Novel regioselectivity: Three-component cascade synthesis of unsymmetrical 1,4- and 1,2-dihydropyridines

Full text of DOI:10.1021/jo900068z

Novel Regioselectivity: Three-Component
Cascade Synthesis of Unsymmetrical 1,4- and
1,2-Dihydropyridines
Jie-Ping Wan,† Shi-Feng Gan,† Gong-Lei Sun,‡ and
Yuan-Jiang Pan*,†
Department of Chemistry, Zhejiang UniVersity, Hangzhou
310027, People’s Republic of China, and College of
Chemistry and Life Science, Zhejiang Normal UniVersity,
Jinhua 321004, People’s Republic of China
FIGURE 1. 1,4-DHP drugs for cardiovascular diseases.
panyuanjiang@zju.edu.cn
antiaggregatory agents, neuroprotection, as well as HIV protease
inhibition, etc.4 Moreover, in terms of synthetic chemistry, the
high reactivity endowed 1,4-DHPs with widespread application
in the synthesis of useful chemicals.5
ReceiVed January 12, 2009
Multicomponent reactions (MCRs) represent one of the most
powerful strategies in modern organic synthesis. Compared to
the traditional multistep methods of heterocycle synthesis, MCRs
require substantially simpler materials and operations, while
providing significantly higher efficiency and molecular com-
plexity. Most importantly yet, the huge compound libraries
perfectly cater to the requirement of high throughput screening
in modern drug discovery.6 The most classical synthesis of
symmetrical 1,4-DHPs is the three-component condensation of
aryl aldehydes, ammonia, or amines and 2 equiv of ꢀ-keto esters,
which was reported in 1882 by Hantzsch.7 Despite the long
history, sustaining interests in more advanced synthetic meth-
odology of 1,4-DHPs have been triggered by the prolific
pharmacological properties imbedded in 1,4-DHPs.8,9
The symmetrical DHP unit, although present in many
commercial drugs, is not a requirement of receptors but the
consequence of the Hantsch synthetic methodology. Actually,
unsymmetrical 1,4-DHPs also represent effective drug moieties
(Felodipine 3, for example) or sometimes display even better
pharmacological activities.10 Therefore, the synthesis of unsym-
metrical 1,4-DHPs justifies equal importance as for the sym-
metrical 1,4-DHPs in terms of drug discovery. However, the
nature of the Hantsch reaction employing two identical ꢀ-keto
The three-component sequential reaction of R,ꢀ-unsaturated
aldehydes, amines, and enaminones proceeded smoothly to
give 1,3,4-trisubstituted 1,4-dihydropyridines in aqueous
DMF. Moreover, the unexpected regioselective formation of
1,2-dihydropyridines has been observed for the first time in
such an approach. On the basis of a systematic study, the
novel regioselectivity could be assigned both to steric and
electronic effects originating from the amine partner.
Nitrogen-containing heterocyclic skeletons are prevalent in
pharmaceuticals and biologically functional molecules. The 1,4-
dihydropyridine (1,4-DHP) skeleton is one of the most versatile
heterocyclic pharmacophores since it has been found as the
central fragment in many clinical pharmaceuticals.1 The most
notable examples are the series of 1,4-DHP-based calcium
channel blocker drugs such as nifedipine, felodipine, and
nicardipine (Figure 1), which are widely used for the treatment
of hypertension and related cardiovascular diseases.1,2 In
addition, the splendid results obtained from the study with 1,4-
DHPs as an R1a adrenoceptor-selective antagonist suggested their
promising potential in treating benign prostatic hyperplasia.3
What is more, 1,4-DHPs have been reported with miscellaneous
new pharmacological functions in recent years. To list but a
few, radioprotection, cerebral anti-ischemic agents, platelet
(3) (a) Wetzel, J. M.; Miao, S. W.; Forray, C.; Borden, L. A.; Branchek,
T. A.; Gluchowski, C. J. Med. Chem. 1995, 38, 1579. (b) Wong, W. C.; Chiu,
G.; Wetzel, J. M.; Marzabadi, M. R.; Nagarathnam, D.; Wang, D.; Fang, J.;
Miao, S. W.; Hong, X.; Forray, C.; Vaysse, P. J.-J.; Branchek, T. A.; Gluchowski,
C.; Tang, R.; Lepor, H. J. Med. Chem. 1998, 41, 2643.
(4) (a) Donkor, I. O.; Zhou, X.; Schmidt, J.; Agrawal, K. C.; Kishore, V.
