Efficient assembly of 1-(1 H-Imidazol-1-yl)-3-methylene-1H-indenes via tandem reaction of (2-(alkynyl)benzylidene)malonates with imidazoles

Article abstract of DOI:10.1021/co100006g

The tandem nucleophilic addition and 5-exo-cyclization of (2-(alkynyl)benzylidene)malonates with imidazole derivatives in the presence of t-BuOK is reported. This reaction proceeds smoothly under mild conditions with high selectivity to afford the corresp

Full text of DOI:10.1021/co100006g

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Efficient Assembly of 1-(1H-Imidazol-1-yl)-3-methylene-1H-indenes
via Tandem Reaction of (2-(Alkynyl)benzylidene)malonates
with Imidazoles
Guanyinsheng Qiu,‡ Qiuping Ding,‡ Ke Gao,† Yiyuan Peng,*,‡ and Jie Wu*,†
†Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
‡Key Laboratory of Green Chemistry of Jiangxi Province, College of Chemistry and Chemical Engineering,
Jiangxi Normal University, Nanchang 330027, China
S Supporting Information
b
ABSTRACT: The tandem nucleophilic addition and 5-exo-
cyclization of (2-(alkynyl)benzylidene)malonates with imid-
azole derivatives in the presence of t-BuOK is reported. This
reaction proceeds smoothly under mild conditions with high
selectivity to afford the corresponding 1-(1H-imidazol-1-yl)-
3-methylene-1H-indene-2,2(3H)-dicarboxylates in good to
excellent yields.
KEYWORDS: 5-exo-cyclization, (2-(alkynyl)benzylidene)malonates, imidazole, nucleophilic addition
’ INTRODUCTION
alcohols.6d Because of the importance of indene compounds,
development of novel approaches for efficient construction of
diverse indenes is still of high interest. In our ongoing program
aimed at developing new approaches10 to generate small molecules
for our specific biological assays, we conceived that the indene with
an imidazole or benzoimidazole substituent might be a good
candidate because of the importance of the imidazole skeleton.
Recently, we described an efficient route for the formation of
1-methylene-2,3-dihydro-1H-indene with an indole substituent via
base-promoted tandem reactions with high efficiency and selec-
tivity.9e,f As mentioned above, our interest in these target imidazole-
corporate indenes is stimulated by the core structures of mole-
cules with known biological activity, and the presence of readily
variable diversity points, which opens extensive possibilities for
the synthesis of diverse library. Thus, we started to explore the
solution-phase parallel method for the synthesis of this kind of
designed compounds.
Recently, (2-(alkynyl)benzylidene)malonate has been identi-
fied as a versatile building block for carbo- and heterocycles
formation.9e,11 Prompted by this result, we envisioned that the
presence of imidazole as a partner in the reaction of (2-(alkynyl)-
benzylidene)malonate would occur to generate the desired
indene derivatives. In the reaction process, the tandem nucleo-
philic addition and 5-exo-cyclization might be involved. With
these considerations in mind, the reaction of (2-(alkynyl)ben-
zylidene)malonate 1{1} with imidazole 2{1} was carried out in
the presence of various bases in acetonitrile at room temperature
(Scheme 1).
The increasing significance of combinatorial chemistry in
pharmaceutical and material sciences is well recognized, which
demands the development of new strategies to generate a collec-
tion of analogues of interesting compounds.1 It is well docu-
mented that imidazole or benzoimidazole derivatives are of
particular interest for drug discovery since they are known to
elicit a broad spectrum of biological activities,2 and their applica-
tions in diverse therapeutic areas (including antivirals, antitumor,
antifungals, etc) have been discovered.3 Thus, the efficient gen-
eration of diversified imidazole-related library is of considerable
interest for both medicinal and organic chemists. Meanwhile,
the indene core may be found in many natural products and
drug candidates as well, which show remarkable biological acti-
vities.4 For instance, indene derivatives could be utilized to selec-
tively modulate estrogen receptor (ER)-mediated transcription.
Moreover, the 2,3-diarylindenes were found to bind with high affi-
nity to the ER subtypes and a range of different biological activities
was demonstrated both in transcriptional reporter gene assays and
inhibition of estradiol-stimulated proliferation of MCF-7 cells.4a In
addition, the function of indene-related compounds has been
found applications in the filed of material science.5 Thus, new
methods continue to appear for the formation of indene-related
compounds.6-9 For example, Sanzreporteda gold-catalyzedcyclo-
isomerization or alkoxycyclization of o-(alkynyl)styrenes that pro-
vided functionalized 1H-indene derivatives in good yields.6a Tian
and co-workers described an useful protocol for the synthesis of
indene derivatives via FeCl3-catalyzed reaction of N-benzylic sul-
fonamides and disubstituted alkynes.6c Roy reported indene forma-
tion via heterobimetallic Ir-Sn catalyzed reaction of propargylic
Received: September 21, 2010
Published: November 9, 2010
r
2010 American Chemical Society
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dx.doi.org/10.1021/co100006g ACS Comb. Sci. 2011, 13, 13–18
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ACS Combinatorial Science
RESEARCH ARTICLE
Figure 1. Diverse reagents 1{1-8}.
