Development and Applications of
Hypervalent Iodine Compounds
Powerful Arylation and Oxidation Reagents
Nazli Jalalian
© Nazli Jalalian, Stockholm 2012
Cover Picture: Round-bottomed flask containing iodine.
ISBN 978-91-7447-505-0
Printed in Sweden by US-AB, Stockholm 2012
Distributor: Department of Organic Chemistry, Stockholm University
ii
Det löser sig, det gör det alltid.
[Toran Aghili a.k.a min mamma]
iii
iv
Abstract
The first part of this thesis describes the efficient synthesis of several
hypervalent iodine(III) compounds. Electron-rich diaryliodonium salts have
been synthesized in a one-pot procedure, employing mCPBA as the oxidant.
Both symmetric and unsymmetric diaryliodonium tosylates can be isolated
in high yields. An in situ anion exchange also enables the synthesis of
previously unobtainable diaryliodonium triflates.
A large-scale protocol for the synthesis of a derivative of Koser’s reagent,
that is an isolable intermediate in the diaryliodonium tosylate synthesis, is
furthermore described. The large-scale synthesis is performed in neat TFE,
which can be recovered and recycled. This is very desirable from an
environmental point of view.
One of the few described syntheses of enantiopure diaryliodonium salts is
discussed. Three different enantiopure diaryliodonium salts bearing electronrich substituents are synthesized in moderate to high yields. The synthesis of
these three salts shows the challenge in the preparation of electron-rich
substituted unsymmetric salts.
The second part of the thesis describes the application of both symmetric
and unsymmetric diaryliodonium salts in organic synthesis. A metal-free
efficient and fast method for the synthesis of diaryl ethers from
diaryliodonium salts has been developed. The substrate scope is wide as both
the phenol and the diaryliodonium salt can be varied. Products such as
halogenated ethers, ortho-substituted ethers and bulky ethers, that are
difficult to obtain with metal-catalyzed procedures, are readily prepared. The
mild protocol allows arylation of racemization-prone α-amino acid
derivatives without loss of enantiomeric excess.
A chemoselectivity investigation was conducted, in which unsymmetric
diaryliodonium salts were employed in the arylation of three different
nucleophiles in order to understand the different factors that influence which
aryl moiety that is transferred to the nucleophile.
v
vi
List of Publications
This thesis is based on the following papers, referred to in the text by
their Roman numerals I-VI. Reprints were made with the kind permission
of the publisher. The contribution by the author to each publication is
clarified in Appendix A.
I.
II.
One-Pot
Synthesis
of
Diaryliodonium
Toluenesulfonic Acid: A Fast Entry to
Diaryliodonium Tosylates and Triflates
Zhu, M.; Jalalian, N.; Olofsson, B.
Synlett, 2008, 592-596.
Salts
using
Electron-Rich
Synthesis of Koser's Reagent and Derivatives
Jalalian, N.; Olofsson, B.
Accepted for publication in Org. Synth.
III.
Design and Asymmetric Synthesis of Chiral Diaryliodonium
Salts
Jalalian, N.; Olofsson, B.
Tetrahedron, 2010, 66, 5793-5800.
IV.
Room Temperature, Metal-Free Synthesis of Diaryl Ethers with
Use of Diaryliodonium Salts
Jalalian, N.: Ishikawa, E. E.: Silva, L. F.: Olofsson, B.
Org. Lett., 2011, 13, 1552-1555.
V.
VI.
Metal-Free
Arylation
of Oxygen
Diaryliodonium Salts
Jalalian, N.: Petersen, T. B.; Olofsson, B.
Submitted for Publication
Nucleophiles
Arylation with Unsymmetric Diaryliodonium
Chemoselectivity Study
Jalalian, N.: Malmgren, J.; Olofsson, B.
Manuscript
Salts
with
–
a
vii
viii
Table of Contents
Abstract ........................................................................................................................ v List of Publications ................................................................................................... vii Abbreviations.............................................................................................................. xi 1. Introduction ............................................................................................................. 1 1.1 Hypervalent Iodine Compounds ........................................................................ 1 1.2 Diaryl-λ3-Iodanes ............................................................................................. 3 1.2.1 Structural Features ..................................................................................... 3 1.2.2 Synthesis .................................................................................................... 4 1.3 Applications of Diaryliodonium Salts ............................................................... 7 1.3.1 α-Arylation of Carbonyl Compounds ........................................................ 7 1.3.2 Cross-Coupling Reactions ......................................................................... 8 1.3.3 Arylation of Heteroatom Nucleophiles ...................................................... 9 1.3.4 Other Applications ................................................................................... 10 1.4 Mechanistic Considerations ............................................................................ 10 1.4.1 Chemoselectivity ..................................................................................... 12 1.5 Objective ......................................................................................................... 13 2. One-pot Synthesis of Electron-Rich Diaryliodonium Salts (Paper I).................... 15 2.1 Results and Discussion .................................................................................... 15 2.1.1 Optimization ............................................................................................ 15 2.1.2 Symmetric Salts ....................................................................................... 16 2.1.3 In Situ Anion Exchange ........................................................................... 18 2.1.4 Unsymmetric Salts ................................................................................... 18 2.1.5 Mechanism ............................................................................................... 20 2.2 Conclusion....................................................................................................... 21 3. Large Scale Synthesis of Koser’s Reagent and Derivatives (Paper II) ................. 23 3.1 Synthetic Strategy ............................................................................................ 24 3.2 Optimization .................................................................................................... 24 3.3 Conclusion....................................................................................................... 26 ix
4. Asymmetric Synthesis of Chiral Diaryliodonium Salts (Paper III) ....................... 27 4.1 Synthetic Strategy ............................................................................................ 28 4.2 Results and Discussion .................................................................................... 29 4.2.1 Synthesis of Monosubstituted Chiral Salt I ............................................. 29 4.2.2 Synthesis of Disubstituted Chiral Salt II ................................................. 30 4.2.3 Synthesis of Trisubstituted Chiral Salt III ............................................... 32 4.2.4 Structural Investigations .......................................................................... 33 4.2.5 Arylation of 2-(Ethoxycarbonyl)cyclohexanone ..................................... 35 4.3 Conclusion....................................................................................................... 35 5. Synthesis of Diaryl Ethers (Paper IV and V) ........................................................ 37 5.1 Results and Discussion .................................................................................... 38 5.1.1 Optimization ............................................................................................ 38 5.1.2 Phenylation of Functionalized Phenols ................................................... 40 5.1.3 Arylation of Phenols with Symmetric Diaryliodonium Salts .................. 42 5.1.4 Arylation of Amino Acid Derivatives ..................................................... 45 5.1.5 Arylation of Phenols with Unsymmetric Diaryliodonium Salts .............. 46 5.2 Conclusion....................................................................................................... 48 6. Chemoselectivity Investigation in Arylations of O, N and C Nucleophiles (Paper
VI) .............................................................................................................................. 49 6.1 Results and Discussions .................................................................................. 49 6.2 Conclusion....................................................................................................... 53 Concluding Remarks ................................................................................................. 55 Appendix A ............................................................................................................... 57 Appendix B ................................................................................................................ 58 Acknowledgements ................................................................................................... 65 References ................................................................................................................. 67 x
Abbreviations
Abbreviations are used in agreement with the standard of the subject.1 Only
nonstandard and unconventional abbreviations that appear in this thesis are
listed here.
CALB
DIB
DMP
DPE
EAS
ee
HFIP
HTIB
IBX
mCPBA
Tf2O
TFE
TfOH
TsOH
Candida Antarctica lipase B
(diacetoxy)iodobenzene
Dess-Martin periodinane
1,1-diphenylethylene
electrophilic aromatic substitution
enantiomeric excess
1,1,1,3,3,3-hexafluoro-2-propanol
[hydroxy(tosyloxy)iodo]benzene
2-iodoxybenzoic acid
3-chloroperbenzoic acid
trifluoromethanesulfonic anhydride
2,2,2-trifluoroethanol
trifluoromethanesulfonic acid
p-toluenesulfonic acid
xi
1. Introduction
The first polyvalent iodine compound was reported in 1886 by the German
chemist Conrad Willgerodt, who synthesized (dichloroiodo)benzene from
iodobenzene and chlorine gas.2 Iodine is the largest, most electropositive and
most polarizable element in group 17 of the periodic table.3 As a result of
these properties, iodine can form stable multivalent compounds. Even
though more than a century has passed since hypervalent iodine compounds
were first discovered, they have only recently begun to receive attention as
mild, non-toxic and selective reagents in organic synthesis.4
1.1 Hypervalent Iodine Compounds
A hypervalent state is defined as when an atom expands its valence shell
beyond the limits of the Lewis octet rule. Hypervalent compounds are
common in elements in group 15-18 of the periodic table.5 The oxidation
process of an iodine compound is described in Scheme 1.
L
I
L
+I
L
I
L
L
Oxidation
L
I
L
L
+III
10-I-3
+III
8-I-2
8-I-1
L
Ligand
Association
Oxidation
L
L
I
L
L
L
L L
L I
L L
+V
+V
10-I-4
12-I-5
Ligand
Association
Scheme 1. Oxidation process for iodine compounds.
According to IUPAC nomenclature guidelines, iodine(III) and iodine(V)
compounds are called λ3- and λ5-iodanes respectively. The most common
type of λ3-iodanes are ArIL2, where L is a heteroatom.5 Figure 1a shows the
pseudotrigonal bipyramid T-shaped geometry of λ3-iodanes with two
heteroatom ligands and two free electron pairs. The least electronegative
group, generally the aryl moiety, and the lone pairs of electrons on the iodine
occupy the equatorial positions, while the two most electronegative ligands
occupy the apical positions.5 The linear hypervalent bond in ArIL2 (L-I-L),
which is weaker than normal covalent bonds, is a three-center four-electron
1
(3c-4e) bond formed from the doubly occupied iodine 5pz orbital and one
orbital from each of the apical ligands. As a result of the filled nonbonding
orbital, which is located on the apical ligands, iodine(III) compounds are
electrophilic at the iodine center (Figure 1b).5-6 The highest electron density
is localized at the ends of the 3c-4e-bond axis. Electronegative ligands
therefore have a stabilizing effect on the molecule by withdrawing the
electron density from the bond. X-ray studies have confirmed that in the
solid phase, diaryliodonium salts exhibit T-shaped geometry, whereas the
geometry of the salts in solution differs, depending on both the anion and the
solvent.6
a.
b.
δ−
antibonding orbital
L
δ+
nonbonding orbital
I
bonding orbital
δ− L
L
I
L
Figure 1a. Pseudotrigonal bipyramid geometry of ArIL2. b. Molecular orbitals in the
hypervalent bond.
Hypervalent iodine compounds are widely used in organic synthesis.4c, 5, 7
Examples of well-known iodine(III) compounds with two heteroatom
ligands are shown in Figure 2. The use of iodosylbenzene,
(diacetoxyiodo)benzene (DIB) and [hydroxy(tosyloxy)iodo]benzene (HTIB)
has become increasingly widespread in recent years. These reagents can be
employed not only in oxidations,4a, 4b but also applied in areas such as
functionalization of carbonyl compounds,8 rearrangements9 and
diaryliodonium salt formation.4d, 10
( I
O )n
Iodosylbenzene
AcO
I OAc
HO
I OTs
(Diacetoxyiodo)benzene
[Hydroxy(tosyloxy)iodo]benzene
DIB
HTIB
Figure 2. Well-known iodine(III) compounds.
Dess-Martin periodinane (DMP) and 2-iodoxybenzoic acid (IBX) are
well-known hypervalent iodine(V) compounds that are frequently used in
mild and selective oxidative transformations in total synthesis of natural
products (Figure 3).7, 11 Recently Wirth and coworkers developed a
tetrafluoro-IBX derivative (FIBX) that showed greater solubility in organic
2
solvents, and hence improved reactivity compared to the nonfluorinated
IBX.12
AcO OAc
I OAc
O
O OH
I
O
F
F
O OH
I
O
F
O
O
Dess-Martin periodinane
2-Iodoxybenzoic acid
DMP
IBX
F
O
FIBX
Figure 3. Widely used iodine(V) compounds.
The focus of this thesis is on iodine(III) compounds and their
applications, iodine(V) compounds will therefore not be discussed further.
1.2 Diaryl-λ3-Iodanes
1.2.1 Structural Features
Diaryliodonium salts are air- and moisture-stable compounds,4c which were
first synthesized by Hartmann and Meyer in 1894.13 As shown in Figure 4,
the salts consist of an iodine atom, two aryl moieties and an anion, which not
only influences the solubility, but also the reactivity of the salt. Salts with
halide anions are generally less soluble in organic solvents, while salts with
anions such as tosylate, triflate and tetrafluoroborate exhibit better solubility.
These non-nucleophilic anions are generally also preferred over the halides
in applications. Symmetric salts (R1=R2) are often preferred over
unsymmetric salts (R1≠R2) as issues of chemoselectivity in reactions do not
arise.4c, 14 The chemistry of iodine(III) compounds bearing two carbon
ligands is comparable to that of heavy metal reagents such as HgII, TlIII and
PbIV, as they can undergo reductive elimination. Iodine(III) compounds can
therefore be employed in organic reactions as mild, inexpensive and nontoxic replacements of heavy metals.15
X
I
R1
R2
X = Cl, Br, I, OTf, OTs, BF4, etc
Figure 4. General structure of diaryliodonium salts.
3
1.2.2 Synthesis
The synthesis of diaryliodonium salts has developed considerably in the last
decade. The most common synthetic strategies are shown in Scheme 2. The
synthesis usually requires two or three steps, where the aryl iodide is initially
oxidized to an iodine(III) compound which is isolated, and the
diaryliodonium salts is subsequent
obtained by a ligand exchange
reaction.4c, 4d Typically an anion exchange is required to obtain a suitable
anion. Pre-oxidized iodine compounds can also be employed as starting
materials, and are further reacted with silanes16 or boron reagents17 to yield
diaryliodonium salts, circumventing the electrophilic aromatic substitution
(EAS) step and its inherent regioselectivity restrictions (vide infra).
