REVIEW
▌A
Developments in the Synthesis of 1,2-Dihydropyridines
review
Eduarda M. P. Silva, Pedro A. M. M. Varandas, Artur M. S. Silva*
1,2-Dihydropyridines
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax +351(234)370714; E-mail: [email protected]
Received: 02.06.2013; Accepted after revision: 08.07.2013
O
Abstract: This review provides a comprehensive compilation of
available literature concerning the synthesis of 1,2-dihydropyridines. The most important recent developments and concepts related to this topic are emphasised.
Introduction
Synthesis of 1,2-Dihydropyridines
Condensation Reactions
Reduction of Pyridines and Pyridinium Salts
Nucleophilic Addition to Pyridines and Pyridinium Salts
Pericyclic Reactions
Other Methods
Conclusions
N
O
H
O P O
O
H
H
NH2
N
O P O
O
H
H
2
H
OH
OH
Me
1
N
N
Introduction
Hantzsch reported the first synthesis of dihydropyridine in
1882 in the course of developing his useful synthetic
method for pyridine.1 This reaction produces 1,4-dihydropyridines, as isolable intermediates, that can then be oxidised to pyridines. The outbreak of interest in this class of
molecules was stimulated by two major discoveries: 1) the
isolation of NADH (1; Figure 1) and its role in biological
oxidation–reduction reactions, and 2) the widespread attention gathered by molecules such as nifedipine (2), an
antihypertensive drug, with most of the initial studies on
this calcium channel blocker being performed in the early
1970s.
From the five theoretically possible isomeric dihydropyridines, the 1,2- and the 1,4-dihydro structures are the most
commonly found in known dihydropyridines.2 The 1,4-dihydropyridines are known to possess a wide range of biological and pharmacological actions and have been used
as calcium-channel modulating agents in the treatment of
cardiovascular disease, as multidrug-resistance-reversing
agents in cancer chemotherapy and as antimycobacterial
and anticonvulsant agents.3
The less studied 1,2-dihydropyridines consist of an important scaffold for the preparation of 2-azabicyclo[2.2.2]octanes (isoquinuclidines).4 The isoquinuclidine ring system
is widely found in natural products such as the alkaloids
ibogaine (3) and dioscorine (4; Figure 1), which have a
SYNTHESIS 2013, 45, 000A–00AK
Advanced online publication: 23.10.20130039-78 1 437-210X
DOI: 10.1055/s-0033-1338537; Art ID: SS-2013-E0386-R
© Georg Thieme Verlag Stuttgart · New York
CO2Me
N
H
N
MeO
1
MeO2C
N
N
O
H
Key words: dihydropyridines, NADH, isoquinuclidines, pericyclic
reactions, heterocyclic compounds
NO2
OH
OH
O
N
H
O
3
4
O
Figure 1 Nature’s reducing agent NADH (1), antihypertensive drug
nifedipine (2), and natural product alkaloids ibogaine (3) and dioscorine (4)
large spectrum of interesting biological properties.4 It was
recently indicated that ibogaine (3) could be used as an
anti-addictive and anti-craving agent since it reduces
cravings for alcohol and other drugs. Dioscorine (4) has
been shown to be a toxic central nervous system depressant and a modulator of the nicotinic acetylcholine receptor.4
It was also recently shown that isoquinuclidines, and consequently the 1,2-dihydropyridines, can be used as synthetic intermediates for the synthesis of oseltamivir
phosphate (Tamiflu) which is an important anti-influenza
drug (Scheme 1). A well-established route to the chiral
ring system that can be found recurrently in the literature
is through the Diels–Alder reaction of 1,2-dihydropyridines with several dienophiles (Scheme 1).5
COOEt
R2
N
R1
dienophile
Diels–Alder
reaction
R1 N
H3PO4
R2
6
O
NH2
NHCH2OMe
5
oseltamivir (Tamiflu)
(7)
Scheme 1 Synthesis of isoquinuclidines 6 through Diels–Alder reaction of 1,2-dihydropyridines with dienophiles
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1
2
2.1
2.2
2.3
2.4
2.5
3
NH2
B
REVIEW
E. M. P. Silva et al.
The chemistry of dihydropyridines developed between
the late 1950s and the early 1970s has been reviewed – by
Eisner and Kuthan in 19722b and by Stout and Meyers in
1982.6 These important reviews should be consulted for
historical and background information. In 2002, Lavilla
revisited the dihydropyridine field in what concerns their
reactivity, their use in organic synthesis, and their incidence in medicinal chemistry.7 More recently Wan and
Liu reviewed the recent advances in new multicomponent
syntheses of structurally diversified 1,4-dihydropyridines.8
The limited availability of synthetic methods for the preparation of 1,2-dihydropyridines and the recent development of resistance against Tamiflu, a potent inhibitor of
neuraminidase, led to considerable efforts toward the development of new and efficient methodologies for the
synthesis of 1,2-dihydropyridines. Therefore, a review
dealing solely with all the recent accomplishments in the
1,2-dihydropyridines field is important and timely.
Herein, a comprehensive compilation of available literature concerning the synthetic methodologies documented
to obtain 1,2-dihydropyridine is presented. The most important developments and concepts related to this topic
are emphasised and discussed. Research describing the
preparation of 1,2-dihydropyridines as intermediates in
the synthesis of other heterocyclic compounds using
known methods will not be considered in this review.
Synthesis 2013, 45, A–AK
Eduarda M. P. Silva studied at the University of
Aveiro and joined the group
of Professor José A. S.
Cavaleiro after her studies
working in the synthesis and
structural characterisation
of new porphyrin derivatives with adequate physicochemical and biological
properties for medicinal applications. She then carried
out her PhD studies under
the guidance of Professor
Laurence M. Harwood at
the University of Reading in
England. The work was
concerned with the total
synthesis of mycaperoxide
B based on a biosynthetic
rationale. She finished her
PhD in 2009 and joined the
group of Professor Artur M.
S. Silva as a postdoctoral
fellow at the University of
Aveiro. Her research interests are now concerned with
catalysis, stereochemistry,
the 1,6-conjugated addition
of nucleophiles to diene systems deficient in electrons,
chemistry of nitrogen heterocyclic compounds and
structural characterisation
by mass spectrometry.
Pedro A. M. M. Varandas
studied at the University of
Coimbra and started his research as an undergraduate
student working on the synthesis of dicationic bolaform
surfactants
and
studying their effect on
DNA compaction at the organic and electrochemistry
groups. He then continued
his studies at the University
of Aveiro, where he joined
the group of Professor Artur
M. S. Silva during his MSc
degree. At this time, he
started working on the synthesis of 1,2-dihydropyridines using (E,E)-cinnamylideneacetophenones as
versatile starting materials
for pericyclic reactions
through 6π-azaelectrocyclisation. Currently he is still
researching the synthesis of
this template because of its
usefulness as a synthetic intermediate in obtaining chiral heterocyclic compounds,
which are known for various
important biological activities.
Artur M. S. Silva is Full
Professor at the University
of Aveiro. He obtained both
BSc (1987) and PhD (1993)
degrees at the University of
Aveiro. He joined the Department of Chemistry of
the same university in 1987
and was appointed to Auxil-
iary Professor in 1996, Associate Professor in 1999
and Full Professor in 2001.
He has published more than
370 SCI papers, 15 book
chapters and delivered more
than 30 lectures at scientific
meetings. His research interests are synthetic organic
chemistry (establishment of
new synthetic methods of
oxygen and nitrogen heterocyclic compounds and
organocatalysed transformations), natural products
identification and structural
characterisation by NMR.
© Georg Thieme Verlag Stuttgart · New York
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Biographical Sketches█
REVIEW
C
1,2-Dihydropyridines
2
Synthesis of 1,2-Dihydropyridines
32:68, respectively. No oxidation product was observed
under these conditions.
2.1
Condensation Reactions
The effect of the solvent on the reaction under catalystfree conditions in an air atmosphere at 20 °C was also investigated (Table 1). A mixture of 1,4- and 1,2-dihydropyridines was obtained in all the tested solvents except for
acetic acid (Table 1, entries 1–6 vs. entry 7), which led to
the formation of 2-phenylpyridine 14 in a good yield
(70.7%).7 The effect of catalyst on the ratio of products
under solvent-free conditions was also explored. The use
of piperidine, ytterbium perfluorooctanoate [Yb(PFO)3]
and indium(III) chloride tetrahydrate [InCl3·4H2O] led to
the formation of 14 in yields ranging from 89 to 94%. The
classical Hantzsch product 11 was produced as a minor
product.
R
O
R
EtO2C
O
CHO +
8
CO2Et
+ NH4OAc
OEt
N
H
9
10
Scheme 2 Hantzsch’s synthesis of dihydropyridine 101
Cao and co-workers recently used this methodology to
synthesise 2-arylpyridines in an environmentally friendly
approach. Using benzaldehyde, ethyl acetoacetate and
ammonium acetate (Scheme 3) as representative reactants, the authors studied the effect of temperature, solvent
and catalyst.9
O
CHO
O
OEt
+
+
NH4OAc
9
8
Ph
EtO2C
Ph
CO2Et
EtO2C
CO2Et
N
H
N
11
12
EtO2C
CO2Et
N
H
13
EtO2C
Ph
CO2Et
N
Ph
14
Scheme 3 Formation of up to four products from the reaction of
benzaldehyde with ethyl acetoacetate and ammonium acetate9
The scope of the reaction was also explored with a range
of structurally diverse aldehydes. Several general conclusions were taken from these studies, namely that low temperature and the use of solvent were favourable towards
the formation of the 1,2-dihydropyridine 13. However,
once this intermediate 13 was formed, the oxidation product 2-phenylpyridine 14 was generated easily in situ by
prolonged exposure (72 h) to air at 20 °C. When the reaction was performed under an argon atmosphere, with careful exclusion of air from the reaction vessel, a mixture of
1,4- and 1,2-dihydropyridines was obtained in a ratio of
© Georg Thieme Verlag Stuttgart · New York
Table 1 Effect of Solvent on the Catalyst-Free Reaction in Air at
20 °C9
Entry
Solvent
Product ratio
Yield (%)
1
MeOH
13/14 = 57:43
40.2
2
THF
13/14 = 60:40
55.5
3
EtOH
13/14 = 62:38
55.7
4
CH2Cl2
13/14 = 59:41
37.2
5
MeCN
13/14 = 69:31
35.7
6
DMSO
13/14 = 26:74
43.2
7
AcOH
11/14 = 10:90
70.7
8
none
11/14 = 6:94
93.5
In 1999 Koike et al. reported an interesting efficient heterocyclic annulation reaction leading to 2-methyl-3-nitro1,2-dihydropyridines 18 (Scheme 4). The reaction occurs
between a secondary nitrodienamine 15 and acetaldehyde
(16) in tetrahydrofuran in a sealed tube at room temperature, affording 18 in excellent yields ranging from 88 to
95% with reaction times between 1.0 to 1.5 hours.10 The
nitrodienamines 15 were prepared by reaction of tertiary
nitrodienamines with several primary amines, namely 2phenylethylamine, benzylamine, octylamine, 2-(3,4-dimethoxyphenyl)ethylamine, (4-pyridyl)methylamine, and
2-(4-pyridyl)ethylamine.
The scope of this reaction was later extended, by the same
group, using several aldehydes.11 This time, the authors
used 4-nitro-1-(2-phenethylamino)buta-1,3-diene (15a;
Scheme 4) as the secondary nitrodienamine and allowed it
to react with propionaldehyde, benzaldehyde, 4-methoxybenzaldehyde, 4-chlorobenzaldehyde, and 4-nitrobenzaldehyde. The corresponding products were obtained in
yields ranging from 44 to 82%. All the reactions were performed at room temperature in a sealed tube except when
propionaldehyde was used. This reaction was performed
at reflux for a prolonged period of time (39 h). The reactions with formaldehyde and cinnamaldehyde gave very
poor yields (2 and 5%, respectively).11
Synthesis 2013, 45, A–AK
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The Hantzsch synthesis of dihydropyridines has been revisited by numerous research groups over the years. This
synthesis allows the efficient preparation of 1,4-dihydropyridines through a one-pot multicomponent condensation reaction of an aldehyde, ethyl acetoacetate and
ammonium acetate performed at 80 °C under solvent-free
conditions (Scheme 2).1
REVIEW
E. M. P. Silva et al.
R
R
NO2 + MeCHO
16
N
H
THF, r.t.
N
1.0–1.5 h
88–95%
HO
NO2
15a R = Bn
15b R = Ph
15c R = (CH2)6Me
15d R = CH2(3,4-OMe)2C6H3
15e R = C5H4N
15f R = CH2C5H4N
17
R
– H2O
N
NO2
18a 92%
18b 95%
18c 93%
18d 88%
18e 88%
18f 89%
Scheme 4 Synthesis of 2-methyl-3-nitro-1,2-dihydropyridines 18 by
reaction of secondary nitrodienamines 15 with acetaldehyde (16)10
The synthesis of chiral 1,2-dihydropyridines 22 from αamino acids was successfully achieved by Kawabata and
co-workers (Scheme 5).12 This reaction involved the preparation of precursor 19 and treatment of this substrate with
potassium hexamethyldisilazide (KHMDS) to afford enamino enolates 20a and 20b by γ-proton abstraction of the
α,β-unsaturated ester 19.
and co-workers.13 A Brønsted acid and a thiourea organocatalyst were used to catalyse the addition of β-enamino
esters 24 to α,β-unsaturated aldehydes 25 (Scheme 6).
Firstly, the reaction between β-enamino ester 24a and aldehyde 25f was studied in what concerns the screening of
several organocatalysts 28–31 (Figure 2), acids, and their
ratios. The reaction was performed in the presence of 28
alone but no product was formed, confirming the necessity of a Brønsted acid in the reaction mixture. From the
several acids tested, the use of difluoroacetic acid (DFA)
with catalyst 28 led to a mixture of 1,4-dihydropyridine 26
(R1 = 4-MeOC6H4, R2 = 4-O2NC6H4, R3 = H) and 1,2-dihydropyridine 27 (R1 = 4-MeOC6H4, R2 = 4-NO2NC6H4,
R3 = H) in a ratio of 35:65 (Scheme 6). This was the best
yield of 1,2-dihydropyridine 27 obtained. All other reactions favoured the formation of the 1,4-dihydropyridine
26.
O
R1 NH
CO2Et
R2
H
R3
24a R1 = 4-MeOC6H4, R3 = H
24b R1 = 4-MeOC6H4, R3 = Me
25a R2 = Ph
25b R2 = 4-MeOC6H4
25c R2 = 4-FC6H4
25d R2 = 3-FC6H4
25e R2 = 2-FC6H4
25f R2 = 4-O2NC6H4
thiourea catalyst
(10 mol%)
acid (10 mol%)
toluene, r.t.
R2
CO2Et
Ph
Boc
CO2tBu
N
KHMDS
CO2Et
Ph
Boc
19
Boc
OtBu
20a
+
O
CO2
Ph
N
tBu
N
OtBu
21
Boc
OH
N
22 (83%)
4 M HCl (56%)
or DDQ (89%)
CO2tBu
Ph
N
27af
Yield (%), [ee(%)]
35
59 [28 (S)]
72 [39 (R)]
71 [28 (R)]
0
65
28 [2]
17 [0]
18 [1]
51 [12]
Scheme 6 Synthesis of 1,4-dihydropyridines 26 and 1,2-dihydropyridines 27 by addition of β-enamino esters 24 to α,β-unsaturated aldehydes 2513
23
Scheme 5 Synthesis of chiral 1,2-dihydropyridine 22 from an α-amino acid12
A Dieckmann cyclisation of the enamino enolate 20b,
with a Z-geometry, afforded the 1,2-dihydropyridine 22 in
83% yield. The enantiomeric excess of 22 was not determined due to its lability and it was converted by removal
of the Boc protecting group and oxidation with a 4 M hydrochloric acid solution or 2,3-dichloro-5,6-dicyano-1,4quinone (DDQ) into trisubstituted pyridine 23. The authors were able to determine the enantiomeric excess of
the 1,2-dihydropyridine formed when the N-benzoyl derivative was considered. The ee was determined by HPLC
analysis to be 80%.12
More recently, an asymmetric synthesis of functionalised
1,4- and 1,2-dihydropyridines was reported by Takemoto
S
S
Ar
Synthesis 2013, 45, A–AK
26af
Yield (%), [ee(%)]
DFA
DFA–(R,R)-29a
DFA–(S,S)-30a
TFA–(S,S)-30a
DFA–(R,R)-31a
20b
OH
Ph
27
Brønsted acid–thiourea
N
R3
R1
R1
26
OK
Ph
Boc
CO2tBu
R2 * N
R3
N
EtO2C
– EtOK
CO2Et
CO2Et
*
OK
Ar
N
H
N
H
Me
N
HN
28
N
H
N
H
Me
X
29a X = Y = H
29b X = OMe, Y = H
S
Ar
N
H
N
H
S
HN
X
Ar
N
H
Thiourea
N
H
O
Y
30a X = F, Y = OMe
30b X = Y = OMe
30c X = F, Y = OiPr
Figure 2
screened13
Y
HO
31
catalysts
28–31
[Ar = 3,5-(F3C)2C6H3]
© Georg Thieme Verlag Stuttgart · New York
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D
REVIEW
E
1,2-Dihydropyridines
The studies performed using several α,β-unsaturated aldehydes 25a–f were completed using conditions favouring
the formation of 1,4-dihydropyridines 26, and these were
obtained in good yields (55–83%) and enantioselectivity
ranging from 38 to 80%.
Pan and co-workers reported in 2009 the regioselective
synthesis of 1,2-dihydropyridines 36 via a three-component sequential reaction of enaminones 32, α,β-unsaturated aldehydes 33, and amines 34 (Scheme 7).14 This new
regioselectivity was proposed to be controlled by both steric and electronic effects of the amine component used.
The authors, when studying the generality of this new synthetic protocol using several substrates, found that the use
of sterically hindered aromatic amines or amines with a
strong electron-withdrawing groups led to the regioselective synthesis of 1,2-dihydropyridines 36 (Table 2). For
example, p-nitroaniline mainly furnished 1,2-dihydropyridines 36 as products (entries 1 and 2). The reactions with
2-fluoro- and 2-bromoaniline afforded the 1,4-dihydropyridines 35 (entries 3, 4 and 8) while 2-chloroaniline
gave 1,2-dihydropyridines 36 as the only product (entries
5–7). These results suggest that the reaction with 2-haloanilines is dependent on both the size and the electronic
characteristics of the ortho substituents. The reaction with
2-methylanilines provided exclusive formation of 1,4-dihydropyridines 35 (entry 10). This result confirmed that a
bulky ortho group is not the only inducing factor for the
synthesis of 1,2-dihydropyridines 36.
O
Me
N
R1
Me
+
R3
32
4-O2NC6H4
H
63/–
2
4-OMe
4-O2NC6H4
H
53/14
3
H
2-FC6H4
H
–/70
4
4-OMe
2-FC6H4
H
–/61
5
H
2-ClC6H4
H
59/–
6
H
2-ClC6H4
2-Cl
52/–
7
4-Cl
2-ClC6H4
2-Me
60/–
8
H
2-BrC6H4
H
<10/46
9
H
2-IC6H4
H
51/27
10
H
2-MeC6H4
H
–/65
11
H
2,4,6-Me3C6H2
H
51/< 10
2.2
1,2/1,4 (%)
Reduction of Pyridines and Pyridinium Salts
The formation of 1,2-dihydropyridines can be accomplished by the addition of hydride sources to N-acylpyridinium salts. Pioneering work on this subject was
developed by Fowler, who carried out the sodium borohydride reduction of N-carbalkoxypyridinium ions formed
in situ from a pyridine and a chloroformate ester (Scheme
8).15 The reaction was carried out in tetrahydrofuran at 10
°C to give a mixture of dihydropyridines 38a and 38b containing about 60% of the 1,2-dihydropyridine 38a. It was
established that the carbomethoxy substituent stabilises
the dihydropyridine structure causing the compounds to
be more resistant, when compared with N-alkyl derivatives, to air oxidation, thus allowing their ready manipulation.