Table 1. Synthesis of 1-(1H-Imidazol-1-yl)-3-methylene-
1H-indene-2,2(3H)-dicarboxylates via Tandem Reaction of
(2-(Alkynyl)benzylidene)malonates with Imidazole Derivatives
Figure 2. Diverse reagents 2{1-5}.
Scheme 1. Initial Studies for Tandem Reaction of (2-(Alkynyl)-
benzylidene)malonate 1{1} with Imidazole 2{1}
entry compound 1 imidazole 2 time (h) product yield (%)a
1
1{1}
1{1}
1{1}
1{1}
1{1}
1{2}
1{2}
1{2}
1{2}
1{3}
1{3}
1{3}
1{4}
1{4}
1{4}
1{4}
1{5}
1{5}
1{5}
1{6}
1{6}
1{6}
1{7}
1{8}
2{1}
2{2}
2{3}
2{4}
2{5}
2{1}
2{3}
2{4}
2{5}
2{1}
2{3}
2{4}
2{1}
2{3}
2{4}
2{5}
2{1}
2{3}
2{4}
2{1}
2{3}
2{5}
2{3}
2 {1}
10
8
3{1,1}
3{1,2}
3{1,3}
3{1,4}
3{1,5}
3{2,1}
3{2,3}
3{2,4}
3{2,5}
3{3,1}
3{3,3}
3{3,4}
3{4,1}
3{4,3}
3{4,4}
3{4,5}
3{5,1}
3{5,3}
3{5,4}
3{6,1}
3{6,3}
3{6,5}
3{7,1}
3{8,1}
93
80
88
85
99
66
80
82
91
72
84
88
80
91
86
83
42
51
60
73
76
72
56
2
3
10
12
10
10
10
8
4
5
6
7
’ RESULT AND DISCUSSION
8
9
10
12
10
12
12
8
In the course of our investigations, we found that treatment of
the reaction in the presence of Cs2CO3 allowed us to obtain the
desired product 3{1,1} in 62% yield. This reaction proceeded
under mild conditions with excellent selectivity (Z/E >99/1). No
reaction occurred in the absence of base. Further investiga-
tion showed that lower yield (54%) of compound 3{1,1} was
obtained when K3PO4 was used as a replacement. Inferior result
was observed with addition of organic base, such as DABCO in
the reaction (29% yield). The yield was dramatically increased
when t-BuOK was utilized as a base (93% yield). This t-BuOK-
promoted result was disclosed in our previous report as well.9e
Subsequently, other solvents were screened (DCE, toluene,
EtOH, and THF). However, no better results were obtained.
In addition, no improvement was observed when an additive
(PdCl2, CuI, AgOTf, etc.) was presented in the reaction.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
10
10
10
12
12
12
12
12
12
12
Encouraged by the optimized conditions (t-BuOK, CH3CN, rt),
we extended our studies to other substrates (Figures 1 and 2) and the
result were shown in Table 1. As expected, for most cases, these base-
promoted reactions of (2-(alkynyl)benzylidene)malonates with
imidazole derivatives furnished the corresponding 1-(1H-imidazol-
1-yl)-3-methylene-1H-indene-2,2(3H)-dicarboxylates in good to
excellent yields. For instance, dimethyl 2-(2-(2-phenylethynyl)-
benzylidene)malonate 1{1} reacted with 4-methyl-1H-imidazole
2{2} gave rise to the desired product 3{1,2} in 80% yield (entry
2). In this case, the substitution was happened at 1N position of
imidazole 2{2} because of the steric effect. Moreover, no relation was
found for each proton from the 1H-1H COSY spectrum of com-
pound 3{1,2}. Whenbenzoimidazole2{3} or 2{4} was employed as
a Isolated yield based on (2-(alkynyl)benzylidene)malonate 1.
substrate in the reaction of (2-(alkynyl)benzylidene)malonate
1{1}, the expected product 3{1,3} or 3{1,4} was generated in
88% and 85% yield, respectively (entries 3 and 4). 1H-Naphtho-
[2,3-d]imidazole 2{5} was a suitable partner as well, which
reacted with compound 1{1} to afford the corresponding
product 3{1,5} in almost quantitative yield (entry 5). Substrate
1{2} was examined meanwhile in the reaction of imidazole or
benzoimidazole, and all reactions worked smoothly to produce
the desired products in good yields (entries 6-9). Reactions of
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ACS Combinatorial Science
RESEARCH ARTICLE
(Z)-Dimethyl 1-Benzylidene-3-(1H-imidazol-1-yl)-1H-indene-
2,2(3H)-dicarboxylate 3{1,1}: yellow oil; H NMR (400 MHz,
1
CDCl3) δ 2.87 (s, 3H), 3.65 (s, 3H), 6.57 (s, 1H), 6.63 (s, 1H),
6.92 (s, 1H), 7.22-7.26 (m, 2H), 7.29-7.33 (m, 3H), 7.35-
7.7.37 (m, 1H), 7.41 (s, 1H), 7.44-7.50 (m, 3H), 7.72 (d, J =
8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 52.4, 53.6, 67.0,
69.7, 121.0, 125.9, 127.9, 128.2, 128.3, 128.6, 128.8, 129.8,
130.5, 135.4, 135.8, 137.1, 142.2, 167.1, 168.7; HRMS calcd for
C23H21N2O4 (MþþH) 389.1501; found 389.1512.
