Synthesis of a library of 5,6-unsubstituted 1,4-dihydropyridines based on a one-pot 4cr/elimination process and their application to the generation of structurally diverse fused nitrogen heterocycles

Article abstract of DOI:10.1021/cc100084b

Indium trichloride is an efficient catalyst for the sequential four-component reaction between aliphatic amines, β-ketoesters, α,β-unsaturated aldehydes, and ethanol to afford 6-ethoxy-1,4,5,6- tetrahydropyridines, which were converted in situ into 5,6-unsubstituted 1,4-dihydropyridines via ethanol elimination in the presence of neutral Al ₂O₃, in a very efficient, one-pot protocol from acyclic, readily available starting materials that involves the generation of two C-N δ and one C-C - bonds. The structural variety of the dihydropyridine library thus generated was extended by base-promoted --alkylation of their C-2 position. The application of these 1,4-dihydropyridines to the facile generation of molecular diversity and complexity was demonstrated by employing them as dienophiles for Yb(OTf)₃-catalyzed imino Diels-Alder (Povarov) reactions leading diastereoselectively to hexahydrobenzo[h][1,6]-naphthyridine derivatives containing three adjacent stereocenters. The synthesis of fused dihydropyridines derived from the pyrido[2,1-a]azepine (homoquinolizine) frameworks was also achieved using a four-component tetrahydropyridine synthesis/ring-closing metathesis/elimination strategy.

Full text of DOI:10.1021/cc100084b

J. Comb. Chem. 2010, 12, 713–722
713
Synthesis of a Library of 5,6-Unsubstituted 1,4-Dihydropyridines
Based on a One-Pot 4CR/Elimination Process and Their Application
to the Generation of Structurally Diverse Fused Nitrogen Heterocycles
Swarupananda Maiti, Vellaisamy Sridharan, and J. Carlos Mene´ndez*
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia, UniVersidad Complutense,
28040 Madrid, Spain
ReceiVed May 18, 2010
Indium trichloride is an efficient catalyst for the sequential four-component reaction between aliphatic amines,
ꢀ-ketoesters, R,ꢀ-unsaturated aldehydes, and ethanol to afford 6-ethoxy-1,4,5,6-tetrahydropyridines, which were
converted in situ into 5,6-unsubstituted 1,4-dihydropyridines via ethanol elimination in the presence of neutral
Al2O3, in a very efficient, one-pot protocol from acyclic, readily available starting materials that involves the
generation of two C-N σ and one C-C π bonds. The structural variety of the dihydropyridine library thus
generated was extended by base-promoted γ-alkylation of their C-2 position. The application of these
1,4-dihydropyridines to the facile generation of molecular diversity and complexity was demonstrated by employing
them as dienophiles for Yb(OTf)3-catalyzed imino Diels-Alder (Povarov) reactions leading diastereoselectively
to hexahydrobenzo[h][1,6]-naphthyridine derivatives containing three adjacent stereocenters. The synthesis of
fused dihydropyridines derived from the pyrido[2,1-a]azepine (homoquinolizine) frameworks was also achieved
using a four-component tetrahydropyridine synthesis/ring-closing metathesis/elimination strategy.
as calcium channel blockers.7 They also have a large number
of other pharmacological activities, including neuroprotection,8
radioprotection,9 noncompetitive inhibition of topoisomerase I,10
anticancer activity (acting both as cytotoxic compounds11 and
multidrug resistance reversal agents12), and HIV protease
inhibition,13 among others. Dihydropyridine systems are also
very interesting in the development of selective drug delivery
strategies since they play a key role in CNS-targeted chemical
delivery systems. These are lipophilic dihydropyridine prodrugs
that enter the brain by passive diffusion and are then oxidized
to a charged pyridinium species, which is trapped in the brain
because of its high hydrophilicity and slowly releases the parent
drug through enzymatic hydrolysis.14 Finally, dihydropyridines
are also important because of their applications in synthesis.
Thus, some types of 1,4-dihydropyridines behave as mimics
of the coenzymes NADH and NADPH and can therefore be
employed as hydrogen transfer reagents.15 Furthermore, dihy-
dropyridines have also been widely used as synthetic intermedi-
ates, specially in the preparation of libraries of alkaloid-like
compounds and related heterocyclic systems.16
Introduction
The concise assembly of molecular diversity and complex-
ity is widely regarded as one of the main goals of modern
organic synthesis, and is also a key paradigm in the design
of libraries of bioactive molecules,1 since the emergence of
high-throughput pharmaceutical screening has led to an
increased demand for the rapid generation of libraries of
small molecules, especially heterocyclic compounds.2 In this
context, the development of reactions that allow the creation
of several bonds in a single operation has become an
exceedingly attractive goal. These reactions lead to obvious
improvements in the efficiency of synthetic methods and also
to diminished production of waste because of the reduction
in the number of purification steps, helping to address the
economic and environmental concerns currently associated
to the practice of organic synthesis. Multicomponent reac-
tions, in which three or more reactants combine sequentially
to give a product in such a way that all the starting materials
significantly contribute atoms to the newly formed product,
are particularly promising for the construction of libraries
of small molecular-weight compounds.3
Dihydropyridines are often obtained by reduction of
pyridinium salts, which in turn need to be prepared by
N-alkylation of pyridines. This increases the step count of
the synthetic protocol and limits the synthetically accessible
structural diversity. A better approach would be one based
on the direct construction of the dihydropyridine framework
from acyclic precursors. The best known of these de noVo
dihydropyridine syntheses is the Hantzsch reaction, one of
the first published multicomponent reactions that, in its
original version, starts from two molecules of a ꢀ-ketoester,
one molecule of an aldehyde and one molecule of am-
1,4-Dihydropyridines are among the most important hetero-
cyclic systems in medicinal chemistry. Indeed, they can be
considered as privileged scaffolds in that they constitute “a
molecular framework able to provide ligands for diverse
receptors”.4–6 More specifically, dihydropyridines are well-
established therapeutic agents against hypertension and angina
pectoris that act primarily by inhibiting the entry of Ca2+ into
the cells of vascular smooth muscle and myocardium by acting
* To whom correspondence should be addressed. E-mail: josecm@
farm.ucm.es.
10.1021/cc100084b  2010 American Chemical Society
Published on Web 07/01/2010

714 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Maiti et al.
monia.17 This is a widely employed method, that has been
improved over the years18 but it cannot be considered as a
general dihydropyridine synthesis. Although alternative
methods exist,19 they do not allow easy access to all possible
types of substitution, and in particular the synthesis of
unsymmetrically tetrasubstituted derivatives has received
little attention. Among them, C5-C6-unsubstituted 1,4-
dihydropyridines are particularly important because this
substitution pattern allows the use of dihydropyridines as
nucleophiles or as the dienophile component in imino
Diels-Alder reactions.20 Furthermore, NAD(P)H mimics
used as hydride donors also require the absence of substit-
uents in the C-5 and C-6 positions of the dihydropyridine
ring. While some of the more recent methods afford this type
of dihydropyridines, they are often restricted to the prepara-
tion of N-aryl derivatives,19b,e which are not promising as
nucleophiles or hydride donors because of their low electron
density on nitrogen, and others give product mixtures.19c
In this context, we have recently disclosed in preliminary
form21 a two-step method for the synthesis of C5-C6-
unsubstituted 1,4-dihydropyridines, based on the preparation
of 6-alkoxy-1,4,5,6-tetrahydropyridines22 through a four-
component reaction between amines, ꢀ-dicarbonyl com-
pounds, R,ꢀ-unsaturated aldehydes, and alcohols catalyzed
by cerium(IV) ammonium nitrate (CAN),23 followed by
alumina-promoted elimination of ethanol. Unfortunately,
when the elimination step was carried out in the presence of
the CAN catalyst, extensive decomposition was observed,
and this prevented carrying out the dihydropyridine synthesis
in a one-pot fashion from acyclic starting materials, which
we considered an essential improvement to allow the use of
this method for library synthesis. Therefore, we set out to
establish suitable conditions to achieve this goal, and describe
in this paper our studies in this area, together with some
synthetic applications of the dihydropyridine derivatives thus
obtained to the generation of molecular diversity.
Figure 1. Building blocks used in the dihydropyridine synthesis.
Scheme 1. One-Pot Synthesis of 1,4-Dihydropyridines from
Primary Amines, ꢀ-Dicarbonyl Compounds, R,ꢀ-Unsaturated
Aldehydes and Ethanol
Results and Discussion
are possible, and also at C-4 (H, methyl and phenyl or
substituted phenyl groups), while C-3 tolerated the presence
of ester or thioester functions. Interestingly, our protocol can
be considered as particularly well suited for the preparation
of N-alkyl-1,4-dihydropyridines and is therefore a useful
complement of previous procedures based on the initial
formation of an imine intermediate that, as previously
mentioned, often afford only N-aryl derivatives.19b,e
We first needed to identify a catalyst able to promote the
four-component reaction while being compatible with the
conditions of the elimination stage. After some experimentation,
we found that indium trichloride met these requirements, since
it catalyzed the formation of ethyl 1-butyl-6-ethoxy-2-methyl-
1,4,5,6-tetrahydropyridine-3-carboxylate from butylamine, ethyl
acetoacetate, acrolein, and ethanol and did not interfere with
its alumina-promoted transformation into dihydropyridine 1a.
We subsequently established that the whole transformation
could be carried out as a one-pot procedure. With these
developments in hand, we decided to examine the use of our
conditions to prepare a library of dihydropyridines using the
building blocks shown in Figure 1.