NaBH4
ClCO2Me
THF, 0 to 10 °C
N
CO2Me
+
N
CO2Me
37
38a (60%)
38b (40%)
Scheme 8 Reduction with sodium borohydride of N-carbalkoxypyridinium ions formed in situ15
R1
N
N
R2
R2
R3
36
Scheme 7 Regioselective synthesis of 1,2-dihydropyridines 36 via a
three-component cascade reaction14
© Georg Thieme Verlag Stuttgart · New York
H
N
O
35
1
+
R3
and/or
R3
R2
DMF–H2O
TMSCI
85 °C
R1
R2
34
33
O
R1
Entry
NH2
CHO
+
Table 2 Regioselective Synthesis of 1,2- (36) versus 1,4-Dihydropyridines (35)14
The Fowler reduction has been studied in detail by
Sundberg et al.16 using several 3-substituted pyridines and
various hydride-transfer reducing agents in the presence
of ethyl and benzyl chloroformate. In these studies, reducing agents such as potassium triisopropoxyborohydride
[K(i-PrO)3BH], lithium tri-tert-butoxyaluminum hydride
[Li(t-BuO)3AlH], sodium tri(sec-butyl)borohydride
[Na(s-Bu) 3 BH], and diisobutylaluminium hydride
[(i-Bu)2AlH] were used. The mixtures of dihydropyridines obtained from reduction of 3-substituted pyridines
Synthesis 2013, 45, A–AK
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The best chemo- and enantioselectivities (86% yield and
50% ee) in the formation of compound 26 were obtained
using organocatalyst 30a and difluoroacetic acid. Catalyst
30a is an N-arylthiourea, whose aniline moiety is a weaker
base than the N,N-dimethylamine moiety of 28. In
Scheme 6 are only shown yields and enantioselectivity of
reactions that allowed for both 1,2- and 1,4-dihydropyridines to be obtained.
REVIEW
E. M. P. Silva et al.
consists, in general, of 1,2-, 1,4- and 1,6-reduction products (Figure 3).
R1
R1
Booker and Eisner studied the reduction of pyridine-3,5dicarboxylate to the corresponding dihydropyridines.17
The preparation of the 3,5-disubstituted 1,4-dihydropyridines involved the reduction of the pyridine derivative
with sodium borohydride while the isomeric 1,2-dihydropyridines were obtained when diborane was used as reducing agent. The composition of the isomer mixtures
produced when several solvents were used was determined and the authors established that both the total yield
and the isomer ratio vary largely and there seems to be no
correlation with factors such as solvent polarity.17
Another interesting work concerning the use of sodium
borohydride as reducing agent to prepare N-sulfonyl-1,4or -1,2-dihydropyridines (Scheme 9) was published by
Knaus and Redda in 1977.18 The authors realised that the
reduction of N-sulfonylpyridinium salts is dependent
upon solvent and temperature. Attack of the hydride anion
at the 2-position of pyridine, in the presence of either
methanesulfonyl chloride or methanesulfonic anhydride,
occurs exclusively using methanol as solvent at –65 °C,
affording N-methanesulfonyl-1,2-dihydropyridine 42 in
32 or 37% yield, respectively. The reaction with benzenesulfonyl chloride provided an isomeric mixture of 42 and
43 in an 8:1 ratio. The 4-position attack was favoured
when pyridine was employed simultaneously as solvent
R1
N
N
N
CO2R2
CO2R2
CO2R2
39
40
41
1,2-product
1,4-product
1,6-product
Figure 3 Reduction of 3-substituted pyridines can generate a mixture of 1,2-, 1,4- and 1,6-dihydropyridines16
The variation of product ratios observed for this reaction
is dependent on the experimental conditions and the reducing agents used and the results are gathered in Table 3.
In what concerns the reductions by sodium borohydride,
an effective regiocontrol is exerted by sterically nondemanding electron-donor substituents (methyl, ethyl, methoxy, methylthio, bromo, and chloro) favouring hydride
addition at the 2-position to an extent of 90% or more (Table 3, entries 1–6).
Trimethylsilyl, trimethylstannyl, and tributylstannyl,
bulkier donor substituents, also favour 1,2-reduction but
the ratio is not as high (Table 3, entries 7–9). Electronwithdrawing substituents such as carbomethoxy and cyano exert a weak regiocontrol with sodium borohydride as
reducing agent (entries 10 and 11). The authors established that the steric effects of the reducing agent do not
disrupt the directive effect of the substituent at position 3,
although the trimethylsilyl and trialkylstannyl groups
gave increased amounts of 1,6-dihydropyridine with reducing agents such as potassium triisopropoxyborohydride, diisobutylaluminum hydride, and sodium tri(secbutyl)borohydride (entries 7–9).
RSO2Cl
or
(RSO2)2O
+
N
37
NaBH4
+
N
R = Me
R = Ph
R = 4-MeC6H4
R = 4-MeCONHC6H4
N
SO2
SO2
R
R
42
43
Scheme 9 Sodium borohydride reduction of N-sulfonylpyridinium
salts18
Table 3 Ratio of 1,2-, 1,4-, 1,6-Reduction Products Obtained in the Reduction of 3-Substituted Pyridines16
R1
NaBH4
K(i-PrO)3BHb
Li(t-BuO)3AlH
(i-Bu)2AlH
Na(s-Bu)3BH
1
Me
95:5:0
95:5:0b
95:5:0b
95:5:0c
60:20:20b
2
Et
95:5:0
95:5:0b
90:5:5b
75:15:10
45:20:35a,b
3
MeO
100:0:0
100:0:0b
100:0:0b
n.a.
n.a.
b
b
n.a.
n.a.
n.a.
n.a.
Entry
4
MeS
100:0:0
100:0:0
100:0:0
5
Cl
85:15:0
n.a.
n.a.
6
Br
90:10:0
n.a.
n.a.
b
n.a.
b
7
Me3Si
65:0:35
40:30:30b
35:0:65
25:0:75
8
Me3Sn
50:25:25
20:0:80b
20:0:80b
b
b
n.a.
c
33:0:67
33:33:33
0:0:100b
n.a.
n.a.
9
Bu3Sn
70:15:15
25:0:75
10:0:90
n.a.
n.a.
10
MeO2C
50:15:35
50:10:40b
n.a.
n.a.
n.a.
11
CN
15:55:30
–d
–d
n.a.
n.a.
a
Ratios were calculated by NMR integration of characteristic peaks; n.a. = not attempted.
In THF.
c
In CH2Cl2.
d
Negligible yield of reduction product.
b
Synthesis 2013, 45, A–AK
© Georg Thieme Verlag Stuttgart · New York
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F
REVIEW
and reactant at 25 °C, giving a product ratio of 2:1 for
compounds 42 and 43.
Kutney et al. considered the use of metal carbonyls such
as tricarbonylchromium(0) complexes in the stabilisation
of the reactive π-electron systems of dihydropyridines
(Scheme 10).19 Sodium borohydride was again considered
as reducing agent of compound 44, yielding the 1,2-dihydropyridine 45 in high yield (79%). However, it was
found that the product would easily form dimers at room
temperature. Therefore, the crude product was treated
with trisacetonitriletricarbonylchromium(0) for stabilisation purposes, affording a mixture of 46a and 46b with a
ratio of 65:35, respectively, in 67% yield. The authors
clarified that the formation of complex 46b should occur
through thermal isomerisation of the double bond during
complexation.19
LDA, –40 °C
(CO)3Cr
N
47
(CO)3Cr
N
48
Li
CH2=CHCH2Br
MeI
N
(CO)3Cr
50 (71%)
(CO)3Cr
1) LDA, –40 °C
2) MeI
(CO)3Cr
(CO)3Cr
1) MeLi, –78 °C
2) MeI
N
52 (90%)
Et2O
2 M NaOH
N
O
Me
45
CO2iPr
OiPr
1) Na, NH3
Cr(MeCN)3(CO)3
Et2O
0–20 °C
i
i
PrO2C
2) RX
X = Cl, Br or I
3) NH4Cl
N
53
N
R H
O
54a R = Me (99%)
54b R = Et (98%)
54c R = iBu (93%)
54d R = allyl (90%)
54e R = (CH2)3Cl (96%)
54f R = (CH2)4Cl (99%)
54g R = (CH2)5Cl (97%)
+2e
Cr(CO)3
Δ
OiPr
N
N
Me
O
Cr(CO)3
46a
Me
46b
Scheme 10 Stable formation of tricarbonylchromium(0) complexes
of 1,2-dihydropyridines 4619
i
PrO
N
O
55
PrO
O
OiPr
Davies, Edwards, and Shipton also showed later that tricarbonyl(η-pyridine)chromium(0) complexes were useful
stable synthetic precursors to 1,2-dihydropyridines.20 The
reaction of these complexes with diisobutylaluminium
hydride (DIBAL-H) or lithium diisopropylamide (LDA)
at –40 °C generated an intermediate stabilised carbanion
48 (Scheme 11), which underwent complete stereoselective electrophilic quenching with alkyl halides to generate
tricarbonyl(η-2-alkylpyridine)chromium(0) complexes
50. These complexes were subsequently subjected to nucleophilic additions with methyllithium followed by
methyl iodide quenching to afford (η-exo-6-alkyl-1,2-dimethyl-1,2-dihydropyridine)chromium(0) complexes 52
in good yield (90%).
The use of dissolving metals in the partial reduction of
pyridines to form 2-alkyl-1,2-dihydropyridines 54
(Scheme 12) was reported by Donohoe et al.21 The Birch
reduction of the electron-deficient pyridine 53 afforded,
according to the authors, 2-alkyl-1,2-dihydropyridines 54
in high yields ranging from 90 to 99% (Scheme 12). Another method was also used to achieve the partial reduction of pyridine 53. This method considered the use of
sodium and naphthalene in tetrahydrofuran, thereby
avoiding the use of liquid ammonia. Slightly lower yields
© Georg Thieme Verlag Stuttgart · New York
RX
iPrO
O
R
H
N
56
Scheme 12 Synthesis of 2-alkyl-1,2-dihydropyridines through partial reduction of electron-deficient pyridines21
ranging from 78 to 96% were obtained, however, for the
same substrates.
The authors discussed the possible formation of a stable
dianion 55 after the addition of two electrons (Scheme
12). The formation of an extended enolate 56 was favoured through the addition of an electrophile at C-2. Final treatment of the crude mixture with an excess of an
ammonium chloride solution promoted the protonation of
enolate 56, which led to the thermodynamically more stable isomer 54.21 These studies led to the conclusion that
the presence of two activating groups on the pyridine nucleus at C-2 and C-5 would allow, under the conditions
described, the alkylation at the most reactive site (C-2)
and subsequent protonation. The synthesised 1,2-dihydropyridines 54 were, however, proven to be sensitive to exposure to air and to easily take part in an autooxidation
and rearomatisation leading to loss of the R group at C-2.
Synthesis 2013, 45, A–AK
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Me
44
N
Me
Scheme 11 Synthesis of (η-exo-6-alkyl-1,2-dimethyl-1,2-dihydropyridine)chromium(0) complexes 5220
NaBH4
I
N
49 (74%)
51 (79%)
N
G
1,2-Dihydropyridines
REVIEW
E. M. P. Silva et al.
This strategy has been used by Donohoe’s research group
in the synthesis of dihydropyridones22 and also in the synthesis of natural product alkaloids of the cylindricine family.23
Marine metabolites such as clathrodin (63a), hymenidin
(63b) and oroidin (63c) have also been prepared through
the synthesis of new N-acylpyridinium salts 58, intermediates obtained directly from pyridine 37 and pyrrole-2carbonyl chlorides 57 by reduction with borohydride
(Scheme 13).24 The authors described that the reaction of
pyridine 37 with pyrrole-2-carbonyl chlorides 57 and subsequent reduction with borohydride led to a mixture of the
desired 1,2-dihydropyridines 59 as the major products
along with the 1,4-dihydropyridines 60 and also methyl2-pyrrole carboxylate. According to this report, the use of
methanol is determinant for the reduction of the N-acylpyridinium salts 58.
10 °C, under constant current conditions (15–20
mA/cm2).
The electrolysis reaction of dimethyl 2,3- and 2,5-pyridinedicarboxylates 64a,b led to the regioselective preparation of 1,2-dihydropyridine derivative 65a,b while the
reaction of 2,6-, 3,4- and 2,4-disubstituted pyridines 66c–
g afforded the corresponding 1,4-dihydropyridines in
good yields (Table 4). The products formed (65a,b and
66c–e) were protonated at the nitrogen atom (Z = NH).25
Table 4 Electroreductive Selective Synthesis of 1,2- or 1,4-Dihydropyridine Dicarboxylic Acid Derivatives25
R4
5
3
R
R6
R
Z
R2
+e
Pt(–)-C(+)
divided cell
MeOH
Et4NOTs
NH4Cl
R4
5
R
R6
64
Cl
H
N
R1
Cl
N
O
N
37
R2
57a R1 = R2 = H
57b R1 = H, R2 = Br
57c R1 = R2 = Br
O
58
NaBH4
MeOH–THF
78 °C
15 min
N
H
N
O
R1
R1
R2
N
H
N
H
N
O
R1
R2
R2
59a R1 = R2 = H (38%)
59b R1 = H, R2 = Br (24%)
59c R1 = R2 = Br (20%)
60a R1 = R2 = H (14%)
60b R1 = H, R2 = Br (5%)
60c R1 = R2 = Br (0%)
1) Br2 and protected
guanidine 61 or 62
2) H+ or NH2OH
O
N
H2N
N
H
NHBoc
H
N
R4
3
Z
5
R
R
R2
R6
65
R3
Z
R2
66
Substrate
Product, yield (%)
64a Z = N, R3 = R4 = R5 = H,
R1 = R2 = CO2Me
65a (Z = NH), 83
64b Z = N, R2 = R3 = R5 = H,
R1 = R4 = CO2Me
65b (Z = NH), 77
64c Z = N, R2 = R3 = R4 = H,
R1 = R5 = CO2Me
66c (Z = NH), 92
64d Z = N, R1 = R4 = R5 = H,
R2 = R3 = CO2Me
66d (Z = NH), 79
64e Z = N, R2 = R4 = R5 = H,
R1 = R3 = CO2Me
66e (Z = NH), 67
64f Z = +NMe I–, R1 = R4 = R5 = H,
R2 = R3 = CO2Me
66f (Z = NMe), 87
64g Z = +NBn Br–, R1 = R4 = R5 = H,
R2 = R3 = CO2Me
66g (Z = NBn), 80
64h Z = N, R1 = R3 = R4 = R5 = H,
R2 = CO2Me
no reaction
61 =
NH2
HN
R1
HN
R2
63a R1 = R2 = H, clathrodin (40%)
63b R1 = H, R2 = Br, hymenidin (42%)
63c R1 = R2 = Br, oroidin (71%)
N
62 =
N
NH2
Scheme 13 Synthesis of marine metabolites via N-acyl-1,2-dihydropyridine intermediates 5924
Nishigushi and co-workers reported the selective synthesis of dihydropyridine dicarboxylic acid derivatives 65 or
66 by direct hydrogenation of the corresponding pyridinecarboxylic acids 64 (Table 4).25 The electroreductive hydrogenation of compounds 64 was accomplished by using
a divided cell containing a platinum plate as the cathode
and a carbon rod as the anode. The reaction was carried
out using methanol as solvent, containing tetraethylammonium p-toluenesulfonate (Et4NOTs) as the supporting
electrolyte and ammonium chloride as the pH buffer, at 5–
Synthesis 2013, 45, A–AK
2.3
Nucleophilic Addition to Pyridines and Pyridinium Salts
The addition of a broad variety of nucleophiles to pyridinium salts has been the method of choice of numerous researchers looking to prepare complex and/or highly
functionalised dihydropyridines. The ability of an N-acyl
substituent to stabilise15 the dihydropyridine system has
prompted the use of these intermediates in the addition of
organometallic reagents to N-acylpyridinium salts. However, there are some potential difficulties in this strategy,
namely the close electrophilicity of 2-, 4- and 6-positions
on N-acylpyridinium salts, resulting in nonregioselective
additions. Also, to achieve high enantioselectivity when
considering asymmetric methods, the carbon–nitrogen
bond of the N-acylpyridinium intermediate should be
© Georg Thieme Verlag Stuttgart · New York
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H
REVIEW
I
1,2-Dihydropyridines
fixed in the transition state. Several research groups working in this field, however, have found ingenious methods
to circumvent both of these problems.
Recently, Charette and co-workers published a comprehensive review concerning the synthesis of pyridine and
dihydropyridine derivatives, by regio- and stereoselective
addition to N-activated pyridines.26 In this section, an
overview regarding exclusively the application of this
methodology to the synthesis of 1,2-dihydropyridine derivatives is described.
Table 5 Synthesis of 1-Acyl-2-alkyl-1,2-dihydropyridines 70a27
Comins et al. reported one of the first efficient chiral-auxiliary-mediated asymmetric synthesis of several 2-substituted 1-acyl-1,2-dihydropyridines 70. This procedure
involved the diastereoselective addition of Grignard reagents to chiral nonracemic N-acylpyridinium salts 69
(Scheme 14).27
N
67
68 R*OCOCl
Cl
N
CO2R*
69
1) RMgX
2) oxalic acid
silica gel
68a R* = (–)-8-(4-phenoxyphenyl)menthyl
68b R* = (–)-8-phenylmenthyl
+
R
N
CO2R*
70a
R
N
CO2R*
70b
Scheme 14 Asymmetric synthesis of 1-acyl-2-alkyl-1,2-dihydropyridines 7027
The authors selected 3-(triisopropylstannyl)pyridine (67)
as the starting material for this reaction since a large
blocking group at C-3 of the chiral pyridinium salts 69
would enhance the diastereoselectivity. The triisopropylstannyl group was also chosen in order to allow its removal under mild conditions, since the 1,2-dihydropyridines
are sensitive to acid. A drawback to this method is the difficulty of removing the chiral auxiliary due to the sensitive nature of the dihydropyridine system, although it
could be removed following reduction to the enantioenriched piperidine later used in the synthesis of (–)-Nmethylconiine.27
Several reactions were performed (Table 5) and the yields
obtained ranged from 58 to 87%. The diastereomeric excess was determined by HPLC or 1H NMR analyses and
reached high values, namely 92% for the reaction with 4tolylmagnesium bromide (Table 5, entry 8). The absolute
stereochemistry at C-2 of the 2-phenyl derivatives 70a
(R = Ph) was determined to be S by comparison to an authentic sample synthesised via a different three-step procedure. The 2-alkyl derivatives were determined to have
the R-configuration at C-2.
