High regio- and stereoselective synthesis of (Z)- or (E)-N-acryl butenedioic monoimide derivatives by a multicomponent reaction

Article abstract of DOI:10.1055/s-0028-1083323

An efficient synthesis of (Z)- or (E)-N-acryl butenedioic monoimide derivatives with high regio- and stereoselectivity by the multicomponent reaction of acetylenic esters/ketones, isocyanides, and carboxylic acids is described. The E-isomers, obtained in

Full text of DOI:10.1055/s-0028-1083323

424
PAPER
High Regio- and Stereoselective Synthesis of (Z)- or (E)-N-Acryl Butenedioic
Monoimide Derivatives by a Multicomponent Reaction
Synthesis of
(
Z
e
)
-
or
(
E
)-
N
n
-Acryl Bute
g
SD
erivatives ha,a Ying Lin,a Xian Huang*a,b
a
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, P. R. of China
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai
b
200032, P. R. of China
Fax +86(571)88807077; E-mail: huangx@mail.hz.zj.cn
Received 11 September 2008; revised 7 October 2008
Although the trapping of the intermediate formed between
butynedioic acid derivatives and isocyanides with active
hydrogen compound5 has been described, the chemistry of
stereoselectivity of these reactions involving propiolic
acid derivatives, has not been investigated yet. On the ba-
sis of our studies,6 we wish to report the multicomponent
reaction of propiolic acid derivatives, isocyanides, and
carboxylic acids to synthesize (Z)- or (E)-N-acryl butene-
dioic monoimide derivatives with high regio- and stereo-
selectivity.
Abstract: An efficient synthesis of (Z)- or (E)-N-acryl butenedioic
monoimide derivatives with high regio- and stereoselectivity by the
multicomponent reaction of acetylenic esters/ketones, isocyanides,
and carboxylic acids is described. The E-isomers, obtained in high
yields via E/Z isomerization, are also reported.
Key words: high regio- and stereoselectivity, multicomponent re-
actions, isocyanides, acetylenic esters/ketones, N-acryl butenedioic
monoimides
Multicomponent reactions (MCRs) provide a powerful
tool towards the one-pot synthesis of diverse and complex
compounds due to their superior atom economy; simple
experimental procedures, one-pot character, and high
bond-forming efficiency.1 Isocyanide-based MCRs
(IMCRs) are more versatile than other MCRs. The great
potential of isocyanides for the development of multicom-
ponent reactions lies in their functional group tolerance,
diversity of bond-forming processes, and high levels of
chemo-, regio-, and stereoselectivity.2
Initially, the reaction of ethyl propiolate (1a) with p-tolyl
isocyanide (2a) and isobutyric acid (3a) was conducted in
MeCN at room temperature for 50 hours, under which
conditions a smooth 1:1:1 addition reaction took place
(Table 1). However, the desired product (Z)-ethyl 7-meth-
yl-4,6-dioxo-5-p-tolyloct-2-enoate (4a) was isolated only
in 44% yield (Table 1, entry 1). Subsequent optimization
studies indicated that when the temperature was raised to
50 °C, the yield of product 4a was greatly increased to
87% (entry 2). Our further investigations proved that
DMF and THF did not work well (entries 4, 5).
Recently, much attention has been paid to the study of IM-
CRs, especially those involving electron-deficient
alkynes.3 Typically, the adduct from butynedioic acid de-
rivatives and isocyanides could provide a zwitterionic ni-
trilium intermediate species (Scheme 1),4 which would be
trapped with E-Nu, leading to two isomers.
Table 1 Optimization of Conditions for the Multicomponent Reac-
tionsa
O
OEt
H
H
H
1a
CO2Et
O
+
E1
E1
E1
N
E1
p-TolNC
O
p-Tol
2a
E1
E1
N
4a
+
N
R3
E2Nu
R3NC
R3
CO2H
3a
Entry
Solvent
MeCN
MeCN
MeCN
DMF
Temp (°C) Time (h)
Yield of 4a (%)b
E1
E2
E1
1
2
3
4
5
r.t.
50
70
50
50
50
6
44
87
79
68
54
N
Z or E
R3
Nu
Scheme 1
3
6
THF
8
a The reactions were conducted using 1 (1.0 mmol), 2 (1.0 mmol), and
3 (1.0 mmol) in 5 mL of solvent.
SYNTHESIS 2009, No. 3, pp 0424–0430
Advanced online publication: 09.01.2009
DOI: 10.1055/s-0028-1083323; Art ID: F19508SS
x
x
.
x
x
.2
0
0
9
b Isolated yields.