Bioorg. Med. Chem. 1998, 6, 563. (b) Bretzel, R. G.; Bollen, C. C.; maeser, E.;
Federlin, K. F. Drug Fut. 1992, 17, 465. (c) Klusa, V. Drug Fut. 1995, 20, 135.
(d) Hilgeroth, A. Mini-ReV. Med. Chem. 2002, 2, 235.
(5) (a) Rudler, H.; Parlier, A.; Hamon, L.; Herson, P.; Daran, J.-C. Chem.
Commun. 2008, 4150. (b) Rudler, H.; Parlier, A.; Sandoval-Chavez, C.; Herson,
P.; Daran, J.-C. Angew. Chem., Int. Ed. 2008, 47, 6843.
(6) For representative reviews, see: (a) Zhu, J.; Bienayme´, H. Multicomponent
Reactions, 1st ed.; Wiley-VCH: Weinheim, Germany, 2005. (b) Do¨mling, A.;
Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (c) Zhu, J. Eur. J. Org. Chem.
2003, 1133. (d) Do¨mling, A. Chem. ReV. 2006, 106, 17.
† Zhejiang University.
‡ Zhejiang Normal University.
(1) For related reviews, see: (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)
Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
(2) (a) Varache-Leme`bge, M.; Nuhrich, A.; Zemb, V.; Devaux, G.; Vacher,
P.; Vacher, A. M.; Dufy, B. Eur. J. Med. Chem. 1996, 31, 547. (b) Alker, D.;
Campbell, S. F.; Cross, P. E.; Burges, R. A.; Carter, A. J.; Gardiner, D. G. J. Med.
Chem. 1990, 33, 585.
(7) Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 1, 215.
(8) For recent reviews on Hantsche 1,4-DHP synthesis, see: (a) Simon, C.;
Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957. (b) Langer, P.
Chem. Eur. J. 2001, 7, 3858. (c) Langer, P. Synthesis 2002, 441.
(9) For alternative synthesis of Hantsch-type 1,4-DHP, see: (a) Cui, S.-L.;
Wang, J.; Lin, X.-F.; Wang, Y.-G. J. Org. Chem. 2007, 72, 7779. (b) Kikuchi,
S.; Iwai, M.; Murayama, H.; Fukuzawa, S. Tetrahedron Lett. 2008, 49, 114.
2862 J. Org. Chem. 2009, 74, 2862–2865
10.1021/jo900068z CCC: $40.75 2009 American Chemical Society
Published on Web 03/03/2009

TABLE 1. Different Conditions for the Synthesis of 1,4-DHP 4aa
TABLE 2. Synthesis of 1,4-DHPs with Various Substratesa
entry
catalyst
HCld
TFA
PTSA
ACOH
InCl3
FeCl3 ·6H2O
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
sovent(s)b
temp (°C)
yield (%)c
entry
R1
R2
R3
DHP
yield (%)b
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
H2O
H2O/EtOH
H2O/DMF
H2O/DMF
H2O/DMF
H2O/DMF
H2O/DMF
H2O/DMF
H2O/DMF
85
85
85
85
85
85
85
85
85
85
85
85
85
85
100
70
27
32
45
trace
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
H
H
H
H
H
H
H
H
4-Cl
4-MeO
4-Cl
4-Cl
4-MeO
4-NO2
4-NO2
H
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
67
80
76
72
64
66
61
83
57
56
68
76
71
62
59
63
60
68
57
<10
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-AcC6H4
3-ClC6H4
Ph
3-ClC6H4
4-FC6H4
4-BrC6H4
4-FC6H4
4-MeOC6H4
4-FC6H4
4-FC6H4
4-BrC6H4
PhCH2
63
trace
9e
10f
11f
12f
13f
14
15
16
34
40
61
41
67
39
<15
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
2-Cl
2-Cl
H
H
H
a Reaction conditions: enaminone (0.3 mmol), aniline (0.3 mmol), and
cinnamaldehyde (0.35 mmol) in 1 mL of solvent, unless specified, the
catalyst was used in 1 equiv mol and reaction time was 10 h. b 0.5 mL
of H2O and 0.5 mL of EtOH/DMF were used in those mixed solvents.
c Isolated yield based on enaminone. d 37% commercial HCl solution
was used. e No target product was detected. f The catalyst amounts used
in entries 10-13 were 2.5, 2.0, 1.5, and 0.5 equiv mol, respectively.