(Z)-Dimethyl 1-Benzylidene-3-(4-methyl-1H-imidazol-1-yl)-
1
1H-indene-2,2(3H)-dicarboxylate 3{1,2}: yellow oil; H NMR
(400 MHz, CDCl3) δ 2.09 (s, 3H), 2.91 (s, 3H), 3.69(s, 3H),
6.32 (s, 1H), 6.48(s, 1H), 7.11 (s, 1H), 7.22-7.26 (m, 1H), 7.29-
7.49(m, 8H), 7.70 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 13.5, 52.3, 53.5, 66.8, 69.5, 115.5, 120.8, 125.7, 127.7,
128.0, 128.2, 128.5, 128.7, 129.5, 130.3, 135.5, 135.7, 136.5, 137.2,
142.1, 167.0, 168.7; HRMS calcd for C24H23N2O4 (Mþ þ H)
403.1658; found 403.1651.
Figure 3. ORTEP illustration of compound 3{5,4}.
(Z)-Dimethyl 1-(1H-Benzo[d]imidazol-1-yl)-3-benzylidene-1H-
1
indene-2,2(3H)-dicarboxylate 3{1,3}: yellow oil; H NMR (400
fluoro-substituted (2-(alkynyl)benzylidene)malonate 1{3} or 1{4}
were also examined, and the results demonstrated that the
imidazole derivatives participated well in this tandem nucleo-
philic addition and 5-exo-cyclization reaction (entries 10-16).
When methoxy-substituted (2-(alkynyl)benzylidene)malonate
1{5} was utilized in the reactions with imidazoles, the desired
products were obtained in moderate yields (entries 17-19). This
result was reasonable since the electron-donating group attached on
the aromatic ring of (2-(alkynyl)benzylidene)malonate might de-
crease the electrophilicity of olefin. The structure of 3{5,4} was
identified meanwhile by X-ray diffraction analysis (Figure 3), which
confirmed the Z configuration. Additionally, the substitution was
found to happen at 1N position of imidazole 2{4}. We further
recognized that in this kind of transformation, the R2 group attached
on the triple bond is crucial. When R2 was replaced by 4-methyl-
phenyl group (1{6}), similar yields were observed in the reactions
of imidazoles (entries 20-22). However, no desired cyclized prod-
uct was detected when dimethyl 2-(2-(hex-1-ynyl)benzylidene)-
malonate 1{8} was used as the substrate in the reaction of imidazole
2{1} (entry 24).
MHz, CDCl3) δ 2.32 (s, 3H), 3.80 (s, 3H), 6.97 (s, 1H), 7.19 (s,
1H), 7.22-7.42 (m, 9H), 7.44 (s, 1H), 7.51-7.55 (m, 1H), 7.63 (d,
J= 8.0 Hz, 1H), 7.71 (d, J= 8.4 Hz, 1H), 7.76 (d, J=8.0Hz,1H);13C
NMR (100 MHz, CDCl3) δ 51.8, 53.6, 64.5, 68.9, 109.9, 120.0,
121.0, 122.5, 123.0, 125.9, 127.7, 127.9, 128.4, 128.7, 129.9, 130.6,
133.9, 135.5, 135.7, 136.6, 142.2, 142.5, 143.2, 166.6, 169.0; HRMS
calcd for C27H23N2O4 (Mþ þ H): 439.1658; found 439.1659.
(Z)-Dimethyl 1-Benzylidene-3-(5-methyl-1H-benzo[d]imidazol-
1
1-yl)-1H-indene-2,2(3H)-dicarboxylate 3{1,4}: yellow oil; H
NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 2.47 (s, 3H), 3.79 (s,
3H), 6.91 (d, J = 3.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.12 (d,
J = 7.7 Hz, 2H), 7.21 (d, J = 7.7 Hz, 2H), 7.25-7.27 (m, 1H),
7.32-7.34 (m, 1H), 7.38-7.43(m, 3H), 7.49-7.58 (m, 3H),
7.76 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.5,
51.9, 53.6, 64.4, 68.9, 109.5, 119.5, 121.0, 124.1, 124.6, 125.9,
127.8, 128.0, 128.5, 128.6, 129.9, 130.6, 133.2, 135.5, 135.7,
136.8, 141.7, 142.4, 142.5, 166.7, 169.0; HRMS calcd for C28H25N2O4
(Mþ þ H) 453.1814; found 453.1807.
(Z)-Dimethyl 1-Benzylidene-3-(1H-naphtho[2,3-d]imidaz-
ol-1-yl)-1H-indene-2,2(3H)-dicarboxylate 3{1,5}: white solid; mp
179-180 °C; 1H NMR (400 MHz, CDCl3) δ 2.27 (s, 3H), 3.82
(s, 3H), 7.08 (s, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.25-7.27 (m, 2H),
7.37-7.43 (m, 7H), 7.46 (s, 1H), 7.53-7.56 (m, 1H), 7.78 (d, J =
8.0 Hz, 1H), 7.95-8.01 (m, 2H), 8.02 (s, 1H), 8.20 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ51.9, 53.7, 64.6, 68.8, 105.8, 117.2, 121.1,
123.6, 124.5, 125.8, 127.7, 127.8, 127.9, 128.3, 128.4, 128.7, 129.9,
130.2, 130.5, 130.7, 134.3, 135.4, 135.7, 136.7, 142.4, 143.2, 145.9,
166.6, 169.1; HRMS calcd for C31H25N2O4 (Mþ þ H) 489.1814;
found 489.1809.
