Molecular diversity of three-component reactions of N-benzylbenzimidazolium salts, isatin, and malononitrile or ethyl cyanoacetate

Article abstract of DOI:10.1002/ejoc.201200269

The three-component reactions of N-benzylbenzimidazolium salts, isatins, and malononitrile or ethyl cyanoacetate showed very interesting molecular diversity depending on the structures of the benzimidazolium salts. The reactions of N-benzyl-N'-p-nitrobenz

Full text of DOI:10.1002/ejoc.201200269

Job/Unit: O20269
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FULL PAPER
DOI: 10.1002/ejoc.201200269
Molecular Diversity of Three-Component Reactions of
N-Benzylbenzimidazolium Salts, Isatin, and Malononitrile or Ethyl
Cyanoacetate
Li Hui,[a] Hong-Yan Li,[a] and Chao-Guo Yan*[a]
Keywords: Multicomponent reactions / Zwitterions / Nitrogen heterocycles / Molecular diversity
The three-component reactions of N-benzylbenzimidazolium
salts, isatins, and malononitrile or ethyl cyanoacetate showed
very interesting molecular diversity depending on the struc-
tures of the benzimidazolium salts. The reactions of N-
benzyl-NЈ-p-nitrobenzylbenzimidazolium salts gave a series
of zwitterionic salts in good yields. Under similar reaction
conditions the reactions of N-benzyl-NЈ-phenacylbenzimid-
azolium salts resulted in the unexpected products with open-
ing of the imidazole ring.
benzimidazoles,[14] a mixture of N-benzyl-NЈ-p-nitrobenz-
ylbenzimidazolium bromide (1a), 5-methylisatin, and
malononitrile with triethylamine as a base catalyst in meth-
anol was stirred at room temperature for several hours. Af-
ter workup, we unexpectedly found that instead of isolating
the expected pyrrolo[1,2-a]benzimidazole, zwitterionic salt
Introduction
Heterocyclic ammonium salts such as pyridinium, quino-
linium, and isoquinolinium salts are readily available from
the alkylation of azaaromatic heterocycles and have been
used in a great variety of synthetic reactions for the synthe-
sis of complex heterocycles.[1–6] Five-membered heterocyclic
ammonium salts such as imidazolium salts have also at-
tracted much attention[7–9] aside from their use as ionic li-
quids and precursors of N-heterocyclic carbenes. The reac-
tivity and synthetic applications of the related benzimidaz-
olium salts remain unexplored, although there are several
reports of the use of their benzimidazolium ylide precursors
in 1,3-dipolar cycloadditions for the preparation of pyr-
rolo[1,2-a]benzimidazoles.[10–13] Recently, we found that the
one-pot reactions of N-benzylbenzimidazolium salts, aro-
matic aldehydes, and active methylene compounds gave a
series of zwitterionic salts or functionalized pyrrolo[1,2-a]-
benzimidazoles in good yields.[14] To evaluate the scope of
this reaction, we investigated the three-component reaction
of N-benzylbenzimidazolium salts with isatin and malono-
nitrile or ethyl cyanoacetate. Here we wish to report the
efficient synthesis of a new type of N-benzylbenzimidazol-
ium zwitterionic salts and the unexpected products with
opening of the imidazole ring.
Table 1. Synthesis of zwitterionic salts 2a–n through a three-com-
ponent reaction.[a]
Entry
Compound
R
RЈ
E
Yield [%]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
CH3
Cl
CH3 CH2C6H5
Cl
F
CH3
Cl
H
H
CN
CN
CN
CN
CN
CN
CN
CN
68
59
84
70
79
82
90
87
71
68
74
76
58
62
CH2C6H5
CH2C6H5
n-C4H9
n-C4H9
n-C4H9
F
Results and Discussion
9
CH3 CH2C6H5
Cl
F
CH3
Cl
F
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
10
11
12
13
14
CH2C6H5
CH2C6H5
n-C4H9
n-C4H9
n-C4H9
According to previously established reaction conditions
for the one-pot reaction of functionalized pyrrolo[1,2-a]-
[a] College of Chemistry & Chemical Engineering,
Yangzhou University,
[a] Reactions were carried out at room temperature by using
N-benzyl-NЈ-p-nitrophenylbenzimidazolium bromide (1.0 mmol),
isatin (1.0 mmol), malononitrile or ethyl cyanoacetate (1.0 mmol),
and triethylamine (1.0 mmol) in methanol (25 mL).
Yangzhou 225002, China
E-mail: cgyan@yzu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200269.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. Hui, H.-Y. Li, C.-G. Yan
FULL PAPER
2a was obtained in 68% yield. Under similar conditions, nent reaction of N-benzyl-NЈ-phenacylbenzimidazolium
other substituted isatins reacted smoothly to afford the cor- bromide (1b), isatins, and malononitrile with triethylamine
responding zwitterionic salt 2b–h in satisfactory yields (59– as the base catalyst gave products 3a–g, in which the imid-
90%; Table 1, Entries 2–8). It should be noted that isatins azole ring is opened and the malononitrile unit is not con-
bearing 1-benzyl and 1-n-butyl groups gave relatively higher nected to isatin (Table 2). Then, the reactions of ethyl cy-
yields than those of other isatins due to the better solubility anoacetate showed similar phenomena and produced the
of the zwitterionic salts. Ethyl cyanoacetate was also suc- corresponding ring-opening products 3h–m in satisfactory
cessfully utilized in the three-component reaction to give yields. Here, the formation of the ring-opening products is
the corresponding zwitterionic salts 2i–n) in good yields completely unexpected. The structures of 3a–m were estab-
(Table 1, Entries 9–14). The structures of prepared zwitter- lished on the basis of spectroscopic methods and were fur-
ionic salts 2a–n were fully confirmed by 1H NMR, 13C ther confirmed by single-crystal determination of com-
NMR, and IR spectroscopy and HRMS and were further pounds 3e (Figure 2) and 3f (Supporting Information).
confirmed by single-crystal X-ray diffraction studies per-
formed for compound 2e (Figure 1). It should be noted that
compounds 2 contains two chiral centers, which means that
Table 2. Synthesis of ring-opening products 3a–m through a three-
component reaction.[a]
more than one diastereomer may exist.
Entry
Compound
R
RЈ
E
Yield [%]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
Cl
H
CN
CN
CN
CN
CN
CN
CN
89
86
77
82
80
67
73
67
60
78
85
63
68
CH3 CH2C6H5
Cl
F
CH3
Cl
F
CH3 CH2C6H5
Cl
F
CH3
Cl
F
CH2C6H5
CH2C6H5
n-C4H9
n-C4H9
n-C4H9
Figure 1. Molecular structure of zwitterionic salt 2e.
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
9
CH2C6H5
CH2C6H5
n-C4H9
n-C4H9
n-C4H9
10
11
12
13
3j
3k
3l
At present we could not determine the major dia-
stereomer or the ratio of the existing two diastereomers by
1H NMR spectroscopy. On the basis of the structure of the
zwitterionic salts, we could propose a rational mechanism
for their formation. At first, isatin reacted with malono-
nitrile to give the condensation isatylidene malononitrile
product;secondly,Michaeladditionoftheinsituformedbenz-
imidazolium ylide to isatylidene malononitrile resulted in
the zwitterionic salt. No further reactions and cyclization
processes were observed if the length of the reaction was
prolonged to several days at room temperature. Trying to
carry out the reaction at elevated temperatures caused the
formation of a very complicated mixture with decomposi-
tion of the zwitterion salts. The formation of the zwitter-
ionic salts in the above reaction is very interesting. The re-
actions of isatylidene malononitrile usually gave cyclized
spiro compounds,[15–18] and our previously reported three-
component reaction of N-benzylbenzimidazolium salts,
aromatic aldehydes, and malononitrile also yielded the
functionalized pyrrolo[1,2-a]benzimidazoles.[14] The reason
for no further cyclization is probably due to heavy steric
hindrance of the substituents in the zwitterionic salts.
To extend the scope of this one-pot reaction, the reacti-
vity of other N-benzylbenzimidazolium salts was also ex-
3m
[a] Reactions were carried out at room temperature by using N-
benzyl-NЈ-phenacylbenzimidazolium. bromide (1.0 mmol), isatin
(1.0 mmol), malononitrile or ethyl cyanoacetate (1.0 mmol), and
triethylamine (1.0 mmol) in methanol (25 mL).
plored. Under similar reaction conditions, the three-compo- Figure 2. Molecular structure of zwitterionic salt 3b.
2
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Molecular Diversity of Three-Component Reactions
Scheme 1. Proposed mechanism for the formation of compound 3.
rator in conjunction with a water aspirator. Melting points were
taken with a hot-plate microscope apparatus. 1H and 13C NMR
spectra were recorded with a Bruker AV-600 instrument. IR spectra
were obtained with a Bruker Tensor 27 spectrometer (KBr disc).