4-Cl
H
H
cyclopropyl
isopropyl
4-Cl
a General conditions: 0.3 mmol of enaminone 1, 0.35 mmol of
aldehyde 2, 0.3 mmol of amine 3, and 0.3 mmol of TMSCl mixed in 1
mL of solvents (0.5 mL of H2O + 0.5 mL of DMF), stirred at 85 °C for
10 h. b Isolated yield based on enaminone.
esters predetermined the symmetrical structure of the products.
The use of different ꢀ-keto esters or analogues to prepare
unsymmetrical 1,4-DHPs suffers from the intervention of side
reactions due to homo-condensations.11
new functional substituents is highly desirable work. Our group
has been engaged in recent years in developing new MCRs to
synthesize novel functional heterocyclic compounds.15 On the
basis of our previous approach in this field, we report herein a
facile three-component synthesis of novel 1,3,4-trisubstituted
unsymmetrical 1,4-DHPs and the first observed regioselective
synthesis of 1,2-DHPs during an R,ꢀ-unsaturated aldehyde-
promoted DHP synthesis.
Our study began with the simultaneous use of enaminone
1a, cinnamaldehyde (2a), and aniline (3a) in 0.3 mmol scale in
DMF by employing 1.0 equiv mol TMSCl as promoter. After10
h at 85 °C conversion was completed (TLC) and the 1,4-DHP
(4a) was isolated in 63% yield (entry 7, Table 1). To improve
the yields, we examined this reaction using different Brønsted
and Lewis acids (entries 1-6). However, the screened candidates
did not display the expected improvements. Subsequently, we
further turned to testing the effect of solvents. EtOH, CH3CN,
or toluene showed no superiority to DMF.
A practical strategy to exclude these side reactions is the two-
step method, in which the amine/ammonia is reacted with active
methylene ketones to form the enamino ester intermediates prior
to further incorporation of the aldehydes and the other active
methylene ketones.8a,12 Recently, R,ꢀ-unsaturated aldehydes
have been disclosed as good reaction partners to incorporate
the enamino intermediate generated from ꢀ-keto esters and an
amine, to give unsymmetrical 5- or 5,6-unsubstituted 1,4-
DHPs.13 Although elegant results have been obtained in those
works, most of the endeavors still focus on the improvement
of the catalyst system in the same reaction and the diversity of
products was not actually widely expanded. To the best of our
knowledge, few alternative strategies in the unsymmetrical 1,4-
DHP syntheses are currently available in the literature.14 Thus,
in terms of designing and screening new lead compounds,
searching for new and facile MCRs to prepare 1,4-DHPs with
Interestingly, it has been found that employing aqueous DMF
as the medium slightly improved the yield of the reaction (entry
14), while no product was observed in aqueous EtOH (entry
9). Finally, by using TMSCl as the promoter, optimal conditions
(1.0 equiv of TMSCl, 85 °C in aqueous DMF) were found.
To validate the generality of this new synthetic protocol,
various substrates have been subjected to the reaction. Both
(10) See also:(a) Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.;
Dimarco, J. D.; Gougoutas, J.; Hedberg, A.; Malley, M.; McCarthy, J. P.; Zhang,
R.; Moreland, S. J. Med. Chem. 1995, 38, 119. (b) Peri, R.; Padmanabhan, S.;
Rutledge, A.; Singh, S.; Triggle, D. J. J. Med. Chem. 2000, 43, 2906. (c) Shan,
R.; Velazquez, C.; Knaus, E. E. J. Med. Chem. 2004, 47, 254.
¨
(11) (a) Ohberg, L.; Westman, J. Synlett 2001, 1296. (b) Cotterill, I. C.;
Usyatinsky, A. Y.; Arnold, J. M.; Clark, D. S.; Dordick, J. S.; Michels, P. C.;
Khmelnitsky, Y. L. Tetrahedron Lett. 1998, 39, 1117. (c) Chowdhurv, U. S.
Tetrahedron 1990, 46, 7893.
(14) Recently, Ishar et al. reported the [4+2] cycloaddition of azadienes with
allenic esters to give novel unsymmetrical 1,4-DHPs, see:(a) Ishar, M. P. S.;
Kumar, K.; Kaur, S.; Kumar, S.; Girdhar, N. K.; Sachar, S.; Marwaha, A.;
Kapoor, A. Org. Lett. 2001, 3, 2133. (b) Singh, L.; Ishar, M. P. S.; Elango, M.;
Subramanian, V.; Gupta, V.; Kanwal, P. J. Org. Chem. 2008, 73, 2224.