As summarized in Scheme 1 and Table 1, the consecutive
reaction sequence proceeded in excellent yields in all cases
and, importantly for future applications, it could be scaled
from 1 to 30 mmol of starting materials without any
noticeable modification in yield (see entries 1-3, 9, 16, 22
and 24). Regarding its scope, the method was quite general
in terms of the type of substitution allowed at the N-1
position, where alkyl, benzyl, allyl, and propargyl substituents
Because of the scarcity of commercial ꢀ-dicarbonyl
compounds able to furnish substituents other than methyl at
C-2, to increase the structural diversity of the dihydropy-
ridines we briefly studied the alkylation of their methyl
substituent, taking advantage of the possibility of carrying
out a side chain metalation because of the conjugation of
the negative charge with the carbonyl substituent at C-3. As
shown in Scheme 2 and Table 2, treatment of compound 1d
with lithium diisopropylamide (LDA) followed by addition
of alkyl iodides afforded the desired C2-substituted deriva-
tives 2 in excellent yields, without any observable formation
of bis-alkylated side products. To our knowledge, these

Multicomponent Dihydropyridine Synthesis
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 715
Table 1. Scope and Yields of the Dihydropyridine Synthesis
Scheme 3. Synthesis of Hexahydrobenzo[h][1,6]naphthyridine
Systems 4 by Povarov Reactions of Dihydropyridines 1
reflux time yield
entry cmpd.
R1
Z
R4
(min)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
n-Bu
n-Heptyl
Allyl
Allyl
Bn
OEt
OEt
OEt
OMe
OMe
OEt
OEt
OEt
H
H
H
H
45
30
25
40
45
25
30
35
15
35
30
30
10
45
45
20
40
20
20
20
20
20
30
25
25
35
87/86a
85/87a
88/86a
78
81
89
H
n-Bu
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
n-Hexyl
n-Heptyl
Allyl
87
87
OEt
85/88a
89
n-Bu
OMe
OMe
OMe
OMe
OEt
n-Hexyl
n-Heptyl
Allyl
n-Bu
n-Hex
n-Bu
n-Heptyl
Allyl
n-Bu
n-Hex
n-Bu
Allyl
89
88
84
85
OEt
89
OMe
OMe
OMe
OEt
OEt
OMe
S-t-Bu
85/86a
87
Table 3. Yields of the Povarov Reactions of Dihydropyridines 1
entry
cmpd.
R1
R2
R3
yield (%)
83
86
80
2-O2NC6H4
2-O2NC6H4
2-O2NC6H4
H
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
Allyl
n-Bu
Allyl
n-Bu
Allyl
n-Bu
H
H
H
H
Me
Me
OMe
OMe
Me
Me
Me
67
62
61
64
75
69
1t
1u
1v
1w
1x
1y
1z
85
85/86a
85
Propargyl OEt
H
Bn
Bn
Bn
OEt
OMe
OMe
Me
Me
Ph
84/86a
80
Me
83
a Yields at a 30 mmol scale.
some compounds 1 and imines 3, derived from anilines and
ethyl glyoxylate, are summarized in Scheme 3 and Table 3.
The reaction shows a remarkable diastereoselectivity as it
generates three contiguous stereocenters and gives only two
diastereomers, with a cis arrangement between the two ring-
fusion hydrogens, which are also cis with respect to the
carboxylate group in the major diastereomer, as assigned
using literature precedent.20a–c The best catalyst for this
transformation turned out to be ytterbium triflate, while
indium trichloride, which would have allowed a one-pot
procedure from acyclic materials, unfortunately led to very
slow Povarov reactions.
Scheme 2. Introduction of Structural Variation at the
Dihydropyridine C-2 Position by γ-Alkylation Reactions
Table 2. Yields of the Alkylation Reactions at C2-Me
entry
product
R2
yield (%)
1
2
3
2a
2b
2c
Et
n-Bu
Allyl
81
85
87
Finally, bearing in mind the mildness and efficiency of
our method for dihydropyridine synthesis, we decided to
examine its application to the preparation of fused dihydro-
pyridine systems with a bridgehead nitrogen atom. We
focused our attention on the pyrido[2,1-a]azepine (homo-
quinolizine) system because of the biological importance of
quinolizine derivatives, which make up about 20% of all
known alkaloids and show a plethora of interesting phar-
macological activities.25 As shown in Scheme 4, in this case
our four-component reaction afforded mixtures of the
expected N-allyl substituted tetrahydropyridines and the
corresponding dihydropyridines. These crude mixtures were
γ-allylated using the previously mentioned method involving
their treatment with LDA followed by addition of allyl
iodide, and the materials thus obtained were submitted to a
ring-closing metathesis reaction that led to the generation
of the azepine ring, remaining only the final elimination of
ethanol to obtain compounds 5. In this particular case, this
reaction did not require heating in the presence of alumina,
as previously described for simpler dihydripyridnes, since it
was achieved during column chromatography of the crude
metathesis products using neutral, activity grade IV, alumina.
The overall yields for the 4CR/γ-alkylation/RCM/elimination
reactions constitute the first examples of functionalization
of dihydropyridine systems based on γ-deprotonation
processes.
To demonstrate the application of the dihydropyridines
obtained by our method to the generation of molecular
diversity, we decided to study their use as the dienophilic
component of the Povarov reaction. This is the imino
Diels-Alder reaction between imines derived from anilines
and electron-rich olefins to give 1,2,3,4-tetrahydroquinolines,
and is normally carried out employing vinyl ethers as
dienophiles.24 While the use of dihydropyridines for this
purpose has been described previously,20a–c the starting
materials for these literature studies were obtained by
reduction of pyridinium compounds, which were in turn
prepared by alkylation of the corresponding pyridines. By
employing our protocol we hoped to be able to decrease the
length of the synthetic sequence by eliminating the alkylation
step and also to gain access to new types of derivatives which
are not available through the current methodology (e.g.,
compounds substituted at C-2), thereby expanding the scope
of the method. Our results for the Povarov reaction between

716 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Maiti et al.
Scheme 4. Three-Step Synthesis of Homoquinolizine Derivatives 5 from Primary Amines, ꢀ-Dicarbonyl Compounds,
R,ꢀ-Unsaturated Aldehydes and Alcohols
sequence leading from acyclic starting materials to 5 were
in the 51%-65% range for the four reactions.
spectra were recorded on a Perkin-Elmer Paragon 1000 FT-
IR spectrophotometer, with all compounds examined as thin
films on NaCl disks. NMR spectra were obtained on Bruker
Avance 250, 300, and 400 MHz spectrometers (CAI de
Resonancia Magne´tica Nuclear, Universidad Complutense).
Elemental analyses were determined by the CAI de Mi-
croana´lisis Elemental, Universidad Complutense, using a
Leco 932 CHNS combustion microanalyzer.
Conclusions
The room temperature InCl3-catalyzed, sequential four-
component reaction between aliphatic amines, ꢀ-ketoesters,
R,ꢀ-unsaturated aldehydes, and ethanol followed by in situ
elimination of ethanol in the presence of neutral Al2O3 under
reflux conditions proved to be an excellent method for the
preparation of a library of synthetically and pharmacologi-
cally relevant 5,6-unsubstituted 1,4-dihydropyridines. The
overall one-pot transformation can be considered as a three-
component process, as only three of the starting materials
contribute atoms to the final product, and involves the
generation of two C-N σ bonds plus one C-C π bond.
Besides starting from acyclic, readily available, and inex-
pensive starting materials and catalysts, it has the advantage
of generating only water and methanol or ethanol as side
products. The use of some of the 1,4-dihydropyridines as
the dienophile component of Povarov reactions allowed the
diastereoselective synthesis of hexahydrobenzo[h][1,6]-naph-
thyridines containing three adjacent stereocenters. Finally,
the combination of the four-component tetrahydropyridine
synthesis and a γ-alkylation/ring-closing metathesis/elimina-
tion process allowed to apply this strategy to the preparation
of hitherto unknown homoquinolizine derivatives containing
a fused dihydropyridine ring.
General Procedure for Dihydropyridine Synthesis. To
a solution of the suitable primary amine (1.1 mmol) and
ꢀ-keto(thio)ester (1 mmol) in dry acetonitrile (15 mL) was
added InCl3 (5 mol %). The reaction mixture was stirred at
room temperature for 30 min, treated with the suitable R,ꢀ-
unsaturated aldehyde (1.1 mmol) and EtOH (3 mmol) and
stirred again for 1 h under the same conditions. Neutral Al2O3
(activity grade I, 5 g) was added, and the suspension was
refluxed for the times specified in Table 1. After completion of
the reaction (checked by NMR), the mixture was diluted with
CH2Cl2 (30 mL) and filtered through Celite, which was then
washed repeatedly with additional CH2Cl2 in 30 mL portions,
followed by methanol (30 mL). The combined organic layers
were washed with water, dried over Na2SO4 and concentrated
to dryness. The residue was purified by chromatography on
neutral Al2O3 (activity grade IV), eluting with an ethyl acetate-
petroleum ether (98:2) mixture containing 1% Et3N.
1-Butyl-2-methyl-1,4-dihydropyridine-3-carboxylic Acid
Ethyl Ester (1a). Colorless viscous liquid. IR (neat): 2960.1,
2932.1, 2873.9, 1680.7, 1567.3, 1233.2, 1178.0, 1145.2,
Experimental Section
1
1073.4 cm-1. H NMR (250 MHz, CDCl3): δ 0.92 (t, J )
General Experimental Information. All reagents (Ald-
rich, Fluka, SDS, Probus) and solvents (SDS) were of
commercial quality and were used as received. Reactions
were monitored by thin layer chromatography, on aluminum
plates coated with alumina with fluorescent indicator.
