Facile isocyanide-based one-pot three-component regioselective synthesis of highly substituted pyridin-2(1H)-one derivatives at ambient temperature

Article abstract of DOI:10.1016/j.tet.2012.03.124

A novel one-pot three-component regioselective synthesis of highly substituted pyridin-2-one derivatives starting from simple and readily available starting materials is described. The reactive zwitterionic intermediate generated by the addition of an isocyanide to dimethyl acetylenedicarboxylate (DMAD) was trapped with N-arylidene-2-cyanoacetohydrazides to afford the title compounds in moderate to good yields at room temperature without using any catalyst and other additives.

Full text of DOI:10.1016/j.tet.2012.03.124

Tetrahedron 68 (2012) 4838e4845
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile isocyanide-based one-pot three-component regioselective synthesis
of highly substituted pyridin-2(1H)-one derivatives at ambient temperature
*
*
Ming Li , Wei Kong, Li-Rong Wen , Fang-Hui Liu
State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel one-pot three-component regioselective synthesis of highly substituted pyridin-2-one de-
rivatives starting from simple and readily available starting materials is described. The reactive zwit-
terionic intermediate generated by the addition of an isocyanide to dimethyl acetylenedicarboxylate
(DMAD) was trapped with N-arylidene-2-cyanoacetohydrazides to afford the title compounds in mod-
erate to good yields at room temperature without using any catalyst and other additives.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 24 December 2011
Received in revised form 21 March 2012
Accepted 30 March 2012
Available online 13 April 2012
Keywords:
Multicomponent reactions
Isocyanides
DMAD
N-Arylidene-2-cyanoacetohydrazides
Pyridin-2-one derivatives
1. Introduction
The exploration of privileged structures in drug discovery is
a rapidly emerging theme in medicinal chemistry.9 Functionalized
The development of simple synthetic routes toward widely used
organic compounds from readily available starting materials is one
of the major tasks in organic synthesis. Multicomponent reactions
(MCRs), by virtue of their convergence, facile execution, and gen-
erally high yields of products, have attracted much attention from
the point of combinatorial chemistry.1,2
pyridin-2(1H)-ones and their dihydro- and tetrahydro derivatives,
as privileged heterocyclic scaffolds, represent an important class of
organic heterocycles for their presence in numerous natural
products and synthetic organic compounds with diverse bio-,
physio-, and pharmacological activities, such as antibacterial10 and
antifungal11 activities, anti-cancer/antitumor,12 and HIV-reverse
transcriptase inhibitors.13 Due to their diverse range of biological
activities, pyridin-2(1H)-ones are recognized as privileged struc-
tures making these structural motifs attractive targets for library
preparation.14
Though many literature reported synthetic approaches for pyr-
idin-2(1H)-ones,15 to the best of our knowledge, so far, there have
been no reports on the application of N-arylidene-2-
cyanoacetohydrazides along with isocyanides and DMAD to syn-
thesize pyridin-2-one derivatives. In continuing our interest in
IMCRs,16 and based on our previous endeavors in exploring novel
and practical MCRs to synthesize useful heterocyclic compounds,17
herein we outline a facile and efficient synthetic approach for the
construction of highly substituted pyridin-2(1H)-ones.
Moreover, the rich and fascinating chemistry that stems from
MCR provides a robust approach for the synthesis of diverse and
complex ‘drug-like’ heterocyclic compounds. Particularly,
isocyanide-based multicomponent reactions (IMCRs) have occu-
pied a major position in multicomponent reactions in recent years.3
The initially formed zwitterionic intermediate from DMAD and
isocyanides has been shown to undergo further reaction with dif-
ferent electrophilic reagents, leading to a variety of complex het-
erocyclic compounds. Due to the unique reactivity of the isocyanide
functional group, there are many reactions reported in the litera-
ture involving isocyanides and DMAD.4 These reactions have been
the subject of detailed investigation by a number of research
groups.5e7 Although significant progress has been made in IMCRs,8
there is still a high demand for new processes aimed at the rapid
assembly of heterocyclic molecules.
2. Results and discussion
Our approach toward the design and development of new
domino and multicomponent procedures involves the use of N-
arylidene-2-cyanoacetohydrazides 3 that contains a number of
chemically distinct functionalities, which could be selectively
* Corresponding authors. Tel.: þ86 0532 84022990; fax: þ86 0532 84023927;
e-mail addresses: liming928@qust.edu.cn (M. Li), wenlirong@qust.edu.cn (L.-R.
Wen).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.124

M. Li et al. / Tetrahedron 68 (2012) 4838e4845
4839
reacted with isocyanides 1 and DMAD 2 to generate molecular
diversity.
The zwitterionic intermediate [A] derived from isocyanides 1
and DMAD 2 could react with N-arylidene-2-cyanoacetohydrazides
3 in two manners (Scheme 1). In direction 1, the [A] captures the NH
Choosing an appropriate solvent is of crucial importance for the
successful synthesis. Firstly, we examined the effects of various
solvents on the reaction using 1a, 2, and 3a as model substrates at
room temperature without using any catalyst for 24 h (Table 1). The
results showed that the reaction did not occur in ethanol even
CN
CN
O
R1
N C
COOCH3
R1
N C
O
N
C
COOCH3
C
N
N
N CH
H3COOC
[A]
CH
H
H3COOC
[B]
direction 1
[C]
3
R2
R1
R2
R1
CN
CN
N
HN
O
O
5
C
C
2
N
N
C
H
N
N C
COOCH3
H3COOC
H3COOC
H
R2
R2
COOCH3
R1
N C
COOCH3
[D]
4 / 5
1
COOCH3
2
H
H
C
N
HN
C
R1
N C
N
HN
COOCH3
R2
R1
N C
O
R2
COOCH3
O
direction 2
CH
HC
H3COOC
[B]
H
CN
H3COOC
[A]
CN
[E]
3
HC
H
R1
N
C
R2
R1
HN
N
HN
N
N
R2
O
C
O
C
5
4
CN
COOCH3
H3COOC
CN
H3COOC
COOCH3
[F]
7 / 8
Scheme 1.
of 3 to produce [B], meanwhile the resulting anion [C] is produced
from 3, which would then react with the cation [B] through Michael
addition to give intermediate [D], which undergoes intramolecular
cyclization to deliver dimethyl 1-(arylideneamino)-5-cyano-4-
(alkylamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-dicarboxylates
4/5. In direction 2, however, the [A] abstracts a proton of methylene
of 3 to give [B], but the resulting anion [E] instead of [C] is obtained
from 3, which would then reacts with the cation [B] to give the in-
termediate [F], next, an intramolecular cyclization of [F] leads to the
formation of (Z)-dimethyl 1-(arylideneamino)-5-cyano-2-(alkyla-
mino)-6-oxo-1,4,5,6-tetrahydropyridine-3,4-dicarboxylates 7/8.
In our experiment, the reaction of cyclohexyl isocyanide 1a with
DMAD 2 and N-benzylidene-2-cyanoacetohydrazide 3a occurred
smoothly in CH2Cl2 at room temperature without any catalyst to af-
ford dimethyl 1-(benzylideneamino)-5-cyano-4-(cyclohexylamino)-
6-oxo-1,2,5,6-tetrahydropyridine-2,3-dicarboxylate 4a exclusively in
good yield of 70%. And the structure of 4awas deduced on the basis of
Table 1
Optimization of solvents for the synthesis of 4a
COOCH3
CN
N
C
HN
H3COOC
O
N
solvent
1a
COOCH3
2
O
C
r.t. 24 h
N
C
H
NC
COOCH3
4a
NHN
C
H
3a
Entry
Solvent
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
EtOH
24
24
24
24
24
24
24
d
1H NMR spectrum, where two singlets at
d¼4.73 and 5.51 ppm for 2-
MeOH
CH2Cl2
CH3CN
THF
Toluene
Acetone
18
70
55
65
40
30
CH and 5-CH were identified, respectively. Whereas two doublets for
4-CH and 5-CH due to coupling interaction should be observed if
another regioisomer7awouldbeformed. These results indicatedthat
the reaction proceeded as the direction 1 rather than the direction 2;
and also suggested that our three-component reaction is highly
regioselective.

