Multicomponent reactions for diverse synthesis of N-substituted and NH 1,4-dihydropyridines

Article abstract of DOI:10.1002/cjoc.201300918

The multicomponent reactions of aldehydes, electron deficient alkynes and amines have been successfully performed to yield a number of symmetrical 2,6-unsubstituted 1,4-dihydropyridines (1,4-DHPs). This method has been found generally applicable for the s

Full text of DOI:10.1002/cjoc.201300918

FULL PAPER
DOI: 10.1002/cjoc.201300918
Multicomponent Reactions for Diverse Synthesis of
N-Substituted and NH 1,4-Dihydropyridines
Jieping Wan,*,a Youyi Zhou,a Yunyun Liu,a Zheng Fang,a and Chengping Wen*,b
a Key Laboratory of Functional Small Organic Molecule, Ministry of Education, and College of Chemistry and
Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, China
b College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
The multicomponent reactions of aldehydes, electron deficient alkynes and amines have been successfully per-
formed to yield a number of symmetrical 2,6-unsubstituted 1,4-dihydropyridines (1,4-DHPs). This method has been
found generally applicable for the synthesis of both N-substituted and N-unsubstituted 1,4-DHPs by employing
secondary amine to activate the alkyne component via enaminoester intermediates. The present method runs
through an enamine type activation, which is different from the known approach employing AcOH as solvent.
Keywords multicomponent reactions, enamine activation, enaminoester, 1,4-dihydropyridine, diversity
Introduction
ing interests in their synthetic research, especially in
designing efficient synthetic routes accessing new
1,4-DHPs derivates. Hantzsch reaction, which involves
in the multicomponent condensation of aldehydes,
β-ketoesters and amines/ammonium has been known as
the most classical method in the synthesis of
1,4-DHPs.[16] This method is able to provide 1,4-DHPs
via facile operation, but suffers from the limit on prod-
uct diversity since only 1,4-DHPs with symmetrical
structure are accessible. Following the daily increasing
requirement on molecular diversity of biologically rele-
vant molecules, developing new MCRs providing
1,4-DHPs containing novel or unprecedented substruc-
tures has become an issue of central importance.[17]
Among the newly designed MCRs towards
1,4-DHPs synthesis, those reactions employing enami-
nones or enaminoesters have been found highly efficient
and flexible for synthesizing different types of
1,4-DHPs, including those with symmetrical and un-
symmetrical structures.[18-25] However, a disadvantage
of enaminone/enaminoester-based MCRs was that
enaminones and enaminoesters are not commercially
available, prior preparation of enaminones and enami-
noesters is required for related synthesis. Therefore,
reactions using commercially available substrates such
as electron deficient alkynes have attracted chemists’
attention. Several different protocols of alkyne-based
MCRs have been recently developed for the synthesis of
1,4-DHPs. For example, Wang and co-workers[26] have
reported the three-component synthesis of 1,4-DHPs
employing electron deficient alkynes (alkyl propiolates),
Molecular diversity consists one of the core issues in
modern organic chemistry. In the last decade, under the
inspiration of diversity-oriented-synthesis (DOS),[1-3]
numerous efforts have been devoted to find powerful
synthetic tools for rapidly accessing maximum molecu-
lar diversity with minimum cost. In the toolbox enabling
DOS for generating molecular libraries, multicompo-
nent reactions (MCRs)[4-9] are now recognized as one of
the most useful and powerful strategies. Following the
rapid progress in the research area of MCRs, wide-
spread application has been found in many different
areas such as chemical biology, natural product synthe-
sis, pharmaceuticals as well as agrochemistry. Among
the numerous types of organic products having been
provided by MCRs, 1,4-DHPs were known as a class of
significantly important and broadly concerned hetero-
cyclic scaffolds. Owing to their splendid pharmaceutical
and biological profiles, 1,4-DHPs have kept attracting
worldwide interests from chemical and medicinal com-
munities. For example, as simple 1,4-DHPs derivatives,
Nifedipine, Felodipine, Amlodipine, Cilnidipine etc.
have been known as most frequently utilized calcium
channel blockers in treating cardiovascular diseases.[10]
What’s more, recent researches have revealed many
new bioactivities[11] with 1,4-DHPs, including neuro-
protective[12] phosphodiesterase 4 (PDE4) inhibitory,[13]
P-glycoprotein (P-gp)[14] and anticoagulant[15] activities,
to name but a few.
As privileged heterocycles, the great potential of
1,4-DHPs in drug discovery also stimulated the sustain-
*
E-mail: wanjieping@gmail.com, cpwen.zcmu@yahoo.com; Fax: 0086-0791-88120380
Received December 29, 2013; accepted February 10, 2014; published online March 13, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201300918 or from the author.
Chin. J. Chem. 2014, 32, 219—226
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Wan et al.
FULL PAPER
Experimental
primary amines and salicylaldehydes with the catalysis
of TFA, but using other aryl aldehydes rather than sali-
cylaldehyde has been found not applicable because of
the indispensable activation effect of hydroxyl group.
