Diastereoselective synthesis of arylidene bis(3-arylaminoacrylates) via one-pot domino reactions

Article abstract of DOI:10.1002/cjoc.201300094

The functionalized arylidene bis(3-arylaminoacrylates) were efficiently prepared by FeCl₃ catalyzed one-pot domino reactions of primary amines, methyl propiolate and aromatic aldehydes. When isatins were utilized under similar conditions, only

Full text of DOI:10.1002/cjoc.201300094

FULL PAPER
DOI: 10.1002/cjoc.201300094
Diastereoselective Synthesis of Arylidene Bis(3-arylamino-
acrylates) via One-pot Domino Reactions
Zhenming Liu,a Lili Zhang,b Jing Sun,b and Chaoguo Yan*,b
a Analysis and Test Center, Yangzhou University, Yangzhou, Jiangsu 225002, China
b College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu 225002, China
The functionalized arylidene bis(3-arylaminoacrylates) were efficiently prepared by FeCl3 catalyzed one-pot
domino reactions of primary amines, methyl propiolate and aromatic aldehydes. When isatins were utilized under
1
similar conditions, only 2-oxoindolinyl 3-arylaminoacrylates were obtained in moderate yields. H NMR data and
single crystal structures indicated that this reaction has high diastereoselectivity.
Keywords domino reaction, electron-deficient alkyne, acrylate, isatin, stereoselectivity
Introduction
tions, we investigated the one-pot domino reactions of
arylamines, methyl propiolate and aromatic aldehydes
and successfully developed a facile synthetic procedure
for the functionalized arylidene bis(3-arylaminoacry-
lates).
During these years the versatile reactivity of Huis-
gen’s 1,4-dipoles, which were easily generated from the
addition reaction of nitrogen-containing aromatic het-
erocycles to electron-deficient alkynes have been widely
recognized as practical synthons to develop versatile
carbon-carbon bond formation reactions and heterocyc-
lic constructions.[1-3] On the other hand the addition of
aliphatic or aromatic primary amine to the activated
alkynes results in an active intermediate β-enamino es-
ters, which are also useful synthetic building blocks for
the synthesis of a wide variety of heterocycles and
pharmaceutical compounds.[4,5] Many domino reactions
have been developed by trapping this kind of in situ
generated β-enamino esters with sequential adding nu-
cleophilic or electrophilic reagents to give versatile ni-
trogen-containing compounds and N,O-heterocycles.[6-14]
We also successfully reported several new domino reac-
tions by using the in situ formed β-enamino esters de-
rived from the reactions of arylamines with electron-
deficient alkynes such as dimethyl acetylenedicarboxy-
late and methyl propiolate.[15-18] It is very interesting to
find that the β-enamino esters derived from the addition
of primary amines to methyl propiolate usually showed
very different reactivity and therefore different reaction
patterns to the β-enamino esters generated from the ad-
dition of the corresponding amines to dimethyl acety-
lenedicarboxylates.[19-22] Recently we found that the
three-component reactions of aromatic aldehydes, aryl
amines and acetylenedicarboxylates could give 2-hy-
droxyhydropyridines, 1,4-dihydropyridines or 2-pyrroli-
dinones under different conditions.[23] Encouraged by
these results and in order to hunt for new domino reac-
Experimental
Reagents and apparatus
All reagents and solvents were commercial available
with analytical grade and used as received. Evaporation
removal of organic solvents was carried out with a ro-
tary evaporator in conjunction with a aspirator. Melting
points were taken on a hot-plate microscope apparatus
and uncorrected. 1H and 13C NMR spectra were recorded
on a Bruker AV-600 instrument. IR spectra were ob-
tained on a Bruker Tensor27 spectrometer (KBr disc).
HRMS were measured at Bruker UHR-TOF maXis
spectrometer. X-ray data were collected on a Bruker
Smart APEX-2 diffractometer.
General procedure for the preparation of com-
pounds 1a－1q from one-pot domino reactions of
arylamines, methyl propiolate and aromatic alde-
hydes
In a round bottom flask, a mixture of arylamine (2.0
mmol) and methyl propiolate (2.0 mmol, 0.168 g) in 5.0
mL ethanol was stirred at room temperature for 8－12 h.
Then aromatic aldehyde (1.0 mmol) and FeCl3 (0.2
mmol, 0.032 g) were added to it. The solution was
stirred at room temperature for an additional 24 h. The
resulting precipitates were collected by filtration and
washed with cold alcohol to give the pure product.
*
E-mail: cgyan@yzu.edu.cn
Received February 2, 2013; accepted March 5, 2013; published online April 3, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201300094 or from the author.
Chin. J. Chem. 2013, 31, 479—484
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
479

Liu et al.
FULL PAPER
(2Z,4Z)-Dimethyl 2,4-bis((4-methoxyphenyl-amino)-
MHz, DMSO-d6) δ: 9.80 (d, J＝12.2 Hz, 2H, NH), 7.35
(d, J＝6.6 Hz, 2H, ArH), 7.15 (d, J＝6.6 Hz, 2H, ArH),
7.04 (d, J＝6.6 Hz, 4H, ArH), 6.89 (d, J＝12.2 Hz, 2H,
CH), 6.80 (d, J＝7.2 Hz, 4H, ArH), 5.17 (brs, 1H, CH),
3.62 (s, 6H, OCH3), 2.19 (s, 6H, CH3), 1.28 (s, 9H,
CH3); 13C NMR (150 MHz, DMSO-d6) δ: 168.8, 142.8,
138.7, 131.0, 129.9, 128.2, 124.9, 115.4, 115.3, 101.2,
50.9, 43.1, 34.1, 31.2, 31.1, 20.1; IR (KBr) ν: 3449,
3023, 2915, 2865, 1885, 1671, 1615, 1517, 1440, 1360,
1280, 1222, 1187, 1108, 1002, 946, 865, 810 cm−1;
HRMS (ESI) calcd for C33H37N2O4 ([M−H]−): 525.2759,
found 525.2755.
