One-pot synthesis of highly functionalized 1,2-dihydropyridines from primary alkylamines, alkyl isocyanides, and acetylenic esters

Article abstract of DOI:10.1016/j.tet.2010.08.016

A novel one-pot isocyanide-based cascade four-component reaction between primary alkylamines, acetylenic esters, and alkyl isocyanides led to tetraalkyl 1-alkyl(aryl)-4-alkylamino-1,2-dihydropyridine-2,3,5,6-tetracarbxylates in good yields.

Full text of DOI:10.1016/j.tet.2010.08.016

Tetrahedron 66 (2010) 7995e7999
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot synthesis of highly functionalized 1,2-dihydropyridines from primary
alkylamines, alkyl isocyanides, and acetylenic esters
*
Issa Yavari , Mohammad J. Bayat, Mehdi Sirouspour, Sanaz Souri
Chemistry Department, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 April 2010
Received in revised form 19 July 2010
Accepted 9 August 2010
Available online 13 August 2010
A novel one-pot isocyanide-based cascade four-component reaction between primary alkylamines,
acetylenic esters, and alkyl isocyanides led to tetraalkyl 1-alkyl(aryl)-4-alkylamino-1,2-dihydropyridine-
2,3,5,6-tetracarbxylates in good yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Primary alkylamine
Alkyl isocyanide
Acetylenic ester
1,2-Dihydropyridine
MCRs
Cascade reaction
1. Introduction
2. Results and discussion
Dihydropyridines have long been recognized as versatile syn-
thetic intermediates1 that provide ready access to a variety of
substituted N-heterocycles, such as piperidines2 and pyridines.3
Historically, 1,4-dihydropyridines have been the most studied,
whereas 1,2-dihydropyridines have received relatively little atten-
tion. The majority of synthetic approaches to 1,2-dihydropyridines
has relied on nucleophilic addition to N-alkyl or N-acylpyridinium
salts.4,5 However, regioisomeric mixtures of addition products are
often obtained if unsymmetrically substituted pyridinium salts are
employed.6 More recently, other strategies for the synthesis of 1,2-
dihydropyridines have emerged that address some of these
limitations.7 Because of the lack of general methods for the regio-
selective synthesis of highly functionalized 1,2-dihydropyridines,
their synthetic and biological potential remains largely unexplored.
One-pot, multi-component reactions continue to be of interest in
the synthesis of various compoundscontaining particularly nitrogen
atoms8,9 owing to the fast assembly of poly-substituted systems
without isolation of unstable intermediates. The importance of
these one-pot reactions in such syntheses has been demonstrated in
the Mannich, Ugi,8 Biginelli,9 and aza-BayliseHillman10 reactions,
and in Hantzsch dihydropyridine synthesis.11
As a part of our current studies on the development of new
routes in heterocyclic synthesis,12e15 we report the results of our
studies involving the reaction of the zwitterionic intermediates
derived from alkyl isocyanides 1 and acetylenic esters 2 with dia-
lkyl 2-(alkyl(aryl)amino)but-2-enedioates [generated in situ from
primary alkyl(aryl)amines and acetylenic esters 4], which consti-
tutes a synthesis of highly functionalized 1,2-dihydropyridines (5)
in good yields (Scheme 1).
The reaction of alkyl isocyanides 1, dimethyl acetylenedi-
carboxylate (2a), and primary amines 3, proceeded smoothly in
CH2Cl2 at rt and produced tetramethyl 4-(alkylamino)-1-alkyl(aryl)-
1,2-dihydropyridine-2,3,5,6-tetracarboxylates 5aek, in good yields
after purification (Scheme 1). A wide range of structurally varied
primary amines were employed in this cyclocondensation reaction.
Addition of a solution of equimolar amounts of primary amine 3 and
2a to a 1:1 mixture of cyclohexyl isocyanide (1a), and diethyl ace-
tylenedicarboxylate (2b) in CH2Cl2 at rt, produced 5,6-diethyl 2,3-
dimethyl 4-(cyclohexylamino)-1-(arylmethyl)-1,2-dihydropyridine-
2,3,5,6-tetracarboxylates 5mep, which contain two different ester
groups (Scheme 1). The formation of a single product when two
different acetylenic esters are used (Scheme 1, compounds 5mep),
is presumably controlled by the sequence in which the reaction is
carried out. When the ethyl and methyl substituents of the alkynes
are reversed, two different products (5m and 5p) were obtained.
Although compounds 5 are well set up to undergo a [1,5]-
* Corresponding author. Tel.: þ98 21 82883465; fax: þ98 21 82883455; e-mail
address: yavarisa@modares.ac.ir (I. Yavari).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.016

7996
I. Yavari et al. / Tetrahedron 66 (2010) 7995e7999
NHR1
CO2R4
CO2R2
R2O2C
CH2Cl2
CO2R4
CO2R4
R1
N
C
+
+
R3NH2
+
r.t., 10 h
R2O2C
N
R3
CO2R4
CO2R2
R1
R4
R2 R3
1
2
R2
4
R4
5
a
b
c
d
e
f
R3
Bn
R1
cHexyl
t-Bu
3
Yield (%)
a
b
c
d
e
f
cHexyl
cHexyl
cHexyl
cHexyl
cHexyl
cHexyl
cHexyl
t-Bu
t-Bu
cHexyl
t-Bu
cHexyl Et
cHexyl
Et
80
95
91
75
83
87
88
93
90
87
59
69
83
80
85
71
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
a
a
b
Bn
a
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Et
Me
Et
p-Tolyl-CH2
4-MeOC6H4CH2
2-ClC6H4CH2
4-ClC6H4CH2
1-NaphthylCH2
n-Bu
b
p-Tolyl-CH2
4-MeOC6H4CH2
2-ClC6H4CH2
4-ClC6H4CH2
1-NaphthylCH2
n-Bu
b
g
h
i
g
h
i
4-MeOC6H4
4-O2NC6H4
p-Tolyl-CH2
4-MeOC6H4CH2
4-MeOC6H4
4-O2NC6H4
Bn
j
k
l
m
n
o
p
Bn
Me
Me
Me
Et
cHexyl
cHexyl
cHexyl
Et
Et
4-MeOC6H4CH2
2-ClC6H4CH2
Bn
Me
Scheme 1. The four-component one-pot synthesis of functionalized 1,2-dihydropyridines 5.
sigmatropic shift, we conclude that no [1,5]-sigmatropic shift is
taking place under the reaction conditions employed.
spectrum of 5a exhibited 24 signals in agreement with the pro-
posed structure. The IR spectrum of 5a displayed characteristic
ester carbonyl bands. The 1H NMR and 13C NMR spectra of 5bep are
similar to those for 5a, except for the alkyl and aryl groups.