Later on, Yan and co-workers[27] have established the
multicomponent synthesis of different 1,4-DHPs by
employing alkynes to incorporate aldehydes, amines
and cyanomethylene substrates or cyclic dicarbonyl
methylene substrates,[28] respectively. On the other hand,
Jiang and co-workers[29] have found that L-proline cata-
lyzes the multicomponent reactions of acyclic 1,3-di-
carbonyl compounds, aldehydes, amines and alkynes to
yield also 1,4-DHPs, and the three-component synthesis
of polysubstituted 1,4-DHPs involving primary amines,
dialkyl acetylenedicarboxylates and methyl (arylmeth-
ylidene) pyruvates has been recently achieved.[30] Inter-
estingly, in despite of their frequent application in
1,4-DHPs synthesis, directly employing electron defi-
cient alkynes to incorporate aldehydes and amines to
access symmetrical 1,4-DHPs is rarely available. Cur-
rently, the dominant methods of this type are perform-
ing the reactions of 1a, aldehydes 2 and amines 3 in
acetic acid to yield 1,4-DHPs of type 4 (Eq. 1), and usu-
ally under the harsh reaction conditions of refluxing
AcOH.[31-39] This kind of 1,4-DHPs have also been re-
cently found achievable by using similar starting mate-
rials under microwave irradiation, but with narrow ap-
plication scope.[40] As particular example, alkynes of
type 1 have been found capable of acting as aldehyde
alternatives for the construction of 1,4-DHPs by incor-
porating β-ketoesters and primary amines.[41] In the type
of 1,4-DHPs synthesis involving aldehydes, propiolates
and amines, the key factor is the formation of enamino-
ester intermediates via the addition of amines to
propiolates. The direct addition of primary amines to
propiolates, however, was not easy. Therefore, to
achieve corresponding 1,4-DHPs via this method,
highly excessive amount of acids (AcOH as solvent) or
harsh conditions were usually required. Considering the
fact that present methods in the synthesis of 1,4-DHPs
of type 4 are still limited, an efficient and generally ap-
plicable approach that allows the synthesis of 4 under
milder conditions is highly desirable.[42]
Synthesis of 1,4-DHPs 4 and 6
General procedure To a 10 mL round-bottle flask
with a stir bar were added alkyl propiolate (0.5 mmol),
aldehyde (0.3 mmol), amines (0.3 mmol), piperazine
(0.15 mmol) and TMSCl (0.45 mmol) in 2 mL DMF.
Then the mixture was stirred at 90 ℃ for 12 h (TLC).
After cooling down to r.t., 5 mL H2O was added to the
flask, and the resulting mixture was extracted with ethyl
acetate (10 mL×3). The combined organic phase was
dried over anhydrous sodium sulfate and filtered. The
solvent was then removed and the residue was subjected
to preparative silica TLC using mixed ethyl acetate and
petroleum ether as eluent (V/V＝1/10).
Diethyl-4-(4-chlorophenyl)-1-phenyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (4a) 73 mg, 71%; pale
yellow solid; m.p. 144－146 ℃; H NMR (400 MHz,
1
CDCl3) δ: 7.67 (s, 2H), 7.47 (t, J＝7.8 Hz, 2H), 7.32－
7.30 (m, 5H), 7.23 (d, J＝8.0 Hz, 2H), 4.95 (s, 1H),
4.11 (q, J＝6.8 Hz, 4H), 1.20 (t, J＝7.2 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ: 166.6, 144.7, 143.1, 135.7,
132.3, 130.0, 129.8, 128.2, 126.5, 120.8, 110.6, 60.4,
37.3, 14.2; IR (KBr) ν: 3028, 2980, 1701, 1666, 1580,
754 cm−1; ESI-HRMS calcd for C23H23ClNO4 [M＋H]＋:
412.1316, found 412.1317.
Diethyl-4-(4-bromophenyl)-1-phenyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (4b) 51 mg, 45%; yellow
solid; m.p. 131－132 ℃; H NMR (400 MHz, CDCl3)
1
δ: 7.66 (s, 2H), 7.47 (t, J＝7.6 Hz, 2H), 7.38 (d, J＝8.0
Hz, 2H), 7.31－7.28 (m, 3H), 7.25 (d, J＝8.0 Hz, 2H),
4.94 (s, 1H), 4.11 (q, J＝7.2 Hz, 4H), 1.20 (t, J＝7.2 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ: 166.6, 145.2,
143.1, 135.7, 131.1, 130.1, 130.0, 126.5, 120.8, 120.5,
110.6, 60.3, 37.4, 14.2; IR (KBr) ν: 3019, 2986, 1711,
1659, 1583, 696 cm−1; ESI-HRMS calcd for
C23H23BrNO4 [M＋H]＋: 456.0810, found 456.0811.
Diethyl-1-phenyl-4-(4-(trifluoromethyl)phenyl)-
1,4-dihydropyridine-3,5-dicarboxylate (4c) 62 mg,
1
56%; orange solid; m.p. 138－139 ℃; H NMR (400
MHz, CDCl3) δ: 7.61 (s, 2H), 7.46－7.38 (m, 6H), 7.25
－7.22 (m, 3H), 4.97 (s, 1H), 4.03 (q, J＝6.8 Hz, 4H),
1.12 (t, J＝7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ:
166.4, 143.1, 136.0, 130.0, 128.7, 126.6, 125.1 (d, JC
－
F
R1
＝3.4 Hz, 1C), 120.8, 110.4, 60.4, 37.8, 14.2; IR (KBr)
ν: 3025, 2985, 1710, 1663, 1584, 1150 cm−1;
ESI-HRMS calcd for C24H23F3NO4[M＋H]＋: 446.1579,
found 446.1588.
EtOOC
COOEt
COOEt
R1
R2
NH2
3
2
(1)
+
+
CHO
N
R2
1a
2
Diethyl-1,4-diphenyl-1,4-dihydropyridine-3,5-
dicarboxylate (4d) 70 mg, 74%; yellow solid; m.p.
4
1
150－151 ℃; H NMR (400 MHz, CDCl3) δ: 7.67 (s,
2H), 7.45 (t, J＝3.6 Hz, 2H), 7.37 (d, J＝6.8 Hz, 2H),
7.31－7.24 (m, 5H), 7.15 (t, J＝6.4 Hz, 1H), 4.97 (s,
1H), 4.10 (q, J＝6.8 Hz, 4H), 1.19 (t, J＝7.2 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ: 166.8, 146.1, 143.2,
135.5, 129.9, 128.4, 128.0, 126.6, 126.3, 120.8, 111.1,
60.2, 37.8, 14.2; IR (KBr) ν: 3027, 2977, 1706, 1667,
1584 cm−1; ESI-HRMS calcd for C23H24NO4 [M＋H]＋:
During our efforts on exploring effective MCRs for
heterocycle synthesis,[18,24,43,44] we have discovered that
the multicomponent synthesis of 1,4-DHPs 4 could be
achieved by employing the activation of secondary
amines as shown in Eq. 1. And we report herein this
synthetic method towards various 2,6-unsubstituted
symmetrical 1,4-DHPs of type 4.