4840
M. Li et al. / Tetrahedron 68 (2012) 4838e4845
though the reaction time was prolonged to 48 h (Table 1, entry 1);
and in methanol also gave only 18% yield (Table 1, entry 2). Then
CH2Cl2, acetonitrile, THF, toluene, and acetone were examined at
ambient temperature under catalyst-free conditions; the corre-
sponding product 4a was obtained in yields of 70%, 55%, 65%, 40%,
and 30%, respectively (Table 1, entries 3e7). It was then concluded
that CH2Cl2 was the optimal solvent for this reaction. However,
subsequently prolonging the reaction time cannot promote the
reaction. So the optimized conditions were CH2Cl2 as a solvent at
room temperature without using any catalyst.
To evaluate the use of this approach, a variety of 3 and 1 were
employed to react with 2 under the optimized conditions. Initially,
to test the scope of substrates 3, cyclohexyl isocyanide 1a and 2
were used as model substrates (Table 2, entries 1e19). As indicated
in Table 2, 3 bearing either electron-withdrawing or electron-
donating substituents on the aryl ring could be converted
The structures of the products 4/5 were deduced from their IR,
1H NMR, 13C NMR, and HRMS spectroscopic data. Take 4a, for ex-
ample. In its IR spectrum, a strong absorption at 2201 cmꢀ1 was
subject to C^N group. The two strong characteristic bands of ester
carbonyl groups were found at 1731 and 1686 cmꢀ1, respectively.
The carbonyl group on the tetrahydropyridine ring appeared at
1629 cmꢀ1 as a strong peak. The imine group was found at
1653 cmꢀ1 as a medium peak.
The 1H NMR spectrum of 4a consisted of a multiplet at
d
1.26e2.04 ppm for the cyclohexyl ring, two singlets at
3.78 ppm for two CH3O groups, a multiplet at 3.62 ppm for
cyclohexyl CH linked to NH, two singlets at 4.73, 5.51 ppm for
CHeCN, CHeCO2Me, respectively; the characteristic signals at
7.42e7.69 ppm for aromatic ring, a singlet at 7.83 ppm for CH]
N, and a broad singlet at
8.32 ppm for NH group. In the 13C NMR
spectrum, the peak at
d 3.73,
d
d
d
d
d
d
169.0 ppm was assigned to the carbonyl
Table 2
The synthesis of compounds 4aes and 5aeg
R1
CN
O
O
C
COOCH3
HN
CH2Cl2
r.t.
NC
R1
N C
NHN
C
H
N
N
C
H
R2
H3COOC
COOCH3
R2
COOCH3
1a-b
2
3
4/ 5
1a, R1 = cyclohexyl; 1b, R1 = ethoxycarbonylmethyl
Entry
1
3
R2
Product
Time (h)
Isolated
yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
H
4-F
4-Cl
4-Br
3-F
3-Cl
3-Br
2-F
4a
4b
4c
4d
4e
4f
4g
4h
4i
24
18
18
18
20
20
20
22
22
19
18
20
20
24
24
26
26
28
28
24
20
20
20
19
22
22
60
72
68
67
65
66
64
50
46
70
71
62
72
63
59
58
66
68
65
61
75
70
68
73
55
50
9
2-Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
2,3-Cl2
4-NO2
3-NO2
4-CF3
4-CH3
3-CH3
4-OCH3
3-OCH3
3,4-OCH3
3,4-OCH2O
H
4-F
4-Cl
3-F
4-NO2
4-CH3
4-OCH3
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
5a
5b
5c
5d
5e
5f
3s
3a
3b
3c
3e
3k
3n
3p
5g
smoothly to their corresponding products in good to excellent
yields. However, the position of substituents also has some in-
fluence on the reaction. The results suggested that the substituents
at para- and meta-positions afforded higher yields than those
counterparts at ortho-position (Table 2, entries 2, 5, and 8).
As for the isocyanide component of the multicomponent re-
action, we adopted initially cyclohexyl isocyanide, ethyl iso-
cyanideacetate. In all these cases, the reactions conducted smoothly
to give the corresponding products, respectively. The results are
summarized in Table 2.
resonance on the tetrahydropyridine ring. The two ester carbonyl
signals were visible at 156.9, 158.8 ppm, respectively. The cyano
carbon signal appeared at 117.3 ppm and the two methoxy car-
bons were observed at 52.3, 53.0 ppm, respectively. The signal at
55.4 was attributed to the carbon atom of cyclohexyl ring adjacent
to the nitrogen. All other signals were also in good agreement with
the proposed structure.
Encouraged by the success of the above reactions, we replaced
1a and 1b with tert-butyl isocyanide 1c to investigate this reaction
with 2 and 3a under the same conditions as described above.
d
d
d
d

M. Li et al. / Tetrahedron 68 (2012) 4838e4845
4841
Unfortunately, the intramolecular nucleophilic attack by the
methylene group on the activated allenyl moiety did not occur, and
the isolated compound was intermediate 6a. Then, other seven N-
arylidene-2-cyanoacetohydrazides 3 were employed to verify this
reaction (Table 3). The results were in accordance with 3a, which
may be subject to the steric hindrance of tert-butyl group.
The structures of the products 6 were characterized from their
IR, 1H NMR, and 13C NMR and HRMS spectra. The IR spectrum of 6a
exhibited a strong absorption at 2091 cmꢀ1 corresponding to N]
C]C stretching vibration. The mass spectrum of 6a displayed the
molecular ion ([MþH]þ) peak at m/z¼413.1815, which is consistent
with dimethyl 2-(2-benzylidene-1-(2-cyanoacetyl)hydrazinyl)-3-
((tert-butylimino)methylene)succinate.
procedure, mild reaction conditions, good functional group toler-
ance, highly regioselectivity, and moderate to good yields. Un-
doubtedly, this synthetic strategy opens a convenient, effective way
to construct the pyridin-2-one derivatives. We hope this approach
may be of value to others seeking novel synthetic fragments with
unique properties for medicinal chemistry.
4. Experimental section
4.1. General
All the reagents were purchased from local suppliers and used
without purification. Melting points were recorded on an RY-1
Table 3
The synthesis of compounds 6aeh
COOCH3
O
O
H3COOC
CN
CH2Cl2
r.t.
NC
C
N
N C
N=CH
COOCH3
NHN CH
N
C
COOCH3
R2
1c
R2
2
3
6
Entry
3
R2
Product
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3g
3h
3l
H
6a
6b
6c
6d
6e
6f
24
20
20
20
20
21
20
24
70
76
74
71
67
65
68
65
4-F
4-Cl
4-Br
3-Br
2-F
3-NO2
4-OCH3
6g
6h
3p
The structures of all compounds
6
were unequivocally
microscopic melting apparatus and uncorrected. 1H NMR spectra
were recorded on 500 MHz and 13C NMR spectra were recorded on
125 MHz in CDCl3 or DMSO-d6 by using a Bruker Avance 500
established by X-ray monocrystal diffraction analysis of 6g (Fig.1).18
spectrometer. Chemical shifts are reported in
TMS as internal standard. IR spectra were recorded on a Nicolet iS10
FT-IR spectrometer and only major peaks are reported in cmꢀ1
d (ppm) relative to
.
HRMS were performed on Ultima Global and Varian spectrometer
with an ESI source. The X-ray single-crystal diffraction was per-
formed on Rigaku Saturn 724þ CCD instrument. The N-arylidene-2-
cyanoacetohydrazides 3 were synthesized by the aromatic alde-
hydes and 2-cyanoacetohydrazide.19
4.2. General procedure for the preparation of products 4aes,
5aeg, and 6aeh
A mixture of isocyanides 1 (1.0 mmol), DMAD 2 (1.0 mmol), and
N-arylidene-2-cyanoacetohydrazides 3 (1.0 mmol) was stirred in
CH2Cl2 for the appropriate reaction time at room temperature. After
completion of the reaction, as indicated by TLC The solvent was
removed under vacuum, and the residue was separated by column
chromatography (silica gel, petroleum ether/EtOAc, 8:1, v/v) to give
the product 4aes, 5aeg, and 6aeh.
Fig. 1. The X-ray crystal structure of 6g.