HRMS were measured with an AB 5800 MALDI-TOF/TOF in-
strument. N-Benzyl-NЈ-p-nitrobenzylbenzimidazolium bromide
(1a) and N-benzyl-NЈ-phenacylbenzimidazolium bromide (1b) were
prepared by heating N-benzylbenzimidazole with p-nitrobenzyl
bromide or α-phenacyl bromide in toluene according to a published
procedure.[14] X-ray data were collected with a Bruker Smart
Even though at present the exact reason for the opening
of the imidazole ring is not very clear, to explain the mecha-
nism for the formation of the unexpected ring-opening
products, we propose a plausible reaction course, which is
illustrated in Scheme 1. At first, 1b is deprotonated by tri-
ethylamine to give benzimidazolium ylide A. Secondly, ylide
A attacks the carbonyl group at the 3-position of isatin to
form condensation intermediate B with elimination of
water. Intermediate B is a cyclic iminium ion, in which the
positive charge can be delocalized to its resonance hybrid APEX-2 diffractometer. CCDC-870084 (for 2e), -870085 (for 3d),
and -870086 (for 3f) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
form C. Thirdly, the combination of the carbanion of ma-
lononitrile with carbocation C results in neutral product D.
Possibly due to the lower stability of the dihydrobenzimid-
azole ring, intermediate D is transformed into final product
3 through opening of the imidazoline ring and formation
of a C=C bond.
General Procedure for the Preparation of Zwitterionic Salts 2a–k
through a Three-Component Reaction: A mixture of N-benzyl-NЈ-
p-nitrobenzylbenzimidazolium bromide (1.0 mmol, 0.423 g), isatin
(1.0 mmol), malononitrile or ethyl cyanoacetate (1.0 mmol), and
triethylamine (1.0 mmol, 0.10 g) in methanol (25 mL) was stirred
at room temperature for 2 d. The resulting precipitate was collected
by filtration and then subjected to preparative thin-layer
chromatography (ethyl acetate/light petroleum ether, 2:1) to give
the pure product for analysis.
Conclusions
In conclusion we found that the three-component reac-
tion of N-benzylbenzimidazolium salts with isatins and
malononitrile or ethyl cyanoacetate show very interesting
molecular diversity, from which the efficient synthesis of N-
benzylbenzimidazolium zwitterionic salts was achieved, and
in some cases, unexpected products resulting from opening
of the imidazole ring were obtained. This protocol has the
advantage of mild reaction conditions, easily accessible
starting materials, and easy purification of the products,
which makes it a useful and attractive method for the syn-
thesis of complex N,O-containing heterocycles in synthetic
and medicinal chemistry. Further expansion of the reaction
scope and synthetic applications of this methodology are in
progress in our laboratory.
2a: Yield: 68%. Yellow solid, m.p. 144–146 °C. IR (KBr): ν = 3065
˜
(w), 2857 (w), 2169 (s), 2100 (vs), 1700 (s), 1623 (w), 1606 (w), 1555
(w), 1525 (m), 1493 (m), 1442 (w), 1379 (w), 1348 (s), 1259 (w),
1193 (m), 1121 (w), 1014 (w), 973 (w), 861 (w) cm–1. 1H NMR
(600 MHz, [D6]DMSO): δ = 10.99 (s, 1 H, ArH), 10.55 (s, 1 H,
NH), 8.23 (d, J = 7.2 Hz, 1 H, ArH), 8.00 (d, J = 7.8 Hz, 2 H,
ArH), 7.88 (d, J = 7.8 Hz, 1 H, ArH), 7.68 (s, 1 H, ArH), 7.65 (d,
J = 6.6 Hz, 2 H, ArH), 7.62 (d, J = 3.6 Hz, 1 H, ArH), 7.53 (d, J
= 7.8 Hz, 3 H, ArH), 7.43 (t, J = 7.2 Hz, 2 H, ArH), 7.39 (d, J =
7.2 Hz, 1 H, ArH), 6.99 (d, J = 7.8 Hz, 1 H, ArH), 6.61 (s, 1 H,
ArH), 6.53 (d, J = 7.8 Hz, 1 H, CH), 6.06 (d, J = 15.6 Hz, 1 H,
CH2), 5.89 (d, J = 15.6 Hz, 1 H, CH2), 2.37 (s, 3 H, CH3) ppm.
13C NMR (150 MHz, [D6]DMSO): δ =: 176.3, 147.4, 144.6, 140.9,
137.6, 133.8, 132.3, 131.4, 130.7, 130.2, 129.7, 129.0, 128.8, 128.6,
128.1, 126.9, 126.8, 126.7, 125.1, 123.0, 114.1, 113.8, 109.1, 64.2,
55.8, 50.6, 21.0 ppm. HRMS (ESI): calcd. for C33H23N6O3 [M –
H]– 551.1837; found 551.1826.
Experimental Section
General Methods: All reagents and solvents were commercially
available in analytical grade and were used as received. The evapo-
ration of the organic solvents was carried out with a rotary evapo-
2b: Yield: 59%. Yellow solid, m.p. 144–146 °C. IR (KBr): ν = 3067
˜
(w), 2165 (s), 2108 (vs), 1710 (s), 1662 (m), 1617 (m), 1555 (w),
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L. Hui, H.-Y. Li, C.-G. Yan
FULL PAPER
1525 (m), 1478 (m), 1443 (w), 1384 (w), 1349 (m), 1255 (w), 1190
(m), 1116 (w), 1079 (w), 1013 (w), 861 (w), 821 (w) cm–1. 1H NMR
(600 MHz, [D6]DMSO): δ = 10.94 (s, 1 H, ArH), 10.83 (s, 1 H,
NH), 8.33 (d, J = 8.4 Hz, 1 H, ArH), 8.06 (d, J = 9.0 Hz, 2 H,
ArH), 7.98 (s, 1 H, ArH), 7.88 (d, J = 8.4 Hz, 1 H, ArH), 7.68–
7.64 (m, 3 H, ArH), 7.63–7.59 (m, 3 H, ArH), 7.42 (t, J = 7.2 Hz,
(d, J = 15.6 Hz, 1 H, CH2), 5.92 (d, J = 15.0 Hz, 1 H, CH2), 4.82
(d, J = 16.2 Hz, 1 H, CH2), 4.75 (d, J = 15.6 Hz, 1 H, CH2) ppm.
13C NMR (150 MHz, [D6]DMSO): δ = 174.1, 157.6, 147.4, 144.9,
140.3, 136.7, 135.3, 133.7, 132.3, 130.1, 129.6, 129.0, 128.6, 128.2,
128.1, 127.4, 127.2, 127.0, 126.9, 126.4, 123.3, 114.8, 114.1, 113.9,
63.8, 56.0, 50.8, 42.9, 19.0 ppm. HRMS (ESI): calcd. for
2 H, ArH), 7.38 (t, J = 7.2 Hz, 1 H, ArH), 7.24–7.22 (m, 1 H, C39H26FN6O3 [M – H]– 645.2056; found 644.9788.
ArH), 6.74 (s, 1 H, ArH), 6.67 (d, J = 8.4 Hz, 1 H, CH), 6.07 (d,
2f: Yield: 82%. Yellow solid, m.p. 114–116 °C. IR (KBr): ν = 3060
˜
J = 15.6 Hz, 1 H, CH2), 5.89 (d, J = 15.6 Hz, 1 H, CH2) ppm. 13C
NMR (150 MHz, [D6]DMSO): δ = 176.0, 147.5, 144.7, 140.7,
138.9, 133.7, 133.1, 132.4, 130.1, 129.7, 129.0, 128.6, 128.4, 128.1,
126.9, 126.8, 126.5, 126.0, 124.7, 123.3, 114.2, 113.8, 110.9, 63.8,
55.9, 50.7, 18.7 ppm. HRMS (ESI): calcd. for C32H21ClN6O3 [M –
H]– 571.1281; found 571.1270.