Separations by flash chromatography were performed on
neutral alumina. Melting points were measured on a Reichert
723 hot stage microscope, and are uncorrected. Infrared
7.2 Hz, 3H), 1.23 (t, J ) 7.1 Hz, 3H), 1.29-1.38 (m, 2H),
1.44-1.56 (m, 2H), 2.31 (s, 3H), 3.1 (d, J ) 3.5 Hz, 2H),
3.2 (t, J ) 7.2 Hz, 2H), 4.05-4.13 (m, 2H), 4.68-4.75 (m,
1H), 5.67 (d, J ) 7.9 Hz, 1H). 13C NMR (62.9 MHz, CDCl3):
δ 14.3, 14.9, 15.8, 20.3, 24.9, 32.7, 50.2, 59.6, 94.9, 104.2,
130.9, 150.9, 169.6. Anal. Calcd. for C13H21NO2: C, 69.92;
H, 9.48; N, 6.27; Found: C, 69.78; H, 9.23; N, 6.15.

Multicomponent Dihydropyridine Synthesis
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 717
1-Heptyl-2-methyl-1,4-dihydropyridine-3-carboxylic Acid
Ethyl Ester (1b). Colorless viscous liquid. IR (neat): 2928.8,
2857.2, 1681.9, 1568.0, 1172.6, 1078.4 cm-1. 1H NMR (250
MHz, CDCl3): δ 0.89 (t, J ) 7.3 Hz, 3H), 1.22-1.31 (m,
11H), 1.49-1.55 (m, 2H), 2.33 (s, 3H), 3.12 (d, J ) 3.3 Hz,
2H), 3.20 (t, J ) 7.5 Hz, 2H), 4.11 (q, J ) 7.3 Hz, 2H),
4.71-4.77 (m, 1H), 5.70 (dt, J ) 1.4, 2.9 Hz, 1H).13C NMR
(62.9 MHz, CDCl3): δ 14.5, 14.9, 15.8, 22.9, 24.9, 26.9, 29.4,
30.6, 32.1, 50.5, 59.6, 94.9, 104.2, 130.9, 150.9, 169.6. Anal.
Calcd. for C16H27NO2: C, 72.41; H, 10.25; N, 5.28; Found:
C, 72.28; H, 10.13; N, 5.21.
3.06-3.16 (m, 1H), 3.30-3.45 (m, 2H), 4.07-4.11 (m, 2H),
4.80 (t, J ) 5.3 Hz, 1H), 5.76 (d, J ) 7.4 Hz, 1H).13C NMR
(75 MHz, CDCl3): δ 13.9, 14.4, 15.6, 22.5, 24.8, 26.2, 28.1,
30.2, 31.5, 49.9, 59.9, 100.7, 108.7, 129.2, 148.7, 169.2.
Anal. Calcd. for C16H27NO2: C, 72.41; H, 10.25; N, 5.28;
Found: C, 72.22, H, 10.07, N, 5.39.
1-Heptyl-2,4-dimethyl-1,4-dihydropyridine-3-carboxyl-
ic Acid Ethyl Ester (1h). Colorless viscous liquid. IR (neat):
2955.4, 2927.8, 2857.9, 1685.4, 1562.5, 1395.9, 1228.5,
1173.0, 1091.7 cm-1. 1H NMR (300 MHz, CDCl3): δ
0.86-0.90 (m, 3H), 0.96 (d, J ) 6.5 Hz, 3H), 1.24-1.55
(m, 13H), 2.36 (s, 3H), 3.09-3.19 (m, 1H), 3.32-3.48 (m,
2H), 4.07-4.18 (m, 2H), 4.85 (dd, J ) 6.0 and 7.4 Hz, 1H),
5,79 (d, J ) 7.5 Hz, 1H).13C NMR (75 MHz, CDCl3): δ
14.0, 14.4, 15.6, 22.5, 24.8, 26.6, 28.1, 28.9, 30.3, 31.7, 50.1,
59.0, 100.7, 108.8, 129.2, 148.7, 169.3. Anal. Calcd. for
C17H29NO2: C, 73.07; H, 10.46; N, 5.01; Found: C, 73.36,
H, 10.36, N, 5.13.
1-Allyl-2-methyl-1,4-dihydropyridine-3-carboxylic Acid
Ethyl Ester (1c). Colorless viscous liquid. IR (neat): 2879.3,
1
1689.4, 1571.0, 1399.7, 1239.9, 1179.9, 1100.0 cm-1. H
NMR (250 MHz, CDCl3): δ 1.28 (t, J ) 7.1 Hz, 3H), 2.34
(s, 3H), 3.17 (d, J ) 3.0 Hz, 2H), 3.87-3.89 (m, 2H), 4.15
(q, J ) 7.1 Hz, 2H), 4.76-4.82 (m, 1H), 5.19-5.29 (m,
2H), 5.67-5.71 (m, 1H), 5.75-5.89 (m, 1H).13C NMR (62.9
MHz, CDCl3): δ 14.9, 15.6, 24.9, 52.3, 59.7, 95.4, 104.3,
116.6, 130.9, 134.3, 151.0, 169.6. Anal. Calcd. for
C12H17NO2: C, 69.54; H, 8.27; N, 6.76; Found: C, 69.25; H,
8.03; N, 6.56.
1-Allyl-2,4-dimethyl-1,4-dihydropyridine-3-carboxyl-
ic Acid Ethyl Ester (1i). Colorless viscous liquid. IR (neat):
2955.9, 2914.8, 2864.3, 1682.1, 1564.4, 1395.1, 1239.3,
1
1179.9, 1104.4 cm-1. H NMR (300 MHz, CDCl3): δ 1.01
1-Allyl-2-methyl-1,4-dihydropyridine-3-carboxylic Acid
Methyl Ester (1d). Colorless viscous liquid. IR (neat):
2947.5, 1691.7, 1573.3, 1401.0, 1241.8, 1181.6, 1102.0 cm-1.
1H NMR (250 MHz, CDCl3): δ 2.31 (s, 3H), 3.12 (d, J )
2.9 Hz, 2H), 3.64 (s, 3H), 3.84-3.86 (m, 2H), 4.72-4.78
(m, 1H), 5.15-5.26 (m, 2H), 5.64 (dd, J ) 1.4 and 7.9 Hz,
1H), 5.71-5.86 (m, 1H).13C NMR (62.9 MHz, CDCl3): δ
15.6, 24.9, 51.1, 52.3, 95.1, 104.4, 116.6, 130.9, 134.2, 151.3,
169.9. Anal. Calcd. for C11H15NO2,: C, 68.37; H, 7.82; N,
7.25; Found: C, 68.17; H, 7.67; N, 7.13.
(d, J ) 6.5 Hz, 3H), 1.27 (t, J ) 7.1 Hz, 3H), 2.35 (s, 3H),
3.36-3.44 (m, 1H), 3.90-3.96 (m, 2H), 4.08-4.20 (m, 2H),
4.85 (dd, J ) 5.9, 7.5 Hz, 1H), 5.13-5.21 (m, 2H),
5.75-5.87 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 14.4,
15.5, 24.9, 28.3, 51.9, 59.1, 101.5, 108.9, 116.2, 129.2, 133.9,
149.1, 169.4. Anal. Calcd. for C13H19NO2: C, 70.56; H, 8.65;
N, 6.33; Found: C, 70.32; H, 8.43; N, 6.21.
1-Butyl-2,4-dimethyl-1,4-dihydropyridine-3-carboxyl-
ic Acid Methyl Ester (1j). Colorless viscous liquid. IR
(neat): 2956.9, 2873.0, 1682.0, 1557.0, 1396.3, 1233.6,
1178.1, 1136.3, 1088.3 cm-1. 1H NMR (300 MHz, CDCl3):
δ 0.87-0.93 (m, 6H), 1.23-1.36 (m, 2H), 1.44-1.54 (m,
2H), 2.34 (s, 3H), 3.08-3.18 (m, 1H), 3.26-3.47 (m, 2H),
3.62 (s, 3H), 4.80-4.85 (m, 1H), 5.75-5.78 (m, 1H). 13C
NMR (75 MHz, CDCl3): δ 13.7, 15.6, 19.8, 24.8, 28.1, 32.4,
49.8, 50.5, 100.4, 108.9, 129.2, 149.0, 169.6. Anal. Calcd.
for C13H21NO2: C, 69.92; H, 9.48; N, 6.27; Found: C, 69.97;
H, 9.39; N, 6.40.
1-Hexyl-2,4-dimethyl-1,4-dihydropyridine-3-carboxyl-
ic Acid Methyl Ester (1k). Colorless viscous liquid. IR
(neat): 2928.7, 2859.0, 1681.9, 1556.5, 1232.4, 1175.8,
1091.1, 776.0, 724.5 cm-1. 1H NMR (300 MHz, CDCl3): δ
0.87-0.96 (m, 6H), 1.29-1.32 (m, 6H), 1.51-1.55 (m, 2H),
2.37 (s, 3H), 3.12-3.20 (m, 1H), 3.29-3.49 (m, 2H), 3.67
(s, 3H), 4.86 (dd, J ) 6.3, 7.1 Hz, 1H), 5.80 (d, J ) 7.5 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 13.9, 15.6, 22.5, 24.8,
26.2, 28.1, 30.2, 31.5, 50.1, 50.6, 100.4, 108.9, 129.2, 149.1,
169.7. Anal. Calcd. for C15H25NO2: C, 71.67; H, 10.02; N,
5.57; Found: C, 71.95; H, 9.97; N, 5.72.