4.2.1. Dimethyl 1-(benzylideneamino)-5-cyano-4-(cyclohexylamino)-
6-oxo-1,2,5,6-tetrahydropyridine-2,3-dicarboxylate
(4a). White
powder, mp 185e187 ꢁC; IR (KBr, cmꢀ1): 3447, 2930, 2851, 2201, 1731,
1686, 1629, 1467, 1411, 1324, 1283, 1099, 774, 721, 690; dH (500 MHz,
CDCl3): 1.26e2.04 (m, 10H, 5ꢂ CH2 of cyclohexyl), 3.73 (s, 3H, OCH3),
3.78 (s, 3H, OCH3), 3.90 (m, 1H, CH of cyclohexyl), 4.73 (s, 1H, CHeCN),
5.51 (s,1H, CHeCOO), 7.42e7.69 (m, 5H, ArH), 7.83 (s,1H, CH]N), 8.32
(s, 1H, NH); dC (125 MHz, CDCl3): 24.3, 25.2, 33.3, 33.8, 50.8, 51.2, 52.2,
3. Conclusion
In conclusion, we have successfully described a novel one-pot
three-component reaction for the synthesis of highly substituted
pyridin-2-one derivatives. The present procedure has advantages,
such as the ready availability of the starting materials, easy workup

4842
M. Li et al. / Tetrahedron 68 (2012) 4838e4845
53.0, 55.4, 70.5,117.3,127.5,128.8,130.7,133.3,142.9,156.9,158.8,166.8,
169.0; HRMS (ESI-TOF, [MþH]þ): calcd for C23H27N4O5, 439.1981;
found, 439.1969.
51.3, 52.4, 53.2, 56.1, 70.5, 117.0, 125.8, 127.3, 130.1, 130.6, 135.1,
135.2, 141.2, 156.9, 158.6, 166.8, 168.8; HRMS (ESI-TOF, [MþH]þ):
calcd for C23H26ClN4O5, 473.1592; found, 473.1586.
4 . 2 . 2 . D i m e t hyl 5 - c ya n o - 4 -( c y c l o h e x yl a m i n o ) - 1 - ( 4 -
fluorobenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-di-
carboxylate (4b). White powder, mp 186e188 ꢁC; IR (KBr, cmꢀ1):
3446, 2937, 2854, 2209, 1738, 1691, 1508, 1463, 1412, 1329, 1286, 1200,
1098, 838, 776, 728; dH (500 MHz, CDCl3): 1.22e2.07 (m,10H, 5ꢂ CH2 of
cyclohexyl), 3.73 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.94 (m, 1H, CH of
cyclohexyl), 4.70 (s, 1H, CHeCN), 5.48 (s, 1H, CHeCOO), 7.09e7.13 (t,
J¼8.5 Hz, 2H, ArH), 7.66e7.69 (m, 2H, ArH), 7.81 (s,1H, CH]N), 8.31 (s,
1H, NH); dC (125 MHz, CDCl3): 24.3, 25.2, 33.3, 33.7, 50.8, 51.2, 52.4, 53.0,
55.5, 70.6,116.0 (d, 2JCF¼22 Hz), 117.1, 129.4 (d, 3JCF¼8.0 Hz),129.6,141.8,
4.2.7. Dimethyl
1-(3-bromobenzylideneamino)-5-cyano-4-(cyclo-
hexylamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-dicarboxylate
(4g). White powder, mp 170e171 ꢁC; IR (KBr, cmꢀ1): 3446, 2929,
2848, 2201, 1731, 1687, 1634, 1459, 1408, 1322, 1099, 787, 775,
726; dH (500 MHz, CDCl3): 1.36e2.08 (m, 10H, 5ꢂ CH2 of
cyclohexyl), 3.78 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.97 (m, 1H,
CH of cyclohexyl), 4.78 (s, 1H, CHeCOO), 5.53 (s, 1H, CHeCN),
7.30e7.79 (m, 4H, ArH), 7.86 (s, 1H, CH]N), 8.32 (s, 1H, NH); dC
(125 MHz, CDCl3): 24.3, 25.2, 33.3, 33.8, 50.8, 51.2, 52.3, 53.1,
56.0, 70.4, 117.0, 123.0, 126.1, 130.2, 130.3, 133.5, 135.4, 141.0,
156.8, 158.5, 166.7, 168.7; HRMS (ESI-TOF, [MþH]þ): calcd for
C23H26BrN4O5, 517.1087; found, 517.1061.
1
156.9, 158.7, 164.2 (d, JCF¼251 Hz), 166.8, 168.9; HRMS (ESI-TOF,
[MþNa]þ): calcd for C23H25FN4O5Na, 479.1701; found, 479.1698.
4.2.3. Dimethyl
1-(4-chlorobenzylideneamino)-5-cyano-4-(cyclo-
4 . 2 . 8 . D i m e t hyl 5 - c ya n o - 4 - ( c y c l o h e x yl a m i n o ) - 1 - ( 2 -
fluorobenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-di-
carboxylate (4h). White powder, mp 180e182 ꢁC; IR (KBr, cmꢀ1):
3442, 2932, 2856, 2208, 1746, 1691, 1636, 1460, 1408, 1294, 1097,
762; dH (500 MHz, CDCl3): 1.23e2.07 (m, 10H, 5ꢂ CH2 of
cyclohexyl), 3.74 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.94 (m, 1H,
CH of cyclohexyl), 4.73 (s, 1H, CHeCN), 5.52 (s, 1H, CHeCOO),
7.11 (t, J¼9.0 Hz, 1H, ArH), 7.20 (t, J¼7.5 Hz, 1H, ArH), 7.40 (q,
J¼6.5 Hz, 1H, ArH), 7.88 (t, J¼7.0 Hz, 1H, ArH), 8.07 (s, 1H, CH]
N), 8.29 (s, 1H, NH); dC (125 MHz, CDCl3): 24.3, 25.2, 33.3, 33.8,
hexylamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-dicarboxylate
(4c). White powder, mp 185e187 ꢁC; IR (KBr, cmꢀ1): 3263, 2930,
2856, 2206, 1746, 1727, 1690, 1635, 1461, 1408, 1294, 1097, 762; dH
(500 MHz, CDCl3): 1.20e2.07 (m, 10H, 5ꢂ CH2 of cyclohexyl), 3.71
(s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.94 (m,1H, CH of cyclohexyl), 4.71
(s, 1H, CHeCN), 5.49 (s, 1H, CHeCOO), 7.39e7.40 (d, J¼8.0 Hz, 2H,
ArH), 7.61e7.63 (d, J¼8.0 Hz, 2H, ArH), 7.79 (s, 1H, CH]N), 8.31 (s,
1H, NH); dC (125 MHz, CDCl3): 24.3, 25.2, 33.3, 33.8, 50.8, 51.2, 52.4,
53.0, 55.7, 70.5, 117.0, 128.6, 129.1, 131.9, 136.7, 141.2, 156.9, 158.6,
166.8, 168.8; HRMS (ESI-TOF, [MþNa]þ): calcd for C23H25ClN4O5Na,
495.1406; found, 495.1404.
2
50.8, 51.2, 52.2, 53.0, 55.8, 70.6, 115.9 (d, JCF¼21 Hz), 117.0, 121.3
3
3
(d, JCF¼9.2 Hz), 124.5, 126.8, 132.1 (d, JCF¼8.0 Hz), 136.0, 156.9,
1
158.7, 161.5 (d, JCF¼251 Hz), 166.8, 168.8; HRMS (ESI-TOF,
4.2.4. Dimethyl
1-(4-bromobenzylideneamino)-5-cyano-4-(cyclo-
[MþNa]þ): calcd for C23H25FN4O5Na, 479.1701; found, 479.1703.
hexylamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-dicarboxylate
(4d). White powder, mp 193e197 ꢁC; IR (KBr, cmꢀ1): 3445,
2930, 2851, 2204, 1731, 1687, 1636, 1468, 1411, 1324, 1289, 1098,
819, 774, 722; dH (500 MHz, CDCl3): 1.20e2.07 (m, 10H, 5ꢂ CH2
of cyclohexyl), 3.73 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.93 (m,
1H, CH of cyclohexyl), 4.89 (s, 1H, CHeCN), 5.75 (s, 1H,
CHeCOO), 7.54 (s, 4H, ArH), 7.77 (s, 1H, CH]N), 8.32 (s, 1H,
NH); dC (125 MHz, CDCl3): 24.3, 25.2, 33.3, 33.8, 50.8, 51.2, 52.3,
53.2, 55.7, 70.5, 117.1, 125.1, 128.9, 132.1, 132.3, 141.5, 156.8, 158.6,
166.8, 168.9; HRMS (ESI-TOF, [MþH]þ): calcd for C23H26BrN4O5,
517.1087; found, 517.1093.