(w), 2958 (w), 2162 (s), 2107 (vs), 1692 (s), 1604 (m), 1554 (w),
1525 (s), 1496 (s), 1453 (m), 1378 (m), 1348 (s), 1288 (w), 1260 (w),
1
1193 (m), 1143 (w), 1107 (w), 1015 (w), 859 (w), 812 (w) cm–1. H
NMR (600 MHz, [D6]DMSO): δ = 11.10 (s, 1 H, ArH), 7.98 (d, J
= 9.0 Hz, 2 H, ArH), 7.90 (d, J = 7.8 Hz, 1 H, ArH), 7.78 (s, 1 H,
ArH), 7.66 (d, J = 7.2 Hz, 2 H, ArH), 7.64–7.59 (m, 2 H, ArH),
7.43 (t, J = 7.8 Hz, 4 H, ArH), 7.38 (t, J = 7.2 Hz, 1 H, ArH),
7.34–7.30 (m, 1 H, ArH), 7.10 (d, J = 7.8 Hz, 1 H, ArH), 6.76 (d,
J = 8.4 Hz, 1 H, ArH), 6.67 (s, 1 H, CH), 6.10 (d, J = 15.6 Hz, 1
H, CH2), 5.93 (d, J = 15.6 Hz, 1 H, CH2), 3.55–3.50 (m, 1 H, CH2),
2c: Yield: 84%. Yellow solid, m.p. 126–128 °C. IR (KBr): ν = 3112
˜
(w), 3063 (w), 2163 (s), 2109 (vs), 1692 (s), 1603 (s), 1553 (m), 1522
(s), 1496 (s), 1541 (m), 1375 (m), 1348 (s), 1288 (w), 1252 (w), 1188
(m), 1122 (w), 1080 (w), 1016 (w), 971 (w), 881 (w) cm–1. 1H NMR
(600 MHz, [D6]DMSO): δ = 11.09 (s, 1 H, ArH), 8.25 (d, J = 3.40–3.36 (m, 1 H, CH2), 2.42 (s, 3 H, CH3), 1.13–1.10 (m, 1 H,
7.8 Hz, 1 H, ArH), 7.89 (d, J = 8.4 Hz, 3 H, ArH), 7.82 (s, 1 H,
ArH), 7.68 (d, J = 7.8 Hz, 2 H, ArH), 7.66–7.60 (m, 2 H, ArH),
7.45–7.40 (m, 4 H, ArH), 7.38 (d, J = 7.2 Hz, 1 H, ArH), 7.16 (t,
CH2), 1.08–1.04 (m, 1 H, CH2), 0.95–0.87 (m, 1 H, CH2), 0.84–
0.79 (m, 1 H, CH2), 0.65 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR
(150 MHz, [D6]DMSO): δ = 174.1, 147.3, 145.0, 144.2, 140.6,
J = 7.8 Hz, 1 H, ArH), 7.09 (t, J = 7.8 Hz, 2 H, ArH), 7.03 (d, J 138.7, 133.9, 132.2, 131.5, 130.8, 130.1, 129.6, 129.0, 128.9, 128.6,
= 7.8 Hz, 2 H, ArH), 6.91 (d, J = 7.8 Hz, 2 H, ArH), 6.72 (s, 1 H,
ArH), 6.64 (d, J = 7.8 Hz, 1 H, CH), 6.10 (d, J = 15.6 Hz, 1 H,
CH2), 5.93 (d, J = 15.6 Hz, 1 H, CH2), 4.75 (d, J = 16.2 Hz, 1 H,
128.1, 127.7, 127.3, 126.8, 126.7, 124.9, 122.9, 122.3, 121.5, 119.5,
114.0, 113.8, 110.7, 108.5, 64.1, 55.7, 50.7, 47.6, 28.9, 21.0, 19.3,
13.4 ppm. HRMS (ESI): calcd. for C37H31N6O3 [M – H]– 607.2453;
CH2), 4.68 (d, J = 15.6 Hz, 1 H, CH2), 2.40 (s, 3 H, CH3) ppm. found 607.2449.
13C NMR (150 MHz, [D6]DMSO): δ =: 174.3, 147.3, 144.9, 140.5,
2g: Yield: 90%. Yellow solid, m.p. 130–132 °C. IR (KBr): ν = 3062
˜
138.2, 135.6, 133.8, 132.3, 131.8, 130.7, 130.1, 129.5, 129.0, 128.8,
128.6, 128.1, 128.0, 127.2, 127.1, 126.9, 126.8, 126.7, 125.0, 123.0,
114.1, 113.9, 109.0, 64.0, 55.9, 50.7, 42.8, 21.0, 19.3 ppm. HRMS
(ESI): calcd. for C40H29N6O3 [M – H]– 641.2307; found 641.2220.
(w), 2963 (w), 2165 (s), 2109 (vs), 1699 (s), 1606 (m), 1555 (w),
1525 (m), 1485 (m), 1446 (w), 1349 (s), 1278 (w), 1259 (w), 1194
(m), 1144 (w), 1110 (m), 1081 (w), 1046 (w), 1015 (w), 979 (w), 860
(w) cm–1. 1H NMR (600 MHz, [D6]DMSO): δ = 11.05 (s, 1 H,
2d: Yield: 70%. Yellow solid, m.p. 146–148 °C. IR (KBr): ν = 3063 ArH), 8.29 (d, J = 8.4 Hz, 1 H, ArH), 8.08 (s, 1 H, ArH), 8.05 (d,
˜
(w), 3036 (w), 2158 (s), 2107 (vs), 1689 (s), 1605 (m), 1555 (w), J = 9.0 Hz, 2 H, ArH), 7.90 (d, J = 8.4 Hz, 1 H, ArH), 7.66 (t, J
1520 (s), 1486 (m), 1446 (w), 1430 (w), 1381 (w), 1348 (s), 1254 (w),
1182 (m), 1163 (m), 1119 (w), 1083 (w), 1052 (w), 1026 (m), 1009
= 7.2 Hz, 3 H, ArH), 7.61 (t, J = 7.8 Hz, 1 H, ArH), 7.50 (d, J =
9.0 Hz, 2 H, ArH), 7.43 (t, J = 7.8 Hz, 2 H, ArH), 7.39 (d, J =
7.2 Hz, 1 H, ArH), 7.37–7.35 (m, 1 H, ArH), 6.95 (d, J = 8.4 Hz,
1 H, ArH), 6.81 (s, 1 H, CH), 6.12 (d, J = 15.6 Hz, 1 H, CH2),
5.94 (d, J = 15.6 Hz, 1 H, CH2), 3.60–3.55 (m, 1 H, CH2), 3.47–
3.42 (m, 1 H, CH2), 1.18–1.14 (m, 1 H, CH2), 1.13–1.08 (m, 1 H,
1
(w), 983 (w), 872 (w) cm–1. H NMR (600 MHz, [D6]DMSO): δ =
11.02 (s, 1 H, ArH), 8.32 (d, J = 8.4 Hz, 1 H, ArH), 8.12 (s, 1 H,
ArH), 7.94 (d, J = 9.0 Hz, 2 H, ArH), 7.89 (d, J = 8.4 Hz, 1 H,
ArH), 7.67 (t, J = 7.2 Hz, 3 H, ArH), 7.62 (t, J = 7.8 Hz, 1 H,
ArH), 7.49 (d, J = 9.0 Hz, 2 H, ArH), 7.43 (t, J = 7.2 Hz, 2 H, CH2), 0.96–0.90 (m, 1 H, CH2), 0.85–0.79 (m, 1 H, CH2), 0.67 (t,
ArH), 7.39 (t, J = 7.8 Hz, 1 H, ArH), 7.31–7.29 (m, 1 H, ArH),
J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR (150 MHz, [D6]DMSO): δ
7.18 (t, J = 7.2 Hz, 1 H, ArH), 7.12 (t, J = 7.2 Hz, 2 H, ArH), 6.93 = 173.9, 147.5, 145.0, 140.3, 139.9, 133.8, 132.5, 132.2, 130.1, 129.6,
(d, J = 7.2 Hz, 2 H, ArH), 6.83 (s, 1 H, ArH), 6.82 (d, J = 8.4 Hz, 129.0, 128.5, 128.1, 126.9, 126.8, 126.7, 126.4, 124.5, 123.2, 114.2,
1 H, CH), 6.11 (d, J = 15.0 Hz, 1 H, CH2), 5.92 (d, J = 15.6 Hz, 113.9, 110.4, 63.7, 56.0, 55.8, 50.7, 28.8, 19.2, 13.4 ppm. HRMS
1 H, CH2), 4.82 (d, J = 16.2 Hz, 1 H, CH2), 4.75 (d, J = 15.6 Hz, 1
(ESI): calcd. for C36H28ClN6O3 [M –
H]– 627.1917; found
H, CH2) ppm. 13C NMR (150 MHz, [D6]DMSO): δ = 174.0, 147.4, 627.1912.
140.3, 139.3, 135.2, 133.8, 132.3, 129.5, 129.0, 128.6, 128.5, 128.2,
2h: Yield: 87%. Yellow solid, m.p. 126–128 °C. IR (KBr): ν = 3061
˜
127.4, 127.1, 127.0, 126.9, 126.8, 126.3, 123.3, 114.2, 110.8, 55.9,
50.7, 42.9, 19.1 ppm. HRMS (ESI): calcd. for C39H26ClN6O3 [M –
H]– 661.1760; found 661.1744.