1-Benzyl-2-methyl-1,4-dihydropyridine-3-carboxylic Acid
Methyl Ester (1e). Colorless viscous liquid. IR (neat):
1686.0, 1569.9, 1432.0, 1338.1, 1241.1, 1197.9, 1171.6,
1
1101.5, 984.5 cm-1. H NMR (250 MHz, CDCl3): δ 2.31
(s, 3H), 3.22 (d, J ) 3.3 Hz, 2H), 3.68 (s, 3H), 4.52 (s, 2H),
4.79-4.85 (m, 1H), 5.77 (d, J ) 7.9 Hz, 1H), 7.23-7.40
(m, 5H).13C NMR (62.9 MHz, CDCl3): δ 16.0, 24.9, 51.3,
53.7, 95.6, 104.6, 126 (2C), 127.7, 129.3 (2C), 131.5, 138.7,
151.4, 169.9. Anal. Calcd. for C15H17NO2: C, 74.05; H, 7.04;
N, 5.76; Found: C, 73.89; H, 6.89; N, 5.64.
1-Butyl-2,4-dimethyl-1,4-dihydropyridine-3-carboxyl-
ic Acid Ethyl Ester (1f). Colorless viscous liquid. IR (neat):
2957.7, 2930.6, 2871.7, 1684.8, 1560.4, 1232.2, 1177.2,
1136.5, 1087.7 cm-1. 1H NMR (250 MHz, CDCl3): δ
0.92-0.98 (m, 6H), 1.27 (t, J ) 6.4 Hz, 3H), 1.33-1.42
(m, 2H), 1.48-1.59 (m, 2H), 2.38 (s, 3H), 3.11-3.23 (m,
1H), 3.32-3.52 (m, 2H), 4.07-4.20 (m, 2H), 4.87 (t, J )
6.7 Hz, 1H), 5.81 (d, J ) 7.5 Hz, 1H). 13C NMR (62.9 MHz,
CDCl3): δ 14.3, 14.9, 16.0, 20.2, 25.3, 28.5, 32.8, 50.2, 59.5,
101.0, 109.2, 129.6, 149.3, 169.7. Anal. Calcd. for
C14H23NO2: C, 70.85; H, 9.77; N, 5.90; Found: C, 70.67, H,
9.60, N, 6.00.
1-Heptyl-2,4-dimethyl-1,4-dihydropyridine-3-carboxyl-
ic Acid Methyl Ester (1l). Colorless viscous liquid. IR
(neat): 2951.4, 2927.0, 2857.3, 1686.5, 1560.1, 1396.2,
1
1-Hexyl-2,4-dimethyl-1,4-dihydropyridine-3-carboxyl-
ic Acid Ethyl Ester (1g). Colorless viscous liquid. IR (neat):
2929.0, 2859.1, 1681.9, 1556.9, 1395.3, 1231.1, 1174.6,
1090.8, 724.3 cm-1. 1H NMR (300 MHz, CDCl3): δ
0.85-0.93 (m, 6H), 1.19-1.49 (m, 11H), 2.33 (s, 3H),
1228.4, 1174.3, 1136.0, 1091.6 cm-1. H NMR (300 MHz,
CDCl3): δ 0.85-0.89 (m, 3H), 0.93 (d, J ) 6.4 Hz, 3H),
1.28-1.57 (m, 10H), 2.36 (s, 3H), 3.09-3.19 (m, 1H),
3.28-3.48 (m, 2H), 3.65 (s, 3H), 4.85 (dd, J ) 6.1, 7.3 Hz,
1H), 5.79 (d, J ) 7.4 Hz, 1H).13C NMR (100 MHz, CDCl3):

718 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Maiti et al.
δ 14.0, 15.6, 22.5, 24.8, 26.5, 28.1, 28.9, 30.3, 31.7, 50.1,
50.5, 100.3, 108.9, 129.2, 149.1, 169.7. Anal. Calcd. for
C16H27NO2: C, 72.41; H, 10.25; N, 5.28; Found: C, 72.44;
H, 10.16; N, 5.45.
5.8, 7.6 Hz, 1H), 5.92 (d, J ) 7.6 Hz, 1H), 7.18-7.30 (m,
5H).13C NMR (62.9 MHz, CDCl3): δ 14.5, 16.2, 23.0, 27.1,
29.5, 30.7, 32.2, 40.3, 50.9, 51.1, 99.5, 108.3, 126.4, 127.6
(2C), 128.6 (2C), 129.4, 149.4, 149.6, 169.9. Anal. Calcd.
for C21H29NO2: C, 77.02; H, 8.93; N, 4.28; Found: C, 76.89;
H, 8.71; N, 4.03.
1-Allyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-car-
boxylic Acid Methyl Ester (1r). Light yellow viscous liquid.
IR (neat): 3060.2, 3024.7, 2946.1, 1688.1, 1558.3, 1393.0,
1238.2, 1184.9, 1105.8 cm-1. 1H NMR (300 MHz, CDCl3):
δ 2.46 (s, 3H), 3.56 (s, 3H), 3.98-4.01 (m, 2H), 4.63 (d, J
) 4.6 Hz, 1H), 4.97-5.01 (m, 1H), 5.19-5.27 (m, 2H),
5.79-5.92 (m, 2H), 7.15-7.33 (m, 5H).13C NMR (100 MHz,
CDCl3): δ 15.6, 40.1, 50.6, 52.3, 99.6, 107.9, 116.6, 125.9,
127.2 (2C), 128.3 (2C), 128.9, 133.7, 148.7, 149.1, 169.5.
Anal. Calcd. for C17H19NO2: C, 75.81 H, 7.11; N, 5.20;
Found: C, 75.48; H, 6.98; N, 5.08.
1-Butyl-2-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-
3-carboxylic Acid Ethyl Ester (1s). Yellow viscous liquid.
IR (neat): 2960.2, 2872.3, 1688.2, 1524.0, 1355.5, 1230.8,
1176.7, 1076.7 cm-1. 1H NMR (300 MHz, CDCl3): δ
0.85-0.97 (m, 6H), 1.23-1.41 (m, 2H), 1.53-1.60 (m, 2H),
2.50 (s, 3H), 3.20-3.30 (m, 1H), 3.40-3.50 (m, 1H),
3.77-3.85 (m, 2H), 5.03-5.13 (m, 2H), 5.86-5.88 (m, 1H),
7.19-7.27 (m, 1H), 7.50-7.52 (m, 2H), 7.66-7.68 (m,
1H).13C NMR (100 MHz, CDCl3): δ 14.1, 15.8, 16.8, 20.2,
32.7, 36.7, 50.6, 59.6, 98.9, 107.1, 123.4, 126.8, 129.9, 131.4,
133.4, 144.3, 147.9, 150.9, 171.5. Anal. Calcd. for
C19H24N2O4: C, 66.26; H, 7.02; N, 8.13; Found: C, 66.01;
H, 6.89; N, 7.98.
1-Hexyl-2-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-
3-carboxylic Acid Ethyl Ester (1t). Yellow viscous liquid.
IR (neat): 2929.6, 2857.6, 1688.0, 1524.4, 1351.6, 1172.8,
1081.4, 742.9 cm-1. 1H NMR (250 MHz, CDCl3): δ 0.93 (t,
J ) 7.1 Hz, 6H), 1.23-1.65 (m, 8H), 2.54 (s, 3H), 3.22-3.34
(m, 1H), 3.43-3.55 (m, 1H), 3.86 (q, J ) 7.1 Hz, 2H), 5.08
(d, J ) 5.2 Hz, 1H), 5.14-5.19 (m, 1H), 5.90 (d, J ) 7.6
Hz, 1H), 7.24-7.31 (m, 1H), 7.55 (d, J ) 3.9 Hz, 2H), 7.72
(d, J ) 8.0 Hz, 1H).13C NMR (62.9 MHz, CDCl3): δ 14.3,
14.4, 15.9, 22.9, 26.9, 30.9, 31.8, 36.6, 51.0, 59.7, 99.2,
107.3, 123.6, 126.7, 129.8, 131.7, 133.2, 144.4, 147.8, 151.1,
168.5. Anal. Calcd. for C21H28N2O4: C, 67.72; H, 7.58; N,
7.52; Found: C, 67.56; H, 7.24; N, 7.48.
1-Allyl-2,4-dimethyl-1,4-dihydropyridine-3-carboxyl-
ic Acid Methyl Ester (1m). Colorless viscous liquid. IR
(neat): 2949.7, 2866.4, 1687.9, 1564.2, 1396.1, 1241.1,
1
1181.9, 1106.4, 920.7 cm-1. H NMR (300 MHz, CDCl3):
δ 0.96-0.99 (m, 3H), 2.33 (s, 3H), 3.32-3.40 (m, 1H), 3.66
(s, 3H), 3.82-3.92 (m, 2H), 4.83-4.88 (m, 1H), 5.12-5.19
(m, 2H), 5.73-5.85 (m, 2H).13C NMR (75 MHz, CDCl3): δ
16.0, 25.4, 28.9, 51.3, 52.6, 101.3, 109.5, 117.0, 129.8, 134.4,
149.6, 170.2. Anal. Calcd. for C12H17NO2: C, 69.54; H, 8.27;
N, 6.76; Found: C, 69.55; H, 8.35; N, 6.71.