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of (Z)- or (E)-N-Acryl Butenedioic Monoimide Derivatives
425
Table 2 Compounds 4 Prepared by the Multicomponent Reactiona
O
R1
O
N
R1
H
R2
R4
1
+
R2
MeCN
50 °C
R3NC
R3
O O
2
4
+
single Z-isomers
R4CO2H
3
Entry
1 (R1, R2)
2 (R3)
3 (R4)
4
Yield (%)b
1
2
1a (H, OEt)
2a (p-tolyl)
3a (i-Pr)
4a
4b
4c
4d
4e
4f
87
92
88
85
80
76
65
61
73
77
75
1a
2b (Bn)
3a
3
1a
2a
3b (Ph)
4
1a
2b
3b
5
1b (n-Bu, OMe)
1b
2a
3a
6
2a
3b
7
1c (Ph, OMe)
1c
2a
3a
4g
4h
4i
8
2b
3a
9
1d (H, 4-FC6H4)
1e (H, 4-MeOC6H4)
1f (H, p-tolyl)
2c (n-C11H23)
2d (p-tolylCH2)
2a
3c (4-ClC6H4)
10
11
3c
3a
4j
4k
a The reactions were conducted using 1 (1.0 mmol), 2 (1.0 mmol), and 3 (1.0 mmol) in MeCN (5 mL) at 50 °C.
b Isolated yields.
With the optimized conditions in hand, we next investi- It is notable that the stereoselectivity of this reaction was
gated the reaction of various propiolic acid derivatives, excellent and only the Z-isomer was observed. The C2, C7
isocyanides, and carboxylic acids under identical condi- stereochemistry was confirmed by X-ray crystallographic
tions.
analysis of (Z)-methyl 3-[benzoyl(p-tolyl)carbam-
oyl]hept-2-enoate (4f) (Figure 2).10
The results, summarized in Table 2, indicate that when the
propiolic acid derivatives were acetylenic esters (Table 2,
entries 1–8) and ketones (entries 9–11), the reaction pro-
ceeded smoothly to give the products 4 in good yields, and
the yields of esters were slightly higher than those of ke-
tones. The results were satisfying in all cases when R1, R3,
and R4 were H, alkyl, and aryl groups. The configuration
was established by the NOESY spectrum studies
(Figure 1). These (Z)-N-acryl butenedioic monoimides
are utilized in Diels–Alder reactions7 and have been used
to synthesize several types of polymers with tailored ma-
terial characteristics.8,9
NOE
O
N
R1
H
R4
R2
R3
O O
4d, 4f, 4i
Figure 2 X-ray crystal structure of 4f
Figure 1 NOE studies in 4
Synthesis 2009, No. 3, 424–430 © Thieme Stuttgart · New York

426
F. Sha et al.
PAPER
Table 4 Compounds 5 Prepared by the Multicomponent Reactiona
Interestingly, when the reaction of (Z)-4d was carried out
in MeCN–CHCl3 at 75 °C for three days, the trans-config-
ured product E-isomer 5a was observed in 97% yield
(Scheme 2).11
O
H
O
R2
1
O
N
H
R2
R4
+
MeCN–CHCl3
75 °C, 3 d
R3NC
O
H
O
N
H
H
R3
O
O
N
H
OEt
Ph
2
3
MeCN–CHCl3
75 °C, 3 d
+
Ph
OEt
5
H
R4CO2H
Bn
O O
Bn
O
5a
4d
97%
Entry R2
R3
R4
Yield of 5
(%)b
Scheme 2
1
2
3
4
5
6
1a (OEt)
1d (4-FC6H4)
2b (Bn)
3b (Ph)
5a, 81
The products of type 5a containing the (E)-butenedioic
compounds structural unit is valuable building blocks in
organic synthesis and in the preparation of polymer mate-
rials.8,9 Therefore, we proceeded to expand the substrate
scope. As shown in Table 3, a number of (E)-N-acryl
butenedioic monoimides 5 were prepared from 4 by
isomerization in excellent yields (Table 3).
2c (n-C11H23)
3c (4-ClC6H4) 5c, 71
1d
2c
3a (i-Pr)
3a
5f, 70
5g, 68
5h, 74
5i, 69
1f (p-tolyl)
2b
1e (4-MeOC6H4) 2b
1f
3d (i-C5H11)
2d (p-tolylCH2) 3a
Table 3 (E)-N-Acryl Butenedioic Monoimides 5 Prepared by the
Isomerization of 4a
a The reaction was carried out using 1 (1.0 mmol), 2 (1.0 mmol), and
3 (1.0 mmol) in MeCN (4 mL) and CHCl3 (1 mL) at 75 °C for 3 d.
b Isolated yields.
O
O
H
H
R2
R4
O
N
H
MeCN–CHCl3
75 °C, 3 d
R4
N
R3
R2
H
O O
R3
O
R1
R1
O
4
5
>93%
R1
R2
N
R3
R2
R2
Entry R2
R3
R4
Ph
Yield of 5 (%)b
5a, 97
1
N
O
O
R3
1
2
3
4
5
OEt
OEt
Bn
+
R3NC
6
p-tolyl
n-C11H23
p-tolylCH2
p-tolyl
i-Pr
5b, 94
R4CO2H
2
4-FC6H4
4-ClC6H4
4-ClC6H4
i-Pr
5c, 98
3
R1
H
4-MeOC6H4
5d, 95
R3
O
R1
H
R4
N
O
R2
p-tolyl
5e, 93
N
R2
O
O
a The reaction was conducted using 4 (0.3 mmol) in MeCN (2 mL)
and CHCl3 (0.5 mL) at 75 °C for 3 d.
b Isolated yields.