(w), 2963 (w), 2166 (s), 2109 (vs), 1698 (s), 1607 (m), 1555 (m),
1525 (s), 1492 (s), 1450 (s), 1379 (m), 1349 (s), 1263 (m), 1188 (s),
1
1145 (w), 1134 (w), 1046 (w), 1016 (w), 984 (w), 872 (w) cm–1. H
2e: Yield: 79%. Yellow solid, m.p. 124–126 °C. IR (KBr): ν = 3128
(w), 3067 (w), 2154 (s), 2105 (vs), 1703 (s), 1607 (m), 1556 (m),
NMR (600 MHz, [D6]DMSO): δ = 11.06 (s, 1 H, ArH), 8.28 (d, J
= 7.8 Hz, 1 H, ArH), 8.04 (d, J = 9.0 Hz, 2 H, ArH), 7.89 (d, J =
˜
1522 (s), 1493 (s), 1453 (s), 1343 (s), 1272 (m), 1237 (m), 1203 (m), 7.8 Hz, 2 H, ArH), 7.67 (t, J = 7.8 Hz, 3 H, ArH), 7.62 (t, J =
1
1174 (s), 1141 (w), 1077 (w), 1016 (w), 984 (w), 854 (w) cm–1. H 7.8 Hz, 1 H, ArH), 7.51 (d, J = 8.4 Hz, 2 H, ArH), 7.43 (t, J =
NMR (600 MHz, [D6]DMSO): δ = 11.05 (s, 1 H, ArH), 8.32 (d, J 7.8 Hz, 2 H, ArH), 7.38 (t, J = 7.2 Hz, 1 H, ArH), 7.17–7.13 (m,
= 8.4 Hz, 1 H, ArH), 7.96–7.92 (m, 3 H, ArH), 7.90 (d, J = 8.4 Hz,
1 H, ArH), 7.68 (t, J = 7.2 Hz, 3 H, ArH), 7.63 (t, J = 7.8 Hz, 1
H, ArH), 7.51 (d, J = 9.0 Hz, 2 H, ArH), 7.43 (t, J = 7.8 Hz, 2 H,
ArH), 7.37 (t, J = 7.2 Hz, 1 H, ArH), 7.18 (t, J = 7.2 Hz, 1 H,
ArH), 7.12 (t, J = 7.8 Hz, 2 H, ArH), 7.09–7.07 (m, 1 H, ArH),
1 H, ArH), 6.94–6.92 (m, 1 H, ArH), 6.75 (s, 1 H, CH), 6.10 (d, J
= 15.6 Hz, 1 H, CH2), 5.93 (d, J = 15.0 Hz, 1 H, CH2), 3.60–3.56
(m, 1 H, CH2), 3.47–3.42 (m, 1 H, CH2), 1.20–1.14 (m, 1 H, CH2),
1.13–1.08 (m, 1 H, CH2), 0.95–0.89 (m, 1 H, CH2), 0.86–0.79 (m,
1 H, CH2), 0.67 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR
6.94 (d, J = 7.2 Hz, 2 H, ArH), 6.81–6.79 (m, 2 H, ArH, CH), 6.10 (150 MHz, [D6]DMSO): δ = 174.0, 157.5, 147.4, 144.9, 140.4,
4
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20269
/KAP1
Date: 23-04-12 11:53:24
Pages: 9
Molecular Diversity of Three-Component Reactions
137.2, 133.8, 132.3, 130.1, 129.6, 129.0, 128.6, 128.1, 127.0 126.9,
126.5, 123.2, 115.0, 114.9, 114.1, 113.9, 109.9, 109.8, 63.8, 55.8,
(m), 1142 (w), 1115 (w), 1073 (w), 1014 (w), 972 (w), 867 (w) cm–1.
1H NMR (600 MHz, [D6]DMSO): δ = 10.23 (s, 1 H, ArH), 7.97
50.7, 28.8, 19.3, 13.4 ppm. HRMS (ESI): calcd. for C36H28FN6O3 (d, J = 9.0 Hz, 2 H, ArH), 7.71 (s, 1 H, ArH), 7.60 (d, J = 8.4 Hz,
[M – H]– 611.2191; found 611.2208.
1 H, ArH), 7.48 (d, J = 7.2 Hz, 3 H, ArH), 7.41 (t, J = 7.8 Hz, 2
H, ArH), 7.36 (t, J = 7.8 Hz, 2 H, ArH), 7.30 (t, J = 7.8 Hz, 1 H,
ArH), 7.21 (d, J = 8.4 Hz, 2 H, ArH), 7.09 (d, J = 7.8 Hz, 1 H,
ArH), 6.73 (s, 1 H, ArH), 6.68 (d, J = 7.8 Hz, 1 H, CH), 5.84 (d,
J = 15.6 Hz, 1 H, CH2), 5.65 (d, J = 15.6 Hz, 1 H, CH2), 3.42–
3.30 (m, 1 H, CH2), 3.22–3.18 (m, 4 H, CH2, CH3), 2.39 (s, 3 H,
CH3), 1.01–0.97 (m, 1 H, CH2), 0.92–0.83 (m, 2 H, CH2), 0.79–
0.74 (m, 1 H, CH2), 0.61 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR
(150 MHz, [D6]DMSO): δ = 175.2, 167.8, 147.3, 141.5, 140.2,
140.0, 135.0, 131.5, 129.2, 129.1, 128.9, 128.1, 127.5, 125.4, 124.7,
124.5, 122.7, 112.9, 108.1, 94.5, 50.5, 28.9, 20.9, 19.3, 13.4 ppm.
HRMS (ESI): calcd. for C38H34N5O5 [M – H]– 640.2565; found
640.2551.
2i: Yield: 71%. Yellow solid, m.p. 150–152 °C. IR (KBr): ν = 3057
˜
(w), 2938 (w), 2135 (s), 1750 (w), 1694 (s), 1626 (vs), 1549 (w), 1517
(m), 1494 (m), 1454 (w), 1435 (m), 1350 (s), 1262 (w), 1210 (w),
1186 (m), 1132 (w), 1108 (m), 1051 (w), 1016 (w), 971 (w), 878
(w) cm–1. 1H NMR (600 MHz, [D6]DMSO): δ = 10.36 (s, 1 H,
ArH), 7.87 (d, J = 8.4 Hz, 2 H, ArH), 7.75 (s, 1 H, ArH), 7.64 (d,
J = 7.8 Hz, 1 H, ArH), 7.51 (d, J = 7.2 Hz, 3 H, ArH), 7.42 (t, J
= 7.2 Hz, 2 H, ArH), 7.40–7.36 (m, 2 H, ArH), 7.33 (t, J = 7.2 Hz,
1 H, ArH), 7.23 (d, J = 7.8 Hz, 2 H, ArH), 7.12 (t, J = 7.2 Hz, 1
H, ArH), 7.04 (t, J = 7.8 Hz, 2 H, ArH), 7.01 (d, J = 7.8 Hz, 1 H,
ArH), 6.85 (d, J = 7.2 Hz, 2 H, ArH), 6.51 (d, J = 7.87 Hz, 1 H,
CH), 5.88 (d, J = 15.6 Hz, 1 H, CH2), 5.69 (d, J = 15.6 Hz, 1 H,
CH2), 4.61 (d, J = 16.2 Hz, 1 H, CH2), 4.51 (d, J = 15.6 Hz, 1 H,
CH2), 3.22 (s, 3 H, CH3), 2.37 (s, 3 H, CH3) ppm. 13C NMR
(150 MHz, [D6]DMSO): δ = 175.7, 167.9, 147.3, 141.4, 139.8,
135.8, 134.9, 131.9, 131.8, 130.5, 129.2, 128.9, 128.8, 128.1, 127.9,
127.7, 127.5, 127.1, 127.0, 125.6, 125.1, 124.7, 122.8, 113.1, 112.3,
108.6, 65.1, 58.4, 50.5, 49.7, 43.1, 20.9 ppm. HRMS (ESI): calcd.
for C41H32N5O5 [M – H]– 674.2409; found 674.2402.