Unambiguous evidence for the structure and stereochemistry of
5c was obtained from a single-crystal X-ray analysis. An ORTEP16
diagram of 5c is shown in the Figure 1. There are two molecules of
5c together with two molecules of CH2Cl2 in the unit cell. The
structure deduced from the crystallographic experiment, by analogy
can be applied to the other products on account of their NMR-
spectroscopic similarities. For details of the structure-determination
and refinement, see the Experimental section.
The structures of compounds 5aep were deduced from their
elemental analyses and their IR, 1H NMR, 13C NMR, and single-
crystal X-ray analyses. The mass spectra of compounds 5aep dis-
played in each case, the molecular ion peak at the appropriate m/z
values. The 1H and 13C NMR spectroscopic data, as well as IR
spectra, are in agreement with the proposed structures. For ex-
ample, the 1H NMR spectrum of 5a in CDCl3 showed six singlets for
the methoxy (
d
¼3.49, 3.65, 3.73, 3.94), methine ( ¼5.13), and
d
amino (d¼8.37) protons, along with a characteristic AB system for
the diastereotopic benzylic methylene protons. The cyclohexyl and
phenyl groups exhibited characteristic multiplets in the appropri-
ate regions of the 1H NMR spectrum. The 1H-decoupled 13C NMR
Although the mechanistic details of the reaction are not known,
a plausible rationalization may be advanced to explain the product
Figure 1. X-ray crystal structure of 5c. ORTEP-III Plot;16 arbitrary atom numbering.

I. Yavari et al. / Tetrahedron 66 (2010) 7995e7999
7997
formation. Presumably, the zwitterionic intermediate 6, formed from
isocyanide 1 and acetylenic ester 2, is protonated by the enami-
noester 7, generated in situ from primary amine 3 and acetylenic
ester, to produce intermediates 8 and 9 (Scheme 2). Ketenimine 10,
produced from addition of 8 to 9, undergoes a cyclization reaction to
afford 11, which is converted to 5 by proton transfer.
(1H, br s, NH) ppm. 13C NMR (125.7 MHz, CDCl3):
d
¼24.6 (CH2), 24.9
(CH2), 25.5 (CH2), 33.2 (CH2), 34.4 (CH2), 50.5, 51.4, 52.5, 53.2, 55.4,
56.4, 58.4 (4MeO, CH2N, 2CHN), 96.1 (C), 125.7 (C), 127.8 (2 CH),
128.3 (CH), 128.7 (2CH), 134.6 (C), 153.5 (C), 154.5 (C), 164.3 (COO),
165.7 (COO), 167.0 (COO), 171.0 (COO) ppm. MS: m/z (%)¼501
(Mþþ1, 9), 500 (Mþ, 3), 469 (30), 441 (70), 236 (20), 166 (10), 177
(15), 91 (85). Anal. Calcd for C26H32N2O8 (500.54): C, 62.39; H, 6.44;
N, 5.60. Found: C, 62.8; H, 6.5; N, 5.7.
3
+
4
3.2.2. Tetramethyl 4-(cyclohexylamino)-1-(4-methylbenzyl)-1,2-di-
hydropyridine-2,3,5,6-tetracarboxylate (5b). Yellow powder; mp:
105e107 ꢁC; yield: 0.97 g (95%). IR (KBr) (nmax/cmꢀ1): 3410, 2935,
1741, 1693, 1647,1597, 1433,1354, 1282,1153, 1015, 798, 762, 590. 1H
CO2R4
CO2R4
7
NR1
CO2R4
CO2R4
CO2R2
CO2R2
R3HN
R2O2C
R2O2C
+
1
2
+
N
R1N
NMR (500.1 MHz, CDCl3):
d
¼1.50e1.58 (4H, m, 2CH2), 1.63e1.70
R3
(4H, m, 2CH2), 1.76e1.80 (2H, m, CH2), 2.32 (3H, s, Me), 3.08e3.15
(1H, m, CH), 3.52 (3H, s, MeO), 3.63 (3H, s, MeO), 3.73 (3H, s, MeO,),
3.93 (3H, s MeO), 4.47 (1H, d, 2J¼15.2 Hz, CHAHB), 4.55 (1H, d,
2J¼15.2 Hz, CHAHB), 5.13 (1H, s, CH), 7.12 (4H, s, 4 CH), 8.32 (1H, br s,
9
6
8
NR1
H
NR1
R2O2C
R2O2C
CO2R4
NH) ppm. 13C NMR (125.7 MHz, CDCl3):
d
¼20.8 (Me), 24.3 (CH2),
C
R2O2C
R2O2C
CO2R4
CO2R4
5
24.6 (CH2), 25.3 (CH2), 33.9 (CH2), 34.2 (CH2), 50.2, 51.1, 52.2, 52.9,
55.2, 55.9, 58.0 (4MeO, CH2N, 2CHN), 95.6 (C), 125.2 (C), 127.6
(2CH), 129.1 (2CH), 131.3 (C), 137.8 (C), 153.3 (C), 154.2 (C), 164.1
(COO), 165.5 (COO), 167.4 (COO), 170.7 (COO). MS: m/z (%)¼515
(Mþþ1, 13), 514 (Mþ, 5), 455 (20), 483 (90), 236 (5), 183 (20), 177
(15),105 (85). Anal. Calcd for C27H34N2O8 (514.57): C, 63.02; H, 6.66;
N, 5.44. Found: C, 63.2; H, 6.6; N, 5.4%.
N
R3
CO2R4
N
R3
11
10
Scheme 2. Plausible mechanism for the formation of functionalized 1,2-dihydropyr-
idines 5.
