Synthesis of unsymmetrical substituted 1,4-dihydropyridines through thermal and microwave assisted [4+2] cycloadditions of 1-azadienes and allenic esters

Article abstract of DOI:10.1021/jo702548b

(Chemical Equation Presented) Thermal and microwave assisted [4+2] cycloadditions of 1,4-diaryl-1-aza-1,3-butadienes with allenic esters lead to cycloadducts, which after a 1,3-H shift afford variedly substituted unsymmetrical 2-alkyl-1,4-diaryl-3-ethoxyc

Full text of DOI:10.1021/jo702548b

Synthesis of Unsymmetrical Substituted 1,4-Dihydropyridines
through Thermal and Microwave Assisted [4+2] Cycloadditions of
1-Azadienes and Allenic Esters
Lakhwinder Singh,† M. P. Singh Ishar,*,† Munusamy Elango,‡ Venkatesan Subramanian,‡
Vivek Gupta,§ and Priyanka Kanwal§
Department of Pharmaceutical Sciences, Guru Nanak DeV UniVersity, Amritsar 143 005, Punjab, India,
Chemical Laboratory, Central Leather Research Institute, Adyar, Chennai 600 020, Tamilnadu, India, and
P. G. Department of Physics, UniVersity of Jammu, Jammu Tawi-180 006, India
mpsishar@yahoo.com
ReceiVed NoVember 28, 2007
Thermal and microwave assisted [4+2] cycloadditions of 1,4-diaryl-1-aza-1,3-butadienes with allenic
esters lead to cycloadducts, which after a 1,3-H shift afford variedly substituted unsymmetrical 2-alkyl-
1,4-diaryl-3-ethoxycarbonyl-1,4-dihydropyridines in high yields. Reactions carried out under microwave
irradiation are cleaner and give higher yields with much shortened reaction times. Density functional
theory (DFT) at the B3LYP/6-31G* level has been used to calculate geometric features of the reactants,
barrier for s-trans to s-cis and reverse isomerization of azadienes (5a-d, 10a-e), dihedral angles between
N1, C2, C3, and C4 atoms of azadienes along with various indices such as chemical hardness (η), chemical
potential (µ), global electrophilicity (ω), and the difference in global electrophilicity (∆ω) between the
reacting pairs and Fukui functions (f + and f -). The results revealed that s-trans is the predominant
conformation of azadienes at ambient temperature and the barrier for conversion of the s-trans rotamer
of 1-azadienes to s-cis may be the major factor influencing the chemoselectivity, i.e., [4+2] verses [2+2]
cycloaddition. The regiochemistry of the observed cycloadditions is collated with the obtained local
electrophilicity indices (Fukui functions). Transition states for the formation of both [4+2] and [2+2]
cycloadducts as located at the PM3 level indicate that the transition state for the formation of [4+2]
cycloadducts has lower energy, again supporting the earlier conclusion that preferred formation of [4+2]
cycloaaducts at higher temperature may be a consequence of barrier for s-trans to s-cis transformation of
1-azadienes.
Introduction
potent calcium channel antagonist (1, 2) and potent calcium
channel agonist (3, 4).2 Besides their overwhelming utilization
in the cardiovascular pharmacology as Ca2+ channel blockers
(CCBs),3 other activities attributed to these molecules include
selective adenosine-A3 receptor antagonism4 and NMDA-
receptor antagonism (anticonvulsant).5
A vast number of pharmacologically active heterocyclic
compounds are known which are in regular clinical use.1 1,4-
Dihydropyridines (1,4-DHPs) such as Nifedipine (1) make up
the most potent and largest series of heterocyclic compounds
available experimentally and clinically; the series embraces both
† Guru Nanak Dev University.
(2) Triggle, D. J.; Rampe, D. Trends Pharmacol. Sci. 1989, 12, 507.
(3) (a) Janis, R. A.; Silver, P. J.; Triggle, D. J. AdV. Drug Res. 1987, 16,
309. (b) Lavilla, R. J. Chem Soc., Perkin 1 2002, 1141. (c) Natale, N. R.;
Rogers, M. E.; Staples, R.; Triggle, D. J.; Rutledge, A. J. Med. Chem. 1999,
42, 3087. (d) Triggle, D. J. CleVeland Clin. J. Med. 1992, 59, 617.
‡ Central Leather Research Institute.
§ University of Jammu.
(1) Katrizky, A. R.; Rees, C. W., Eds. ComprehensiVe Heterocyclic
Chemistry; Pergamon Press: Oxford, UK, 1984; Vol. 1.
10.1021/jo702548b CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/13/2008
2224
J. Org. Chem. 2008, 73, 2224-2233

Unsymmetrical Substituted 1,4-Dihydropyridines
that the absolute configuration at the C4 position of the 1,4-
DHP nucleus is indispensable for activity modulation. Indeed
enantiomers of an unsymmetrically 4-substituted 1,4-DHP
usually differ in their biological properties, and sometimes they
could have exactly the opposite action profile (e.g., calcium
channel antagonist vs calcium channel agonist).15 Also, the
presence of different substituents or heteroatoms has allowed
an expansion of the structure-activity relationship thus provid-
ing a better insight into the molecular interaction at the receptor
level. The knowledge of stereochemical/conformational require-
ments for any biological activity requires the study of other
related analogues of the DHP ring.16 Consequently, with
attribution of many other types of biological activities to 1,4-
DHPs, the design, synthesis, and evaluation of novel 1,4-DHPs
with a varied pattern of substitution assumes a lot of signifi-
cance.
Since the first report of the Hantzsch synthesis of 1,4-
dihydropyridines, a number of strategies involving different
catalysts and conditions have been developed but all suffer from
one or more drawbacks including low yields, use of costly
reagents, and drastic reaction conditions.3b,12 Hetero-Diels-
Alder methodology is of tremendous synthetic utility in organic
synthesis, and recently, besides definite advancements in
theoretical understanding, a number of novel catalytic conditions
have been developed for easy realization of hetero-Diels-Alder
reactions.17 However, there are very few reports available on
cycloadditions involving allenes and heterodienes.18 Contrary
to the earlier reported18c cycloaddition reactions of 1-azadienes
with allenes leading to the formation of cyclohexanones through
rearrangement of [2+2] cycloadducts, it was observed19 that
reaction of 1-aza-1-aryl-4-phenyl-1,3-butadienes (5) with allenic
esters (6), in refluxing benzene led to [4+2] cycloadducts, which
after a 1,3-H shift, furnish valuable substituted-1,4-dihydropy-
Some recently discovered biological activities of 1,4-dihy-
dropyridines include HIV-I protease inhibition,6 neuromodula-
tory (anticonvulsant),7 and nitric oxide-like activities.8 Dihy-
dropyridines have also been found to be potent R1a-adrenoreceptor
antagonists acting as inhibitors of human prostate contraction
and hence are useful for treatment of benign prostate hyper-
plasia;9 they are also useful NADH models.10 Recently, these
molecules have also been investigated for other pharmacological
activities such as antidiabetic, antiviral, antibacterial, membrane
protecting, anticancer,11 antitubercular,12 and antimicrobial.13
Though the chemistry and biomedical applications of 1,4-
dihydropyridines have been comprehensively reviewed,3a,b the
details of subtle stereoelectronic requirements for interactions
at various receptors are still being investigated. However, as
with many other drugs, the symmetrical substitution pattern in
medicinally active 1,4-dihydropyridines such as Nifedipine (1)
has proven to be more of a consequence of synthetic methodol-
ogy rather than a receptor requirement, and recently the
unsymmetrically substituted variants have been shown to display
better pharmacological properties.14 It now has been recognized
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J. Org. Chem, Vol. 73, No. 6, 2008 2225

Singh et al.
SCHEME 1. Formation of [2+2] and [4+2] Cycloadducts at Different Reaction Conditions
SCHEME 2. Thermal and Microwave Assisted Reactions of 1-Azadienes and Allenic Esters
ridines (9) in high yields and the earlier reported cyclohexanones
(8) were formed in low yields (Scheme 1).
mechanism of cycloaddition, density functional theoretical
(DFT) calculations were also carried out.