220
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 219—226

Multicomponent Reactions for Diverse Synthesis of N-Substituted and NH 1,4-Dihydropyridines
378.1705, found 378.1713.
1662, 1583 cm−1; ESI-HRMS calcd for C23H24NO5 [M
Diethyl-1-phenyl-4-p-tolyl-1,4-dihydropyridine-
3,5-dicarboxylate (4e) 52 mg, 53%; yellow solid; m.p.
＋H]＋: 394.1654, found 394.1658.
Diethyl-4-(2,4-dichlorophenyl)-1-phenyl-1,4-dihy-
dropyridine-3,5-dicarboxylate (4j) 68 mg, 61%;
1
110－111 ℃; H NMR (400 MHz, CDCl3) δ: 7.58 (s,
1
2H), 7.37 (t, J＝7.6 Hz, 2H), 7.19 (q, J＝8.0 Hz, 5H),
6.98 (d, J＝7.6 Hz, 2H), 4.85 (s, 1H), 4.02 (q, J＝6.4
Hz, 4H), 2.21 (s, 3H), 1.12 (t, J＝7.2 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ: 166.8, 143.3, 143.2, 136.0, 135.4,
129.9, 128.8, 128.2, 126.3, 120.7, 111.2, 60.2, 37.2,
21.1, 14.2; IR (KBr) ν: 3034, 2987, 1693, 1664, 1584,
1389, 1200, 061, 736 cm−1; ESI-HRMS calcd for
C24H26NO4 [M＋H]＋: 392.1862, found 392.1864.
yellow solid; m.p. 164－165 ℃; H NMR (400 MHz,
CDCl3) δ: 7.67 (s, 2H), 7.46 (t, J＝7.2 Hz, 2 H), 7.34－
7.26 (m, 5H), 7.17 (d, J＝8.4 Hz, 1H), 5.39 (s, 1H),
4.09 (q, J＝6.8 Hz, 4H), 1.20 (t, J＝6.4 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ: 166.5, 143.0, 142.4, 136.6,
134.1, 132.6, 132.5, 130.0, 129.1, 127.1, 126.6, 120.7,
110.0, 60.4, 35.2, 14.2; IR (KBr) ν: 3021, 2987, 1712,
1659, 1592, 742 cm−1; ESI-HRMS calcd for
C23H22Cl2NO4 [M＋H]＋: 446.0926, found 446.0926.
Diethyl-4-(furan-2-yl)-1-phenyl-1,4-dihydropyri-
dine-3,5-dicarboxylate (4k) 47 mg, 51%; brown
Diethyl-4-(4-methoxyphenyl)-1-phenyl-1,4-di-
hydropyridine-3,5-dicarboxylate (4f) 74 mg, 73%;
orange solid; m.p. 145－146 ℃; H NMR (400 MHz,
1
1
CDCl3) δ: 7.65 (s, 2H), 7.45 (t, J＝7.2 Hz, 2H), 7.29 (t,
J＝7.6 Hz, 5H), 6.80 (d, J＝7.6 Hz, 2H), 4.91 (s, 1H),
4.11 (q, J＝6.4 Hz, 4H), 3.76 (s, 3H), 1.21 (t, J＝7.2 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ: 166.8, 158.3,
143.3, 138.7, 135.3, 129.9, 129.3, 126.3, 120.7, 113.4,
111.3, 60.2, 55.1, 36.8, 14.2; IR (KBr) ν: 3014, 2987,
1705, 1664, 1582 cm−1; ESI-HRMS calcd for
C24H26NO5 [M＋H]＋: 408.1811, found 408.1807.
solid; m.p. 104－106 ℃; H NMR (400 MHz, CDCl3)
δ: 7.58 (s, 2H), 7.37 (t, J＝7.8 Hz, 2H), 7.22－7.19 (m,
4H), 6.20－6.19 (m, 1H), 6.05 (d, J＝3.2 Hz, 1H), 5.07
(s, 1H), 4.10 (q, J＝7.2 Hz, 4H), 1.17 (t, J＝7.2 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ: 166.7, 157.3, 143.2,
141.2, 136.5, 129.9, 126.4, 121.0, 110.4, 107.8, 105.7,
60.3, 31.3, 14.3; IR (KBr) ν: 3056, 2978, 1706, 1668,
1585 cm−1; ESI-HRMS calcd for C21H21NNaO5 [M＋
Na]＋: 390.1317, found 390.1317.
Diethyl-1,4-bis(4-chlorophenyl)-1,4-dihydropyri-
dine-3,5-dicarboxylate (4l) 71 mg, 64%; yellow solid;
m.p. 118－121 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.60
(s, 2H), 7.41 (d, J＝8.4 Hz, 2H), 7.29 (d, J＝8.4 Hz,
2H), 7.25－7.22 (m, 4H), 4.94 (s, 1H), 4.11 (q, J＝7.2
Hz, 4H), 1.20 (t, J＝7.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ: 166.4, 144.4, 141.6, 135.2, 132.4, 132.0,
130.0, 129.8, 128.2, 122.0, 111.1, 60.4, 37.3, 14.2 cm−1;
Diethyl-4-(2-chlorophenyl)-1-phenyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (4g) 86 mg, 84%; yellow
1
solid; m.p. 176－177 ℃; H NMR (400 MHz, CDCl3)
δ: 7.67 (s, 2H), 7.45 (t, J＝7.2 Hz, 2H), 7.38 (d, J＝7.6
Hz, 1H), 7.31－7.25 (m, 4 H), 7.18 (t, J＝7.2 Hz, 1H),
7.08 (t, J＝7.2 Hz, 1H), 5.42 (s, 1H), 4.08 (q, J＝7.6 Hz,
4H), 1.17 (t, J＝7.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ: 166.7, 143.7, 143.1, 136.3, 133.4, 131.7,
129.9, 129.4, 127.7, 126.8, 126.4, 120.7, 110.5, 60.3,
35.4, 14.2; IR (KBr) ν: 3021, 2984, 1705, 1664, 1573,
751 cm−1; ESI-HRMS calcd for C23H23ClNO4 [M＋H]＋:
412.1316, found 412.1321.