Comins and co-workers also combined the use of 4-methoxypyridine, a trialkylsilyl blocking group at C-3, and a
chiral nonracemic acyl chloride as an alternative approach
© Georg Thieme Verlag Stuttgart · New York
R*OCOCla RMgX
Yield (%) de (%)
1
68a
n-PrMgCl
72
82
2
68b
n-PrMgCl
81
78
3
68a
c-HexMgCl
81
91
4
68a
BnMgCl
58
76
5
68a
H2C=CHMgBr
71
90
6
68a
PhMgCl
85
89
7
68b
PhMgCl
87
84
8
68a
4-MeC6H4MgBr
86
92
a
Chiral auxiliaries: (–)-8-(4-phenoxyphenyl)menthyl chloroformate
(68a) and (–)-8-phenylmenthyl chloroformate (68b)
to blocking addition at the 4-position and produce dihydropyridones.28 This methodology generally involved the
diastereoselective addition of Grignard reagents to chiral
N-acyl pyridinium salts, formed from 4-methoxy-3-(triisopropylsilyl)pyridine (72) and the chloroformates of
menthyl derivatives (68b and 73a,b). Subsequent hydrolysis of the intermediate 4-methoxy-1,2-dihydropyridines
74 led to the formation of the desired dihydropyridones 75
(Scheme 15). The influence of the C-3 blocking group and
the chiral auxiliary was studied with the large triisopropylsilyl group being optimal, providing up to 97:3
diastereoselectivity for the synthesis of 2-(S)-phenyldihydropyridone.
OMe
N
71
LDA
Si(iPr)3Cl
THF
OMe
OMe
Si(iPr)3
N
72
Si(iPr)3
1) 73 (or 68b)
R*OCOCl
2) RMgX
3) H3O
R
N
CO2R*
74
68b R* = (–)-8-phenylmenthyl
73a R* = trans-(α-cumyl)cyclohexyl
73b R* = trans-(α-cumyl)-4-isopropylcyclohexyl
O
Si(iPr)3
R
N
CO2R*
75
Scheme 15 Diastereoselective addition of Grignard reagents to 4methoxy-3-(triisopropylsilyl)pyridine 7228
The formation of the dihydropyridones 75 was shown to
be rather valuable since they are stable products that allow
easier manipulation in the removal of both blocking group
and chiral auxiliary without disrupting the newly formed
chiral centre.
The advantage of transforming enantiopure heterocycles
such as dihydropyridones 75 was recognised by Comins’s
research group and a strategy to convert N-acyl-2,3-diSynthesis 2013, 45, A–AK
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Sn(iPr)3
Sn(iPr)3
Entry
REVIEW
E. M. P. Silva et al.
hydro-4-pyridones 76 into 4-chloro-1,2-dihydropyridines
77 using the Vilsmeier reagent was developed (Table 6).29
Si(iPr)3
O
Si(iPr)3
Table 6 Synthesis of 4-Chloro-1,2-dihydropyridines 77 by Conversion of N-Acyl-2,3-dihydro-4-pyridones 76 Using Vilsmeier
Reagent29
N
O
78
O
O
79a X = Br
79b X = Cl
Cl
O
O
O
80a X = Br
80b X = OTf (from 79b
using TMSOTf)
POCl3 (1 equiv), DMF
R1
ClCHCCl2, r.t., 2 d
N
R1
X
N
X
+
Si(iPr)3
N
MgBr
O
R2
O
R2
O
O
N
77
76
O
Entry
R1
R2
Yield (%)
1
n-Pr
OBn
96
2
c-Hex
(CH2)3Br
83
3
c-Hex
OCH2CH=CH2
92
4
Ph
OBn
86
5
(CH2)3CH=CHCO2Et
OBn
83
The scope of the reaction was studied by using several racemic N-acyl-2,3-dihydro-4-pyridones 76 with various Nacyl groups. In all cases, the desired product was obtained
in very good to excellent yields (Table 6). The use of only
one equivalent of Vilsmeier reagent under mild conditions
allowed the reaction to proceed successfully even when
the side chain (R1) was an α,β-unsaturated ester (Table 6,
entry 5).
Wanner and co-workers employed 3-(triisopropylsilyl)pyridine (78) and a chiral auxiliary acyl group derived
from 79 in the diastereoselective addition of Grignard reagent 81 to chiral N-acylpyridinium ions 80 (Scheme
16).30 This procedure allowed the synthesis of chiral Nacyl-1,2-dihydropyridine 82 in very high regio- and diastereoselectivity. The use of acyl chloride/bromide 79a or
79b led to compound 82 in modest yield but provided excellent diastereoselectivity. The yields were improved by
changing the bromide or chloride counterion of the
N-acylpyridinium to triflate with trimethylsilyl triflate
(TMSOTf), but this led to slightly reduced selectivity.
This method was applied to other substituted pyridine derivatives and also to several other Grignard reagents.
The addition of metal enolates or equivalents to pyridines
occurs at the 2-position only if a suitably substituted pyridine is used as substrate. Bennasar et al. explored the nucleophilic addition of ester enolates derived from 86 to 3acyl-2-fluoropyridinium salts 85, aiming to prepare 2and/or 4-substituted dihydropyridines (Scheme 17).31
Synthesis 2013, 45, A–AK
O
81
O
O
O
82 41%, dr 100:0 from 80a
62%, dr 94:6 from 80b
Scheme 16 Diastereoselective addition of Grignard reagent 81 to
chiral N-acylpyridinium ions 8030
R1OTf
84a R1 = Me
84b R1 = Bn
F
N
R1
TfO
N
F
O
85a R1 = Me
85b R1 = Bn
O
83
SMe
R2
CO2Me
86a R2 = H
86b R2 = Et
R1
N
F
R1
MeS
H
+
H
MeO2C
MeO2C
N
F
R2
O
2
SMe
R
O
88a R1 = Me, R2 = H (30%)
88b R1 = Me, R2 = Et (44%)
88c R1 = Bn, R2 = H (42%)
88d R1 = Bn, R2 = Et (55%)
87a R1 = Me, R2 = H (30%)
87b R1 = Me, R2 = Et (11%)
87c R1 = Bn, R2 = H (8%)
Scheme 17 Reactions of 3-acetyl-2-fluoropyridinium salts 85a,b
with lithium enolates derived from esters 86a,b31
The addition of the lithium enolate prepared from ester
86a to compound 85a led, however, to an equimolar mixture of 1,2- and 1,4-dihydropyridines 87a and 88a in 60%
yield (Scheme 17). The reaction was regioselective towards the formation of the 1,4-dihydropyridine 88c when
the reaction was performed using N-benzylpyridinium triflate 85b as electrophilic substrate and lithium enolate
prepared from ester 86a. A similar outcome was observed
when using the enolate derived from butyric ester 86b as
nucleophile and N-methylpyridinium triflate 85a. The
1,4-dihydropyridine 88d was the only product obtained by
reaction of compound 85b with the enolate derived from
86b.
© Georg Thieme Verlag Stuttgart · New York
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J
REVIEW
Wenkert et al., while studying the interaction of the indole-tethered pyridinium salt 89 with a mixture of lithium
diisopropylamide (LDA) and ethyl (methylthio)acetate,
reported that the carbanion 90 thus formed then reacted at
the C-6 position of the N-alkylpyridinium salt 89 (Scheme
18). The resulting 1,2-dihydropyridine 91 would then undergo ring-opening on treatment with one equivalent of
base to form a conjugated triene derivative 92 in 43%
yield.32
Et2OC
N
NH
H
MeS
MeS
O
Li
O
R1
+ Ph
R2
N
R2
N
+
–40 °C to r.t.
Ph
Me 2) R2MgX
N
93
1) TfO2, CH2Cl2
NH
N
94
Ph
N
Me
Me
95a
95b
Entry
R1
R2
1
Me
Me
89:11
80
2
Me
Ph
79:21
72
3
OMe
Me
>95:5
100
4
OMe
Ph
>95:5
94
5
Cl
Me
95:5
85
6
Cl
Ph
78:22
66
7
Br
Me
92:8
80
95a
/95b
Yield (%)
of 95a
O
CO2Et
The addition of organomagnesium reagents to 3-substituted N-imidoylpyridinium salts 96 derived from 93 and amide 94 (Table 7 and Figure 4), bearing an electrondonating group (EDG), has been studied by Charette and
co-workers.33 The approach relied upon the directing ability of the imidate group and resulted in a highly regioselective formation of 2,3-substituted 1,2-dihydropyridines
95a (Table 7).
According to the authors, it is the stereoselective formation of 96a with an E-conformation of the N-pyridinium
imidate (Figure 4) that leads to the formation of the 1,2adduct, explaining the regiocontrol of this reaction. In this
species, the nitrogen imidate lone pair is oriented toward
the C-2 position of the pyridinium, the correct positioning
to direct the delivery of an organometallic reagent to C-2
through chelation with the nitrogen lone pair. Also, the
success of this reaction has been attributed to the higher
reactivity of the pyridinium salts formed with a triflate as
counterion (less nucleophilic).
R2
N
TfO
Ph
Scheme 18 Addition of nucleophile 90 to the C-6 position of indoletethered pyridinium salt 8932
4
R1
SMe
92 (43%)
© Georg Thieme Verlag Stuttgart · New York
O
R1
R1
H
91
H
N
HN
NH
CO2Et
90
89
N
Table 7 Nucleophilic Addition of Methyl- and Phenylmagnesium
Bromide to 3-Substituted Pyridinium Salts Derived from 93 and Amide 9433
N
Me
(E)-96a
6
N
R1
2
MgBr
Ph
N
OTf
Me
(Z)-96b
Figure 4 Formation of (E)-imidate pyridinium salt 96a leads to the
regioselective addition of Grignard reagents33
The scope of this methodology was studied and the addition reactions were performed by using methyl- and
phenylmagnesium reagents as nucleophiles, N-methylbenzamide (94) and several substituted pyridines 93
(Table 7). The authors reported that all the reactions proceeded with good to excellent yields (66–100%) and gave
predominantly, and in some cases almost exclusively, 2,3disubstituted 1,2-dihydropyridines 95a. The minor isomers 95b occurred from nucleophile addition at C-6 and,
according to the authors, the 1,4-adducts were not observed in any of the reactions performed.
The authors also developed a diastereoselective version of
this reaction by using a chiral auxiliary integrated in the
amide (Scheme 19).33a,b
The addition of 4-methoxypyridine (71) to a mixture of
amide 97 and triflic anhydride at –78 °C led to the formation of the desired pyridinium salt 98. The pyridinium salt
solution was then cooled to –20 °C, and the ethereal solution of the Grignard reagent was added. Acidic workup of
the intermediate methyl enol ether led to the pyridinones
99 (Scheme 19). The addition of different Grignard re-
Synthesis 2013, 45, A–AK
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Through these studies the authors concluded that the regioselectivity of these reactions is ruled by steric effects.
Therefore, the C-4 attack seemed to be favoured by the introduction of bulky substituents at the pyridine nitrogen
and enolate. This practical strategy allowed the synthesis
of (+)-camptothecin and (±)-20-deoxycamptothecin starting from an N-(2-bromo-3-quinolylmethyl)-2-fluoropyridinium salt.31
Br
K
1,2-Dihydropyridines
REVIEW
E. M. P. Silva et al.
Table 8 Nucleophilic Addition to Pyridinium Salts 98 Derived from
4-Methoxypyridine 71 and Amide 9733
OMe
O
OMe
RMgBr
Yield (%)a
1
Me
85
95:5
2
Et
76
93:7
3
n-Bu
71
>95:5
4
t-Bu
61
93:7
Scheme 19 Nucleophilic addition to pyridinium salts 98 derived
from 4-methoxypyridine (71) and amide 9733a
5
(CH2)6OTBS
70
>95:5
6
(CH2)5CH=CH2
84
93:7
agents was attempted in these studies and all the reactions
performed led to the desired product (Table 8).
The best results were obtained with the use of methylmagnesium bromide, which furnished the product in 85%
yield and 95:5 diastereoselectivity. Even the use of tertbutylmagnesium bromide (Table 8, entry 4), a bulkier nucleophile, also led to the addition adduct in moderate yield
(61%) and excellent diastereoselectivity (93:7). The addition of vinyl-, phenyl- and furanylmagnesium bromides
led to the desired product with excellent stereocontrol (entries 7, 10 and 11). The addition of alkynylmagnesium reagents resulted in a lower selectivity (entries 8 and 9). The
diastereoselective variant of this method was used in the
total synthesis of (–)-L-733,061 and (–)-CP-99,994, two
substituted piperidines recognised as substance P antagonists.33b
7
CH=CH2
64
92:8
8
C≡CMe
52d
83:17
9
C≡CPh
65
89:11
10
Ph
66
91:9
11
furanyl
65
95:5
Entry
N
TfO2
CH2Cl2
71
+
O
Ph
N
–78 °C to r.t. Ph
N
H
RMgBr
Et2O
OTf
Ph
then HCl
N
R
N
N
OMe
OMe
OMe
99a–k (60–85%)
98
97
a
Products isolated as a single diastereomer.
Determined by 1H NMR of the crude product.
c
Mixture of diastereomers (dr = 13:1).
d
The minor diastereomer was isolated in 8% yield.
b
groups at the 3- and 5-positions. The additional electronwithdrawing substituent at the C-5 position ensured a
higher stability of the final product.
Several organocuprate reagents were tested in this reaction and the results obtained in these studies are gathered
in Table 9. The authors reported that the use of alkyl cyanocuprates (entries 1 and 2) gave low yields of mixtures
containing C-4 and C-6 products (102b,c and 103b,c).
The most efficient copper reagents for the regioselective
introduction of an alkyl group at the C-4 position of the
pyridine ring were the Gilman homocuprates (entries 3
and 4).
The (phenylethynyl)copper reagents (entries 5–7) gave
mixtures of C-2 and C-6 adducts (104a and 104c), reacting preferentially at the α-position of the pyridine ring. Interestingly, the Grignard reagent (PhC≡C)Cu(CN)(ZnCl)
The addition of organocopper reagents to N-alkyl- and Nacylpyridinium salts has found application in this field
and the most common copper sources used in the preparation of the organocopper reagents are copper(I) iodide and
copper(I) chloride. Bennasar et al. considered the addition
of a series of nonaromatic organocuprates (alkyl, vinyl,
allyl and ethynyl) to 3-acyl-N-alkylpyridinium salts 100
(Scheme 20), followed by acylation of the intermediate
1,4- or 1,2-dihydropyridines with trichloroacetic anhydride (TCAA).34 The use of this type of nucleophile allowed the preparation of diversely substituted 1,2- and
1,4-dihydropyridines bearing electron-withdrawing
Me
N
Me
Me
I
‘RCu’
101c
Me
Me
N
R
R
+
Cl3COC
CO2Me
R
101b
101a
Me
CO2Me
102a–107a
N
+
CO2Me
CO2Me
100
TCAA
R
+
CO2Me
N
Me
N
R
N
N
+
Cl3COC
c
drb
CO2Me
R
102b–107b
Cl3COC
CO2Me
102c–107c
102 R = Me
103 R = Bu
104 R = Ph
105 R = CH2=CH-CH2
106 R = CH2=CH
107 R = PhC(=CH2)
Scheme 20 Addition of organocopper reagents to N-alkylpyridinium salts 100 followed by acylation of the intermediate 101a–c with trichloroacetic anhydride34a
Synthesis 2013, 45, A–AK
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L
1,2-Dihydropyridines
Table 9 Reactions of Pyridinium Salt 100 with Organocopper Reagents with Subsequent TCAA Acylation34a
Entry
RCu
Ratio a/b/c
(product)
Yield
(%)
1
Me2Cu(CN)Li2
0:10:90 (102)
20
2
Bu2Cu(CN)Li2
0:55:45 (103)
20
3
Me2CuLi
0:70:30 (102)
40
4
Bu2CuLi
0:90:10 (103)
77
5
(PhC≡C)2Cu(CN)Li2
50:0:50 (104)
68
6
(PhC≡C)Cu(CN)Li
40:0:60 (104)
30
7
(PhC≡C)2Cu(CN)(ZnCl)2
20:0:80 (104)
18
8
(PhC≡C)Cu(CN)(ZnCl)
0:0:100 (104)
<10
9
(PhC≡C)MgBr, CuI (cat.)
100:0:0 (104)
65
10
(CH2=CHCH2)2CuLi
40:20:40 (105)
86
11
(CH2=CHCH2)2Cu(CN)Li2
50:0:50 (105)
75
12
(CH2=CH)2CuLi
50:0:50 (106)
30
13
(CH2=CH)2Cu(CN)Li2
40:20:40 (106)
55
14
(CH2=CH)MeCu(CN)Li2
30:40:30 (106)
60
15
[(PhC(=CH2)]MeCu(CN)Li2
0:20:80 (107)
90
16
[(PhC(=CH2)]MgBr, CuI (cat.)
0:15:85 (107)
65
(entry 8) afforded exclusively the C-6 product 104c, albeit
in very low yield (< 10%). In contrast, the copper-catalysed Grignard reagent (PhC≡C)MgBr (entry 9) afforded
exclusively the C-2 product 104a in 65% yield. The authors attribute this perfect regioselectivity to a probable
coordination between magnesium and the carbonyl oxygen atom of compound 100. This preferential attack at the
α-position was also observed for the allylcopper reagents
(entries 10 and 11) with the adducts 105a,c being formed
in good yields. The introduction of a non-substituted vinyl
group also led preferentially to the α-adducts (entries 12
and 13). The results obtained showed that mostly dialkylcuprates showed preferential addition at the C-4 position
(entries 2–4), whereas harder alkynyl and alkenyl cuprates
displayed higher C-2 and C-6 selectivity. The authors
concluded that lower basicity of the organocuprates could
be correlated with higher C-6 selectivity, although the
products were obtained with considerably lower yields
when these reagents were used (entries 7 and 8).34a
In 2002, the same research group extended the scope of
this reaction to the use of functionalised arylmagnesium
reagents. These nucleophiles possessed different electronwithdrawing groups at the ortho or meta positions and the
electrophile selected was the N-methylpyridinium iodide
100 (Table 10).35 Some of the experiments performed produced significant amounts of C-6 or C-2 adducts. In fact,
the only product obtained when the reaction was performed using 2- or 3-(ethoxycarbonyl)phenylmagnesium
bromide and no copper source was the C-2 adduct 109 in
© Georg Thieme Verlag Stuttgart · New York
M
54 and 35% yield, respectively (entries 12 and 15). Interestingly, when these reactions were performed using a
copper salt, the proportion of the C-4 adduct increased
(compare entries 12–14 and 15–17). An increase of the C6 regioselectivity, along with a higher overall yield, was
also observed when the organomagnesium cyanocuprate
was used (entries 7 and 11). The authors then focused
their attention in improving the C-4 regioselectivity by using a pyridinium substrate that had the 2- and 6-positions
sterically shielded by a bulky and easily removable substituent on the nitrogen atom.35
In 2011, Pineschi and co-workers reported the activation
of acetic anhydride using catalytic amounts of copper(II)
triflate and subsequent regioselective introduction of a
methoxycarbonylmethyl group at the C-2 position of unsubstituted pyridine. This method allowed the practical
synthesis of N-acetyl-1,2-dihydropyridyl acetic acid 113
(Table 11).36
In their studies, Pineschi and co-workers surveyed several
Lewis acids as promoters of this reaction and analysed the
regioisomeric ratios of the addition products in the crude
mixture. The results obtained by the authors are summarised in Table 11. A lack of reactivity was observed in
a control reaction where no metal was used, confirming
the need of a Lewis acid that coordinates to the carbonyl
oxygen of the acetic anhydride, thereby assisting the formation of a metal enolate species. No reactivity was observed when copper(II) chloride or copper(I) chloride was
used (Table 11, entries 2 and 3).
The best result was obtained with copper(II) triflate (entry
1) and it was observed that with the increase of the reaction time, the molar amount of products per mole of catalyst (turnover number; TON) also improved (entry 8). A
similar regioselectivity was observed with zinc(II) triflate
(entry 7) leading to a 80:20 ratio of compounds 113 and
114.