M = B(OH)2, SiMe3, SnBu3
oxidant
acid
a.
Ar1 I
b.
Ar1 I +
Ar2 H
Ar2 H or Ar2 M
acid
Ar1 IL2
oxidant
acid
X
Ar1
I
Ar2
X
I
Ar1
Ar2
anion exchange
from X to Y
Ar2IY
c.
I2 + 4 Ar H
d. IL3
oxidant
acid
Ar H or Ar M
acid/base
2 X I
Ar
Ar
X
Ar
X
I
Ar
Scheme 2. General strategies for synthesis of diaryliodonium salts.
Basic conditions can be used to generate both symmetric and
unsymmetric diaryliodonium salts, both with organic and inorganic
iodine(III) starting materials. Scheme 3a describes a synthesis that involves a
very unstable intermediate, trans-chlorovinyliodoso dichloride,18 which is
reacted with a lithiated arene to afford symmetric salts in low to good
yields.18 Alkynes can be reacted with (diacetoxyiodo)benzene and
trifluoromethanesulfonic acid (triflic acid, TfOH) to give a more stable
aryl(vinyl)iodonium triflate intermediate,19 which also is treated with a
lithiated arene.20 This method provides unsymmetric salts in moderate to
high yields (Scheme 3b).
4
a.
b.
H
H
R
H
ICl2
ICl3
HCl
Cl
highly unstable
-78 °C
R TfO
I
PhI(OAc)2
TfO
TfOH
Ar-Li
Cl
I
Ar
Ar
32-100%
TfO
Ar-Li
Ph
Ph
I
Ar
67-93%
Scheme 3. Synthesis of diaryliodonium salts under basic conditions.
Beringer and co-workers developed methods whereby iodosyl sulfate,
together with an acid and an arene, was used to prepare symmetric salts in
moderate yields (Scheme 4a).21 More recently, Zhdankin and coworkers
demonstrated the use of inorganic compounds such as (dicyano)iodonium
triflate and iodosyl triflate in the synthesis of diaryliodonium salts.22 The
preformed iodine(III) compound reacts with activated TMS-substituted
arenes to deliver diaryliodonium salts in moderate to high yields (Scheme
4b). The major drawback associated with preparation of diaryliodonium salts
from inorganic iodine(III) compounds is that such precursors are often very
unstable.
HSO4
a.
(IO)2SO4 + 4 ArH
H2SO4
2 Ar
I
X
anion exchange
Ar
2 Ar
I
Ar
39-62%
TfO
b.
O I OTf
+
TMS
2
I
R
R
R
57-93%
Scheme 4. Preparation of diaryliodonium salts from inorganic iodine(III)
compounds.
One of the main limitations of many of the general methods outlined
above arises from the electrophilic aromatic substitution mechanism
operating in the addition of the arene to the iodine(III) intermediate.
Conventional substitution pattern rules apply, i.e. activated arenes show
ortho- and para-selectivity, and in reactions with iodine(III) species a high
para-selectivity is observed (Scheme 5). Deactivated arenes are generally
not reactive enough and result in byproduct formation and decomposition.
5
Major Regioisomer
X
X
I
Activating
IIII
L
+
R
R = EDG
L
R
I
R
R = EWG
X
I
Deactivating
R
+ byproduct formation
Scheme 5. Electrophilic aromatic substitution of ArIL2.
Several efficient one-pot protocols for the synthesis of diaryliodonium
salts have been developed in our group over recent years (Scheme 6).23 The
synthesis of diaryliodonium salts, from either aryl iodides and arenes or by
in situ iodination of an arene using molecular iodine, is illustrated in Scheme
6a.23a-c 3-Chloroperbenzoic acid (mCPBA) is employed as the oxidizing
agent and TfOH is used both to activate the oxidant and to provide the anion
in the salt. This method proved to be very general and simple as the salts
were prepared in only 10 minutes at room temperature and purified by
precipitation with ether from the crude reaction mixture.
A more environmentally benign version of the protocol was subsequently
developed where urea-hydrogen peroxide was used as the oxidant instead of
mCPBA, and Tf2O was used as the activator (Scheme 6b).23d A regiospecific
one-pot reaction, employing mCPBA and boron trifluoride etherate was
developed in order to overcome regiochemistry limitations imposed by the
EAS reaction (Scheme 6c).23e Using an arylboronic acid in place of the
arene, diaryliodonium salts with alternative substitution patterns could be
prepared as an ipso attack of the boron-bearing carbon provides the desired
C-C bond. Symmetric and unsymmetric tetrafluoroborate and triflate salts
could be synthesized in high yields.
6
TfO
Ar1 I + Ar2 H
a.
I
mCPBA, TfOH
or
CH2Cl2, rt, 10 min - 21 h
I2 + Ar H
R1
R2
up to 94%
TfO
I
b.
+
R2
R1
I
H2O2⋅urea, Tf2O
CH2Cl2/TFE, 40 °C, 3 h
R2
R1
up to 86%
B(OH)2
c.
I
R1
mCPBA, BF3⋅OEt2
BF4
R2
CH2Cl2, rt, 30 min
I
R1
rt, 15 min
R2
up to 88%
Scheme 6. One-pot protocols for the synthesis of diaryliodonium salts.
1.3 Applications of Diaryliodonium Salts
1.3.1 α-Arylation of Carbonyl Compounds
α-Arylated carbonyl compounds occur widely in natural products and
pharmaceutically active compounds. Standard procedures for synthesis of αarylated carbonyl compounds often require toxic reagents and/or harsh
reaction conditions.24 The introduction of diaryliodonium salts into this field
enabled the use of milder reaction conditions and eliminated the need for
toxic reagents. In 1960 Beringer and co-workers reported the first αarylation procedure using diphenyliodonium chloride, albeit in low yields
and with diphenylated byproducts (Scheme 7).25
O
OH
O
O
O
O
Ph
Ph2ICl
+
t-BuONa
OH
22%
Ph
Ph
O
23%
Scheme 7. The first reported α-arylation reaction with diaryliodonium salts.
Many α-arylation protocols using diaryliodonium salts have since been
reported. Oh and co-workers demonstrated the arylation of substituted
malonates with various para-substituted diaryliodonium salts in high
yields.26 They observed a transfer of the most electron-deficient aryl group to
the nucleophile in arylations with unsymmetric diaryliodonium salts.
7
There are only a few reports on asymmetric α-arylation of carbonyl
compounds with diaryliodonium salts. Ochiai and co-workers reported the
first asymmetric α-arylation of carbonyl compounds with enantiopure
diaryliodonium salts in 1999. 1,1’-Binaphthyl-2-yl(phenyl)iodonium
tetrafluoroborates were used to arylate β-keto esters in moderate yields and
enantiomeric excesses (Scheme 8).10
O
O
CO2Me
t-BuOK
I
R
CO2Me
Ph
t-BuOH, rt, 20 h
Ph
BF4
37% yield, 53% ee
Scheme 8. Asymmetric phenylation with chiral diaryliodonium salt.
Aggarwal and Olofsson reported a total synthesis of (–)-epibatidine,
where the key step was an asymmetric α-arylation of a substituted cyclic
ketone. Employing the chiral Simpkins’ base enabled the reaction to proceed
in an asymmetric fashion with high diastereoselectivity and
enantioselectivity, albeit in moderate yields (Scheme 9).27
O
1. 2 equiv Ph
2.
Cl
N(Boc)2
Cl
N
N
Li
Ph , THF, -118 oC
HN
N(Boc)2
N
Cl
N
N
DMF, -45 oC
I
Cl
Cl
O
41%, d.r. >20:1, 94% ee
(−)-epibatidine
6 steps
31% overall yield
Scheme 9. Asymmetric synthesis of (–)-epibatidine.
1.3.2 Cross-Coupling Reactions
The outstanding leaving-group ability of iodobenzene makes iodonium salts
more reactive than aryl halides, and the salts are therefore commonly used in
metal-catalyzed cross-coupling reactions. The use of diaryliodonium salts in
C-H bond arylation is an excellent example of how versatile the salts are.
Zaitsev and Daugulis reported selective ortho-arylation of anilides
employing PdII catalysis in high yields (Scheme 10a).28 Phipps and Gaunt
reported a remarkable protocol in 2009, in which anilides where selectively
meta-arylated (Scheme 10b).14c The use of 10 mol% Cu(OTf)2 with
diaryliodonium triflates or tetrafluoroborates resulted in a highly
electrophilic Cu(III)-aryl species, which selectively adds to the arene meta to
the amino substituent, enabling meta-arylated products to be obtained in
8
moderate to good yields. In metal-catalyzed reactions the more electron-rich
or the least sterically hindered aryl group is generally transferred to the
nucleophile.14c, 29
a.
R
HN
Pd(II) catalysis
O
Ph
HN
R
b.
R
O
Ph2IPF6
HN
Cu(II) catalysis
O
Ph2IBF4
Ph
meta-arylation
ortho-arylation
Scheme 10. Ortho- and meta-selective C-H arylation.
There are only a few metal-free C-C cross-coupling reactions reported
with diaryliodonium salts, even though the demand for more
environmentally benign reaction conditions is increasing. The first crosscoupling of unfunctionalized aromatic compounds was reported by Kita.30
The reaction proceeds via an α-thienyliodonium tosylate, and sequential
addition of TMSBr and an arene afforded the biaryl product in high yield
(Scheme 11).
MeO
X
S
I
R1
R2
S
1,3-dimethoxybenzene
TMSBr, HFIP, rt
Ph
R1
R2
OMe
42-98%
Scheme 11. Metal-free cross-coupling reaction.
1.3.3 Arylation of Heteroatom Nucleophiles
The synthesis of diaryl ethers from diaryliodonium salts and phenols was
first reported by Beringer in 1953 (Scheme 12).31 Several protocols have
since been published but the reactions still required prolonged reaction times
and high temperatures.32 Protic solvents such as water are often used, which
is detrimental to the reactivity, as the oxygen nucleophile can hydrogen bond
to the solvent and therefore become less reactive.33
Br
I
PhOH
5 equiv
+
NaOMe (5 equiv)
Ph
O
MeOH, reflux, 24 h
1 equiv
76%
Scheme 12. Original phenylation protocol by Beringer.
9
Nitrogen nucleophiles can be arylated with diaryliodonium salts, as
shown by Carroll and Wood in 2007 (Scheme 13).34 In their arylations with
unsymmetric salts, they observed the transfer of the most electron-deficient
arene in the salt, which also had been observed with other nucleophiles.35
X
I
ArNH2
Ar
+
H
N
DMF, 130 °C, 24 h
50-92%
Scheme 13. Arylation of anilines.
The usage of diaryliodonium salts in the field of fluorine-18 labeling has
increased intensively.36 [18F]fluoride ions can be introduced onto both
electron-rich and electron-deficient arenes by a reaction with diaryliodonium
salts. The need for reagents such as [18F]F2 is therefore avoided.
1.3.4 Other Applications
Diaryliodonium salts are mostly used in arylation reactions but they
nevertheless find applications outside this field. Kitamura and co-workers
reported generation of benzynes through diaryliodonium salts in 1999
(Scheme 14).37 The benzyne intermediate could be trapped with various
dienes to give cycloaddition products in high yields. Diaryliodonium salts
have also been employed in photochemistry,38 polymerizations39 and
macromolecular chemistry.40
O
TMS
I
Ph
Bu4NF
O
TfO
Scheme 14. Benzyne generation with hypervalent iodine.
1.4 Mechanistic Considerations
Chen and Koser proposed a mechanism for the formation of α-phenyl
ketones from silyl enol ethers, in which they postulate that an enolate
performs a nucleophilic attack on the iodine with either the oxygen or the
carbon, giving intermediate A or B respectively (Scheme 15).41 The αarylated product is then obtained through either a reductive elimination or a
radical reaction.
10
A
A
OLi
Ph
I
X
Ph
O
R3
R1
OLi
Ph
R3
R1
B
R2
B
Ph
I
and/or
R1
Ph
I
Ph
R2 R3
R2
O
Ph
I
Ph
O
R3
R1
I
Ph +
R1
R2 R3
R2
Scheme 15. Suggested mechanism for α-arylation of carbonyl compounds.
Ochiai and coworkers performed a mechanistic study on the phenylation
of β-keto ester enolates with diaryliodonium salts. An aryl radical trap was
added to the reaction without affecting the outcome, which indicates that
radical pathways are unlikely.42
More recently, computational studies have indicated that an enolate reacts
either with a neutral iodine(III) molecule A or a cationic compound B, which
would lead to an O-I intermediate (C) or a C-I intermediate (D) respectively
(Scheme 16). However, the isomerization barrier between the two different
pathways is small and thus a fast equilibrium between C and D is likely. The
product is formed via a [2,3] rearrangement from the O-I intermediate and a
[1,2] rearrangement from the C-I intermediate, with the first pathway being
favored.
L
Ar
A
I
Ar
L
Ar
+
R
I
Ar
C
O-I bond
forms
B
O
Ar
I
[2,3]
Ar
R
O
O
fast
R
C-I bond
forms
O
I
R
D
Ar
Ar
[1,2]
Ar
Scheme 16. Calculated reaction pathways in the arylation of enolates.
Ozanne-Beaudenon and Quideau reported a thorough investigation on
dearomatization of phenols with diaryliodonium salts, where they discounted
the radical mechanism.43 Addition of a radical scavenger
11
(1,1-diphenylethylene, DPE) to their system did not affect the outcome of
the reaction and therefore a radical mechanism is unlikely.