1-Butyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-car-
boxylic Acid Ethyl Ester (1n). Light yellow viscous liquid.
IR (neat): 2959.3, 2872.7, 1681.6, 1556.8, 1392.9, 1230.0,
1178.5, 1144.8, 1077.8 cm-1. 1H NMR (250 MHz, CDCl3):
δ 0.99 (t, J ) 7.3 Hz, 3H), 1.13 (t, J ) 7.1 Hz, 3H),
1.31-1.46 (m, 2H), 1.55-1.68 (m, 2H), 2.49 (s, 3H),
3.21-3.32 (m, 1H), 3.44-3.56 (m, 1H), 3.99 (q, J ) 7.1
Hz, 2H), 4.60 (d, J ) 5.6 Hz, 1H), 4.96 (dd, J ) 5.6, 7.5
Hz, 1H), 5.91 (d, J ) 7.6 Hz, 1H), 7.15-7.55 (m, 5H). 13
C
NMR (62.9 MHz, CDCl3): δ 14.3, 14.7, 16.2, 20.1, 32.7,
40.5, 50.4, 59.5, 99.9, 108.2, 126.3, 127.7 (2C), 128.6 (2C),
129.3, 149.1, 149.7, 169.6. Anal. Calcd. for C19H25NO2: C,
76.22; H, 8.42; N, 4.68; Found: C, 76.36; H, 8.31; N, 4.42.
1-Hexyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-car-
boxylic Acid Ethyl Ester (1o). Light yellow viscous liquid.
IR (neat): 2928.9, 2858.1, 1687.0, 1555.8, 1392.6, 1227.1,
1174.6, 1174.6, 1082.6 cm-1. 1H NMR (250 MHz, CDCl3):
δ 0.93 (t, J ) 6.3 Hz, 3H), 1.13 (t, J ) 7.1 Hz, 3H), 1.34 (s,
6H), 1.59-1.65 (m, 2H), 2.49 (s, 3H), 3.19-3.31 (m, 1H),
3.44-3.56 (m, 1H), 4.01 (q, J ) 7.1 Hz, 2H), 4.60 (d, J )
5.6 Hz, 1H), 4.96 (dd, J ) 6.1, 7.5 Hz, 1H), 5.91 (d, J )
7.6 Hz, 1H), 7.14-7.32 (m, 5H).13C NMR (62.9 MHz,
CDCl3): δ 14.5, 14.6, 16.1, 23.0, 26.8, 30.7, 32.0, 40.6, 50.8,
59.6, 99.9, 108.3, 126.3, 127.8 (2C), 128.6 (2C), 129.3,
149.3, 149.6, 169.5. Anal. Calcd. for C21H29NO2: C, 77.02;
H, 8.93; N, 4.28; Found: C, 76.80; H, 8.70; N, 4.32.
1-Butyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-car-
boxylic Acid Methyl Ester (1p). Light yellow viscous liquid.
IR (neat): 2956.4, 2867.9, 1684.5, 1557.9, 1231.1, 1180.1,
1
1145.2, 1079.3, 698.6 cm-1. H NMR (250 MHz, CDCl3):
1-Butyl-2-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-
3-carboxylic Acid Methyl Ester (1u). Yellow viscous liquid.
IR (neat): 2958.5, 2873.7, 1691.1, 1525.0, 1356.9, 1232.8,
δ 0.98 (t, J ) 7.2 Hz, 3H), 1.30-1.42 (m, 2H), 1.55-1.67
(m, 2H), 2.48 (s, 3H), 3.21-3.33 (m, 1H), 3.45-3.55 (m,
1H), 3.56 (s, 3H), 4.58 (d, J ) 5.7 Hz, 1H), 4.99 (dd, J )
5.9, 7.6 Hz, 1H), 5.92 (d, J ) 7.6 Hz, 1H), 7.16-7.49 (m,
5H).13C NMR (62.9 MHz, CDCl3): δ 14.3, 16.1, 20.3, 32.8,
40.3, 50.6, 51.0, 99.5, 108.3, 126.4, 127.6 (2C), 128.7 (2C),
129.3, 149.4, 149.5, 170.0. Anal. Calcd. for C18H23NO2: C,
75.76; H, 8.12; N, 4.91; Found: C, 75.45; H, 7.98; N, 4.65.
1-Heptyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-car-
boxylic Acid Methyl Ester (1q). Light yellow viscous liquid.
IR (neat): 2928.0, 2856.3, 1688.1, 1556.4, 1409.3, 1226.5,
1
1179.0, 1079.6 cm-1. H NMR (250 MHz, CDCl3): δ 0.99
(t, J ) 7.3 Hz, 3H), 1.31-1.47 (m, 2H), 1.57-1.68 (m, 2H),
2.52 (s, 3H), 3.24-3.36 (m, 1H), 3.40 (s, 3H), 3.41-3.66
(m, 1H), 5.06-5.17 (m, 2H), 5.96 (d, J ) 5.6 Hz, 1H),
7.23-7.31 (m, 1H), 7.54 (d, J ) 4.6 Hz, 2H), 7.70 (d, J )
7.9 Hz, 1H).13C NMR (62.9 MHz, CDCl3): δ 14.3, 15.9,
20.4, 32.8, 36.2, 50.8, 51.2, 98.9, 107.1, 123.4, 126.9, 130.2,
131.6, 133.4, 143.8, 148.0, 150.9, 169.1. Anal. Calcd. for
C18H22N2O4: C, 65.44; H, 6.71; N, 8.48; Found: 65.23; H,
6.64; N, 8.31.
1
1174.8, 1085.6, 698.4 cm-1. H NMR (250 MHz, CDCl3):
δ 0.93 (t, J ) 6.5 Hz, 3H), 1.32-1.34 (m, 8H), 1.59-1.65
(m, 2H), 2.49 (s, 3H), 3.19-3.32 (m, 1H), 3.45-3.55 (m,
1H), 3.57 (s, 3H), 4.59 (d, J ) 5.7 Hz, 1H), 4.99 (dd, J )
1-Allyl-2-methyl-1,4-dihydropyridine-3-carbothioic acid
S-tert-butyl ester (1v). Colorless viscous liquid. IR (neat):
2960.2, 1627.0, 1537.8, 1404.8, 1233.3, 1156.8, 1072.2,

Multicomponent Dihydropyridine Synthesis
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 719
919.7, 762.0 cm-1. 1H NMR (300 MHz, CDCl3): δ 1.49 (m,
9H), 2.28 (s, 3H), 3.25 (d, J ) 3.7 Hz, 2H), 3.87-3.89 (m,
2H), 4.81-4.87 (m, 1H), 5.15-5.32 (m, 2H), 5.66 (d, J )
7.8 Hz, 1H), 5.73-5.86 (m, 1H).13C NMR (75 MHz, CDCl3):
δ 16.2, 25.1, 30.4 (3C), 47.0, 52.2, 103.6, 104.6, 116.7, 130.6,
133.8, 148.6, 192.5. Anal. Calcd. for C14H21NOS: C, 66.89;
H, 8.42; N, 5.57; S, 12.76; Found: C, 66.65; H, 8.23; N,
5.32; S, 12.56.
drofuran (10 mL) was added LDA [prepared from diisopro-
pylamine (2 eq) and n-BuLi (1.6 M hexane solution, 2.05
eq), 30 min, 0 °C]. The reaction mixture was stirred at -5
to 0 °C for 30 min, and then the suitable alkyl iodide (1.1
equiv.) was added. The resulting solution was stirred at 0
°C for the 2 h, and, after verifying the completion of the
reaction by TLC, a few drops of cold saturated aqueous
NH4Cl solution were added and the organic layer was
concentrated to dryness. The residue was dissolved in
dichloromethane and washed with water. The organic layer
was dried over Na2SO4 and concentrated to dryness. The
crude residue was chromatographed on neutral Al2O3 (activ-
ity grade IV), eluting with a 98:2 petroleum ether-ethyl
acetate mixture containing 0.25% Et3N.
2-Methyl-1-prop-2-ynyl-1,4-dihydropyridine-3-carbox-
ylic Acid Ethyl Ester (1w). Colorless viscous liquid. IR
(neat): 3290.9, 2979.8, 1691.3, 1579.9, 1398.1, 1240.0,
1
1175.6, 1103.4 cm-1. H NMR (250 MHz, CDCl3): δ 1.28
(t, J ) 7.1 Hz, 3H), 2.34 (t, J ) 2.4 Hz, 1H), 2.44 (s, 3H),
3.14 (d, J ) 2.9 Hz, 2H), 4.00 (d, J ) 2.4 Hz, 2H), 4.15 (q,
J ) 7.1 Hz, 2H), 4.82-4.89 (m, 1H), 5.77 (d, J ) 6.4 Hz,
1H). 13C NMR (62.9 MHz, CDCl3): δ 14.9, 15.7, 24.8, 40.1,
59.8, 73.0, 79.5, 97.7, 105.1, 130.3, 149.9, 169.3. Anal.
Calcd. for C12H15NO2: C, 70.22; H, 7.37; N, 6.82; Found:
C, 69.97; H, 7.12; N, 6.58.