methylene)-3-(4-methoxyphenyl)pentanedioate (1a)
1
White solid, 45%. m.p. 122－125 ℃; H NMR (600
MHz, DMSO-d6) δ: 9.78 (d, J＝12.6 Hz, 2H, NH), 7.14
(d, J＝9.0 Hz, 2H, ArH), 6.92 (brs, 1H, ArH), 6.90－
6.88 (m, 6H, ArH, CH), 6.87－6.85 (m, 5H, ArH), 5.12
(s, 1H, CH), 3.74 (s, 3H, OCH3), 3.68 (s, 6H, OCH3),
3.61 (s, 6H, OCH3); 13C NMR (150 MHz, DMSO-d6) δ:
168.9, 157.4, 154.8, 143.3, 135.3, 134.6, 129.5, 116.8,
114.9, 113.5, 100.7, 56.0, 55.2, 54.9, 50.8, 42.7, 18.5;
IR (KBr) ν: 3385, 3002, 2946, 2834, 2060, 1619, 1514,
1438, 1360, 1325, 1286, 1213, 1171, 1101, 1033, 948,
823, 769 cm−1; HRMS (ESI) calcd for C30H31N2O7
([M−H] −): 531.2137, found 531.2127.
(2Z,4Z)-Dimethyl 2,4-bis((3-nitrophenylamino)-
methylene)-3-(4-methylphenyl)pentanedioate
(1f)
1
(2Z,4Z)-Dimethyl 2,4-bis((4-methoxyphenylamino)-
Yellow solid, 73%. m.p. 170－172 ℃; H NMR (600
MHz, DMSO-d6) δ: 9.92 (d, J＝12.6 Hz, 2H, NH), 8.06
(brs, 2H, ArH), 7.76 (d, J＝7.2 Hz, 1H, ArH), 7.59 (t,
J＝8.4 Hz, 1H, ArH), 7.15 (d, J＝12.6 Hz, 2H, CH),
7.07 (d, J＝7.2 Hz, 4H, ArH), 6.92 (d, J＝7.8 Hz, 4H,
ArH), 5.29 (brs, 1H, CH), 3.61 (s, 6H, OCH3), 2.20 (s,
6H, CH3); 13C NMR (150 MHz, DMSO-d6) δ: 168.7,
147.7, 146.5, 143.9, 138.4, 135.4, 131.2, 129.9, 129.4,
122.8, 121.1, 115.6, 99.5, 50.9, 43.8, 20.1; IR (KBr) ν:
3281, 2918, 1677, 1611, 1528, 1524, 1352, 1220, 1104,
1000, 949, 817 cm−1; HRMS (ESI) calcd for
C29H28N3O6 ([M−H]−): 514.1984, found 514.1974.
(2Z,4Z)-Dimethyl 2,4-bis((4-methylphenylamino)-
methylene)-3-(4-methylphenyl)pentanedioate
(1b)
1
White solid, 68%. m.p. 144－147 ℃; H NMR (600
MHz, DMSO-d6) δ: 9.80 (d, J＝12.6 Hz, 2H, NH), 7.12
(brs, 4H, ArH), 6.92－6.86 (m, 10H, ArH, CH), 5.13
(brs, 1H, CH), 3.68 (s, 6H, OCH3), 3.60 (s, 6H, OCH3),
2.28 (s, 3H, CH3); 13C NMR (150 MHz, DMSO-d6) δ:
168.9, 154.8, 143.5, 140.5, 134.8, 134.6, 128.8, 128.4,
116.8, 114.9, 100.5, 55.2, 50.8, 43.1, 20.6; IR (KBr) ν:
3450, 2998, 2949, 2837, 2063, 1667, 1619, 1514, 1443,
1400, 1356, 1322, 1216, 1177, 1103, 1035, 998, 947,
825, 770 cm−1; HRMS (ESI) calcd for C30H31N2O6
([M−H]−): 515.2188, found 515.2182.
(2Z,4Z)-Dimethyl 2,4-bis((4-methoxyphenylamino)-
methylene)-3-(4-bromohenyl)pentanedioate
(1g)
1
methylene)-3-(4-chlorophenyl)pentanedioate
(1c)
White solid, 61%. m.p. 146－148 ℃; H NMR (600
MHz, DMSO-d6) δ: 9.87 (d, J＝10.2 Hz, 2H, NH), 7.48
(brs, 2H, ArH), 7.22 (brs, 2H, ArH), 7.07 (brs, 6H, ArH,
CH), 6.88 (brs, 4H, ArH), 5.14(s, 1H, CH), 3.61 (s, 6H,
OCH3), 2.20 (s, 6H, CH3); 13C NMR (150 MHz,
DMSO-d6) δ: 168.8, 143.2, 138.5, 131.1 130.9, 130.8,
129.9, 118.9, 115.4, 100.3, 50.9, 43.3, 20.1; IR (KBr) ν:
3277, 2950, 1671, 1608, 1519, 1437, 1302, 1263, 1192,
1074, 993, 945, 864, 814, 793 cm−1; HRMS (ESI) calcd
for C29H28BrN2O4 ([M−H]−): 547.1238, found
547.1231.