1.4.1 Chemoselectivity
When using unsymmetric salts it has been shown that the most electrondeficient aryl group is transferred to the nucleophile with varying
selectivities (Scheme 17). A fast pseudorotation occurs between
intermediates A and B, which provides two different transition states C and
D.10 A partial negative charge will develop as the nucleophile interacts with
the ipso carbon of the aryl group that is to be transferred. The more electrondeficient aryl group will be more able to stabilize this negative charge than
the more electron-rich aryl group, which makes transition state D more
favorable. The electron-rich aryl group can also stabilize the positive charge
on the iodine(III) more effectively than an electron-deficient aryl group.42
Nu
EDG
A
Nu
δ+
Nu
I
EDG
δ−
Minor path
I
C
EWG
I
+
EDG
EWD
Nu
I
EWG
Ψ
Nu
δ+
Nu
I
EWG
EWG
B
δ−
D
EDG
Major path
I
EDG
Favored
+
EWG
EDG
Scheme 17. Chemoselectivity of the reductive elimination.
The so-called ortho-effect can sometimes be seen in reactions between a
nucleophile and a diaryliodonium salt where one aryl ligand is orthosubstituted. In such reactions the ortho-substituted arene is often transferred,
even if it is more electron-rich.44 This can be rationalized by the most bulky
aryl ligand and the two lone pairs occupying the equatorial position for steric
reasons in the Nu-I intermediate (Scheme 18). This will lead to a reductive
elimination and transfer of the aryl group situated in the equatorial position,
with a substituent in ortho position, even though it is the more electron-rich.
12
Nu
I
I
Me
Nu
+
Me
Scheme 18. T-shaped model of the iodine(III) intermediate.
1.5 Objective
The objective of this thesis has been to develop a wide range of synthetic
procedures for the preparation of hypervalent iodine(III) compounds. We
envisaged a facile one-pot synthesis of electron-rich diaryliodonium salts as
a further development of the previous one-pot procedures. The developed
protocols were assumed to aid the synthesis of novel hypervalent iodine
compounds that had previously been difficult to synthesize.
The chemistry of hypervalent iodine(III) compounds in organic synthesis
was thought to be broadened by employing products from the developed
protocols in applications such as arylation reactions.
13
14
2. One-pot Synthesis of Electron-Rich
Diaryliodonium Salts (Paper I)
The TfOH-mediated protocol previously developed within the group was not
without limitations.23a, 23b The synthesis of diaryliodonium salts from
electron-rich precursors proved problematic due to over-oxidation of the
arenes under the highly acidic conditions (see Scheme 6a). We therefore
aimed at finding conditions that would enable the one-pot synthesis of
electron-rich diaryliodonium salts. It was hypothesized that use of a weaker
acid would prevent over-oxidation of electron-rich arenes, enabling the
synthesis of electron-rich salts.
2.1 Results and Discussion
2.1.1 Optimization
A number of acids were screened together with molecular iodine, anisole
(1a) and mCPBA, in hope of finding a suitable acid for the synthesis of
electron-rich diaryliodonium salt 2a (Table 1). TfOH and perchloric acid
were too reactive as expected, while both p-toluenesulfonic acid (TsOH) and
trifluoroacetic acid (TFA) gave promising yields at elevated temperatures
(entries 1-4). Further optimization was carried out using TsOH (entries 6-9).
The yield was improved from 73% to 89% by carrying out the reaction at
room temperature for 14 h (entry 6). The stoichiometry of acid was also
optimized and it was found that 3 equivalents of acid were sufficient for
obtaining obtain the desired salt in good yields (entries 7-9). Slow
decomposition of the product was observed upon prolonged heating (cf.
entries 8 and 9).
15
Table 1. Screening of acids and optimization.a
mCPBA, HX
I2 + 4
OMe
CH2Cl2
X
I
2
MeO
1a
OMe
2a
Acid (equiv)
Temp (°C)
Time
Anion (X)
Yieldb (%)
1
TfOH (4)
0
10 min
OTf
0c
2
HClO4 (4)
rt
30 min
ClO4
0c
3
TsOH (4)
80
10 min
OTs
73
4
TFA (6)
60
30 min
O2CCF3
64
5
AcOH (6)
60
1h
OAc
0
6
TsOH (4)
rt
14 h
OTs
89
7
TsOH (3)
rt
14 h
OTs
87
8
TsOH (2)
rt
14 h
OTs
75
9
TsOH (2)
80
14 h
OTs
61
Entry
a
I2 (1 equiv), 1a (4 equiv) and mCPBA (3 equiv) in CH2Cl2 were used in all
reactions. b Isolated yields. c Black tar was formed, no product could be isolated.
2.1.2 Symmetric Salts
The optimized reaction conditions were applied to various arenes to explore
the scope of the developed procedure (Table 2). Thiophene afforded salt 2b
in acceptable yield, both at room temperature and at 40 ºC (entries 2 and 3).
Since the alkyl-substituted arenes are less electron-rich, the reactivity of
these arenes is lower and either longer reaction times or elevated
temperatures were needed to obtain salts 2c-f (entries 4-8). Toluene gave a
regioisomeric mixture of the symmetric salt 2f and the unsymmetric salt 2f’
in a 2:1 ratio due to the possibility of iodination occurring both para and
ortho to the methyl substituent (entry 8). Unfortunately, diphenyliodonium
tosylate 2g could not be obtained directly from molecular iodine and
benzene.
2,2,2-Trifluoroethanol (TFE) had previously been reported to enhance the
reaction rate of hypervalent iodine compounds with arenes.45 This
phenomenon was also observed in this reaction when a 1:1 mixture of TFE
and CH2Cl2 was used as the solvent. Higher yields were obtained than in
pure CH2Cl2 for some of the salts (entry 7 and Table 3).
16
Table 2. Application to various arenes.a
ArH + I2
mCPBA, TsOH⋅H2O
TsO
CH2Cl2
Ar
I
2
1
Entry
Arene 1
Ar
Temp
(°C)
Time
rt
14 h
Yield
(%)b
Product 2
TsO
1
1a
MeO
2
3
I
MeO
S
1b
1b
rt
40
2a
89
2b
2b
66
68
2c
59
2d
66
2e
2e
10
76
2f
2f’
49d
2g
0e
OMe
TsO
14 h
15 min
I
S
S
TsO
4
1c
rt
20 h
I
TsO
5
1d
80
1h
6
7c
1e
1e
rt
80
18 h
30 min
t-Bu
I
TsO
I
t-Bu
t-Bu
TsO
I
8
1f
80
10 min
TsO
I
TsO
9
1g
80
1h
I
a
Iodine (1 equiv), 1 (4 equiv), mCPBA (3 equiv) and TsOH (3-4 equiv) were used in
all reactions. b Isolated yields of 2. c TFE was used as co-solvent. d Regioisomeric
mixture (2:1). e No reaction took place.
17
Unfortunately, the facile purification in the previously developed
procedure with TfOH, where ether was added to the concentrated crude
reaction mixture to precipitate the salt, could not be applied to this
procedure. Since an excess of TsOH is needed in the reaction, the treatment
with ether also precipitated the remaining TsOH and the salts had to
consequently be purified by column chromatography.
2.1.3 In Situ Anion Exchange
Diaryliodonium triflates are generally more desirable than the corresponding
diaryliodonium tosylates, due to the non-nucleophilic properties of the
triflate anion.14a, 14b, 46 Therefore an investigation was carried out in order to
see whether an anion exchange from the tosylate 2a to the triflate 3a could
be achieved. Fortunately, it was discovered that addition of one equivalent of
TfOH at room temperature to the crude reaction mixture, after complete
conversion to the tosylate salt, followed by 1 hour of stirring resulted in a
complete in situ anion exchange, yielding 3a in 71% (Scheme 19). The in
situ anion exchange provides a one-pot route for the synthesis of electronrich diaryliodonium triflates that are unobtainable by the TfOH-mediated
reaction (see Scheme 6a).
TfO
TsO
+ I2
MeO
)2 I
mCPBA, TsOH⋅H2O
rt, 1 h
40 °C, 15 min
MeO
MeO
1a
)2 I
TfOH
2a
3a 71%
Scheme 19. In situ anion exchange.
2.1.4 Unsymmetric Salts
The one-pot procedure mediated by TsOH could also deliver unsymmetric
salts 5 from aryl iodides 4 and arenes 1 in high yields (Table 3). Iodobenzene
4a was reacted with biphenyl 1h to give salt 6b (entry 3). This salt was not
accessible previously via the TfOH-mediated protocol.23a, 23b Alkylsubstituted arenes could also be employed, affording the corresponding salts
in good to excellent yields (entries 4-8). Notably, synthesis of
diphenyliodonium tosylate 2g was achieved from 4a and benzene in 85%
yield (cf. Table 2, entry 9 and Table 3, entry 8), which indicates that the
iodination step is more difficult than the oxidation.
1-Iodonaphtalene, which is both electron-rich and sterically hindered,
was also successfully employed, affording unsymmetric salt 5h on reaction
with mesitylene, albeit in moderate yield (entry 9).
18
Table 3. Synthesis of diaryliodonium salts from aryl iodides.a
Ar1I + Ar2H
4
Entry
1
c
TsO
mCPBA, TsOH⋅H2O
Ar1
I
Ar2
TfOH
TfO
rt, 1 h
Ar1
5
1
ArI 4
ArH 1
4a
5a
6a
100
100d
5b
98
5c
6b
50
48d
5d
97
5e
79
5f
72
5g
79f
I
2g
85f
I
5h
34
I
1a
TsO
4a
I
1b
S
X
3
e
4c,e
Yield (%)b
Salt 5/6
OMe
2e
Ar2
6
X
I
I
4a
I
1h
Ph
Ph
TsO
4a
I
1c
TsO
5c,e
4a
I
1d
TsO
6
4a
1e
I
t-Bu
TsO
7
4a
1f
8
4a
1g
I
TsO
TsO
9
e
I
4b
1c
a
4 (1 equiv), 1 (1 equiv), mCPBA (1 equiv) and TsOH (1-2 equiv) in CH2Cl2.
Isolated yields of 5. c The arene was added after 1 h. d Isolated yields of 6 after in
situ anion exchange. e TFE was used as co-solvent. f NMR yield, salt could not be
separated from TsOH.
b
19
To prevent side reactions between the oxidant and the arene, this reaction
was initially run in a stepwise manner, with formation of
[hydroxy(tosyloxy)iodo]benzene (Koser’s reagent, HTIB)47 and subsequent
addition of the arene 1c. However, in this case the one-pot procedure proved
to be more efficient than the stepwise protocol, which failed to yield 5h.
All reactions were found to be completely regioselective yielding only
para-substituted salts. Using TFE as a co-solvent simplified the purification,
as 1 equivalent of TsOH was now sufficient and treatment of the crude
reaction mixture with ether precipitated the pure salt.
The in situ anion exchange could also be employed in the synthesis of
unsymmetric salts. In the case of both salts 6a and 6b the anion exchange
took place in almost quantitative yield (entries 1 and 3).
The main limitation of this novel protocol became apparent when
employing more electron-deficient arenes, such as fluorobenzene, where
tosylate salt 5i was identified as the only product (Scheme 20). This is the
product of a reaction between oxidized iodobenzene and the aryl moiety of
TsOH, rather than with the desired fluorobenzene.
TsO
I
mCPBA, TsOH⋅H2O
+
F
I
CH2Cl2, 80 °C
5i
Scheme 20. Byproduct formation by reaction with TsOH.
2.1.5 Mechanism
The mechanism for the synthesis of diaryliodonium salts has not been
established but a proposed mechanism is shown in Scheme 21. The
iodoarene attacks the protonated mCPBA, forming a reactive iodine(III)
compound, which is further activated with a second equivalent of TsOH. An
electrophilic aromatic substitution reaction then occurs between the arene
and the highly reactive hypervalent iodine compound, completing the
synthesis.
20
mCPBA
Activation
TsOH
Ar
HO
O
I
H2O
O
H
OH
TsOH
I
Oxidation
Activation
TsO
mCBA
TsO
OTs
R
I
TsO
I
R
EAS
Scheme 21. Proposed mechanism for the synthesis of diaryliodonium salts.
2.2 Conclusion
An efficient one-pot synthesis of both electron-rich and electron-neutral
diaryliodonium salts has been developed, employing TsOH in combination
with mCPBA. Both symmetric and unsymmetric salts can be synthesized in
high yields, either starting with molecular iodine and arene or with iodoarene
and arene. The tosylate salts can easily be converted to previously
unobtainable electron-rich diaryliodonium triflates with a simple in situ
anion exchange. We have later discovered that an aqueous anion exchange
with NaOTf works as well (see appendix B)
21
22
3. Large Scale Synthesis of Koser’s Reagent
and Derivatives (Paper II)
The first synthesis of [hydroxy(tosyloxy)iodo]benzene (HTIB) was reported
in 1970 by Neilands and Karele.48 Gerald Koser discovered and developed
several applications of this iodine(III) compound, which is now commonly
referred to as “Koser’s reagent” in the chemical literature. The range of
applications with this versatile reagent expanded over the following decades
to include oxidation of olefins, ring contractions and expansions,
dearomatization of phenols, synthesis of iodonium salts, and α-oxidation of
carbonyl compounds (Figure 5).4c, 4d, 30, 49
S
Ar
O
S
HO
I OTs
R
ArH
O
R
OTs
R
R
TMS
ArH
TsO
R
CH(OMe)2
I
TsO
R
I
R
Ar
Figure 5. Applications of HTIBs in organic synthesis.