R3
O O
R4
7
4
Scheme 3
Furthermore, we performed the reaction of acetylenic es-
ters/ketones, isocyanides, and carboxylic acids in MeCN– In conclusion, we have demonstrated the multicomponent
CHCl3 at 75 °C for three days. As expected, the reaction reaction of acetylenic esters/ketones, isocyanides and car-
directly afforded (E)-N-acryl butenedioic monoimide de- boxylic acids as a direct, efficient and operationally con-
rivatives 5 in good yields (Table 4).
venient approach to (Z)- or (E)-N-acryl butenedioic
monoimide derivatives with high regio- and stereoselec-
tivity. The reactions could be useful due to their atom-
economical manner, control of stereoselectivity, and po-
tential synthetic utilities in organic synthesis.
A plausible mechanism of the multicomponent reaction is
shown in Scheme 3. On the basis of the well-established
chemistry of isocyanides,12 it is reasonable to assume that
the nucleophilic addition of isocyanide 2 to alkyne 1
forms the Z-zwitterionic intermediate 6,13 which could be
trapped with carboxylic acid 3 to produce the imidoyl car-
boxylate 7. Subsequently, an acyl group shift from oxygen
to nitrogen occurs to produce the final product 4.14
All reactions were performed under N2. Anhyd solvents were dis-
tilled prior to use: THF and toluene were distilled from sodium–
benzophenone; MeCN was distilled from P2O5. Petroleum ether
(PE) refers to the fraction with boiling point in the range of 60–
90 °C. All 1H NMR and 13C NMR spectra were recorded in CDCl3
with TMS as the internal standard. Chemical shifts are expressed in
ppm and J values are given in Hz. Melting points are uncorrected.
Synthesis 2009, No. 3, 424–430 © Thieme Stuttgart · New York

PAPER
Synthesis of (Z)- or (E)-N-Acryl Butenedioic Monoimide Derivatives
427
Multicomponent Reaction of Acetylenic Esters/Ketones, Isocy-
anides, and Carboxylic Acids Leading to 4a–k; General Proce-
dure
Alkyne 1 (1.0 mmol), isocyanide 2 (1.0 mmol), and carboxylic acid
3 (1.0 mmol) were mixed in anhyd MeCN (5 mL). The mixture was
then allowed to stir at 50 °C for 6–17 h. The solvent was removed
under reduced pressure, and the residue was purified by silica gel
chromatography (PE–EtOAc, 8:1 to 4:1) to afford 4 (Table 2).
MS: m/z (%) = 337 (M+, 4), 105 (100).
Anal. Calcd for C20H19NO4 (337.13): C, 71.20; H, 5.68; N, 4.15.
Found: C, 71.23; H, 5.75; N, 4.14.
4e
Oil.
IR (neat): 3412, 2958, 1723, 1698, 1643, 1202, 1156 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35–7.24 (m, 4 H), 5.65–5.63 (m,
1 H), 3.70 (s, 3 H), 2.69–2.56 (m, 1 H), 2.47 (t, J = 7.4 Hz, 2 H),
2.41 (s, 3 H), 1.63–1.53 (m, 2 H), 1.44–1.36 (m, 2 H), 1.03 (d,
J = 6.8 Hz, 6 H), 0.93 (t, J = 7.3 Hz, 3 H).
(Z)-Ethyl 4-Oxo-4-(N-p-tolylisobutyramido)but-2-enoate (4a)
Mp 79–81 °C.
IR (KBr): 2979, 1719, 1701, 1632, 1388, 1210, 1170 cm–1.
13C NMR (100 MHz, CDCl3): d = 179.8, 172.0, 166.0, 157.7, 138.9,
135.0, 130.2, 128.5, 113.1, 51.4, 34.3, 33.9, 28.7, 22.2, 21.2, 19.0,
13.8.
1H NMR (400 MHz, CDCl3): d = 7.31–7.25 (m, 4 H), 6.75 (d,
J = 11.8 Hz, 1 H), 5.84 (d, J = 11.8 Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2
H), 2.81–2.69 (m, 1 H), 2.40 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H), 1.07
(d, J = 6.7 Hz, 6 H).
MS: m/z (%) = 345 (M+, 10), 169 (100).
13C NMR (100 MHz, CDCl3): d = 180.6, 169.3, 165.2, 139.7, 139.1,
Anal. Calcd for C20H27NO4 (345.19): C, 69.54; H, 7.88; N, 4.05.
Found: C, 69.51; H, 7.93; N, 4.09.
134.8, 130.3, 128.4, 119.0, 60.7, 34.1, 21.2, 19.0, 14.1.
MS: m/z (%) = 303 (M+, 5), 99 (100), 107 (100).