’ CONCLUSION
In conclusion, our present methodology allows efficient prepara-
tion of 1-methylene-2,3-dihydro-1H-indenes with an imidazole sub-
stituent via a tandem reaction of (2-(alkynyl)benzylidene)malonate
with imidazole. This transformation, which involves nucleophilic
addition and 5-exo-cyclization, proceeds smoothly under mild con-
ditions with excellent selectivity and broad scope. Focused library
construction and biological evaluation of these compounds are
ongoing, and the results will be reported in due course.
(Z)-Diethyl 1-Benzylidene-3-(1H-imidazol-1-yl)-1H-indene-
2,2(3H)-dicarboxylate 3{2,1}: yellow oil; 1H NMR (400 MHz,
CDCl3) δ 0.50 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H),
3.23-3.32 (m, 2H), 4.09-4.31 (m, 2H), 6.58 (s, 1H), 6.62
(s, 1H), 6.89 (s, 1H), 7.24-7.40 (m, 6H), 7.41 (s, 1H), 7.42-
7.50 (m, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 12.7, 13.6, 62.2, 62.8, 66.6, 69.8,
119.3, 120.8, 125.7, 127.7, 127.9, 128.2, 128.5, 128.8, 129.6,
130.3, 135.2, 135.8, 137.2, 142.3, 166.6, 168.0; HRMS calcd for
C25H25N2O4 (Mþ þ H) 417.1814; found 417.1811.
’ EXPERIMENTAL PROCEDURES
General Procedure for Tandem Reaction of (2-(Alkynyl)-
benzylidene)malonates with Imidazole Derivatives. Imid-
azole 2 (0.2 mmol) was added to a solution of 2-(2-(alkyny)ben-
ylidene)malonate 1 (0.24 mmol) and t-BuOK (0.2 mmol) in
CH3CN (2.0 mL), and the mixture was stirred at room tem-
perature. After completion of reaction as indicated by TLC, the
mixture was quenched with saturated aqueous NH4Cl, extracted
with EtOAc, and dried by anhydrous Na2SO4. Evaporation of the
solvent followed by purification on silica gel provided the product 3.
(Z)-Diethyl 1-(1H-Benzo[d]imidazol-1-yl)-3-benzylidene-1H-
1
indene-2,2(3H)-dicarboxylate 3{2,3}: yellow oil; H NMR (400
MHz, CDCl3) δ 0.16 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.3 Hz, 3H),
15
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ACS Combinatorial Science
RESEARCH ARTICLE
2.60-2.69 (m, 2H), 4.18-4.40 (m, 2H), 6.99 (s, 1H), 7.19-7.35
(m, 6H), 7.40 (t, J = 7.3 Hz, 1H), 7.45 (s, 1H), 7.47-7.54 (m, 4H),
7.65-7.71 (m, 2H), 7.76 (d, J = 7.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ12.2, 13.7, 62.0, 62.9, 64.3, 69.3, 110.1, 119.9, 121.0, 122.5,
123.0, 125.9, 127.7, 127.8, 127.9, 128.7, 129.8, 130.6, 134.0, 135.6,
135.7, 136.8, 142.3, 142.6, 143.2, 166.5, 168.5; HRMS calcd for
C29H27N2O4 (Mþ þ H) 467.1971; found 467.1963.
164.5 (d, 1JCF = 249 Hz), 166.4, 168.8; HRMS calcd for C28H24-
FN2O4 (Mþ þ H) 471.1720; found 417.1718.
(Z)-Dimethyl 1-Benzylidene-5-fluoro-3-(1H-imidazol-1-yl)-
1H-indene-2,2(3H)-dicarboxylate 3{4,1}: yellow oil; 1H NMR (400
MHz, CDCl3) δ 2.89 (s, 3H), 3.70 (s, 3H), 6.54 (s, 1H), 6.62 (s,
1H), 6.93 (s, 1H), 7.00 (dd, J = 2.2, 8.0 Hz, 1H), 7.20-7.33 (m,
6H), 7.43 (d, J = 7.7 Hz, 2H), 7.67-7.70 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 52.4, 53.5, 66.3, 69.7, 112.5 (d, 2JCF = 23.7 Hz),
118.3 (d, 2JCF = 23.7 Hz), 119.0, 122.4 (d, 3JCF = 9.16 Hz), 127.8,
127.9, 128.0, 128.6, 128.9, 134.1, 135.5, 137.3, 138.1, 138.8 (d,
3JCF = 8.40 Hz), 163.5 (d, 1JCF = 249 Hz), 166.6, 168.5; HRMS calcd
for C23H20FN2O4 (Mþ þ H) 407.1407; found 407.1401.