In conclusion, the zwitterionic 1:1 intermediates generated by
addition of alkyl isocyanides to acetylenic esters is trapped by
enaminoesters generated in situ from primary amines and dialkyl
acetylenedicarboxylates, to yield tetraalkyl 1-alkyl(aryl)-4-alkyla-
mino-1,2-dihydropyridine-2,3,5,6-tetracarbxylates in good yields.
The present method may be considered as a practical route for the
synthesis of functionalized 1,2-dihydropyridine-ring systems.
3.2.3. Tetramethyl 4-(cyclohexylamino)-1-(4-methoxybenzyl)-1,2-di-
hydropyridine-2,3,5,6-tetracarboxylate (5c). Yellow powder; mp:
96e98 ꢁC; yield: 0.96 g (91%). IR (KBr) (nmax/cmꢀ1): 3380, 2955,1741,
1699, 1581, 1533, 1433, 1410, 1290, 1213, 1140, 1082, 1028, 991, 622,
739. 1H NMR (500.1 MHz, CDCl3):
d¼1.53e1.60 (4H, m, CH2),
1.62e1.71 (4H, m, CH2), 1.90e1.95 (2H, m, CH2), 3.05e3.15 (1H, m,
CH), 3.45 (3H, s, MeO), 3.55 (3H, s, MeO), 3.63 (3H, s, MeO), 3.70 (3H,
s, MeO), 3.86 (3H, s, MeO), 4.39 (1H, d, 2J¼14.9 Hz, CHAHB), 4.45 (1H,
d, 2J¼14.9 Hz, CHAHB), 5.07 (1H, s, CH), 6.78 (2H, d, 3J¼8.5 Hz, CH),
7.10 (2H, d, 3J¼8.5 Hz, CH), 8.26 (1H, br s, NH) ppm. 13C NMR
3. Experimental
3.1. General
(125.7 MHz, CDCl3):
d
¼24.3 (CH2), 24.6 (CH2), 25.3 (CH2), 32.9 (CH2),
Primary amines 3, isocyanides 1, and the dialkyl acetylenedi-
carboxylates 2 were obtained from Merck and used without further
purification. Mp: Electrothermal-9100 apparatus. IR Spectra: Shi-
34.1 (CH2), 50.1, 51.0, 52.0, 52.9, 54.9, 55.0, 55.5, 57.8 (5MeO, CH2N,
2CHN), 95.4 (C), 113.7 (2CH), 126.2 (C), 129.1 (2CH), 131.7 (C), 153.3
(C), 154.1 (C), 159.4 (C), 164.0 (COO), 165.5 (COO), 166.6 (COO), 170.6
(COO). MS: m/z (%)¼531 (Mþþ1, 11), 530 (Mþ, 4), 499 (20), 471 (80),
236 (10), 199 (20), 177 (10), 121 (90). Anal. Calcd for C27H34N2O9
(530.57): C, 61.12; H, 6.46; N, 5.28. Found: C, 61.4; H, 6.4; N, 5.3%.
madzu IR-460 spectrometer; in cmꢀ1 1H and 13C NMR Spectra:
.
Bruker DRX-500 AVANCE instrument; in CDCl3 at 500.1 and
125.7 MHz, respectively; in parts per million, J in hertz. EIMS:
d
Finnigan-MAT-8430 mass spectrometer, at 70 eV; in m/z. Elemental
analyses: Heraeus CHNeO-Rapid analyzer.
3.2.3.1. X-ray crystal-structure determination of 5c$CH2Cl2.
Structure-determination and refinement data: formula, C27H34
N2O9.CH2Cl2:, Mr 615.49; crystal size, 0.14ꢂ0.11ꢂ0.08 mm3; crystal
system, Triclinic, a¼8.4612(9), b¼11.2718(12), c¼16.3865(17) Å,
3.2. Compounds 5ael: general procedure
To a stirred solution of amine 3 (2 mmol) and acetylenic ester 2
(4 mmol) in CH2Cl2 (10 mL), was added the isocyanide 1 (2 mmol)
at ꢀ5 ꢁC. The mixture was allowed to reach rt. After completion of
the reaction (6e12 h; TLC (AcOEt/hexane 1:4) monitoring), the
solvent was evaporated, and the residue was purified by column
chromatography (silica gel (230e400 mesh; Merck), hexane/AcOEt
5:1): pure product.
a
¼73.625(2)ꢁ,
b
¼83.472(2)ꢁ,
g
¼88.267(2)ꢁ; space group P-1; Z¼2,
V¼1489.7(3) Å3, Dcalcd¼1.372 Mg/m3; R¼0.0349 (for 7900 re-
flections), Rw¼0.0539; ꢀ11ꢃhꢃ11; ꢀ15ꢃkꢃ15; ꢀ22ꢃlꢃ22; Mo K
a
radiation (0.71073 Å); T¼120(2) K. The crystallographic data of
5c$CH2Cl2 have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication number CCDC-
737929. Copies of the data can be obtained, free of charge, via the
internet (http://www.ccdc.cam.ac.uk/data_request/cif), e-mail
(data_request@ccdc.cam.ac.uk), or fax (þ44 1223 336033).
3.2.1. Tetramethyl 1-benzyl-4-(cyclohexylamino)-1,2-dihydropyridine-
2,3,5,6-tetracarboxylate (5a). Yellow powder; mp: 99e101 ꢁC; yield:
0.80 g (80%). IR (KBr) (nmax/cmꢀ1): 3460, 2940, 1743, 1694, 1647,
1597, 1523, 1432, 1357, 1281, 1231, 1110, 1081, 809, 772, 693. 1H NMR
3.2.4. Tetramethyl 1-(2-chlorobenzyl)-4-(cyclohexylamino)-1,2-dihy-
dropyridine-2,3,5,6-tetracarboxylate (5d). Yellow powder; mp:
104e106 ꢁC; yield: 0.80 g (75%). IR (KBr) (nmax/cmꢀ1): 3375, 2935,
1742, 1696, 1648, 1596, 1523, 1434, 1282, 1231, 1140, 1013, 794, 753.