1
White solid, 69%. m.p. 120－122 ℃; H NMR (600
MHz, DMSO-d6) δ: 9.83 (d, J＝12.6 Hz, 2H, NH), 7.35
(d, J＝8.4 Hz, 2H, ArH), 7.27 (d, J＝7.8 Hz, 2H, ArH),
6.97－6.92 (m, 6H, ArH, CH), 6.86 (d, J＝9.0 Hz, 4H,
ArH), 5.15 (brs, 1H, CH), 3.68 (s, 6H, OCH3), 3.60 (s,
6H, OCH3); 13C NMR (150 MHz, DMSO-d6) δ: 168.8,
154.9, 143.8, 142.9, 134.5, 130.3, 128.0, 116.9, 114,9,
99.8, 55.2, 50.8, 43.2; IR (KBr) ν: 3322, 3285, 3010,
2951, 2834, 2061, 1868, 1671, 1615, 1514, 1442, 1403,
1354, 1285, 1205, 1169, 1099, 1031, 951, 864, 822, 770
cm−1; HRMS (ESI) calcd for C29H28ClN2O6 ([M-H] −):
535.1641, found 535.1632.
(2Z,4Z)-Dimethyl 2,4-bis(phenylamino)methylene)-
3-(4-chlorophenyl)pentanedioate (1h) White solid,
75%. m.p. 142－144 ℃; 1H NMR (600 MHz, DMSO-d6)
δ: 9.92 (d, J＝12.7 Hz, 2H, NH), 7.37 (d, J＝8.4 Hz, 2H,
ArH), 7.30－7.25 (m, 6H, ArH), 7.09 (d, J＝12.7 Hz,
2H, CH), 6.98 (d, J＝8.4 Hz, 4H, ArH), 6.94 (t, J＝7.2
Hz, 2H, ArH), 5.19 (brs, 1H, CH), 3.63 (s, 6H, OCH3);
13C NMR (150 MHz, DMSO-d6) δ: 168.8, 142.8, 142.5,
140.9, 130.5, 130.4, 129.5, 128.1, 122.1, 115.4, 101.1,
51.0, 43.3; IR (KBr) ν: 3390, 3337, 2948, 1669, 1594,
1498, 1438, 1359, 1307, 1190, 1085, 1002, 947, 854,
748 cm−1; HRMS (ESI) calcd for C28H24ClN2O4
([M−H]−): 475.1430, found 475.1419.
(2Z,4Z)-Dimethyl 2,4-bis((4-methylphenylamino)-
methylene)-3-(4-methoxyphenyl)pentanedioate (1d)
1
White solid, 46%. m.p. 132－135 ℃; H NMR (600
MHz, DMSO-d6) δ: 9.82 (d, J＝12.6 Hz, 2H, NH), 7.14
(d, J＝8.4 Hz, 2H, ArH), 7.06 (d, J＝7.8 Hz, 4H, ArH),
6.97 (d, J＝12.6 Hz, 2H, CH), 6.88 (d, J＝8.4 Hz, 2H,
ArH), 6.83 (d, J＝8.4 Hz, 4H, ArH), 5.13 (brs, 1H, CH),
3.74 (s, 3H, OCH3), 3.61 (s, 6H, OCH3), 2.20 (s, 6H,
CH3); 13C NMR (150 MHz, DMSO-d6) δ: 168.9, 157.5,
142.7, 138.6, 135.1, 131.0, 130.0, 129.5, 115.3, 113.6,
101.3, 54.9, 50.9, 42.8, 20.1; IR (KBr) ν: 3449, 3014,
2951, 1699, 1614, 1516, 1439, 1357, 1298, 1220, 1183,
1100, 1034, 994, 808, 676 cm−1; HRMS (ESI) calcd for
C30H31N2O5 ([M−H]−): 499.2238, found 499.2230.
(2Z,4Z)-Dimethyl-2,4-bis((4-methylphenylamino)-
methylene)-3-(4-tert-butylphenyl)pentanedioate (1e)
(2Z,4Z)-Dimethyl-2,4-bis((4-chlorophenylamino)-
methylene)-3-(4-methoxyphenyl)pentanedioate (1i)
1
White solid, 76%. m.p. 156－159 ℃; H NMR (600
MHz, DMSO-d6) δ: 9.90 (d, J＝12.6 Hz, 2H, NH), 7.30
(d, J＝9.0 Hz, 4H, ArH), 7.16 (d, J＝8.4 Hz, 2H, ArH),
7.00－6.98 (m, 5H, ArH, CH), 6.97 (brs, 1H, ArH), 6.88
1
White solid, 66%. m.p. 157－160 ℃; H NMR (600
480
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 479—484

Diastereoselective Synthesis of Arylidene Bis(3-arylaminoacrylates) via One-pot Domino Reactions
(d, J＝8.4 Hz, 2H, ArH), 5.14 (brs, 1H, CH), 3.74 (s, 3H,
OCH3), 3.62 (s, 6H, OCH3); 13C NMR (150 MHz,
DMSO-d6) δ: 168.8, 157.5, 142.0, 140.0, 134.5, 129.6,
129.3, 125.5, 116.9, 113.6, 102.7, 54.9, 51.0, 42.9; IR
(KBr) ν: 3393, 2949, 2836, 2069, 1880, 1668, 1624,
1502, 1438, 1358, 1317, 1257, 1221, 1188, 1097, 1037,
1001, 942, 818, 744, 710, 663, 506 cm−1; HRMS (ESI)
calcd for C28H25Cl2N2O5 ([M−H]−) 539.1146, found
539.1139.