(Z)-Diethyl 3-(1H-Benzo[d]imidazol-1-yl)-1-benzylidene-
5-fluoro-1H-indene-2,2(3H)-dicarboxylate 3{4,3}: white solid; mp
150-151 °C; 1H NMR (400 MHz, CDCl3) δ 2.34 (s, 3H), 3.80 (s,
3H), 6.93 (s, 1H), 7.05 (dd, J = 2.2, 7.7 Hz, 1H), 7.18-7.33 (m,
7H), 7.36 (s, 1H), 7.39 (d, J = 7.7 Hz, 2H), 7.60 (d, J = 8.1 Hz, 1H),
7.71-7.75 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 51.9, 53.7,
63.9, 69.2, 109.7, 112.6 (d, 2JCF = 22.9 Hz), 118.5 (d, 2JCF = 22.9
Hz), 120.1, 122.6, 122.7, 123.2, 127.8, 128.0, 128.3, 128.4, 128.7,
133.7, 134.5, 135.4, 138.4, 138.5, 141.9, 143.1, 163.6 (d, 1JCF = 249.6
Hz), 166.3, 168.8; HRMS calcd for C27H22FN2O4 (Mþ þ H)
457.1564; found 457.1566.
(Z)-Diethyl 1-Benzylidene-3-(5-methyl-1H-benzo[d]imidazol-
1-yl)-1H-indene-2,2(3H)-dicarboxylate 3{2,4}: yellow oil; 1H NMR
(400 MHz, CDCl3) δ 0.19 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1 Hz,
3H), 2.47 (s, 3H), 2.63-2.72 (m, 2H), 4.18-4.39 (m, 2H), 6.94 (d,
J = 3.2 Hz, 1H), 7.05 (d, J = 7.3 Hz, 1H), 7.12 (d, J = 6.2 Hz, 1H),
7.19-7.21 (m, 1H), 7.24-7.28 (m, 1H), 7.32 (d, J = 7.7 Hz, 1H),
7.37-7.40 (m, 1H), 7.44 (s, 1H), 7.46-7.58 (m, 4H), 7.65-7.71
(m, 2H), 7.76 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 12.3, 13.7, 62.0, 62.9, 64.3, 69.3, 109.5, 119.4, 120.9, 124.0,
124.5, 125.8, 127.8, 127.9, 128.6, 128.7, 129.0, 129.8, 130.5, 132.1,
132.9, 135.7, 136.9, 141.8, 142.5, 166.4, 168.5; HRMS calcd for
C30H29N2O4 (Mþ þ H) 481.2127; found 481.2125.
(Z)-Diethyl 1-Benzylidene-3-(1H-naphtho[2,3-d]imidazol-
1-yl)-1H-indene-2,2(3H)-dicarboxylate 3{2,5}: white solid; mp
138-139 °C; 1H NMR (400 MHz, CDCl3) δ 0.18 (t, J = 7.3 Hz,
3H), 1.37 (t, J = 7.3 Hz, 2H), 2.61-2.70 (m, 2H), 4.30-4.50 (m,
2H), 7.17 (s, 1H), 7.23-7.27 (m, 1H), 7.30-7.35(m, 3H), 7.41-
7.50 (m, 5H), 7.54 (s, 1H), 7.56-7.62 (m, 3H), 7.86 ((d, J = 7.7
Hz, 1H), 8.01-8.07 (m, 2H), 8.13 (s, 1H), 8.26 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 12.3, 13.8, 62.1, 63.0, 64.5, 69.2,
105.9, 117.1, 121.1, 123.6, 124.5, 125.9, 127.6, 127.8, 127.9, 128.4,
128.7, 128.8, 129.9, 130.5, 130.6, 134.5, 135.6, 135.8, 136.9, 142.6,
146.1, 166.5, 168.6; HRMS calcd for C33H29N2O4 (Mþ þ H)
517.2127; found 517.2125.
(Z)-Dimethyl 1-Benzylidene-5-fluoro-3-(5-methyl-1H-benzo-
[d]imidazol-1-yl)-1H-indene-2,2(3H)-dicarboxylate 3{4,4}: yellow
oil; 1H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 2.47 (s, 3H), 3.79
(s, 3H), 6.88(d, J= 3.7 Hz, 1H), 7.01-7.08 (m, 1H), 7.12-7.18 (m,
1H), 7.20-7.29 (m, 4H), 7.39-7.41 (m, 4H), 7.49(s, 1H), 7.58
(d, J = 8.4 Hz, 1H), 7.71-7.74 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ21.4, 52.0, 53.7, 63.9, 69.2, 109.3, 112.6 (d, 2JCF =23.6Hz),
118.5 (d, 2JCF = 23.6 Hz), 119.6, 122.6 (d, 3JCF = 8.30 Hz), 124.2,
124.7, 127.8, 128.0, 128.3, 128.4, 128.8, 132.2, 133.3, 134.5, 135.4,
138.3 (d, 4JCF = 2.29 Hz), 138.7, 141.5, 141.8, 163.6 (d, 1JCF = 248.8
Hz), 166.4, 168.9; HRMS calcd for C28H24FN2O4 (Mþ þ H)
471.1720; found 471.1711.