In the one-pot synthesis of diaryliodonium tosylates described in Chapter
2, the likely intermediate is a Koser’s reagent derivative (see Scheme 21),
which is not isolated but further reacted with an arene to deliver the salt. Our
group subsequently developed a fast and efficient synthesis of a wide range
of electron-deficient and electron-rich HTIBs starting with either an
iodoarene or molecular iodine and an arene (Scheme 22).50 The reaction
rates were increased compared to previously reported oxidations of
iodoarenes by the use of TFE as co-solvent. The method represented the first
synthesis of HTIBs directly from iodine and an arene.
23
HO I OTs
I
mCPBA, TsOH⋅H2O
R
CH2Cl2/TFE 1:1, rt
R
up to 95%
I2 +
2
R1
mCPBA (3 equiv)
R2SO2OH (2 equiv)
CH2Cl2/TFE 1:1, rt
HO I OSO2R3
2
R1
up to 88%
Scheme 22. Previously developed protocol for the synthesis of HTIBs.50
3.1 Synthetic Strategy
The previously developed methodology utilized a CH2Cl2/TFE (1:1) solvent,
which has been widely used in hypervalent iodine chemistry to enhance
reaction rates.45b, 50-51 In large-scale syntheses designed for the industry, it is
of great importance to bear in mind the environmental aspects of a protocol,
as well as health and safety concerns.52 When designing a large-scale
reaction, it is desirable to have both high atom economy and to make use of
non-toxic and recyclable solvents and reagents where possible.
We set out to develop a large-scale synthesis where the chlorinated
solvent was avoided due to its toxicity, and carried out the reactions in neat
TFE. Since the change in solvent would also increase the total cost of the
reaction, the TFE should be recovered and recycled, which is also preferable
from an environmental point of view.
3.2 Optimization
Initially, iodobenzene (4a) was used as a substrate to determine whether the
desired reaction could be performed in neat TFE (Scheme 23). The result
was promising as 82% of the desired product 7 was isolated, which is
comparable to the original protocol (94% yield). The lower yield can be
explained by the fact that pure TFE can promote other reaction pathways as
well, such as SET mechanisms.45b
24
I
I OTs
HO
mCPBA (1 equiv)
TsOH⋅H2O (1 equiv)
TFE, rt, 35 min
7 82%
4a, 1 equiv
Scheme 23. Initial optimization reaction in neat TFE.
As HTIBs are used as electrophiles in various organic reactions, an
electron-deficient analogue of Koser’s reagent can enhance the reactivity of
the substrate and 3-iodobenzotrifluoride (4c) was therefore selected as the
model substrate for further optimization reactions.53
The oxidization of an iodine(I) compound to iodine(III) by mCPBA is not
generally initiated until acid is added to activate the oxidant. The mixing
order of the different reagents can thus become a concern, with electron-rich
arenes, as a fast exothermic reaction can occur. To make a more general
procedure we therefore decided to firstly dissolve the mCPBA and the
iodoarene in TFE and subsequently add TsOH. After completion of the
reaction, the solvent was removed and diethyl ether was added to the crude
reaction mixture to precipitate the product that was filtered and washed with
additional diethyl ether.
A small time and temperature study was performed, which revealed that a
slightly elevated temperature was required to obtain product 8 in high yield
(Table 4, entries 1-2). Reduced yield was observed however with longer
reaction times at 40 °C (entry 3). The reaction was somewhat sensitive to
temperature, as the yield decreased when the reaction was conducted at 80
°C, possibly due to partial decomposition of the product (entry 4).
Table 4. Temperature and time optimization.a
I
HO
mCPBA (1 equiv)
TsOH⋅H2O (1 equiv)
TFE (0.1 M)
F3C
I OTs
F3C
4c
8
Entry
Temp (°C)
Time (h)
Yield (%)
1
rt
2
67
2
40
1
90
3
40
2
83
4
80
1
76
a
mCPBA (1 equiv) and 4c (1 equiv) was dissolved in TFE, followed by addition of
TsOH (1 equiv).
25
Due to the decomposition of the product at elevated temperature, the
recovery of TFE by distillation had to be performed at reduced pressure
(86 mmHg at 40 °C). The optimized reaction conditions were applied to a
large-scale synthesis as shown in Scheme 24. The length of the condenser
turned out to be critical to recovering the solvent in appreciable quantities.
Only a sufficiently long condenser was able to collect adequate amounts of
the solvent (>90%) due to the low boiling point of TFE (77-80 °C at 760
mmHg). The product was precipitated from the crude residue by addition of
diethyl ether, after removal of the solvent by distillation. As 8 is nearly
insoluble in TFE the product could be isolated without distillation of the
solvent if solvent recovery is of no interest.
I
mCPBA (1 equiv)
TsOH⋅H2O (1 equiv)
TFE (65 mL), 40 °C, 1 h
F3C
4c
4.62 g
HO
I OTs
F3C
8
7.45 g 95%
Scheme 24. Optimized reaction conditions for the large-scale synthesis of 8.
3.3 Conclusion
A large scale synthesis of [hydroxy(tosyloxy)iodo]-3-trifluoromethylbenzene
8 was developed where neat TFE was used as the solvent. The solvent can be
recovered and recycled, which is desirable from an environmental point of
view. The optimized large-scale protocol was repeated several times and the
desired product was constantly obtained in 94-95% yield, which indicates
high reproducibility of the procedure.
26
4.
Asymmetric
Synthesis
Diaryliodonium Salts (Paper III)
of
Chiral
The synthesis of organic compounds with an α-arylated carbonyl moiety is
of considerable interest. It has been shown that many compounds with these
features possess interesting pharmacological and biological properties.54
There are two main ways of synthesizing these compounds from an enolate:
nucleophilic aromatic substitution,55 which is limited by the necessity of
electron-withdrawing substituents on the aryl moiety, and transition metal
catalysis.56 Although the transition metal-catalyzed α-arylation reactions are
fairly efficient, they suffer from disadvantages including cost and toxicity. In
addition, the reactions are often run at elevated temperatures and the reaction
times are relatively long. The reactions are also often limited to form only
quaternary centers.57
Reactions employing diaryliodonium salts offer milder reaction
conditions, less toxic reagents and easier handling, which makes the
reactions more attractive, not only from an environmental but also from an
industrial point of view. There have recently been several reports on the
application of diaryliodonium salts in metal-mediated asymmetric αarylation of carbonyl compounds with excellent results,29 however there are
only a few examples of asymmetric reactions in which chiral enantiopure
diaryliodonium salts are employed.
Ochiai and co-workers reported the synthesis of enantiopure
1,1’-binaphthyl-2-yl(phenyl)iodonium tetrafluoroborates in 1999, by
treatment of a preoxidized iodine(III) compound with a stannane.10 Zhdankin
and co-workers have also reported an enantiomerically pure salt, which was
synthesized in a similar fashion (Figure 6).58
I
R
TfO
O
Ph
BF4
MeO
O
Ochiai 1999
I
Ph
N
H
Zhdankin 2003
Figure 6. Enantiopure diaryliodonium salts in the literature.
27
As there are only a few reports on the asymmetric α-arylation of carbonyl
compounds, we set out to develop the synthesis of three enantiopure
diaryliodonium salts, which would subsequent be used in arylation reactions.
4.1 Synthetic Strategy
When unsymmetric diaryliodonium salts are employed, it has been shown
that the most electron-deficient aryl moiety will generally be transferred to
the nucleophile in the reductive elimination.10b, 26, 35b We therefore envisioned
a diaryliodonium salt where one of the aryl moieties would be more
electron-rich and have substituents bearing stereocenters. The substituents
would be located ortho to the iodine and possess steric bulk in order to
promote asymmetric induction in the transfer of the other, more electrondeficient aryl group to the nucleophile. When using the chiral salt in an αarylation reaction, the chiral aryl iodide would be recovered and reoxidized,
re-forming the chiral salt so that the reaction proceeds with good atom
economy (Scheme 25).
O
R
O
1. Base
2.
∗
Ar
X
I
Ph
∗
Ar
R
I
Ph
recover and reoxidize
Scheme 25. Expected chemoselectivity in the arylation of enolates.
Figure 7 shows the structures of the three salts that we set out to
synthesize. The previously developed one-pot synthesis of electron-rich
diaryliodonium salts, mediated by TsOH and mCPBA (Chapter 2), was
thought to be suitable for the synthesis of the planned electron-rich salts
I-III. The protocol would also enable the reoxidation of the recovered
enantiopure iodoarene. This strategy had to be abandoned however, as many
problems were encountered in the synthesis of the three target compounds,
and we had to change approach several times.
28
( )5
( )5
O
( )5
O
X
I
O
X
I
( )5
O
I
II
X
I
O
O
III
( )5
( )5
( )5
O
OH
I
OH
I +
( )5
Figure 7. Retrosynthetic analysis.
4.2 Results and Discussion
4.2.1 Synthesis of Monosubstituted Chiral Salt I
An enzymatic kinetic resolution of alcohol 9 with CALB (Candida
Antarctica lipase B) and isopropenyl acetate (10) as acyl donor afforded
enantiopure alcohol (R)-9 in 42% yield and >99% ee (Scheme 26).59 A
catalytic amount of Na2CO3 was found to be crucial for complete
conversion. The reason is that the weak base prevents isopropenyl acetate
from hydrolyzing into acetic acid and acetone in presence of water in the
reaction mixture. The reverse reaction, whereby the resulting acetate 11 is
hydrolyzed, is also prevented in the presence of Na2CO3.
OAc
OH
( )5
rac-9
10
CALB
Na2CO3, i-Pr2O
OH
( )5
OAc
+
(R)-9
42%, >99% ee
( )5
11
Scheme 26. Enzymatic kinetic resolution of 2-octanol.
The enantiopure alcohol was mesylated to give (R)-13 in 99% yield. 2Iodophenol (12) was then alkylated with (R)-13 to deliver the desired
iodoarene 14, with no loss of enantiomeric purity (Scheme 27). Attempts to
oxidize 14 using the TsOH protocol proved to be problematic, possibly due
to steric hindrance from the ortho-substituent.
The oxidation was instead accomplished using the boronic acid protocol,
(see Scheme 6c) with some slight modifications. As attempts to oxidize 14 at
29
ambient temperature in the presence of BF3⋅OEt2 led to decomposition,
pre-oxidation of 14 had to be accomplished with mCPBA at elevated
temperature, followed by cooling to −78 °C and addition of phenylboronic
acid and BF3⋅OEt2. Diaryliodonium salt 15 and 16 could then be isolated in
modest yield (Scheme 27). Salt 16 which is not separable from 15, is a
byproduct which can be explained by incomplete oxidation of 14, resulting
in a competing undesired EAS reaction between 14 and the iodine(III)
intermediate.
( )5
OMs
OH
O
( )5 (R)-13
I
1. mCPBA, 80 °C
I
K2CO3, MeCN
12
2. PhB(OH)2,
BF3.OEt2, -78 °C
14 93%, >99% ee
( )5
( )5
O
I
O BF4
I
BF4
+
I
O
15 17%
16 ≤ 9%
( )5
Scheme 27. Synthesis of monosubstituted diaryliodonium tetrafluoroborate.
As it was clear that the substituent was acid-sensitive and byproduct
formation was detected, we decided to change strategies and use basic
conditions. Lithiation of 14, followed by reaction with vinyliodonium triflate
17,20a yielded the enantiopure diaryliodonium triflate 18 (Scheme 28,
Pe = Pentyl).
Pe
( )5
I
TfO
O
I
n-BuLi
THF
H
TfO
( )5
Ph
17
O
I
TfO
Et2O, -78 °C to rt
14
18 38%
Scheme 28. Synthesis of monosubstituted triflate salt 21.
4.2.2 Synthesis of Disubstituted Chiral Salt II
Several conventional sets of reaction conditions were examined for the
alkylation of 2-iodoresorcinol (19)60 with either mesylate rac-13 or the
30
corresponding tosylate rac-22. However, the results were poor and unreacted
starting materials could always be recovered. The most encouraging result
was obtained with the use of alcohol rac-9 under Mitsunobu conditions,61
which yielded iodoarene 20 in 33% yield (Scheme 29a.). Attempts to oxidize
20 with the TsOH protocol proved again to be problematic since the
substituents in ortho position did not tolerate the acidic conditions.
Decomposition was observed even at low temperatures and using BF3⋅OEt2
and phenylboronic acid gave similarly negative results. The characteristic
protons on the aliphatic oxygen-bearing carbon atoms could never be
detected in 1H-NMR of the crude product.
( )5
OH
OH
I
a.
OH
( )5 rac-9
( )5
O
Et3N, PPh3,
DIAD, THF
O
mCPBA, acid
I
PhH or PhB(OH)2
O
O
( )5
( )5
Target II
20 33%
19
( )5
OTs
OH
Br
b.
( )5 rac-22
K2CO3, MeCN
OH
( )5
O
O
Br
1. n-BuLi
B(OH)2
O
2. B(OiPr)3
O
( )5
21
X
I
23 24%
Target II
( )5
24 99%
Scheme 29. Attempted synthesis of disubstituted salt II.
As both the synthesis of 20 and further conversion to the desired target
salt II proved to be difficult we decided to change approach and employ the
boronic acid protocol.23e Alkylation of 2-bromoresorcinol62 with tosylate
rac-22 afforded disubstituted bromoarene 23, which was subsequently
lithiated and treated with triisopropyl borate to finally afford arylboronic
acid 24 (Scheme 29b). Unfortunately, all attempts at converting 24 to the
corresponding diaryliodonium salt failed, both when using the one-pot
method previously developed in the group23e and when applying preformed
iodine(III) reagents such as (diacetoxyiodo)benzene or Koser’s reagent.17b
We were once again forced to change approach and use the basic
conditions, which had proved fruitful in the synthesis of the monosubstituted
salt. The disubstituted salt was synthesized from 23 in 44% yield by
lithiation and subsequent reaction with 17 (Scheme 30).
31
TfO
Pe
I
TfO
23
O
Ph
TfO
I
17
H
n-BuLi
THF
( )5
Et2O, -78 °C to rt
O
( )5
24 44%
Scheme 30. Successful synthesis of 24.