4f
Oil.
Anal. Calcd for C17H21NO4 (303.15): C, 67.31; H, 6.98; N, 4.62.
Found: C, 67.35; H, 6.89; N, 4.69.
IR (neat): 3448, 2964, 1711, 1693, 1681, 1274, 1169 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.56 (d, J = 7.3 Hz, 2 H), 7.35–
7.18 (m, 5 H), 7.08 (d, J = 8.1 Hz, 2 H), 5.71 (s, 1 H), 3.68 (s, 3 H),
2.62 (t, J = 3.8 Hz, 2 H), 2.26 (s, 3 H), 1.69–1.57 (m, 2 H), 1.49–
1.38 (m, 2 H), 0.94 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 172.2, 172.0, 166.0, 157.0, 137.9,
135.4, 134.2, 131.6, 129.7, 129.6, 128.2, 127.9, 114.3, 51.5, 34.8,
29.0, 22.3, 21.1, 13.8.
4b
Oil.
IR (neat): 3033, 2979, 1720, 1690, 1386, 1155 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.33 (t, J = 7.3 Hz, 2 H), 7.26 (t,
J = 7.3 Hz, 1 H), 7.21 (d, J = 7.3 Hz, 2 H), 6.71 (d, J = 11.8 Hz, 1
H), 5.90 (d, J = 11.8 Hz, 1 H), 5.03 (s, 2 H), 4.16 (q, J = 7.1 Hz, 2
H), 3.19–3.07 (m, 1 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.11 (d, J = 6.8 Hz,
6 H).
MS: m/z (%) = 379 (M+, 4), 169 (100).
13C NMR (100 MHz, CDCl3): d = 180.8, 169.6, 164.9, 139.1, 136.8,
Anal. Calcd for C23H25NO4 (379.18): C, 72.80; H, 6.64; N, 3.69.
Found: C, 72.83; H, 6.69; N, 3.74.
128.7, 127.4, 126.4, 120.0, 60.8, 47.1, 34.4, 19.0, 14.0.
MS: m/z (%) = 304 [(M + 1)+, 27], 106 (100).
4g
Anal. Calcd for C17H21NO4 (303.15): C, 67.31; H, 6.98; N, 4.62.
Found: C, 67.27; H, 7.06; N, 4.68.
Mp 140–142 °C.
IR (KBr): 3398, 2990, 1714, 1686, 1619, 1353, 1197, 1175 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.57–7.45 (m, 2 H), 7.44–7.35 (m,
3 H), 7.34–7.12 (m, 4 H), 6.12 (s, 1 H), 3.77 (s, 3 H), 3.07–2.48 (m,
1 H), 2.40 (s, 3 H), 1.18–0.75 (m, 6 H).
4c
Mp 37–39 °C.
IR (KBr): 3342, 2983, 1715, 1684, 1601, 1516, 1268, 1159 cm–1.
13C NMR (100 MHz, CDCl3): d = 179.3, 167.9, 166.1, 153.7, 139.0,
134.9, 134.2, 130.1, 130.0, 128.8, 128.6, 126.8, 113.5, 51.7, 34.1,
21.2, 18.8.
1H NMR (400 MHz, CDCl3): d = 7.62 (d, J = 7.6 Hz, 2 H), 7.27–
7.22 (m, 4 H), 7.11 (t, J = 7.6 Hz, 3 H), 6.85 (d, J = 11.9 Hz, 1 H),
5.92 (d, J = 11.9 Hz, 1 H), 4.21 (q, J = 7.2 Hz, 2 H), 2.28 (s, 3 H),
1.26 (t, J = 7.2 Hz, 3 H).
MS: m/z (%) = 365 (M+, 20), 189 (100).
13C NMR (100 MHz, CDCl3): d = 172.6, 169.4, 165.2, 139.0, 138.0,
135.2, 133.9, 131.9, 129.8, 129.6, 128.0, 127.9, 120.3, 60.8, 21.0,
14.0.
Anal. Calcd for C22H23NO4 (365.16): C, 72.31; H, 6.34; N, 3.83.
Found: C, 72.28; H, 6.41; N, 3.78.
MS: m/z (%) = 337 (M+, 24), 105 (100).
4h
Oil.
Anal. Calcd for C20H19NO4 (337.13): C, 71.20; H, 5.68; N, 4.15.
Found: C, 71.15; H, 5.62; N, 4.19.
IR (neat): 3447, 2973, 1718, 1677, 1621, 1179, 1156 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.56–7.44 (m, 2 H), 7.43–7.35 (m,
3 H), 7.34–7.19 (m, 5 H), 6.16 (s, 1 H), 4.89 (s, 2 H), 3.68 (s, 3 H),
3.06–2.94 (m, 1 H), 1.25–1.15 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 170.4, 165.7, 162.3, 137.0, 130.3,
129.0, 128.6, 128.5, 128.1, 127.5, 127.3, 126.9, 126.7, 51.8, 43.1,
32.8, 19.2.
4d
Oil.