4.2.9. Dimethyl
1-(2-chlorobenzylideneamino)-5-cyano-4-(cyclo-
hexylamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-dicarboxylate
(4i). White powder, mp 182e184 ꢁC; IR (KBr, cmꢀ1): 3448, 2944,
2851, 2204, 1739, 1692, 1626, 1462, 1414, 1321, 1299, 1103, 760, 718;
dH (500 MHz, CDCl3): 1.28e1.80 (m, 10H, 5ꢂ CH2 of cyclohexyl),
3.79 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.97 (m, 1H, CH of cyclo-
hexyl), 4.77 (s, 1H, CHeCN), 5.54 (s, 1H, CHeCOO) 7.30e7.96(m,
4H, ArH), 8.28 (s, 1H, CH]N), 8.32 (s, 1H, NH); dC (125 MHz,
CDCl3): 24.3, 25.2, 33.3, 33.8, 50.8, 51.2, 52.5, 53.0, 55.9, 70.4, 117.1,
127.2, 127.4, 129.9, 130.9, 131.5, 134.6, 139.5, 156.8, 158.7, 166.8,
168.9; HRMS (ESI-TOF, [MþH]þ): calcd for C23H26ClN4O5, 473.1592;
found, 473.1599.
4 . 2 . 5 . D i m e t hyl 5 - c ya n o - 4 -( c y c l o h e x yl a m i n o ) - 1 - ( 3 -
fluorobenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-di-
carboxylate (4e). White powder, mp 182e184 ꢁC; IR (KBr, cmꢀ1):
3446, 2930, 2860, 2201, 1735, 1687, 1630, 1467, 1410, 1326, 1268,
1221, 1101, 775, 723; dH (500 MHz, CDCl3): 1.26e2.04 (m, 10H, 5ꢂ
CH2 of cyclohexyl), 3.74 (s, 3H, OCH3),3.78 (s, 3H, OCH3), 3.95 (m,
1H, CH of cyclohexyl), 4.73 (s, 1H, CHeCN), 5.49 (s, 1H, CHeCOO),
7.11e7.13 (m, 1H, ArH), 7.36e7.43 (m, 3H, ArH), 8.14 (s, 1H, CH]N),
8.33 (s, 1H, NH); dC (125 MHz, CDCl3): 24.3, 25.2, 33.3, 33.9, 50.8,
4.2.10. Dimethyl 5-cyano-4-(cyclohexylamino)-1-(3,4-
dichlorobenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine -2,3-
dicarboxylate (4j). White powder, mp 190e193 ꢁC; IR (KBr,
cmꢀ1): 3440, 2933, 2856, 2208, 1743, 1691, 1636, 1462, 1409,
1297, 1100, 775; dH (500 MHz, CDCl3): 1.22e2.07 (m, 10H, 5ꢂ
CH2 of cyclohexyl), 3.74 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.95
(m, 1H, CH of cyclohexyl), 4.73 (s, 1H, CHeCN), 5.49 (s, 1H,
CHeCOO), 7.49e7.53 (m, 2H, ArH), 7.73(s, 1H, ArH), 7.77 (s, 1H,
CH]N), 8.32 (s, 1H, NH); dC (125 MHz, CDCl3): 24.3, 25.2, 33.2,
33.8, 50.8, 51.3, 52.4, 53.2, 56.2, 70.3, 116.9, 126.3, 129.0, 130.9,
133.4, 134.7, 139.9, 156.8, 158.4, 166.8, 168.7; HRMS (ESI-TOF,
[MþH]þ): calcd for C24H25Cl2N4O5, 507.1202; found, 507.1215.
2
51.3, 52.3, 53.1, 55.9, 70.6, 113.6 (d, JCF¼22 Hz), 117.0, 117.6 (d,
2JCF¼21 Hz), 123.7, 130.5, 135.6, 141.2, 156.8, 158.6, 163.0 (d,
1JCF¼246 Hz), 166.8, 168.8; HRMS (ESI-TOF, [MþNa]þ): calcd for
C23H25FN4O5Na, 479.1701; found, 479.1705.
4.2.6. Dimethyl
1-(3-chlorobenzylideneamino)-5-cyano-2-(cyclo-
hexylamino)-6-oxo-1,4,5,6-tetrahydropyridine-3,4-dicarboxylate
(4f). White powder, mp 186e182 ꢁC; IR (KBr, cmꢀ1): 3448, 2930,
2859, 2201, 1731, 1687, 1630, 1467, 1409, 1324, 1101, 775, 719; dH
(500 MHz, CDCl3): 1.36e2.05 (m, 10H, 5ꢂ CH2 of cyclohexyl), 3.75
(s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.98 (m,1H, CH of cyclohexyl), 4.75
(s, 1H, CHeCN), 5.50 (s, 1H, CHeCOO), 7.35e7.41 (m, 2H, ArH),
7.55e7.56 (d, J¼7.5 Hz, 1H, ArH), 7.68 (s, 1H, ArH), 7.77 (s, 1H, CH]
N), 8.31 (s, 1H, NH); dC (125 MHz, CDCl3): 24.4, 25.3, 33.4, 33.8, 50.9,
4. 2.11. Dimethyl 5-c ya no-4- (cyc lohexyl amino)-1-(4-
nitrobenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-di-
carboxylate (4k). Yellow powder, mp 201e202 ꢁC; IR (KBr, cmꢀ1):
3446, 2933, 2853, 2208, 1736, 1693, 1637, 1521, 1460, 1405, 1342,
1142, 1102, 845; dH (500 MHz, CDCl3): 1.19e2.11 (m, 10H, 5ꢂ CH2 of
cyclohexyl), 3.76 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.94 (m,1H, CH of
cyclohexyl), 4.78 (s, 1H, CHeCN), 5.55 (s, 1H, CHeCOO), 7.84e8.29
(m, 5H, ArH, CH]N), dC (125 MHz, DMSO-d6): 24.7, 25.1, 33.0, 33.5,

M. Li et al. / Tetrahedron 68 (2012) 4838e4845
4843
51.2, 51.7, 51.8, 53.7, 55.6, 72.3, 117.7, 124.4, 129.2, 140.2, 142.7, 148.6,
156.9, 159.2, 166.6, 169.0; HRMS (ESI-TOF, [MþH]þ): calcd for
C23H26N5O7, 484.1832; found, 484.1845.
ArH), 7.81 (s,1H, CH]N),8.31(s,1H,NH);dC (125MHz, DMSO-d6): 24.6,
25.1, 33.0, 33.4, 51.0, 51.6, 51.7, 53.5, 53.7, 55.8, 72.2, 118.2, 126.5, 129.9,
133.7, 145.5, 156.8, 159.5, 161.7, 166.5, 169.4; HRMS (ESI-TOF, [MþH]þ):
calcd for C24H29N4O6, 469.2087; found, 469.2066.
4. 2.12. Dimethyl 5-cyano-4-(cyclohexylamino)-1-(3-
nitrobenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-di-
carboxylate (4l). Yellow powder, mp 169e170 ꢁC; IR (KBr, cmꢀ1):
3447, 2930, 2854, 2206, 1731, 1687, 1638, 1532, 1471, 1410, 1383,
1287,1103, 774, 725; dH (500 MHz, DMSO-d6): 1.33e2.01 (m,10H, 5ꢂ
CH2 of cyclohexyl), 3.67 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.82 (m,1H,
CH of cyclohexyl), 5.04 (s,1H, CHeCN), 5.82 (s,1H, CHeCOO), 7.73 (t,
J¼8.0 Hz, 1H, ArH), 8.12e8.13 (d, J¼7.0 Hz, 1H, ArH), 8.25e8.28 (dd,
J1¼8.0 Hz, J2¼1.5 Hz, 1H, ArH), 8.33e8.34(d, J¼7.5 Hz, 1H, ArH), 8.40
(s, 1H, CH]N), 8.61 (s, 1H, NH); dC (125 MHz, DMSO-d6): 24.7, 25.1,
33.0, 33.5, 51.2, 51.7, 51.8, 53.7, 55.3, 72.5, 117.7, 123.3, 125.2, 130.8,
133.4, 135.9, 143.2, 148.7, 156.9, 159.3, 166.6, 169.1; HRMS (ESI-TOF,
[MþH]þ): calcd for C23H26N5O7, 484.1832; found, 484.1845.