This methodology was then repeated with enantiomerically pure material.
Dialkylation of 2-bromoresorcinol with mesylate (R)-13 proved to be the
most efficient way to obtain the required dialkylated bromoarene 25 (89%
yield, Scheme 31). Bromoarene 25 was subsequently treated with BuLi and
17, furnishing the disubstituted target compound 26 in 36% yield.
( )5
OMs
OH
OH
O
I
TfO
( )5 (R)-13
Br
TfO
Pe
Br n-BuLi
THF
O
K2CO3, MeCN
21
( )5
O
Ph
TfO
17
H
I
Et2O, -78 °C to rt
O
( )5
( )5
25 89%
26 36%
Scheme 31. Synthesis of enantiopure disubstituted diaryliodonium salt 26.
4.2.3 Synthesis of Trisubstituted Chiral Salt III
Synthesis of the trisubstituted salt proved to be far more straightforward.
Commercially available phloroglucinol (27) was alkylated with rac-13, in
the same fashion as previously, to provide compound 28 in 72% yield
(Scheme 32). As the arene was symmetric, no regioselectivity issues had to
be taken into account, and Koser’s reagent (7) could be reacted with 28 to
give the desired diaryliodonium tosylate 29 in 96% yield.16
( )5
OMs
OH
( )5
HO
OH
Ph
O
rac-13
K2CO3, MeCN
( )5
OH
I
7
( )5
CH2Cl2, -10 °C
O
O
27
TsO
I
( )5
O
O
( )5
28 72%
Scheme 32. Synthesis of the trisubstituted racemic salt 29.
32
O
OTs
( )5
29 96%
However, alkylation of 27 with enantiopure (R)-13 proved to be
unachievable. The optimized reaction conditions shown in Scheme 32 did
not yield the desired product and provided mainly mono- and dialkylated
arenes. The procedure was therefore abandoned and as an alternative route a
nucleophilic aromatic substitution was performed on trifluorobenzene (30)
with enantiopure (R)-9 to afford compound 31 in 51% yield (Scheme 33).
Compound 31 was subsequently reacted with Koser’s reagent (7) to afford
the enantiopure trisubstituted diaryliodonium salt 32 in 82% yield.
( )5
OH
F
( )5
F
F
( )5
OH
Ph
O
(R)-9
I
7
O
OTs
NaH, NMP, 100 °C
( )5
CH2Cl2, -10 °C
O
O
30
TsO
I
( )5
( )5
O
O
( )5
31 51%
(R,R,R)-32 82%
Scheme 33. Synthesis of enantiopure diaryliodonium salt 32.
The enantiopurity of 31 or 32 proved to be difficult to determine by chiral
GC or HPLC and the reaction between 31 and Koser’s reagent reagent was
believed to not affect the enantiopurity. A nucleophilic aromatic substitution
was therefore performed on fluorobenzene (33), under the same conditions
used for the alkylation of 30 (Scheme 34). As the enantiopurity was retained
after the model nucleophilic aromatic substitution, the enantiomeric excess
of compound 31 was also expected to be >99.99%.63
OH
( )5
F
(R)-9
NaH, NMP, 100 °C
33
O
( )5
34 >99% ee
Scheme 34. Nucleophilic aromatic substitution on fluorobenzene.
4.2.4 Structural Investigations
The surprising difference in the synthesis of 29 and 32 led us to investigate
the different structures of the salts. In the racemic synthesis of the
trisubstituted salt, three different diastereomers can be formed (Figure 8).
33
( )5
( )5
O
( )5
O
TsO
I
( )5
O
O
TsO
I
( )5
O
( )5
O
O
TsO
I
O
O
( )5
( )5
( )5
(R,R,R)-29
+
(R,S,R)-29
+
(R,R,S)-29
+
(S,S,S)-29
(S,R,S)-29
(S,S,R)-29
Figure 8. Possible diastereomers of 29.
Figure 9 shows a selected region in the 13C-NMR spectra of 29 and 32,
where the ortho- and para-substituted carbons are clearly differentiated. The
NMR data indicate that two diastereomers of 29 are formed,
(R,S,R/S,R,S)-29 and (R,R,S/S,S,R)-29. This indicates that there is a
diastereoselective synthesis of only the (R,S,R/S,R,S) diastereomer of arene
28, as only two unsymmetric diastereomers of 29 are detected. This
conclusion also explains the different reactivity observed in alkylations of
27 with racemic and enantiopure mesylate 13. The third alkylation becomes
more difficult, due to steric hindrance, and thus the conditions needed to be
modified for the enantiopure synthesis.
( )5
H C
( )5
O
H C
TsO
I
H
C
( )5 O
29
O
C ()
5
H
O
TsO
I
H
( )5
C
O
C
O
32
H
Figure 9. Characteristic peaks in 13C-NMRs of 29 (green) and 32 (red).
34
( )5
4.2.5 Arylation of 2-(Ethoxycarbonyl)cyclohexanone
Due to the lack of reports on the successful asymmetric α-arylation of
ketones with diaryliodonium salts with high enantioselectivity in the
literature, we decided to investigate our enantiopure diaryliodonium salts in
reactions with β-keto esters, a substrate that has previously been used with
some success.10b, 26 The results obtaining with salt 32 were not encouraging
as the product was obtained with both low yields and enantiomeric purity
(Scheme 35). One explanation for the poor results could be a ligand
exchange in the salt, as recently reported in the literature (see Chapter 6).64
O
O
O
OEt
1. t-BuOK, t-BuOH
2. (R,R,R)-32
O
OEt
Ph
18% yield, 10% ee
Scheme 35. Attempts toward asymmetric arylation of a carbonyl compound.
4.3 Conclusion
Three different enantiopure diaryliodonium salts were synthesized in
moderate to high yields. The route toward the three salts varies depending on
the structure of the salts. Few examples of enantiopure salts are reported in
the literature and the syntheses of these are more difficult than of
enantiopure iodine(III) compounds with two heteroatom ligands.
The enantiomerically pure trisubstituted salt 32 was used in an αarylation of a β-keto ester with poor results. Further mechanistic
investigations need to be performed in order to design chiral salts that are
able to induce high enantioselectivity in arylation reactions.
35
36
5. Synthesis of Diaryl Ethers (Paper IV and V)
Diaryl ethers are compounds of great importance in organic chemistry and
numerous naturally occurring and synthetic compounds that contain this
substructure are biologically active (Figure 10).65
OH
H2N
O
O
HO
HN
O
N
H
I
O
Cl
H
N
O
OH
NH2
O
Synthroid
HO
O
O
I
O
OH
HO
I
HO
I
Cl
O
O
O
N
H
O H N
2
OH
O
H
N
O
N
H
HO
H
N
O
OH
Rodgersinol
O
HO
OH
OH
Vancomycin
HO
Figure 10. Important diaryl ethers.
The conventional method for synthesizing diaryl ethers is the classic
Ullmann ether synthesis, with the major drawbacks being harsh reaction
conditions and stoichiometric amounts of copper.66 Recently, there have
been many modified Ullmann-type reactions reported, with slightly milder
reaction conditions and copper used in catalytic amounts.67 With the
introduction of copper(II)-catalyzed cross-coupling reactions of phenols with
arylboronic acids, diaryl ethers could be obtained in higher yields at room
temperature.67-68 Pd-catalyzed coupling of phenols with aryl halides has also
been intensely investigated over the last decade. Buchwald and co-workers
recently reported a catalytic system that employs a reactive Pd source, that in
combination with a ligand allows the synthesis of diaryl ethers under
relatively mild reaction conditions.69
As mentioned in Chapter 1, the first synthesis of diaryl ethers from
diaryliodonium salts and phenols was reported by Beringer in 1953.31 The
37
more recent protocols still utilize protic solvents that influence the reactivity
of the nucleophiles.33 We anticipated that the use of polar aprotic solvents
would increase the rate of the reaction between the diaryliodonium salt and
the oxygen nucleophile. To this end, it was envisaged that varying the anion
of the diaryliodonium salt, to improve the solubility in polar aprotic solvents
would have a significant impact on the reaction, as would the nature of the
solvent itself.
5.1 Results and Discussion
5.1.1 Optimization
The initial optimization reactions were performed using diphenyliodonium
triflate 3b and phenol 35a as model substrates. Aprotic solvents were
examined and reactions with DMF, toluene, THF and dichloromethane all
gave high conversions (>90%), within 4 hours at room temperature, using
NaH as base. Acetonitrile gave significantly lower conversion and was
therefore discarded. We also wanted to avoid halogenated solvents such as
dichloromethane. THF was therefore regarded as the optimal solvent seeing
that toluene and DMF both have high boiling points and DMF is further
considered to be carcinogenic.
Optimization reactions were performed and the results are listed in Table
5. Strong inorganic bases such as NaH, NaOH, KOH, t-BuOK and t-BuONa
provided the desired diaryl ether at room temperature, within 4 h and in
almost quantitative yields (entries 1-5). Weak inorganic bases such as
K2CO3, Na2CO3 and K3PO4 were less efficient in the synthesis of the ether
(entries 6-8). These outcomes are probably due to the low solubility of these
bases in THF. Raising the reaction temperature to 40 °C afforded the product
in quantitative yields within 15 min using either NaOH or t-BuOK (entries
10 and 11). The reaction could also be carried out at room temperature with
longer reaction times to give the product in high yields (entries 12 and 13).
The effect of the anion of the salt was also investigated. It was shown that
salts with OTf, BF4 and Br anions afforded the product in high yields (entries
9, 14 and 15), whereas employing the tosylate salt resulted in the formation
trace amounts of product, and the reaction mixture turned black as soon as
the salt was added (entry 16). This result could be rationalized by the
formation of byproducts by radical reactions as full conversion of the salt to
iodobenzene could be observed, but not the corresponding arylated phenol.
This theory was supported as the diphenyl ether could be isolated in 88%
yield after addition of a radical scavenger (DPE) (entry 17),70 while addition
of DPE to a reaction with the triflate salt did not affect the outcome of the
reaction (entry 18).
38
Table 5. Optimization of the model reaction.a
OH
O
1. Base, THF
2. Ph2IX
35a
36a
Entry
Base
Salt (X)
T (°C)
Time
Yield
(%)b
1
NaH
3b (OTf)
rt
4h
93
2
NaOH
3b (OTf)
rt
4h
>99
3
KOH
3b (OTf)
rt
4h
>99
4
t-BuOK
3b (OTf)
rt
4h
97
5
t-BuONa
3b (OTf)
rt
4h
99
6
K2CO3
3b (OTf)
rt
4h
32
7
Na2CO3
3b (OTf)
rt
4h
1
8
K3PO4
3b (OTf)
rt
4h
6
9
NaOH
3b (OTf)
40
1h
99
10
NaOH
3b (OTf)
40
15 min
>99
11
t-BuOK
3b (OTf)
40
15 min
>99
12
t-BuOK
3b (OTf)
rt
2h
95
13
t-BuOK
3b (OTf)
rt
1h
85
14
NaOH
37a (BF4)
40
1h
>99
15
NaOH
38 (Br)
40
1h
>99
16
NaOH
2g (OTs)
40
1h
<1
17c
NaOH
2g (OTs)
40
1h
88
18c
t-BuOK
3b (OTf)
40
15 min
>99
NaOH
2g (OTs)
40
1h
89
t-BuOK
3b (OTf)
40
30 min
82
19
d
20e
a
To a solution of base (1.1 equiv) in THF was added 35a (1.1 equiv) at 0 °C and the
mixture was stirred for 15 min. Ph2IX (1 equiv) was added and the reaction was
stirred at the tabulated temperature and time. b Determined by GC with 1,4dimethoxybenzene as internal standard. c DPE (1 equiv) was added. d Toluene was
used as solvent. e All reagents added at once, without deprotonation time.
39
Performing the reaction with the tosylate salt in toluene, which is known
to act as a radical scavenger,71 yielded the product in 89% without need for
DPE (entry 19). Adding the salt to the reaction mixture before allowing the
base to fully deprotonate the phenol resulted in a slight decrease in yield
(entry 20).
5.1.2 Phenylation of Functionalized Phenols
The scope of the method was explored by phenylation of substituted phenols
with diphenyliodonium triflate 3b and tetrafluoroborate 37a. Diaryl ether
36a could be obtained in excellent isolated yield at 40 °C, from either salt
(Table 6, entries 1 and 2). High yields were also obtained by using NaOH or
performing the reaction at room temperature (entries 3 and 4). Phenols
containing electron-withdrawing substituents could be phenylated in high
yields (entries 5-7), and this was also the case for phenols with electrondonating substituents (entries 8-10).
One of the major concerns with metal-catalyzed arylation reactions are
issues with the chemoselectivity when the starting materials bear more than
one halogen substituent.65a Pentachlorophenol was however phenylated in
excellent yield with the developed methodology (entry 11). Additionally,
para-chlorophenol and both para- and ortho-iodo phenol were phenylated in
equally high yields (entries 12-14). Ortho-substituted phenols are also
problematic substrates in metal-catalyzed reactions but these compounds
were phenylated in high yields (entries 15-17), illustrating the potential of
this methodology. Carbonyl-substituted ethers were synthesized both at
room temperature and at 40 °C, in moderate to high yields (entries 18-22).
Both heteroatom containing and vinyl-substituted phenols can also be
phenylated and ethers 36q and 36r were isolated in high yields (entries 23
and 24).