IR (neat): 3296, 2982, 1719, 1694, 1661, 1342, 1220, 1174 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.56–7.46 (m, 3 H), 7.41–7.35 (m,
2 H), 7.31–7.18 (m, 5 H), 6.28 (d, J = 11.9 Hz, 1 H), 5.64 (d,
J = 11.9 Hz, 1 H), 5.12 (s, 2 H), 4.19 (q, J = 7.1 Hz, 2 H), 1.27 (t,
J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 173.5, 168.8, 164.6, 137.5, 136.9,
135.5, 132.5, 128.7, 128.5, 128.5, 128.1, 127.5, 121.4, 61.0, 48.6,
14.0.
MS: m/z (%) = 365 (M+, 24), 106 (100).
Anal. Calcd for C22H23NO4 (365.16): C, 72.31; H, 6.34; N, 3.83.
Found: C, 72.27; H, 6.38; N, 3.89.
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F. Sha et al.
PAPER
J = 15.3 Hz, 1 H), 5.09 (s, 2 H), 4.10 (q, J = 7.1 Hz, 2 H), 1.20 (t,
J = 7.2 Hz, 3 H).
Mp 72–75 °C.
IR (KBr): 2924, 1688, 1655, 1594, 1236, 1091 cm–1.
13C NMR (100 MHz, CDCl3): d = 173.2, 167.5, 164.6, 136.7, 135.5,
135.3, 133.0, 130.9, 128.9, 128.8, 128.5, 128.1, 127.6, 61.0, 49.2,
13.9.
1H NMR (400 MHz, CDCl3): d = 7.93 (t, J = 8.4 Hz, 2 H), 7.61 (d,
J = 8.2 Hz, 2 H), 7.43 (d, J = 8.2 Hz, 2 H), 7.13 (t, J = 8.4 Hz, 2 H),
6.63 (d, J = 11.8 Hz, 1 H), 6.43 (d, J = 11.8 Hz, 1 H), 3.78 (t, J = 7.3
Hz, 2 H), 1.65–1.44 (m, 2 H), 1.38–0.99 (m, 16 H), 0.87 (t, J = 6.3
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 189.9, 172.9, 168.6, 167.2, 164.7,
138.9, 134.4, 133.6, 132.7, 132.6, 131.3, 131.2, 130.1, 129.5, 129.0,
116.0, 115.7, 46.2, 31.8, 29.5, 29.4, 29.4, 29.4, 29.0, 28.5, 26.7,
22.6, 14.1.
MS: m/z (%) = 337 (M+, 1), 105 (100).
Anal. Calcd for C20H19NO4 (337.13): C, 71.20; H, 5.68; N, 4.15.
Found: C, 71.24; H, 5.73; N, 4.13.
5c
Mp 36–38 °C.
IR (KBr): 2929, 1680, 1671, 1561, 1235, 1102 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.94–7.86 (m, 2 H), 7.70 (d,
J = 15.1 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 2 H), 7.42 (d, J = 8.4 Hz, 2
H), 7.13 (t, J = 8.6 Hz, 2 H), 6.93 (d, J = 15.1 Hz, 1 H), 3.86 (t,
J = 7.4 Hz, 2 H), 1.71–1.60 (m, 2 H), 1.36–1.13 (m, 16 H), 0.86 (t,
J = 6.4 Hz, 3 H).
MS: m/z (%) = 485 (M+, 43), 139 (100).
Anal. Calcd for C27H33ClFNO3 (485.21): C, 69.19; H, 6.84; N, 2.88.
Found: C, 69.23; H, 6.91; N, 2.83.
4j
Oil.
13C NMR (100 MHz, CDCl3): d = 187.6, 172.6, 167.8, 167.3, 164.7,
139.4, 134.7, 133.7, 133.6, 133.0, 132.9, 131.5, 131.4, 130.2, 129.2,
116.0, 115.9, 46.7, 31.8, 29.5, 29.5, 29.4, 29.2, 29.1, 28.9, 26.8,
22.6, 14.0.
IR (neat): 3321, 2996, 1703, 1652, 1611, 1248, 1179, 843 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.87 (d, J = 8.8 Hz, 2 H), 7.53 (d,
J = 8.4 Hz, 2 H), 7.37 (d, J = 8.4 Hz, 2 H), 7.11 (d, J = 7.9 Hz, 2 H),
7.06 (d, J = 7.9 Hz, 2 H), 6.94 (d, J = 8.8 Hz, 2 H), 6.66 (d, J = 11.8
Hz, 1 H), 6.30 (d, J = 11.8 Hz, 1 H), 4.99 (s, 2 H), 3.88 (s, 3 H), 2.29
(s, 3 H).
13C NMR (100 MHz, CDCl3): d = 189.5, 172.5, 169.1, 164.1, 138.8,
137.2, 134.0, 133.9, 133.8, 131.0, 130.2, 129.9, 129.4, 129.2, 128.9,
128.1, 114.0, 55.5, 48.7, 21.1.