(2Z,4Z)-Dimethyl-2,4-bis((benzylamino)methylene)-
3-(4-methoxyphenyl)pentanedioate (1j) White solid,
60%. m.p. 136－139 ℃; 1H NMR (600 MHz, DMSO-d6)
δ: 8.14 (brs, 2H, NH), 7.31－7.24 (m, 6H, ArH), 7.15
(brs, 4H, ArH), 6.95－6.94 (m, 2H, ArH), 6.78 (brs, 2H,
ArH), 6.36 (d, J＝12.6 Hz, 2H, CH), 4.93 (s, 1H, CH),
4.23 (brs, 4H, CH2), 3.70 (s, 3H, OCH3), 3.47 (s, 6H,
OCH3); 13C NMR (150 MHz, DMSO-d6) δ: 169.1, 157.0,
152.2, 140.0, 136.7, 129.1, 128.4, 127.0, 126.8, 113.3,
96.9, 54.8, 51.2, 50.1, 42.0; IR (KBr) ν: 3333, 3027,
2950, 2915, 1663, 1608, 1509, 1443, 1363, 1318, 1177,
974 cm−1; HRMS (ESI) calcd for C30H31N2O5 ([M−H]−):
499.2238, found 499.2231.
(150 MHz, DMSO-d6) δ: 168.9, 152.5, 139.9, 130.7,
130.6, 130.5, 130.4, 130.3, 128.7, 128.6, 128.5, 128.4,
128.3, 128.2, 127.2, 127.1, 127.0, 126.9, 95.9, 51.2,
51.1, 50.2; IR (KBr) ν: 3363, 3026, 2947, 1668, 1488,
1441, 1354, 1207, 1123, 1070, 1030, 964, 793 cm−1;
HRMS (ESI) calcd for C29H28BrN2O4 ([M−H]−):
547.1238, found 547.1230.
(2Z,4Z)-Dimethyl 3-phenyl-2,4-bis((phenethylamino)-
methylene)pentanedioate (1n) White solid, 65%.
1
m.p. 128－130 ℃; H NMR (600 MHz, DMSO-d6) δ:
8.17－8.15 (m, 2H, NH), 7.32－7.29 (m, 4H, ArH),
7.25－7.20 (m, 4H, ArH), 7.15－7.11 (m, 5H, ArH),
7.05 (d, J＝7.2 Hz, 2H, ArH), 6.37 (d, J＝13.2 Hz, 2H,
CH), 4.99 (s, 1H, CH), 4.23－4.22 (m, 4H, CH2), 3.47
(s, 6H, OCH3); 13C NMR (150 MHz, DMSO-d6) δ:
169.1, 152.4, 145.0, 140.0, 128.4, 128.2, 127.8, 127.0,
126.9, 125.4, 96.6, 51.2, 50.1, 42.9; IR (KBr) ν: 3343,
3057, 3023, 2948, 1946, 1665, 1609, 1492, 1442, 1362,
1326, 1210, 1179, 1121, 1071, 1032, 1000, 966, 793
cm−1; HRMS (ESI) calcd for C29H29N2O4 ([M−H]−):
469.2133, found 469.2130.
(2Z,4Z)-Dimethyl 3-(4-methoxyphenyl)-2,4-bis((phen-
(2Z,4Z)-Dimethyl-2,4-bis((benzylamino)methylene)-
3-(4-methylphenyl)pentanedioate (1k) White solid,
63%. m.p. 146－149 ℃; 1H NMR (600 MHz, DMSO-d6)
δ: 8.16－8.14 (m, 2H, NH), 7.31－7.29 (m, 4H, ArH),
7.25－7.24 (m, 2H, ArH), 7.15－7.14 (m, 4H, ArH),
7.02－7.01 (m, 2H, ArH), 6.93－6.92 (m, 2H, ArH),
6.37 (d, J＝12.6 Hz, 2H, CH), 4.94 (s, 1H, CH), 4.23
(brs, 4H, CH2), 3.47 (s, 6H, OCH3), 2.24 (s, 3H, CH3);
13C NMR (150 MHz, DMSO-d6) δ: 169.1, 152.3, 141.9,
140.0, 134.1, 128.4, 128.1, 127.0, 126.8, 96.7, 51.2,
50.2, 42.4, 20.5; IR (KBr) ν: 3363, 3025, 2944, 1937,
1666, 1609, 1511, 1442, 1358, 1207, 1178, 1121, 1068,
964, 853, 794 cm−1; HRMS (ESI) calcd for C30H31N2O4
([M−H]−): 483.2289, found 483.2288.
(2Z,4Z)-Dimethyl-2,4-bis((benzylamino)methylene)-
3-(4-chlorophenyl)pentanedioate (1l) White solid,
68%. m.p. 144－147 ℃; 1H NMR (600 MHz, DMSO-d6)
δ: 8.20－8.17 (m, 2H, NH), 7.31 (t, J＝7.2 Hz, 4H,
ArH), 7.26－7.25 (m, 4H, ArH), 7.15 (d, J＝7.2 Hz, 4H,
ArH), 7.06 (d, J＝8.4 Hz, 2H, ArH), 6.39 (d, J＝13.2Hz,
2H, CH), 4.94 (s, 1H, CH), 4.25 (d, J＝6.0 Hz, 4H,
CH2), 3.47 (s, 6H, OCH3); 13C NMR (150 MHz,
DMSO-d6) δ: 168.9, 152.5, 144.3, 139.9, 129.9, 129.8,
128.6, 128.5, 128.4, 128.3, 128.2, 127.8, 127.0, 126.9,
96.0, 51.2, 50.2, 42.5; IR (KBr) ν: 3728, 3361, 3311,
3025, 2948, 1668, 1610, 1490, 1443, 1359, 1315, 1208,
1179, 1123, 1007, 965, 856, 794 cm−1; HRMS (ESI)
calcd for C29H28ClN2O4 ([M−H]−): 503.1743, found
503.1737.