In view of the above recorded observations that the sym-
metrical structure of Nifedipine is a consequence of the synthetic
methodology, i.e., Hantzsch synthesis, rather than any receptor
requirement and the fact that in the case of unsymmetrical 1,4-
dihydropyridines differential selectivity is displayed by receptors
for configuration (R/S) at C4,14 it was decided to synthesize
unsymmetrical substituted 1,4-dihydropyridines with varied
patterns of substitution utilizing thermal cycloadditions of 1,4-
diaryl-1-aza-1,3-butadiens with allenic esters. However, as
extended reaction times are a major problem with thermal
methodology under reflux conditions and yields are low,
employment of microwave irradiation, a nonconventional
technique that has made a mark in organic synthesis,20 was also
investigated. Though the exact mechanism is still to be
investigated, it seems, however, to be accepted that the different
temperature range caused by the microwave dielectric heating
is the main contributing factor to any observed acceleration of
reaction.13,20 Furthermore, to have a better insight into the
Results and Discussion
Initially, thermal cycloadditions of 1,4-diaryl-1-azadienes
(10a-e) were carried out with a number of allenic esters (6a-
c) by refluxing the solutions of addends (1:1.2 molar, respec-
tively) in dry benzene under N2 atmosphere. The obtained
unsymmetrical 1,4-dihydropyrpyridines (11a-o, 73-87%,
Scheme 2) were isolated by column chromatography over silica
gel and characterized spectroscopically.
Alternatively, solutions of 1-azadienes (10a-e) and allenic
esters (6a-c) (1:1.2 molar, respectively) in 2 mL of dry benzene
as a solvent were exposed to microwave irradiation using a
focused monomode microwave reactor (CEM-Discover), and
the formed unsymmetrical 1,4-dihydropyridines (11a-o, 83-
96%, Scheme 2) were purified by column chromatography and
characterized spectroscopically; the results of thermal as well
as microwave assisted reactions are summarized in Table 1.
All 1,4-DHPs were obtained as yellow crystalline compounds
and were characterized by spectroscopic techniques (1H NMR,
13C NMR, IR, mass spectroscopy) and microanalytical data. The
1H NMR spectrum of compound 11a displayed, besides
resonances in the aromatic region, a 1H doublet at δ 6.10 (J )
6.3 Hz) assigned to C6-H. Overlapping C4-H and C5-H
(20) (a) Ohberg, L.; Westman, J. Synlett 2001, 8, 1296 and references
cited therein. (b) Loupy, A.; Maurel, F.; Sabatie-Gogova, A. Tetrahedron
2004, 60, 1683. (c) Loupy, A., Ed. MicrowaVe in Organic Synthesis; Wiley-
VCH: Weinheim, Germany, 2002. (d) Perreux, L.; Loupy, A. Tetrahedron
2001, 57, 9199. (e) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225. (f) Wipf, P.; Janjic, J.; Stephenson, C. R. J.
Org. Biol. Chem. 2004, 2, 443.
2226 J. Org. Chem., Vol. 73, No. 6, 2008

Unsymmetrical Substituted 1,4-Dihydropyridines
TABLE 1. Reaction Times and Product Yields for Reactions of
Various 1-Azadienes with Allenic Esters
B. The intermediate B can collapse to either a [2+2] cycloadduct
13 or a [4+2] cycloadduct 11. It also has been suggested that
the [4+2] cycloaddition, favored at high temperature, may be
proceeding via a concerted process,19 which is thermodynami-
cally controlled, and formation of the [2+2] cycloadduct at
ambient temperature proceeds via a stepwise mechanism through
intermediate B. In the case of 1-aryl-4-(o-nitrophenyl)-1-
azadiene (10a-e) cycloadditions, which are presently investi-
gated, only [4+2] cycloadducts (11a-o) were isolated under
both thermal and microwave irradiation conditions; [2+2]
cycloadducts were detected in trace amounts in some cases on
NMR analysis of column chromatography fractions. Therefore,
to gain an insight into the mechanistic details of the cycload-
ditions involving 1-azadienes and allenic esters, a recourse was
made to density functional theory (DFT)22 due to its recent
resounding success in affording an alternative paradigm for
explaining both reactivities and selectivities for a variety of
cycloaddition processes.22c,23 Though a number of reports on
theoretical investigations involving reactions of 1-azadienes/
imines and ketenes17B, 24 exist, there is no available report of
similar investigations involving 1-azadienes and allenic esters.
microwave
thermal reflux irradiation
time, h
time, min
entry
R′
-H
-CH3
R
1,4-DHP
(yield,a %)
(yield,a %)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
-H
-H
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
11o
76 (74)
69 (80)
56 (84)
72 (87)
64 (73)
40 (81)
44 (77)
48 (75)
40 (79)
42 (78)
36 (73)
33 (82)
34 (78)
38 (76)
35 (80)
5 (85)
7 (90)
8 (92)
9 (96)
5 (84)
12 (89)
10 (86)
15 (83)
17 (89)
07 (91)
08 (86)
09 (94)
10 (85)
13 (87)
08 (92)
-OCH3 -H
-Cl
-H
-H
-CN
-H
-CH3
-CH3
-CH3
-OCH3 -CH3
-Cl
-CH3
-CH3
-CH2CH3
-CH2CH3
-CN
-H
-CH3
-OCH3 -CH2CH3
-Cl
-CN
-CH2CH3
-CH2CH3
a Yield refers to isolated pure product.
According to the DFT formalism, components involved in a
cycloaddition process are characterized by their global electro-
philicity index25 (ω) as electrophilic and nucleophilic (less
electrophilic) leading to the classification of a cycloaddtion
reactions as normal or inverse electron demand. Thus the
mechanism of a cycloaddition changes progressively from
nonpolar-concerted-synchronous to polar-asynchronous and
ultimately to polar-stepwise as the electrophilicity difference
between addends (∆ω ) ωA - ωB) increases. The regioselec-
tivity is predicted in terms of local descriptors of electrophilicity
and nucleophilicity (less electrophilicity) by Fukui functions fk+
+
and fk-; the site with maximum fk is the site that has high
propensity to favor a nucleophilic attack, whereas the site with
(22) (a) Parr, R. G.; Yang, W. Density Functional Theory of atoms and
Molecules; Oxford University Press: New York, 1989. (b) Geerling, P.;
De Proft, F.; Langenaeker, W. Chem. ReV. 2003, 103, 1793. (c) Domingo,
L. R. Tetrahedron 2002, 58, 3765. (d) Domingo, L. R.; Picher, M. T.;
Tetrahedron 2004, 60, 5053. (e) Aurell, M. J.; Domingo, L. R.; Perez, P.;
Contreras, R. Tetrahedron 2004, 60, 11503.
FIGURE 1. ORTEP view of 11a.
(23) (a) Domingo, L. R.; Aurell, M. J.; Perez, P.; Contreras, R. J. Phys.
Chem. 2002, 106, 6871. (b) Corsaro, A.; Pistara, V.; Rescifina, A.; Piperno,
A.; Chiacchio, M. A.; Romeo, G. Tetrahedron, 2004, 60, 6443. (c) Herrera,
R.; Nagarajan, A.; Morales, M. A.; Mendez, F.; Jimenez-Vazquez, H. A.;
Zepeda, L. G.; Tamariz, J. J. Org. Chem. 2001, 66, 1252. (d) Domingo, L.
R.; Aurell, M. J.; Perez, P.; Contreras, R. J. Org. Chem. 2003, 68, 3884.
(e) Domingo, L. R. Eur. J. Org. Chem. 2004, 4788.