MS: m/z (%) = 485 (M+, 51), 139 (100).
Anal. Calcd for C28H33ClFNO3 (485.21): C, 69.19; H, 6.84; N, 7.29.
Found: C, 69.23; H, 6.91; N, 7.22.
5f
Oil.
MS: m/z (%) = 447 (M+, 3), 139 (100).
IR (neat): 2970, 1700, 1658, 1653, 1239, 1152, 1010 cm–1.
Anal. Calcd for C26H22ClNO4 (447.12): C, 69.72; H, 4.95; N, 3.13.
Found: C, 69.74; H, 5.07; N, 3.10.
1H NMR (400 MHz, CDCl3): d = 8.11–8.06 (m, 2 H), 7.77 (d,
J = 15.0 Hz, 1 H), 7.41 (d, J = 15.0 Hz, 1 H), 7.18 (t, J = 8.6 Hz, 2
H), 3.74 (t, J = 7.7 Hz, 2 H), 3.28–3.09 (m, 1 H), 1.67–1.54 (m, 2
H), 1.38–1.19 (m, 22 H), 0.88 (t, J = 6.5 Hz, 3 H).
4k
Oil.
13C NMR (100 MHz, CDCl3): d = 188.0, 181.2, 168.4, 167.4, 164.8,
136.0, 133.3, 133.2, 133.0, 131.6, 131.5, 116.1, 115.9, 44.7, 34.5,
31.9, 29.6, 29.5, 29.5, 29.4, 29.3, 29.2, 26.8, 22.6, 19.4, 14.1.
IR (neat): 3675, 2972, 1697, 1661, 1605, 1204, 1173, 1077 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.88 (d, J = 8.2 Hz, 2 H), 7.39–
7.24 (m, 6 H), 6.89 (d, J = 11.8 Hz, 1 H), 6.82 (d, J = 11.8 Hz, 1 H),
2.89–2.76 (m, 1 H), 2.43 (s, 3 H), 2.42 (s, 3 H), 1.09 (d, J = 6.7 Hz,
6 H).
13C NMR (100 MHz, CDCl3): d = 189.9, 180.8, 170.0, 144.2, 139.0,
137.4, 135.0, 134.3, 130.3, 129.3, 128.7, 128.5, 125.2, 34.2, 21.6,
21.2, 19.0.
MS: m/z (%) = 417 (M+, 100).
Anal. Calcd for C25H36FNO3 (417.27): C, 71.91; H, 8.69; N, 3.35.
Found: C, 71.94; H, 8.76; N, 3.36.
5g
Mp 65–67 °C.
MS: m/z (%) = 349 (M+, 8), 71 (100).
IR (KBr): 2974, 2932, 1704, 1661, 1604, 1294, 1152 cm–1.
Anal. Calcd for C22H23NO3 (349.17): C, 75.62; H, 6.63; N, 4.01.
Found: C, 75.61; H, 6.69; N, 4.03.
1H NMR (400 MHz, CDCl3): d = 7.89 (d, J = 7.6 Hz, 2 H), 7.84 (d,
J = 15.0 Hz, 1 H), 7.46 (d, J = 15.0 Hz, 1 H), 7.33–7.22 (m, 5 H),
7.20 (d, J = 7.6 Hz, 2 H), 5.04 (s, 2 H), 3.23–3.10 (m, 1 H), 2.40 (s,
3 H), 1.15 (d, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 188.7, 181.1, 168.7, 144.6, 136.6,
134.8, 134.1, 129.4, 128.8, 128.7, 128.4, 127.5, 126.3, 47.3, 34.8,
21.6, 19.2.
Multicomponent Reaction of Acetylenic Esters/Ketones, Isocy-
anides, and Carboxylic Acids Leading to 5a, c, f–i; General Pro-
cedure
To a stirred solution of alkyne 1 (1.0 mmol) and isocyanide 2 (1.0
mmol) in anhyd MeCN (4 mL) was added a solution of carboxylic
acid 3 (1.0 mmol) in anhyd CHCl3 (1 mL). The mixture was then al-
lowed to stir at 75 °C for 3 d. The solvent was removed under re-
duced pressure, and the residue was purified by silica gel
chromatography (PE–EtOAc, 10:1) to afford 5 (Table 4).
MS: m/z (%) = 349 (M+, 42), 71 (100).
Anal. Calcd for C22H23NO3 (349.17): C, 75.62; H, 6.63; N, 4.01.
Found: C, 75.68; H, 6.71; N, 4.04.
5h
Oil.
(E)-Ethyl 4-(N-Benzylbenzamido)-4-oxobut-2-enoate (5a)
Oil.
IR (neat): 2959, 1699, 1658, 1257, 1161 cm–1.