ethylamino)methylene)pentanedioate (1o)
White
1
solid, 60%. m.p. 102－105 ℃; H NMR (600 MHz,
DMSO-d6) δ: 7.84－7.81 (m, 2H, NH), 7.28 (t, J＝7.2
Hz, 4H, ArH), 7.22－7.19 (m, 2H, ArH), 7.14 (d, J＝7.2
Hz, 4H, ArH), 6.77－6.74 (m, 4H, ArH), 6.06 (d, J＝
13.2 Hz, 2H, CH), 4.82 (s, 1H, CH), 3.72 (s, 3H, OCH3),
3.44 (s, 6H, OCH3), 3.33－3.29 (m, 2H, CH2), 3.28－
3.26 (m, 2H, CH2), 2.71－2.70 (m, 4H, CH2); 13C NMR
(150 MHz, DMSO-d6) δ: 169.0, 156.9, 151.9, 138.8,
136.8, 129.1, 128.7, 128.3, 126.1, 113.1, 95.8, 54.8,
50.1, 49.3, 41.6, 37.2; IR (KBr) ν: 3324, 3061, 2946,
1664, 1605, 1507, 1440, 1357, 1318, 1270, 1175, 1108,
1080, 987, 856, 836, 793, 751 cm−1; HRMS (ESI) calcd
for C32H35N2O5 ([M−H]−): 527.2551, found 527.2543.
(2Z,4Z)-Dimethyl 3-(4-chlorophenyl)-2,4-bis((phen-
ethylamino)methylene)pentanedioate (1p)
White
1
solid, 63%. m.p. 115－118 ℃; H NMR (600 MHz,
DMSO-d6) δ: 7.88 (brs, 2H, NH), 7.28 (brs, 4H, ArH),
7.22 (brs, 4H, ArH), 7.17 (brs, 4H, ArH), 6.86－6.85 (m,
2H, ArH), 6.06 (d, J＝12.6 Hz, 2H, CH), 4.83 (s, 1H,
CH), 3.44 (s, 6H, OCH3), 3.28 (brs, 4H, CH2), 2.72 (brs,
4H, CH2); 13C NMR (150 MHz, DMSO-d6) δ: 168.9,
152.2, 144.4, 138.8, 129.9, 129.7, 128.8, 128.5, 128.3,
128.1, 127.7, 126.1, 94.9, 50.1, 49.4, 42.1, 37.2; IR
(KBr) ν: 33322, 3046, 3023, 1664, 1584, 1490, 1440,
1358, 1313, 1270, 1182, 1112, 1085, 1015, 978, 856,
789 cm−1; HRMS (ESI) calcd for C31H32ClN2O4
([M−H]−): 531.2056, found 531.2050.
(2Z,4Z)-Dimethyl 3-(4-bromophenyl)-2,4-bis((phen-
(2Z,4Z)-Dimethyl-2,4-bis((benzylamino)methylene)-
3-(4-bromophenyl)pentanedioate (1m) White solid,
62%. m.p. 147－150 ℃; 1H NMR (600 MHz, DMSO-d6)
δ: 8.19 (brs, 2H, NH), 7.39－7.38 (m, 2H, ArH), 7.31－
7.25 (m, 6H, ArH), 7.15 (brs, 4H, ArH), 7.01－7.00 (m,
2H, ArH), 6.40 (d, J＝12.6 Hz, 2H, CH), 4.93 (s, 1H,
CH), 4.25 (brs, 4H, CH2), 3.47 (s, 6H, OCH3); 13C NMR
ethylamino)methylene)pentanedioate (1q)
White
1
solid, 62%. m.p. 113－115 ℃; H NMR (600 MHz,
DMSO-d6) δ: 7.88 (brs, 2H, NH), 7.35 (d, J＝7.2 Hz,
2H, ArH), 7.28－7.27 (m, 4H, ArH), 7.22－7.20 (m, 2H,
ArH), 7.17－7.16 (m, 4H, ArH), 6.80 (d, J＝7.2 Hz, 2H,
ArH), 6.07 (d, J＝13.2 Hz, 2H, CH), 4.81 (s, 1H, CH),
3.44 (s, 6H, OCH3), 3.28－3.27 (m, 4H, CH2), 2.72－
Chin. J. Chem. 2013, 31, 479—484
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FULL PAPER
2.71 (m, 4H, CH2); 13C NMR (150 MHz, DMSO-d6) δ:
168.8, 152.2, 144.8, 138.8, 130.6, 130.4, 128.8, 128.3,
126.1, 118.2, 94.7, 50.1, 49.4, 42.1, 37.1; IR (KBr) ν:
3349, 3063, 2946, 1663, 1607, 1488, 1439, 1354, 1192,
1176, 1109, 1079, 986, 857, 790 cm−1; HRMS (ESI)
calcd for C31H32BrN2O4 ([M−H]−): 575.1551, found
575.1545.
3.30 (s, 3H, OCH3); 13C NMR (150 MHz, DMSO-d6) δ:
179.1, 166.9, 160.2, 158.5, 156.9, 151.2, 139.8, 138.8,
136.2, 132.7, 128.5, 127.2, 114.4, 114.3, 110.7, 110.6,
109.6, 109.5, 93.0, 76.2, 74.4, 51.7, 49.8; IR (KBr) ν:
3336, 2951, 1719, 1676, 1611, 1484, 1448, 1372, 1322,
1259, 1220, 1185, 1159, 1048, 1010, 965, 882, 807 cm−1;
HRMS (ESI) calcd for C19H16FN2O4 ([M−H]−):
355.1100, found 355.1102.
General procedure for the preparation of com-
pounds 2a－2d from one-pot domino reactions of
benzylamine, methyl propiolate and isatins
(Z)-Methyl-3-(benzylamino)-2-(5-chloro-3-hydroxy-
2-oxoindolin-3-yl)acrylate (2d) White solid, 60%.