IR (KBr) ν: 3029, 2979, 1679, 1666, 1577, 756;
＋
ESI-HRMS calcd for C23H22Cl2NO4 [M ＋ H]
:
446.0926, found 446.0919.
Diethyl-4-(2-bromophenyl)-1-phenyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (4h) 90 mg, 79%; yellow
solid; m.p. 173－174 ℃; H NMR (400 MHz, CDCl3)
Diethyl-4-(4-chlorophenyl)-1-(4-methoxyphenyl)-
1,4-dihydropyridine-3,5-dicarboxylate (4m) 45 mg,
1
1
41%; yellow solid; m.p. 119－120 ℃; H NMR (400
δ: 7.69 (s, 2H), 7.49 (d, J＝7.6 Hz, 1H), 7.45 (d, J＝8.0
Hz, 1H), 7.38 (d, J＝7.6 Hz, 1H), 7.33－7.22 (m, 5H),
7.01 (t, J＝7.6 Hz, 1H), 5.41 (s, 1H), 4.11 (q, J＝7.2 Hz,
4H), 1.19 (t, J＝7.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ: 166.8, 145.6, 143.1, 136.3, 132.8, 131.7,
129.9, 127.9, 127.5, 126.4, 123.7, 120.7, 110.8, 60.3,
37.6, 14.3; IR (KBr) ν: 3025, 2981, 1709, 1663, 1579,
679 cm−1; ESI-HRMS calcd for C23H23BrNO4 [M＋
H]＋: 456.0810, found 456.0808.
MHz, CDCl3) δ: 7.55 (s, 2H), 7.31 (d, J＝8.0 Hz, 2H),
7.22 (d, J＝8.0 Hz, 4H), 6.96 (d, J＝8.8 Hz, 2H), 4.95
(s, 1H), 4.10 (q, J＝7.2 Hz, 4H), 3.83 (s, 3H), 1.19 (t,
J＝7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ: 166.7,
158.3, 145.0, 136.6, 136.5, 132.2, 129.8, 128.1, 122.9,
115.0, 109.9, 60.2, 55.6, 37.2, 14.2; IR (KBr) ν: 3011,
2979, 1711, 1666, 1582, 757 cm−1; ESI-HRMS calcd for
C24H25ClNO5 [M＋H]＋: 442.1421, found 442.1422.
Diethyl-4-(4-chlorophenyl)-1-(4-nitrophenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (4n) 46 mg, 40%;
Diethyl-4-(3-hydroxyphenyl)-1-phenyl-1,4-dihy-
dro pyridine-3,5-dicarboxylate (4i) 50 mg, 51%;
1
orange solid; m.p. 152－153 ℃; H NMR (400 MHz,
1
pale yellow solid; m.p. 199－200 ℃; H NMR (400
CDCl3) δ: 8.27 (d, J＝8.4 Hz, 2H), 7.69 (s, 2H), 7.37 (d,
J＝8.4 Hz, 2H), 7.21－7.15 (m, 4H), 4.88 (s, 1H), 4.05
(q, J＝7.2 Hz, 4H), 1.15 (t, J＝7.2 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ: 166.0, 147.3, 144.9, 143.5, 133.5,
132.7, 129.8, 128.3, 125.8, 119.4, 113.3, 60.8, 37.5,
14.2; IR (KBr) ν: 3041, 2984, 1712, 1648, 1593, 1519,
752 cm−1; ESI-HRMS calcd for C23H21ClN2NaO6 [M＋
Na]＋: 479.0986, found 479.0983.
MHz, CDCl3) δ: 7.67 (s, 2H), 7.41 (t, J＝7.20 Hz, 2H),
7.28 (t, J＝3.6 Hz, 1H), 7.23 (d, J＝8.4 Hz, 2H), 7.14 (t,
J＝7.6 Hz, 1H), 6.95 (d, J＝8.0 Hz, 1H), 6.93 (s, 1H),
6.68 (d, J＝8.0 Hz, 1H), 6.33 (brs, 1H), 4.93 (s, 1H),
4.09 (t, J＝7.2 Hz, 4H), 1.21 (t, J＝7.2 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ: 167.1, 156.1, 147.7, 143.0,
135.7, 129.9, 129.1, 126.2, 120.6, 115.5, 113.8, 110.9,
60.5, 37.6, 14.2; IR (KBr) ν: 3341, 3024, 2981, 1705,
Diethyl-1-(3-chlorophenyl)-4-(4-chlorophenyl)-
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1,4-dihydropyridine-3,5-dicarboxylate (4o) 83 mg,
75%; pale solid; m.p. 109－110 ℃; H NMR (400
hydropyridine-3,5-dicarboxylate (4t) 83 mg, 80%;
yellow solid; m.p. 118－119 ℃; H NMR (400 MHz,
1
1
MHz, CDCl3) δ: 7.62 (s, 2H), 7.39 (t, J＝8.0 Hz, 1H),
7.31－7.28 (m, 4H), 7.24－7.19 (m, 3H), 4.94 (s, 1H),
4.12 (q, J＝7.2 Hz, 4H), 1.21 (t, J＝7.2 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ: 166.4, 144.3, 144.0, 135.7,
135.0, 132.4, 131.0, 129.8, 128.2, 126.5, 120.9, 118.7,
111.4, 60.5, 37.3, 14.2; IR (KBr) ν: 3025, 2983, 1703,
1659, 1584, 739 cm−1; ESI-HRMS calcd for C23H22Cl2-
NO4 [M＋H]＋: 446.0926, found 446.0923.