(24) (a) Sisti, N. J.; Motorina, I. A.; Dau, M. E. T. H.; Riche, C.; Fowler,
F. W.; Grierson, D. S. J. Org. Chem. 1996, 61, 3715. (b) Motorina, I. A.;
Grierson, D. S. Tetrahedron Lett. 1999, 40, 7211. (c) Arrastia, I.; Arrieta,
A.; Ugalde, J. M.; Cossio, F. P.; Lecea, B. Tetrahedron Lett. 1994, 35,
7825. (d) Lecea, B.; Arrastia, I.; Arrieta, A.; Roa, G.; Lopez, X.; Arriortua,
M. I.; Ugalde, J. M.; Cossio, F. P. J. Org. Chem. 1996, 61, 3070. (e) Arrieta,
A.; Cossio, F. P.; Lecea, B. J. Org. Chem. 1999, 64, 1831. (f) Lopez, R.;
Sordo, T. L.; Sordo, J. A.; Gonzalez, J. J. Org. Chem. 1993, 58, 7036. (g)
Sordo, J. A.; Gonzalez, J.; Sordo, T. J. Am. Chem. Soc. 1992, 114, 6249.
(h) Cossio, F. P.; Ugalde, J. M.; Lopez, X.; Lecea, B.; Palomo, C. J. Am.
Chem. Soc. 1993, 115, 995. (i) Pacansky, J.; Chang, J. S.; Brown, D. W.;
Schwarz, W. J. Org. Chem. 1982, 47, 2233. (j) Moore, H. W.; Hughes, G.
Tetrahedron Lett. 1982, 23, 4003. (k) Arrieta, A.; Lecea, B.; Cossio, F. P.
J. Org. Chem. 1998, 63, 5869. (l) Avalos, M.; Babiano, R.; Clemente, F.
R.; Cintas, P.; Gordillo, R.; Jimenez, J. L.; Palacios, C. J. Org. Chem. 2000,
65, 8251.
resonances led to a multiplet (2H) at δ 5.19-5.16. Protons of
ester function showed up as a quartet at δ 3.87 (2H, J ) 7.0
Hz) and a triplet at δ 0.94 (3H, J ) 7.0 Hz). A 3H singlet at δ
2.20 was due to C2-CH3. The assigned structure was also
corroborated by 13C NMR, IR, and mass spectroscopy data.
Subsequently, the structure of 11a was confirmed by X-ray
crystallography (Figure 1).21
The investigations were further extended by reacting 1-aza-
dienes (10a-e) with allenic esters (12a,b) both by the conven-
tional benzene reflux method and microwave assisted irradiation.
However, none of the reactions led to the formation of any
[4+2] cycloadduct (Scheme 3).
Mechanistically, it has been postulated19 that reaction of
electron neutral 1-aza-1,3-dienes with allenic esters is initiated
by interaction of azadiene nitrogen with central allenic carbon
(Scheme 4) leading to formation of the common intermediate
(25) (a) Parr, R. G.; Szentpaly, L. V.; Liu, S. J. Am. Chem. Soc. 1999,
121, 1922. (b) Chermette, H. J. Comput. Chem. 1999, 20, 129. (c) Domingo,
L. R.; Aurell, M. J.; Perez, P.; Contreras, R. Tetrahedron, 2002, 58, 4417.
(d) Perez, P.; Domingo, L. R.; Aurell, M. J.; Contreras, R. Tetrahedron,
2003, 59, 3117.
(21) The crystal data of 11a has already been submitted to The Cambridge
Crystallographic Data Centre (CCDC No. 283396). The X-ray analysis
reveals the possible H-bonding involving hydrogens of the ester function
and nitro group.
J. Org. Chem, Vol. 73, No. 6, 2008 2227

Singh et al.
SCHEME 3
SCHEME 4
TABLE 2. Activation Barrier for s-Trans Rotamer to s-Cis (Eq
and Vice Versa (EqCT) and Energy Difference (∆E, kcal/mol)
between Both Rotamers Calculated at the B3LYP/6-31G* Level
)
TC
stable and the barrier for s-trans to s-cis transformation (10.1-
11.2 kcal/mol) is higher than for the reverse, i.e., s-cis to s-trans
conversion (7.2-8.9 kcal/mol). Figure 2 shows both rotamers
and transition state separating them for azadienes 5a and 10a.
azadiene
R′
Eq
Eq
∆E ) ET - EC
TC
CT
5a
5b
5c
5d
10a
10b
10c
10d
10e
H
11.0
11.0
11.2
11.2
10.1
10.2
10.5
10.2
11.1
8.7
2.3
2.3
2.4
2.3
2.9
2.9
2.9
2.9
2.8
Dihedral angles (D) between N1, C2, C3, and C4 atoms of the
diene part for various azadienes 5a-d and 10a-e for both
rotamers and for transition states between them were also
determined (Table 3). Apparently one of the plausible reasons
for obtaining the [2+2] adduct at low reaction temperature could
be the higher energy barrier of s-trans to s-cis isomerization;
only the latter geometric isomer can ensure the formation of
the [4+2] cycloadduct.
Me
OMe
Cl
8.7
8.8
8.9
7.2
7.2
7.5
7.3
8.3
H
Me
OMe
Cl
CN
In the next step chemical hardness (η), chemical potential
(µ), global electrophilicity (ω, Table 4, all values in eV), and
difference in global electrophilicity (∆ω, Table 5, all values in
eV) between the reacting pairs were computed at the B3LYP/
6-31G* level.
-
maximum fk is considered as the site most amenable to an
electrophilic attack.22c,23a,c,26
Initially, geometric features of the reactants and barrier for
s-trans to s-cis and reverse isomerization of azadienes 5a-d
and 10a-e were calculated at the B3LYP/6-31G* level. The
results (Table 2, Figure 2) indicate that s-trans is the predominant
conformation at embient temperature: it is energetically more
The difference in the electrophilicity values of the reacting
species (∆ω) is used to predict the polarity of the transition
state and to characterize the reactants as donor or acceptor in a
cycloaddition process. The results indicate that azadienes have
a higher value of ω, therefore, they shall be acting as acceptors
in these cycloadditions. It has been shown that the higher the
(26) Fuentealba, P.; Perez, P.; Contreras, R. J. Chem. Phys. 2000, 113,
2544.
2228 J. Org. Chem., Vol. 73, No. 6, 2008

Unsymmetrical Substituted 1,4-Dihydropyridines
TABLE 4. Chemical Hardness (η), Chemical Potential (µ), and
Global Electrophilicity (ω) Calculated at the B3LYP/6-31G* Level
azadiene
species
η, eV
µ, eV
ω, eV
5a
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
1.85
1.90
1.81
1.86
1.71
1.76
1.82
1.87
1.69
1.67
1.63
1.61
1.51
1.49
1.68
1.67
1.77
1.76
3.10
3.05
3.05
3.00
-3.78
-3.79
-3.70
-3.70
-3.53
-3.53
-3.93
-3.93
-4.25
-4.31
-4.15
-4.21
-3.97
-4.03
-4.35
-4.41
-4.63
-4.68
-4.10
-3.93
-3.91
-3.73
3.87
3.77
3.78
3.68
3.64
3.53
4.24
4.12
5.33
5.56
5.28
5.52
5.22
5.46
5.62
5.85
6.05
6.24
2.71
2.53
2.51
2.31
5b
5c
5d
10a
10b
10c
10d
10e
s-trans
s-cis
s-trans
R ) H
R) Me
R ) Et
R1) Me
R2 ) Et
R3) Me
6a
6b
6c
12a
12b
2.66
-3.97
2.96
TABLE 5. Global Electrophilicity Difference (∆ω) between the
Reactant Pairs Calculated at the B3LYP/6-31G* Level
∆ω, eV (ωazadiene - ωallene
)
12a
6a
6b
6c
R1 ) Me
12b
azadiene species R ) H R ) Me R ) Et R2 ) Et R3 ) Me
5a
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
s-trans
s-cis
1.16
1.08
1.07
0.97
0.93
0.82
1.53
1.41
2.62
2.86
2.57
2.81
2.51
2.76
2.92
3.14
3.34
3.53
1.34
1.24
1.25
1.15
1.11
1.00
1.71
1.59
2.80
3.04
2.75
2.99
2.69
2.94
3.10
3.32
3.52
3.71
1.38
1.26
1.29
1.27
1.13
1.02
1.73
1.61
2.82
3.05
2.77
3.01
2.71
2.95
3.11
3.34
3.54
3.73
1.56
1.46
1.47
1.37
1.33
1.22
1.93
1.81
3.01
3.25
2.96
3.21
2.91
3.14
3.31
3.53
3.74
3.93
0.91
0.81
0.82
0.72
0.68
0.67
1.28
1.16
2.36
2.60
2.31
2.56
2.26
2.49
2.66
2.88
3.09
3.28
5b
5c
5d
10a
10b
10c
10d
10e
FIGURE 2. Optimized geometrical structures of s-trans, s-cis rotamers
and the corresponding transition state between two forms of azdienes
5a and 10a calculated at the B3LYP/6-31G* level.