1-Allyl-2-propyl-1,4-dihydropyridine-3-carboxylic Acid
Methyl Ester (2a). Colorless viscous liquid. IR (neat):
3063.5, 2872.7, 1693.3, 1565.0, 1433.6, 1338.1, 1252.2,
1
1180.7, 1104.6 cm-1. H NMR (250 MHz, CDCl3): δ 0.99
(t, J ) 7.4 Hz, 3H), 1.45-1.61 (m, 2H), 2.64-2.71 (m, 2H),
3.14-3.16 (m, 2H), 3.66 (s, 3H), 3.83-3.85 (m, 2H),
4.74-4.80 (m, 1H), 5.18-5.29 (m, 2H), 5.65 (dt, J ) 1.4
and 7.9 Hz, 1H), 5.75-5.89 (m, 1H).13C NMR (62.9 MHz,
CDCl3): δ 13.2, 21.5, 23.5, 29.1, 49.7, 50.5, 93.0, 103.2,
115.3, 129.5, 133.1, 154.0, 167.9. Anal. Calcd. for
C13H19NO2: C, 70.56; H, 8.65; N, 6.33; Found: C, 70.23; H,
8.45; N, 6.07.
1-Allyl-2-pentyl-1,4-dihydropyridine-3-carboxylic Acid
Methyl Ester (2b). Colorless viscous liquid. IR (neat):
3064.5, 2859.9, 1693.8, 1651.7, 1433.8, 1398.5, 1234.0,
1102.4, 991.0 cm-1. 1H NMR (250 MHz, CDCl3): δ
0.89-0.95 (m, 3H), 1.27-1.51 (m, 6H), 2.66-2.73 (m, 2H),
3.15-3.17 (m, 2H), 3.67 (s, 3H), 3.84-3.85 (m, 2H),
4.75-4.81 (m, 1H), 5.15-5.29 (m, 2H), 5.65 (dd, J ) 1.4
and 7.9 Hz, 1H), 5.76-5.89 (m, 1H).13C NMR (62.9 MHz,
CDCl3): δ 13.1, 21.5, 23.5, 27.2, 27.8, 31.0, 49.7, 50.5, 92.9,
103.2, 115.3, 129.5, 133.1, 154.2, 167.9. Anal. Calcd. for
C15H23NO2: C, 72.25; H, 9.30; N, 5.62; Found: C, 72.01; H,
9.12; N, 5.43.
1-Allyl-2-but-3-enyl-1,4-dihydropyridine-3-carboxylic
Acid Methyl Ester (2c). Colorless viscous liquid. IR (neat):
2947.5, 1684.2, 1560.0, 1242.2, 1180.3, 1103.7, 915.3 cm-1.
1H NMR (250 MHz, CDCl3): δ 2.19-2.32 (m, 2H),
2.77-2.84 (m, 2H), 3.15-3.17 (m, 2H), 3.68 (s, 3H),
3.82-3.89 (m, 2H), 4.76-4.82 (m, 1H), 4.98-5.32 (m, 4H),
5.65-5.69 (m, 1H), 5.72-5.99 (m, 2H). 13C NMR (62.9
MHz, CDCl3): δ 24.9, 27.9, 33.4, 51.2, 52.0, 98.8, 104.7,
115.2, 116.8, 131.0, 134.4, 138.1, 154.7, 169.2. Anal. Calcd.
for C14H19NO3: C, 72.07; H, 8.21; N, 6.00; Found: C, 71.88;
H, 8.02; N, 5.84.
General Procedure for the Povarov Reactions of Di-
hydripyridines. A solution of the suitable arylamine (2
mmol) and ethyl glyoxylate26 (2 mmol) in CH2Cl2 (10 mL)
containing anhydrous Na2SO4 (1 g) was stirred for 30 min.
The reaction mixture was filtered and concentration of the
filtrate furnished the imines in quantitative yields with enough
purity for the next reaction. To a mixture of the freshly
prepared imine 1 (2 mmol) and dihydropyridine 2 (2 mmol)
in acetonitrile (10 mL) was added Yb(OTf)3 (10 mol %) and
the mixture was stirred for 1.5 h at room temperature. After
1-Benzyl-2,4-dimethyl-1,4-dihydropyridine-3-carboxyl-
ic Acid Ethyl Ester (1x). Colorless viscous liquid. IR (neat):
2954.7, 2867.4, 1681.9, 1567.4, 1394.6, 1238.9, 1171.5,
1
1104.2, 965.0, 729.3, 696.6 cm-1. H NMR (250 MHz,
CDCl3): δ 1.07 (d, J ) 6.5 Hz, 3H), 1.29 (t, J ) 7.1 Hz,
3H), 2.35 (s, 3H), 3.47 (t, J ) 6.2 Hz, 1H,), 4.12-4.22 (m,
2H), 4.51 (d, J ) 17.2 Hz, 1H), 4.67 (d, J ) 17.2 Hz, 1H),
4.93 (q, J ) 5.8 Hz, 1H), 5.89 (d, J ) 7.5 Hz, 1H),
7.21-7.51 (m, 5H). 13C NMR (62.9 MHz, CDCl3): δ 14.9,
16.2, 25.6, 28.8, 53.8, 59.5, 101.9, 109.4, 129.3 (2C), 127.7,
129.2 (2C), 130.4, 138.9, 149.3, 169.5. Anal. Calcd. for
C17H21NO2: C, 75.25; H, 7.80; N, 5.16; Found: C, 75.01; H,
7.61; N, 4.99.
1-Benzyl-2,4-dimethyl-1,4-dihydropyridine-3-carboxyl-
ic Acid Methyl Ester (1y). Colorless viscous liquid. IR
(neat): 2949.2, 1682.6, 1558.0, 1395.2, 1240.7, 1172.3,
1
1105.8, 729.1 cm-1. H NMR (250 MHz, CDCl3): δ 1.07
(d, J ) 6.5 Hz, 3H), 2.36 (s, 3H), 3.46 (quint, J ) 6.3 Hz,
1H), 3.71 (s, 3H), 4.52 (d, J ) 17.2 Hz, 1H), 4.60 (d, J )
17.2 Hz, 1H), 4.92-4.97 (m, 1H), 5.91 (d, J ) 7.5 Hz, 1H),
7.21 (d, J ) 7.6 Hz, 2H), 7.29-7.41 (m, 3H). 13C NMR
(62.9 MHz, CDCl3): δ 16.3, 25.6, 28.8, 51.1, 53.9, 109.6,
101.7, 129.4 (2C), 127.7, 129.2 (2C), 130.3, 138.8, 149.6,
170.1. Anal. Calcd. for C16H19NO2: C, 74.68; H, 7.44; N,
5.44; Found: C,; 74.45: H, 7.21; N, 5.32.
1-Benzyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-car-
boxylic Acid Methyl Ester (1z). Light yellow viscous liquid.
IR (neat): 3026.2, 2946.1, 1688.9, 1564.5, 1394.0, 1237.2,
1
1172.0, 1104.5, 698.4 cm-1. H NMR (250 MHz, CDCl3):
δ 2.46 (s, 3H), 3.57 (s, 3H), 4.60 (d, J ) 17.1 Hz, 1H), 4.72
(d, J ) 17.1 Hz, 1H), 4.67-4.69 (m, 1H), 5.01- 5.07 (m,
1H), 5.99 (d, J ) 7.6 Hz, 1H), 7.20-7.43 (m, 10H). 13C
NMR (62.9 MHz, CDCl3): δ 16.5, 40.5, 51.2, 54.2, 100.5,
100.8, 126.5, 126.7 (2C), 127.8 (2C), 127.9, 128.8 (2C),
129.4 (2C), 130.0, 138.5, 149.1, 149.6, 169.9. Anal. Calcd.
for C21H21NO2: C, 78.97; H, 6.63; N, 4.39; Found: C, 78.75;
H, 6.45; N, 4.21.
General procedure for the γ-alkylation reactions:
Preparation of compounds 2: To a solution of the suitable
1,4-dihydropyridine derivative 1 (1 mmol) in dry tetrahy-

720 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Maiti et al.
1
completion of the reaction, the mixture was diluted with
CH2Cl2 and washed with water followed by brine. The
organic layer was dried over anhyd. Na2SO4, and evaporated.
The crude mixture was purified by silica column chroma-
tography using petroleum ether-ethyl acetate (9:1 to 8:2, v/v)
mixture as eluent.
2959.5, 1735.1, 1675.6, 1565.4, 1223.3, 1110.1 cm-1. H
NMR (250 MHz, CDCl3): δ 0.90-1.11 (m, 6H, A & B),
1.15-1.50 (m, 20H, A & B), 1.93-2.03 (m, 2H, A & B),
2.21 (s, 3H, A), 2.22-2.50 (m, 4H, A & B), 2.25 (s, 3H,
B), 2.48 (s, 3H, A), 2.51 (s, 3H, B), 3.13-3.25 (m, 4H, A
& B), 3.97-4.48 (m, 12H, A & B), 6.50-6.71 (m, 4H, A &
B), 6.97-7.05 (m, 2H, A & B). 13C NMR (62.5 MHz,
CDCl3): δ (A & B) 14.3, 14.4, 14.5, 15.1, 16.6, 16.9, 20.4,
20.9, 21.2, 30.9, 31.2, 32.2, 35.9, 53.0, 56.6, 58.6, 59.1, 59.2,
61.6, 62.0, 92.6, 94.2, 114.3, 114.6, 114.7, 115.6, 120.0,
126.8, 127.1, 129.2, 130.1, 130.2, 139.8, 145.2, 152.6, 154.9,
169.5, 169.6, 172.3. Anal. Calcd. for C24H34N2O4: C, 69.54;
H, 8.27; N, 6.76; Found: C, 69.41; H, 8.12; N, 6.65.