IR (neat): 3064, 2982, 1724, 1696, 1661, 1301, 1173 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.59–7.50 (m, 3 H), 7.45–7.37 (m,
2 H), 7.36–7.22 (m, 5 H), 6.83 (d, J = 15.3 Hz, 1 H), 6.62 (d,
1H NMR (400 MHz, CDCl3): d = 7.99 (d, J = 8.8 Hz, 2 H), 7.85 (d,
J = 15.0 Hz, 1 H), 7.49 (d, J = 15.0 Hz, 1 H), 7.37–7.25 (m, 3 H),
7.21 (d, J = 7.6 Hz, 2 H), 6.95 (d, J = 8.8 Hz, 2 H), 5.03 (s, 2 H),
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PAPER
Synthesis of (Z)- or (E)-N-Acryl Butenedioic Monoimide Derivatives
429
3.87 (s, 3 H), 2.57 (d, J = 6.8 Hz, 2 H), 2.26–2.15 (m, 1 H), 0.93 (d,
J = 6.6 Hz, 6 H).
5e
Oil.
13C NMR (100 MHz, CDCl3): d = 187.5, 175.8, 168.7, 164.0, 136.5,
134.6, 134.3, 131.1, 129.6, 128.7, 127.5, 126.3, 113.9, 55.4, 47.3,
46.0, 25.1, 22.3.
IR (neat): 2973, 1701, 1697, 1663, 1311, 1179 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.95–7.81 (m, 3 H), 7.36–7.26 (m,
4 H), 7.22 (d, J = 15.1 Hz, 1 H), 7.07 (d, J = 8.0 Hz, 2 H), 3.19–3.08
(m, 1 H), 2.43 (s, 3 H), 2.42 (s, 3 H), 1.20 (d, J = 6.8 Hz, 6 H).
MS: m/z (%) = 379 (M+, 29), 106 (100).
Anal. Calcd for C23H25NO4 (379.18): C, 72.80; H, 6.64; N, 3.69.
Found: C, 72.74; H, 6.71; N, 3.73.
13C NMR (100 MHz, CDCl3): d = 189.0, 181.0, 167.8, 144.7, 139.2,
135.1, 134.7, 134.5, 134.3, 130.6, 129.5, 129.0, 128.4, 34.9, 21.7,
21.2, 19.3.
5i
MS: m/z (%) = 349 (M+, 11), 173 (100).
Mp 80–82 °C.
Anal. Calcd for C22H23NO3 (349.17): C, 75.62; H, 6.63; N, 4.01.
Found: C, 75.66; H, 6.71; N, 3.97.
IR (KBr): 3031, 2980, 1687, 1656, 1603, 1291, 1177 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.90 (d, J = 7.6 Hz, 2 H), 7.83 (d,
J = 15.0 Hz, 1 H), 7.46 (d, J = 15.0 Hz, 1 H), 7.27 (d, J = 7.6 Hz, 2
H), 7.13 (d, J = 7.9 Hz, 2 H), 7.09 (d, J = 7.9 Hz, 2 H), 5.00 (s, 2 H),
3.20–3.09 (m, 1 H), 2.43 (s, 3 H), 2.32 (s, 3 H), 1.16 (d, J = 6.6 Hz,
6 H).
13C NMR (100 MHz, CDCl3): d = 188.9, 181.3, 168.8, 144.7, 137.3,
135.0, 134.3, 134.2, 133.7, 129.5, 129.5, 129.0, 126.4, 47.3, 35.0,
21.7, 21.0, 19.4.
Acknowledgment
We are grateful to the National Natural Science Foundation of
China (Project Nos. 20732005, 20872127, and 20672095), National
Basic Research Program of China (973 Program, 2009CB825300),
and The CAS Academic Foundation of Zhejiang Province for finan-
cial support.
MS: m/z (%) = 363 (M+, 10), 105 (100).
Anal. Calcd for C23H25NO3 (363.18): C, 76.01; H, 6.93; N, 3.85.
Found: C, 76.04; H, 6.99; N, 3.86.
References
(1) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(2) Dömling, A. Chem. Rev. 2006, 106, 17.
Isomerization of 4 Leading to 5a–e; General Procedure
Compound 4 (0.3 mmol) and MeCN (2 mL) were mixed in CHCl3
(0.5 mL). The mixture was then allowed to stir at 75 °C for 3 d and
then concentrated in vacuo. The residue was purified by silica gel
chromatography using PE–EtOAc (10:1) as eluent (Table 3).
(3) (a) Cyr, D. J. S.; Martin, N.; Arndtsen, B. A. Org. Lett. 2007,
9, 449. (b) Lu, K.; Luo, T.; Xiang, Z.; You, Z.; Fathi, R.;
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M. G. J. Comb. Chem. 2007, 9, 14. (f) Teimouri, M. B.;
Bazhrang, R.; Eslamimanesh, V.; Nouri, A. Tetrahedron
2006, 62, 3016. (g) Ahmadi, E.; Ramazani, A.; Haghighi,
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Rostamnia, S.; Esmaili, A. A. Synthesis 2007, 709.
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2007, 37, 2593.
5b
Oil.