TABLE 3. The Dihedral Angle (D) of the Diene Part in Various
Azadienes
s-trans
s-cis
s-trans
D, deg
s-cis
rotamer
transition
state
s-trans
rotamer
azadiene
R′
TABLE 6. Site with Higher f + Value in Azadienes (10a-e)
5a
5b
5c
5d
10a
10b
10c
10d
10e
H
2.2
2.3
2.9
2.4
7.1
7.1
6.8
7.1
6.5
95.1
95.0
95.0
95.1
94.9
94.7
94.8
95.0
93.2
179.9
180.0
180.0
179.7
179.8
179.7
179.4
179.8
179.8
Me
OMe
Cl
entry
species
N1
C2
C3
C4
10a
10b
10c
10d
10e
R′ ) H
0.076
0.067
0.047
0.062
0.073
0.053
0.052
0.051
0.049
0.045
0.017
0.015
0.015
0.015
0.020
0.063
0.060
0.057
0.057
0.058
R′ ) Me
R′ ) OMe
R′ ) Cl
H
Me
OMe
Cl
R′ ) CN
CN
Fukui functions (f + and f -) have also been calculated for
understanding the regiochemical outcome of these cycloaddi-
tions. The results reveal the most reactive sites in 1-azadienes
(10a-e) and allenic esters (6a-c and 12a,b). It was observed
that the site with the higher f + value is the N-atom of azadienes
(10a-e, Table 6) and the site with the higher f - value is the
C3-carbon atom of allenes (6a-c and 12a,b, Table 7).
value of ∆ω, the more polar the transition state is.23d,e,24a,25c
The above results show that the ∆ω values are in the range
1.0-3.0 eV indicating highly polarized transition states. It is
pertinent to mention here that ∆ω values are higher for reacting
pairs involving azadienes 10a-e and allenic esters 6a-c,
and these reactions predominently afford [4+2] cycloaddi-
tions.
J. Org. Chem, Vol. 73, No. 6, 2008 2229

Singh et al.
TABLE 7. Site with Higher f - Value in Allenes (6a-c, 12a,b)
entry
species
C2
C3
C4
6a
6b
6c
12a
12b
R ) H
0.110
0.103
0.100
0.094
0.085
0.141
0.133
0.130
0.123
0.127
0.110
0.085
0.081
0.062
0.101
R ) Me
R ) Et
R1 ) Me, R2 ) Et
R3) Me
FIGURE 5. Common reaction intermediate.
FIGURE 3.
FIGURE 4. Common transition state leading to intermediate.
The results are in agreement with the obtained regiochemistry
for [2+2] cycloadditions;19 however, the f - values for C2 and
C4 of allenic ester are close and a different regiochemistry, i.e.,
involvement of C2-C3π, is obtained for [4+2] cycloadditions
(Figure 3).
Although the most reactive atom (in the diene part) of the
azadienes is the nitrogen atom and the present calculations
predict the azadienes to be acceptors, earlier theoretical attempts
at rationalization17b,24 of cycloadditions of azadienes and imines
with ketenes and other heterocumulenes have invoked the
interaction of the nonbonding lone pair of azadiene nitrogen
with the central heterocumulenic carbon leading to a dipolar
intermediate as the first step in a stepwise reaction process. It
is pertinent to mention here that the nonbonding lone pair
represents the HOMO of the azadienes.24l
An attempt was made to locate the transition states for a
stepwise cycloaddition process involving the intraction of the
nitrogen lone pair of azadiene 10a and the central allenic carbon
of allenic ester 6a at the PM3 level for [4+2] and [2+2]
cycloadditions. Figure 4 shows the common transition state TS
I resulting from intraction of the N-atom of azadiene 10a and
the allenic ester 6a and leading to the common intermediate B
(Figure 5) for both modes of addition, wherein the diene and
dienophile orientation is perpendicular to each other due to steric
encumbrance.
FIGURE 6. (A) Rotation leading to [2+2] cycloadduct; (B) transition
state TS-IIA for [2+2] addition; (C) [2+2] cycloadduct; (D) rotation
for conversion of s-trans rotamer into s-cis facilitating [4+2] cycload-
dition; (E) transition state TS-IIB for [4+2] addition; and (F) [4+2]
cycloadduct.
Rotation of a specific bond as shown in Figure 6A transforms
the intermediate B to transition state TS IIA (Figure 6B), leading
to the [2+2] cycloadduct (Figure 6C). Alternatively, a rotation
converting s-trans azadiene into s-cis as shown in Figure 6D
propells this intermediate B to transition state TS IIB (Figure
6E) leading to formation of the [4+2] cycloadduct (Figure 6F),
which undergo 1,3-H shift to afford valuable unsymmetrical
substituted 1,4-dihydropyridines (11a-o). It is important to note
that conversion of the s-trans rotamer into the s-cis rotamer is
favored at high temperature.
Activation energy barriers for both types of addition using
azadiene 10a and various allenic esters (6a-c) were also
calculated (Figure 7). The difference in the activation energy
for both types of additions is shown in Table 8.
It is clear from the investigations that the activation energy
for [4+2] addition is less than that for [2+2] addition, hence,
the limiting factor for the reaction between 1-azadienes and
2230 J. Org. Chem., Vol. 73, No. 6, 2008

Unsymmetrical Substituted 1,4-Dihydropyridines
calculations. Location of the transition states at the PM3 level
for [2+2] and [4+2] cycloadditions showed that the activation
energy required for [4+2] cycloaddition is less than that for
[2+2] cycloaddition. Apparently, the preferred formation of
[4+2] cycloadducts at higher reaction temperature may be
attributed to the facile conversion of the s-trans rotamer of
azadienes into the s-cis rotamer. Alternatively, as postulated
earlier, the [2+2] cycloaddition may be proceeding through a
concerted (π2 + π2 + π2 ) process and, hence, preferred at
s
s
s
low temperature. Though higher level theoretical calculations
are required to gain a deeper insight into the mechanistic details,
the present investigations have provided an efficient route to
unsymmetrical substituted 1,4-dihydropyridines.
Experimental Section
Starting materials and reagents were purchased from commercial
suppliers and purified/distilled/crystallized before use. Hexane,
petroleum ether, and ethyl acetate used in column chromatography
were distilled before use; the petroleum ether employed was the
fraction boiling in the range of 40-60 °C. Allenic esters were
prepared by the method of Lang and Hansen and characterized
spectroscopically.27 1,4-Diaryl-1-azadienes were also prepared
according to the literature method and characterized spectroscopi-
cally.28
Bruker AC-200 FT (200 MHz) and JEOL AL-300FT (300 MHz)
spectrometers were used to record 1H NMR and 13C NMR (50 and
75 MHz) spectra. Chemical shifts (δ) are reported as downfield
displacements from TMS used as internal standard and coupling
constants (J) are reported in Hz. IR spectra were recorded with a
Shimadzu FT-IR-8400S spectrophotometer on KBr pellets. Mass
spectra, EI and ESI methods, were recorded on Shimadzu GCMS-
QP-2000A and Bruker Daltonics Esquire 300 mass spectrometers,
respectively. Elemental analyses were carried out on a Perkin-Elmer
240C elemental analyzer and are reported in percent atomic
abundance. The CEM-Discover Focused Monomode Microwave
apparatus (2450 MHz, 300w) was used for microwave irradiation.