1-Allyl-2-methyl-8-methoxy-1,4,4a,5,6,10b-hexahydroben-
zo[h][1,6]-naphthyridine-3,5-dicarboxylic Acid Diethyl
Ester (4a). Obtained as a mixture of two diastereomers A
and B, in the form of a pale brown oil. IR (neat) 3370.3,
1
2979.1, 2899.3, 1736.3, 1676.5, 1512.3, 1240.5 cm-1. H
NMR (250 MHz, CDCl3): δ 1.11-1.46 (m, 12H, A & B),
1.92-2.61 (m, 6H, A & B), 2.51 (s, 3H, A), 2.53 (s, 3H,
B), 3.81 (s, 3H, A), 3.83 (s, 3H, B), 3.87-4.65 (m, 16H, A
& B), 5.19-5.33 (m, 4H, A & B), 5.75-6.00 (m, 2H, A &
B), 6.55-6.72 (m, 6H, A & B). 13C NMR (62.5 MHz,
CDCl3): δ (A & B) 14.6, 14.9, 15.0, 16.7, 16.8, 20.9, 30.6,
30.7, 55.2, 56.1, 56.7, 57.7, 58.2, 59.3, 61.7, 62.1, 94.9, 95.0,
112.9, 113.6, 115.2, 115.4, 115.7, 116.8, 117.3, 121.7, 134.1,
134.2, 136.2, 152.3, 152.6, 169.3, 169.4, 172.3, 174.1. Anal.
Calcd. for C23H30N2O5: C, 66.65; H, 7.30; N, 6.76; Found:
C, 66.43; H, 7.18; N, 6.66.
1-Allyl-2,7,9-trimethyl-1,4,4a,5,6,10b-hexahydroben-
zo[h][1,6]-naphthyridine-3,5-dicarboxylic Acid Diethyl
Ester (4e). The major diastereoisomer was isolated as a pale
brown oil. IR (neat) 3406.2, 2978.1, 1735.1, 1676.6, 1567.4,
1223.8, 1177.4 cm-1. H NMR (250 MHz, CDCl3): δ 1.20
1
(t, J ) 7.1 Hz, 3H), 1.44 (t, J ) 7.1 Hz, 3H), 1.89-2.01 (m,
1H), 2.16 (s, 3H), 2.22 (s, 3H), 2.28-2.51 (m, 2H), 2.54 (s,
3H), 3.51 (bs, 1H), 3.80-4.37 (m, 8H), 5.17-5.34 (m, 2H),
5.85-5.98 (m, 1H), 6.63 (s, 1H), 6.93 (s, 1H). 13C NMR
(62.5 MHz, CDCl3): δ 14.7, 14.9, 16.7, 17.6, 17.7, 21.2, 30.5,
55.3, 56.6, 58.4, 59.2, 62.1, 94.3, 115.4, 117.0, 119.6, 122.0,
127.9, 131.6, 134.3, 137.7, 152.6, 169.5, 172.5. Anal. Calcd.
for C24H32N2O4: C, 69.88; H, 7.82; N, 6.79; Found: C, 69.71;
H, 7.61; N, 6.65.
1-Butyl-2-methyl-9-methoxy-1,4,4a,5,6,10b-hexahy-
drobenzo[h][1,6]-naphthyridine-3,5-dicarboxylic Acid Di-
ethyl Ester (4b). Obtained as a mixture of two diastereomers
A and B, in the form of a pale brown oil. IR (neat) 3356.4,
1
2959.1, 1732.7, 1672.8, 1513.1, 1237.5, 1113.6 cm-1. H
NMR (250 MHz, CDCl3): δ 0.91-1.03 (m, 6H, A & B),
1.19-1.80 (m, 20H, A & B), 1.90-2.61 (m, 6H, A & B),
2.43 (s, 3H, A), 2.51 (s, 3H, B), 3.05-3.25 (m, 4H, A &
B), 3.65 (s, 3H, A), 3.67 (s, 3H, B), 3.92-4.45 (m, 12H, A
& B), 6.55-6.69 (m, 4H, A & B), 6.76-6.81 (m, 2H, A &
B). 13C NMR (62.5 MHz, CDCl3): δ (A & B) 14.3, 14.7,
14.7, 14.9, 15.1, 16.6, 16.9, 20.4, 20.9, 26.7, 30.7, 31.2, 35.9,
36.3, 51.6, 56.0, 56.8, 58.6, 59.2, 60.6, 61.4, 62.0, 92.6, 94.8,
112.8, 113.7, 115.2, 116.1, 121.8, 136.2, 141.4, 141.5, 152.3,
153.5, 154.9, 169.5, 169.6, 172.3, 173.7. Anal. Calcd. for
C24H34N2O5: C, 66.95; H, 7.96; N, 6.51; Found: C, 66.60;
H, 7.88; N, 6.42.
The minor diastereoisomer was isolated as a pale brown
oil. IR (neat) 3421.4, 2978.1, 1736.4, 1675.9, 1565.6, 1235.8,
1119.9 cm-1. 1H NMR (250 MHz, CDCl3): δ 1.19-1.37 (m,
6H), 2.14 (s, 3H), 2.21 (s, 3H), 2.17-2.33 (m, 2H),
2.51-2.63 (m, 1H), 2.55 (s, 3H), 3.71-3.80 (m, 1H),
3.98-4.32 (m, 6H), 4.50-4.59 (m, 1H), 5.14-5.26 (m, 2H),
5.78-5.92 (m, 1H), 6.64 (s, 1H), 6.80 (s, 1H). 13C NMR
(62.5 MHz, CDCl3): δ 14.7, 15.0, 16.7, 17.5, 21.1, 25.7, 30.7,
54.7, 55.5, 57.5, 59.2, 61.2, 94.5, 116.6, 119.8, 121.7, 124.7,
126.5, 130.5, 134.2, 137.4, 153.1, 169.5, 174.1. Anal. Calcd.
for C24H32N2O4: C, 69.88; H, 7.82; N, 6.79; Found: C, 69.71;
H, 7.67; N, 6.60.
1-Allyl-2,9-dimethyl-1,4,4a,5,6,10b-hexahydroben-
zo[h][1,6]-naphthyridine-3,5-dicarboxylic Acid Diethyl
Ester (4c). Obtained as a single diastereoisomer as a yellow
solid. Mp. 161-62 °C. IR (neat) 3392.2, 2980.0, 1734.1,
1-Butyl-2,7,9-trimethyl-1,4,4a,5,6,10b-hexahydroben-
zo[h][1,6]-naphthyridine-3,5-dicarboxylic Acid Diethyl
Ester (4f). Obtained as a mixture of two diastereomers A
and B, in the form of a pale brown oil. IR (neat) 3422.3,
1
1674.4, 1567.5, 1224.7, 1105.8 cm-1. H NMR (250 MHz,
1
2978.2, 1733.4, 1677.8, 1561.3, 1233.3, 1118.8 cm-1. H
CDCl3): δ 1.19 (t, J ) 7.1 Hz, 3H), 1.36 (t, J ) 7.1 Hz,
3H), 1.93-2.05 (m, 1H), 2.22 (s, 3H), 2.25-2.32 (m, 1H),
2.39-2.51 (m, 1H), 2.53 (s, 3H), 3.78-3.88 (m, 1H),
3.94-4.10 (m, 2H), 4.23-4.47 (m, 4H), 4.56-4.65 (m, 1H),
5.24-5.33 (m, 2H), 5.84-5.97 (m, 1H), 6.53 (d, J ) 8.1
Hz, 1H), 6.72 (d, J ) 1.8 Hz, 1H), 6.86 (dd, J ) 8.1, 1.8
Hz, 1H). 13C NMR (62.5 MHz, CDCl3): δ 14.7, 14.9, 16.7,
20.9, 21.2, 30.7, 55.3, 56.5, 58.1, 59.3, 62.1, 94.5, 114.7,
117.1, 119.9, 126.7, 127.2, 129.3, 134.2, 139.8, 152.5, 169.6,
172.3. Anal. Calcd. for C23H30N2O4: C, 69.32; H, 7.59; N,
7.03; Found: C, 68.98; H, 7.41; N, 6.92.
NMR (250 MHz, CDCl3): δ 0.91-1.03 (m, 6H, A & B),
1.19-1.70 (m, 20H, A & B), 1.85-2.00 (m, 2H, A & B),
2.14 (s, 3H, A), 2.15 (s, 3H, B), 2.20 (s, 3H, A), 2.25 (s,
3H, B), 2.12-2.30 (m, 2H, A & B), 2.52 (s, 3H, A), 2.54
(s, 3H, B), 3.13-3.25 (m, 4H, A & B), 3.49 (bs, 2H, A &
B), 3.87-4.52 (m, 12H, A & B), 6.60 (s, 1H, A), 6.63 (s,
1H, B), 6.79 (s, 1H, A), 6.90 (s, 1H, B). 13C NMR (62.5
MHz, CDCl3): δ (A & B) 14.3, 12.4, 15.0, 15.1, 16.6, 17.6,
17.8, 20.4, 20.6, 20.7, 20.8, 21.1, 21.2, 30.5, 30.6, 32.1, 32.2,
53.1, 56.8, 57.7, 58.7, 59.1, 59.2, 61.6, 62.1, 94.0, 94.3,
115.4, 119.7, 121.9, 122.7, 123.7, 124.5, 126.5, 127.7, 128.0,
130.4, 131.5, 137.7, 142.5, 143.2, 152.6, 169.4, 169.6, 172.5,
173.7. Anal. Calcd. for C25H36N2O4: C, 70.06; H, 8.47; N,
6.54; Found: C, 69.78; H, 8.28; N, 6.41.