IR (neat): 3032, 2994, 1698, 1673, 1675, 1501, 1193, 979 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.31–7.21 (m, 3 H), 7.08–6.99 (m,
2 H), 6.79 (d, J = 15.2 Hz, 1 H), 4.23 (q, J = 7.6 Hz, 2 H), 3.03–2.95
(m, 1 H), 2.40 (s, 3 H), 1.29 (t, J = 7.2 Hz, 3 H), 1.16 (d, J = 6.4 Hz,
6 H).
(4) (a) Yavari, I.; Esnaashari, M. Synthesis 2005, 1049.
(b) Shaabani, A.; Rezayan, A. H.; Rahmati, A.; Sarvary, A.
Synlett 2007, 1458. (c) Adib, M.; Koloogani, S. A.; Abbasi,
A.; Bijanzadeh, H. R. Synthesis 2007, 3056. (d) Adib, M.;
Sayahi, M. H.; Ziyadi, H.; Bijanzadeh, H. R.; Zhu, L. G.
Tetrahedron 2007, 63, 11135. (e) Adib, M.; Sayahi, M. H.;
Nosrati, M.; Zhu, L. G. Tetrahedron Lett. 2007, 48, 4195.
(f) Alizadeh, A.; Rostamnia, S.; Hu, M. L. Synlett 2006,
1592. (g) Alizadeh, A.; Rostamnia, S.; Zoreh, N.; Oskueyan,
Q. Synlett 2007, 1610. (h) Alizadeh, A.; Oskueyan, Q.;
Rostamnia, S. Synthesis 2007, 2637. (i) Teimouri, M. B.
Tetrahedron 2006, 62, 10849.
(5) (a) Yavari, I.; Alizadeh, A.; Anary-Abbasinejad, M.;
Bijanzadeh, H. R. Tetrahedron 2003, 59, 6083. (b) Yavari,
I.; Anary-Abbasinejad, M.; Alizadeh, A.; Hossaini, Z.
Tetrahedron 2003, 59, 1289. (c) Yavari, I.; Esmaili, A. A.;
Asghari, S.; Bijanzadeh, H. R. J. Chem. Res., Synop. 1999,
368. (d) Yavari, I.; Hazeri, N.; Maghsoodlou, M. T.;
Zabarjad, S. N. Monatsh. Chem. 2001, 132, 683.
(e) Alizadeh, A.; Rostamnia, S.; Zhu, L. G. Tetrahedron
2006, 62, 5641. (f) Yavari, I.; Karimi, E. Synth. Commun.
2007, 37, 1189.
13C NMR (100 MHz, CDCl3): d = 167.3, 165.2, 163.0, 139.2, 136.1,
135.0, 131.4, 130.6, 128.3, 61.2, 34.7, 21.2, 19.2, 14.1.
MS: m/z (%) = 303 (M+, 3), 107 (100).
Anal. Calcd for C17H21NO4 (303.15): C, 67.31; H, 6.98; N, 4.62.
Found: C, 67.34; H, 7.08; N, 4.66.
5d
Mp 42–44 °C.
IR (KBr): 2971, 1683, 1658, 1595, 1250, 1170 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.84 (d, J = 8.8 Hz, 2 H), 7.72 (d,
J = 15.0 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 2 H), 7.37 (d, J = 8.4 Hz, 2
H), 7.22 (d, J = 7.9 Hz, 2 H), 7.11 (d, J = 7.9 Hz, 2 H), 6.92 (d,
J = 8.8 Hz, 2 H), 6.87 (d, J = 15.0 Hz, 1 H), 5.06 (s, 2 H), 3.87 (s, 3
H), 2.31 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 187.3, 172.4, 168.2, 164.2, 139.5,
137.5, 134.8, 133.8, 133.7, 133.6, 131.2, 130.3, 129.5, 129.4, 129.3,
128.0, 114.0, 55.5, 49.3, 21.1.
MS: m/z (%) = 447 (M+, 1), 139 (100).
Anal. Calcd for C26H22ClNO4 (447.12): C, 69.72; H, 4.95; N, 7.92.
Found: C, 69.76; H, 4.87; N, 7.94.
(6) Huang, X.; Sha, F. J. Org. Chem. 2008, 73, 1173.
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F. Sha et al.
PAPER
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Tsutsumi, H. Polymer J. 2000, 32, 543. (c) Oishi, T.
Polymer J. 1981, 13, 65.
(10) The crystal structure of 4f has been deposited at the
Cambridge Crystallographic Data Centre and allocated the
deposition number CCDC 696375. The data can be obtained
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html
[or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax:
+44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk].
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Fabian, J. J. Org. Chem. 2003, 68, 4108.
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(13) It is interesting to note that the reactions exclusively gave the
products possessing the Z-stereochemistry (Table 2). For
more information about this type of intermediates, see
references 5a, 5b, and 5e.
(14) (a) Passerini, M.; Ragni, G. Gazz. Chim. Ital. 1931, 61, 964.
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Rosendahl, K. Chem. Ber. 1961, 94, 2233.
Synthesis 2009, No. 3, 424–430 © Thieme Stuttgart · New York