4. 2.17. Dimethyl 5-cyano-4-(cyclohexylamino)-1-(3-
methoxybenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-
dicarboxylate (4q). White powder, mp 169e170 ꢁC; IR (KBr, cmꢀ1):
3450, 2930, 2857, 2202, 1732, 1687, 1635, 1467, 1410, 1322, 1285, 1099,
784, 775, 729; dH (500 MHz, CDCl3): 1.26e2.08 (m, 10H, 5ꢂ CH2 of
cyclohexyl), 3.78 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.91 (s, 3H, m-OCH3),
3.98 (m, 1H, CH of cyclohexyl), 4.76 (s, 1H, CHeCN), 5.54 (s, 1H,
CHeCOO), 7.00e7.02 (m, 1H, ArH), 7.26e7.30 (m, 2H, ArH), 7.35e7.38
(m,1H, ArH), 7.83 (s,1H, CH]N), 8.36 (s,1H, NH); dC (125 MHz, CDCl3):
24.3, 25.2, 33.3, 33.8, 50.8, 51.3, 52.2, 53.1, 55.3, 55.4, 70.6, 111.7, 117.0,
117.3, 120.0, 129.9, 134.6, 142.8, 156.8, 158.7, 159.9, 166.8, 169.0; HRMS
(ESI-TOF, [MþH]þ): calcd for C24H29N4O6, 469.2087; found, 469.2073.
4.2.13. Dimethyl
5-cyano-4-(cyclohexylamino)-6-oxo-1-(4-(tri-
4.2.18. Dimethyl 5-cyano-4-(cyclohexylamino)-1-(3,4-
dimethoxybenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-
dicarboxylate (4r). White powder, mp 110e112 ꢁC; IR (KBr, cmꢀ1):
3425, 2935, 2856, 2206, 1748, 1639, 1539, 1514, 1266, 1167, 1144, 1024,
813, 745; dH (500 MHz, CDCl3): 1.22e1.98 (m, 10H, 5ꢂ CH2 of cyclo-
hexyl), 3.36 (m, 1H, CH of cyclohexyl), 3.76 (s, 3H, OOCH3), 3.83 (s, 3H,
OOCH3), 3.91 (s, 3H, ArOCH3), 3.94 (s, 3H, ArOCH3), 4.39 (s,1H, CHeCN),
5.23 (s, 1H, CHeCOO), 6.85e6.87 (d, J¼8.0 Hz, 1H, ArH), 7.13e7.16 (dd,
J1¼8.0 Hz, J2¼1.5 Hz, 1H, ArH), 7.34 (s, 1H, CH]N), 9.12 (s, 1H, NH); dC
(125 MHz, CDCl3):24.8, 33.1, 34.4, 44.1, 53.6, 53.9, 55.9, 63.4,108.5,110.7,
115.9, 122.6, 127.7, 149.2, 151.2, 153.7, 158.3, 160.4, 166.3, 169.8; HRMS
(ESI-TOF, [MþH]þ): calcd for C25H31N4O7, 499.2193; found, 499.2185.
fluoromethyl)benzylideneamino)-1,2,5,6-tetrahydro pyridine-2,3-
dicarboxylate (4m). White powder, mp 196e198 ꢁC; IR (KBr,
cmꢀ1): 3445, 2930, 2860, 2208, 1731, 1688, 1610, 1468, 1410, 1325,
1101, 1067, 837, 755, 725; dH (500 MHz, DMSO-d6): 1.17e1.93 (m,
10H, 5ꢂ CH2 of cyclohexyl), 3.66 (s, 3H, OCH3), 3.69 (s, 3H, OCH3),
3.76 (m, 1H, CH of cyclohexyl), 5.01 (s, 1H, CHeCN), 5.83 (s, 1H,
CHeCOO), 7.78e7.79 (d, J¼8.0 Hz, 2H, ArH), 8.03e8.05 (d, J¼8.0 Hz,
2H, ArH), 8.14 (s, 1H, NH), 8.29 (s, 1H, CH]N); dC (125 MHz, DMSO-
d6): 24.7, 25.1, 33.0, 33.5, 51.1, 51.7, 53.6, 55.2, 72.3,117.8,123.4,126.1,
128.8, 130.5, 137.9, 143.5, 156.8, 159.3, 166.6, 169.1; HRMS (ESI-TOF,
[MþH]þ): calcd for C24H26F3N4O5, 507.1855; found, 507.1859.
4. 2.14. Dimethyl 5-cyano-4-(cyclohexylamino)-1-(4-
methylbenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-
dicarboxylate (4n). White powder, mp 168e170 ꢁC; IR (KBr, cmꢀ1):
3440, 2931, 2857, 2205,1745,1731,1690,1634,1463,1410,1320,1286,
1099, 815, 775, 720; dH (500 MHz, CDCl3): 1.37e2.07 (m,10H, 5ꢂ CH2
of cyclohexyl), 2.38 (s, 3H, CH3), 3.73 (s, 3H, OCH3), 3.77 (s, 3H, OCH3),
3.94 (m, 1H, CH of cyclohexyl), 4.71 (s, 1H, CHeCN), 5.49 (s, 1H,
CHeCOO), 7.21e7.23 (d, J¼8.0 Hz, 2H, ArH), 7.56e7.68 (d, J¼8.5 Hz,
2H, ArH), 7.81 (s, 1H, CH]N) 8.31 (s, 1H, NH); dC (125 MHz, CDCl3):
21.5, 24.3, 25.2, 33.3, 33.8, 50.8, 51.2, 52.2, 53.0, 55.1, 70.5,117.4,127.5,
129.6, 130.6, 141.2, 143.2, 156.9, 158.8, 166.9, 169.1; HRMS (ESI-TOF,
[MþNa]þ): calcd for C24H28N4O5Na, 475.1952; found, 475.1950.
4.2.19. Dimethyl 1-(benzo[d][1,3]dioxol-5-ylmethyleneamino)-5-
cyano-4-(cyclohexylamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-
dicarboxylate (4s). White powder, mp 138e140 ꢁC; IR (KBr, cmꢀ1):
3442, 2950, 2859, 2204, 1742, 1652, 1607, 1452, 1400, 1256, 1151, 1033,
818, 742; dH (500 MHz, CDCl3): 1.19e1.97 (m, 10H, 5ꢂ CH2 of cyclo-
hexyl), 3.35 (m, 1H, CH of cyclohexyl), 3.77 (s, 3H, OCH3), 3.81 (s, 3H,
OCH3), 4.38 (s, 1H, CHeCN), 5.18 (s, 1H, CHeCOO), 6.85e6.87 (m, 3H,
ArH,CH2), 6.78e6.79 (d, J¼8.0 Hz, 1H, ArH), 7.03e7.04 (dd, J1¼8.0 Hz,
J2¼1.5 Hz, 1H, ArH), 7.29 (s, 1H, CH]N), 9.12 (s, 1H, NH); dC (125 MHz,
CDCl3): 24.6, 24.8, 32.9, 34.2, 53.6, 53.7, 60.3, 63.6, 101.3, 105.6, 108.1,
115.5, 124.1, 129.4, 148.1, 149.5, 153.1, 158.5, 160.5, 166.2, 169.7; HRMS
(ESI-TOF, [MþH]þ): calcd for C24H27N4O7, 483.1880; found, 483.1879.
4. 2.15. Dimethyl 5-cyano-4-(cyclohexylamino)-1-(3-
methylbenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-di-
carboxylate (4o). White powder, mp 186e182 ꢁC; IR (KBr, cmꢀ1):
3448, 2930, 2859, 2201, 1732, 1689, 1633, 1467, 1410, 1324, 1101,
775, 724; dH (500 MHz, DMSO-d6): 1.21e2.08 (m, 10H, 5ꢂ CH2 of
cyclohexyl), 2.40 (s, 3H, CH3), 3.65 (s, 3H, OCH3), 3.70 (s, 3H, OCH3),
3.77 (m, 1H, CH of cyclohexyl), 4.93 (s, 1H, CHeCN), 5.78 (s, 1H,
CHeCOO), 7.25e7.27 (d, J¼8.0 Hz, 1H, ArH), 7.32 (t, J¼7.5 Hz, 1H,
ArH), 7.59e7.61 (d, J¼7.5 Hz, 1H, ArH), 7.66 (s, 1H, CH]N), 8.14 (s,
1H, NH); dC (125 MHz, DMSO-d6): 21.3, 24.7, 25.2, 33.0, 33.5, 51.1,
51.7, 53.6, 54.5, 72.2, 117.9, 125.6, 128.5, 129.2, 131.8, 133.9, 138.6,
145.5, 156.9, 159.5, 166.6, 169.3; HRMS (ESI-TOF, [MþH]þ): calcd for
C24H29N4O5, 453.2138; found, 453.2145.