CDCl3) δ: 7.29 (s, 2H), 7.23－7.17 (m, 4H), 4.87 (s,
1H), 4.07 (q, J＝7.2 Hz, 4H), 3.27－3.19 (m, 1H), 1.98
－1.76 (m, 4H), 1.74 (t, J＝12.4 Hz, 2H),1.60－1.50 (m,
2H), 1.34 (q, J＝12.8 Hz, 2H), 1.19 (t, J＝7.2 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ: 167.0, 145.6, 136.1,
131.9, 129.5, 128.0, 108.1, 63.7, 60.0, 37.5, 32.6, 25.6,
25.0, 14.3; IR (KBr) ν: 3019, 2979, 1702, 1663, 1573,
758 cm−1; ESI-HRMS calcd for C23H29ClNO4 [M＋H]＋:
418.1785, found 418.1795.
Diethyl-4-(4-chlorophenyl)-1-(2-methoxyphenyl)-
1,4-dihydropyridine-3,5-dicarboxylate (4p) 67 mg,
Diethyl-4-(4-chlorophenyl)-1-isobutyl-1,4-dihy-
dropyridine-3,5-dicarboxylate (4u) 82 mg, 84%;
1
61%; pale yellow solid; m.p. 143－144 ℃; H NMR
1
(400 MHz, CDCl3) δ: 7.44 (s, 1H), 7. (s, 1H), 7.40 (s,
2H), 7.36 (d, J＝7.8 Hz, 1H), 7.28－7.25 (m, 3H), 7.05
(t, J＝7.2 Hz, 2H), 4.95 (s, 1H), 4.10 (q, J＝7.2 Hz, 4H),
3.93 (s, 3H), 1.21 (t, J＝7.2 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ: 166.8, 154.1, 145.4, 138.2, 132.1,
132.0, 129.9, 129.2, 128.0, 126.0, 121.2, 112.3, 108.9,
60.1, 55.9, 37.0, 14.2; IR (KBr) ν: 3019, 2989, 1708,
1671, 1586, 751 cm−1; ESI-HRMS calcd for C24H25Cl-
NO5 [M＋H]＋: 442.1421, found 442.1419.
yellow solid; m.p. 129－131 ℃; H NMR (400 MHz,
CDCl3) δ: 7.24 (d, J＝7.2 Hz, 2H), 7.20 (d, J＝8.4 Hz,
2H), 7.17 (s, 2H) 4.87 (s, 1H), 4.07 (q, J＝7.2 Hz, 4H),
3.19 (d, J＝5.6 Hz, 2H), 2.02－1.96 (m, 1H), 1.19 (t,
J＝7.2 Hz, 6H), 0.98 (d, J＝6.4 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ: 166.9, 145.3, 138.0, 132.0, 129.6,
128.0, 107.8, 62.6, 60.1, 36.9, 29.4, 19.7, 14.2; IR (KBr)
ν: 3028, 2984, 1712, 1665, 1590, 756 cm−1; ESI-HRMS
calcd for C23H27ClNO4 [M＋H]＋: 392.1629, found
392.1638.
Diethyl-4-(4-chlorophenyl)-1-(2-iodophenyl)-
1,4-dihydropyridine-3,5-dicarboxylate (4q) 64 mg,
Dimethyl-4-(4-chlorophenyl)-1-phenyl-1,4-dihy-
dropyridine-3,5-dicarboxylate (4v) 60 mg, 63%;
1
48%; yellow solid; m.p. 170－172 ℃; H NMR (400
1
MHz, CDCl3) δ: 7.96 (d, J＝7.8 Hz, 1H), 7.51－7.44 (m,
3H), 7.34 (s, 1H), 7.32 (s, 2H), 7.25 (d, J＝8.0 Hz, 2H),
7.12 (t, J＝7.8 Hz, 1H), 4.97 (s, 1H), 4.09 (q, J＝6.8 Hz,
4H), 1.19 (t, J＝7.6 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ: 166.5, 145.6, 144.9, 140.6, 137.3, 132.2,
130.3, 130.0, 129.9, 128.1, 127.4, 109.4, 95.8, 60.3,
37.1, 14.2; IR (KBr) ν: 3021, 2985, 1701, 1660, 1581,
751, 605 cm−1; ESI-HRMS calcd for C23H22ClINO4
[M＋H]＋: 538.0282, found 538.0281.
yellow solid; m.p. 149－152 ℃; H NMR (400 MHz,
CDCl3) δ: 7.59 (s, 2H), 7.37 (t, J＝8.0 Hz, 2H), 7.22 (t,
J＝8.4 Hz, 5H), 7.15 (d, J＝8.4 Hz, 2H), 4.88 (s, 1H),
3.57 (s, 6H); 13C NMR (100 MHz, CDCl3) δ: 166.9,
144.5, 143.0, 135.9, 132.4, 130.0, 129.6, 128.3, 126.6,
120.7, 110.4, 51.5, 37.2; IR (KBr) ν: 3035, 2984, 1705,
1668, 1576, 751 cm−1; ESI-HRMS calcd for C21H19Cl-
NO4 [M＋H]＋: 384.1003, found 384.1003.
Dimethyl-4-(3-methoxyphenyl)-1-phenyl-1,4-di-
hydropyridine-3,5-dicarboxylate (4w) 28 mg, 30%;
Diethyl-1-(2-bromophenyl)-4-(4-chlorophenyl)-
1,4-dihydropyridine-3,5-dicarboxylate (4r) 67 mg,
1
pale yellow solid; m.p. 129－130 ℃; H NMR (400
1
55%; faint yellow solid; m.p. 169－171 ℃; H NMR
MHz, CDCl3) δ: 7.67 (s, 2H), 7.45 (t, J＝8.0 Hz, 2H),
7.30－7.28 (m, 3H), 7.19 (t, J＝8.0 Hz, 1H), 6.97 (d,
J＝8.0 Hz, 1H), 6.94 (s, 1H), 6.73 (t, J＝8.0 Hz, 1H),
4.96 (s, 1H), 3.78 (s, 3H), 3.67 (s, 6H); 13C NMR (100
MHz, CDCl3) δ: 167.2, 159.5, 147.4, 143.1, 135.8,
130.0, 129.1, 126.4, 120.8, 120.6, 114.3, 111.8, 110.6,
55.1, 51.5, 37.5; IR (KBr) ν: 3022, 2989, 1705, 1664,
1583 cm−1; ESI-HRMS calcd for C22H22NO5 [M＋H]＋:
380.1498, found 384.1486.