40
Table 6. Phenylation of functionalized phenols.a
OH
O
1. t-BuOK , THF
R
2. Ph2IX (3b/37a)
R
35
Entry
Phenol 35
36
Salt
T
(°C)
Yield
(%)b
Product 36
TfO
OH
1
I
35a
O
40
36a
93
36a
36a
36a
98
95
99
36b
82
36c
68
36d
72
36e
36e
96
99
36f
79
36g
99
36h
97
36i
87
36j
89
36k
75
3b
2
3c
4
5
6
7
8
9
BF4
35a
35a
35a
F3C
OH
NO2
OH
NC
OH
MeO
OH
OH
10
37a
40
40
rt
35b
3b
40
35c
3b
40
35d
3b
40
35e
37a
37a
40
rt
35f
3b
40
I
F3C
O
NO2
O
NC
O
MeO
O
O
MeO
MeO
Cl
Cl
11
Cl
OH
Cl
Cl
35g
3b
40
Cl
O
Cl
Cl
Cl
Cl
OH
12
35h
3b
Cl
Cl
OH
13
35i
3b
I
OH
35j
3b
40
OH
O
I
I
15
O
40
I
14
O
40
35k
3b
40
O
41
16
OH
17d
18
19
20
21
22
OH
OH
35
m
3b
40
O
35l
3b
40
O
O
35n
3b
37a
40
rt
O
OH
OH
35o
EtO
O
37a
37a
40
rt
37a
40
3b
40
OH
O
35p
N
H
OH
23
35q
N
a
b
O
O
EtO
O
89
36l
99
36n
36n
75
80
36o
36o
97
91
36p
67
36q
87
36r
93
O
O
N
H
O
N
OMe
OMe
24
O
36
m
OH
35r
3b
40
O
35 (1.0−1.1 equiv), t-BuOK (1.1 equiv), and 3b/37a (1.0−1.2 equiv) were used.
Isolated yields. c NaOH as base. d 2 equiv of 3b.
5.1.3 Arylation of Phenols with Symmetric Diaryliodonium Salts
The scope of the methodology was further investigated by employing
functionalized phenols and symmetric diaryliodonium salts (Table 7).
Electron-deficient salt 37b was used to arylate 35a, delivering
CF3-substituted ether 36b in 90% yield (entry 1). Electron-rich salt 3a was
used to prepare dimethoxy-substituted aryl ether 36s (entry 2). As mentioned
previously, the synthesis of sterically hindered diaryl ethers can be
problematic in metal mediated reactions. However, using this methodology
ortho-substituted salts 37c and 37d were used to arylate phenols 35a and
35d respectively, delivering the desired ethers in good yields (entries 3-5).
To our delight, introducing even more steric bulk to the salt 3c did not
influence the outcome of the reaction and trimethyl-substituted diaryl ether
36w was isolated in almost quantitative yield (entry 6). However, further
increasing the steric bulk in the ortho-position of the phenol resulted in a
slight reduction in yield (cf. entries 8-9).
42
Salt 3d was also employed in a large-scale synthesis of ether 36x, which
was isolated in 98% yield (entry 7). The resulting 4-tert-butyliodobenzene
that is produced as a byproduct in this reaction could be recovered in
quantitative yields and easily oxidized to reform the salt, providing better
atom economy in large-scale reactions. The mild protocol also allows the
synthesis of ether 36aa, which is a common substructure in pharmaceutics,
in excellent yield from quinolin-8-ol (entry 10).
Polybrominated diphenyl ethers (PBDEs) are a class of compounds that
are widely used as flame retardants. Polyhalogenated diaryl ether 36ab was
synthesized in 80% yield under the mild reaction conditions (entry 11).
Additional diaryl ethers with alkyl substituents were also synthesized in
excellent yields (entries 12-15).
Table 7. Arylation of functionalized phenols with diaryliodonium salts.
OH
R1
Entry
X
2.
35
O
1. t-BuOK, THF
R1
R2
I
R2
36
R2
Phenol
35
Product
36
Salt
BF4
OH
I
F3C
1
35a
O
CF3
Yield
(%)b
CF3
37b
36b
I
O
90
TfO
OH
2
MeO
MeO
OMe
35f
3a
F
3
MeO
35a
BF4
OMe
86
36s
F
F
I
O
37c
36t
72
BF4
4
35a
NC
I
O
37d
36u
OH
5
NC
90
O
37d
35d
90
36v
43
TfO
I
OH
6
35k
O
3c
99
36w
TfO
I
7
c
35a
t-Bu
O
t-Bu
t-Bu
3d
98
36x
TfO
I
OH
8
Cl
t-Bu
O
Cl
35s
t-Bu
Cl
3e
36y
t-Bu
OH
9
t-Bu
O
3e
t-Bu
t-Bu
Cl
35t
81
36z
N
N
OH
10
99
O
3e
98
Cl
35u
36aa
Br
Br
TfO
Br
Cl
Br
35v
MeO
Br
Cl
3f
80
36ab
MeO
OH
12
O
I
OH
11
O
37d
>99
35e
36ac
TfO
I
13
MeO
O
35e
93
3g
36ad
TfO
I
14
35e
MeO
3h
O
90
36ae
TfO
I
15
35e
3c
a
MeO
O
96
36af
35 (1.0−1.1 equiv), t-BuOK (1.1 equiv), and 3/37 (1.0−1.2 equiv) were used at
40 °C. b Isolated yields. c Performed on a 3.1 mmol scale.
44
5.1.4 Arylation of Amino Acid Derivatives
Diaryl ethers bearing racemization-prone amino acid residues are found in
many natural products with medicinal properties.72 Classical Ullmann-type
couplings tend to racemize the amino acid moiety, due to the generally harsh
reaction conditions. Our mild protocol was therefore applied to the arylation
of L-tyrosine derivative 36ag (Scheme 36a). The standard conditions were
demonstrated to be adequate, affording the desired product in 95% yield and
99% ee. However, when the same conditions were used for the arylation of
the racemization-prone 4-hydroxy-D-phenylglycine (35x),73 only small
quantities of the desired product could be isolated. Surprisingly, an
unexpected byproduct was isolated and later identified as the
tetrahydrofuranylated phenol 39 (Scheme 36b).
Boc
a.
OH
NH
MeO
2. Ph2IOTf
40 °C, 35 min
O
OH
Boc
O
1. t-BuOK, THF
2. Ph2IBF4
40 °C, 2 h
MeO
NH
O
NH
MeO
35w
O
b.
Boc
1. t-BuOK, THF
36ag
95% yield, 99% ee
O
O
O
MeO
MeO
Boc
O
O
+
NH
Boc
NH
39 21%
36ah 28%
35x
Scheme 36a. Arylation of L-tyrosine derivative 35w. b. Byproduct formation in the
arylation of 4-hydroxy-D-phenylglycine 35x.
There are previous reports on the tetrahydrofuranylations of alcohols
enabled by hypervalent iodine(III) compounds74 and iodonium salts,75
although none where diaryliodonium salts have been utilized. In order to
prevent this byproduct formation without resorting to additives, the solvent
was changed. The initial optimization studies had revealed that solvents such
as toluene and CH2Cl2 gave comparable results to THF and to our delight,
the reaction in CH2Cl2 yielded the desired product 36ah in excellent yield
and enantiomeric excess (Scheme 37).
OH
O
MeO
Boc
NH
35x (96% ee)
1. t-BuOK, CH2Cl2
2. Ph2IBF4
40 °C, 20 min
O
O
MeO
Boc
NH
36ah
99% yield, 96% ee
Scheme 37. Successful arylation of 4-hydroxy-D-phenylglycine 35x in CH2Cl2.
45
5.1.5 Arylation of Phenols with Unsymmetric Diaryliodonium
Salts
The use of an unsymmetric diaryliodonium salt can cause chemoselectivity
problems. As mentioned previously, it is known that the most electrondeficient arene is generally transferred to the nucleophile. However, the
steric bulk of the substituents can also influence the outcome of the
reaction.44 Control of the chemoselectivity is therefore clearly a concern
when utilizing unsymmetric diaryliodonium salts. We thus synthesized
several unsymmetric salts with methoxy substituents on one aryl group in
order to investigate this phenomenon (see Chapter 6). It was clear that the
number of substituents did not affect the outcome of the reaction, and only
phenylated product was obtained in high yields (Table 8, entries 1-6).
Several salts with anisyl moieties were subsequently synthesized and used in
further arylations of phenols. Both ortho-substituted and electron-deficient
arenes were transferred in the reactions in high yields (entries 7-9).
Furthermore, pyridyl ether 36al was obtained using unsymmetric salt 6j,
thereby avoiding the need for a difficult synthesis of a symmetric pyridyl salt
(entry 10).27
Table 8. Arylation of functionalized phenols with unsymmetric diaryliodonium salts.a
OH
R1
2.
35
Entry
O
1. t-BuOK, THF
X
R1
36
R2
MeO
Phenol
35
R2
I
Product
36
Salt
Yield
(%)b
TfO
1
MeO
I
OH
O
OMe
35e
6a
TfO
94
MeO
36f
OMe
I
2
35e
36f
93
36f
82
6c
TfO
OMe
I
3
35e
OMe
6d
46
OMe
I
4
35e
36f
90
36f
>99
36f
85
OMe
6e
TfO
OMe
I
5
35e
MeO
6f
TfO
OMe
I
6
35e
MeO
OMe
6g
TfO
MeO
I
7
35e
94
MeO
36ai
6h
TsO
36aj
5j
OH
O
I
OEt
MeO
35y
O
6i
TfO
35k
OEt
NC
O
36ak
N
N
MeO
6j
93
O
I
10
CF3
94
TfO
NC
O
CF3
MeO
35k
9
I
OH
8c
O
69
36al
a
35 (1.0−1.1 equiv), t-BuOK (1.1 equiv), and 5/6 (1.0−1.2 equiv) were used at 40
°C. b Isolated yields. c Performed in toluene.
When the standard conditions were employed in the reaction between
phenol 35z and the extremely bulky salt 37e, several byproducts were
formed (Scheme 38a). This outcome can be explained by either a radical
byproduct formation (see section 5.1.1) or a ligand exchange in the salt (see
section 6.1).64
We decided to carry out the reaction in toluene as we had observed that
reactions in toluene showed comparable results to those in THF and toluene
had inhibited radical reactions in the optimization study (Table 5, entry 19).
Changing the solvent to toluene also allowed us to use the more easily
prepared tosylate salt 5k. The exceptionally bulky ether 36am was isolated
in satisfactory yield, as the problematic byproduct formation was suppressed
in toluene (Scheme 38b).
47
i-Pr
i-Pr
t-Bu
OH
ArO
i-Pr
BF4
I
t-BuOK
+
a.
i-Pr
MeO
35z
i-Pr
I
+
i-Pr i-Pr
i-Pr
THF, 40 °C
i-Pr
+
37e
i-Pr
b.
t-Bu
i-Pr
TsO
I
35z
t-BuOK
+
MeO
i-Pr
5k
i-Pr
i-Pr
Toluene, 40 °C
i-Pr
i-Pr
O
i-Pr
i-Pr
36am 61%
Scheme 38a. Observed byproduct formation in the reaction of 35z and salt 37e.
b. Successful synthesis of bulky diaryl ether 36am.
5.2 Conclusion
A fast and efficient method has been developed for the synthesis of diaryl
ethers from diaryliodonium salts. Unsymmetric salts and salts with different
anions can be employed, which widens the substrate scope considerably. The
developed procedure permits facile preparation of products such as
halogenated ethers, ortho-substituted ethers and bulky ethers in high yields,
both in room temperature and at 40 °C. These are compounds that are
generally difficult to obtain with metal-catalyzed procedures. The mildness
of the protocol was also demonstrated by the synthesis of racemizationprone amino acid substituted diaryl ethers in excellent yields and
enantiomeric excess.
48
6.
Chemoselectivity
Investigation
in
Arylations of O, N and C Nucleophiles (Paper
VI)
One of the main drawbacks in the application of diaryliodonium salts is the
stoichiometric use of the salt, which results in one equivalent of iodoarene as
a byproduct in any reaction. It is therefore of large interest to develop
catalytic arylation systems in which an unsymmetric diaryliodonium salt is
employed. The iodoarene acts as a “dummy” ligand and is reoxidized,
reforming the diaryliodonium salt in situ. An advantage of a catalytic system
like this would be that re-optimization of the reaction conditions for each
arene would be unnecessary.
Another approach to achieve greater atom efficiency is to use a polymerbound diaryliodonium salt. The same principle applies as in this case; the
iodoarene that is on solid support will act as a “dummy” ligand.
The chemoselectivity in arylation reactions with unsymmetric
diaryliodonium salts can however be problematic. As mentioned in Chapter
1, both the electronic and steric properties (the so-called ortho-effect) of the
salt and the nucleophile will influence the outcome of which aryl group will
be transferred.
Even though the field of hypervalent iodine was discovered more than
100 years ago, the mechanism behind reactions with diaryliodonium salts
have still not been thoroughly investigated. In order to create efficient
catalytic systems that employ diaryliodonium salts, as well as designing
polymer-bound reagents, it is important to have a deeper mechanistic insight
into reactions with diaryliodonium salts. We therefore set out to study how
steric and electronic properties influence the arylation of three different
nucleophiles under previously reported conditions.26, 34, 76
6.1 Results and Discussions
Figure 11 shows a selection of methyl- and methoxy-substituted
unsymmetric salts that were synthesized and used in the investigation. The
salts were chosen so that steric bulk and electronic effects would be
represented to different extents.
49
6a R = 4-OMe
6c R = 2-OMe
6d R = 2,4-(OMe)2
6e R = 2,6-(OMe)2
6f R = 2,4,6-(OMe)3
6g R = 2,5-(OMe)2
6k R = 4-Me
6l R = 2-Me
6m R = 2,4-Me2
6n R = 2,6-Me2
6o R = 2,4,6-Me3
6p R = 2,5-OMe2
TfO
Ph
I
R
Figure 11. Salts employed in the study.