2m: Yield: 58%. Yellow solid, m.p. 158–160 °C. IR (KBr): ν = 3051
˜
(w), 2931 (w), 2142 (s), 1750 (w), 1685 (s), 1600 (vs), 1556 (m),
1524 (m), 1486 (m), 1436 (m), 1344 (s), 1258 (w), 1206 (w), 1190
(w), 1052 (w), 1014 (w), 891 (w), 808 (w) cm–1. 1H NMR
(600 MHz, [D6]DMSO): δ = 10.85 (s, 1 H, ArH), 8.00 (d, J =
9.0 Hz, 2 H, ArH), 7.96 (s, 1 H, ArH), 7.82–7.77 (m, 2 H, ArH),
7.50 (d, J = 7.8 Hz, 3 H, ArH), 7.47 (d, J = 8.4 Hz, 1 H, ArH),
7.42 (t, J = 7.2 Hz, 2 H, ArH), 7.38 (d, J = 6.6 Hz, 1 H, ArH),
7.29 (t, J = 8.4 Hz, 3 H, ArH), 7.09 (s, 1 H, ArH), 6.80 (d, J =
8.4 Hz, 1 H, CH), 6.05 (d, J = 15.6 Hz, 1 H, CH2), 5.88 (d, J =
15.6 Hz, 1 H, CH2), 3.45–3.41 (m, 1 H, CH2), 3.26–3.22 (m, 1 H,
CH2), 3.14 (s, 3 H, CH3), 1.04–0.97 (m, 1 H, CH2), 0.92–0.87 (m,
2 H, CH2), 0.78–0.76 (m, 1 H, CH2), 0.63 (t, J = 7.2 Hz, 3 H,
CH3) ppm. 13C NMR (150 MHz, [D6]DMSO): δ = 175.9, 168.7,
147.4, 141.2, 140.8, 134.3, 132.6, 129.5, 129.0, 128.3, 128.2, 127.7,
127.5, 126.4, 126.2, 126.1, 124.2, 122.7, 113.8, 113.1, 109.6, 63.4,
57.7, 50.3, 49.1, 28.8, 19.3, 13.4 ppm. HRMS (ESI): calcd. for
C37H31ClN5O5 [M – H]– 660.2019; found 660.2008.
2j: Yield: 68%. Yellow solid, m.p. 162–164 °C. IR (KBr): ν = 3042
˜
(w), 3016 (w), 2138 (s), 1750 (w), 1698 (s), 1624 (vs), 1552 (s), 1518
(m), 1496 (m), 1438 (m), 1350 (s), 1262 (w), 1207 (w), 1190 (m),
1166 (m), 1127 (m), 1112 (m), 1080 (w), 1053 (w), 1017 (w), 967
1
(w), 886 (w) cm–1. H NMR (600 MHz, [D6]DMSO): δ = 10.89 (s,
1 H, ArH), 7.99 (s, 1 H, ArH), 7.89 (d, J = 9.0 Hz, 2 H, ArH),
7.84–7.79 (m, 2 H, ArH), 7.52 (t, J = 7.2 Hz, 2 H, ArH), 7.50 (d,
J = 7.8 Hz, 1 H, ArH), 7.43 (t, J = 7.8 Hz, 2 H, ArH), 7.38 (t, J
= 7.2 Hz, 1 H, ArH), 7.28 (d, J = 9.0 Hz, 2 H, ArH), 7.26–7.24
(m, 1 H, ArH), 7.13 (t, J = 7.2 Hz, 2 H, ArH), 7.06 (t, J = 7.8 Hz,
2 H, ArH), 6.87 (d, J = 7.2 Hz, 2 H, ArH), 6.63 (d, J = 7.8 Hz, 1
H, CH), 6.07 (d, J = 15.6 Hz, 1 H, CH2), 5.90 (d, J = 15.0 Hz, 1
H, CH2), 4.64 (d, J = 16.2 Hz, 1 H, CH2), 4.55 (d, J = 16.2 Hz, 1 H,
CH2), 3.18 (s, 3 H, CH3) ppm. 13C NMR (150 MHz, [D6]DMSO): δ
= 176.3, 168.7, 147.3, 140.8, 140.7, 135.5, 134.3, 129.4, 129.0, 128.4,
128.1, 127.9, 127.5, 127.2, 126.7, 126.3, 124.2, 122.8, 120.0, 110.0,
63.2, 57.9, 50.3, 49.1, 43.2 ppm. HRMS (ESI): calcd. for
C40H29ClN5O5 [M – H]– 694.1863; found 694.1853.
2n: Yield: 62%. Yellow solid, m.p. 166–168 °C. IR (KBr): ν = 3047
˜
(w), 2932 (w), 2134 (s), 1751 (w), 1694 (m), 1630 (vs), 1556 (w),
1524 (m), 1492 (s), 1439 (w), 1347 (m), 1261 (s), 1026 (m), 1183
(w), 1140 (m), 1118 (w), 1051 (w), 1015 (w), 978 (w), 854 (w) cm–1.
1H NMR (600 MHz, [D6]DMSO): δ = 10.77 (s, 1 H, ArH), 7.99
(d, J = 9.0 Hz, 2 H, ArH), 7.79–7.77 (m, 1 H, ArH), 7.75 (d, J =
7.8 Hz, 2 H, ArH), 7.50 (d, J = 7.2 Hz, 2 H, ArH), 7.48–7.44 (m,
2 H, ArH), 7.41 (t, J = 7.2 Hz, 2 H, ArH), 7.37 (t, J = 7.2 Hz, 1
H, ArH), 7.28 (d, J = 8.4 Hz, 2 H, ArH), 7.12–7.08 (m, 1 H, ArH),
7.07 (s, 1 H, ArH), 6.81–6.79 (m, 1 H, CH), 6.01 (d, J = 15.6 Hz,
1 H, CH2), 5.84 (d, J = 15.6 Hz, 1 H, CH2), 3.46–3.41 (m, 1 H,
CH2), 3.27–3.23 (m, 1 H, CH2), 3.14 (s, 3 H, CH3), 1.02–0.99 (m,
1 H, CH2), 0.92–0.87 (m, 2 H, CH2), 0.79–0.76 (m, 1 H, CH2), 0.62
(t, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR (150 MHz, [D6]DMSO):
δ = 175.7, 168.8, 159.2, 157.6, 147.4, 141.0, 138.5, 134.4, 132.8,
129.4, 129.0, 128.3, 127.5, 126.1, 126.0, 122.7, 114.8, 114.6, 113.7,
113.0, 112.0, 111.8, 109.1, 109.0, 63.6, 58.1, 50.3, 49.2, 28.8, 19.3,
13.4 ppm. HRMS (ESI): calcd. for C37H31FN5O5 [M – H]–
644.2315; found 644.2290.
2k: Yield: 74%. Yellow solid, m.p. 184–186 °C. IR (KBr): ν = 3043
˜
(w), 3007 (w), 2139 (s), 1750 (w), 1697 (s), 1625 (vs), 1553 (w), 1520
(m), 1492 (s), 1441 (m), 1350 (s), 1263 (m), 1212 (w), 1178 (m),
1142 (m), 1120 (w), 1054 (w), 1016 (w), 967 (w), 882 (w) cm–1. H
1
NMR (600 MHz, [D6]DMSO): δ = 10.83 (s, 1 H, ArH), 7.89 (d, J
= 9.0 Hz, 2 H, ArH), 7.83 (d, J = 1.8 Hz, 1 H, ArH), 7.77 (d, J =
7.8 Hz, 2 H, ArH), 7.52 (d, J = 7.2 Hz, 2 H, ArH), 7.50–7.45 (m,
2 H, ArH), 7.42 (t, J = 7.2 Hz, 2 H, ArH), 7.38 (t, J = 7.2 Hz, 1
H, ArH), 7.30 (d, J = 8.4 Hz, 2 H, ArH), 7.13 (t, J = 7.2 Hz, 2 H,
ArH), 7.06 (t, J = 7.8 Hz, 3 H, ArH), 6.88 (d, J = 7.2 Hz, 2 H,
ArH), 6.63–6.61 (m, 1 H, CH), 6.04 (d, J = 15.6 Hz, 1 H, CH2),
5.86 (d, J = 15.6 Hz, 1 H, CH2), 4.65 (d, J = 15.6 Hz, 1 H, CH2),
4.56 (d, J = 16.2 Hz, 1 H, CH2), 3.17 (s, 3 H, CH3) ppm. 13C NMR
(150 MHz, [D6]DMSO): δ = 176.2, 168.7, 159.3, 157.8, 147.3,
140.8, 138.1, 135.6, 134.4, 132.7, 129.4, 129.0, 128.9, 128.3, 127.9,
127.7, 127.5, 127.2, 127.1, 126.2, 126.1, 122.9, 122.8, 114.6, 113.7,
112.0, 109.5, 63.4, 58.2, 50.3, 49.2, 43.2 ppm. HRMS (ESI): calcd.
for C40H29FN5O5 [M – H]– 678.2158; found 678.2156.