A further advance came in 2005 as Kim and co-workers
developed the synthesis of 1-acyl-1,2-dihydropyridines
115 by efficient introduction of aryl acetylenes at the C-2
position of pyridinium salts mediated by the use of zinc
salts in stoichiometric quantity (Scheme 21).37 The reaction was performed by in situ generation of the 1-ethoxycarbonylpyridinium chloride by mixing pyridine and
ethyl chloroformate in acetonitrile at room temperature.
Phenylacetylene was then added in the presence of zinc
bromide and N,N-diisopropylethylamine (DIPEA), affording the desired product 115a in 72% yield (Scheme
21). When benzoyl chloride was used to form the 1-acylpyridinium salt, the desired product 115b was obtained in
a lower yield (63%).
1-Acylquinolinium and 1-acylisoquinolinium salts were
also successfully used as electrophiles in this reaction. Ma
and co-workers38 reported an asymmetric version of this
reaction, demonstrating that the copper-catalysed reaction
can be performed in high levels of enantioselectivity using
chiral bis(oxazoline) ligands. The reaction of ethyl propiolate with 1-acylpyridinium salts 116 (Scheme 22) was
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REVIEW
N
REVIEW
E. M. P. Silva et al.
Table 10 Copper-Mediated Addition of Aryl Cuprates Reagents 108 to N-Alkylpyridinium Salts 10035
Me
N
Me
I
+
R1
CO2Me
2) TCAA
N
N
1) Cu(I)
Cl3COC
+
Cl3COC
CO2Me
109
108
N
+
CO2Me
Cl3COC
R1
100
Me
R1
R1
110
CO2Me
111
X
R1
Cu(I) salt (equiv)
Ratioa 109/110/111
Overall yield (%)
1
Cl
H
CuI (0.025)
0:1:0
90
2
Cl
H
CuI (0.5)
0:5:1
95
3
Cl
H
CuCN (0.5)
0:1:0
35
4
Cl
2-CF3
none
1:3:2
80
5
Cl
2-CF3
CuI (0.025)
0:2:1
70
6
Cl
2-CF3
CuI (0.5)
0:5:4
80
7
Cl
2-CF3
CuCN (0.5)
0:1:4
90
8
Cl
2-Cl
none
1:0:8
80
9
Cl
2-Cl
CuBr·SMe2 (0.025)
1:5:8
80
10
Cl
2-Cl
CuI (0.5)
0:1:1
90
11
Cl
2-Cl
CuCN (0.5)
0:1:2
87
12
Br
2-CO2Et
none
1:0:0
54
13
Br
2-CO2Et
CuI (0.025)
1:2:1
30
14
Br
2-CO2Et
CuI (0.5)
0:1:0
35
15
Br
3-CO2Et
none
1:0:0
35
16
Br
3-CO2Et
CuI (0.025)
3:1:0
40
17
Br
3-CO2Et
CuI (0.5)
1:3:0
45
Entry
a
The regioisomeric ratio was determined by 1H NMR analysis based on the chemical shifts of the dihydropyridine moiety.
used as model reaction to study the influence of the several selected ligands, solvents, and bases. An initial screening of the best ligand was performed using N,Ndiisopropylethylamine as base and dichloromethane as
solvent. The best results obtained were observed with the
less bulky bis(oxazoline) ligands 119b and 119c, leading
to enantioselectivities of 87 and 88%, respectively. When
the base was replaced by N,N-diisopropylpropylamine
[(i-Pr)2N(n-Pr)] and 119c used as ligand, the greatest enantioselectivity was achieved (94%).
The solvent was found to have an influence on the asymmetric induction. Under the same conditions (119c as ligand and DIPEA as base), the best result was obtained
using dichloromethane (72% yield and 86% ee). The use
of chloroform led to a higher yield (77%) and a slightly
lower enantioselectivity (83% ee). The enantioselectivity
dropped to 55% when the reaction was performed in acetonitrile.
Synthesis 2013, 45, A–AK
The authors studied the scope of the reaction using the optimised conditions and varying the 1-alkyne reagent. The
experiments performed and the results collected in Table
12 led to some important conclusions. For example, the
size of the propiolate had a direct influence on the enantioselectivity of the reaction. The use of benzyl propiolate
(Table 12, entry 3) decreased the enantioselectivity (86%
ee) when compared with the use of methyl or ethyl propiolate that gave almost identical yields and selectivity (entries 1 and 2). It was also found that the increase of the
chain length of the ynones (entries 5–8) led to a gradual
decrease of the enantioselectivity, with the highest value
being obtained when using pent-1-yn-3-one (entry 5). The
use of unactivated alkynes (entries 9–11) led to the desired product in good yields ranging from 63 to 77%;
however, almost no asymmetry was induced when using
these alkynes. These experiments led to the reasoning that
the carbonyl group in the 3-position of the 1-alkynes was
© Georg Thieme Verlag Stuttgart · New York
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MgX
Me
REVIEW
Table 11 Screening of Lewis Acid as Promoter of the Regioselective
Synthesis of N-Acetyl-1,2-dihydropyridyl Acetic Acid 11336
CuI, ligand, base
+
O
OAc
N
Entry
N
N
116a R = Me
116b R = iBu
116c R = Bn
117a R = Me
117b R = iBu
117c R = Bn
R1
O
Ratio 113/114
1
Cu(OTf)2
85:15
2
CuCl2
–
3
CuCl
–
4
FeCl3
70:30
5
Sc(OTf)3
75:25
6
MgBr2
68:32
7
Zn(OTf)2
80:20
Cu(OTf)2
85:15
8b
a
O
O
N
N
CO2Et
R2
O
a
Lewis acid (LA)
N
CO2R
Ac
114
Ac
113
Ac
112
CO2Et
N
N
N
R
R
118a R = Ph
118b R = Bn
119a R1 = R2 = Me
119b R1–R2 = CH2CH2
119c R1 = R2 = H
Scheme 22 Enantioselective addition of terminal alkynes to 1-acylpyridinium salts 116 catalysed by copper–bis(oxazoline) complexes38
Table 12 Copper Iodide Catalysed Addition of 1-Alkynes to
1-Acylpyridinium Salt 116a Using Chiral Ligand 119c38
Entry
Alkyne
Time (h) Yield (%) ee (%)
1
HC≡CCO2Et
15
72
94
2
HC≡CCO2Me
15
74
95
3
HC≡CCO2Bn
15
81
86
4
HC≡CAc
15
69
93
5
HC≡CCOEt
15
65
99
Ph
6
HC≡CCO(CH2)3Me
15
70
91
115a R = OEt (72%)
115b R = Ph (63%)
7
HC≡CCO(CH2)4Me
15
68
90
8
HC≡CCO(CH2)3OBn
15
70
77
9
HC≡CPh
12
75
1
10
HC≡C(CH2)3Me
17
63
11
11
HC≡CCH2OAc
15
77
3
1
Determined by H NMR of the crude mixture.
b
Reaction time was 7 days. All the other reactions were left for 24
hours.
1) PhCOCl or ClCOOEt (1.3 equiv)
2) PhC≡CH (1.2 equiv)
N
37
3) ZnBr2 (1.2 equiv)
4) DIPEA (1.2 equiv)
CH3CN, r.t., 30 min
N
O
R
Scheme 21 Synthesis of 1-acyl-1,2-dihydropyridines 115 by efficient introduction of aryl acetylenes to pyridinium salts37
essential for the enantioselectivity of the addition. The authors provided some hypotheses to justify the importance
of this functional group, namely that the electron-withdrawing property of the carbonyl group would enhance
the conformational stability of the transition state, or
would result in π-stacking with another group in the substrate or with the copper complex, thereby leading to a
high degree of asymmetric induction.
In 2008, an asymmetric copper(I)-catalysed version of
this reaction using chiral phosphorus ligands was reported
by Arndtsen and co-workers.39 The authors developed a
regioselective and mild room-temperature method to directly alkynylate the pyridine ring at the 2-position using
copper iodide as catalyst. A screening of several commercially available chiral phosphorus- and nitrogen-donor ligands, using the pyridine as substrate and phenylacetylene
as nucleophile, resulted in racemic mixtures. These ligands included (R)-Tol-BINAP, (R)-iPr-PYBOX, (R)-
© Georg Thieme Verlag Stuttgart · New York
i
Bu-BOX, (R)-MONOPHOS, and (R)-MOP. The only encouraging result obtained by the authors involved the use
of (R)-QUINAP which yielded the functionalised 1,2-dihydropyridine 122 (R1 = H) in low yield (17%) although
with moderate enantiomeric excess (49%). Similar selectivity was observed in the alkynylation of quinoline, but
the desired product was obtained in higher yield (86%).
Several PINAP derivatives were also tested and the enantioselectivity was generally improved with this series of
chiral ligands (41–81% ee). Since these ligands can be
easily modulated, the authors prepared two new variants
of these ligands, 123a and 123b (Scheme 23). In the case
where ligand 123b was used, the 1,2-adduct was obtained
in 92% yield and up to 81% enantioselectivity.
Synthesis 2013, 45, A–AK
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37
LA
HO2C
solvent, –78 °C, 15 h
CO2R
LA
Ac2O
Cl
N
HOOC
N
O
1,2-Dihydropyridines
REVIEW
E. M. P. Silva et al.
O
N
Ph
+
+
Cl
EtO
R1
H
121
CuCl (5 mol%)
123 (5.5 mol%)
120
X
i
Pr2NEt
CH2Cl2–MeCN
–78 °C, 14 h
O
OEt
HN
Ph
N
N
Ph
N
PPh2
MeO
R1 122
up to 92% yield
up to 81% ee
123a X = C(Bn)2OH
123b X = Me
Scheme 23 Copper-catalysed addition of terminal alkynes 121 to
pyridine 120 using chiral phosphorus ligands 12339
The scope of this copper-catalysed nucleophilic addition
of alkynes was explored by testing the reactivity of other
heterocycles. It was shown that a considerable number of
nitrogen-containing heterocycles, including quinoline,
isoquinoline, and their functionalised counterparts, could
also undergo alkynylation exclusively at the 2-position of
the heterocyclic ring. Electron-rich and electron-poor alkynes were also employed in this coupling and most of
these reactions proceeded in high yield (72–92%) and reasonable enantioselectivity (62–84% ee).
Nadeau et al.40 recently described the highly enantioselective catalytic asymmetric addition of aryl and alkenylboronic acids to N-benzylnicotinate salt 124 (Scheme 24).
The methodology was developed with consideration of
the possible transformation of the obtained 1,2-dihydropyridine products 125 into synthetically useful piperidines. These studies led to the preparation of 6-substituted
dihydropyridines 125 isolated in 23–83% yields and 83–
99% enantioselectivities. The reaction limitations were
evaluated with regard to the best solvent, ligand and rhodium source.
The addition reaction of phenylboronic acid to compound
124 was initially performed at 60 °C using BINAP as ligand and, as rhodium source, the bis(1,5-cyclooctadi-
ene)rhodium(I) tetrafluoroborate [Rh(cod)2BF4] catalyst.
Under these conditions, a solvent screening was performed. The authors realised that the solvents have an important impact on reaction yield with 1,4-dioxane
providing the best result (82%) while 2-methyltetrahydrofuran led to the lowest conversion (43%). In all cases the
dihydropyridine 125 (R = Ph) was obtained in high enantioselectivity. The solvent change had little effect on the
asymmetric addition (90–93% ee). All other rhodium
sources tested led to lower yield or decreased enantioselectivity. The use of sodium carbonate was found to be
critical with no product being formed in its absence. More
than 120 ligands were screened for this reaction and, generally, axial chiral biphosphines gave higher enentioselectivities for dihydropyridine 125 (R = Ph). The ligand
giving the best enantioselectivity (99% ee) was found to
be CTH-P-Phos (126; Scheme 24).
The scope of this transformation in what concerns the boronic acids was also investigated using the optimised conditions (Table 13). Overall, an evident regioselective
preference towards the 6-substituted dihydropyridines
125 over the 4-substituted isomers (> 20:1) was observed.
The reaction tolerated para- or ortho-alkyl substituents on
the arylboronic acid, leading to good yields and good enantioselectivities (Table 13, entries 2 and 3). No effect
was observed in the good enantioselectivities obtained in
this transformation by the use of either electron-donating
or electron-withdrawing substituents on the aromatic ring
(entries 4–7, 94–97% ee), but the nitro group led to a considerably lower isolated yield (23%; entry 7). Halogensubstituted arylboronic acids afforded the corresponding
dihydropyridines 125 in excellent enantioselectivities
(99% ee). The reactivity of an alkenylboronic acid was
also studied and the desired product was obtained in 40%
yield and 83% ee (entry 10).
The treatment of quinoline or isoquinoline with acyl chloride and potassium cyanide gives, after hydrolysis of the
Reissert product, quinaldic acid. This transformation,
Table 13 Enantioselective Addition of Boronic Acids to N-Benzylnicotinate Salt 12440
Entry
O
OMe
Br
R
OMe
Ph
Yield (%)
ee (%)
1
Ph
73
99
2
4-MeC6H4
83
97
3
2-MeC6H4
70
84
4
4-MeOC6H4
77
95
5
4-MeO2CC6H4
68
97
6
4-AcC6H4
71
96
7
4-O2NC6H4
23
94
8
4-ClC6H4
64
99
9
4-FC6H4
69
99
Me(CH2)2CH=CH
40
83
OMe
dioxane–H2O, 60 °C
N
R [RB(OH)2]
O
RB(OH)2, Rh(cod)2BF4
(R)-CTH-P-Phos, Na2CO3
N
Ph
N
124
125
MeO
PPh2
MeO
PPh2
N
OMe
(R)-CTH-P-Phos
126
Scheme 24 Rhodium-catalysed enantioselective addition of boronic
acids to N-benzylnicotinate salt 12440
Synthesis 2013, 45, A–AK
10
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P
REVIEW
R1
O
R2
N
127
TMSCN (2 equiv)
NC
R3OCOCl (1.4 equiv)
CH2Cl2, 60 °C
R1
O
Et2AlCl (5 or 10 mol%)
ligand (10 mol%)
O
R2
R2
+
N
N
OR3
O
CN
OR3
O
128
129
X
S
lents of ethyl chloroformate at –78 °C in dichloromethane.
The two isomeric products were obtained in a 1:1 ratio. To
study the effect of sulfoxide as Lewis acid and try to improve these results, the authors used catalysts 131a–c.
These bifunctional catalysts also contained additional chirality in the sulfur atoms which was proved to enhance the
regio- and enantioselectivity of the reaction.
The metal-to-ligand ratio was also screened for optimal
results. Excellent regioselectivities (from 12:1 to 50:1) for
the 1,6-adduct 128 and enantioselectivities of up to 96%
were achieved using several chloroformates (Table 14,
entries 1–4).
Suginome and co-workers42 recently reported the addition
of silylboronic esters to pyridine in the presence of a palladium catalyst leading to N-boryl-4-silyl-1,4-dihydropyridines in high yield. Regioselective 1,4-siloboration
was observed in the reaction of 2-methylpyridine and 3substituted pyridines. In what concerns the 4-substituted
pyridines 132, the 1,2-silaboration took place to give Nboryl-2-silyl-1,2-dihydropyridines 134 regioselectively
(Scheme 26).
X1
Y1
OH
OH
OH
OH
R
+
X2
X
131a X1, X2 = O ; Y1, Y2 = Ph
131b X1, X2 = Ph; Y1, Y2 = O
131c X1, X2 = Ph; X2, Y1 = O
X
N
132a R = Me
132b R = Ph
132c R = SiMe2Ph
O
R
(2.0 mol%)
Si B
Me
S
Y2
130a X = P(O)Ph2
130b X = P(S)Ph2
130c X = P(S)(2-EtC6H4)2
Me
Cl
Pd
PHCy3
O
133a X = Ph
133b X = Cl
C6D6
50 °C
N
SiMe2X
B(pin)
134a R = Me, X = Ph (79%)
134b R = Ph, X = Ph (81%)
134c R = Ph, X = Cl (93%)
134d SiMe2Ph, X = Cl (91%)
Scheme 25 Catalytic enantioselective Reissert reaction of pyridine
derivatives 127 using a bifunctional Lewis acid–Lewis base
catalysts41
Scheme 26 Palladium-catalysed regioselective synthesis of silylated
dihydropyridines 13442
When the reaction was performed using compound 127
(R1 = H, R2 = NMe2) the two possible dihydropyridines
128 and 129 were obtained in excellent yield (91%) using
10 mol% of diethylaluminium chloride, 10 mol% of 130a,
2 equivalents of trimethylsilyl cyanide, and 1.4 equiva-
The introduction of boryl and silyl groups in these substrates was achieved efficiently using a palladium catalyst
bearing tricyclohexylphosphine (PCy3) as ligand. The
complex consisted of palladium and ligand in a 1:1 ratio
which was found to be crucial for the high catalyst activi-
Table 14 Catalytic Enantioselective Reissert Reaction of Pyridine Derivatives 12741
Entry
R 1, R 2
R3
Ligand
1
NMe2, H
Me
131c
5
98
91
2
NMe2, H
Fmb
131c
5
89
93
3
Ni-Pr2, H
Fm
b
131c
5
98
96
4
Ni-Pr2, H
neopentyl
131c
5
98
93
5
OMe, H
Fmb
131c
5
42c
>99c
6
Ni-Pr2, Cl
neopentyl
130c
27
92
91
7
Ni-Pr2, Br
neopentyl
130c
36
91
86
Time (h)
Yield (%)a
ee (%)
a
Isolated yield of the 1,6-adduct.
Fm = fluorenylmethyl.
c
After recrystallisation.
b
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, A–AK
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known as the Reissert reaction, was applied by Shibasaki
and co-workers41 to pyridine derivatives 127 yielding two
possible products, the 1,6-adduct 128 and 1,2-adduct 129
(Scheme 25). It was found that achiral nicotinic amide 127
(R1 = H, R2 = NMe2) was a suitable substrate for this
strategy and a catalytic enantioselective Reissert reaction
was developed using bifunctional catalysts such as 130
and 131. According to the authors, the basic concept of
this methodology comprised dual activation of the electrophile (N-acylpyridinium salt) and nucleophile
(TMSCN) by the Lewis acid (aluminum) and the Lewis
base (phosphine oxide or sulfoxide) moieties of the asymmetric catalysts 130 or 131, which would control the access of the nucleophile to the substrate.
R1
Q
1,2-Dihydropyridines
REVIEW
E. M. P. Silva et al.
ty. The temperature also played an important role in this
reaction, with high conversion into the desired product being obtained at 50 °C in toluene (94%), no reaction at 25
°C, and reduced yield (44%) at 80 °C. A possible catalytic
cycle was proposed by the authors and is shown in
Scheme 27.
SiMe2X
LPd(0)
N
B(pin)
B(pin)
XMe2Si
SiMe2X
N
Cl
N
R1O2C
B(pin)
N
B(pin)
II
L Pd B(pin)
SiMe2X
I
Scheme 27 Possible reaction mechanism for the synthesis of dihydropyridines catalysed by palladium42
The coordination of pyridine and oxidative addition of silylboronic ester to palladium(0) leads to the formation of
complex I. A π-allyl–palladium complex II is formed
through the regioselective insertion of pyridine into the
palladium–boron bond with introduction of the boryl
group onto the nitrogen atom. Finally, reductive elimination from complex II leads to the formation of dihydropyridine and regeneration of palladium(0). Formation of
the stable boron–nitrogen bond may, according to the authors, facilitate the formation of complex II in the catalytic cycle.
The same group reported in 2012 a similar strategy, this
time using a rhodium catalyst.43 The regioselective synthesis of N-boryl-1,2-dihydropyridines was achieved in
high yields using a rhodium catalyst bearing tricyclohexylphosphine as ligand. This reaction also took place when
substituted pyridines were used, with the desired product
being obtained in yields ranging from 58 to 96%.