4.2.20. Dimethyl 1-(benzylideneamino)-5-cyano-4-(2-ethoxy-2-
oxoethylamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-dicarboxylate
(5a). White powder, mp 159e161 ꢁC; IR (KBr, cmꢀ1): 3435, 2982,
2955, 2206, 1742, 1694, 1637, 1474, 1412, 1208, 1110, 758, 694; dH
(500 MHz, CDCl3): 1.31 (t, J¼7.0 Hz, 3H, CH3), 3.81 (s, 3H, OCH3),
3.90 (s, 3H, OCH3), 4.15e4.19 (dd, J1¼6.0 Hz, J2¼18.5 Hz, 1H, C(O)
CH2N), 4.27 (q, J¼7.0 Hz, 2H, OCH2), 4.32e4.37 (dd, J1¼6.0 Hz,
J2¼18.5 Hz, 1H, C(O)CH2N), 4.74 (s, 1H, CHeCN), 5.53 (s, 1H,
CHeCOO), 7.41e7.43 (m, 3H, ArH), 7.67e7.69 (m, 2H, ArH), 7.84 (s,
1H, CH]N), 8.62 (s, 1H, NH); dC (125 MHz, CDCl3): 14.1, 42.8, 51.7,
52.2, 53.2, 55.8, 62.0, 72.7, 117.1, 127.6, 128.9, 130.8, 133.2, 143.1,
158.4, 166.5, 168.8, 168.9, 171.2; HRMS (ESI-TOF, [MþH]þ): calcd for
C21H23N4O7, 443.1567; found, 443.1576.
4. 2.16. Dimethyl 5-cyano-4-(cyclohexylamino)-1-(4-
methoxybenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-
dicarboxylate (4p). White powder, mp 201e202 ꢁC; IR (KBr, cmꢀ1):
3443, 2931, 2851, 2201, 1744, 1729, 1688, 1634, 1515, 1466, 1412, 1324,
1254, 1099, 830; dH (500 MHz, CDCl3): 1.35e2.05 (m, 10H, 5ꢂ CH2 of
cyclohexyl), 3.74 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.84 (s, 3H, ArOCH3),
3.94 (m, 1H, CH of cyclohexyl), 4.68 (s, 1H, CHeCN), 5.47 (s, 1H,
CHeCOO), 6.93e6.94 (d, J¼8.5 Hz, 2H, ArH), 7.62e7.64(d, J¼8.5 Hz, 2H,
4.2.21. Dimethyl 5-cyano-4-(2-ethoxy-2-oxoethylamino)-1-(4-
fluorobenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-
dicarboxylate (5b). White powder, mp 170e173 ꢁC; IR (KBr, cmꢀ1):
3435, 2982, 2850, 2206, 1744, 1691, 1636, 1474, 1408, 1233, 1112,
839; dH (500 MHz, CDCl3): 1.31 (t, J¼7.0 Hz, 3H, CH3), 3.73 (s, 3H,
OCH3), 3.81 (s, 3H, OCH3), 4.14e4.19 (dd, J1¼5.7 Hz, J2¼18.5 Hz, 1H,
C(O)CH2N), 4.28 (q, J¼7.0 Hz, 2H, OCH2), 4.32e4.37 (dd, J1¼5.7 Hz,
J2¼18.5 Hz, 1H, C(O)CH2N), 4.71 (s, 1H, CHeCN), 5.50 (s, 1H,

4844
M. Li et al. / Tetrahedron 68 (2012) 4838e4845
CHeCOO), 7.09e7.12 (m, 2H, ArH), 7.66e7.69 (m, 2H, ArH), 7.82 (s,
1H, CH]N), 8.64 (s, 1H, NH); dC (125 MHz, CDCl3): 14.1, 42.9, 51.6,
dicarboxylate (5g). White powder, mp 173e175 ꢁC; IR (KBr, cmꢀ1):
3439, 2955, 2920, 2208, 1737, 1693, 1637, 1515, 1473, 1411, 1254, 1111,
832; dH (500 MHz, CDCl3): 1.32 (t, J¼7.5 Hz, 3H, CH3), 3.73 (s, 3H, OCH3),
3.81 (s, 3H, OCH3), 3.85 (s, 3H, AreOCH3), 4.15e4.20 (dd, J1¼5.7 Hz,
J2¼18.2 Hz,1H, C(O)CH2N), 4.28 (q, J¼7.5 Hz, 2H, OCH2), 4.32e4.37 (dd,
J1¼5.7 Hz, J2¼18.2 Hz, 1H, C(O)CH2N), 4.69 (s, 1H, CHeCN), 5.49 (s, 1H,
CHeCOO), 6.92e6.94 (d, J¼9.0 Hz, 2H, ArH), 7.62e7.64(d, J¼9.0 Hz, 2H,
ArH), 7.82 (s, 1H, CH]N), 8.65 (s, 1H, NH); dC (125 MHz, CDCl3): 14.1,
42.9, 51.5, 52.4, 53.1, 55.2, 55.4, 62.0, 73.0,114.4,117.3,126.0,129.3,143.7,
145.2, 157.0, 158.5, 161.9, 166.5, 168.9; HRMS (ESI-TOF, [MþH]þ): calcd
for C22H25N4O8, 473.1672; found, 473.1685.
2
52.4, 53.2, 55.9, 62.0, 72.9, 116.1 (d, JCF¼22 Hz), 116.9, 129.5(2c),
142.0, 158.3, 164.2 (d, 1JCF¼250 Hz), 166.4, 168.8, 168.9, 171.1; HRMS
(ESI-TOF, [MþH]þ): calcd for C21H22FN4O7, 461.1473; found,
461.1462.
4.2.22. Dimethyl 1-(4-chlorobenzylideneamino)-5-cyano-4-(2-
ethoxy-2-oxoethylamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-
dicarboxylate (5c). White powder, mp 179e180 ꢁC; IR (KBr, cmꢀ1):
3442, 2954, 2852, 2208,1741,1695,1636,1474,1408,1210,1111, 822;
dH (500 MHz, CDCl3): 1.32 (t, J¼7.0 Hz, 3H, CH3), 3.81 (s, 3H, OCH3),
3.88 (s, 3H, OCH3), 4.15e4.19 (dd, J1¼5.7 Hz, J2¼18.0 Hz, 1H, C(O)
CH2N), 4.28 (q, J¼7.0 Hz, 2H, OCH2), 4.33e4.38 (dd, J1¼5.7 Hz,
J2¼18.0 Hz, 1H, C(O)CH2N), 4.73 (s, 1H, CHeCN), 5.51 (s, 1H,
CHeCOO), 7.39e7.40 (d, J¼8.5 Hz, 2H, ArH), 7.61e7.63 (d, J¼8.0 Hz,
2H, ArH), 7.86 (s, 1H, CH]N) 8.62 (s, 1H, NH); dC (125 MHz, CDCl3):
14.1, 42.9, 51.6, 52.4, 53.3, 56.1, 62.0, 72.8, 116.9, 128.7, 129.2, 131.8,
136.8, 141.8, 146.3, 158.3, 166.4, 168.7, 168.9; HRMS (ESI-TOF,
[MþH]þ): calcd for C21H22ClN4O7, 477.1177; found, 477.1189.
4.2.27. (E)-Dimethyl
2-(2-benzylidene-1-(2-cyanoacetyl)hydra-
zinyl)-3-((tert-butylimino)methylene)succinate (6a). White powder,
mp 119e121 ꢁC; IR (KBr, cmꢀ1): 2979, 2261, 2091, 1761, 1701, 1624,
1429, 1369, 1106, 1013, 872, 794, 757, 689; dH (500 MHz, DMSO-d6),
1.40 ( s, 9H, C(CH3)3), 3.60 ( s, 3H, OCH3), 3.65 ( s, 3H, OCH3), 4.41 (s,
2H, CH2eCN), 6.12 (s, 1H, CHeCOO), 7.47e7.49 (m, 2H, ArH),
7.76e7.77 (m, 2H, ArH), 8.34 (s,1H, CH]N); dC (125 MHz, DMSO-d6)
25.8, 30.0, 52.0, 53.0, 53.2, 60.4, 62.6, 116.1, 127.9, 129.3, 130.8, 134.2,
143.5, 163.8, 165.2, 167.5, 169.8; HRMS (ESI-TOF, [MþH]þ): calcd for
C21H25N4O5, 413.1825; found, 413.1815.