(Z)-Dimethyl 3-Benzylidene-5-fluoro-1-(1H-imidazol-1-yl)-
1
1H-indene-2,2(3H)-dicarboxylate 3{3,1}: yellow oil; H NMR
(400 MHz, CDCl3) δ 2.87 (s, 3H), 3.72 (s, 3H), 6.52 (s, 1H),
6.61 (s, 1H), 6.91 (s, 1H), 7.00-7.10 (m, 1H), 7.23-7.38 (m, 7H),
7.43 (d, J= 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ52.4, 53.6,
(Z)-Dimethyl 1-Benzylidene-5-fluoro-3-(1H-naphtho[2,3-d]im-
idazol-1-yl)-1H-indene-2,2(3H)-dicarboxylate 3{4,5}: white solid;
2
66.2, 70.1, 107.6 (d, 2JCF = 23.7 Hz), 117.3 (d, JCF = 23.6 Hz),
119.1, 127.3 (d, 3JCF = 9.16 Hz), 128.2, 128.8, 128.9, 132.7, 134.4 (d,
mp 200-201 °C; H NMR (400 MHz, CDCl3) δ 2.29 (s, 3H),
1
3
4JCF = 3.0 Hz), 135.3, 137.3, 144.5 (d, JCF = 9.16 Hz), 164.4
3.82 (s, 3H), 7.04-7.09 (m, 2H), 7.20 (d, J = 7.7 Hz, 1H), 7.24-
7.28 (m, 3H), 7.34-7.46 (m, 6H), 7.74-7.77 (m, 1H), 7.95-8.00
(m, 3H), 8.21 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 52.1, 53.8,
(d, 1JCF = 248 Hz), 166.6, 168.4; HRMS calcd for C23H20FN2O4
(Mþ þ H) 407.1407; found 407.1396.
(Z)-Dimethyl 1-(1H-Benzo[d]imidazol-1-yl)-3-benzylidene-
5-fluoro-1H-indene-2,2(3H)-dicarboxylate 3{3,3}: yellow solid;
64.2, 69.1, 105.8, 112.6 (d, 2JCF = 21.9 Hz), 117.4, 118.6 (d, 2JCF
=
23.6 Hz), 122.7 (d, 3JCF = 8.39 Hz), 123.8, 124.7, 127.5, 127.9, 128.0,
128.4, 128.5, 130.3, 130.5, 134.5, 135.3, 138.3 (d, 4JCF = 2.29 Hz),
138.6, 145.6, 163.6 (d, 1JCF = 249.5 Hz), 166.4, 169.0; HRMS calcd
for C31H24FN2O4 (Mþ þ H) 507.1720; found 507.1718.
(Z)-Dimethyl 1-Benzylidene-3-(1H-imidazol-1-yl)-5,6-
dimethoxy-1H-indene-2,2(3H)-dicarboxylate 3{5,1}: white solid;
mp 166-167 °C; 1H NMR (400 MHz, CDCl3) δ 2.86 (s, 3H),
3.73 (s, 3H), 3.85 (s, 3H), 4.01 (s, 3H), 6.48 (s, 1H), 6.65 (s, 1H),
6.74 (s, 1H), 6.94 (s, 1H), 7.12(s, 1H), 7.20-7.24 (m, 2H),
7.28-7.32 (m, 3H), 7.43 (d, J = 7.3 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 53.3, 53.5, 56.5, 56.5, 66.9, 70.0, 102.4, 106.9,
125.7, 127.5, 128.0, 128.5, 129.3, 135.1, 135.5, 135.8, 151.3, 151.6,
167.0, 168.8; HRMS calcd for C25H25N2O6 (Mþ þ H) 449.1713;
found 449.1707.
1
mp 74-75 °C; H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H),
3.81 (s, 3H), 6.92 (s, 1H), 7.10-7.13 (m, 1H), 7.19-7.33 (m, 7H),
7.37-7.43 (m, 4H), 7.61 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 51.9, 53.7, 63.7, 69.5, 107.8
(d, 2JCF = 23.6 Hz), 109.9, 117.4 (d, 2JCF = 23.7 Hz), 120.0, 122.5,
123.1, 127.5, 127.5, 128.0, 128.1, 128.5, 128.7, 130.0, 132.2, 133.7,
134.8 (d, 4JCF = 3.0 Hz), 135.0, 141.9, 143.1, 144.8 (d, 3JCF = 8.4
1
Hz), 164.5 (d, JCF = 249 Hz), 166.3, 168.7; HRMS calcd for
C27H22FN2O4 (Mþ þ H) 457.1564; found 457.1564.