Loh et al. reported an indium-promoted allylation of
N-acylpyridinium salts. This reaction was carried out in
N,N-dimethylformamide and allowed the regioselective
synthesis of 1,2-dihydropyridines 137 in good yields
(Scheme 28).44 The allylation was performed using several substituted allyl bromides and all the reactions gave exclusively the 1,2-product in moderate to high yields,
except for the allylation reaction using the 1-ethoxycarbonylpyridinium salt. This methodology was afterwards applied in a short and efficient synthesis of the alkaloid (±)dihydropinidine (138).
Activated η2-pyridinium species coordinated to tungsten
have been used to block addition at undesired sites.45 This
strategy developed by Harman and co-workers provides
access to η2-1,2-dihydropyridine complexes. The authors
showed that N-acylpyridinium complex 139 reacted with
Synthesis 2013, 45, A–AK
R2
137a R1 = Et, R2 = R3 = H (23%)
137b R1 = Ph, R2 = R3 = H (65%)
137c R1 = Ph, R2 = H, R3 = Me (68%)
137d R1 = Ph, R2 = H, R3 = CO2Me (70%)
137e R1 = Ph, R2 = Me, R3 = H (75%)a
137f R1 = Ph, R2 = Me, R3 = CO2Me (75%)a
137g R1 = Ph, R2 = CO2Et, R3 = H (70%)a
a Relative stereochemistry not assigned.
XMe2Si
N
Br
R3
136
R3
X = Ph or Cl
Pd
L
R2
CO2R1
135
N
H
138
(±)-dihydropinidine
N
37
or
N
In, DMF, 16 h
R1OCOCl
N
37
Scheme 28 Regioselective indium-mediated synthesis of allylated
dihydropyridines 13744
a broad range of nucleophilic reagents, including trimethylsilyl cyanide, Grignard reagents, indole, allyl bromide,
and nitromethane, in moderate to good yields (Table 15).
Table 15 Broad Scope of Nucleophilic Addition to Tungsten Complexes of N-Acylpyridinium Salts 13945
[W]
[W]
a
conditions
N
N
OTf
R
COMe
COMe
139
140
[W] = {TpW(NO)(PMe3)}
Entry
Conditions
R
Yield (%)
1
NaBH4, MeOH
H
89
2
ZnEt2
Et
88
3
TMSCN, DABCO
CN
88
4
indole, 2,6-lutidine
3-indolyl
61
5
MeMgBr
Me
57
6
Zn(0), BrCH2CO2Me
BrCH2CO2Me
87
7
Zn(0), BrCH2CH=CH2
CH2CH=CH2
89
8
MeLi, HC≡CSiMe3, ZnBr2
C≡CSiMe3
89
9
MeNO2, Et3N
CH2NO2
88
a
With coordination dr > 10:1.
In all cases examined, the addition occurred at C-2 of the
pyridinium salt with high regio- and diastereoselectivity,
where the nucleophile added to the face opposite (anti) to
the metal fragment. Subsequently, the authors explored
the reactivity of the 1,2-dihydropyridine complexes in cyclocondensation reactions and reductive transformations
leading to a variety of substituted piperidines.46
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R
REVIEW
Lavilla et al. performed the nucleophilic addition of indoles and pyrroles to various N-acetyl- and N-alkylpyridinium salts under phase-transfer-catalysis conditions
(Scheme 29).47 The interaction of 141 with 142 in the
presence of 50% aqueous sodium hydroxide with tetrabutylammonium hydrogen sulfate afforded the desired products in modest to high yields. In all cases the reactions
were performed at room temperature for 24 hours.
Table 16 Addition of Indole 142 to N-Alkylpyridinium Salts 141 Using Phase-Transfer Catalysis47
R1
R2
Solvent
Ratio
C-2/C-4
Total yield
(%)
1
Bn
CN
CH2Cl2
50:50
26
2
Bn
CN
toluene
0:100
99
3
Bn
Ac
CH2Cl2
100:0
20
4
Bn
Ac
toluene
–
–
5
Bn
CO2Me
CH2Cl2
88:12
75
6
Bn
CO2Me
toluene
50:50
90
7
Bn
CONH2
CH2Cl2
100:0
35
N
8
Bn
CONH2
toluene
0:100
99
R1
9
(CH2)3Ph
CONH2
CH2Cl2
0:100
84
10
(CH2)3Ph
CONH2
toluene
0:100
94
R2
NH
N
Entry
I
R1
141
S
1,2-Dihydropyridines
R2
R2
Bu4N HSO4
N
50% NaOH (aq)
solvent
R1
NH
143
NH
144
Scheme 29 Addition of indole 142 to N-alkylpyridinium salts 141
using phase-transfer catalysis47
The regioselectivity of this reaction was greatly influenced by the nature of the solvent (Table 16). The authors
demonstrated that 1,2-dihydropyridines 143 were the favoured products when dichloromethane was used (Table
16, entries 3, 5 and 7), whereas 1,4-dihydropyridines 144
were isolated as the major regioisomers when toluene was
used as solvent (entries 2, 8 and 10). Entry 9, where dichloromethane was used, was the exception in that it favoured formation of the 1,4-isomer 144. The asymmetric
version of this reaction was also studied concerning the
reaction
of
compounds
141
[R1 = (CH2)3Ph,
2
R = CONH2] and 142 in the presence of N-benzylcinchonidinium chloride leading to compound 144
[R1 = (CH2)3Ph, R2 = CONH2] in 84% yield. Resolution
of the racemic mixture of 144 was performed by HPLC on
a chiral stationary phase but the results obtained were
quite modest (11% ee).
Pericyclic Reactions
One of the main synthetic approaches for the synthesis of
1,2-dihydropyridines is the 6π-electrocyclisation of 1azatrienes. This strategy relies on chemical access to 1azatrienes which can be obtained by the reaction of primary amines with 2,4-dienals. Okamura and co-workers reported that the Schiff base 146 (Scheme 30), obtained by
the reaction of 13-tert-butyl-13-cis-retinal (145) with nbutylamine, unexpectedly produced the corresponding
1,2-dihydropyridine derivative 148 at 23 °C.48 The rationale given by the authors for this outcome was based on a
conformational analysis. A necessary and predominant
12,13-s-cis arrangement of the Schiff base 146, leading to
intermediate 147, would allow a smooth 6π-electrocyclisation. Structure–reactivity studies of various 4-tert-butyl-1-azatrienes were carried out in order to investigate
how the steric and electronic factors affected the disrotatory 6π-electrocyclisation of this type of compound. The
authors determined that the introduction of either an electron-donor or an acceptor group at the 1-azatriene terminus moderately accelerated the reaction rate of the
electrocyclisation in comparison with the parent azatriene
system.
tBu
tBu
nBuNH ,
2
EtOH
MS 4 Å
13
6
2.4
12
H
145
O
0 °C, 2 h
H
146
NnBu
n-BuNH2, EtOH
MS 4 Å
0 °C, 1 h; r.t., 1 h
nBu
nBu
N
t
11
Bu
148
N
12
13 tBu
147
Scheme 30 6π-Electrocyclisation of 1-azatrienes 145 to 1,2-dihydropyridines 14848
© Georg Thieme Verlag Stuttgart · New York
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142
REVIEW
E. M. P. Silva et al.
One aspect related to steric effects was clearly shown by
the results obtained when the substituents on the nitrogen
atom were changed. As the steric bulk of the nitrogen substituents decreased (tert-butyl < sec-butyl < n-butyl), the
relative rate of cyclisation increased. Also, there was no
great difference in reactivity whether a tert-butyl or a phenyl group was attached to the nitrogen or terminal carbon
(C-11) of the dienimine. In what concerns the electronic
effects, a few dienimines with para-substituted aryl moieties at C-11 were studied. The relative order of reactivity
for the cyclisation was determined to be phenyl < p-chlorophenyl < p-methoxyphenyl. When these substituents
were located at the nitrogen terminus, the same relative
order of cyclisation was observed. However, it should be
mentioned that these were only modest increases and that
the placement of either a donor or an acceptor group at either position led to a minor difference over the parent system.
Following on this pioneering work, Katsumura and coworkers published studies relating to the acceleration of
6π-azaelectrocyclisation of 1-azatrienes by the combination of a C-4 ester and a C-6 alkenyl or phenyl substituent.49 This phenomenon would be related to the important
orbital interaction between the HOMO and the LUMO of
1-azatrienes and was supported with molecular orbital
calculations.49c These C-4 and C-6 functions contributed
to a strong HOMO–LUMO interaction between the C-5
and C-6 olefin moiety and the N-1 and C-4 azadiene moiety of 1-azatrienes under the inverse-electron-demand
mode. Following this strategy the authors quantitatively
obtained the corresponding dihydropyridine derivatives
151 (Scheme 31) within five minutes at room temperature
by the reaction of (2E,4E,6E)-3-alkoxycarbonyltrienals
149 with n-propylamine.49c The activation of the 6π-azaelectrocyclisation was also observed in systems containing some different electron-withdrawing groups at C-4
(CO2Et, CONHPr). The reaction of 149b and 149c
(Scheme 31) with n-propylamine smoothly produced the
corresponding dihydropyridines 151b and 151c within
one and three hours, respectively. Both 150b and 150c
showed a rate of azaelectrocyclisation slower than that observed for compound 150a. No dihydropyridine was
formed, even after seven hours, in experiments performed
with a substrate lacking the C-4 carbonyl group in the azatriene system.49c
Interestingly, no cyclisation of azatrienes containing, at
the N-1 terminus, a hydroxy or methoxy group occurred
for a period of 60 minutes at 23 °C. However, the azatriene with an acetoxy group at N-1 produced the corresponding pyridine derivative within 40 minutes at 23 °C.
The pyridine derivative would be formed through elimination of acetic acid from the intermediate dihydropyridine.49c
The activation of the electrocyclisation reaction was also
observed in systems containing phenyl groups at C-6 and
the azatrienes 153a–c (Scheme 32) produced the corresponding dihydropyridines 154a–c within 10 minutes,
and no clear rate effect from the aryl group’s para substituents was observed. Through these experiments the auSynthesis 2013, 45, A–AK
nPr
O
R
149a R = CO2Me
149b R = CO2H
149c R = CONHPr
N
nPrNH
2
n
4 R
150a R = CO2Me
150b R = CO2H
150c R = CONHPr
Pr
N
R
151a R = CO2Me
151b R = CO2H
151c R = CONHPr
Scheme 31 6π-Azaelectrocyclisation of C-4 carbonyl- and C-6 alkenyl-substituted 1-azatrienes 150a–c49c
thors concluded that C-6 phenyl substituents in 1azatrienes accelerate the azaelectrocyclisation similarly to
compounds containing a C-6 double bond (compound
150, Scheme 31).49c
n
O
nPrNH
2
CO2Me
R
Pr
N
4
CO2Me
R
152a R = H
152b R = OMe
152c R = CO2Me
153a R = H
153b R = OMe
153c R = CO2Me
nPr
N
CO2Me
R
154a R = H
154b R = OMe
154c R = CO2Me
Scheme 32 6π-Azaelectrocyclisation of C-4 carbonyl- and C-6 phenyl-substituted 1-azatrienes 153a–c49c
An asymmetric version of this 6π-azaelectrocyclisation
was later developed by the same research group.49a,b The
authors envisioned that a chiral auxiliary on the nitrogen
atom of the azatriene system would allow control of the
facial selectivity during the disrotatory azaelectrocyclisation. A highly stereoselective asymmetric 6π-azaelectrocyclisation was achieved in the reaction of the
(2E,4E,6E)-3-alkoxycarbonyltrienal compounds 155–157
and chiral amines such as (–)-7-alkyl-cis-1-amino-2-indanol derivatives 158–163 (Scheme 33).49a,b The diastereomeric ratios obtained in these reactions are collected in
Table 17.49a
In what concerns the several reactions performed with trienal 155 (Table 17, entries 1–6) it was suggested that the
1-aminoindan structure and its cis-substituent with respect to the amino group, especially the cis-hydroxy
group, would be important for giving a good diastereoselectivity. This is evident from the results obtained for the
reaction using chiral amines 162 and 163a (entries 5 and
6) where a 10:1 diastereoselectivity at the C-2 position
was obtained. A single diastereoisomer was obtained
© Georg Thieme Verlag Stuttgart · New York
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T
REVIEW
1,2-Dihydropyridines
R*NH2 (1.1 equiv)
R
CDCl3, 24 °C
CHO
156 R = TBSO
155 R =
R*
R
Table 17 Diastereoselectivity Obtained in the Azaelectrocyclisation
of Trienals 155–157 with Amines 158–16349a
N
2
*
CO2Et
NH2
Aldehyde
Amine
dr (at C-2)
1
155
158
3:1
2
155
159
complex mixture
3
155
160
no cyclisation
4
155
161
3:1
5
155
162
10:1
6
155
163a
10:1
7
156
158
1:1
8
156
159
1:1b
9
156
160
no cyclisation
10
156
161
1:1
11
156
162
1:1
12
156
163a
1:1
13
157
158
1:1
14
157
159
2:1b
15
157
160
1:1b
16
157
161
1:1
17
157
162
1:1
18
157
163a
1:1
157 R =
OH
158
Entrya
OH
NH2
NH2
159
160
OR
NH2
NH2
161
NH2
163a R = Me
163b R = H
162
Scheme 33 Stereoselective asymmetric 6π-azaelectrocyclisation of
1-azatrienes 155–157 with cis-aminoindanol derivatives 158–163 as
chiral auxiliary49a
when the reaction was performed between trienal 155 and
amine 163b. The reactions with aldehydes 156 and 157
(entries 7–18) led to almost no diastereoselectivity even
when the amines 162 or 163a were used. However, once
more, the use of cis-aminoindanol 163b with the trienal
156 yielded the corresponding piperidine derivatives
(aminoacetal formation) as a mixture of four stereoisomers in a ratio of 15:5:3:1.
To rationalise the results obtained, the authors performed
some computational analysis of the azaelectrocyclisation
of 1-azatriene 164 (Scheme 34). This computational analysis supported the observed results. Both the cis-hydroxy
group and a possible alkyl substituent of the aminoindanol
contribute to improve the stereoselectivity of the reaction
through the formation of a favourable 2,3-s-cis, 4,5-s-cis
conformation of 165, thereby leading to major diastereoisomer (R)-166 (Scheme 34). In isomer (R)-165, no steric
interaction between the isopropyl group of the indan moiety and the proton Ha of the azatriene occurs as observed
a
Each reaction was monitored by 1H NMR, and the ratio of the produced dihydropyridine was determined by analysis of characteristic
signals.
b
The products obtained were the aminoacetal derivatives of the corresponding dihydropyridines.
in intermediate (S)-165. Therefore, the major isomer (R)166 would be preferentially formed through the conformer (R)-165 by disrotatory azaelectrocyclisation. The formal synthesis of 20-epiuleine was efficiently achieved by
Katsumura and Tanaka using this strategy.49b
EtO2C
EtO2C
Ph
Ph
H
N H
Ind
N
hydrogen bond
O
O
N
H
*
CO2Et
164 (Ind = indan)
major (2R)-166
(R)-165
disrotatory cyclisation
H
EtO2C
EtO2C
H
Ph
N
N H
Ind
Ph
Ha
O
O
hydrogen bond
N
*
164
(S)-165
CO2Et
minor (2S)-166
Scheme 34 Favourable formation of 2,3-s-cis, 4,5-s-cis conformation of 165 leading to major diastereoisomer (R)-16649a
© Georg Thieme Verlag Stuttgart · New York
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CO2Et
U
REVIEW
E. M. P. Silva et al.
Using a one-pot 6π-azaelectrocyclisation–aromatisation
protocol, Katsumura and co-workers obtained 2-arylpyridines 173 in moderate to high yields (Scheme 35).50 This
strategy relied firstly on a palladium-catalysed Stille coupling of 168 and 169 to afford dienal 170. Aldehyde 170
subsequently reacted with methanesulfonamide 167, the
nitrogen source, to give imine 171. This intermediate
swiftly underwent a 6π-azaelectrocyclisation leading to
1,2-dihydropyridine 172. Interestingly, the authors gave
evidence that the palladium catalyst acts as Lewis acid
during imine formation since aldehyde 170 did not react
with compound 167 without a palladium catalyst. To obtain the desired pyridine 173, compound 172 was then
treated with 1,8-diazabicyclo[5.4.0]undec-7-ene and sulfinic acid was eliminated.
+
MeSO2NH2
I
168
CO2Et
169
Stille coupling Pd cat.
OHC
167
Pd cat.
Ph
MeO2S
CO2Et
N
Ph
imine
formation
170
CO2Et
171
6π-azaelectrocyclisation
MeO2S
DBU
N
Ph
173
aromatisation
CO2Et
X
H
R*
174
N
Ph
172
CO2Et
Scheme 35 One-pot 6π-azaelectrocyclisation–aromatisation leading
to the synthesis of 173 through formation of 1,2-dihydropyridine
17250
Hsung and co-workers developed the first highly stereoselective reaction of vinylogous amides 175 with α,β-unsaturated iminium salts 174 (Scheme 36).51 This attractive
strategy relied on a stereoselective pericyclic ring closure
of 1-azatrienes 176 to lead to chiral 1,2-dihydropyridines
177.
175
R*
H
N
P
X
+
R*
Ph
179
178
L
R
S
O
a
H N
H
Ph
Ph
A
H
177a
aza-[3+3]
annulation
N
P
n
X
177b
Through the analysis of several aza-[3+3]-annulation reactions with different iminium salts prepared from chiral
α,β-unsaturated aldehydes and N-benzyltetronamide, the
authors were able to provide a mechanistic elucidation.
Two main factors were identified as responsible for inducing the observed diastereoselectivity and will be presented
next in detail. The torqueoselectivity was rationalised
through a potential rotational preference given the high
degree of conformational freedom at the C-terminus of the
1-azatrienes. Therefore, the size of the nitrogen substituent would influence that rotational preference with the
larger substituent providing higher diastereoselectivity.
Also, a greater 1,3-diaxial strain (structure B, Scheme 37)
could improve the selectivity since it would drive the nitrogen substituent in the direction of the C-terminus allylic fragment. This would, once more, favour conformation
A and consequently a disrotatory ring closure in the direction (a) shown in Scheme 37. Experimental results reported by the authors supported this rationale. More
specifically, the use of N-diphenylmethyl group as the nitrogen moiety afforded the desired cycloadducts in 36%
yield in an 87:13 ratio. A less bulky substituent such as
methyl in a same system led to a higher yield (82%) but
with a clear loss of stereoselectivity (63:37).
O
OAc
OAc
+
N
OAc
Ph
180a
H
176
stereoselectivity
up to 92:8
H
OAc OAc
Ph
HN
Ph
OAc
RO
n
X
+
n
X
C-terminus chirality
O
X
N
P
O
36%
OAc
P
R*
n
O
H
OAc
X
P = protecting group
X = O, NMe or CH2
n = 0 or 1
O
NR2
AcO
N
X
+
Ph
167
Knoevenagel
condensation
Scheme 36 Pericyclic ring closure of 1-azatrienes 176 with acyclic
chirality at the C-terminus51
OHC
SnBu3
O
O
AcO
NR2
a: favoured
H
OAc
Ph
N
Ph
180b
dr 92:8
H OR
O
S
L
R H N
120°
H
Ph
enhanced
A1.3
Ph
enhanced
B
Scheme 37 Suggested rotational preference to rationalise the observed torqueoselectivity in the formation of 180a51
Synthesis 2013, 45, A–AK
© Georg Thieme Verlag Stuttgart · New York
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V
REVIEW
W
1,2-Dihydropyridines
Palacios et al. reported an interesting azadiene-mediated
synthesis of 1,2-dihydropyridines 184 and 187 (Scheme
38).52 The heterodienes underwent efficient [4+2] cycloaddition with a high degree of regiochemical control. The
cycloaddition reaction between electron-deficient 2-azadienes 181 and phosphazenes 182 (route a, Scheme 38)
led to 1,2-dihydropyridines 184 in yields ranging from 39
to 72%. Alternatively, a wide variety of tetrasubstituted
1,2-dihydropyridines 187 were synthesised in a regiospecific manner by reaction of enamines 185 and 2-azadienes
181, prepared by aza-Wittig reactions, followed by pyrrolidine elimination (route b, Scheme 38). With this procedure, the 1,2-dihydropyridines 187 were obtained in
yields ranging from 42 to 62%. The results reported by the
authors concerning these two strategies are presented in
Table 18.