(15) (a) Zhu, Y.-L.; Huang, S.-L.; Pan, Y.-J. Eur. J. Org. Chem. 2005, 2354.
(b) Huang, S.-L.; Pan, Y.-J.; Zhu, Y.-L.; Wu, A.-X. Org. Lett. 2005, 7, 3797.
(c) Zhu, Y.-L.; Huang, S.-L.; Wan, J.-P.; Yan, L.; Pan, Y.-J.; Wu, A.-X. Org.
Lett. 2006, 8, 2599. (e) Wan, J.-P.; Zhou, J.; Mao, H.; Pan, Y.-J.; Wu, A.-X.
Tetrahedron 2008, 64, 11115.
(12) For selected examples, see: (a) Bossert, F.; Meyer, H.; Wehinger, E.
Angew. Chem. 1981, 93, 755. (b) Wang, G.-W.; Miao, C.-B. Green Chem. 2006,
8, 1080.
(13) (a) Vohra, R. K.; Bruneau, C.; Renaud, J.-L. AdV. Synth. Catal. 2006,
348, 2571. (b) Moreau, J.; Duboc, A.; Hubert, C.; Hurvois, J.-P.; Renaud, J.-L.
Tetrahedron Lett. 2007, 48, 8647. (c) Sridharan, V.; Perumal, P. T.; Anvendan˜o,
C.; Mene´ndez, J. C. Tetrahedron 2007, 63, 4407. (d) Kumar, A.; Maurya, R. A.
Tetrahedron 2008, 64, 3477. (e) Das, B.; Suneel, K.; Venkateswarlu, K.;
Ravikanth, B. Chem. Pharm. Bull. 2008, 56, 366.
J. Org. Chem. Vol. 74, No. 7, 2009 2863

TABLE 3. Regioselective Synthesis of 1,4-DHPs and 1,2-DHPsa
a Identical conditions as used in Table 2. b Isolated yield based on enaminone. c nd ) not detected.
aromatic (Table 2, entries 1-17) and aliphatic amines (entries
18-19) were able to afford the corresponding 1,4-DHPs
smoothly. The results displayed in Table 2 confirmed that
reactants with diversified substituents tolerated the protocol well.
However, unexpected products were observed when sterically
hindered aromatic amines or amines with strong electron
withdrawing groups were used. In the case of p-nitroaniline,
the observed product was not, as in the previous cases, the 1,4-
DHP but the 1,2-DHP 5a (eq 1), while 6a was isolated as a
side product. Similarly, the 1,2-DHP was observed in the
subsequent reaction employing o-chloroaniline as the substrate.
The structure of these 1,2-DHPs was clearly assigned on the
basis of spectral analysis and X-ray crystal diffraction (see the
Supporting Information for the crystal structure determination
of 5e). To the best of our knowledge, such a regioselective
synthesis of 1,2-DHPs had not been reported previously.
To examine the factors contributing to the selectivity, a series
of reactions, applying p-nitroaniline and ortho-substituted
anilines, have been implemented. The results are highlighted
in Table 3. As displayed by the results, both 1,2-DHPs and/or
2864 J. Org. Chem. Vol. 74, No. 7, 2009

SCHEME 1. Preliminary mechanistic investigations
for the first time during the R,ꢀ-unsaturated aldehyde-based
DHPs synthesis.
Experimental Section
General Procedure for the Synthesis of 1,4-DHPs and
1,2-DHPs. Enaminone 1 (0.3 mmol) and amine 3 (0.3 mmol) were
placed in a round-bottomed flask. Cinnamaldehyde (2) (0.35 mmol)
was subsequently added together with 0.5 mL of DMF and 0.5
mL of H2O. Finally, 0.04 mL of TMSCl (∼0.3 mmol) was injected
into the mixture. The mixture was stirred at 85 °C for 10 h. After
being cooled to room temperature, the reaction mixture was
extracted with 3 × 10 mL of ethyl acetate and the combined organic
layer was dried with anhydrous Na2SO4. The corresponding 1,4-
and 1,2-DHPs were then obtained by silica gel chromatography.
1,4-Diphenyl-3-benzoyl-1,4-dihydropyridine (4a): colorless
1,4-DHPs could be furnished depending on the properties of
the substituent. p-Nitroaniline mainly offered 1,4-DHPs as
products, while the results with different o-anilines indicate that
the regioselectivity was affected by both the size and the
electronic profiles of the ortho groups. In the reaction of
2-haloanilines, fluoro- and bromoaniline led to 1,4-DHP as the
dominant product (entries 3, 4, and 8), while 2-chloroaniline
gave 1,2-DHP as the only isolated product (entries 5-7).