1
m.p. 144－146 ℃; H NMR (600 MHz, DMSO-d6) δ:
In a round bottom flask, a mixture of benzylamine
(2.0 mmol, 0.214 g) and methyl propiolate (2.0 mmol,
0.168 g) in 5.0 mL ethanol was stirred at room tem-
perature for 8－12 h. Then isatins (2.0 mmol) and FeCl3
(0.2 mmol, 0.032 g) were added to it. The solution was
stirred at room temperature for an additional 24 h. The
resulting precipitates were collected by filtration and
washed with cold alcohol to give the solid product,
which were recrystallized from ethanol to give the pure
product.
10.19 (s, 1H, NH), 8.17－8.15 (s, 1H, NH), 7.53 (d, J＝
13.8 Hz, 1H, CH), 7.41－7.38 (m, 2H, ArH), 7.36－
7.35 (m, 2H, ArH), 7.32－7.29 (m, 1H, ArH), 7.17 (d,
J＝7.5 Hz, 1H, ArH), 6.92 (s, 1H, ArH), 6.75 (d, J＝8.1
Hz, 1H, ArH), 6.21 (s, 1H, OH), 4.48 (d, J＝5.8 Hz, 2H,
CH2), 3.31 (s, 3H, OCH3); 13C NMR (150 MHz,
DMSO-d6) δ: 178.8, 166.8, 151.1, 141.6, 139.8, 136.5,
128.5, 128.1, 127.3, 127.2, 124.9, 123.1, 110.4, 92.8,
74.2, 51.7, 49.8; IR (KBr) ν: 3330, 2951, 1717, 1676,
1619, 1444, 1370, 1320, 1222, 1174, 1072, 1007, 957,
887, 817, 790 cm−1; HRMS (ESI) calcd for
C19H16ClN2O4 ([M−H]−): 371.0804, found 371.0805.
(Z)-Methyl-3-(benzylamino)-2-(3-hydroxy-2-oxoin-
dolin-3-yl)acrylate (2a)
White solid, 48%. m.p.
1
158－160 ℃; H NMR (600 MHz, DMSO-d6) δ: 10.03
(s, 1H, NH), 8.16－8.14 (m, 1H, NH), 7.54 (d, J＝13.8
Hz, 1H, CH), 7.41－7.38 (m, 2H, ArH), 7.35－7.34 (m,
2H, ArH), 7.31－7.29 (m, 1H, ArH), 7.13－7.10 (m, 1H,
ArH), 6.94 (d, J＝7.2 Hz, 1H, ArH), 6.85－6.82 (m, 1H,
ArH), 6.74 (d, J＝7.6 Hz, 1H, ArH), 6.00 (s, 1H, OH),
4.48 (d, J＝6.0 Hz, 2H, CH2), 3.27 (s, 3H, OCH3); 13C
NMR (150 MHz, DMSO-d6) δ: 179.1, 167.0, 151.0,
142.7, 139.9, 134.3, 128.5, 128.3, 127.2, 123.0, 120.9,
108.9, 93.5, 74.1, 51.6, 49.7; IR (KBr) ν: 3333, 3032,
2946, 1719, 1674, 1617, 1447, 1377, 1331, 1221, 1179,
1099, 1072, 1049, 1011, 939, 906, 764 cm−1; HRMS
(ESI) calcd for C19H17N2O4 ([M−H]−): 337.1194, found
337.1195.
(Z)-Methyl 3-(benzylamino)-2-(3-hydroxy-5-methyl-
2-oxoindolin-3-yl)acrylate (2b) White solid, 63%.
m.p. 97－99 ℃; 1H NMR (600 MHz, DMSO-d6) δ: 9.94
(s, 1H, NH), 8.16 (s, 1H, NH), 7.53 (d, J＝12.2 Hz, 1H,
CH), 7.40－7.31 (m, 5H, ArH), 6.92 (s, 1H, ArH), 6.76
(s, 1H, ArH), 6.63 (s, 1H, ArH), 5.97 (s, 1H, OH), 4.48
(s, 2H, CH2), 3.29 (s, 3H, OCH3), 2.19 (s, 3H, CH3); 13C
NMR (150 MHz, DMSO-d6) δ: 179.1, 167.0, 150.9,
140.3, 139.9, 134.3, 129.5, 128.5, 127.3, 127.2, 123.8,
108.7, 93.7, 74.2, 51.6, 49.8, 20.6; IR (KBr) ν: 3335,
3025, 2950, 1713, 1672, 1617, 1492, 1445, 1369, 1324,
1219, 1188, 1158, 1123, 1050, 1010, 960, 892, 814 cm−1;
HRMS (ESI) calcd for C20H19N2O4 ([M−H]−): 351.1350,
found 351.1347.
Results and Discussion
Recently we reported that FeCl3 catalyzed domino
reactions of arylamines, methyl propiolate, aromatic
aldehydes and indole in ethanol to give methyl 2-(1H-
indol-3-yl)arylmethyl-3-arylaminoacrylates in good
yields.[24] In this domino reaction process we found that
a new compound could be separated occasionally from
reaction mixture, which was characterized as arylidene
bis(3-arylaminoacrylates). Thus the domino reactions of
primary amines, methyl propiolate and aldehydes with
FeCl3 as catalyst were systematically investigated. In
our initial endeavour, p-methoxyaniline reacted firstly
with methyl propiolate in ethanol overnight to give the
desired β-enamino ester according to the previously re-
ported method.[19-22] Then the sequential reaction of this
in situ generated β-enamino ester with p-chlorobenzal-
dehyde as a simple model substrate was investigated to
establish the feasibility of the strategy and optimize the
reaction conditions. When the reaction was carried out
at room temperature in ethanol for 24 h with anhydrous
FeCl3 (20% mole) as catalyst, we are pleased to find
that the polysubstituted acrylate 1c was obtained in 69%
yields. Under this simple condition various arylamine
and aromatic aldehydes are employed in the reactions,
and the results are listed in Table 1 (Entries 1－9). It is
clearly seen that all reactions preceded very smoothly
and a series of arylidene bis(3-arylaminoacrylates) 1a－
1i were obtained in moderate to good yields. Ben-
zylamine and 2-phenylethylamine were also utilized in
the reaction and the higher yields of the desired products
were successfully obtained (Table 1, Entries 10－17).