(500.1 MHz, CDCl3):
d
¼1.50e1.59 (4H, m, 2CH2), 1.65e1.73 (4H, m,
2CH2), 1.76e1.82 (2H, m, CH2), 3.24e3.26 (1H, m, CH), 3.49 (3H, s,
MeO), 3.65 (3H, s, MeO), 3.73 (3H, s, MeO), 3.94 (3H, s, MeO), 4.52
(1H, d, 2J¼15.3 Hz, CHAHB), 4.60 (1H, d, 2J¼15.3 Hz, CHAHB), 5.13
(1H, s, CH), 7.25 (2H, d, 3J¼8.2 Hz, CH), 7.34e7.36 (3H, m, CH), 8.35
1H NMR (500.1 MHz, CDCl3):
(4H, m, CH2), 1.71e1.81 (2H, m, CH2), 3.13e3.15 (1H, m, CH), 3.55
d
¼1.51e1.60 (4H, m, CH2), 1.63e1.69
(3H, s, MeO), 3.69 (3H, s, MeO), 3.73 (3H, s, MeO), 3.93 (3H, s, MeO),

7998
I. Yavari et al. / Tetrahedron 66 (2010) 7995e7999
4.70 (2H, s, CH2), 5.11 (1H, s, CH), 7.25e7.28 (3H, m, CH), 7.37e7.39
1741, 1693, 1647, 1597, 1520, 1432, 1282, 1230, 1140, 1083, 1014, 888,
777. 1H NMR (500.1 MHz, CDCl3):
(1H, m, CH), 8.30 (1H, br s, NH) ppm. 13C NMR (125.7 MHz, CDCl3):
d
¼1.39 (9H, s, 3 Me), 2.31 (3H, s,
d
¼24.5 (CH2), 24.9 (CH2), 25.5 (CH2), 33.5 (CH2), 34.5 (CH2), 50.5,
Me), 3.58 (3H, s, MeO), 3.65 (3H, s, MeO), 3.71 (3H, s, MeO), 3.91
(3H, s, MeO), 4.49 (1H, d, 2J¼15.1 Hz, CHAHB), 4.55 (1H, d,
2J¼15.1 Hz, CHAHB), 4.71 (1H, s, CH), 7.09 (4H, s, CH), 8.35 (1H, br s,
51.4, 52.6, 53.2, 53.9, 55.4, 58.8 (4MeO, CH2N, 2CHN), 96.7 (C), 126.2
(C), 127.7 (CH), 129.1 (CH), 129.4 (CH), 129.7 (CH), 132.5 (C), 133.4
(C), 153.3 (C), 154.5 (C), 164.1 (COO), 165.6 (COO), 167.0 (COO), 171.0
(COO). MS: m/z (%)¼535 (Mþþ1, 12), 534 (Mþ, 6), 529 (30), 475 (85),
236 (50), 200 (15), 177 (10), 125 (90). Anal. Calcd for C26H31ClN2O8
(534.98): C, 58.37; H, 5.84, N, 5.24. Found: C, 58.7; H, 5.9; N, 5.3%.
NH) ppm. 13C NMR (125.7 MHz, CDCl3):
d
¼20.97 (Me), 30.1 (3Me),
50.7, 51.2, 51.7, 52.5, 52.8, 60.3, 62.5 (4MeO, CH2N, CHN, CeN), 88.9
(C), 126.4 (2CH), 127.7 (C), 128.9 (2CH), 132.9 (C), 136.5 (C), 153.5 (C),
163.7 (C), 165.5 (COO), 167.5 (COO), 168.9 (COO), 169.4 (COO) ppm.
MS: m/z (%)¼489 (Mþþ1, 11), 488 (Mþ, 4), 473 (20), 429 (85), 236
(10), 180 (15), 177 (20), 105 (85), 72 (5). Anal. Calcd for C25H32N2O8
(488.53): C, 61.46; H, 6.60; N, 5.73. Found: C, 61.7; H, 6.5; N, 5.8%.
3.2.5. Tetramethyl 1-(4-chlorobenzyl)-4-(cyclohexylamino)-1,2-di-
hydropyridine-2,3,5,6-tetracarboxylate (5e). Yellow oil; yield: 0.88 g
(83%). IR (KBr) (nmax/cmꢀ1): 3490, 2940, 1741, 1694, 1649, 1597,
1525, 1432, 1278, 1231, 1157, 1087, 1013, 773, 730. 1H NMR
3.2.9. Tetramethyl 4-(tert-butylamino)-1-(4-methoxybenzyl)-1,2-di-
hydropyridine-2,3,5,6-tetracarboxylate (5i). Yellow powder; mp:
98e100 ꢁC; yield: 0.90 g (90%). IR (KBr) (nmax/cmꢀ1): 3390, 2955,
1740, 1698, 1579, 1510, 1433, 1365, 1250, 1171, 1107, 1031, 972, 813,
(500.1 MHz, CDCl3):
d
¼1.53e1.59 (4H, m, CH2), 1.63e1.70 (4H, m,
CH2), 1.71e1.80 (2H, m, CH2), 3.08e3.11 (1H, m, CH), 3.58 (3H, s,
MeO), 3.67 (3H, s, MeO), 3.74 (3H, s, MeO), 3.95 (3H, s, MeO), 4.49
(1H, d, 2J¼15.0 Hz, CHAHB), 4.57 (1H, d, 2J¼15.0 Hz, CHAHB), 5.09
(1H, s, CH), 7.21 (2H, d, 3J¼8.4 Hz, CH), 7.33 (2H, d, 3J¼8.4 Hz, CH),
780, 731. 1H NMR (500.1 MHz, CDCl3):
d
¼1.39 (9H, s, 3Me), 3.58 (3H,
s, MeO), 3.65 (3H, s, MeO), 3.70 (3H, s, MeO), 3.78 (3H, s, MeO), 3.91
(3H, s, MeO), 4.35 (1H, d, 2J¼14.5 Hz, CHAHB), 4.43 (1H, d,
2J¼14.5 Hz, CHAHB), 4.71 (1H, s, CH), 6.82 (2H, d, 3J¼8.3 Hz, CH), 7.15
(2H, d, 3J¼8.3 Hz, CH), 8.35 (1H, br s, NH) ppm. 13C NMR
8.36 (1H, br s, NH) ppm. 13C NMR (125.7 MHz, CDCl3):
d
¼24.3 (CH2),
24.7 (CH2), 25.3 (CH2), 32.9 (CH2), 34.2 (CH2), 50.4, 51.2, 52.3, 53.0,
55.2, 55.4, 58.2, (4MeO, CH2N, 2CHN), 96.4 (C), 127.1 (C), 128.7
(2CH), 128.9 (2CH), 133.1 (C), 134.0 (C), 153.0 (C), 153.9 (C), 164.0
(COO), 165.5 (COO), 167.3 (COO), 170.6 (COO). MS: m/z (%)¼535
(Mþþ1, 8), 534 (Mþ, 2), 529 (30), 475 (80), 236 (50), 200 (25), 177
(10), 125 (90). Anal. Calcd for C26H31ClN2O8 (534.98): C, 58.37; H,
5.84, N, 5.24. Found: C, 58.7; H, 5.9; N, 5.3%.