Analysis of the results collected in Table 18 reveals that
the pattern of substitution in the azadienes 181 can play an
important role in the reactivity with either phosphazenes
182 or enamines 185. In what concerns the series of reactions performed between 2-azadienes 181 and phosphazenes 182 (entries 1–9) the 1-methoxy-substituted
azadiene (R3 = 4-MeOC6H4) led to the highest yield (en-
R3
R3
R4O2C
N
+
N
CO2
CO2R2
185
R2
186
181
LiClO4
Et2O
25 °C
CO2R2
– HN
route b
route a
N
R1
R1
R3
R1
N
CO2R4
N
[4+2]
CO2R4
HN
PPh2R
182a R = Ph
182b R = Me
R1
CO2R2
187
R3
R3
CO2R2
N
CO2R2
HN
R1
N=PPh2R
– HNPPh2R
CO2R2
R1
CO2R2
183
184
Scheme 38 Synthesis of 1,2-dihydropyridines 184 and 187 mediated
by azadienes 18152
tries 3 and 7). The highest yield observed in the series of
reactions performed between 2-azadienes 181 and enamines 185 according to route b (entries 10–15) was the
one involving the use of 1-nitro-substituted azadiene
(R3 = 4-O2NC6H4).
Table 18 Synthesis of 1,2-Dihydropyridines 184 and 18752b
R1
R2
R3
1
Me
Me
4-O2NC6H4
2
Me
Me
Ph
3
Me
Me
4
Me
5
Entry
R4
Temp (°C)
Time (h)
Yield (%)
60
72
44a
100
165
43a
4-MeOC6H4
60
280
65a
Me
4-Me2NC6H4
60
300
44a
Ph
Et
4-MeC6H4
100
48
55a
6
H
Et
4-O2NC6H4
60
4
39a
7
H
Et
4-MeOC6H4
60
48
72a
8
H
Et
4-O2NC6H4
r.t.
112
55a
9
H
Et
4-MeOC6H4
75
70
45a
10
H
Et
4-O2NC6H4
Me
r.t.
160
62b
11
H
Et
Ph
Me
60
17
43b
12
H
Et
4-MeOC6H4
Me
60
68
42b
13
Me
Me
4-O2NC6H4
Et
100
15
61b
14
Me
Me
Ph
Et
60
120
44b
15
Ph
Et
4-O2NC6H4
Me
100
48
51b
a
b
Yield of compound 184 formed through route a.
Yield of compound 187 formed through route b.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, A–AK
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The reaction shown in Scheme 37, between amine 179
and iminium salts 178, provided dihydropyridine 180
with the highest selectivity (92:8). The reasoning for this
result is that a larger internal angle of the six-membered
ring should lead to a disfavoured enhanced interaction between the N-benzyl group and the allylic fragment for
conformation B of the 1-azatriene.51
REVIEW
E. M. P. Silva et al.
The reaction between 2-azadiene 181 (R1 = H, R2 = Et,
R3 = 4-O2NC6H4) and enamine 185 (R4 = Me) led to the
desired product in 62% after 160 hours at room temperature (Table 18, entry 10). In contrast, the reaction between
2-azadiene 181 (R1 = R2 = Me, R3 = 4-O2NC6H4) and enamine 185 (R4 = Et) led to the desired product in 61% after 15 hours at 100 °C (entry 13).
A different methodology for the synthesis of 1,2-dihydropyridines was reported in 2008 by Ellman and coauthors.53 The 1,2-dihydropyridines 191 were prepared by
reaction of α,β-unsaturated N-benzyl aldimines 188 with
alkyne 189 via C–H activation (Scheme 39). These reactions proceeded by way of a useful one-pot alkenylation–
electrocyclisation sequence.
N
Bn
+
[RhCl(coe)2]2 (2.5 mol%)
FcPCy2 (10 mol%)
toluene, 50 °C, 12 h
(5 equiv)
R
188a R = H
188b R = Me
N
189
Bn
N
R
Bn
reaction. Also, the corresponding diaryl alkyl phosphines
194a–c were screened to further investigate the effect of
electronic properties of the ligand in the catalytic system.
These studies showed that ligand 193b (R = Et) delivered
a more efficient catalyst than ligand 193a (R = Cy) or
193c (R = Me). None of the ligands 194a–c gave better results that those observed for ligand 193b. An alkyne
screening was also performed and generally nonsymmetric alkynes afforded the desired 1,2-dihydropyridines in
most cases as a single regioisomer. The same research
group later exploited the use of these highly substituted
1,2-dihydropyridines such as 191 in a sequence leading to
highly substituted pyridines.54
Tong and co-workers55 developed a synthesis of highly
substituted 1,2-dihydropyridines 197 comprising of a
[2+2+2] annulation between 1-phenylpropynones 195 and
aryl N-tosylimines 196 catalysed by triphenylphosphine
(Scheme 40). The reactions were reported to proceed
smoothly for a broad range of substrates and the 1,2-dihydropyridines 197 were obtained in good to excellent
yields (59–90%). These studies showed that a high temperature and the use of 3.0 equivalents of compound 195
was required for a good yield of the desired product.
R
O
Ph
O
191a R = H
191b R = Me
190
Me
N
PEt2
192
+
R
(D)H
Me
Fe
NTs
PR2
Me
N
Me
193a R = Cy
193b R = Et
193c R = Me
PR
2
194a R = Cy
194b R = Et
194c R = Me
Scheme 39 Synthesis of 1,2-dihydropyridines 191 from imines 188
and alkyne 189 via C–H activation, and the ligands that were
screened53
Aromatisation of compounds 191 allowed for the preparation of highly substituted pyridine derivatives. A new
class of ligands was also developed in the course of this
study in order to achieve a broader scope in the C–H alkenylation step.
The use of a catalytic system involving the electron-donating (dicyclohexylphosphinyl)ferrocene ligand in a 2:1
ligand-to-rhodium ratio in the reaction between compound 188a and 189 provided the corresponding azatriene
190 (R = H) that yielded the 1,2-dihydropyridine 191a after electrocyclisation. This catalytic system was, however,
inefficient when the reaction was performed with aldimines bearing a β-substituent (188b, R = Me), even when
high temperatures were used. Since none of the large
number of commercially available ligands tested by the
authors provided a suitable catalytic system for this particular substrate, the authors prepared a series of novel ligands 193a–c and 194a–c (Scheme 39). These ligands, as
aniline-based substituted phosphines, would, according to
the authors, hold various steric properties suitable for this
Synthesis 2013, 45, A–AK
195
196
Ph3P (20 mol%)
O
Ph
Ph
toluene, reflux
N
Ts
R
197a R = Ph (75%)
197b R = 4-MeOC6H4 (90%))
197c R = 4-MeC6H4 (59%)
197d R = 4-ClC6H4 (67%)
197e R = 4-BrC6H4 (85%)
Scheme 40 Synthesis of 1,2-dihydropyridines 197 via triphenylphosphine-catalysed [2+2+2]-annulation reaction between 195
and 19655
A triphenylphosphine-catalysed [4+2]-annulation reaction was also performed between alkyl propiolates 198
and aryl N-tosylimines 199 (Scheme 41). The same good
results were obtained in this reaction using the experimental conditions described above. The 1,2-dihydropyridines
200 were obtained once more in good to excellent yields
(59–96%). Experiments performed using labelled substrates allowed the authors to clarify the mechanism for
these reactions. The [2+2+2]-annulation reaction with
deuterated compound 196 (Scheme 40) revealed the formation of an important intermediate with the structure of
compound 199 (Scheme 41) deuterated at the C-4 position.
This intermediate 199 would be formed by a Mannichtype reaction of a zwitterion (formed through addition of
triphenylphosphine to propiolate 198) with N-tosylimine
196 followed by two consecutive proton transfers and
[1,5]-elimination of triphenylphosphine. Intermediate 199
would then undergo a Michael-type addition with another
molecule of the zwitterion formed in situ. A subsequent
conjugate addition, [1,2]-elimination of triphenylphos© Georg Thieme Verlag Stuttgart · New York
Downloaded by: Beijing Normal University. Copyrighted material.
X
REVIEW
phine and [1,3]-proton transfer would then result in the
desired 1,2-dihydropyridines 200 (or 197).55
NTs
R1
O
Y
1,2-Dihydropyridines
COR1
Ph3P
R2
(D)H
R2
TsN
196
(D)H
1) [1,2]-H(D)
2) [1,5]-H(D)
3) – Ph3P
PPh3
198
COR1
199
COR3
O
1) conjugate addition
2) [1,2]-elimination of Ph3P
3) [1,3]-H(D)
D(H)
COR1
R3
(D)H
PPh3
R2
N
Ts
200a R1 = OMe, R2 = Ph, R3 = Ph (59%)
200b R1 = OMe, R2 = 4-MeOC6H4, R3 = Ph (96%)
200c R1 = OMe, R2 = 4-BrC6H4, R3 = Ph (86%)
200d R1 = OMe, R2 = 4-MeOC6H4, R3 = 4-MeOC6H4 (59%)
200e R1 = OMe, R2 = 4-BrC6H4, R3 = 4-MeC6H4 (60%)
200f R1 = OMe, R2 = 4-BrC6H4, R3 = 4-MeOC6H4 (50%)
200g R1 = OBn, R2 = 4-MeOC6H4, R3 = Ph (63%)
Early this year, an annulation reaction of α,β-unsaturated
imines 201 and alkynes 202 catalysed by a cobalt–triarylphosphine complex was reported by Yamakawa and
Yoshikai.56 This reaction was performed under mild conditions and led to highly substituted 1,2-dihydropyridines
203 in moderate to good yields (Table 19). The authors
performed a screening of the reaction conditions and established that the Grignard reagent chosen exerted a significant influence. The use of a secondary alkyl Grignard
reagent such as isopropylmagnesium bromide improved
the reaction significantly in comparison with (trimethylsilyl)methylmagnesium chloride and methylmagnesium
chloride, for example, which provided poor results.
Scheme 41 Triphenylphosphine-catalysed [4+2] annulation leading
to 1,2-dihydropyridines 20055
N
R1
PMP
R4
CoBr2 (5–10 mol%)
(3-ClC6H4)3P (10 mol%)
i
PrMgBr (22.5–45 mol%)
R3
R2
201
THF, 40 °C, 3 h
R5
R4
N
R1
R5
PMP
R3
R2
203
202 (1.2 equiv)
R1
R2
R3
R4
R5
203 (%)
1
Ph
H
Me
Ph
Ph
91a
2
4-MeC6H4
H
Me
Ph
Ph
95
3
4-MeOC6H4
H
Me
Ph
Ph
95
4
4-ClC6H4
H
Me
Ph
Ph
85
5
4-BrC6H4
H
Me
Ph
Ph
70
6
4-IC6H4
H
Me
Ph
Ph
23
7
4-NCC6H4
H
Me
Ph
Ph
84
8
Ph
H
Et
Ph
Ph
98
9
4-ClC6H4
H
Ph
Ph
Ph
96
10
Ph
Me
Me
Ph
Ph
77
11
Ph
Ph
Me
Me
Me
71
12
Ph
H
H
Ph
Ph
79
13
Ph
H
Me
n-Pr
n-Pr
59
14
Ph
H
Me
Me
Ph
72b
15
Ph
H
Me
Ph
Et
93c
16
Ph
H
Me
4-MeOC6H4
4-MeOC6H4
83
17
Ph
H
Me
3-BrC6H4
3-BrC6H4
60
18
Ph
H
Me
4-F3CC6H4
4-MeOC6H4
86d
Entry
a
Gram-scale reaction (5 mmol).
Regioisomeric ratio = 85:15 (major isomer reported).
c
Regioisomeric ratio = 53:47 (major isomer reported).
d
Regioisomeric ratio = 89:11 (major isomer reported).
b
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, A–AK
Downloaded by: Beijing Normal University. Copyrighted material.
Table 19 Scope of α,β-Unsaturated Imines 201 and Alkynes 20256
REVIEW
E. M. P. Silva et al.
The scope of the annulation reaction was studied using the
optimised conditions described in Table 19. Several α,βunsaturated imines 201 were firstly tested with diphenylacetylene (Table 19, entries 1–10). These experiments revealed that this reaction displayed tolerance for functional
groups such as chloro, bromo, and cyano groups. All the
reactions afforded the desired product in high yields ranging from 70 to 98% except for the reaction with an α,β-unsaturated imine bearing an iodine atom (entry 6). Next,
using the same α,β-unsaturated imines 201 (R1 = Ph,
R2 = H, R3 = Me) different alkynes were examined (entries 13–18).
The authors proposed a catalytic cycle, shown in Scheme
42, that involves an oxidative addition of the cobalt catalyst to the olefinic C–H bond assisted by the nitrogen, affording a five-membered-ring intermediate (I).
Subsequent insertion of the alkyne occurs, followed by reductive elimination leading to the essential azatriene intermediate (III). This azatriene readily undergoes 6πelectrocyclisation to furnish the dihydropyridine product.
CO2R1
O
1) AuCl (5 mol%), 23 °C
2) R4NH2
3) p-TsOH (20 mol%), 40 °C
R4
CH2Cl2
R2
R2
R3
Scheme 43 Synthesis of highly substituted 1,2-dihydropyridines
205 using propargyl vinyl ethers 204 as substrates57a,b
1) [cat.]
2) R4NH2
3) [H ]
CO2R1
O
R4
R2
R2
R3
204
CO2R1
N
R3
205
1) Claisen rearrangement
2) condensation
R4
6π-electrocyclisation
R4
NH
CO2R1
N
CO2R1
R
R
PMP
R
N
PMP
R3
6π-electrocyclisation
H
III
N
PMP
R2
+H
R4
208
reductive
elimination
R
[Co]
N
CO2
206
R1
R3
207
oxidative
addition
PMP
H
[Co]
N
PMP
R
I
II
insertion
R
R
Scheme 42 Proposed catalytic cycle for the cobalt-catalysed olefinic
C–H activation56
Kirsh and co-workers57 have devoted part of their research
work to the use of propargyl vinyl ethers as substrates for
the synthesis of a broad variety of heterocyclic compounds through transition-metal catalysis. In addition to
the preparation of furans, pyrroles and pyrans, the catalysed synthesis of 1,2-dihydropyridines starting from
propargyl vinyl ethers has also been reported (Scheme
43).57a,b
The highly substituted 1,2-dihydropyridines were obtained in moderate to excellent yields (55–89%) through a
reaction sequence that proceeded via a transition-metalcatalysed propargyl Claisen rearrangement, a subsequent
condensation step, and a Brønsted acid induced 6π-electrocyclisation (Scheme 44). To achieve these results, several studies involving catalyst and substrate screening
were performed.
Synthesis 2013, 45, A–AK
–H
NH
R2
[Co]
H
R3
R2
R
N
R3
205
(55–89%)
R1 = Me, Et
R2 = alkyl, H, aryl
R3 = alkyl, aryl
R4 = alkyl, aryl
204
CO2R1
N
Scheme 44 Mechanism proposed for the formation of 1,2-dihydropyridines 205 from propargylic vinyl ethers 20457a
In what concerns the catalyst screening, the use of 0.5
mol% of gold(I) chloride in dichloromethane at 25 °C led,
after 22 hours, to the best result and the propargyl vinyl
ether 204 (R1 = R2 = Et, R3 = Ph) was smoothly transformed into the desired allene product. A substrate scope
study for this transformation was conducted and all of the
reactions performed led to a 100% conversion. Studies on
the final cyclisation step revealed that p-toluenesulfonic
acid was necessary as an additive to catalyse this step. The
authors reported that without the Brønsted acid, the reaction was slow and never actually reached full conversion
even after prolonged reaction times. With their standard
protocol developed, the authors performed a substrate
scope investigation of the conversion of 204 into 1,2-dihydropyridine 205 (Table 20).
This reaction was considered to have a broad scope with
regard to the internal alkynes. The formation of 1,2-dihydropyridines occurred in moderate to good yields even
considering substitutions at R2 and R3 with both aryl and
alkyl groups (entries 9–15). When a propargyl vinyl ether
bearing no substitution at the 2-position (R2 = H) was
used, the product was obtained in only moderate yield (entry 12). In what concerns the amine counterpart, the reaction with anilines as well as aliphatic amines furnished the
corresponding 1,2-dihydropyridines 205 (entries 1–8) in
yields ranging from 62 to 88%.
© Georg Thieme Verlag Stuttgart · New York
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Z
1,2-Dihydropyridines
microwave irradiation at 120 °C in the absence of transition-metal catalysis.58 This strategy followed the same
concept. The tetrasubstituted 1,2-dihydropyridines 211
(Scheme 45) would be formed through a propargyl
Claisen rearrangement and isomerisation, amine condensation and 6π-azaelectrocyclisation process. The propagyl
enol ethers 209 used in these reactions have a wide variety
of substitution across the molecule including an ester
group at the 3-position. According to the authors, this ester group plays a vital role in controlling the reactivity
during the process and also, since it is incorporated in the
final product, furnishes a convenient chemical handle for
further derivatisation. When the reaction was performed
using the propargyl enol ether 209 (R1 = R3 = H, R2 = Ph)
and p-anisidine, the enal 213 (R1 = R3 = H, R2 = Ph) was
isolated in 59% yield as a mixture of E- and Z-isomers.
After the rearrangement, this group was found to be
placed at the sp3 position of the intermediate allene 212,
thereby allowing the energetically favoured 1,3-proton rearrangement of allenes 212 to take place, leading to the
dienals 213. Since the 1,2-dihydropyridine 211 was obtained in quantitative yield, the geometry of the double
bond had no apparent impact on the yield of this cyclisation process.