All melting points are uncorrected and measured in open glass
capillaries on a Veego (make) MP-D digital melting point apparatus.
All the calculations were performed with the Gaussian 98 package.
The molecules have been optimized at the B3LYP/6-31G* level.
All of them were found to be minimum on the potential energy
surface with zero imaginary frequency. Global reactivity indexes
were calculated by using the working equations available in the
literature. Local reactivity indices, Fukui functions, have been
calculated by using the DMOL program implemented in the Cerius2
package employing the Hershfeld populations scheme.
FIGURE 7. Activation energy barrier for [2+2] and [4+2] addition.
TABLE 8. ∆E for Both Types of Addition
azadiene
allenic ester
∆E,a kcal/mol
10a
10a
10a
6a
6b
6c
5.5
3.0
3.7
a Difference in activation energy for [2+2] and [4+2] cycloadditions.
allenic esters to yield either a [2+2] cycloadduct or a [4+2]
cycloadduct is not the overall activation energy of the reaction,
rather it is the energy required to convert s-trans azadienes into
their s-cis forms. We were not able to get transition states and
difference in activation energy of both types of cycloadditions
for allenic esters 12a,b with 1-azadienes 10a-e (Scheme 3);
reactions of these allenic esters did not lead to the formation of
any cycloadduct. Possibly an increase in the number of electron
releasing alkyl groups on the allenic moiety, making the central
carbon atom of allenic esters 12a,b less electron deficient, along
with the steric hindrance caused by these bulky groups may be
the reason for the failure of these allenes to undergo cycload-
dition reactions with 1-azadienes.
Conclusion
Procedure for the Thermal Reaction of 1,4-Diaryl-1-aza-1,3-
butadienes (10) with Allenic Esters (6). A solution of 1,4-diaryl-
1-azadiene (10a-e, 200 mg) and allenic ester (6a-c) (1.2 molar
equiv) in dry benzene (20 mL) was refluxed under an atmosphere
of nitrogen until the 1-azadiene was completely consumed. After
the completion of the reaction (TLC basis), solvent was removed
under vacuum and the formed 1,4-DHPs (11a-o) were purified
by column chromatography (silica gel 60-120 mesh, eluent hexane:
EtOAc 9:1).
Procedure for Microwave Assisted Reaction of 1,4-Diaryl-
1-aza-1,3-butadienes (10) with Allenic Esters (6). In a 50 mL
round-bottomed flask, the solutions of 1,4-diaryl-1-azadiene (10a-
e, 200 mg) and allenic ester (6a-c) (1.2 molar equiv) in dry benzene
(2 mL) were exposed to microwave radiation (150 W, 100 °C) for
the time as given in Table 1. After the completion of the reaction
(TLC basis), solvent was removed under vacuum and the formed
The investigations have established the general applicability
of thermal cycloadditions of 1-azadienes with allenic esters as
a facile route to novel variedly substituted unsymmetrical 1,4-
dihydropyridines. The reactions carried out under microwave
irridiation are cleaner, attended with higher yields, and require
much shorter reaction times. Theoretical calculations for the
optimized geometry of reactants, energy barriers between the
two rotamers of azadienes, and the electrophilicity index of
diene/dienophile pairs were carried out at the B3LYP/6-31G*
level. Results indicate that s-trans is the preferred low-energy
conformation of azadienes. The high-energy barrier for conver-
sion of s-trans azadienes to s-cis may be the reason for formation
of the [2+2] cycloadduct at low temperature. The ∆ω values
(1.0-3.0 eV) indicate that the transition states for these
cycloadditions are highly polar. The Fukui function results
clearly support the observed regiochemistry in the case of [2+2]
cycloadducts; however, altered regiochemistry of addition for
[4+2] cycloadducts is not unequivocally supported by these
(27) Lang, R. W.; Hansen, H. J. HelV. Chim. Acta 1980, 63, 438.
(28) (a) Brady, W. T.; Shieh, C. H. J. Org. Chem. 1983, 48, 2499. (b)
Anteuis, N.; Bruyn, A.; De Sandhu, J. S. J. Magn. Reson. 1972, 8, 7.
J. Org. Chem, Vol. 73, No. 6, 2008 2231

Singh et al.
1,4-DHPs (11a-o) were purified by column chromatography (silica
gel 60-120 mesh, eluent hexane:EtOAc 9:1).
2.20 (s, 3H), 0.94 (t, J ) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 167.48, 149.60, 148.01, 143.48, 143.41, 132.95, 131.17, 129.86,
129.68, 127.67, 126.50, 123.11, 106.35, 100.50, 59.33, 36.27, 18.51,
13.91 ppm; IR (KBr) ν 1691.46, 1670.24, 1560.30, 1523.66,
1490.87, 1380.94, 1355.86, 1332.72, 1220.86, 1209.28, 1107.06,
1074.28; MS (ESI) m/z (%) 387.1 [M+ + Na]. Anal. Calcd (%)
for C21H20N2O4 (364.14): C 69.22, H 5.53, N 7.69. Found: C 69.18,
H 5.49, N 7.60.
All the 1,4-DHPs were obtained as yellow crystalline compounds,
recrystallized from dichloromethane-hexane (1:1), in good yields
(Table 1). The physical and spectroscopic data for various 1-aza-
dienes (10a-e) and 1,4-dihydropyridines (11a-o) are as follows:
1-Aza-4-(o-nitrophenyl)-1-phenyl-1,3-butadiene (10a): Rf 0.54
(CHCl3/hexane 9:1); mp 121-122 °C; 1H NMR (200 MHz, CDCl3)
δ 8.30 (d, J ) 8.87 Hz, 1H), 8.04 (dd, J ) 8.11, 1.28 Hz, 1H),
7.76-7.52 (m, 4H), 7.37-7.32 (m, 3H), 7.15-6.98 (m, 3H); 13C
NMR (50 MHz, CDCl3) δ 160.49, 149.54, 148.02, 138.22, 133.13,
132.97, 132.21, 131.09, 129.52, 129.22, 128.30, 124.92, 122.16;
IR (KBr) ν 1608.52, 1583.45, 1568.02, 1517.87, 1483.16, 1473.51,
1448.44, 1342.36, 1317.29, 1303.79, 1249.79, 1157.21, 1135.99,
3-Ethoxycarbonyl-2-methyl-4-(o-nitrophenyl)-1-p-tolyl-1,4-di-
hydropyridine (11b): Rf 0.57 (CHCl3/hexane 8:2); mp 125-
1
126 °C; H NMR (300 MHz, CDCl3) δ 7.74-7.07 (m, 8H), 6.08
(d, J ) 6.9 Hz, 1H), 5.18-5.16 (m, 2H), 3.87 (q, J ) 6.7 Hz, 2H),
2.38 (s, 3H), 2.20 (s, 3H), 0.93 (t, J ) 7.0 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 167.87, 150.12, 147.84, 143.51, 140.80, 137.65,
133.09, 131.13, 130.23, 130.06, 127.42, 126.52, 123.12, 106.05,
99.92, 59.34, 36.66, 21.02, 18.35, 13.82 ppm; IR (KBr) ν 1681.81,
1660.60, 1560.30, 1517.87, 1510.16, 1380.94, 1352.01, 1340.43,
1222.79, 1205.43, 1114.78, 1070.42; MS (ESI) m/z (%) 378.0 [M+].
Anal. Calcd (%) for C22H22N2O4 (378.16): C 69.83, H 5.86, N
7.40. Found: C 69.76, H 5.81, N 7.37.
1072.35; MS (70 eV, EI) m/z (%) 252 (15) [M+], 251 (30) [M+
-
H], 205 (45), 169 (100). Anal. Calcd (%) for C15H12N2O2
(252.09): C 71.42, H 4.79, N 11.10. Found: C 71.16, H 4.60, N
11.03.