Integrating the 1,2- and/or 1,4-DHP furnished in the 2-iodo-
aniline, 2-methylaniline, and 2,4,6-trimethylaniline entries (en-
tries 9-11), it is evident that the bulky ortho group is important,
but not the only inducing factor for 1,2-DHP formation. What
is notable is that the sequence of adding the reactants did not
make a visible difference in the regioselectivity of the reactions.
To explore the possible pathways of these cascade transfor-
mations, we attempted to prepare likely intermediates. Two
potential pathways might account for the DHP formation: one
is the formation of an imine intermediate 8a, the other is the
formation of an enaminone 9a (Scheme 1). At first, aniline 2a
and cinnamaldehyde were subjected to the standard reaction
conditions. However, the reaction led to the formation of a paste-
like residue, the ESI-MS analysis of which did not indicate the
presence of 8a. Moreover, adding enaminone 1a to the mixture
did not provide the target product 4a, either. Conversely,
however, the enaminone intermediate 9a was immediately
formed upon addition of TMSCl to the mixture of enaminone
1a and aniline at room temperature. The isolated 9a was then
subjected to standard catalysis condition with cinnamaldehyde
to give the 1,4-DHPs 4a in 70% yield. Thus, the formation of
9a plausibly served as the key step in this multicomponent
cascade reaction (Scheme 1).
1
crystal; mp 135-138 °C; H NMR (DMSO-d6, 500 MHz) δ 7.55
(d, 2 H, J ) 6.8 Hz), 7.45-7.36 (m, 8 H), 7.34-7.27 (m, 4 H),
7.19-7.16 (m, 2 H), 6.75 (d, 1 H, J ) 7.8 Hz), 5.26 (dd, 1 H, J )
7.8, 4.8 Hz), 4.81 (d, 1 H, J ) 4.8 Hz); 13C NMR (DMSO-d6, 500
MHz) δ 195.0, 148.1, 144.2, 143.2, 140.5, 131.8, 131.0, 129.5,
129.3, 128.7, 127.3, 126.4, 126.2, 120.7, 115.3, 112.4, 38.6; IR
(KBr, cm-1) 3027, 2853, 1672, 1627, 1591, 1493, 1331, 1260, 1134,
937, 839, 720, 693; HRMS calcd for C24H19NONa ([M + Na]+)
360.1359, found 360.1346.
1-(2-Chlorophenyl)-2-phenyl-5-benzoyl-1,2-dihydropyridine
(5e): colorless crystal; mp 182-185 °C; 1H NMR (DMSO-d6, 500
MHz) δ 7.54 (d, 2 H, J ) 6.6 Hz), 7.46-7.41 (m, 5 H), 7.32 (d,
5 H, J ) 10.0 Hz), 7.28-7.24 (m, 3H), 7.03 (s, 1 H), 6.71 (d, 1 H,
J ) 10.1 Hz), 5.84 (d, 1 H, J ) 4.2 Hz), 5.53 (dd, 1 H, J ) 10.1
Hz, 4.2 Hz); 13C NMR (DMSO-d6, 500 MHz) δ 190.7, 151.2, 142.4,
142.3, 140.5, 131.8, 131.4, 130.8, 130.4, 129.9, 129.8, 129.6, 129.5,
129.3, 129.2, 128.6, 120.0, 119.6, 109.2, 65.0; IR (KBr, cm-1) 3050,
3026, 1638, 1608, 1557, 1480, 1416, 1320, 1263, 1060, 910, 777,
698; HRMS calcd for C24H18ClNONa ([M + Na]+) 394.0969, found
394.0964.
Acknowledgement. We thank the NSFC of China (No.
20775069) and NCET-06-0520 of the National Ministry of
Education of China for financial support on this work. We also
thank Professor Henry Rudler (Universite´ Pierre et Marie Curie)
for his valuable help during the manuscript preparation.
Supporting Information Available: General experimental
1
procedure, copies of H and 13C NMR spectra, analytical data
for all products, the ORTEP structure of 5e, as well as a cif
file. This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have presented a facile and novel three-
component version for the synthesis of a new class of unsym-
metrical 1,4-DHPs. Also, the interesting regioselective formation
of 1,2-DHPs has been disclosed and systematically surveyed
JO900068Z
J. Org. Chem. Vol. 74, No. 7, 2009 2865