(125.7 MHz, CDCl3):
d
¼30.1 (3Me), 50.7, 51.0, 51.7, 52.5, 52.8, 55.1,
60.2, 62.5 (5MeO, CH2N, CHN, CeN), 88.9 (C), 113.7 (2CH), 114.5 (C),
127.7 (2CH), 127.9 (C), 153.6 (C), 158.7 (C), 163.6 (C), 165.5 (COO),
167.5 (COO), 168.9 (COO), 169.4 (COO). MS: m/z (%)¼505 (Mþþ1, 8),
504 (Mþ, 5), 473 (20), 445 (80), 236 (20), 196 (10), 177 (10), 121 (90),
72 (5). Anal. Calcd for C25H32N2O9 (504.53): C, 59.52; H, 6.39; N,
5.55. Found: C, 59.5; H, 6.3; N, 5.6%.
3.2.6. Tetramethyl 4-(cyclohexylamino)-1-(1-naphthylmethyl)-1,2-
dihydropyridine-2,3,5,6-tetracarboxylate (5f). Yellow powder; mp:
106e108 ꢁC; yield: 0.96 g (87%). IR (KBr) (nmax/cmꢀ1): 3475, 3280,
2935,1744,1689,1651,1597,1521,1432,1359,1277,1243,1196,1083,
3.2.10. Tetramethyl 4-(cyclohexylamino)-1-(4-methoxyphenyl)-1,2-
dihydropyridine-2,3,5,6-tetracarboxylate (5j). Yellow powder; mp:
107e109 ꢁC; yield: 0.87 g (84%). IR (KBr) (nmax/cmꢀ1): 3381, 2950,
1735, 1690, 1575, 1540, 1430, 1409, 1293, 1215, 1146, 1080, 1010, 980,
1011, 906, 791, 730. 1H NMR (500.1 MHz, CDCl3):
d
¼1.50e1.58 (4H,
m, CH2), 1.61e1.69 (4H, m, CH2), 1.72e1.78 (2H, m, CH2), 3.07e3.09
(1H, m, CH), 3.20 (3H, s, MeO), 3.63 (3H, s, MeO), 3.72 (3H, s, MeO),
3.95 (3H, s, MeO), 4.05 (1H, d, 2J¼14.8 Hz, CHAHB), 4.14 (1H, d,
2J¼14.8 Hz, CHAHB), 5.00 (1H, s, CH), 7.37e7.48 (5H, m, CH),
7.81e7.85 (2H, m, CH), 8.22 (1H, br s, NH) ppm. 13C NMR
610, 725. 1H NMR (500.1 MHz, CDCl3):
d¼1.12e1.32 (4H, m, CH2),
1.53e1.57 (4H, m, CH2), 1.63e1.67 (2H, m, CH2), 3.18e3.22 (1H, m,
CH), 3.60 (3H, s, MeO), 3.62 (3H, s, MeO), 3.63 (3H, s, MeO), 3.65
(3H, s, MeO), 3.81 (3H, s, MeO), 5.46 (1H, s, CH), 6.84 (2H, d,
3J¼8.5 Hz, CH), 7.26 (2H, d, 3J¼8.5 Hz, CH), 8.37 (1H, br s, NH) ppm.
(125.7 MHz, CDCl3):
d
¼24.5 (CH2), 24.8 (CH2), 25.5 (CH2), 33.1
(CH2), 34.4 (CH2), 50.1, 51.3, 52.4, 53.3, 54.1, 57.5, 65.7 (4MeO, CH2N,
2CHN), 96.6 (C), 122.0 (C), 122.7 (CH), 125.0 (CH), 125.9 (CH), 126.4
(CH), 126.5 (CH), 128.6 (CH), 129.3 (CH), 129.7 (C), 131.2 (C), 133.8
(C), 153.2 (C), 154.3 (C), 164.5 (COO), 165.7 (COO), 166.8 (COO), 171.2
(COO). MS: m/z (%)¼551 (Mþþ1, 10), 550 (Mþ, 3), 500 (25), 441 (70),
314 (20), 236 (10), 177 (10), 141 (80). Anal. Calcd for C30H34N2O8
(550.60): C, 65.44; H, 6.22; N, 5.09. Found: C, 65.7; H, 6.1; N, 5.1%.
13C NMR (125.7 MHz, CDCl3):