The structures of the bis(3-arylaminoacrylates) (1a
－1q) were established on the spectroscopic methods
(Z)-Methyl 3-(benzylamino)-2-(5-fluoro-3-hydroxy-
2-oxoindolin-3-yl)acrylate (2c) White solid, 57%.
1
m.p. 146－149 ℃; H NMR (600 MHz, DMSO-d6) δ:
10.07 (s, 1H, NH), 8.17 (s, 1H, NH), 7.53 (d, J＝13.8
Hz, 1H, CH), 7.41－7.29 (m, 5H, ArH), 6.95－6.93 (m,
1H, ArH), 6.77－6.76 (m, 1H, ArH), 6.73－6.71 (m, 1H,
ArH), 6.17 (s, 1H, OH), 4.48 (d, J＝5.7 Hz, 2H, CH2),
482
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 479—484

Diastereoselective Synthesis of Arylidene Bis(3-arylaminoacrylates) via One-pot Domino Reactions
Table 1 Synthesis of arylidene bis(3-arylaminoacrylates) 1a－1q
Ar'
CO2CH3
CH3O2C
CO2CH3
EtOH Ar'CHO
r.t.
ArNH2
+
FeCl3, r.t.
ArHN
NHAr
Yield/%
45
Entry Compd.
Ar
Ar'
1
2
1a
1b
1c
1d
1e
1f
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
C6H5
p-CH3OC6H4
p-CH3C6H4
p-ClC6H4
68
3
69
4
p-CH3OC6H4
p-(CH3)3CC6H4
m-NO2C6H4
p-BrC6H4
46
5
66
6
73
7
1g
1h
1i
61
Figure 2 Molecular structure of compound 1c.
8
p-ClC6H4
75
9
p-ClC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3C6H4
p-ClC6H4
42
in Scheme 1. At first arylamine adds to methyl propio-
late to form the β-enamino ester (A). Secondly nucleo-
philic addition of β-enamino ester to carbonyl group of
aromatic aldehyde forms the adduct intermediate (B).
Thirdly in the presence of Lewis acid FeCl3 as the cata-
lyst, the new generated electrophilic reagent (C) reacted
with another molecular β-enamino ester (A) to give the
final arylidene bis(3-arylaminoacrylate) 1. The stereo-
chemistry of bis(3-arylaminoacrylates) was obviously
controlled by the cis/trans configuration of the in situ
formed β-enamino ester (A) and the sequential reaction
steps in the reaction mechanism. It has been reported
that the trans-isomer (A) and cis-isomer (A') is in equi-
librium and the different ratios of two isomers were
found to be variable with solvent, substituent and con-
centration of the reactants.[25-27] The sequential reactions
are all reversible and in thermodynamically equilibrium.
Thus the substituted acrylates exist in both Z- and
E-isomers. In Z-isomer one intramolecular hydrogen
bond can be formed between the amino group and ester
group, which might increase the stability of the
10
11
12
13
14
15
16
17
1j
C6H5CH2
60
1k
1l
C6H5CH2
63
C6H5CH2
68
1m
1n
1o
1p
1q
C6H5CH2
p-BrC6H4
62
C6H5CH2
C6H5
65
C6H5CH2CH2 p-CH3OC6H4
C6H5CH2CH2 p-ClC6H4
C6H5CH2CH2 p-BrC6H4
60
63
62
and were ambiguously confirmed by single-crystal
structure determinations of compounds 1a (Figure 1)
and 1c (Figure 2). 1H NMR spectra of compounds 1a－
1q usually show a one set of absorption peaks for each
characterized groups, which clearly means only one
isomer existed in each sample. Single crystal structures
of 1a and 1c clearly indicated that both units of acry-
lates are in E-configuration with 3-arylamino group and
ester group existing in cis-position of double band. One
N－H－O hydrogen bond was formed between the
amino group and the carbonyl group. These results also
indicates that this domino reaction is a highly stereose-
lective reaction.
Scheme 1 The proposed formation mechanism for bis(3-
arylaminoacrylates)
To explain the formation of the arylidene bis(3-
arylaminoacrylates), a proposed mechanism is outlined
OCH 3
CH3O2C
CO2CH3
EtOH
O
H
ArNH2
+
NHAr
OCH3
A
N
Ar
A'
OCH3
Ar'
Ar'
O
H
FeCl3
O
Ar'CHO
OH
OH
H
FeCl3
N
N
Ar
Ar
C
B
OCH3
Ar'
O
H
CH3O2C
ArHN
CO2CH3
NHAr
N
Ar
Figure 1 Molecular structure of compound 1a.
1a−1q
Chin. J. Chem. 2013, 31, 479—484
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
483

Liu et al.
FULL PAPER
Z-isomer.
complex acrylates in synthetic and medicinal chemistry.