(Z)-Dimethyl 3-Benzylidene-5-fluoro-1-(5-methyl-1H-benzo-
[d]imidazol-1-yl)-1H indene-2,2(3H)-dicarboxylate 3{3,4}: yellow
oil; 1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 2.47 (s, 3H), 3.80
(s, 3H), 6.87 (d, J = 3.3 Hz, 1H), 7.05-7.14 (m, 3H), 7.22 (d, J =
7.7 Hz, 1H), 7.26-7.31 (m, 2H), 7.36-7.42 (m, 5H), 7.48 (d, J =
8.4 Hz, 1H), 7.57 (d, J= 8.4 Hz, 1H); 13CNMR(100MHz, CDCl3)
δ 21.5, 52.0, 53.7, 63.7, 69.4, 107.8 (d, 2JCF = 22.9 Hz), 109.7, 117.5
(d, 2JCF = 23.6 Hz), 119.5, 123.9, 124.2, 124.7, 127.5(d, 3JCF = 9.16
Hz), 128.0, 128.1, 128.6, 129.9, 132.3 (d, 3JCF = 7.0 Hz), 132.5, 133.2,
134.9 (d, 4JCF = 2.29 Hz), 135.1, 141.5, 144.8 (d, 3JCF = 8.40 Hz),
(Z)-Dimethyl 1-(1H-Benzo[d]imidazol-1-yl)-3-benzylidene-
5,6-dimethoxy-1H-indene-2,2(3H)-dicarboxylate 3{5,3}: white
1
solid; mp 240-241 °C; H NMR (400 MHz, CDCl3) δ 2.31
(s, 3H), 3.82 (s, 3H), 3.83 (s, 3H), 4.04 (s, 3H), 6.78 (s, 1H), 6.88
(s, 1H), 7.17-7.19 (m, 2H), 7.23-7.27 (m, 5H), 7.30 (d, J =
8.1 Hz, 1H), 7.39 (d, J = 7.3 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.71
16
dx.doi.org/10.1021/co100006g |ACS Comb. Sci. 2011, 13, 13–18

ACS Combinatorial Science
RESEARCH ARTICLE
(d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 51.8, 53.6,
56.1, 56.1, 64.5, 69.4, 102.6, 107.0, 110.0, 120.0, 122.5, 123.0,
126.5, 127.5, 127.9, 128.4, 128.9, 133.8, 135.4, 135.7, 135.9, 142.3,
143.3, 151.4, 151.7, 166.7, 169.2; HRMS calcd for C29H27N2O6
(MþþH) 499.1869; found 499.1866.
compounds 3. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(Z)-Dimethyl 1-Benzylidene-5,6-dimethoxy-3-(5-methyl-1H-
benzo[d]imidazol-1-yl)-1H-indene-2,2(3H)-dicarboxylate
Corresponding Author
*E-mail: jie_wu@fudan.edu.cn (J.W.) or yypeng@jxnu.edu.cn (Y.P.).
1
3{5,4}: white solid; mp 227-228 °C; H NMR (400 MHz,
CDCl3) δ 2.35 (s, 3H), 2.47 (s, 3H), 3.81 (s, 3H), 3.82 (s, 3H),
4.06 (s, 3H), 6.75 (d, J = 3.7 Hz, 1H), 6.83 (d, J = 3.0 Hz, 1H), 7.06
(d, J = 8.4 Hz, 1H), 7.16-7.19 (m, 3H), 7.24-7.27 (m, 3H),
7.36-7.39 (m, 2H), 7.48-7.50 (m, 1H), 7.58 (d, J = 8.1 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 21.5, 51.8, 53.6, 56.1, 56.1, 64.5,
69.4, 102.6, 106.9, 109.7, 119.5, 119.7, 124.1, 124.5, 126.1, 127.5,
127.9, 128.4, 129.2, 132.1, 133.1, 135.3, 135.7, 135.9, 141.8, 142.2,
151.4, 151.6, 166.7, 169.2; HRMS calcd for C30H29N2O6 (Mþþ H)
513.2026; found 513.2011.
’ ACKNOWLEDGMENT
Financial support from the National Natural Science Founda-
tion of China (No. 20972030) and the Science & Technology
Commission of Shanghai Municipality (09JC1404902) is grate-
fully acknowledged.
’ REFERENCES
(1) (a) Walsh, D. P.; Chang, Y.-T. Chem. Rev. 2006, 106, 2476–2530.
(b) Arya, P.; Chou, D. T. H.; Baek, M.-G. Angew. Chem., Int. Ed. 2001,
40, 339–346. (c) Schreiber, S. L. Science 2000, 287, 1964–1969.
(d) Spaller, M. R.; Burger, M. T.; Fardis, M.; Bartlett, P. A. Curr. Opin.
Chem. Biol. 1997, 1, 47–53.
(Z)-Dimethyl 1-(4-methyl)benzylidene-3-(1H-imidazol-1-yl)-
1
1H-indene-2,2(3H)-dicarboxylate 3{6,1}: yellow oil; H NMR
(400 MHz, CDCl3) δ 2.32 (s, 3H), 2.91 (s, 3H), 3.72 (s, 3H),
6.56 (s, 1H), 6.62 (s, 1H), 6.91 (s, 1H), 7.12 (d, J = 8.1 Hz, 2H),
7.23 (s, 1H), 7.29-7.37 (m, 5H), 7.46-7.49 (m, 1H), 7.70 (d, J =
8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.2, 52.4, 53.5, 66.9,
69.6, 119.3, 120.7, 125.7, 128.3, 128.6, 128.7, 128.8, 129.4, 130.4,
132.7, 134.4, 136.9, 137.4, 137.8, 142.4, 167.0, 168.5; HRMS calcd
for C24H23N2O4 (Mþ þ H) 403.1658; found 403.1645.