d
¼24.6 (CH2), 24.9 (CH2), 25.6 (CH2),
33.2 (CH2), 34.5 (CH2), 50.8, 51.5, 52.7, 52.8, 55.4, 55.7, 63.6 (5MeO,
2CHN), 99.0 (C), 114.3 (2CH), 115.1 (C), 127.1 (2CH), 135.6 (C), 152.6
(C), 152.8 (C), 159.1 (C), 163.7 (COO), 165.5 (COO), 167.1 (COO), 171.4
(COO). MS: m/z (%)¼517 (Mþþ1, 9), 516 (Mþ, 4), 485 (20), 457 (60),
177 (10). Anal. Calcd for C26H32N2O9 (516.54): C, 60.46; H, 6.24; N,
5.42. Found: C, 61.2; H, 6.4; N, 5.3%.
3.2.7. Tetramethyl
1-butyl-4-(cyclohexylamino)-1,2-dihydropyr-
3.2.11. Tetramethyl 4-(tert-butylamino)-1-(4-nitrophenyl)-1,2-dihy-
dropyridine-2,3,5,6-tetracarboxylate (5k). Yellow powder; mp:
110e112 ꢁC; yield: 0.62 g (59%). IR (KBr) (nmax/cmꢀ1): 3395, 2935,
1755, 1699, 1580, 1554, 1433, 1415, 1297, 1225, 1154, 1075, 1011, 984,
idine-2,3,5,6-tetracarboxylate (5g). Yellow oil; yield: 0.82 g (88%). IR
(KBr) (nmax/cmꢀ1): 3385, 2940, 1741, 1704, 1649, 1596, 1537, 1433,
1359, 1249, 1144, 1094, 1042, 907, 808, 733, 688. 1H NMR
(500.1 MHz, CDCl3):
d
¼0.92 (3H, t, 3J¼6.9 Hz, Me), 1.15e1.43 (8H, m,
613, 737. 1H NMR (500.1 MHz, CDCl3):
d
¼1.49 (9H, s, 3Me), 3.69 (3H,
4CH2), 1.54e1.74 (4H, m, 2CH2), 1.76e1.83 (2H, m, CH2), 3.33e3.39
(1H, m, CH), 3.67 (3H, s, MeO), 3.70 (3H, s, MeO), 3.75 (3H, s, MeO),
3.76e3.90 (2H, m, CH2N), 3.95 (3H, s, MeO), 5.11 (1H, s, CH), 8.31
s, MeO), 3.75 (3H, s, MeO), 3.81 (3H, s, MeO), 3.86 (3H, s, MeO), 5.92
(1H, s, CH), 6.78 (2H, d, 3J¼8.9 Hz, CH), 6.85 (2H, d, 3J¼8.9 Hz, CH),
8.38 (1H, br s, NH) ppm. 13C NMR (125.7 MHz, CDCl3):
d¼28.3
(1H, br s, NH) ppm. 13C NMR (125.7 MHz, CDCl3):
d¼13.2 (Me), 19.2
(3Me), 52.2, 51.4, 52.7, 52.9, 53.1, 53.2 (4MeO, 2CHN), 95.0 (C), 121.7
(CH), 122.3 (CH), 124.5 (CH), 124.8 (CH), 127.6 (C), 142.5 (C), 148.1
(C), 156.1 (C), 157.3 (C), 163.5 (COO), 163.9 (COO), 164.1 (COO), 165.5
(COO). MS: m/z (%)¼532 (Mþþ1, 10), 531 (Mþ, 8), 500 (20), 472 (65),
231 (10). Anal. Calcd for C25H29N3O10 (531.51): C, 56.49; H, 5.50; N,
7.91. Found: C, 56.7; H, 5.4; N, 7.8%.
(CH2), 24.4 (CH2), 24.9 (CH2), 25.4 (CH2), 30.5 (CH2), 33.1 (CH2), 34.6
(CH2), 49.1, 50.4, 51.0, 52.3, 52.8, 55.3, 59.1 (4MeO,CH2eN, 2CHN),
95.5 (C), 125.0 (C), 153.6 (C), 154.4 (C), 163.6 (COO), 164.0 (COO),
165.5 (COO), 170.7 (COO). MS: m/z (%)¼467 (Mþþ1, 9), 452 (20), 452
(80), 236 (10), 133 (20), 177 (10), 55 (90). Anal. Calcd for C23H34N2O8
(466.52): C, 59.21; H, 7.35; N, 6.00. Found: C, 59.2; H, 7.3; N, 6.1%.
3.2.12. 2,3,5,6-Tetraethyl 1-benzyl-4-(cyclohexylamino)-1,2-dihydropy-
ridine-2,3,5,6-tetracarboxylate (5l). Yellow powder; mp: 112e114 ꢁC;
yield: 0.76 g (69%). IR (KBr) (nmax/cmꢀ1): 3445, 2930, 1745, 1688,
1648, 1581, 1525, 1427, 1354, 1288, 1233, 1119, 1079, 801, 789, 699.
3.2.8. Tetramethyl 4-(tert-butylamino)-1-(4-methylbenzyl)-1,2-di-
hydropyridine-2,3,5,6-tetracarboxylate (5h). Yellow powder; mp:
102e104 ꢁC; yield: 0.90 g (93%). IR (KBr) (nmax/cmꢀ1): 3410, 2935,

I. Yavari et al. / Tetrahedron 66 (2010) 7995e7999
7999
1H NMR (500.1 MHz, CDCl3):
d
¼1.04 (3H, t, 3J¼7.1 Hz, Me), 1.17 (3H,
158.1 (C), 159.6 (COO), 163.9 (COO), 164.3 (COO), 171.1 (COO) ppm.
MS: m/z (%)¼559 (Mþþ1, 25), 558 (Mþ, 3), 527 (20), 499 (80), 264
(10), 191 (10), 186 (20), 121 (90). Anal. Calcd for C29H38N2O9
(558.62): C, 62.35; H, 6.86; N, 5.01. Found: C, 62.0; H, 6.7; N, 5.1.