1-Aza-4-(o-nitrophenyl)-1-p-tolyl-1,3-butadiene (10b): Rf 0.56
1
(CHCl3/hexane 9:1); mp 81-82 °C; H NMR (200 MHz, CDCl3)
δ 8.34 (d, J ) 8.87 Hz, 1H), 8.02 (dd, J ) 8.02, 1.24 Hz, 1H),
7.77-7.61 (m, 3H), 7.54-7.50 (m, 1H), 7.20-7.01 (m, 5H); 13C
NMR (50 MHz, CDCl3) δ 159.29, 148.50, 147.97, 137.07, 136.34,
133.39, 133.10, 131.25, 129.70, 129.27, 128.24, 124.84, 120.89,
21.03; IR (KBr) ν 1608.52, 1585.38, 1569.95, 1525.59, 1502.44,
1473.51, 1342.36, 1313.43, 1299.93, 1253.64, 1155.28, 1135.99,
1-p-Anisyl-3-ethoxycarbonyl-2-methyl-4-(o-nitrophenyl)-1,4-
dihydropyridine (11c): Rf 0.67 (CHCl3/hexane 8:2); mp 111-
1
112 °C; H NMR (300 MHz, CDCl3) δ 7.74-6.92 (m, 8H), 6.06
(d, J ) 6.9 Hz,1H), 5.19-5.14 (m, 2H), 3.87 (q, J ) 6.9 Hz, 2H),
3.84 (s, 3H), 2.19 (s, 3H), 0.93 (t, J ) 7.0 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 167.77, 158.77, 150.31, 147.69, 143.47, 136.06,
133.05, 131.05, 130.12, 128.74, 126.45, 123.02, 114.65, 105.83,
99.54, 59.23, 55.41, 36.13, 18.18, 13.73 ppm; IR (KBr) ν 1685.67,
1670.24, 1550.66, 1521.73, 1508.23, 1490.87, 1346.22, 1249.79,
1220.86, 1203.50, 1103.21, 1076.21; MS (ESI) m/z (%) 417.1 [M+
+ Na]. Anal. Calcd (%) for C22H22N2O5 (394.15): C 66.99, H 5.62,
N 7.10. Found: C 66.90, H 5.54, N 7.02.
1108.99; MS (70 eV, EI) m/z (%) 266 (20) [M+], 265 (25) [M+
-
H], 219 (65), 169 (100). Anal. Calcd (%) for C16H14N2O2
(266.29): C 72.16, H 5.30, N 10.52. Found: C 72.02, H 5.26, N
10.42.
1-p-Anisyl-1-aza-4-(o-nitrophenyl)-1,3-butadiene (10c): Rf 0.68
(CHCl3/hexane 9:1); mp 113-114 °C; 1H NMR (200 MHz, CDCl3)
δ 8.35 (d, J ) 8.84 Hz, 1H), 8.00 (d, J ) 8.04 Hz, 1H), 7.77-7.58
(m, 3H), 7.51-7.44 (m, 1H), 7.22 (d, J ) 8.7 Hz, 2H), 7.06 (dd,
1-p-Chlorophenyl-3-ethoxycarbonyl-2-methyl-4-(o-nitrophe-
nyl)-1,4-dihydropyridine (11d): Rf 0.70 (CHCl3/hexane 8:2); mp
J ) 15.7, 8.8 Hz, 1H), 6.92 (d, J ) 8.6 Hz, 2H), 5.82 (s, 3H); 13
C
1
130-131 °C; H NMR (300 MHz, CDCl3) δ 7.73-7.13 (m, 8H),
NMR (50 MHz, CDCl3) δ 158.79, 157.88, 148.00, 143.89, 136.45,
133.56, 133.05, 131.38, 129.14, 128.17, 124.85, 122.33, 114.30,
55.16 ppm; IR (KBr) ν 1623.95, 1608.52, 1569.95, 1525.59,
1502.44, 1467.73, 1344.29, 1294.15, 1247.86, 1211.21, 1159.14,
1107.06, 1033.77; MS (70 eV, EI) m/z (%) 283 (60) [M+ + 1],
282 (27) [M+], 281 (20), 236 (10), 170 (10), 169 (100). Anal. Calcd
(%) for C16H14N2O3 (282.10): C 68.07, H 5.00, N 9.92. Found: C
67.81, H 4.95, N 9.85.
6.04 (d, J ) 7.5 Hz, 1H), 5.20-5.14 (m, 2H), 3.87 (q, J ) 7.0 Hz,
2H), 2.19 (s, 3H), 0.93 (t, J ) 7.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 167.30, 148.99, 148.05, 143.08, 141.95, 133.51, 132.95,
131.04, 129.87, 129.49, 128.96, 126.60, 123.18, 106.70, 101.16,
59.43, 36.26, 18.47, 13.86 ppm; IR (KBr) ν 1685.67, 1665.46,
1560.30, 1527.52, 1487.01, 1357.79, 1220.86, 1209.28, 1107.06,
1095.49, 1068.49; MS (ESI) m/z (%) 421.0 [M+ + Na]. Anal. Calcd
(%) for C21H19ClN2O4 (398.10): C 63.24, H 4.80, N 7.02. Found:
C 63.22, H 4.77, N 7.01.
1-Aza-1-p-chloro-4-(o-nitrophenyl)-1,3-butadiene (10d): Rf
1
0.76 (CHCl3/hexane 9:1); mp 109-110 °C; H NMR (200 MHz,
1-p-Cyanophenyl-3-ethoxycarbonyl-2-methyl-4-(o-nitrophe-
nyl)-1,4-dihydropyridine (11e): Rf 0.45 (CHCl3/hexane 8:2); mp
CDCl3) δ 8.29 (d, J ) 8.85 Hz, 1H), 7.99 (dd, J ) 8.08, 1.09 Hz,
1H), 7.73-7.60 (m, 3H), 7.50-6.99 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 160.91, 149.57, 147.91, 138.50, 133.39, 132.81, 132.11,
130.99, 129.71, 129.25, 128.38, 124.90, 122.21 ppm; IR (KBr) ν
1606.59, 1596.95, 1569.95, 1517.87, 1485.09, 1446.51, 1353.01,
1342.36, 1153.35, 1089.71, 1010.63; MS (70 eV, EI) m/z (%) 287
(17) [M+ + 1], 286 (25) [M+], 285 (35), 284 (60), 283 (60), 240
(30), 169 (100). Anal. Calcd (%) for C15H11ClN2O2 (286.05): C
62.84, H 3.87, N 9.77. Found: C 62.61, H 3.83, N 9.71.
1-Aza-1-p-cyano-4-(o-nitrophenyl)-1,3-butadiene (10e): Rf 0.53
(CHCl3/hexane 9:1); mp 135-136 °C; 1H NMR (300 MHz, CDCl3)
δ 8.27 (d, J ) 9.0, 1H), 8.12-8.02 (m, 1H), 7.79-7.53 (m, 6H),
7.22 (d, J ) 7.4, 2H), 7.09-7.0 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 162.92, 155.14, 147.21, 140.30, 133.34, 132.59, 132.35,
130.14, 129.02, 128.57, 125.04, 121.53, 118.78, 109.59, IR (KBr)
ν 2223.77, 1629.74, 1614.31, 1589.23, 1569.95, 1521.73, 1494.73,
1440.73, 1346.22, 1307.65, 1257.50, 1159.14, 1137.92, 1112.85;
MS (ESI) m/z (%) 277.9 [M+]. Anal. Calcd (%) for C16H11N3O2
(277.09): C 69.31, H 4.00, N 15.15. Found: C 69.26, H 3.93, N
15.10.