4.2.23. Dimethyl 5-cyano-4-(2-ethoxy-2-oxoethylamino)-1-(3-
fluorobenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-
dicarboxylate (5d). White powder, mp 168e170 ꢁC; IR (KBr, cmꢀ1):
3448, 2956, 2852, 2209, 1739, 1694, 1640, 1473, 1409, 1210, 1111, 777,
689; dH (500 MHz, CDCl3): 1.31 (t, J¼7.5 Hz, 3H, CH3), 3.75 (s, 3H, OCH3),
3.81 (s, 3H, OCH3), 4.14e4.19 (dd, J1¼6.0 Hz, J2¼18.2 Hz,1H, C(O)CH2N),
4.28 (q, J¼7.5 Hz, 2H, OCH2), 4.33e4.38 (dd, J1¼6.0 Hz, J2¼18.2 Hz, 1H,
C(O)CH2N), 4.74 (s, 1H, CHeCN), 5.51 (s, 1H, CHeCOO), 7.37e7.42 (m,
4H, ArH), 7.82 (s,1H, CH]N) 8.64 (s,1H, NH); dC (125 MHz, CDCl3): 14.1,
42.9, 51.6, 52.4, 53.3, 56.3, 62.0, 72.9,113.7 (d, 2JCF¼22.7 Hz),116.8,117.7
4.2.28. (E)-Dimethyl 2-((tert-butylimino)methylene)-3-(1-(2-
cyanoacetyl)-2-(4-fluorobenzylidene)hydrazinyl)succinate
(6b). White powder, mp 124e126 ꢁC; IR (KBr, cmꢀ1): 2978, 2955,
2259, 2079, 1752, 1693, 1512, 1433, 1267, 1237, 1177, 1109, 1014, 847,
770; dH (500 MHz, DMSO-d6), 1.39 (s, 9H, C(CH3)3), 3.60 (s, 3H,
OCH3), 3.65 (s, 3H, OCH3), 4.41 (s, 2H, CH2eCN), 6.10 (s, 1H,
CHeCOO), 7.32 (t, J¼9.0 Hz, 2H, ArH), 7.80e7.83(m, 2H, ArH), 8.35
(s, 1H, CH]N); dC (125 MHz, DMSO-d6) 25.8, 30.1, 52.1, 53.1, 53.3,
2
2
3
(d, JCF¼21 Hz), 123.7, 130.5, 135.5, 141.5, 157.0, 158.2, 164.0 (d,
60.5, 62.7, 116.2, 116.4 (d, JCF¼22 Hz), 130.2(d, JCF¼8.0 Hz), 130.9,
142.5, 163.7, 163.8 (d, 1JCF¼248 Hz), 165.2, 167.5, 169.9; HRMS (ESI-
TOF, [MþH]þ): calcd for C21H24FN4O5, 431.1731; found, 431.1720.
1JCF¼246 Hz), 166.4, 168.6, 168.9; HRMS (ESI-TOF, [MþH]þ): calcd for
C21H22FN4O7, 461.1473; found, 461.1465.
4.2.24. Dimethyl 5-cyano-4-(2-ethoxy-2-oxoethylamino)-1-(4-
nitrobenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-
dicarboxylate (5e). Yellow powder, mp 197e199 ꢁC; IR (KBr,
cmꢀ1): 3434, 2925, 2853, 2209, 1734, 1700, 1637, 1522, 1472,
1408, 1345, 1216, 1109, 845; dH (500 MHz, CDCl3): 1.31 (t,
J¼7.0 Hz, 3H, CH3), 3.72 (s, 3H, OCH3), 3.81 (s, 3H, OCH3),
4.13e4.18 (dd, J1¼6.0 Hz, J2¼18.5 Hz, 1H, C(O)CH2N), 4.28 (q,
J¼7.0 Hz, 2H, OCH2), 4.33e4.38 (dd, J1¼6.0 Hz, J2¼18.5 Hz, 1H,
C(O)CH2N), 4.77 (s, 1H, CHeCN), 5.55 (s, 1H, CHeCOO), 7.82e7.84
(d, J¼8.5 Hz, 2H, ArH), 7.87 (s, 1H, CH]N), 8.26e8.28 (d,
J¼8.5 Hz, 2H, ArH), 8.61 (s, 1H, NH); dC (125 MHz, CDCl3): 14.1,
42.9, 51.7, 52.4, 53.5, 57.2, 62.1, 72.7, 116.4, 124.2, 128.1, 139.1,
139.7, 148.7, 157.9, 168.3, 168.9; HRMS (ESI-TOF, [MþH]þ): calcd
for C21H22N5O9, 488.1418; found, 488.1425.
4.2.29. (E)-Dimethyl 2-((tert-butylimino)methylene)-3-(2-(4-
chlorobenzylidene)-1-(2-cyanoacetyl)hydrazinyl)succinate
(6c). White powder, mp 119e122 ꢁC; IR (KBr, cmꢀ1): 2980, 2251,
2077,1750,1693,1435,1265,1176,1104,1013, 831, 769; dH (500 MHz,
DMSO-d6),1.40 (s, 9H, C(CH3)3), 3.60 (s, 3H, OCH3), 3.65 (s, 3H, OCH3),
4.42 (s, 2H, CH2eCN), 6.11 (s, 1H, CHeCOO), 7.53e7.55 (d, J¼8.5 Hz,
2H, ArH), 7.77e7.78 (d, J¼7.5 Hz, 2H, ArH), 8.35 (s, 1H, CH]N); dC
(125 MHz, DMSO-d6) 25.9, 30.1, 52.1, 53.1, 53.3, 60.5, 62.7, 116.2,
129.5,129.6,133.2,135.4,142.3,163.7,165.3,167.5,169.9; HRMS (ESI-
TOF, [MþH]þ): calcd for C21H24ClN4O5, 447.1435; found, 447.1439.
4.2.30. (E)-Dimethyl 2-(2-(4-bromobenzylidene)-1-(2-cyanoacetyl)
hydrazinyl)-3-((tert-butylimino)methylene)succinate
(6d). White
powder, mp 128e130 ꢁC; IR (KBr, cmꢀ1): 2956, 2920, 2247, 2063,
1733, 1688, 1434, 1367, 1312, 1267, 1176, 1102, 1009, 828, 769; dH
(500 MHz, CDCl3), 1.49 (s, 9H, C(CH3)3), 3.73 (s, 3H, OCH3), 3.77 (s,
3H, OCH3), 3.95 (s, 2H, CH2eCN), 5.73 (s, 1H, CHeCOO), 7.57e7.58
(m, 4H, ArH), 8.16 (s, 1H, CH]N); dC (125 MHz, CDCl3) 25.5, 30.1,
51.9, 53.3, 54.0, 58.7, 62.7, 114.0, 125.0, 129.1, 132.1, 132.6, 142.6,
160.2, 163.8, 167.1, 170.6; HRMS (ESI-TOF, [MþH]þ): calcd for
C21H24BrN4O5, 491.0930; found, 491.0920.
4.2.25. Dimethyl 5-cyano-4-(2-ethoxy-2-oxoethylamino)-1-(4-
methylbenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-
dicarboxylate (5f). White powder, mp 178e180 ꢁC; IR (KBr, cmꢀ1):
3439, 2958, 2923, 2206, 1741,1693, 1636,1474,1415,1209,1111, 812;
dH (500 MHz, CDCl3): 1.31 (t, J¼7.0 Hz, 3H, CH3), 2.39 (s, 3H, CH3), 3.73
(s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.14e4.19 (dd, J1¼5.7 Hz, J2¼18.5 Hz,
1H, C(O)CH2N), 4.27 (q, J¼7.0 Hz, 2H, OCH2), 4.32e4.37 (dd,
J1¼5.7 Hz, J2¼18.5Hz,1H, C(O)CH2N), 4.72 (s,1H, CHeCN), 5.50(s,1H,
CHeCOO), 7.21e7.22 (d, J¼8.0 Hz, 2H, ArH), 7.56e7.58 (d, J¼8.0 Hz,
2H, ArH), 7.82 (s, 1H, CH]N), 8.60 (s, 1H, NH); dC (125 MHz, CDCl3):
14.1, 21.5, 42.9, 51.6, 52.2, 53.2, 55.5, 62.0, 72.6, 117.3, 127.7, 129.6,
130.6, 141.3, 143.5, 157.0, 158.5, 166.6, 168.9, 171.1; HRMS (ESI-TOF,
[MþH]þ): calcd for C22H25N4O7, 457.1723; found, 457.1735.