t, 3J¼7.0 Hz, Me), 1.26 (3H, t, 3J¼7.1 Hz, Me), 1.32 (3H, t, 3J¼7.0 Hz,
Me), 1.53e1.59 (4H, m, 2CH2),1.63e1.70 (4H, m, 2CH2), 1.75e1.83
(2H, m, CH2), 3.17e3.22 (1H, m, CH), 4.05 (2H, q, 3J¼7.1 Hz, CH2O),
4.17 (2H, q, 3J¼7.0 Hz, CH2O), 4.23 (2H, q, 3J¼7.1 Hz, CH2O), 4.33 (2H,
q, 3J¼7.0 Hz, CH2O), 4.56 (1H, d, 2J¼15.1 Hz, CHAHB), 4.63 (1H, d,
2J¼15.1 Hz, CHAHB), 5.41 (1H, s, CH), 6.88 (2H, d, 3J¼7.5 Hz, CH),
7.23e32 (3H, m, CH), 8.29 (1H, br s, NH) ppm. 13C NMR (125.7 MHz,
3.3.3. 2,3-Diethyl
5,6-dimethyl
1-(2-chlorobenzyl)-4-(cyclo-
hexylamino)-1,2-dihydropyridine-2,3,5,6-tetracarboxylate
(5o). Yellow oil; yield: 0.95 g (85%). IR (KBr) (nmax/cmꢀ1): 3360,
2930, 1745, 1705, 1665, 1592, 1529, 1434, 1282, 1231, 1140, 1013, 794,
CDCl3):
d
¼13.8 (Me),14.0 (Me),14.2 (Me),14.4 (Me), 24.6 (CH2), 24.9
(CH2), 25.1 (CH2), 33.1 (CH2), 34.3 (CH2), 48.6, 55.1, 56.2, 58.9, 60.3,
61.4, 62.4 (4OCH2, CH2N, 2CHN), 96.7 (C), 125.8 (C), 127.9 (2CH),
128.2 (CH), 128.7 (2CH), 134.9 (C), 153.7 (C), 154.2 (C),161.8 (COO),
163.9 (COO), 165.4 (COO), 170.7 (COO) ppm. MS: m/z (%)¼557
(Mþþ1, 10), 556 (Mþ, 7), 513 (37), 483 (16), 91 (52). Anal. Calcd for
C30H40N2O8 (556.65): C, 64.73; H, 7.24; N, 5.03. Found: C, 64.6; H,
7.4; N, 5.5.
753. 1H NMR (500.1 MHz, CDCl3):
d
¼1.09 (3H, t, 3J¼7.1 Hz, CH3),1.22
(3H, t, 3J¼7.1 Hz, CH3), 1.26e1.35 (4H, m, CH2), 1.46e1.57 (4H, m,
CH2), 1.67e1.74 (2H, m, CH2), 3.14e3.16 (1H, m, CH), 3.74 (3H, s,
MeO), 3.94 (3H, s, MeO), 4.10 (2H, q, 3J¼7.1 Hz, CH2O), 4.21 (2H, q,
3J¼7.1 Hz, CH2O), 4.70 (2H, s, CH2), 5.12 (1H, s, CH), 7.25e7.28 (2H,
m, CH), 7.30e7.32 (1H, m, CH), 7.37e7.39 (1H, m, CH), 8.38 (1H, br s,
NH) ppm. 13C NMR (125.7 MHz, CDCl3):
d¼14.0 (Me),14.1 (Me), 24.6
(CH2), 24.9 (CH2), 25.5 (CH2), 33.2 (CH2), 34.5 (CH2), 51.4, 53.2, 53.8,
55.4, 58.7, 59.0,61.5 (2OCH2, 2MeO, CH2N, 2CHN), 96.8 (C), 127.2
(CH), 129.3 (CH), 129.5 (CH), 129.7 (CH), 126 (C), 133.5 (C), 132.6 (C),
153.2 (C), 154.5 (C), 164.2 (COO), 165.7 (COO), 166.8 (COO), 170.5
(COO) ppm. MS: m/z (%)¼564 (Mþþ1, 25), 563 (Mþ, 3), 532 (35),
504 (75), 438 (85), 299 (50), 264 (10), 125 (5).Anal. Calcd for
C28H35ClN2O8 (563.04): C, 59.70; H, 6.27, N, 4.98. Found: C, 59.5; H,
6.2; N, 4.9%.
3.3. Compounds 5mep: general procedure
To a stirred solution of amine 3 (2 mmol) and the first acetylenic
ester (2 mmol) in CH2Cl2 (10 mL), was added the isocyanide 1
(2 mmol) and the second acetylenic ester (2 mmol) at ꢀ5 ꢁC. The
mixture was allowed to reach rt. After completion of the reaction
(6e12 h; TLC (AcOEt/hexane 1:4) monitoring), the solvent was
evaporated, and the residue was purified by column chromatog-
raphy (silica gel (230e400 mesh; Merck), hexane/AcOEt 5:1): pure
product.
3.3.4. 2,3-Dimethyl 5,6-diethyl 1-benzyl-4-(cyclohexylamino)-1,2-
dihydropyridine-2,3,5,6-tetracarboxylate (5p). Yellow powder; mp:
111e113 ꢁC; yield: 0.75 g (71%). IR (KBr) (nmax/cmꢀ1): 3436, 2921,
1744, 1682, 1668, 1571, 1507, 1412, 1345, 1283, 1255, 1115, 1076, 825,
3.3.1. 2,3-Diethyl 5,6-dimethyl 1-benzyl-4-(cyclohexylamino)-1,2-di-
hydropyridine-2,3,5,6-tetracarboxylate (5m). Yellow powder; mp:
103e105 ꢁC; yield: 0.88 g (83%). IR (KBr) (nmax/cmꢀ1): 3455, 2925,
1751, 1692, 1659, 1585, 1515, 1426, 1363, 1281, 1231, 1110, 1081, 809,
789, 677. 1H NMR (500.1 MHz, CDCl3):
d
¼1.25 (3H, t, 3J¼7.1 Hz, Me),
1.32 (3H, t, 3J¼7.0 Hz, Me), 1.52e1.57 (4H, m, 2CH2), 1.62e1.70 (4H,
m, 2CH2),1.73e1.81 (2H, m, CH2), 3.18e3.23 (1H, m, CH), 3.52 (3H, s,
MeO), 3.57 (3H, s, MeO), 4.18 (2H, q, 3J¼7.1 Hz, CH2O), 4.39 (2H, q,
3J¼7.0 Hz, CH2O), 4.54 (1H, d, 2J¼15.5 Hz, CHAHB), 4.62 (1H, d,
2J¼15.5 Hz, CHAHB), 5.13 (1H, s, CH), 7.25 (2H, d, 3J¼7.0 Hz, CH),
7.29e7.38 (2H, m, CH), 8.33 (1H, br s, NH) ppm. 13C NMR
772, 691. 1H NMR (500.1 MHz, CDCl3):
d
¼1.04 (3H, t, 3J¼7.1 Hz, Me),
1.18 (3H, t, 3J¼7.1 Hz, Me), 1.52e1.57 (4H, m, 2CH2), 1.65e1.71 (4H,
m, 2CH2), 1.75e1.81 (2H, m, CH2), 3.17e3.19 (1H, m, CH), 3.72 (3H, s,
MeO), 3.94 (3H, s, MeO), 4.07 (2H, q, 3J¼7.1 Hz, CH2O), 4.48 (2H, q,
3J¼7.1 Hz, CH2O), 4.46 (1H, d, 2J¼15.1 Hz, CHAHB), 4.64 (1H, d,
2J¼15.1 Hz, CHAHB), 5.44 (1H, s, CH), 7.26e7.29 (3H, m, CH), 7.35
(2H, d, 3J¼7.0 Hz, CH), 8.34 (1H, br s, NH) ppm. 13C NMR
(125.7 MHz, CDCl3):
d¼13.8 (Me), 14.2 (Me), 24.9 (CH2), 25.2 (CH2),
25.6 (CH2), 33.1 (CH2), 34.2 (CH2), 50.5, 52.4, 55.1, 56.3, 58.6, 60.4,
62.4 (2OCH2, 2MeO, CH2N, 2CHN), 96.3 (C), 121.8 (C), 125.1 (C),127.8
(2CH), 128.2 (CH), 128.7 (2CH), 134.8 (C), 153.9 (C), 163.8 (COO),
164.5 (COO), 165.1 (COO), 171.1 (COO) ppm. MS: m/z (%)¼529
(Mþþ1, 9), 528 (Mþ, 5), 497 (35), 469 (11), 264 (20), 91 (45). Anal.