(400 MHz, CDCl3) δ: 7.97 (d, J＝8.0 Hz, 1H), 7.47 (t,
J＝8.0 Hz, 3H), 7.33 (d, J＝7.8 Hz, 1H), 7.31 (s, 2H),
7.25 (d, J＝8.0 Hz, 2H), 7.13 (t, J＝7.8 Hz, 1H), 4.97 (s,
1H), 4.09 (q, J＝7.2 Hz, 4H), 1.19 (t, J＝7.2 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ: 166.5, 145.5, 144.9,
140.6, 137.3, 132.2, 130.3, 130.0, 129.9, 128.1, 127.3,
109.4, 95.8, 60.3, 37.1, 14.2; IR (KBr) ν: 3029, 2989,
1709, 1667, 1586, 761, 663 cm−1; ESI-HRMS calcd for
C23H22BrClNO4 [M＋H]＋: 490.0421, found 490.0428.
Diethyl-1-benzyl-4-(4-chlorophenyl)-1,4-dihy-
dropyridine-3,5-dicarboxylate (4s) 72 mg, 68%;
Diethyl-4-(4-chlorophenyl)-1,4-dihydropyridine-
1
3,5-dicarboxylate (6a) 38 mg, 45%; orange oil; H
NMR (400 MHz, CDCl3) δ: 7.24 (d, J＝5.6 Hz, 2H),
7.19 (d, J＝8.4 Hz, 2H), 7.13 (d, J＝8.8 Hz, 2H), 6.55
(brs, 1H), 4.80 (s, 1H), 4.00 (q, J＝7.2 Hz, 4H), 1.12 (t,
J＝7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ: 167.0,
145.5, 133.8, 132.1, 129.7, 128.1, 108.2, 60.1, 37.2,
14.2; IR (KBr) ν: 3335, 3019, 2985, 1706, 1659, 1586,
741 cm−1; ESI-HRMS calcd for C17H19ClNO4 [M＋H]＋:
336.1003, found 336.1003.
1
pale yellow oil; H NMR (400 MHz, CDCl3) δ: 7.44－
7.37 (m, 3H), 7.27 (d, J＝7.2 Hz, 4H), 7.20 (q, J＝7.6
Hz, 4H), 4.90 (s, 1H), 4.58 (s, 2H), 4.07 (q, J＝6.0 Hz,
4H), 1.12 (t, J＝7.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ: 166.7, 145.1, 137.7, 136.1, 132.1, 129.6,
129.2, 128.5, 128.0, 127.2, 108.8, 60.1, 58.3, 37.0, 14.2;
IR (KBr) ν: 3030, 2979, 1702, 1661, 1582, 750 cm−1;
ESI-HRMS calcd for C24H25ClNO4 [M＋H]＋: 426.1472,
found 426.1478.
Diethyl-4-(4-methoxyphenyl)-1,4-dihydropyri-
dine-3,5-dicarboxylate (6b) 45 mg, 54%; orange oil;
1H NMR (400 MHz, CDCl3) δ: 7.21 (d, J＝5.6 Hz, 2H),
Diethyl-4-(4-chlorophenyl)-1-cyclohexyl-1,4-di-
222
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Multicomponent Reactions for Diverse Synthesis of N-Substituted and NH 1,4-Dihydropyridines
7.17 (d, J＝8.8 Hz, 2H), 6.70 (d, J＝8.4 Hz, 2H), 6.62
(brs, 1H), 4.76 (s, 1H), 4.00 (q, J＝7.2 Hz, 4H), 3.67 (s,
3H), 1.12 (t, J＝7.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ: 167.2, 158.1, 139.5, 133.4, 129.3, 113.3,
108.8, 60.0, 55.1, 36.7, 14.2; IR (KBr) ν: 3329, 3025,
2984, 1706, 1664, 1583 cm−1; ESI-HRMS calcd for
C18H21NNaO5 [M＋Na]＋: 354.1317, found 354.1327.
Diethyl-4-(2-bromophenyl)-1,4-dihydropyridine-
3,5-dicarboxylate (6c) 46 mg, 49%; orange solid; m.p.
found 283.1650.
Results and Discussion
Initially, the reaction of ethyl propiolate 1a,
p-chlorobenzaldehyde 2a and aniline 3a was selected as
model reaction for optimizing reaction conditions. The
control experiments employing only trimethylsilyl chlo-
ride (TMSCl) or morpholine were first carried out, re-
spectively. And no target transformation forming 4a
was observed in neither Entry after heating at 90 ℃ for
12 h (Scheme 1). While simultaneously employing both
species in the reaction gave 4a with 53% yield (Entry 1,
Table 1). Further optimization was then conducted
based on the fact that both acid and secondary amine
were required for the reaction. Firstly, on TMSCl load-
ing, reaction temperature and catalyst species demon-
strated that the combination of piperazine (0.5 equiv.)
and TMSCl (1.5 equiv.) in DMF at a brief screening on
different secondary amines and reaction media implied
that piperazine was more efficient in promoting the re-
action with 50 mol% loading (Entries 2－8, Table 1).
1
138－141 ℃; H NMR (400 MHz, CDCl3) δ: 7.38 (d,
J＝6.8 Hz, 1H), 7.29 (d, J＝8.0 Hz, 1H), 7.23 (d,
J＝5.6 Hz, 2H), 7.16－7.12 (m, 1H), 6.92－6.88 (m,
1H), 6.75 (brs, 1H), 5.26 (s, 1H), 4.00 (q, J＝7.2 Hz,
4H), 1.10 (t, J＝7.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ: 167.2, 146.8, 134.3, 132.5, 131.6, 127.8,
127.5, 123.2, 108.6, 60.1, 37.3, 14.3; IR (KBr) ν: 3324,
3029, 2981, 1707, 1665, 1584, 665 cm−1; ESI-HRMS
calcd for C17H19BrNO4 [M＋H]＋: 380.0497, found
380.0483.
Diethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-
1
3,5-dicarboxylate (6d) 57 mg, 66%; orange oil; H
NMR (400 MHz, CDCl3) δ: 8.10 (s, 1H), 7.95 (d, J＝
7.2 Hz, 1H), 7.66 (d, J＝6.8 Hz, 1H), 7.36－7.31 (m,
3H), 6.89 (brs, 1H), 4.96 (s, 1H), 4.00 (q, J＝7.2 Hz,
4H), 1.20 (t, J＝7.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ: 166.7, 149.0, 148.4, 134.8, 134.4, 128.7,
123.3, 121.7, 107.6, 60.3, 37.8, 14.2; IR (KBr) ν: 3319,
3025, 2985, 1709, 1684, 1515 cm−1; ESI-HRMS calcd
for C17H18N2O6 [M＋H]＋: 347.1243, found 347.1246.
Diethyl-4-(2,4-dichlorophenyl)-1,4-dihydropyri-
dine-3,5-dicarboxylate (6e) 37 mg, 40%; orange oil;
1H NMR (400 MHz, CDCl3) δ: 7.36－7.31(m, 4H), 7.17
(d, J＝8.4 Hz, 1H), 6.77 (brs, 1H), 5.35 (s, 1H), 4.08 (q,
J＝7.2 Hz, 4H), 1.20 (t, J＝7.2 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ: 167.0, 143.6, 134.5, 133.4, 132.5,
132.4, 128.8, 127.2, 107.8, 60.2, 34.7, 14.2; IR (KBr) ν:
3321, 3022, 2984, 1701, 1661, 1581, 747 cm−1; ESI-
HRMS calcd for C17H18Cl2NO4 [M＋H]＋: 370.0613,
found 370.0611.
Scheme 1 Control experiments on single catalyst system
Cl
COOEt
Ph
TMSCl
2
NH2
EtO2C
CO2Et
DMF
3a
1a
Cl
90 oC/12 h
morpholine
N
CHO
Ph
4a
2a
Table 1 Optimization on reaction conditionsa
Entry Amine
Catalyst
Solvent
DMF
DMF
DMF
EtOH
Toluene
H2O
T/℃ Yieldb/%
1
Morpholine TMSCl
Pyrrolidine TMSCl
Piperazine TMSCl
Piperazine TMSCl
Piperazine TMSCl
Piperazine TMSCl
Piperazine TMSCl
Piperazine TMSCl
Piperazine TMSCl
Piperazine TMSCl
Piperazine TMSCl
Piperazine p-TSA
Piperazine AcOH
90
90
90
90
90
90
90
90
90
90
80
90
90
90
53
44
63
34
34
36
43
63
71
58
58
48
Trace
61
2
3
4
5
Synthesis of intermediate 7a
6
To a 25 mL round bottom flask was added ethyl
propiolate (0.6 mmol) and piperazine (0.3 mmol), 1.5
mL DMF was added and the mixture was stirred at r.t.
for 8 h (TLC). Upon completion, 10 mL water was
added and the resulting mixture was extracted with
EtOAc (10 mL×3). The combined organic layer was
dried with anhydrous Na2SO4. After filtering out the
solid, evaporation on solution gave product 6a as white
solid.
(2E,2'E)-Diethyl 3,3'-(piperazine-1,4-diyl) dia-
crylate (7a) 76 mg, 90%; white solid, m.p. 206－207
℃; 1H NMR (400 MHz, CDCl3) δ: 7.31 (d, J＝13.2 Hz,
2H), 4.65 (d, J＝13.2 Hz, 2H), 4.07 (q, J＝6.8 Hz, 4H),
3.20 (s, 8H), 1.19 (t, J＝6.8 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ: 169.17, 151.02, 87.11, 59.17, 47.47,
14.51; IR (KBr) ν: 2977, 2916, 1685, 1378 cm−1;
ESI-HRMS calcd for C14H23N2O4 [M＋H]＋: 283.1658,
7c
8c
9d
10d
11d
12d
13d
14d
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Piperazine CF3COOH DMF
a Unless otherwise specified, the reaction conditions are: 1a (0.5
mmol), 2a (0.3 mmol), 3a (0.3 mmol), 0.5 equiv. secondary
amine and 2.0 equiv. TMSCl in 2.0 mL solvent and stirred for 12
c
h. b Yield of purified products based on 1a. Piperazine was used
in 0.3 equiv. and 0.6 equiv. for Entries 7 and 8, respectively.
d The acid catalyst was employed in 1.0 equiv. for Entry 10, and
1.5 equiv. for Entries 9 and 11－14.
Chin. J. Chem. 2014, 32, 219—226
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
223

Wan et al.
FULL PAPER
Later on, the optimization temperature of 90 ℃ is the
best condition among all the investigated Entries (Entry
9, Table 1).
to good yields without showing evident impact of sub-
stituents (Entries 1－11, Table 2). Similar results have
been obtained in the Entries using different aryl amines
(Entries 12－18, Table 2). An interesting point of the
protocol was that alkyl amines were also tolerated well
as aryl amines, and corresponding N-alkyl 1,4-DHPs
were provided with good to excellent yields (Entries 19
－21, Table 2). When methyl propiolate was employed
instead of ethyl propiolate, corresponding 1,4-DHPs 4w
and 4y were acquired smoothly with reasonable yield as
expected (Entries 22, 23, Table 2). The Entry employing
aliphatic aldehyde, however, was not successful under
present conditions (Entry 24, Table 2). All products
have been fully characterized with standard spectro-
scopic analysis, and the X-ray single crystal diffraction
on 4r further confirmed the structures of synthesized
1,4-DHPs (Figure 1).[45]
Under the standard conditions from optimization
experiments, the general applicability of this multicom-
ponent protocol was then investigated by subjecting a
number of different aldehydes, amines and alkynes. The
results on the synthesis of different 1,4-DHPs were
shown in Table 2. In general, benzaldehydes possessing
various substitution groups such as halides, alkyl,
alkoxyl, fluorinated alkyl in different sites and het-
eroaryl aldehydes were tolerable to this transformation.