General Procedure for the Preparation of Products 3a–m through a
Three-Component Reaction: A mixture of N-benzyl-NЈ-phenacyl-
benzimidazolium bromide (1.0 mmol, 0.407 g), isatin (1.0 mmol),
malononitrile or ethyl cyanoacetate (1.0 mmol), and triethylamine
(1.0 mmol, 0.10 g) in methanol (25 mL) was stirred at room tem-
perature for 2 d. The resulting precipitate was collected by filtration
and then subjected to preparative thin-layer chromatography (ethyl
2l: Yield: 76%. Yellow solid, m.p. 172–174 °C. IR (KBr): ν = 3060
˜
(w), 2934 (w), 2145 (w), 1752 (vs), 1701 (s), 1602 (m), 1522 (s), acetate/light petroleum ether, 1:3) to give the pure product for
1489 (s), 1453 (w), 1437 (w), 1350 (s), 1316 (w), 1252 (m), 1206 analysis.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20269
/KAP1
Date: 23-04-12 11:53:24
Pages: 9
L. Hui, H.-Y. Li, C.-G. Yan
FULL PAPER
3a: Yield: 89%. Yellow solid, m.p. 210–212 °C. IR (KBr): ν = 3338
(m), 1163 (w), 1124 (m), 1080 (w), 1003 (w), 950 (w), 804 (w) cm–1.
˜
(m), 2217 (m), 1659 (s), 1615 (vs), 1589 (s), 1513 (m), 1447 (m), 1H NMR (600 MHz, [D6]DMSO): δ = 12.00 (s, 1 H, NH), 8.64 (s,
1362 (m), 1300 (m), 1216 (m), 1194 (m), 1116 (w), 1079 (w), 1017 1 H, ArH), 8.32–7.99 (m, 1 H, ArH), 7.81–7.73 (m, 2 H, ArH),
1
(w), 900 (w), 812 (w) cm–1. H NMR (600 MHz, [D6]DMSO): δ =
7.54 (d, J = 7.2 Hz, 2 H, ArH), 7.27 (s, 4 H, ArH), 7.15 (t, J =
12.18 (s, 1 H, NH), 11.21 (s, 1 H, NH), 8.70 (s, 1 H, ArH), 8.17– 7.8 Hz, 2 H, ArH), 7.00–6.92 (m, 5 H, ArH), 6.52–6.25 (m, 1 H,
8.02 (m, 1 H, ArH), 7.85 (s, 1 H, ArH), 7.78 (d, J = 6.6 Hz, 1 H, ArH), 5.21 (s, 1 H, CH2), 4.82 (d, J = 13.8 Hz, 1 H, CH2), 3.69 (s,
ArH), 7.76–7.57 (m, 2 H, ArH), 7.32–7.26 (m, 4 H, ArH), 7.20 (t, 2 H, CH2), 2.03 (s, 3 H, CH3), 1.66 (t, J = 6.0 Hz, 2 H, CH2), 1.38–
J = 8.4 Hz, 2 H, ArH), 7.08 (s, 1 H, ArH), 6.96 (d, J = 7.2 Hz,1 1.35 (m, 2 H, CH2), 0.94 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR
H, ArH), 6.92 (s, 2 H, ArH), 6.32–6.31 (m, 1 H, CH), 5.16 (d, J = (150 MHz, [D6]DMSO): δ = 165.7, 135.4, 134.4, 130.6, 129.9,
14.4 Hz,1 H, CH2), 4.80 (d, J = 14.4 Hz,1 H, CH2) ppm. 13C NMR
(150 MHz, [D6]DMSO): δ = 170.3, 136.4, 136.3, 133.9, 131.2,
130.2, 130.1, 129.5, 129.4, 129.2, 128.6, 128.5, 124.9, 122.8, 117.1,
111.9, 111.3, 62.2, 50.8 ppm. HRMS (ESI): calcd. for
C33H21ClN5O2 [M – H]– 554.1380; found 554.1367.
129.8, 129.3, 129.2, 128.4, 128.3, 120.4, 113.8, 108.7, 72.8, 60.3,
51.7, 29.6, 20.9, 19.6, 13.6 ppm. HRMS (ESI): calcd. for
C38H32N5O2 [M – H]– 590.2549; found 590.2532.
3f: Yield: 67%. Yellow solid, m.p. 196–198 °C. IR (KBr): ν = 2958
˜
(w), 2871 (w), 2216 (m), 1656 (s), 1612 (vs), 1591 (w) 1513(s), 1476
(s), 1451 (w), 1419 (m), 1351 (m), 1311 (m), 1279 (m), 1250 (m),
1210 (w), 1192 (w), 1144 (w), 1124 (w), 1082 (w), 1049 (w), 1026
3b: Yield: 86%. Yellow solid, m.p. 170–172 °C. IR (KBr): ν = 3031
˜
(w), 2922 (w), 2190 (m), 1681 (s), 1653 (s), 1613 (vs), 1593 (s), 1511
(w), 1487 (w), 1451 (m), 1350 (s), 1275 (w), 1200 (w), 1189 (m), (w), 1002 (w), 948 (w), 875 (w) cm–1. 1H NMR (600 MHz, [D6]
1159 (w), 1129 (w), 1078 (w), 1047 (w), 1029 (w), 1002 (w), 962
DMSO): δ = 12.06 (s, 1 H, NH), 8.76 (s, 1 H, ArH), 8.18–7.98 (m,
(w), 869 (w) cm–1. 1H NMR (600 MHz, CDCl3): δ = 12.32 (s, 1 H, 1 H, ArH), 7.78 (s, 2 H, ArH), 7.68–7.56 (m, 2 H, ArH), 7.35–7.32
NH), 8.19–8.00 (m, 2 H, ArH), 7.68 (s, 1 H, ArH), 7.56 (s, 3 H,
(m, 1 H, ArH), 7.27 (t, J = 6.6 Hz, 3 H, ArH), 7.20 (t, J = 7.2 Hz,
ArH), 7.38 (s, 3 H, ArH), 7.35 (d, J = 3.6 Hz, 4 H, ArH), 7.29–
4 H, ArH), 7.07–6.98 (m, 2 H, ArH), 6.94–6.86 (m, 1 H, ArH),
7.27 (m, 4 H, ArH), 7.22–7.17 (m, 2 H, ArH), 7.06 (s, 1 H, ArH), 6.60–6.33 (m, 1 H, CH), 5.13–5.12 (m, 1 H, CH2), 4.86 (d, J =
6.94 (t, J = 7.8 Hz, 1 H, ArH), 6.85–6.81 (m, 2 H, ArH), 6.68 (d, 14.4 Hz, 1 H, CH2), 3.93 (s, 2 H, CH2), 1.69 (s, 2 H, CH2), 1.42–
J = 7.8 Hz, 1 H, ArH), 6.56 (s, 1 H, CH), 5.15 (s, 1 H, CH2), 5.06
1.38 (m, 2 H, CH2), 0.97 (t, J = 7.2 Hz, 3 H, CH3) ppm. HRMS
(s, 2 H, CH2), 4.71–4.69 (m, 1 H, CH2), 2.08 (s, 3 H, CH3) ppm. (ESI): calcd. for C37H29ClN5O2 [M
13C NMR (150 MHz, [D6]DMSO): δ = 168.5, 163.4, 136.2, 135.9, 610.2009.
135.2, 134.0, 132.2, 130.4, 130.0, 129.9, 129.8, 129.7, 129.3, 129.0,
128.8, 128.6, 128.4, 128.3, 128.1, 127.4, 127.2, 127.0, 120.6, 118.6,
109.0, 98.0, 52.9, 47.9, 20.9 ppm. HRMS (ESI): calcd. for
C41H30N5O2 [M – H]– 624.2405; found 624.2302.