We decided to use 3-methoxy phenol (35e), m-anisidine (40) and
diethylmethyl malonate (41) as nucleophiles for the phenylation vs. the
arylation study. The choice of nucleophiles gives an indication of possible
differences in O, N, and C arylations and the combined yields for the
reactions are given in Scheme 39.
MeO
OH
a.
t-BuOK, THF
MeO
O
Ph
PhArIOTf
40 °C, ≤120 min
MeO
O
+
Ar
78-99%
Ar
30-75%
OEt
26-95%
35e
NH2
MeO
b.
c.
O
O
NaH, DMF
OEt
EtO
H
N
MeO
Ph
PhArIOTf
130 °C, 24 h
40
O
DMF
PhArIOTf
rt, 18 h
+
O
EtO
O
OEt
Ph
H
N
MeO
+
O
EtO
Ar
41
Scheme 39. Arylation conditions for a. phenol 35e; b. aniline 40; c. malonate 41.
Results for the arylations of the three nucleophiles using salts 6k-p are listed
in Table 9. The chemoselectivity in the arylation of phenol 35e influenced
both by the ortho-effect and the electronic properties of the salt. Salt 6k
gives a 3:1 preference for phenylation (i.e. electronic factors), while salt 6l
gives a 1:2.5 transfer of the aryl group (entries 1 and 2). The two factors
contradict each other in the case of salt 6m and 6n, which gives unselective
reactions (entries 3 and 4). Two ortho-substituents in salt 6o show a clear
ortho-effect (entry 5), while an additional methyl in para position diminish
the apparent strong ortho-effect and the reaction becomes less selective
(entry 6).
Reactions with m-anisidine (40) show preferential phenylation in all cases
(entries 1-6), which indicates that the ortho-effect is not important with this
nucleophile. One methyl-substituent gives a slight selectivity for phenylation
(entries 1 and 2), which is increased with two methyl-substituents (entries 35), and mesityl salt 6p gave high selectivity (entry 6).
50
The reactions with malonate 41 all showed a preferential phenylation but
the selectivity decreased despite added electron-donating substituents
(entries 1-4). A surprising “anti-ortho-effect” could be observed in the
arylation with salts 6k-p, as one ortho-substituent gives a ratio of 11:1 and
two ortho-substituents give almost complete selectivity for phenylation
(entries 2,5,6). The best selectivities were observed with salts bearing two
ortho-substituents (entries 5 and 6).
Table 9. Phenylation vs. arylation of the three nucleophiles using salts 6k-p.a
Entry
MeO
Salt 6
O
Ph/Ar
MeO
H
N
O
Ph/Ar
EtO
O
OEt
Ph/Ar
TfO
1
Ph
I
6k
2.9:1
1.4:1
3.3:1
6l
1:2.5
1.4:1
11:1
6m
1.3:1
4.5:1
7:1
6n
1:1.7
2.5:1
2:1
6o
1:9
6.5:1
>20:1
6p
1:1.9
15:1
>20:1
TfO
2
I
Ph
TfO
3
Ph
I
TfO
4
Ph
5
Ph
I
TfO
I
TfO
6
Ph
I
a
Product ratios from 1H NMR of isolated diaryl ether and crude mixtures from
reactions with m-anisidine and malonate.
Methoxy-substituted salts 6a,c-g showed complete chemoselectivity in
the arylation of 35e, yielding only phenylated product (Table 10). The
electronic factors have greater influence in these reactions, as the
substitution pattern does not affect the phenylation vs. arylation ratio (entries
1-6). This effect was observed in the arylation of m-anisidine, however to a
smaller extent, as complete phenylation was only observed with salts 6d,f,g
(entries 3, 5, 6). Salts 6a,c,d gave selectivities similar to the corresponding
methyl-substituted salts 6k-m (Table 9, entries 1-3).
In the reaction with malonate 41 and para-substituted salt 6a there was a
13:1 ratio in favor of phenylation while the ortho-substituted salt 6c showed
less selectivity, which is an indication of an existing ortho-effect. This is
surprising, as the opposite effect was seen with the methyl-substituted salts
51
(cf. Table 9, entries 1 and 2). Complete selectivity was however observed
with disubstituted salts 6d-f and trisubstituted salt 6g (entries 4-6).
Table 10. Phenylation vs. arylation of the three nucleophiles using salt 6a,c-g.a
Entry
MeO
Salt 6
O
Ph/Ar
H
N
MeO
O
Ph/Ar
EtO
O
OEt
Ph/Ar
TfO
1
I
Ph
6a
Only Ph
5.4:1
13:1
6c
Only Ph
3:1
2.6:1
6d
Only Ph
Only Ph
Only Ph
6e
Only Ph
2.3:1
Only Ph
6f
Only Ph
Only Ph
Only Ph
6g
Only Ph
Only Ph
Only Ph
OMe
OMe
TfO
2
Ph
I
OMe
TfO
3
I
Ph
OMe
OMe
TfO
Ph
4
I
OMe
OMe
TfO
5
Ph
I
MeO
OMe
TfO
6
Ph
I
MeO
OMe
1
a
Product ratios from H NMR of isolated diaryl ether and crude mixtures from
reactions with m-anisidine and malonate.
Surprisingly, our results with 3-methoxyaniline differ from those
previously reported with aniline and salts 6p and 6a with a trifluoroacetate
anion instead of the triflate.34 The malonate results match those previously
reported in terms of product ratios, but lower yields were consistently
observed.26
We decided to investigate if the low chemoselectivity in the reaction of
m-anisidine with salt 6e (Table 10, entry 4) could arise from a ligand
exchange in the salt, as recently reported by DiMagno.64 They had observed
a fluoride promoted aryl ligand exchange in reactions using an unsymmetric
diaryliodonium salt in acetonitrile and benzene (Scheme 40).
X
Ar1
F
I
Ar2
X
Ar1
I
+
Ar1
X
Ar2
I
Ar2
Scheme 40. Fluoride-promoted ligand exchange in diaryliodonium salts.
52
This phenomenon was notDisplay
observed
in the reaction of m-anisidine with
Report
6e,
according
to
HRMS
analysis
of
the
reaction
mixture. However, HRMS
Analysis Info
Acquisition Date 2012-04-12 09:56:14
analysis
the arylation of malonate 41 with salt 6e showed peaks
Analysis
Name of
H:\Data2\Joel\JMC031-5min000001.d
Method
tune_low_dirk.m
Operator
pia
corresponding
to salts 3b and 3j within 5 min Instrument
at room/ Ser#
temperature
(Figure
Sample
Name
JMC031-5min
micrOTOF
125
Comment
12). This result is unexpected as the phenylated product was isolated in 57%
Acquisition
Parameter
yield with
complete
selectivity
(Table Positive
10, entry 4),Setwhich
indicates
that salt
Source Type
ESI
Ion Polarity
Nebulizer
0.4 Bar
Focus
Not active
Set Dry Heater
170 °C
3j
is
very
unreactive
compared
to
3b
and
6e.
Set Dry Gas
4.0 l/min
Scan Begin
50 m/z
Set Capillary
4500 V
Scan End
3000 m/z
Intens.
x104
Set End Plate Offset
-500 V
Set Divert Valve
I
I
8
Source
+MS, 0.8-0.9min #(50-55)
OMe
OMe
OMe
401.0237
OMe
OMe
6e C14H14IO2+
m/z 341,0033
6
4
I
OMe
3j C16H18IO4+
m/z 401,0244
341.0030
304.2618
3b C12H10I+
m/z 280,9822
287.0346
2
348.9416
280.9822
369.1537
325.9791
0
C14H14IO2, M ,341.00
2000
Figure 12. HRMS of ligand exchange observed in salt 6e.
1500
341.0033
6.2 Conclusion
Chemoselectivity in arylations with unsymmetric diaryliodonium salts
1000
depends on the type of nucleophile. Both the electronic properties and the
ortho-effect influence the arylation of phenols when using the methylsubstituted salts 6k-p. The electronic properties override the ortho-effect
500
when
using the methoxy-substituted salts 6a,c-g. In the arylation of
m-anisidine it is clear that only electronic properties influenced the outcome.
A clear “anti-ortho-effect” was observed in the reaction of malonate 41 with
0
methyl-substituted
salts 6k-p
while reactions
with
methoxy-substituted
salts
280
300
320
340
360
380
400
m/z
followed both electronic and ortho-effects. Methoxy-substituted aryls are
Bruker
Compass appropriate
DataAnalysis 4.0
2012-04-13
09:26:58
Page 1 of 1
generally
to use as printed:
dummy
ligands
in the salts, regardless
of
what nucleophile that is employed.
The different chemoselectivities observed for the three nucleophiles
could be a result of different transition states for the reductive elimination or
of a radical mechanism in some reactions. Ligand exchange in the salts could
also be an explanation for the low selectivities in some cases. The low yield
and enantiomeric excess obtained in the arylation of 253
(ethoxycarbonyl)cyclohexanone (section 4.2.5) could also be a result of this
types of ligand exchange. Only phenylated product could be observed in
those reactions albeit in low yields. Further mechanistic and computational
studies need to be performed in order to draw more precise conclusions.
54
Concluding Remarks
In this thesis, new and efficient methodology for the synthesis of hypervalent
iodine(III) compounds has been developed. Both symmetric and
unsymmetric salts can be synthesized in high yields, starting with either
molecular iodine and an arene or an iodoarene. These salts can further be
converted to the corresponding diaryliodonium triflates. An environmentally
benign large-scale synthesis of a Koser’s reagent derivative has been
developed. The use of this new methodology together with other synthetic
routes enabled the synthesis of three different enantiopure diaryliodonium
salts.
A fast and high-yielding synthesis of diaryl ethers has also been
developed. The reaction conditions are mild, metal-free, and avoid the use of
halogenated solvents, additives, or excess reagents. The scope of the reaction
is wide and ortho-, halo- and bulky-substituted diaryl ethers were
synthesized in good to excellent yields. A chemoselectivity study on the
reaction of unsymmetrical diaryliodonium salts with nucleophiles has been
conducted.
55
56
Appendix A
Contribution to Paper I-VI
I. Shared the synthetic work with Dr. Mingzhao Zhu.
II. Performed the synthetic work and took part in writing the paper.
III. Performed the synthetic work.
IV. Performed the major part of the synthetic work and supervised the
work done by diploma worker Eloisa E. Ishikawa. Wrote the
supporting information.
V. Performed the synthetic work done on diaryl ethers. Took part in
writing the supporting information.
VI. Developed the synthesis of the various salts. Performed the arylation
of the phenol and took part in writing the supporting information.
57
Appendix B
Synthesis of Diaryliodonium Salts Used in
Chapter 5 and 6
Numerous diaryliodonium salts have been synthesized for Chapter 5 and 6.
The various methods used are listed here.
Method I and II.23a-c
mCPBA (1 equiv)
TfOH (2-3 equiv)
I
I.
+
R1
1 equiv
II.
R2
I
R1
CH2Cl2, rt, 1 h
R2
51-92%
1 equiv
I2 + 4
1 equiv
TfO
R
TfO
mCPBA (3 equiv)
TfOH (4-6 equiv)
I
2 R
CH2Cl2, rt, 10 min - 21 h
R
24-93%
4 equiv
Method III and IV.77
III.
Ar1 I + Ar2 H
1 equiv
1 equiv
TsO
CH2Cl2/TFE, rt, 6 h
Ar1
1 equiv
I2 + 4 Ar H
IV.
mCPBA (1 equiv)
TsOH (1 equiv)
4 equiv
I
Ar2
TfOH
(1 equiv)
rt, 1 h
TfO
Ar1
CH2Cl2, rt, 6 h
or 80 °C, 1 h
TsO
Ar
I
Ar
Ar2
quant.
32-100%
mCPBA (3equiv)
TsOH (4 equiv)
I
TfOH
(1 equiv)
rt, 1 h
TfO
I
Ar
58-89%
Ar
80%
Method V.23e
B(OH)2
I
V.
R1
mCPBA, BF3⋅OEt2
CH2Cl2, rt, 30 min
BF4
R2
rt, 15 min
I
R1
R2
31-88%
Method VI. PhI2X (5 mmol) was dissolved in dichloromethane (30 mL) and
extracted with an aqueous NaX solution (3 x 50 mmol). The organic layer
was concentrated without drying. Et2O (20 mL) was added and the mixture
was stirred at room temperature for 30 min to precipitate a solid. The solid
was isolated by filtration, washed with Et2O and dried under vacuum to give
the desired salt. The anion exchange was confirmed by NMR analysis.
58
Novel salts and other methods for synthesis of different diaryliodonium salts
are listed below.
Table 11. Synthesis of Salts in Chapter 5-6.
Salt
Acid
(equiv)
Temp
(ºC)
Time
Yield
(%)
V+VI
2
rt
30 min +
15 min
50
IV
1
rt
6h
71
Method
TsO
2g
I
TfO
I
3a
MeO
OMe
TfO
I
3b
I
II
3
4
rt
80
10 min
10 min
92
93
I
3c
I
2
rt
3h
64
II
4
rt
10 min
78
3e
I
II
3
4
rt
rt
19 h
21 h
83
57
3f
II
3
0
1h
91
I
3g
II
4
rt
12 h
47
I
3h
II
4
rt
24 h
88
3k
II
4
rt
2h
88
III
1
40
65 h
70
III
1
rt
6h
>99
TfO
TfO
I
3d
t-Bu
t-Bu
TfO
I
Cl
Cl
TfO
I
Br
Br
TfO
TfO
TfO
I
i-Pr
TsO
I
5k
i-Pr
MeO
i-Pr
TfO
I
6a
OMe
59
TfO
I
OEt
MeO
6i
III+VI
1
rt
20 min
60
O
TfO
I
6j
I
4
60→0
30 min +
15 min
91
6k
I
2
0→rt
25 min
90
6l
I
2
rt
30 min
52
6m
I
2
0
2h
95
6n
I
2
rt
5h
69
6o
V
2.5
rt
30 min +
30 min
76
6p
I
2
rt
1h
79
37a
V
2
rt
30 min +
15 min
82
37d
V
2
rt
30 min +
15 min
74
37c
V
2.5
rt
30 min +
4h
91
37b
V
2
rt
60 min +
30 min
51
N
MeO
TfO
I
Ph
TfO
I
Ph
TfO
I
Ph
TfO
I
Ph
TfO
I
Ph
TfO
I
Ph
BF4
I
BF4
I
F
BF4
F
I
BF4
I
F3C
CF3
TfO
I
3k
Isolated in 88% yield as a beige solid; mp 173-174 °C; 1H NMR (500 MHz,
DMSO-d6) δ 8.14 (d, J = 8.2, 2H), 7.35 (s, 2H), 7.10 (dd, J = 1.9, 8.3, 2H),
2.54 (s, 6H), 2.30 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ 143.1, 140.3,
60
137.0, 132.1, 129.9, 120.7 (q, 1JC-F = 322), 117.0, 24.7, 20.7; HRMS (ESI)
m/z calculated for C16H18O+ ([M-OTf]+) 337.0448, found 337.0466.