1-Butyl-2,9-dimethyl-1,4,4a,5,6,10b-hexahydroben-
zo[h][1,6]-naphthyridine-3,5-dicarboxylic Acid Diethyl
Ester (4d). Obtained as a mixture of two diastereomers A
and B, in the form of a pale brown oil. IR (neat) 3367.6,

Multicomponent Dihydropyridine Synthesis
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 721
General Procedure for the Synthesis of Compounds
5. To a solution of the suitable primary amine (1.1 mmol) and
ꢀ-ketoester (1 mmol) in dry acetonitrile (10 mL) was added
InCl3 (5 mol %), and the resulting solution was stirred at room
temperature for 30 min. After addition of the suitable R,ꢀ-
unsaturated aldehyde (1.1 mmol) and EtOH (3 mmol), stirring
at room temperature was maintained for 1 h. The mixture was
diluted with CH2Cl2 (30 mL), washed with water (2 × 10 ml),
dried over Na2SO4, and concentrated to dryness. The crude
residue was passed through a neutral Al2O3 (activity grade IV)
column eluting with EtOAc-petroleum ether (98:2) mixture
containing 1% Et3N. The mixture of tetrahydro- and dihydro-
pyridine derivatives was dissolved in dry tetrahydrofuran (THF,
10 mL) and this solution was added dropwise to a solution of
LDA [2 equiv, prepared from diisopropylamine (2 equiv) and
n-BuLi (1.6 M hexane solution, 2.05 equiv), 30 min, 0 °C] in
dry THF (10 mL). The reaction mixture was stirred at -5 to 0
°C for 30 min. After this time, allyl iodide (1.1 mmol) was
added, and the resulting mixture was stirred at 0 °C for 2 h.
Upon completion of the reaction (checked by TLC), a few drops
of cold water were added, and the reaction mixture was
concentrated to dryness. The residue was dissolved in CH2Cl2
(15 mL) and washed with brine (20 mL). The organic layer
was dried over Na2SO4 and concentrated to dryness. The crude
residue was eluted through a pad of neutral Al2O3 (activity grade
IV) using a EtOAc-petroleum ether mixture (98:2) containing
0.25% Et3N. After evaporation of the eluant, the residue was
dissolved in dry CH2Cl2 (10 mL), and Grubbs first generation
catalyst (10 mol %) was added. The reaction mixture was stirred
at room temperature until completion (checked by TLC). The
organic layer was concentrated to dryness, and the crude residue
was purified by chromatography on neutral Al2O3 (activity grade
I), eluting with a EtOAc-petroleum ether mixture (96:4)
containing 0.25% Et3N.
2-Phenyl-2,6,9,10-tetrahydropyrido[1,2-a]azepine-1-
carboxylic Acid Ethyl Ester (5c). Pale brown viscous liquid.
IR (neat): 3024.3, 2976.9, 1682.2, 1558.1, 1450.8, 1236.6,
1
1173.8, 1094.1, 698.4 cm-1. H NMR (250 MHz, CDCl3):
δ 1.15 (t, J ) 7.1 Hz, 3H), 2.47-2.53 (m, 2H), 3.26-3.37
(m, 1H), 3.48-3.58 (m, 1H), 3.89-4.06 (m, 3H), 4.16-4.24
(m, 1H), 4.56 (d, J ) 5.7 Hz, 1H), 4.89-4.95 (m, 1H),
5.72-5.87 (m, 2H), 5.95 (d, J ) 7.6 Hz, 1H), 7.14-7.29
(m, 5H). 13C NMR (62.9 MHz, CDCl3): δ 14.6, 26.3, 29.3,
40.2, 49.4, 59.7, 99.0, 107.4, 124.3, 126.4, 127.8 (2C), 128.6
(2C), 130.3, 133.5, 149.5, 154.5, 169.1. Anal. Calcd. for
C19H21NO2: C, 77.26; H, 7.17; N, 4.74; Found: C, 76.99; H,
7.17; N, 4.47.
2-Phenyl-2,6,9,10-tetrahydropyrido[1,2-a]azepine-1-
carboxylic Acid Methyl Ester (5d). Pale brown viscous
liquid. IR (neat): 3024.0, 2946.4, 1682.1, 1557.4, 1237.4,
1
1173.0, 1094.2, 699.0 cm-1. H NMR (250 MHz, CDCl3):
δ 2.52-2.54 (m, 2H), 3.26-3.37 (m, 1H), 3.49-3.60 (m,
1H), 3.58 (s, 3H), 3.88-3.97 (m, 1H), 4.18-4.26 (m, 1H),
4.55 (d, J ) 5.8 Hz, 1H), 5.92-5.98 (m, 1H), 5.72-5.87
(m, 2H), 5.97 (d, J ) 7.5 Hz, 1H), 7.15-7.46 (m, 5H). 13
C
NMR (62.9 MHz, CDCl3): δ 26.1, 29.3, 39.9, 49.4, 51.2,
98.6, 107.5, 124.3, 126.5, 127.6 (2C), 128.7 (2C), 130.4,
133.5, 149.3, 154.9, 169.6. Anal. Calcd. for C18H19NO2: C,
76.84; H, 6.81; N, 4.98; Found: C, 77.07; H, 6.66; N, 4.68.
Acknowledgment. We gratefully acknowledge financial
support from MICINN (Grant CTQ2009-12320-BQU) and
UCM (Grupos de Investigacio´n, Grant 920234).
Supporting Information Available. Copies of 1H NMR
and 13C NMR spectra of selected compounds. This material
is available free of charge via the Internet at http://
pubs.acs.org.
References and Notes
2-Methyl-2,6,9,10-tetrahydropyrido[1,2-a]azepine-1-
carboxylic Acid Ethyl Ester (5a). Colorless viscous liquid.
IR (neat): 2952.9, 2921.6, 1681.3, 1560.7, 1445.7, 1249.2,
(1) For selected reviews of diversity-oriented synthesis and its
impact in the discovery of bioactive compounds, see: (a)
Schreiber, S. L. Science 2000, 287, 1964. (b) Spring, D. R. Org.
Biomol. Chem. 2003, 1, 3867. (c) Burke, M. D.; Berger, E. M.;
Schreiber, S. L. Science 2003, 302, 5645. (d) Burke, M. D.;
Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46. (e) Tan,
D. S. Nat. Chem. Biol. 2005, 1, 74. (f) Wessjohann, L. A.; Ruijter,
E. Top. Curr. Chem. 2005, 243, 137. (g) Spandl, R. J.; Bender,
A.; Spring, D. R. Org. Biomol. Chem. 2008, 6, 1149.
(2) For some recent examples, see: (a) Carranco, I.; D´ıaz, J. L.; Jime´nez,
O.; Vendrell, M.; Albericio, F.; Royo, M.; Lavilla, R. J. Comb.
Chem. 2005, 7, 33. (b) Chang, W. J.; Kulkami, M. V.; Sun, C. M.
J. Comb. Chem. 2006, 8, 141. (c) Bogolubsky, A. V.; Ryabukhin,
S. V.; Stetsenko, S. V.; Chupryna, A. A.; Volochnyuk, D. M.;
Tolmachev, A. A. J. Comb. Chem. 2007, 9, 661. (d) Agarkov,
D. A.; Gilbertson, S. R. J. Comb. Chem. 2008, 10, 655. (e) Roy,
S.; Roy, S.; Neuenswander, B.; Hill, D.; Larock, R. C. J. Comb.
Chem. 2009, 11, 1061. (f) Sharma, V.; McLaughlin, M. L.
J. Comb. Chem. 2010, 12, 327. (g) Kim, K.; Kim, I. J. Comb.
Chem. 2010, 12, 379.
1
1173.3, 1095.7 cm-1. H NMR (250 MHz, CDCl3): δ 1.0
(d, J ) 6.5 Hz, 3H), 1.29 (t, J ) 7.1 Hz, 3H), 2.45-2.49
(m, 2H), 3.04-3.16 (m, 1H), 3.30-3.41 (m, 1H), 3.49-3.59
(m, 1H), 3.69-3.78 (m, 1H), 4.09-4.30 (m, 3H), 4.79-4.85
(m, 1H), 5.66-5.80 (m, 2H), 5.87 (d, J ) 7.5 Hz, 1H). 13
C
NMR (62.9 MHz, CDCl3): δ 14.7, 24.8, 26.2, 28.4, 29.4,
49.1, 59.6, 100.1, 108.4, 124.4, 130.7, 133.5, 154.7, 169.3.
Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00;
Found: C, 71.93; H, 8.23; N, 5.76.
2-Methyl-2,6,9,10-tetrahydropyrido[1,2-a]azepine-1-
carboxylic Acid Methyl Ester (5b). Colorless viscous liquid.
IR (neat): 2948.4, 2917.4, 1681.7, 1563.5, 1431.8, 1251.5,
1
1175.2, 1098.0 cm-1. H NMR (250 MHz, CDCl3): δ 0.98
(d, J ) 7.5 Hz, 3H), 2.37-2.46 (m, 2H), 3.06-3.17 (m,
1H), 3.28-3.39 (m, 1H), 3.50-3.59 (m, 1H), 3.68 (s, 3H),
3.77-3.79 (m, 1H), 4.08-4.36 (m, 1H), 4.81-4.86 (m, 1H),
5.66-5.79 (m, 2H), 5.87 (d, J ) 7.5 Hz, 1H). 13C NMR
(62.9 MHz, CDCl3): δ 24.8, 26.3, 28.3, 29.4, 49.2, 51.1,
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