–
H]– 610.2015; found
3g: Yield: 73%. Yellow solid, m.p. 178–180 °C. IR (KBr): ν = 2932
˜
(w), 2216 (m), 1655 (s), 1614 (vs), 1591 (s), 1514 (w), 1481 (m),
1453 (m), 1418 (w), 1353 (s), 1310 (w), 1281 (w), 1192 (m), 1137
1
(w), 953 (w), 852 (w) cm–1. H NMR (600 MHz, [D6]DMSO): δ =
3c: Yield: 77%. Yellow solid, m.p. 194–196 °C. IR (KBr): ν = 3031
12.09 (s, 1 H, NH), 8.76–8.68 (m, 1 H, ArH), 8.18–7.97 (m, 1 H,
˜
(m), 2205 (m), 1633 (s), 1593 (vs), 1574 (s), 1519 (m), 1495 (w), ArH), 7.78 (s, 2 H, ArH), 7.65–7.55 (m, 2 H, ArH), 7.33 (d, J =
1451 (m), 1421 (m), 1366 (s), 1336 (m), 1309 (w), 1252 (w), 1210 14.4 Hz, 1 H, ArH), 7.27 (s, 3 H, ArH), 7.19 (d, J = 7.8 Hz, 3 H,
(w), 1182 (m), 1120 (w), 1080 (w), 1021 (w), 954 (w), 891 (w) cm–1. ArH), 7.03 (d, J = 6.0 Hz, 1 H, ArH), 6.97 (s, 2 H, ArH), 6.92–
1H NMR (600 MHz, [D6]DMSO): δ = 12.05 (s, 1 H, NH), 8.78 (s,
1 H, ArH), 8.21–7.99 (m, 1 H, ArH), 7.78 (d, J = 4.2 Hz, 2 H,
6.86 (m, 1 H, ArH), 6.37–6.12 (m, 1 H, CH), 5.14 (s, 1 H, CH2),
4.88 (s, 1 H, CH2), 3.92 (s, 2 H, CH2), 1.69 (s, 2 H, CH2), 1.40 (d,
ArH), 7.65–7.58 (m, 2 H, ArH), 7.42 (s, 2 H, ArH), 7.39 (t, J = J = 6.6 Hz,2 H, CH2), 0.96 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C
7.2 Hz, 2 H, ArH), 7.30 (t, J = 7.2 Hz, 2 H, ArH), 7.26 (t, J =
NMR (150 MHz, [D6]DMSO): δ = 168.3, 136.3, 136.2, 133.8,
6.6 Hz, 2 H, ArH), 7.22 (t, J = 7.8 Hz, 3 H, ArH), 7.11–7.01 (m, 131.2, 130.2, 130.1, 130.0, 129.9, 129.3, 129.2, 128.6, 128.4, 128.3,
4 H, ArH), 6.91 (s, 1 H, ArH), 6.60–6.36 (m, 1 H, CH), 5.18 (s, 3 128.2, 117.1, 111.9, 109.8, 109.7, 50.9, 29.6, 19.6, 13.7 ppm. HRMS
H, CH2), 4.91 (d, J = 7.2 Hz, 1 H, CH2) ppm. 13C NMR (ESI): calcd. for C37H29FN5O2 [M – H]– 594.2284; found 594.2302.
(150 MHz, [D6]DMSO): δ = 168.3, 136.6, 136.3, 133.8, 131.3,
3h: Yield: 67%. Yellow solid, m.p. 194–196 °C. IR (KBr): ν = 3031
˜
130.2, 130.1, 129.4, 129.3, 128.7, 128.6, 128.5, 128.4, 127.5, 127.3,
122.1, 117.1, 111.9, 110.8, 50.9, 42.3 ppm. HRMS (ESI): calcd. for
C40H27ClN5O2 [M – H]– 644.1845; found 644.1854.
(w), 2946 (w), 2206 (m), 1713 (m), 1653 (m), 1617 (vs), 1591 (s),
1568 (s), 1515 (w), 1486 (w), 1447 (m), 1358 (m), 1339 (m), 1311
(w), 1275 (m), 1250 (w), 1211 (w), 1188 (m), 1162 (w), 1124 (m),
1103 (w), 1079 (w), 1032 (w), 959 (w), 866 (w) cm–1. 1H NMR
(600 MHz, CDCl3): δ = 12.22 (s, 1 H, NH), 8.34 (s, 1 H, ArH),
8.19 (d, J = 1.8 Hz, 1 H, ArH), 8.05–7.85 (m, 1 H, ArH), 7.66–
7.62 (m, 1 H, ArH), 7.53–7.46 (m, 2 H, ArH), 7.39 (s, 1 H, ArH),
7.33 (s, 6 H, ArH), 7.23 (s, 2 H, ArH), 7.12–7.01 (m, 2 H, ArH),
3d: Yield: 82%. Yellow solid, m.p. 186–188 °C. IR (KBr): ν = 3032
˜
(w), 2215 (m), 1656 (s), 1613 (vs), 1591 (s), 1513 (w), 1480 (m),
1452 (m), 1418 (w), 1357 (s), 1306 (w), 1217 (w), 1168 (m), 1114
1
(w), 967 (w), 851 (w) cm–1. H NMR (600 MHz, [D6]DMSO): δ =
12.08 (s, 1 H, NH), 8.78 (s, 1 H, ArH), 8.32–8.00 (m, 1 H, ArH),
7.78 (d, J = 7.8 Hz, 2 H, ArH), 7.57 (s, 2 H, ArH), 7.43 (s, 2 H, 6.90 (t, J = 7.2 Hz, 1 H, ArH), 6.81–6.72 (m, 2 H, ArH), 6.65 (d,
ArH), 7.39 (t, J = 7.8 Hz, 2 H, ArH), 7.30 (t, J = 7.2 Hz, 2 H,
ArH), 7.27 (t, J = 6.6 Hz, 2 H, ArH), 7.21 (t, J = 7.2 Hz, 3 H,
ArH), 7.06–7.00 (m, 3 H, ArH), 6.91 (s, 2 H, ArH), 6.38–6.14 (m,
J = 7.8 Hz, 1 H, ArH), 6.59–6.51 (m, 1 H, CH), 5.09 (s, 3 H, CH2),
4.74–4.72 (m, 1 H, CH2), 4.24 (s, 2 H, CH2), 2.09 (s, 3 H, CH3),
1.29 (s, 3 H, CH3) ppm. 13C NMR (150 MHz, [D6]DMSO): δ =
1 H, CH), 5.18 (s, 3 H, CH2), 4.91 (s, 1 H, CH2) ppm. 13C NMR 168.4, 165.7, 136.7, 135.9, 135.3, 134.4, 130.6, 130.3, 130.2, 130.1,
(150 MHz, [D6]DMSO): δ = 168.5, 136.5, 133.8, 131.3, 130.2,
130.0, 129.3, 128.7, 128.6, 128.5, 128.4, 128.3, 127.5, 127.3, 117.1,
111.9, 79.1, 59.7, 50.9, 42.6 ppm. HRMS (ESI): calcd. for
C40H27FN5O2 [M – H]– 628.2144; found 628.2127.
130.0, 129.9, 129.8, 129.6, 129.5, 129.3, 129.2, 128.7, 128.6, 128.4,
127.4, 127.2, 120.5, 113.9, 109.1, 72.9, 60.3, 51.8, 42.4, 20.8,
14.3 ppm. HRMS (ESI): calcd. for C43H35N4O4 [M – H]– 671.2637;
found 671.2656.
3e: Yield: 80%. Yellow solid, m.p. 184–186 °C. IR (KBr): ν = 2948
3i: Yield: 60%. Yellow solid, m.p. 198–200 °C. IR (KBr): ν = 3064
˜
˜
(m), 2871 (w), 2206 (m), 1713 (m), 1654 (s), 1619 (vs), 1516 (m),
1487 (w), 1450 (m), 1352 (s), 1314 (w), 1277 (m), 1202 (m), 1186
(w), 2929 (w), 2206 (m), 1710 (m), 1659 (s), 1615 (vs), 1570 (s),
1516 (w), 1496 (m), 1476 (m), 1450 (m), 1367 (m), 1340 (m), 1309
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20269
/KAP1
Date: 23-04-12 11:53:24
Pages: 9
Molecular Diversity of Three-Component Reactions
(w), 1274 (w), 1251 (w), 1206 (w), 1182 (w), 1124 (w), 1103 (w), 3m: Yield: 68%. Yellow solid, m.p. 196–198 °C. IR (KBr): ν = 2952
˜
1081 (w), 1031 (w), 1004 (w), 958 (w), 893 (w) cm–1. 1H NMR (w), 2929 (w), 2206 (m), 1658 (s), 1617 (vs), 1573 (s), 1516 (w),
(600 MHz, [D6]DMSO): δ = 12.04 (s, 1 H, NH), 8.64 (s, 1 H, ArH),
8.21–8.03 (m, 1 H, ArH), 7.93–7.76 (m, 2 H, ArH), 7.67–7.56 (m,
2 H, ArH), 7.38 (s, 4 H, ArH), 7.30 (d, J = 6.0 Hz, 4 H, ArH),
7.19 (t, J = 7.8 Hz, 3 H, ArH), 7.05 (s, 5 H, ArH), 6.61–6.29 (m,
1477 (w), 1451 (m), 1415 (w), 1351 (m), 1309 (w), 1277 (m), 1252
(w), 1208 (w), 1192 (m), 1123 (m), 1081 (w), 1047 (w), 1013 (w),
950 (w), 860 (w) cm–1. 1H NMR (600 MHz, [D6]DMSO): δ = 12.07
(s, 1 H, NH), 8.63 (s, 1 H, ArH), 8.18–7.99 (m, 1 H, ArH), 7.82–
1 H, CH), 5.12 (s, 3 H, CH2), 4.88 (d, J = 14.4 Hz, 1 H, CH2), 7.75 (m, 2 H, ArH), 7.65–7.55 (m, 2 H, ArH), 7.33 (s, 1 H, ArH),
4.17–4.14 (m, 2 H, CH2), 1.19 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C
NMR (150 MHz, [D6]DMSO): δ = 165.1, 136.4, 134.4, 130.7,
130.1, 129.4, 129.3, 128.7, 128.5, 127.5, 127.2, 124.9, 122.2, 60.4,
7.28 (d, J = 5.4 Hz, 3 H, ArH), 7.17 (t, J = 7.8 Hz, 3 H, ArH),
7.01–6.96 (m, 4 H, ArH), 6.38–6.07 (m, 1 H, CH), 5.21 (s, 1 H,
CH2), 4.84 (d, J = 14.4 Hz, 1 H, CH2), 4.18–4.15 (m, 2 H, CH2),
42.5, 14.3 ppm. HRMS (ESI): calcd. for C42H32ClN4O4 [M – H]– 3.87 (t, J = 7.2 Hz, 2 H, CH2), 1.66 (t, J = 6.6 Hz, 2 H, CH2),
691.2118; found 691.2111.