TsO
I
CF3
5j
A previously published procedure4 was modified slightly: anisole (1.0 equiv)
was added dropwise at 0 °C to a stirred solution of 8 in 1:1 CH2Cl2:TFE (6
mL/mmol). The reaction mixture was allowed to reach rt and stirring was
continued overnight before concentrating to dryness by rotary evaporation.
This crude material was triturated with Et2O. Isolation by filtration and
multiple washes with Et2O yielded salt 5j.
Isolated in 94% yield as a colorless solid; mp 180–182 °C; 1H NMR (400
MHz, DMSO-d6) δ 8.71 (s, 1H), 8.49 (d, J = 8.4, 1H), 8.25–8.21 (m, 2H),
8.03 (d, J = 8.0, 1H), 7.74 (t, J = 7.8, 1H), 7.48–7.45 (m, 2H), 7.11–7.08 (m,
4H), 3.80 (s, 3H), 2.28 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 162.1,
145.5, 139.0, 137.8, 137.5, 132.5, 131.6 (q, 3JC-F = 3.6), 131.2 (q, 2JC-F =
32.6), 128.5 (q, 3JC-F = 3.5), 128.1, 125.5, 123.0 (q, 1JC-F = 271.5), 117.5,
117.4, 105.9, 55.7, 20.8; 19F NMR (376 MHz, DMSO-d6) δ −61; HRMS
(ESI) m/z calculated for C14H11F3IO+ ([M-OTs]+) 378.9801, found 378.9803.
MeO
i-Pr
TsO
I
5k
Isolated in 70% yield as a light orange oil; 1H NMR (400 MHz, DMSO-d6) δ
7.87 (m, 2H), 7.47 (m, 2H), 7.28 (s, 2H), 7.09 (m, 4H), 3.78 (s, 3H), 3.42 (m,
2H), 2.96 (m, 1H), 2.29 (s, 3H), 1.23 (m, 18H); 13C NMR (100 MHz,
DMSO-d6) δ 162.2, 154.5, 151.4, 146.3, 138.0, 136.6, 128.5, 126.0, 125.0,
124.2, 118.1, 104.2, 56.2, 39.0, 33.8, 24.5, 24.0, 21.2; HRMS (ESI) m/z
calculated for C22H30IO+ ([M-OTs]+) 437.1336, found 437.1347.
MeO
i-Pr
OMe
TfO
Ph
i-Pr
I
6c
Synthesized by a known method,36a followed by an anion exchange.
Isolated as a light yellow solid in 56% yield over 2 steps; mp 148-150 °C; 1H
NMR (400 MHz, DMSO-d6) δ 8.3 (dd, J = 1.4, 7.9, 1H), 8.2-8.1 (m, 2H),
7.70-7.61 (m, 2H), 7.54-7.47 (m, 2H), 7.31 (dd, J = 1.3, 8.4, 1H), 7.09 (td, J
= 1.4, 7.9, 1H), 3.94 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 156.4, 137.2,
135.1, 134.9, 131.9, 131.6, 123.4, 120.7 (q, 1JC-F = 322), 115.8, 113.1, 106.5,
57.1; HRMS (ESI) m/z calculated for C13H12O+ ([M-OTf]+) 310.9927, found
310.9912.
61
OMe
TfO
Ph
I
6d
Synthesized by a known method,16 followed by an anion exchange.
Isolated as a light yellow solid in 96% yield over 2 steps; mp 92-94 °C; 1H
NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 8.8, 1H), 8.09- 8.03 (m, 2H),
7.66-7.59 (m, 1H), 7.53- 7.45 (m, 2H), 6.80 (d, J = 2.6, 1H), 6.69 (dd, J =
2.6, 8.8, 1H), 3.93 (s, 3H), 3.83 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ
164.7, 158.2, 138.3, 134.62, 131.7, 131.5, 122.3, 120.7 (q, 1JC-F = 322),
119.1, 116.3, 108.9, 99.7, 95.8, 57.3, 56.0; HRMS (ESI) m/z calculated for
C14H14IO2+ ([M-OTf]+) 314.0033, found 314.0030.
OMe
OMe
TfO
Ph
I
6e
Synthesized by a known method,36a followed by an anion exchange.
Isolated as a light yellow solid in 68% yield over 2 steps; mp 168-170 °C; 1H
NMR (400 MHz, DMSO-d6) δ 8.12 (app. d, J = 7.4, 2H), 7.96 (d, J = 2.5,
1H), 7.65 (t, J = 7.4, 1H), 7.51 (m, 2H), 7.29-7.18 (m, 2H), 3.86 (s, 3H), 3.77
(s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 154.2, 150.7, 135.0, 131.9, 131.6,
122.1, 120.7 (q, 1JC-F = 322), 119.9, 115.9, 113.5, 106.3, 57.4, 56.2; HRMS
(ESI) m/z calculated for C14H14IO2+ ([M-OTf]+) 314.0033, found 314.0030.
OMe
OMe
TfO
Ph
I
6f
Synthesized by a known method,36a followed by an anion exchange.
Isolated as a light yellow solid in 47% yield over 2 steps; mp 152-153 °C; 1H
NMR (400 MHz, DMSO-d6) δ 7.95 (dd, J = 1.0, 8.3, 2H), 7.62-7.54 (m, 2H),
7.48-7-41 (m, 2H), 6.87 (t, J = 8.4, 2H), 3.94 (s, 6H); 13C NMR (100 MHz,
DMSO-d6) δ 158.1, 135.7, 134.6, 131.4, 131.4, 116.8, 105.3, 99.1, 57.3;
HRMS (ESI) m/z calculated for C14H14IO2+ ([M-OTf]+) 314.0033, found
314.0023.
MeO
OMe
TfO
Ph
I
MeO
OMe 6g
Synthesized by a known method,16 followed by an anion exchange.
Isolated as a white solid in 94% yield over 2 steps; mp 114-116 °C; 1H NMR
(400 MHz, DMSO-d6) δ 1H NMR (500 MHz, DMSO-d6) δ 7.92 (d, J = 7.4,
2H), 7.61 (t, J = 7.4, 1H), 7.47 (t, J = 7.8, 2H), 6.46 (s, 2H), 3.94 (s, 6H),
3.86 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 166.2, 159.4, 134.4, 131.6,
128.1, 125.5, 122.31, 120.7 (q, 1JC-F = 322), 119.1, 116.1, 92.1, 87.0, 57.4,
62
56.2; HRMS (ESI) m/z calculated for C15H16IO2+ ([M-OTf]+) 371.0139,
found 371.0144.
TfO
I
6h
The salt was synthesized through a modification of a previously published
procedure:17b 4-Iodoanisole (468 mg, 2 mmol) was dissolved in CH2Cl2 (20
mL), followed by addition of mCPBA (371 mg, 2 mmol, 93%) and
TsOH·H2O (380 mg, 2 mmol). The reaction mixture was stirred at rt for 50
min and 2,6-dimethylphenylboronic acid (315 mg, 2.1 mmol) was added.
Stirring was continued 18 h before concentrating to dryness by rotary
evaporation. Et2O was added to the crude residue to precipitate the tosylate
salt, which was submitted to an aqueous anion exchange without further
purification to give salt 6h in 40 % yield over 2 steps.
Isolated as a light white solid; mp 190-191 °C; 1H NMR (400 MHz, DMSOd6) δ 7.97 (d, J = 9.1, 2H), 7.47 (d, J = 7.5, 1H), 7.39 (d, J = 7.5, 2H), 7.06
(d, J = 9.1, 2H), 3.80 (s, 3H), 2.67 (s, 6H); 13C NMR (100 MHz, DMSO-d6)
δ 161.8, 141.6, 136.8, 132.7, 129.1, 126.8 (q, 1JC-F = 322) 126.7, 117.6,
103.2, 55.7, 26.5; HRMS (ESI) m/z calculated for C15H16IO+ ([M-OTf]+)
339.0240, found 339.0245.
MeO
TfO
I
OEt
MeO
6i
Isolated in 60% yield over 2 steps as a beige solid; mp 158-160 °C; 1H NMR
(400 MHz, DMSO-d6) δ 8.30 (d, J = 8.6, 2H), 8.19 (d, J = 9.4, 2H), 8.00 (d,
J = 8.6, 2H), 7.08 (d, 9.4, 2H), 4.32 (q, J = 7.1, 2H), 3.80 (s, 3H), 1.30 (t, J =
7.1, 3H); 13C NMR (100 MHz, DMSO-d6) δ 164.6, 162.1, 137.3, 135.0,
132.6, 131.7, 125.5, 121.8, 120.7 (q, 1JC-F = 322) 117.6, 105.6, 61.4, 55.7,
14.0; HRMS (ESI) m/z calculated for C16H16IO3+ ([M-OTf]+) 383.0139,
found 383.0152.
O
TfO
I
6j
Isolated in 91% yield as a brown oily residue; 1H NMR (400 MHz, MeODd4) δ 9.19 (dd, J = 0.5, 2.3, 1H), 8.82 (dd, J = 1.4, 4.8, 1H), 8.56 (ddd, J =
1.4, 2.4, 8.4, 1H), 8.14 (app. d, J = 9.2, 2H), 7.56 (ddd, J = 0.7, 4.8, 8.3, 1H),
7.09 (app. d, J = 9.2, 2H), 3.86 (s, 3H); 13C NMR (100 MHz, MeOD-d4) δ
164.8, 154.3, 153.4, 143.6, 138.8, 128.2, 121.8 (q, J = 316), 119.1, 116.1,
104.4, 56.4; HRMS (ESI) m/z calculated for C12H11NOI+ ([M-OTf]+)
311.9880, found 311.9891.
MeO
N
63
Br
I
38
Known salt in the literature and synthesized by a known method.78 Isolated
in 58% yield as a beige solid.
64
Acknowledgements
Berit Olofsson för att du gav mig möjligheten att doktorera i din grupp. Din
dörr har alltid stått öppen och du har delat med dig av din kunskap på bästa
möjliga sätt. Tack även för ditt stöd och din uppmuntra, både i framgång och
när det har varit riktigt tungt.
Jan-Erling Bäckvall för visat intresse i mitt arbete och för att jag fick göra
mitt examensarbete i din grupp.
Joel Malmgren, Dr Tue B. Petersen, Thore Frister, Eloisa E. Ishikawa, Jan
Caspar and Dr Mingzhao Zhu for fruitful collaborations.
Dr Ellie Merritt and Joel Malmgren for linguistic improvements of the
thesis.
Past and present members of the BO group! Special thanks to Ellie for all
your support and help during these years.
Iris Tébéka and her mother Alda Simonetti. Eu adorava passar o tempo com
vocês e muito obrigado por ser como uma família para mim quando eu
estava no Brasil \o/
All the people at Universidade de São Paulo that made my stay in Brazil
rememberable.
All of the people at the Department of Organic Chemistry for making it a
nice place to work.
TA-personalen för all hjälp med saker runt omkring.
Tack
till
K&A
Wallenberg
Stiftelsen,
Ångpanneföreningens
Forskningsstiftelse, Kungliga Skogs och Lantbruks Akademin, AstraZenecas
resestipendium till minne av Nils Löfgren, Svenska Kemistsamfundet och
John Söderbergs fond för finansiellt stöd.
Elina, min “partner in crime”, för att du har gjort 1/3 av mitt liv lite lättare
och framför allt mycket roligare. Tiden som doktorand hade inte varit den
samma utan dig.
65
Andreas, för att ha gjort hela min studietid roligare. Allt från Betapet till
meningslösa ramsor till galna danser, du får mig alltid att bli på bättre
humör!
Mina alldeles underbara vänner, även om ni inte alltid har förstått vad jag
har sysslat med de senaste 5 åren så har ni alltid funnits där med råd och stöd
(ibland även lite alkohol )! Ni är bäst!!!
Tack till min fantastiska bonusfamilj Jan, Karin, Sara, Markus, Nora, Ella,
Viggo och Pompe.
Min älskade Mamma, Pappa och Negin! Tack för att ni alltid tror på mig.
Jag har allt jag någonsin gjort och åstadkommit er att tacka för!
‫ﺵشﻡمﺍا ﺏبﻩه ﺍاﻥنﺩدﺍاﺯزﻱيﻩه ﯼیﮎک ﺩدﻥنﯼیﺍا ﺏبﺭرﺍاﯼی ﻡمﻥن ﺍاﺭرﺯزﺵش ﺩدﺍاﺭرﯼیﺩد‬
Viktigaste av allt, Johan. Ditt stöd och din uppmuntran under de här åren har
varit ovärderlig. Du är det finaste jag vet och jag är så glad över att jag
hittade just dig. Älskar dig! ♥
66
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