1
162-163 °C; H NMR (300 MHz, CDCl3) δ 7.76-7.52 (m, 8H),
6.17 (d, J ) 7.8 Hz, 1H), 5.28 (dd, J ) 7.8, 4.9 Hz, 1H), 5.20 (d,
J ) 4.2 Hz, 1H), 3.90 (q, J ) 6.9 Hz, 2H), 2.17 (s, 3H), 0.94 (t,
J ) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.33, 155.65,
148.04, 147.94, 142.26, 133.58, 133.16, 130.81, 128.91, 127.78,
126.89, 123.38, 116.30, 110.91, 107.33, 103.16, 59.75, 36.27, 18.85,
13.72 ppm; IR (KBr) ν 2229.56, 1685.67, 1666.38, 1566.09,
1521.73, 1504.37, 1444.58, 1386.72, 1353.94, 1218.93, 1112.85,
1105.14, 1093.56, 1066.56, 1016.42; MS (ESI) m/z (%): 412.1 [M+
+ Na]. Anal. Calcd (%) for C22H19N3O4 (389.14): C 67.86, H 4.92,
N 10.79. Found: C 67.79, H 4.84, N 10.71.
3-Ethoxycarbonyl-2-ethyl-4-(o-nitrophenyl)-1-phenyl-1,4-di-
hydropyridine (11f): Rf 0.64 (CHCl3/hexane 8:2); mp 106-
1
107 °C; H NMR (300 MHz, CDCl3) δ 7.74-7.25 (m, 9H), 6.06
(d, J ) 6.3 Hz, 1H), 5.20-5.14 (m, 2H), 3.88 (q, J ) 6.9 Hz, 2H),
2.72-2.68 (m, 2H), 1.01 (t, J ) 7.2 Hz, 3H), 0.95 (t, J ) 7.2 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 167.91, 155.80, 147.80, 143.47,
143.11, 133.03, 130.83, 130.28, 129.51, 128.11, 127.87, 126.47,
123.11, 106.15, 98.83, 59.02, 36.02, 22.84, 13.80, 13.38 ppm; IR
(KBr) ν 1691.46, 1674.10, 1556.45, 1519.80, 1492.80, 1373.22,
1350.08, 1263.29, 1215.07, 1197.71, 1110.92, 1083.92, 1033.71;
MS (ESI) m/z (%) 401.1 [M+ + Na]. Anal. Calcd (%) for
3-Ethoxycarbonyl-2-methyl-4-(o-nitrophenyl)-1-phenyl-1,4-di-
hydropyridine (11a): Rf 0.62 (CHCl3/hexane 8:2); mp 105-
1
106 °C; H NMR (300 MHz, CDCl3) δ 7.73-7.20 (m, 9H), 6.10
(d, J ) 6.3 Hz, 1H), 5.19-5.16 (m, 2H), 3.87 (q, J ) 7.0 Hz, 2H),
2232 J. Org. Chem., Vol. 73, No. 6, 2008

Unsymmetrical Substituted 1,4-Dihydropyridines
C22H22N2O4 (378.16): C 69.83, H 5.86, N 7.40. Found: C 69.74,
H 5.78, N 7.37.
1H NMR (300 MHz, CDCl3) δ 7.74-7.11 (m, 8H), 6.03 (d, J )
6.9 Hz, 1H), 5.19-5.14 (m, 2H), 3.88 (q, J ) 7.0 Hz, 2H), 2.64-
2.59 (m, 2H), 2.40 (s, 3H), 1.53-1.41 (m, 2H), 0.94 (t, J ) 7.0
Hz, 3H), 0.74 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
167.26, 154.92, 147.75, 143.65, 140.61, 137.79, 133.10, 130.90,
130.45, 130.15, 127.82, 126.48, 123.14, 105.97, 98.86, 59.28, 36.13,
31.47, 22.54, 21.08, 14.16, 13.82 ppm; IR (KBr) ν 1685.67,
1670.24, 1552.59, 1525.59, 1510.16, 1444.58, 1353.94, 1209.28,
1114.78, 1078.13, 1033.77; MS (ESI) m/z (%) 429.2 [M+ + Na].
Anal. Calcd (%) for C24H26N2O4 (406.19): C 70.92, H 6.45, N
6.89. Found: C 70.87, H 6.40, N 6.85.
1-p-Anisyl-3-ethoxycarbonyl-4-(o-nitrophenyl)-2-propyl-1,4-
dihydropyridine (11m): Rf 0.71 (CHCl3/hexane 8:2); mp 81-
82 °C; 1H NMR (300 MHz, CDCl3) δ 7.73-6.90 (m, 8H), 5.98 (d,
J ) 6.6 Hz, 1H), 5.15-5.11 (m, 2H), 3.87 (q, J ) 6.7 Hz, 2H),
3.84 (s, 3H), 2.62-2.57 (m, 2H), 1.49-1.42 (m, 2H), 0.94 (t, J )
7.2 Hz, 3H), 0.75 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 167.07, 158.96, 154.99, 147.92, 143.76, 136.09, 132.97, 130.97,
130.55, 129.29, 126.43, 123.14, 114.64, 106.06, 98.89, 59.23, 55.40,
36.20, 31.52, 22.61, 14.31, 13.91 ppm; IR (KBr) ν 1689.53,
1672.17, 1562.23, 1517.87, 1508.23, 1350.08, 1245.93, 1211.21,
1182.28, 1078.13, 1039.56; MS (ESI) m/z (%) 445.2 [M+ + Na].
Anal. Calcd (%) for C24H26N2O5 (422.18): C 68.23, H 6.20, N
6.63. Found: C 68.15, H 6.13, N 6.55.
3-Ethoxycarbonyl-2-ethyl-4-(o-nitrophenyl)-1-p-tolyl-1,4-di-
hydropyridine (11g): Rf 0.59 (CHCl3/hexane 8:2); mp 153-
1
154 °C; H NMR (300 MHz, CDCl3) δ 7.74-7.12 (m, 8H), 6.02
(d, J ) 5.2 Hz, 1H), 5.18-5.13 (m, 2H), 3.87 (q, J ) 7.0 Hz, 2H),
2.71-2.67 (m, 2H), 2.40 (s, 3H), 1.01 (t, J ) 7.3 Hz, 3H), 0.94 (t,
J ) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.04, 156.14,
147.82, 143.66, 140.58, 137.84, 133.06, 130.91, 130.45, 130.20,
127.93, 126.46, 123.14, 106.07, 98.54, 59.28, 36.08, 22.88, 21.10,
13.84, 13.45 ppm; IR (KBr) ν 1685.67, 1668.31, 1556.45, 1517.87,
1512.09, 1440.73, 1371.29, 1355.86, 1211.21, 1114.78, 1108.99,
1078.13, 1026.06; MS (ESI) m/z (%) 392.0 [M+]. Anal. Calcd (%)
for C23H24N2O4 (392.17): C 70.39, H 6.16, N 7.14. Found: C 70.34,
H 6.12, N 7.11.
1-p-Anisyl-3-ethoxycarbonyl-2-ethyl-4-(o-nitrophenyl)-1,4-di-
hydropyridine (11h): Rf 0.69 (CHCl3/hexane 8:2); mp 138-
1
139 °C; H NMR (300 MHz, CDCl3) δ 7.75-6.93 (m, 8H), 6.01
(d, J ) 6.9 Hz, 1H), 5.18-5.14 (m, 2H), 3.89 (q, J ) 6.3 Hz, 2H),
3.84 (s, 3H), 2.73-2.65 (m, 2H), 1.01 (t, J ) 7.3 Hz, 3H), 0.94 (t,
J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.13, 158.93,
156.39, 147.73, 143.67, 135.84, 133.11, 130.87, 130.59, 129.28,
126.48, 123.14, 114.64, 105.92, 98.30, 59.27, 55.48, 36.05, 22.87,
13.79, 13.38 ppm; IR (KBr) ν 1689.53, 1674.10, 1560.30, 1510.16,
1458.08, 1440.73, 1352.01, 1247.86, 1213.14, 1199.64, 1184.21,
1114.781107.06, 1080.06; MS (ESI) m/z (%) 431.2 [M+ + Na].