1.39–1.35 (m, 2 H, CH2), 1.21 (t, J = 7.2 Hz, 3 H, CH3), 0.95 (t, J
= 7.2 Hz, 3 H, CH3) ppm. 13C NMR (150 MHz, [D6]DMSO): δ =
168.3, 165.1, 136.2, 135.0, 134.4, 130.6, 130.1, 130.0, 129.9, 129.3,
128.4, 128.3, 121.6, 121.5, 113.8, 109.7, 73.3, 60.3, 29.5, 19.5, 14.3,
13.6 ppm. HRMS (ESI): calcd. for C39H34FN4O4 [M – H]–
641.2543; found 641.2564.
3j: Yield: 78%. Yellow solid, m.p. 194–196 °C. IR (KBr): ν = 2980
˜
(w), 2207 (m), 1703 (s), 1657 (s), 1615 (vs), 1572 (s), 1514 (w), 1481
(m), 1451 (m), 1363 (m), 1275 (m), 1215 (w), 1168 (m), 1124 (w),
1101 (w), 1030 (w), 966 (w), 851 (w) cm–1. 1H NMR (600 MHz,
CDCl3): δ = 12.34 (s, 1 H, NH), 8.35 (s, 1 H, ArH), 8.17 (d, J =
5.4 Hz, 1 H, ArH), 8.03–7.85 (m, 1 H, ArH), 7.70–7.64 (m, 1 H,
ArH), 7.56 (s, 2 H, ArH), 7.36 (d, J = 7.2 Hz, 1 H, ArH), 7.34 (s,
5 H, ArH), 7.28 (t, J = 6.6 Hz, 3 H, ArH), 7.13–7.02 (m, 3 H,
ArH), 6.93 (t, J = 7.2 Hz, 1 H, ArH), 6.77 (s, 1 H, ArH), 6.65 (d,
J = 4.2 Hz, 2 H, ArH), 6.51–6.40 (m, 1 H, CH), 5.11 (t, J =
14.4 Hz, 2 H, CH2), 5.04 (d, J = 15.0 Hz, 1 H, CH2), 4.72 (d, J =
Supporting Information (see footnote on the first page of this arti-
cle): Molecular structure of zwitterionic salt 3f, general procedure
for the preparation of products (3a–m) from three-component reac-
1
tions, H and 13C NMR spectra.
13.2 Hz, 1 H, CH2), 4.25 (s, 2 H, CH2), 1.29 (s,3 H, CH3) ppm. 13
C
Acknowledgments
NMR (150 MHz, [D6]DMSO): δ = 165.1, 136.5, 135.0, 134.4,
130.6, 130.1, 130.0, 129.9, 129.3, 129.2, 128.7, 128.5, 127.5, 127.3,
113.8, 73.3, 60.3, 42.5, 14.3 ppm. HRMS (ESI): calcd. for
C42H32FN4O4 [M – H]– 675.2413; found 675.2409.
This work was financially supported by the National Natural Sci-
ence Foundation of China (Grant No. 20972132) and the Priority
Academic Program Development of Jiangsu Higher Education In-
stitutions.
3k: Yield: 85%. Yellow solid, m.p. 166–168 °C. IR (KBr): ν = 2951
˜
(m), 2871 (w), 2209 (m), 1691 (s), 1654 (s), 1619 (vs), 1591 (s), 1517
(m), 1488 (w), 1451 (m), 1414 (w), 1354 (s), 1315 (w), 1276 (s), 1204
(m), 1165 (w), 1125 (m), 1102 (w), 1005 (w), 950 (w), 812 (w) cm–1.
1H NMR (600 MHz, [D6]DMSO): δ = 11.99 (s, 1 H, NH), 8.62 (s,
1 H, ArH), 8.17–7.99 (m, 1 H, ArH), 7.81–7.73 (m, 2 H, ArH),
7.64–7.55 (m, 2 H, ArH), 7.32 (s, 1 H, ArH), 7.28 (d, J = 6.0 Hz,
3 H, ArH), 7.15 (t, J = 7.8 Hz, 2 H, ArH), 7.00–6.97 (m, 2 H,
ArH), 6.92 (s, 3 H, ArH), 6.52–6.24 (m, 1 H, CH), 5.20 (s, 1 H,
CH2), 4.81 (d, J = 14.4 Hz, 1 H, CH2), 4.17–4.15 (m, 2 H, CH2),
3.84 (t, J = 7.2 Hz, 2 H, CH2), 2.07 (s, 3 H, CH3), 1.66 (t, J =
6.6 Hz, 2 H, CH2), 1.38–1.34 (m, 2 H, CH2), 1.21 (t, J = 7.2 Hz, 3
H, CH3), 0.94 (t, J = 7.8 Hz, 3 H, CH3) ppm. 13C NMR (150 MHz,
[D6]DMSO): δ = 165.2, 135.4, 134.4, 130.5, 130.0, 129.9, 129.8,
129.3, 128.4, 120.4, 113.9, 108.6, 73.1, 60.3, 29.6, 20.9, 19.6, 14.3,
13.6 ppm. HRMS (ESI): calcd. for C40H37N4O4 [M – H]– 637.2820;
found 637.2819.
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(w), 2930 (w), 2206 (m), 1707 (w), 1659 (s), 1617 (vs), 1573 (s),
1517 (w), 1478 (w), 1451 (m), 1351 (w), 1310 (s), 1277 (w), 1252
(m), 1208 (w), 1185 (w), 1123 (m), 1081 (m), 1047 (w), 1014 (w),
950 (w), 860 (w) cm–1. 1H NMR (600 MHz, [D6]DMSO): δ = 12.04
(s, 1 H, NH), 8.63 (s, 1 H, ArH), 8.26–7.98 (m, 1 H, ArH), 7.82 (s,
1 H, ArH), 7.75 (s, 1 H, ArH), 7.65 (s, 1 H, ArH), 7.56 (d, J =
7.8 Hz, 1 H, ArH), 7.33 (s, 1 H, ArH), 7.27 (s, 3 H, ArH), 7.17 (d,
J = 7.2 Hz, 4 H, ArH), 7.01–6.95 (m, 3 H, ArH), 6.60–6.30 (m, 1
H, CH), 5.21 (s, 1 H, CH2), 4.83 (d, J = 14.4 Hz, 1 H, CH2), 4.17–
4.16 (m, 1 H, CH2), 3.88 (s, 2 H, CH2), 3.69 (s, 1 H, CH2), 1.66 (s,
2 H, CH2), 1.36 (d, J = 6.6 Hz, 2 H, CH2), 1.21 (t, J = 7.2 Hz, 3
H, CH3), 0.94 (d, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR
(150 MHz, [D6]DMSO): δ = 168.1, 165.1, 136.3, 136.2, 135.0,
134.4, 130.6, 130.2, 130.1, 130.0, 129.9, 129.8, 129.3, 129.1, 128.6,
128.5, 128.4, 128.3, 128.2, 127.3, 125.3, 122.1, 120.9, 113.8, 73.3,
60.3, 51.8, 29.5, 19.5, 14.3, 13.6 ppm. HRMS (ESI): calcd. for
C39H34ClN4O4 [M – H]– 657.2234; found 657.2266.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20269
/KAP1
Date: 23-04-12 11:53:24
Pages: 9
L. Hui, H.-Y. Li, C.-G. Yan
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Received: March 6, 2012
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20269
/KAP1
Date: 23-04-12 11:53:24
Pages: 9
Molecular Diversity of Three-Component Reactions
Molecular Diversity
L. Hui, H.-Y. Li, C.-G. Yan* ............ 1–9
Molecular Diversity of Three-Component
Reactions of N-Benzylbenzimidazolium
Salts, Isatin, and Malononitrile or Ethyl
Cyanoacetate
Keywords: Multicomponent reactions
/
Zwitterions / Nitrogen heterocycles / Mo-
lecular diversity
The three-component reactions of N-
benzylbenzimidazolium salts, isatins, and
malononitrile or ethyl cyanoacetate showed
very interesting molecular diversity de-
pending on the structures of the benzimid-
azolium salts: zwitterionic or ring-opened
products were obtained.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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