
4.12
4.09
4.08
4.07
4.06
4.00
3.99
3.94
3.93
3.89
3.87
3.80
3.75
4.39
4.34
O
Ph
Ph
4.39
4.34
4.08
4.07
4.06
3.99
3.94
3.93
3.80
3.75
3.28
3.27
3.10
3.10
3.04
7.13
7.12
7.09
7.07
7.03
7.02
TMS
9.0
8.5
8.0
7.5
3.5
1.00 1.04
7.0
6.5
6.0
5.5
5.0
4.5
1.02
3.0
1.03
4.0
3.5
1.06
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
-1.0
C-NMR of compound 80 (CDCl3, 50.32MHz)
128.5
200
190
180
170
160
150
140
130
120
110
100
90
80
46.57
127.64
127.52
127.47
127.33
127.89
67.91
67.47
77.00
N
H
(±)-80
128.08
Ph
O
85.25
Ph
140.12
139.09
128.08
127.89
127.64
127.33
Chloroform-d
128.0
70
60
127.5
50
127.0
40
30
20
10
0
186
200
46.57
N
H
(±)-80
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
H-NMR of compound 92 (CDCl3, 200MHz)
0.95
0.00
4.98
1.87
1.84
1.80
1.77
1.74
1.70
0.95
0.91
0.88
4.63
4.59
4.56
TMS
7.36
7.33
7.31
7.29
7.29
7.26
7.26
1
190
67.91
67.47
O
Ph
Ph
85.24
128.08
127.89
127.65
127.53
127.34
DEPT NMR of compound 80
OH
(-)-92
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
3.27
4.0
3.5
3.0
2.5
2.0
3.00
1.5
1.0
0.5
0.0
-0.5
-1.0
187
H-NMR of compound 94 (CDCl3, 200MHz)
0.00
1.60
1.51
2.59
TMS
7.27
7.25
7.23
7.22
7.16
1
Me
OH
Ph
Me
OH
Ph
dl-94
9.96
9.5
9.0
8.5
8.0
7.5
7.0
1.91
6.5
6.0
5.5
5.0
4. 5
4.0
3.5
3.0
2.5
6.00
2.0
1.5
1.0
0.5
0.0
-0.5
188
Determination of enantiomeric excess for chiral 2,3-diphenyl
morpholines
Ph
O
Ph
N
H
(±)-79
Ph
O
Ph
N
H
(−)-79
>99% ee Kromasil-5-Amycoat column; i-PrOH:PE:TFA (20:80:0.1); 0.5 mL/min.;
220 nm; major isomer: tR = 7.76 min; minor isomer tR = 9.34 min.
189
Ph
O
Ph
N
H
(+)-79
>99% ee Kromasil-5-Amycoat column; i-PrOH:PE:TFA (20:80:0.1); 0.5 mL/min.;
220 nm; minor isomer: tR = 8.10 min; major isomer tR = 9.04 min.
Ph
Ph
O
N
H
(±)-80
190
O
Ph
Ph
N
H
(−)-80
92% ee Kromasil-5-Amycoat column; i-PrOH:PE:TFA (20:80:0.1); 0.5 mL/min.;
220 nm; minor isomer: tR = 9.06 min.; major isomer tR = 10.32 min.
Ph
Ph
O
N
H
(+)-80
>99% ee Kromasil-5-Amycoat column; i-PrOH:PE:TFA (20:80:0.1); 0.5 mL/min.;
220 nm; major isomer: tR = 8.68 min; minor isomer tR = 10.77 min.
191
X-ray Data (Collection, Structure Solution and Refinement)
Single crystal X-ray studies were carried out on a Bruker SMART APEX
single crystal X-ray CCD diffractometer with graphite-monochromatized (Mo
Kα?= 0.71073Å) radiation. The X-ray generator was operated at 50 kV and 30
mA. Diffraction data were collected with ω scan width of 0.3° at different
settings of ϕ (0°, 90°, 180° and 270°) keeping the sample-to-detector distance
fixed at 6.145 cm and the detector position (2θ) fixed at -28°. The X-ray data
acquisition was monitored by SMART program (Bruker, 2003). All the data
were corrected for Lorentzian and polarization effects using SAINT programs
(Bruker, 2003). A semi-empirical absorption correction based on symmetry
equivalent reflections was applied by using the SADABS program (Bruker,
2003). Lattice parameters were determined from least squares analysis of all
reflections. The structure was solved by direct method and refined by full
matrix least-squares, based on F2, using SHELX-97 software package.
(Sheldrick, G. M. Acta Cryst. 2008, A64, 112). Molecular diagrams were
generated using ORTEP-32 (Farrugia, L. J. J. Appl. Cryst. 1997, 30, 565).
192
cis-5,6-diphenylmorpholin-3-one (85)
ORTEP diagram for 85
Crystal data table for compound 85
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system, Space group
Unit cell dimensions
Volume
Z, Calculated density
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Limiting indices
Reflections collected / unique
Completeness to theta = 25.00°
Absorption correction
Max. and min. transmission
C16 H15 NO2
253.29
293(2)
0.71073
monoclinic, P21/c
a = 9.346(12) Å, α = 90°.
b = 5.483(7) Å, β = 104.64(4)°.
c = 26.74(3) Å, γ = 90°.
1326(3) Å3
4, 1.269 Mg/m3
0.084 mm-1
536
0.94 x 0.05 x 0.04 mm
2.25 to 25.00°.
-10<=h<=11, -6<=k<=6, -31<=l<=31
11825 / 2330 [R(int) = 0.1109]
99.7 %
Semi-empirical from equivalents
0.9967 and 0.9253
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices[I>2sigma(I)]
R indices (all data)
Largest diff. peak and hole
Full-matrix least-squares on F2
2330 / 0 / 176
0.982
R1 = 0.0556, wR2 = 0.0990
R1 = 0.1338, wR2 = 0.1179
0.141 and -0.161 e.Å-3
193
cis-1-(2,3-diphenylmorpholino)ethanone (89)
ORTEP diagram for 89
Crystal data table for compound 89
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system, Space group
Unit cell dimensions
Volume
Z, Calculated density
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Limiting indices
Reflections collected / unique
Completeness to theta = 25.00°
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices[I>2sigma(I)]
R indices (all data)
Largest diff. peak and hole
C18 H19 NO2
281.34
297(2)
0.71073
Triclinic, P-1
a = 8.950(4) Å, α = 84.580(7)°.
b = 12.098(5) Å, β = 82.993(7)°.
c = 14.211(6) Å , γ= 81.209(7)°.
1504.9(10) Å3
4, 1.242 Mg/m3
0.081 mm-1
600
0.66 x 0.37 x 0.06 mm
2.85 to 25.00°.
-10<=h<=10, -14<=k<=14, -16<=l<=16
14533 / 5282 [R(int) = 0.0290]
99.5 %
Semi-empirical from equivalents
0.9952 and 0.9487
Full-matrix least-squares on F2
5282 / 0 / 381
1.046
R1 = 0.0437, wR2 = 0.0973
R1 = 0.0580, wR2 = 0.1058
0.148 and -0.131 e.Å-3