Anal. Calcd (%) for C23H24N2O5 (408.17): C 67.63, H 5.92, N
6.86. Found: C 67.57, H 5.87, N 6.82.
1-p-Chlorophenyl-3-ethoxycarbonyl-4-(o-nitrophenyl)-2-pro-
pyl-1,4-dihydropyridine (11n): Rf 0.78 (CHCl3/hexane 8:2); mp
1
108-109 °C; H NMR (300 MHz, CDCl3) δ 7.75-7.19 (m, 8H),
6.01 (d, J ) 6.6 Hz, 1H), 5.21-5.15 (m, 2H), 3.88 (q, J ) 7.0 Hz,
2H), 2.66-2.58 (m, 2H), 1.49-1.41 (m, 2H), 0.94 (t, J ) 7.0 Hz,
3H), 0.76 (t, J ) 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.09,
154.05, 147.88, 143.20, 141.81, 133.66, 133.10, 130.77, 129.96,
129.81, 129.45, 126.63, 123.28, 106.49, 99.96, 59.45, 36.17, 31.39,
22.53, 14.10, 13.79 ppm; IR (KBr) ν 1685.67, 1674.10, 1556.45,
1523.66, 1490.87, 1350.08, 1340.43, 1211.21, 1114.78, 1080.06;
MS (ESI) m/z (%) 449.2 [M+ + Na]. Anal. Calcd (%) for C23H23-
ClN2O4 (426.13): C 64.71, H 5.43, N 6.56. Found: C 64.67, H
5.37, N 6.52.
1-p-Chlorophenyl-3-ethoxycarbonyl-2-ethyl-4-(o-nitrophenyl)-
1,4-dihydropyridine (11i): Rf 0.72 (CHCl3/hexane 8:2); mp 127-
1
128 °C; H NMR (300 MHz, CDCl3) δ 7.76-7.19 (m, 8H), 6.02
(d, J ) 7.2 Hz, 1H), 5.22-5.15 (m, 2H), 3.88 (q, J ) 6.9 Hz, 2H),
2.72-2.67 (m, 2H), 1.01 (t, J ) 7.2 Hz, 3H), 0.94 (t, J ) 7.0 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 166.80, 155.23, 147.75, 143.07,
141.56, 130.65, 133.58, 133.02, 129.73, 129.68, 129.40, 126.53,
123.12, 106.35, 99.37, 59.30, 36.03, 22.70, 13.66, 13.24 ppm; IR
(KBr) ν 1691.46, 1679.88, 1562.23, 1517.87, 1488.94, 1460.01,
1352.01, 1213.14, 1197.71, 1112.85, 1083.92; MS (ESI) m/z (%)
435.2 [M+ + Na]. Anal. Calcd (%) for C22H21ClN2O5 (412.12): C
64.00, H 5.13, N 6.79. Found: C 63.97, H 5.07, N 6.72.
1-p-Cyanophenyl-3-ethoxycarbonyl-4-(o-nitrophenyl)-2-pro-
pyl-1,4-dihydropyridine (11o): Rf 0.58 (CHCl3/hexane 8:2); mp
1
178-179 °C; H NMR (300 MHz, CDCl3) δ 7.78-7.26 (m, 8H),
1-p-Cyanophenyl-3-ethoxycarbonyl-2-ethyl-4-(o-nitrophenyl)-
1,4-dihydropyridine (11j): Rf 0.47 (CHCl3/hexane 8:2); mp 112-
6.11 (d, J ) 7.5 Hz, 1H), 5.27 (dd, J ) 5.1, 4.8 Hz, 1H), 5.18 (d,
J ) 5.1 Hz, 1H), 3.91 (q, J ) 7.2 Hz, 2H), 2.81-2.74 (m, 1H),
2.58-2.49 (m, 1H), 1.46-1.39 (m, 2H), 0.95 (t, J ) 7.0 Hz, 3H),
0.75 (t, J ) 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.81,
152.89, 147.23, 142.37, 138.46, 133.56, 133.13, 131.22, 130.53,
128.42, 126.82, 123.41, 117.89, 111.23, 107.37, 102.12, 59.69,
36.17, 31.25, 22.61, 13.91, 13.71 ppm; IR (KBr) ν 2231.49,
1697.24, 1602.74, 1564.16, 1514.02, 1440.73, 1371.29, 1350.08,
1265.22, 1215.07, 1112.85, 1083.92, 1022.20; MS (ESI) m/z (%)
440.2 [M+ + Na]. Anal. Calcd (%) for C24H23N3O4 (417.17): C
69.05, H 5.55, N 10.07. Found: C 69.00, H 5.50, N 10.03.
1
113 °C; H NMR (300 MHz, CDCl3) δ 7.77-7.26 (m, 8H), 6.10
(d, J ) 7.8 Hz, 1H), 5.26 (dd, J ) 7.5, 5.1 Hz, 1H), 5.17 (d, J )
4.8 Hz, 1H), 3.90 (q, J ) 7.2 Hz, 2H), 2.85-2.81 (m, 1H), 2.65-
2.58 (m, 1H), 0.99 (t, J ) 7.2 Hz, 3H), 0.96 (t, J ) 7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 166.69, 154.27, 147.94, 147.10,
142.40, 133.59, 133.15, 130.52, 129.42, 128.53, 126.82, 123.40,
117.88, 111.35, 107.33, 101.46, 59.67, 36.04, 22.75, 13.69, 13.29
ppm; IR (KBr) ν 2225.70, 1674.10, 1566.09, 1521.73, 1504.37,
1469.66, 1371.29, 1336.58, 1257.50, 1236.29, 1190.00, 1118.64,
1095.49, 1024.13; MS (ESI) m/z (%) 426.1 [M+ + Na]. Anal. Calcd
(%) for C23H21N3O4 (403.15): C 68.47, H 5.25, N 10.42. Found:
C 68.41, H 5.19, N 10.37.
Acknowledgment. Financial support for this research work
by the Council of Scientific and Industrial Research (CSIR),
New Delhi, under research project 01(1961)/04/EMR-II is
gratefully acknowledged.
3-Ethoxycarbonyl-4-(o-nitrophenyl)-1-phenyl-2-propyl-1,4-di-
hydropyridine (11k): Rf 0.66 (CHCl3/hexane 8:2); mp 78-79 °C;
1H NMR (300 MHz, CDCl3) δ 7.75-7.24 (m, 9H), 6.07 (d, J )
7.2 Hz, 1H), 5.20-5.17 (m, 2H), 3.88 (q, J ) 7.0 Hz, 2H), 2.70-
2.55 (m, 2H), 1.52-1.40 (m, 2H), 0.95 (t, J ) 7.0 Hz, 3H), 0.72
(t, J ) 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.22, 154.61,
147.80, 143.51, 143.20, 133.10, 130.87, 130.30, 129.57, 128.09,
127.85, 126.52, 123.19, 106.11, 99.25, 59.33, 36.14, 31.47, 22.51,
14.11, 13.82 ppm; IR (KBr) ν 1687.60, 1670.24, 1556.45, 1521.73,
1492.80, 1353.94, 1211.21, 1116.71, 1076.21; MS (ESI) m/z (%)
415.2 [M+ + Na]. Anal. Calcd (%) for C23H24N2O4 (392.17): C
70.39, H 6.16, N 7.14. Found: C 70.33, H 6.13, N 7.08.
Supporting Information Available: 1H NMR spectras of
compounds 10a-e and 11a-o, geometrical structures of both
rotamers and transition states between them for various azadienes
(5a-e and 10a-e), activation energy barriers for [2+2] and [4+2]
cycloaddtions of azadiene 10a and allenic esters 6a-c, and a
crystallographic information file. This material is available free of
charge via the Internet at http://pubs.acs.org.
3-Ethoxycarbonyl-4-(o-nitrophenyl)-2-propyl-1-p-tolyl-1,4-di-
hydropyridine (11l): Rf 0.59 (CHCl3/hexane 8:2); mp 84-85 °C;
JO702548B
J. Org. Chem, Vol. 73, No. 6, 2008 2233