All these aldehydes incorporated ethyl propiolate and
aniline to afford corresponding 1,4-DHPs with moderate
Table 2 Multicomponent synthesis of different N-substituted
1,4-DHPsa
Ar
R1O2C
piperazine/TMSCl
DMF/90 oC
CO2R1
COOR1
R2
NH2
3
Ar
2
+
+
CHO
2
N
R2
4
1
Entry Ar
R1
Et
Et
Et
Et
Et
R2
Product Yieldb/%
1
4-ClC6H4
4-BrC6H4
Ph
4a
4b
4c
4d
4e
4f
71
45
56
74
53
73
84
79
51
61
51
64
41
40
75
61
48
55
68
80
84
63
30
nr
2
Ph
3
4-CF3C6H4
Ph
Ph
4
Ph
5
4-MeC6H4
Ph
6
4-MeOC6H4 Et
Ph
7
2-ClC6H4
2-BrC6H4
3-HOC6H4
Et
Et
Et
Ph
4g
4h
4i
8
Ph
9
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24c
2,4-Cl2C6H3 Et
Ph
4j
Figure 1 X-ray single crystal structure of 4r.
Furan-2-yl
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Ph
4k
4l
4-ClC6H4
In order to further demonstrate the application scope
of the protocol, the reactions utilizing ammonium salt as
hetero N resource have also been performed. To our
delight, a class of different 1,4-DHPs 6a－6e containing
free NH group were given when ammonium acetate was
subjected to react with ethyl propiolate and different
aryl aldehydes, albeit with moderate yields (Scheme 2).
These results further confirmed the general applicability
of the present method for 1,4-DHPs synthesis.
4-CH3OC6H4 4m
4-O2NC6H4
3-ClC6H4
4n
4o
2-CH3OC6H4 4p
2-IC6H4
2-BrC6H4
PhCH2
Cyclohexyl
i-Butyl
Ph
4q
4r
4s
In order to explore the possible functions of secon-
dary amine, the control experiments on reaction of al-
kyne with secondary amine and subsequent transforma-
tion of obtained intermediate with aldehyde and amines
have been carried out. As outlined in Scheme 3, the in-
corporation of piperazine with ethyl propiolate could be
easily performed to give enaminoester intermediate 7a.
The subsequent assembly of 7a with p-chlorobenzalde-
hyde and aniline under standard conditions without us-
ing secondary amine led to production of 1,4-DHP 4a in
72% yield. These data, together with the results shown
4t
4u
4v
4w
－
3-MeOC6H4 Me
Ph
Et Et
Ph
a Unless otherwise specified, the reaction conditions are: 1 (0.5
mmol), 2 (0.3 mmol) and 3 (0.3 mmol), TMSCl (1.5 equiv.) and
piperazine (0.5 equiv.) in 2 mL DMF, stirred at 90 ℃ for 12 h.
b Yield of purified products based on 1. c No reaction was ob-
served.
224
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Chin. J. Chem. 2014, 32, 219—226

Multicomponent Reactions for Diverse Synthesis of N-Substituted and NH 1,4-Dihydropyridines
Scheme
2
Multicomponent synthesis of NH-containing
Scheme 3 Function of secondary amines in the 1,4-DHPs syn-
1,4-DHPs
thesis
Ar
COOEt
COOEt
EtO2C
CO2Et
Ar
piperazine/TMSCl
DMF/90 oC
H
2
+
+ AcONH4
COOEt
N
CHO
N
N
DMF, r.t.
90%
N
H
6
+
1a
2
5
2
N
H
OMe
Cl
7a
COOEt
CHO
Cl
Br
TMSCl
PhNH2
7a
4a
+
+
EtO2C
CO2Et
DMF/90 oC
EtO2C
CO2Et
CO2Et
EtO2C
72%
N
H
N
H
N
6c, 49%
H
noesters 7. Under the activation of TMSCl, the nucleo-
philic intermediates 7 incorporated aldehydes to provide
8 via aldol-type reaction. Subsequently, the dehydration
condensation of 8 with another molecule of 7 generated
intermediates 9.[47] The transamination between N,N-di-
methylamino functionalized 9 and primary amines read-
ily ran at the acidic reaction conditions to provide in-
termediates 10.[48] And the intramolecular transamina-
tion of 10 finally led to the production of 1,4-DHPs as
products.
6b, 54%
6a, 45%
Cl
NO2
Cl
CO2Et
EtO2C
CO2Et
EtO2C
N
N
H
H
6d, 66%
6e, 40%
Conditions: 1a (0.5 mmol), 2 (0.3 mmol), 5 (0.3 mmol), TMSCl (1.5
equiv.) and piperazine (0.5 equiv.) in 2 mL DMF, stirred at 90 ℃
for 12 h. And the yields were reported as purified products based on
1.
Conclusions
In conclusion, a multicomponent tactic employing
alkyl propiolates, aldehydes and amines/ammonium has
been successfully established for the synthesis of di-
verse 1,4-DHPs. The key factor initiating the reaction
was the activation of secondary amine to the electron
deficient alkynes. This method allows the synthesis of
2,6-unsubstituted 1,4-DHPs starting from a variety of
different aldehydes, primary amines/ammonium and
alkyl propiolates. Considering the broad application
in Scheme 1, clearly proved that the enamine-type acti-
vation of secondary amine to electron deficient alkynes
was crucial for the present multicomponent reaction.[46]
A proposed mechanism for the present multicomponent
reactions involving the activation of secondary amine to
propiolates was outlined in Scheme 4. At first, the fast
addition of secondary amine to propiolates gave enami-
Scheme 4 Proposed reaction mechanism
Chin. J. Chem. 2014, 32, 219—226
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
225

Wan et al.
FULL PAPER
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The work is financially supported by the National
Natural Science Foundation of China (Nos. 21102059
and 21202064), a research project from the Department
of Education of Jiangxi Province (No. GJJ13245) as
well as a program sponsored by Zhejiang Provincial
Program for the Cultivation of High-level Innovative
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