4.2.31. (E)-Dimethyl 2-(2-(3-bromobenzylidene)-1-(2-cyanoacetyl)
hydrazinyl)-3-((tert-butylimino)methylene)succinate
(6e). White
powder, mp 140e143 ꢁC; IR (KBr, cmꢀ1): 2975, 2261, 2077, 1759,
1695, 1435, 1266, 1177, 1108, 1069, 1015, 872, 700, 719, 689; dH
(500 MHz, DMSO-d6), 1.40 (s, 9H, C(CH3)3), 3.61 (s, 3H, OCH3),
3.66 ( s, 3H, OCH3), 4.47 (s, 2H, CH2eCN), 6.11 (s, 1H, CHeCOO),
7.45 (t, J¼8.0 Hz, 1H, ArH), 7.65e7.66 (d, J¼8.0 Hz, 1H, ArH),
7.72e7.74 (d, J¼8.0 Hz, 1H, ArH), 7.98 (s, 1H, ArH), 8.33 (s, 1H,
CH]N); dC (125 MHz, DMSO-d6) 25.9, 30.0, 52.0, 53.1, 53.3, 60.4,
4.2.26. Dimethyl 5-cyano-4-(2-ethoxy-2-oxoethylamino)-1-(4-
methylbenzylideneamino)-6-oxo-1,2,5,6-tetrahydropyridine-2,3-

M. Li et al. / Tetrahedron 68 (2012) 4838e4845
4845
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62.6, 116.1, 122.7, 127.3, 129.9, 131.4, 133.4, 136.5, 141.9, 163.6,
165.4, 167.4, 169.8; HRMS (ESI-TOF, [MþH]þ): calcd for
C21H24BrN4O5, 491.0930; found, 491.0936.
4.2.32. (E)-Dimethyl 2-((tert-butylimino)methylene)-3-(1-(2-
cyanoacetyl)-2-(2-fluorobenzylidene)hydrazinyl)succinate
(6f). White powder, mp 166e168 ꢁC; IR (KBr, cmꢀ1): 2977, 2259,
2076, 1756, 1697, 1612, 1436, 1264, 1177, 1109, 1037, 1016, 872,
764; dH (500 MHz, DMSO-d6), 1.40 (s, 9H, C(CH3)3), 3.61 (s, 3H,
OCH3), 3.65 ( s, 3H, OCH3), 4.43 (s, 2H, CH2eCN), 6.17 (s, 1H,
CHeCOO), 7.28e7.33 (m, 2H, ArH), 7.50e7.54 (m, 1H, ArH), 8.00
(t, J¼7.5 Hz, 1H, ArH), 8.45 (s, 1H, CH]N); dC (125 MHz, DMSO-
d6) 25.9, 30.1, 52.1, 53.2, 53.3, 60.2, 62.7, 116.1, 116.5 (d,
€
3. (a) Domling, A. Chem. Rev. 2006, 106, 17e89; (b) Sadjadi, S.; Heravi, M. M.
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7995e7999.
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3624e3630; (b) Shaabani, A.; Ghadari, R.; Sarvary, A.; Rezayan, A. H. J. Org.
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Mofakham, H.; Khavasi, H. R. J. Comb. Chem. 2008, 10, 323e326.
7. (a) Nair, V.; Menon, R. S.; Sreekumar, B. V.; Bindu, S. Org. Lett. 2004, 5, 767e769;
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3
2JCF¼20 Hz), 121.8 (d, JCF¼9.1 Hz), 125.4, 127.7, 132.9, 136.4,
1
161.5(d, JCF¼250 Hz), 163.5, 165.5, 167.5, 169.9; HRMS (ESI-TOF,
[MþH]þ): calcd for C21H24FN4O5, 431.1731; found, 431.1726.
4.2.33. (E)-Dimethyl 2-((tert-butylimino)methylene)-3-(1-(2-
cyanoacetyl)-2-(3-nitrobenzylidene)hydrazinyl)succinate
(6g). Yellow powder, mp 134e136 ꢁC; IR (KBr, cmꢀ1): 2985,
2261, 2091, 1759, 1694, 1529, 1437, 1271, 1178, 1111, 1020, 871,
773,675; dH (500 MHz, DMSO-d6), 1.39 (s, 9H, C(CH3)3), 3.59 (s,
3H, OCH3), 3.65 (s, 3H, OCH3), 4.48 (s, 2H, CH2eCN), 6.13 (s, 1H,
CHeCOO), 7.76 (t, J¼8.0 Hz, 1H, ArH), 8.20e8.22 (d, J¼8.0 Hz, 1H,
ArH), 8.27e8.29 (dd, J1¼8.0 Hz, J2¼2.0, 1H, CH]N), 8.49e8.51
(m, 2H, ArH); dC (125 MHz, DMSO-d6) 26.0, 30.1, 52.1, 53.3, 53.4,
60.4, 62.7, 116.1, 122.5, 125.2, 131.0, 133.7, 136.0, 141.5, 148.8,
163.5, 165.5, 167.4, 169.9; HRMS (ESI-TOF, [MþH]þ): calcd for
C21H24N5O7, 458.1676; found, 458.1685.
8. (a) Weber, L. Curr. Med. Chem. 2002, 9, 2085e2093; (b) Krasavin, M.; Shkavrov,
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453e457.
4.2.34. Dimethyl 2-((tert-butylimino)methylene)-3-(1-(2-
cyanoacetyl)-2-(4-methoxybenzylidene)hydrazinyl)succinate
(6h). White powder, mp 166e168 ꢁC; IR (KBr, cmꢀ1): 3010, 2959,
2259, 2103, 1748,1687,1655,1607,1515,1436,1254, 1176,1109, 1031,
876, 833, 770; dH (500 MHz, DMSO-d6), 1.37 (s, 9H, C(CH3)3), 3.59 (s,
3H, OCH3), 3.64 (s, 3H, OCH3), 3.80 (s, 3H, ArOCH3), 4.36 (s, 2H,
CH2eCN), 6.04 (s, 1H, CHeCOOCH3), 7.00e7.02 (d, J¼8.5 Hz, 2H,
ArH), 7.68e7.70 (d, J¼9.0 Hz, 2H, ArH), 8.24 (s, 1H, CH]N); dC
(125 MHz, DMSO-d6) 25.7, 30.0, 52.0, 53.0, 53.2, 55.8, 60.5, 62.6,
114.8, 116.2, 126.7, 129.6, 143.4, 161.5, 164.0, 164.9, 167.6, 169.8;
HRMS (ESI-TOF, [MþH]þ): calcd for C22H27N4O6, 443.1931; found,
443.1926.
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This work was financially supported by the National Natural
Science Foundation of China (Nos. 20872074 and 21072110), and
the Natural Science Foundation of Shandong Province (Nos.
Z2008B03 and ZR2010BM007).
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.03.124. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this
18. Crystallographic data for 6g have been deposited in the Cambridge Crystallo-
graphic Data Centre with the deposition number CCDC 798675. Copies of these
data can be obtained free of charge via www.ccdc.cam.ac.uk (or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK; fax: þ44 (0) 1223 336033; or e-mail: deposit@ccdc.cam.ac.uk).
19. (a) Gorobets, N. Y.; Yousefi, B. H.; Belaj, F.; Kappe, C. O. Tetrahedron 2004, 60,
8633e8644; (b) Bondock, S.; Khalifa, W.; Fadda, A. Eur. J. Med. Chem. 2007, 42,
948e954.
References and notes
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B.; Rajale, T.; Wever, W.; Tu, S.-J.; Li, G.-G. Chem.dAsian J. 2010, 5, 2318e2335.