Under the similar reaction conditions, when isatins
were employed to replace aromatic aldehydes in the
one-pot domino reactions, the oxindolyl substituted
acrylates (2a－2d) were obtained in moderate yields
(Table 2). The reason for no bis(3-arylaminoacrylate)
being formed in this reaction might be due to that the
dehydration of 3-hydroxyoxindole unit is very slow un-
der such mild conditions. The single crystal structure
determination of compound 2a (Figure 3) also showed
that one hydrogen bond formed between the benzyl-
amino group and methoxycarbonyl group, and the
Z-configuration of the substituted acrylate exists.
Acknowledgement
This work was financially supported by the National
Natural Science Foundation of China (Grant No.
21172189) and the Priority Academic Program Devel-
opment of Jiangsu Higher Education Institutions.
Supplementary Information
Single crystal data for compounds 1a (CCDC
892280), 1c (CCDC 888177), and 1a (CCDC 888176)
have been deposited in the Cambridge Crystallographic
Data Center.
Table 2 Synthesis of oxindolyl substituted acrylates
O
References
O
R
CH3O
HO
H
N
NH2
O
CO2CH3
[1] Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.;
Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899.
[2] Nair, V.; Menon, R. S.; Sreekanth, A.; Abhilash, N.; Biju, A. T. Acc.
Chem. Res. 2006, 39, 520.
[3] Kielland, N.; Lavilla, R. Top. Heterocycl. Chem. 2010, 25, 127.
[4] Shaabani, A.; Rezayan, A. H.; Sarvary, A. Mol. Divers. 2011, 15, 41.
[5] Han, Y.; Sun, J.; Sun, Y.; Gao, H.; Yan, C. G. Chin. J. Org. Chem.
2012, 32, 1577.
N
H
EtOH
r. t.
R
O
FeCl3, r.t.
N
H
2a−2d
Compd.
R
2a
H
2b
CH3
63
2c
F
2d
Cl
60
[6] Li, X.; Wang, J. Y.; Yu, W.; Wu, L. M. Tetrahedron 2009, 65, 1140.
[7] Zhu, Q. H.; Jiang, H. F.; Li, J. H.; Zhang, M.; Wang, X. J.; Qi, C. R.
Tetrahedron 2010, 66, 9721.
Yield/%
48
57
[8] Nguyen, T. B.; Martel, A.; Dhal, R.; Dujardin, G. Org. Lett. 2008, 10,
4493.
[9] Fan, M. Q.; Yan, Z. Y.; Liu, W. M.; Liang, Y. M. J. Org. Chem. 2005,
70, 8204.
[10] Srikrishna, A.; Sridharan, M.; Prasad, K. R. Tetrahedron Lett. 2010,
51, 3651.
[11] Bezenšek, J.; Koleša, T.; Grošelj, U.; Wagger, J.; Stare, K.; Meden,
A.; Svete, J.; Stanovnik, B. Tetrahedron Lett. 2010, 51, 3392.
[12] Lu, L.; Wei, J. M.; Chen, J.; Zhang, J. P.; Deng, H. M.; Shao, M.;
Zhang, H.; Cao, W. G. Tetrahedron 2009, 65, 9152.
[13] Alizadeh, A.; Rostamnia, S.; Hosseinpour, N. Tetrahedron Lett. 2009,
50, 1533.
[14] Teimouri, M. B.; Abbasi, T. Tetrahedron 2010, 66, 3795.
[15] Sun, J.; Xia, E. Y.; Wu, Q.; Yan, C. G. Org. Lett. 2010, 12, 3678.
[16] Sun, J.; Sun, Y.; Gao, H.; Yan, C. G. Eur. J. Org. Chem. 2011,
6952.
Figure 3 Molecular structure of compound 2a.
[17] Sun, J.; Xia, E. Y.; Wu, Q.; Yan, C. G. ACS Comb. Sci. 2011, 13, 421.
[18] Sun, J.; Sun, Y.; Gong, H.; Xue, Y. J.; Yan, C. G. Org. Lett. 2012, 14,
5172.
Conclusions
[19] Sun, J.; Sun, Y.; Xia, E. Y.; Yan, C. G. ACS Comb. Sci. 2011, 13, 436.
[20] Sun, Y.; Sun, J.; Yan, C. G. Mol. Divers. 2012, 16, 163.
[21] Han, Y.; Sun, J.; Sun, Y.; Gao, H.; Yan, C. G. Chin. J. Org. Chem.
2012, 32, 1577.
[22] Sun, J.; Wu, Q.; Zhang, L. J.; Yan, C. G. Chin. J. Chem. 2012, 30,
1548.
[23] Sun, J.; Wu, Q.; Xia, E. Y.; Yan, C. G. Eur. J. Org. Chem. 2011,
2981.
[24] Zhang, L. L.; Sun, J.; Yan, C. G. Tetrhedron Lett. 2012, 53, 6965.
[25] Cho, C. S. Tetrahedron Lett. 2005, 46, 1415.
[26] Ziyaei-Halimehjani, A.; Saidi, M. R. Tetrahedron Lett. 2008, 49,
1244.
In conclusion, we have systematically investigated
the one-pot domino reactions of primary amine, methyl
propiolate and aromatic aldehydes with Lewis acid as
catalyst. The scope and limitation of this domino reac-
tion was established and the reaction mechanism was
briefly discussed. Thus an efficient and diastereoselective
synthetic protocol for the functionalized arylidene
bis(3-arylaminoacrylates) in good yields was success-
fully developed. This protocol has advantages of mild
reaction conditions, easily accessible starting material
and easy purification of the products, which makes it a
useful and attractive method for the synthesis of the
[27] Zhu, Q. H.; Jiang, H. F.; Li, J. H.; Zhang, M.; Wang, X. J.; Qi, C. R.
Tetrahedron 2009, 65, 4604.
(Pan, B.; Qin, X.)
484
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Chin. J. Chem. 2013, 31, 479—484