The scope of this reaction was studied with regard to both
propargylic and amine components and the results are
compiled in Table 21. This metal-free protocol afforded
the desired 1,2-dihydropyridines 211 even when terminal
alkynes were used. In contrast, the protocol developed by
Kirsch and Harschneck57a in the methodology described
above led to a mixture of inseparable unknown compounds when a similar reaction was performed. Aliphatic
and aromatic substituents at the terminal position of the
triple blond (Table 21, entries 5 and 6) produced, likewise,
the corresponding compounds 211 in 55% and 95% yield,
respectively. The reaction performed using the unsubstituted propargyl enol ether 209 (R1 = R2 = R3 = H) furnished the predicted product but in the poorest yield, even
when forcing reaction conditions were used (entry 2). Also, the presence of a methyl group at the double bond of
the propargyl enol ether 209 (R3 = Me) generated the 1,2dihydropyridines 211 in low yields even under vigorous
conditions (entries 7 and 8). These results allowed the authors to conclude the necessity of some conformational
Table 20 Substrate Scope of the Conversion of 204 into 1,2-Dihydropyridine 20557a
Entry 1,2-Dihydropyridine 205
Yield
(%)
R1
R2
R3
R4
1
Et
Et
Ph
Ph
88
2
Et
Et
Ph
4-MeOC6H4CH2
62
3
Et
Et
Ph
i-Pr
75
4
Et
Et
Ph
(S)-PhCHMe
67
5
Me
Et
Ph
4-BrC6H4
69
6
Me
Et
Ph
3-O2NC6H4
78
7
Me
Et
Ph
4-MeOC6H4
85
8
Me
Et
Ph
Bn
81
9
Et
Me
Ph
Ph
84
10
Et
i-Pr
Ph
Ph
77
11
Et
Ph
Ph
Ph
72
12
Et
H
Ph
Ph
55
13
Et
(CH2)2Ph n-C5H11
Ph
55
14
Et
Et
4-MeO2CC6H4 Ph
74
15
Et
Et
4-MeOC6H4
89
Ph
The mechanistic details of this cascade reaction were
studied and the authors proposed, based on the isolation of
enamine intermediate 208, the pathway outlined in
Scheme 44. A probable gold-catalysed cyclisationinduced rearrangement leads to the formation of allene
206. Protonation of this intermediate leads to the achiral
iminium ion 207, which is in turn converted into azatriene
208 through tautomerisation of 206 into 208. Subsequent
6π-electrocyclisation provides the desired 1,2-dihydropyridine 205.
Independent research performed by Tejedor, MéndezAbt, and García-Tellado, during the same time period,
showed that 1,2-dihydropyridines could be obtained from
propargylic vinyl ethers and primary amines when using
R2
R1
R3
O
CO2Me
+
CO2Me
MW
R4NH2
toluene
120 °C, 30 min
210
R1
R2
N
R3
4
R
211
209
R2
AA
H
R1
R3
O
O
CO2Me
R4NH2
MeO2C
R1
R3
CO2Me
212
R2
R1
R2
213
N
R3
R4
214
Scheme 45 Domino synthesis of substituted 1,2-dihydropyridines 211 from propargyl enol ether 209 and primary amines 210 using microwave irradiation58
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, A–AK
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REVIEW
REVIEW
E. M. P. Silva et al.
control and/or a certain degree of substitution at the terminal double bond in this type of procedure. The reaction
was also tolerant of an electron-withdrawing group at the
double bond of the propargylic enol ether 209 and the corresponding 1,2-dihydropyridine 211 was obtained in 80%
yield (entry 9, where the methyl ester moiety was replaced
with p-toluenesulfonyl). It was shown that R2 could be either hydrogen, aliphatic, or aromatic when terminal alkynes were used (entries 1–4). When the alkyne was
substituted with aromatic or aliphatic groups, R2 had to be
aromatic (entries 5 and 6). However, when R2 was an aliphatic substituent such as n-propyl, and the terminal alkyne substituent (R1) was either aliphatic (n-butyl) or
aromatic (phenyl), no 1,2-dihydropyridine 211 was obtained (data not shown). The product was also obtained in
good yields for a wide range of amines tested, namely aliphatic and aromatic amines (Table 21).
The use of a commercially available chiral amine, (S)methylbenzylamine, allowed the preparation of the 1,2dihydropyridine 211 in 83% yield and 50% diastereomeric excess (Table 21, entry 13). An experiment using a chiral alkyne, prepared from commercially available (R)-1phenylprop-2-yn-1-ol, was also performed, and this produced the 1,2-dihydropyridine 211 in 100% yield as a racemic mixture (entry 17).
59
In 2010, Xu and co-workers reported a sequence related
to the one described above leading to 1,2-dihydropyridines 220 catalysed by gold and silver salts (Scheme 46).
Therein, propargyl vinyl ethers 215 or allenic vinyl ethers
217 furnished 2,4-dienals 219 through a gold-catalysed
[3,3]-sigmatropic rearrangement and isomerisation. The
intermediate 2,4-dienals 219 would in turn condense with
tosylamine and complete, with a 6π-azaelectrocyclisation,
the formation of 1,2-dihydropyridines 220 (Scheme 46).
CO2Me
O
R1
R2
CHO
Au(PPh3)Cl (5 mol%)
AgSbF6
R2
216
isomerisation
path a
TsNH2 (2.0 equiv)
CH2Cl2, r.t.
CO2Me
R1
CO2Me
Au-catalysed Claisen
rearrangement
215
TsN
R1
R2
R2
CO2Me
R1
6π-aza
eletrocyclisation
CHO
219
path b: R2 = Me
220
isomerisation
path b
CO2Me
O
R1
Au(PPh3)Cl (5 mol%)
AgBF4
Au-catalysed Claisen
rearrangement
217
OHC
CO2Me
R1
218
Scheme 46 Gold-catalysed synthesis of 1,2-dihydropyridines 220
from propargyl vinyl ethers 215 or allenic vinyl ethers 21759
Synthesis 2013, 45, A–AK
Table 21 Domino Synthesis of Substituted 1,2-Dihydropyridines
211 from Propargyl Enol Ether 209 and Primary Amines 210 Using
Microwave Irradiation58
Entry
1,2-Dihydropyridine 211
Yield
(%)
R1
R2
R3
R4
1
H
Ph
H
4-MeOC6H4
100
2
H
H
H
4-MeOC6H4
51
3
H
Me
H
4-MeOC6H4
87
4
H
n-Pent
H
4-MeOC6H4
71
5
Ph
Ph
H
4-MeOC6H4
95
6
c-Hex
Ph
H
4-MeOC6H4
55
7
H
Ph
Me
4-MeOC6H4
24
8
H
Me
Me
4-MeOC6H4
17
9a
H
Ph
H
4-MeOC6H4
80
10
H
Ph
H
Bn
83
11
H
Ph
H
allyl
72
12
H
Ph
H
Ad
87
13
H
Ph
H
(S)-PhCHMe
83b
14
H
Ph
H
PMB
78
15
H
Ph
H
Ph
93
16
H
Ph
H
4-ClC6H4
88
17
H
Ph
H
4-MeOC6H4
100c
a
CO2Me in compound 209 substituted by SO2Tol.
Compound 211 obtained with 50% de.
c
Product obtained as a racemic mixture.
b
The reactions of propargyl vinyl ether 215 (R1 = Ph,
R2 = H) were investigated with regard to the choice of
gold catalyst and solvent. The authors described that the
optimal result, 96% yield, was obtained with a combination of chloro(triphenylphosphine)gold(I) [Au(PPh3)Cl]
and silver hexafluoroantimonate. The reaction did not
take place when each of the catalysts was used alone. It
was hypothesised that silver(I) could serve to abstract the
chloride from chloro(triphenylphosphine)gold(I) with resulting formation of a more electrophilic catalyst. The
best solvent proved to be dichloromethane.
The use of chloro(triphenylphosphine)gold(I) and silver
hexafluoroantimonate as catalysts in the reaction of allenic vinyl ethers 217 (R1 = Ph) led to a low yield (34%) of
the desired product. Therefore, and considering the results
obtained with propargyl vinyl ether 215, the combination
of chloro(triphenylphosphine)gold(I) with several different silver catalysts was tested. Silver tetrafluoroborate in
combination with chloro(triphenylphosphine)gold(I), using dichloromethane as solvent, gave the best result and
1,2-dihydropyridine 220 (R1 = Ph, R2 = H) was obtained
in 69% yield.
© Georg Thieme Verlag Stuttgart · New York
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AB
REVIEW
Table 22 Synthesis of 1,2-Dihydropyridines 220 from Propargyl Vinyl Ethers 215 and Tosylamine Catalysed by Chloro(triphenylphosphine)gold(I) Silver Hexafluoroantimonate59
1
R
1
Ph
H
92
2
2-MeC6H4
H
90
3
4-MeC6H4
H
91
4
3-MeC6H4
H
80
5
3,4-Me2C6H3
H
78
6
2-MeOC6H4
H
89
7
4-ClC6H4
H
85
8
2-ClC6H4
H
84
9
2-naphthyl
H
88
n-Hex
H
82
10
11
R
Ph
2
Yield (%)
Table 23 Synthesis of 1,2-Dihydropyridines 220 Allenic Vinyl
Ethers 217 and Tosylamine Catalysed by Chloro(triphenylphosphine)gold(I) and Silver Tetrafluoroborate59
Entry
R1
Yield (%)
1
Ph
69
2
2-MeC6H4
67
3
4-MeC6H4
65
4
3-MeC6H4
56
5
4-ClC6H4
55
6
4-BrC6H4
48
7
2-naphthyl
62
8
n-Hex
no reaction
synthesis of 1,2-dihydropyridines 222 and 3-iodo-1,2-dihydropyridines 223 (Scheme 47).60 The 3-aza-1,5-enynes
221 would, according to the authors, undergo a metal-free
cyclisation or an N-iodosuccinimide-induced electrophilic iodocyclisation to afford 1,2-dihydropyridines 222 or
223, respectively.
R2
CO2Me
MeOH
n-Pent
60
Ar, 60 °C
(in sealed tube)
R2
© Georg Thieme Verlag Stuttgart · New York
N
CO2Me
SO2R3
CO2Me
222
R1
N
R2
CO2Me
I
SO2R3
221
The highest yield was obtained for the derivative possessing a phenyl group at the propargylic position (Table 22,
entry 1). The effect of the substitution and the position of
the substituent on the phenyl ring was also studied. A similar yield was obtained with o- or p-tolyl-substituted derivatives (entries 2 and 3). However, when the methyl
substituent was located at the meta-position of the phenyl
ring, giving an m-tolyl group, the yield dropped to 80%
(entry 4). Substrates bearing chloro or methoxy functional
groups also furnished the desired products in good yields
(entries 6–8).
An identical study was carried out using allenic vinyl
ethers 217 and tosylamine (2 equiv) catalysed by chloro(triphenylphosphine)gold(I) and silver tetrafluoroborate
(5 mol%). Generally, these reactions led to lower yields
(Table 23, entries 1–7) when compared with those performed using propargyl vinyl ethers 215 (Table 22). The
product was not even observed for the derivative 217 possessing an alkyl substituent at the propargylic position
(Table 23, entry 8). The substrate containing a p-bromophenyl group afforded the desired product in 48% yield,
the lowest of this series (Table 23, entry 6).
Wan and co-workers reported early this year the use of 3aza-1,5-enynes 221 as versatile substrates for the selective
R1
CO2Me
NIS (1.2 equiv)
DMF, 80 °C
R1
N
CO2Me
SO2R3
223
Scheme 47 Synthesis of 1,2-dihydropyridines 222 and 3-iodo-1,2dihydropyridines 223 via cyclisation or electrophilic iodocyclisation
of 3-aza-1,5-enynes 22160
In what concerns the synthesis of 1,2-dihydropyridines
222, the model study using substrate 221 (R1 = R2 = Ph,
R3 = p-tolyl) furnished exclusively the corresponding
compound 222 in 95% yield after 48 hours in methanol at
60 °C. The scope of this reaction was explored and all the
reactions performed resulted in the desired product in
good to excellent yields ranging from 69 to 97% (Table
24).
Several aryl R1 groups bearing a diversity of substituents
at different positions were tested and all were well tolerated (Table 24, entries 1–8). One of the lowest yields was
obtained when the R1 substituent consisted of 1-naphthyl,
although the desired product was still obtained in 72%
yield (entry 9). It was also observed that when the substrate 221 contained an alkyl substituent at R1, the reaction
required the use of higher temperatures (entries 10 and
11). The lowest yield obtained in these studies was actuSynthesis 2013, 45, A–AK
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With the optimised conditions established, the authors
proceeded to study a variety of substrates containing electron-rich or electron-deficient aryl groups at the propargylic position (R1). The reaction performed in
dichloromethane at room temperature using propargyl vinyl ethers 215 and tosylamine (2 equiv), catalysed by
chloro(triphenylphosphine)gold(I) and silver hexafluoroantimonate (5 mol%), furnished the desired product in
each case with moderate to good yields (Table 22, entries
1–11). The lowest yield (60%) was obtained with alkylsubstituted-alkyne propargyl vinyl ether 215 (entry 11).
Entry
AC
1,2-Dihydropyridines
REVIEW
E. M. P. Silva et al.
Table 24 Scope of the Synthesis of 1,2-Dihydropyridines 22260
Entry
Substrate 221
R1
222 (%)
R
2
R
+ O
Ph
Ph
4-MeC6H4
95
2
2-MeC6H4
Ph
4-MeC6H4
91
3
3-MeC6H4
Ph
4-MeC6H4
92
4
4-MeC6H4
Ph
4-MeC6H4
78
5
2-CF3C6H4
Ph
4-MeC6H4
81
6
4-FC6H4
Ph
4-MeC6H4
88
7
2-ClC6H4
Ph
4-MeC6H4
87
8
2-BrC6H4
Ph
4-MeC6H4
86
9
1-naphthyl
Ph
4-MeC6H4
72
10a
i-Pr
Ph
4-MeC6H4
97
b
c-Pr
Ph
4-MeC6H4
69
12
Ph
3-MeC6H4
4-MeC6H4
95
13
Ph
4-MeC6H4
4-MeC6H4
93
14
Ph
4-FC6H4
4-MeC6H4
95
15
Ph
4-ClC6H4
4-MeC6H4
97
16
Ph
n-Pr
4-MeC6H4
96
17
Ph
n-Bu
4-MeC6H4
97
18
Ph
Ph
Ph
92
19
Ph
Ph
2-ClC6H4
95
a
b
R1
N
SO2
ally observed when using compound 221 with a cyclopropyl substituent at R1 (entry 11). The authors also
mentioned that the electronic properties of the sulfonyl
group (R3) seemed to have a small impact on the yield
(compare entries 1, 18 and 19). The authors proceeded to
study the synthesis of structurally enriched 3-iodo-1,2-dihydropyridines 223 (Scheme 47), which are suitable for
further elaboration. The scope of this reaction was also explored and the desired product was obtained with moderate to high yields (23–93%). The reaction mechanism
proposed by the authors is depicted in Scheme 48.
For this transformation, an initial attack of the iodonium
ion to the alkyne moiety of compound 221 is postulated.
This attack would lead to the formation of cation 225 and
succinimide anion. Subsequent cyclisation of cation 225
would generate cation 226 and the final product would be
formed by the trapping of a proton from 226 by the succinimide anion (Scheme 48).
Our group has recently started a project entailing the synthesis of 1,2-dihydropyridines 229 using (E,E)-cinnamylideneacetophenone 227 as a versatile starting material.61
(E,E)-Cinnamylideneacetophenone derivatives are a ma-
R1
I
R3
224
O
221
R2
R1
H
N
SO2
N
O
O
N
CO2Me
I
CO2Me
R1
O
CO2Me
SO2R3
225
CO2Me
N
CO2Me
SO2R3
223
O
N
H
226
N
R2
O
CO2Me
R3
R2
O
N
CO2Me
I
At 140 °C.
At 100 °C.
Synthesis 2013, 45, A–AK
I
CO2Me
3
1
11
R2
Scheme 48 Proposed mechanism of N-iodosuccinimide-induced cyclisation of 3-aza-1,5-enynes 22160
jor group of α,β,γ,δ-diunsaturated ketones, widely used in
a variety of synthetic transformations primarily by our research group.62 In this work, a one-pot synthetic route to
prepare N-substituted 1,2-dihydropyridines 229 using
compound 227 as starting material and several primary
amines was developed (Scheme 49). This reaction proceeded by formation of ketimine intermediate 228 that,
through a 6π-electrocyclisation, afforded the desired
product 229 in moderate yields. The preliminary results
obtained revealed that the best yields were obtained with
aliphatic amines such as pentylamine (229e, 48% yield) or
aromatic amines bearing an electron-donating group
(229b, 48% yield). No product was formed when 4-nitroaniline was used as primary amine. Additional studies
are currently being carried out to elucidate and support the
obtained results.
O
N
R
RNH2
Ph
Ph
Ph
227
Ph
228
R
Ph
N
Ph
6π-electrocyclisation
229a R = Ph (41%)
229b R = 4-MeOC6H4 (48%)
229c R = 4-O2NC6H4 (no reaction)
229d R = CH2CH2Ph (40%)
229e R = CH2(CH2)3Me (48%)
Scheme 49 Synthesis of N-substituted 1,2-dihydropyridines 229 via
a 6π-electrocyclisation of ketimine 22861
2.5
Other Methods
Some other methods have been reported for the synthesis
of 1,2-dihydropyridines. These transformations are discussed in this section rather than in the previous sections
given that they do not relate to any of the formerly described methodologies.
Matsumura and co-workers63 developed a synthesis of enantiomerically pure 1,2-dihydropyridine 233 from L-lysine that employed an anodic oxidation as key step
(Scheme 50). This new 1,2-dihydropyridine 233 was sub© Georg Thieme Verlag Stuttgart · New York
Downloaded by: Beijing Normal University. Copyrighted material.
AD
REVIEW
1) NaBH4
DME–MeOH
NH
NHCO2Me
CO2Me
2) Ac2O
pyridine
NH
OAc
NHCO2Me
CO2Me
231 (89%)
230
1) – 2e
MeOH–AcOH
2) H2SO4
3) NH4Cl, heat
1) Br2, Et3N
MeOH
N
OAc
CO2Me
2) DBU, heat
3) NH4Br, heat
233 (75%)
N
OAc
CO2Me
232 (66%)
> 99.9% ee
Scheme 50 Synthesis of enantiomerically pure 1,2-dihydropyridine
23363
O
OAc
O
PtCl2 (10 mol%)
NTs
Ph
toluene (0.2 M)
100 °C, 3 h
Ph
N
Ts
234
(> 99% ee)
235
(70% yield, 98% ee)
Pt(II)
O
O
N
Ph
Ts
OAc
OAc
H
H
N
[Pt]
Ph
236
Ts
[Pt]
N
[Pt]
Ts
Ph
237
238
Scheme 51 Platinum(II)-catalysed synthesis of 1,2-dihydropyridine
235 from aziridine 23464
The authors studied the scope of this reaction and realised
that acetates, 4-chlorobenzoate, pivalate, and benzoate
propargylic esters could be successfully employed, furnishing the desired products in good yields (72–76%). Also, azyridine propargylic esters bearing cyclopropyl or
phenyl substituents at the alkyne terminus, as well as cyclic substrates, participated in this transformation to give
the desired products in good yields (62–76%). Importantly, retention of chirality was observed in converting the
aziridinyl propargyl ester 234 (> 99% ee), as 235 was obtained in 70% yield with only a minor loss of enantiomeric
excess (98%).
Ogoshi et al.65 reported in 2007 a sequential reaction process leading to 1,2-dihydropyridines 241 through a nickel(0)-catalysed [2+2+2] cycloaddition of two alkynes 240
and imine 239 (Scheme 52). A previous publication by
Wender and co-workers66 also described the formation of
1,2-dihydropyridine by this methodology; in that example, however, the 1,2-dihydropyridine was an undesired
product and the strategy was not pursued.
R2
A platinum(II)-catalysed cycloisomerisation of aziridine
propargylic ester 234 to afford 1,2-dihydropyridine 235 in
good yield and excellent enantioselectivity (Scheme 51)
was developed by Sarpong and co-workers64 The mechanistic proposal for this strategy involved a platinum(II)catalysed cascade sequence starting with the formation of
zwitterion 236. Zwitterion 236 would be formed via a 5exo-dig cyclisation of the ester carbonyl functionality
onto the alkyne. A subsequent rearrangement of intermediate 236 would afford metallocarbenoid 237. Nucleophilic attack of the aziridinyl nitrogen on the
metallocarbenoid functionality would lead to the formation of strained [3.1.0]bicycle 238. The driving strainrelease ring-opening of aziridine together with irreversible valence bond isomerisation would produce 1,2-dihydropyridine 235.