Calcd for C28H36N2O8 (528.59): C, 63.62; H, 6.86; N, 5.30. Found: C,
63.4; H, 7.0; N, 5.4.
(125.7 MHz, CDCl3):
d¼13.9 (Me), 14.1 (Me), 24.6 (CH2), 24.9 (CH2),
25.6 (CH2), 33.1 (CH2), 34.4 (CH2), 51.3, 53.1, 55.4, 56.3, 58.3, 58.9,
61.6 (2OCH2, 2MeO, CH2N, 2CHN), 96.2 (C), 125.8 (C), 127.9 (2CH),
128.4 (CH), 128.7 (2CH), 134.8 (C), 153.3 (C), 154.4 (C), 164.4 (COO),
165.8 (COO), 167.1 (COO), 170.5 (COO) ppm. MS: m/z (%)¼529
(Mþþ1, 25), 528 (Mþ, 4), 497 (65), 469 (15), 437 (80), 264 (20), 91
(40). Anal. Calcd for C28H36N2O8 (528.59): C, 63.62; H, 6.86; N, 5.30.
Found: C, 63.4; H, 6.9; N, 5.4.
References and notes
1. Lavilla, R. J. Chem. Soc., Perkin Trans. 1 2002, 1141.
2. Charette, A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel, J. J. Am. Chem.
Soc. 2001, 123, 11829.
3. Chai, L.; Zhao, Y.; Sheng, Q.; Liu, Z.-Q. Tetrahedron Lett. 2006, 47, 9283.
4. Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 233.
5. Comins, D. L.; Hong, H.; Salvador, J. M. J. Org. Chem. 1991, 56, 7197.
6. Bennasar, M. L.; Roca, R.; Monerris, M.; Juan, C.; Bosch, J. Tetrahedron 2002, 58,
8099.
3.3.2. 2,3-Diethyl 5,6-dimethyl 4-(cyclohexylamino)-1-(4-methox-
ybenzyl)-1,2-dihydropyridine-2,3,5,6-tetracarboxylate (5n). Yellow
powder; mp: 108e110 ꢁC; yield: 0.89 g (80%). IR (KBr) (nmax/cmꢀ1):
3450, 2941, 1741, 1690, 1645, 1589, 1521, 1430, 1359, 1279, 1240,
1081, 811, 765, 690. 1H NMR (500.1 MHz, CDCl3):
d¼1.31 (3H, t,
3J¼7.1 Hz, Me), 1.38 (3H, t, 3J¼7.1 Hz, Me), 1.53e1.57 (4H, m, CH2),
1.62e1.70 (4H, m, CH2), 1.76e1.83 (2H, m, CH2), 3.33e3.39 (1H, m,
CH), 3.54 (3H, s, MeO,), 3.65 (3H, s, MeO), 3.81 (3H, s, MeO), 4.18
(2H, q, 3J¼7.1 Hz, CH2O), 4.22 (2H, q, 3J¼7.1 Hz, CH2O), 4.48 (1H, d,
2J¼15.5 Hz, CHAHB), 4.56 (1H, d, 2J¼15.5 Hz, CHAHB), 5.15 (1H, s,
CH), 6.87 (2H, d, 2J¼8.6 Hz, CH), 7.19 (2H, d, 2J¼8.6 Hz, CH), 8.36 (1H,
7. Brunner, B.; Stogaitis, N.; Lautens, M. Org. Lett. 2006, 8, 3473.
€
8. Ugi, I.; Domling, A.; Werner, B. J. Heterocycl. Chem. 2000, 37, 647.
9. Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
10. Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521.
11. Jones, G. Comprehensive Heterocyclic Chemistry; Pergamon: Oxford, 1984; Vol. 2,
pp 482.
12. Yavari, I.; Khalili, G.; Mirzaei, A. Tetrahedron Lett. 2010, 51, 1190.
13. Yavari, I.; Mirzaei, A.; Moradi, L.; Khalili, G. Tetrahedron Lett. 2010, 51, 396.
14. Yavari, I.; Souri, S.; Sirouspour, M.; Bayat, M. J. Synlett 2009, 1921.
15. Yavari, I.; Piltan, M.; Moradi, L. Tetrahedron 2009, 65, 2067.
16. Burnett, A.M.N.; Johnson, C.K.; ‘Oak Ridge National Laboratory Report ORNL-
6895’, 1996.
br s, NH) ppm. 13C NMR (125.7 MHz, CDCl3):
24.6 (CH2), 24.9 (CH2), 25.6 (CH2), 31.4 (CH2), 33.1 (CH2), 50.5, 51.4,
55.1, 55.2, 55.8, 58.2, 60.4, 62.4 (3MeO, 2CH2O, CH2N, 2CHN), 96.1
(C), 114.1 (2CH), 124.9 (C), 129.4 (2CH), 131.9 (C), 154.0 (C), 154.2 (C),
d
¼13.8 (Me), 14.1 (Me),