© Georg Thieme Verlag Stuttgart · New York
NSO2Ph
+ 2
Ph
R1
R2
[Ni(cod)2] (10 mol%)
phosphine (20 mol%)
H
C6D6, 100 °C
240
239
1
R1
R
R2
N
Ph
SO2Ph
241
1
240a R =
R2
= Me
MetBu2P
241a 87%
Cy3P
nBu P
3
(o-tol)3P
64%
17%
6%
240b R1 = R2 = Et
MetBu2P
Cy3P
241b 64%
26%
240c R1 = TMS, R2 = H
MetBu2P
241c 58%
Scheme 52 Synthesis of 1,2-dihydropyridines 241 via nickel(0)-catalysed [2+2+2] cycloaddition of two alkynes 240 and imine 23965
Synthesis 2013, 45, A–AK
Downloaded by: Beijing Normal University. Copyrighted material.
sequently used in the construction of an optically active 2azabicyclo[2.2.2]octane derivative. This synthesis employs easily available α-amino acids such as L-lysine derivative 230 as starting materials. 1,2-Dihydropyridine
233 was prepared through a sequence of three steps starting from the reduction of L-lysine derivative 230 with sodium borohydride leading, after acetylation, to the
diamino acetate 231 in 89% yield (Scheme 50). The electrochemical oxidation followed by acid-catalysed cyclisation and elimination of methanol furnished compound 232
in 66% yield. The last step of this sequence comprised a
β-bromo-α-methoxylation of 232, dehydrobromination
with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and
elimination of methanol, providing the final product 233
in 75% yield and an enantiomeric excess of > 99.9%. The
acetyl group at the 2-position of the 1,2-dihydropyridine
233 was found to be fundamental for the extremely high
enantiomeric excess obtained. When the reaction was performed starting from compound 230, and without performing the acetylation step, the corresponding
methoxycarbonyl dihydropyridine was formed in lower
yield and in an enantiomeric excess of approximately
77%.
MeO2C
AE
1,2-Dihydropyridines
AF
REVIEW
E. M. P. Silva et al.
Several reactions were performed with the purpose of understanding the mechanism and how this transformation
would occur. The authors concluded from these studies
that the reaction would proceed according to the catalytic
cycle shown in Scheme 53. Oxidative cyclisation of alkyne 242 and imine 243 catalysed by nickel(0) would afford nickelpyrroline 244. Insertion of a second alkyne 242
would form nickeldihydroazepine 245. Reductive elimination of 245 would then give rise to 1,2-dihydropyridine
246 and regenerate nickel(0).
R2
R2
N
R1
N
+
cat. [Ni]
2
H
R2
N
R1
R2
248
247
N
R2
R2
249
R2
R2
N
N
R1
[1,5]-H shift
R2
R2
Ni(0)
250
242
246
NSO2Ph
245
243
oxidative
cyclisation
reductive
elimination
Ni
NSO2Ph
Ni
insertion
NSO2Ph
244
Scheme 53 Catalytic cycle proposed for the reaction between two
equivalents of an alkyne and one equivalent of an imine65
Once the mechanism of this transformation was elucidated, the authors continued to study the scope of the reaction. The [2+2+2] cycloaddition of 239 and two molecules
of alkyne 240a (R1 = R2 = Me) in the presence of
[Ni(cod)2] and di(tert-butyl)methylphosphine at 100 °C
afforded the expected 1,2-dihydropyridine 241a in a good
87% yield (Scheme 52). A study of different phosphine ligands was performed, but di(tert-butyl)methylphosphine
provided the best result. Studies involving hex-3-yne
(240b; R1 = R2 = Et) and trimethylsilylacetylene (240c;
R1 = TMS, R2 = H) also gave the corresponding 1,2-dihydropyridines 241b and 241c, but in lower yields (Scheme
52).
A nickel-catalysed [2+2+2] cycloaddition of aldimine
247, bearing a 3-methyl-2-pyridyl group on the nitrogen
atom, and two alkynes 248 was the strategy developed by
Yoshikai and co-workers for the synthesis of 1,2-dihydropyridine derivatives 250 (Scheme 54).67 According to the
authors, the initially formed [2+2+2]-cycloadduct 249
would subsequently undergo a thermal 1,5-sigmatropic
hydrogen shift leading to the formation of the desired 1,2dihydropyridine 250. The initial studies were performed
using an imine derived from benzaldehyde and 2-amino3-methylpyridine (247a, R1 = Ph), which efficiently underwent a coupling reaction with two molecules of oct-4yne (R2 = n-Pr). The reaction was performed using a nickel catalyst generated from nickel(II) chloride (10 mol%),
methyl(diphenyl)phosphine (20 mol%) and manganese
powder (100 mol%) at 100 °C in N,N-dimethylformamide
and afforded 1,2-dihydropyridine 250a (R1 = Ph, R2 = nPr) in 82% yield. This was the best result obtained in the
screening of the reaction conditions.67 Other imines, such
as those bearing N-phenyl or N-sulfonyl groups, did not
react under the conditions described above.
Synthesis 2013, 45, A–AK
Scheme 54 Nickel-catalysed [2+2+2] cycloaddition of imines 247
and two alkynes 24867
The authors also studied the scope of this reaction and the
results are shown in Table 25. Several aldimines derived
from substituted benzaldehyde derivatives were tested in
the cycloaddition with oct-4-yne (R2 = n-Pr) and in all
cases the desired 1,2-dihydropyridine 250 was obtained in
moderate to good yield (Table 25, entries 1–8). The lowest yield obtained in this series involved the use of an aldimine bearing a 4-cyano substituent (entry 4). The
authors suggested that a possible coordination of the cyano group to the nickel catalyst would lead to a lower yield.
The best result was achieved when using an aldimine substituted at the ortho position by an electron-donating
group (entry 7); this afforded the corresponding 1,2-dihydropyridine 250 in 92% yield. When an electron-withdrawing fluorine atom was present at the ortho position,
the yield dropped to 38% (entry 8). Other aliphatic alkynes were tested using aldimine 247a (R1 = Ph) and the
Table 25 Scope of the Synthesis of 1,2-Dihydropyridines 25067
Entry
1,2-Dihydropyridine 250
R2
R1
Time (h)
Yield
(%)
1
4-F3CC6H4
n-Pr
24
82
2
4-t-BuC6H4
n-Pr
15
72
3
4-MeOC6H4
n-Pr
24
59
4
4-NCC6H4
n-Pr
15
36
5
3-MeOC6H4
n-Pr
24
62
6
2-MeOC6H4
n-Pr
15
89
7
2-MeC6H4
n-Pr
24
92
8
2-FC6H4
n-Pr
24
38
9
1-naphthyl
n-Pr
15
76
10
2-thienyl
n-Pr
15
39
11
Ph
Et
15
81
12
Ph
n-Bu
15
90
13
Ph
Ph
20
14
© Georg Thieme Verlag Stuttgart · New York
Downloaded by: Beijing Normal University. Copyrighted material.
+
NSO2Ph
REVIEW
AG
1,2-Dihydropyridines
An asymmetric rhodium-catalysed [2+2+2] cycloaddition
of diyne 252 to sulfonimines 251 that allowed the enantioselective synthesis of 1,2-dihydropyridines 253 in good
yields was reported earlier this year by Aubert and coworkers (Scheme 55).68 The first stage of this research
was finding a suitable catalytic system for this transformation, as well as conducting an assessment of the influence
of ligands and reaction conditions. Through these studies,
the authors established that the best compromise between
chemoselectivity and conversion was obtained when the
neutral rhodium complex [Rh(hexadiene)Cl]2 in association with a silver salt (AgSbF6) and a hindered ligand [(R)ditBu-MeOBiphep] was used. The scope of this asymmetric reaction was then explored with regard to the collection of imines 251 (Scheme 55). All the reactions afforded
the desired 1,2-dihydropyridines 253 in moderate to good
yields (54–86%) and good to excellent enantioselectivities (61–96%). Only the reaction performed with a sulfonimine bearing an electron-poor aryl group (4MeO2CC6H4) did not provide the corresponding 1,2-dihydropyridine 253. Some of these examples are shown in
Scheme 55. Likewise, the extension of the reaction to different diynes was studied. The authors proposed a mechanism for this rhodium-catalysed cycloaddition of diynes
and sulfonimines; this is presented in Scheme 56.
The proposed mechanism describes an initial coordination of, for example, diyne 254 with the rhodium catalyst
followed by oxidative cyclisation with consequent formation of rhodacyclopentadiene A. The regioselective insertion
of
sulfonimine
239
would
furnish
rhodadihydroazepine C stabilised by coordination of the
sulfonyl group to rhodium as shown in Scheme 56. A final
reductive elimination would provide 1,2-dihydropyridine
255. The authors considered that in the case of unsymmetrical or nonsubstituted diyne, a β-hydride elimination followed by reductive elimination may occur and
intermediate D would thus be formed. A 6π-electrocycli-
NR1
sation of this intermediate would furnish a more stable
1,2-dihydropyridine 256. Compound 256 could also be
formed from 255 through a [1,5]-hydrogen shift.
R
[1,5]-H
shift
NSO2Ph
X
R
255
R
Rh(I)
X
N
R
NSO2Ph
A
Ph
βH-elimination,
reductive elimination
MeO2C
NSO2Ph
MeO2C
MeO2C
Ph
MeO2C
O
Rh
X
R
S
O
N
Ph
Ph
239
Scheme 56 Proposed mechanism for the rhodium-catalysed cycloaddition of diynes 254 and sulfonimines 23968
Pérez and co-workers69 recently described an elaborate
transformation involving four consecutive catalytic cycles
leading to the synthesis of N-substituted 1,2-dihydropyridines 261 (Scheme 57). This sequential reaction is a process involving two molecules of mono- or dialkylsubstituted furans 257 and 260, one molecule of PhI=NTs
(258) and a TpXM complex (TpX = hydrotrispyrazolylborate ligand; M = Cu, Ag) as the catalyst. Complete mechanistic studies were performed by the authors and this
novel transformation was monitored by 1H NMR spectroscopy. The general mechanism, comprising four consecutive catalytic cycles I–IV, for the reaction of 2methylfuran (263) and nitrene 258 in the presence of
TpxM (M = Cu) was schematically presented by the authors as shown in Scheme 58.
NR1
MeO2C
MeO2C
R2
253
NTs
Ph
MeO2C
MeO2C
NTs
MeO2C
NTs
MeO2C
Cl
253a 77% yield, 92% ee
NSO2Ph
B
252
251
Ph
R
R
R
C
Ph
D
Rh
X
Ph
S
O
R
X
O
Rh
X
AgSbF6 (5 mol%)
DCE, r.t., 3 h, slow addition
MeO2C
H
R
R
R 256
6π-electrocyclisation
254
oxidative
cyclisation
Ph
+
R2
X
NSO2Ph
[Rh(hexadiene)Cl]2 (2.5 mol%)
(R)-ditBu-MeOBiphep (5 mol%)
MeO2C
reductive
elimination
Ph
253b 77% yield, 96% ee
253c 86% yield, 86% ee
OMe
253d 73% yield, 95% ee
Scheme 55 Rhodium-catalysed [2+2+2] cycloaddition of imine 251 and diyne 25268
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, A–AK
Downloaded by: Beijing Normal University. Copyrighted material.
corresponding 1,2-dihydropyridines 250 were obtained in
good yields (entries 11 and 12). In contrast, the use of diphenylacetylene afforded the desired product in a rather
low yield (entry 13). The catalytic cycle proposed for this
reaction is essentially similar to that proposed by Ogoshi
and co-workers (Scheme 53).65
REVIEW
E. M. P. Silva et al.
O
R1
TpBr3Cu(NCMe)
r.t., 7 h
R2
+
PhI=NTs
O
R1
R2
– PhI
257
NTs
258
259
O
O
R1
Ts
R3
R2
N
4
260 R
R4
R3
O
261
Scheme 57 Copper-catalysed synthesis of N-substituted 1,2-dihydropyridines 261 from mono- or dialkyl-substituted furans 257 and
260 and nitrene 25869
The studies performed revealed that the first step consisted of an aziridination of the furan 263 and subsequent
spontaneous opening of the aziridine moiety to give aldehyde 264 (Scheme 58). These transformations belong to
the first catalytic cycle (I). In cycle II, where water and
the metal complex could both act as catalysts, the aldehyde 264 is converted into imine 265 through a catalytic
transimination step. The intermediate 265 reacts with a
second molecule of furan 263 affording bicyclic compound 266. This step can be explained as a metal-induced
aza-Diels–Alder reaction. According to the authors, in
this cycle III, the TpxM fragment plays a critical role since
it displays a necessary degree of Lewis basicity. Finally,
the bicyclic compound 266 is converted into the 1,2-dihydropyridine 267 by a metal-catalysed hydrogen-elimination and migration process. This constitutes an
unprecedented transformation consisting of four concurrent catalytic cycles.
O
II
TpXM or H2O
I
263
TpXM
Ts
PhI=NTs
N
O
H
264
258
O
H
NTs
IV
TpXM
265
O
III
O
Ts
Ts
N
N
O
266
TpXM
O
O
267
263
Scheme 58 Concurrent tandem catalytic system to convert 2-methylfuran (263) and PhI=NTs (258) into 1,2-dihydropyridine 26769
In 2006, the synthesis of 2,3,5-trisubstituted-1,2-dihydropyridines 270 using 2-vinyloxirane 268 and aldimines 269
Synthesis 2013, 45, A–AK
in the presence of a Lewis acid (Table 26) was been described by Lautens and co-workers.70 This new one-pot
procedure was catalysed successfully by scandium(III)
and was very broad with regards to the substituents on the
aldimine 269. The corresponding 1,2-dihydropyridines
270 were obtained in moderate to good yields. The lowest
yields were obtained with the phenyl- (Table 26, entry 4),
nitro- (entry 5) and boronic ester (entry 7) substituted aldimines 269. The considerable decrease in the yield obtained with boronic ester substituted aldimines is,
according to the authors, related to the bulky substituent
at the ortho position of the phenyl ring.
Table 26 Synthesis of 1,2-Dihydropyridines 270 via Vinylogous
Iminoaldol with Substituted 2-Vinyloxirane 26870
EtO2C
O
N
R1
268
R2
H
269
Sc(OTf)3 (15 mol%)
THF, MS 5 Å
0–50 °C, 2–3 h
R2
N
R1
CO2Et
270
R1
R2
270 (%)
1
4-FC6H4
CH(Ph)2
61
2
4-ClC6H4
CH(Ph)2
60
3
4-BrC6H4
CH(Ph)2
62
4
Ph
CH(Ph)2
37
5
4-O2NC6H4
CH(Ph)2
43
6
2,4-ClC6H3
CH(Ph)2
53
7
2-BpinC6H4
CH(Ph)2
19
8
furan
CH(Ph)2
37
9
CO2Et
CH(Ph)2
63
10
Ph
2-IC6H4
51
11
Ph
2-BrC6H4
37
12
Ph
2-Br-4-MeOC6H3
41
Entry
Mechanistic studies led to the inference that the reaction
would proceed through the Lewis acid catalysed opening
of the epoxide followed by 1,2-hydride shift and a subsequent enolisation. The intermediate formed would then react with aldimine 269 to afford an (E)-amino-α,βunsaturated aldehyde. This aldehyde would isomerise to
the Z-configuration, under the influence of scandium(III)
triflate, then cyclise, and lead, through elimination of water, to the desired 1,2-dihydropyridine 270.
An additional study into the synthesis of 1,2-dihydropyridines 281 by means of a one-pot reaction was reported in
2010 by Yavari and co-workers.71 This new protocol consisted of the reaction of primary alkylamines 274, alkyl
isocyanides 271, and acetylenic esters 272 and 275
(Scheme 59). More specifically, zwitterionic intermediates 273 derived from alkyl isocyanides 271 and acetylenic
esters
272
reacted
with
dialkyl
2© Georg Thieme Verlag Stuttgart · New York
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AH
REVIEW
1,2-Dihydropyridines
CO2R2
CO2R2
CO2R2
R1 N CH
271
CO2R2
272
R1N
273
CO2R4
R3NH2
274
NR1
2
R O2C
R2O2C
CO2R4
CO2R4
R3HN
CO2R4
276
275
AI
N
277
CHO2R4
R O2C
C
NR1
CO2R4
R2O2C
N
CO2R4
2
CO2R4
R3
NHR1
R O2C
NR1
H CO R4
2
R2O2C
R2O2C
N
CO2R4
R2O2C
2
CO2R4
N
R3
R3
R3
279
280
281
CO2R4
278
Scheme 59 Proposed mechanism for the formation of highly functionalised 1,2-dihydropyridines 28171
The reaction was performed by the addition of an equimolar solution of primary amine 274 and compound 275 to a
1:1 mixture of isocyanide 271 and compound 272 in dichloromethane at room temperature; this was then left to
stir for 10 hours. A range of structurally diverse amines
were employed in this condensation reaction and the results obtained are shown in Table 27. All the reactions resulted in the desired product, with yields ranging from 59
to 95%. The lowest yield was obtained when an aromatic
primary amine bearing an electron-withdrawing group at
the para position was used (Table 27, entry 11).
Interestingly, when two different acetylenic esters were
employed, only one single product was observed (Table
27, entries 13–16). The formation of a single product was
controlled, according to the authors, by the sequence in
which the reaction was carried out. This reasoning is supported by the results obtained when the ethyl and methyl
substituents of the alkynes were reversed, as for the reactions reported in entries 13 and 16.
3
Conclusions
Despite the notable advances reviewed herein, the synthetic potential of 1,2-dihydropyridines remains largely
unexplored namely in what concerns their stereo and enantioselective formation. Also, the diversity of new or
modified methodologies clearly demonstrates that the unpredictable stability of these structures is not limiting this
field of study. Driving the scientist in this quest is the recognised significant value of 1,2-dihydropyridines in therapeutics along with possible new applications for these
molecules. The challenge remains and the merging of
these methods with other approaches, for example, combinatorial chemistry, will greatly simplify the preparation
of these heterocycles.
© Georg Thieme Verlag Stuttgart · New York
Table 27 One-Pot Synthesis of 1,2-Dihydropyridines 28171
Entry 1 R1
R2
R3
R4
Yield
(%)
1
c-Hex
Me
Bn
Me
80
2
c-Hex
Me
4-MeC6H4CH2
Me
95
3
c-Hex
Me
4-MeOC6H4CH2
Me
91
4
c-Hex
Me
2-ClC6H4CH2
Me
75
5
c-Hex
Me
4-ClC6H4CH2
Me
83
6
c-Hex
Me
1-NaphthylCH2
Me
87
7
c-Hex
Me
n-Bu
Me
88
8
t-Bu
Me
4-MeC6H4CH2
Me
93
9
t-Bu
Me
4-MeOC6H4CH2
Me
90
10
c-Hex
Me
4-MeOC6H4
Me
87
11
t-Bu
Me
4-O2NC6H4
Me
59
12
c-Hex
Et
Bn
Et
69
13
c-Hex
Et
Bn
Me
83
14
c-Hex
Et
4-MeOC6H4CH2
Me
80
15
c-Hex
Et
2-ClC6H4CH2
Me
85
16
c-Hex
Me
Bn
Et
71
Acknowledgment
Thanks are due to the University of Aveiro, Portuguese Foundation
for Science and Technology (FCT), European Union, QREN,
FEDER and COMPETE for funding the QOPNA research unit (project PEst-C/QUI/UI0062/2011). E.M.P. Silva is grateful to FCT for
a postdoctoral grant (SFRH/BPD/66961/2009).
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