(2) (a) Tebbe, M. J.; Spitzer, W. A.; Victor, F.; Miller, S. C.; Lee, C. C.;
Sattelberg, T. R., Sr.; Mckinney, E.; Tang, J. C. J. Med. Chem. 1997, 40,
3937. (b) Trivedi, R.; De, S. K.; Gibbs, R. A. J. Mol. Catal. A. 2006, 245, 8.
(3) For selected examples, see: (a) Erhardt, P. W. J. Med. Chem.
1987, 30, 231. (b) Tomczuk, B. E.; Taylor, C. R., Jr.; Moses, L. M.;
Sutherland, D. B.; Lo, Y. S.; Johnson, D. N.; Kinnier, W. B.; Kilpatrick,
B. F. J. Med. Chem. 1991, 34, 2993. (c) Spasov, A. A.; Yozhitsa, I. N.;
Bugaeva, L. I.; Anisimova, V. A. Pharm. Chem. J. 1999, 33, 232.
(d) Gravatt, G. L.; Baguley, B. C.; Wilson, W. R.; Denny, W. A.
J. Med. Chem. 1994, 37, 4338. (e) Soderlind, K.-J.; Gorodetsky, B.;
Singh, A. K.; Bachur, N.; Miller, G. G.; Lown, J. W. Anti-Cancer Drug Des.
1999, 14, 19. (f) Kim, J. S.; Gatto, B.; Yu, C.; Liu, A.; Liu, L. F.; Lavoie,
E. J. J. Med. Chem. 1996, 39, 992. (g) Chen, A. Y.; Yu, C.; Gatto, B.; Liu,
L. F. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 8131. (h) Roth, T.;
Morningstar, M. L.; Boyer, P. L.; Hughes, S. H.; Buckheit, R. W.;
Michejda, C. J. J. Med. Chem. 1997, 40, 4199.
(4) (a) Clegg, N. J.; Paruthiyil, S.; Leitman, D. C.; Scanlan, T. S.
J. Med. Chem. 2005, 48, 5989. (b) Lautens, M.; Marquardt, T. J. Org.
Chem. 2004, 69, 4607. (c) Korte, A.; Legros, J.; Bolm, C. Synlett 2004,
2397. (d) Maguire, A. R.; Papot, S.; Ford, A.; Touhey, S.; O'Connor, R.;
Clynes, M. Synlett 2001, 41. (e) Gao, H.; Katzenellenbogen, J. A.; Garg,
R.; Hansch, C. Chem. Rev. 1999, 99, 723. (f) Senanayake, C. H.; Roberts,
F. E.; DiMichele, L. M.; Ryan, K. M.; Liu, J.; Fredenburgh, L. E.; Foster,
B. S.; Douglas, A. W.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J.
Tetrahedron Lett. 1995, 36, 3993. (g) Shanmugam, P.; Rajasingh, P.
Chem. Lett. 2005, 34, 1494.
(5) For selected examples, see: (a) Yang, J.; Lakshmikantham, M. V.;
Cava, M. P.; Lorcy, D.; Bethelot, J. R. J. Org. Chem. 2000, 65, 6739.
(b) Barbera, J.; Rakitin, O. A.; Ros, M. B.; Torroba, T. Angew. Chem.,
Int. Ed. 1998, 37, 296.
(6) (a) Martinez, A.; Garcia-Garcia, P.; Fernandez-Rodriguez, M. A.;
Rodriguez, F.; Sanz, R. Angew. Chem., Int. Ed. 2010, 49, 4633. (b) Becker,
C.; McLaughlin, M. Synlett 1991, 642. (c) Prough, J. D.; Alberts, A. W.;
Deanna, A. A.; Gilfillian, J. L.; Huff, J. W.; Smith, R. L.; Wiggins, J. M.
J. Med. Chem. 1990, 33, 758. (c) Liu, C. R.; Yang, F.-L.; Jin, Y.-Z.; Ma,
X.-T.; Cheng, D.-J.; Li, N.; Tian, S.-K. Org. Lett. 2010, 12, 3832.
(d) Chatterjee, P. N.; Roy, S. J. Org. Chem. 2010, 75, 4413.
(Z)-Dimethyl 1-(1H-Benzo[d]imidazol-1-yl)-3-(4-methyl)ben-
zylidene-1H-indene-2,2(3H)-dicarboxylate 3{6,3}: yellow oil; 1H
NMR (400 MHz, CDCl3) δ 2. 28 (s, 3H), 2.36 (s, 3H), 3.80 (s,
3H), 6.96 (s, 1H), 7.07 (d, J = 8.0 Hz, 2H), 7.19 (s, 1H), 7.23-7.27
(m, 1H), 7.29-7.35 (m, 4H), 7.37-7.40 (m, 2H), 7.50-7.54 (m,
1H), 7.66 (d, J = 7.7 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.75 (d, J =
8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.2, 51.9, 53.6, 64.6,
69.0, 110.1, 120.0, 120.9, 122.5, 123.1, 125.9, 128.6, 128.7, 128.8,
129.7, 130.6, 132.6, 133.9, 134.7, 136.5, 137.8, 142.3, 142.7, 166.7,
169.1; HRMS calcd for C28H25N2O4 (Mþ þ H) 453.1814; found
453.1815.
(Z)-Diethyl 1-Benzylidene-3-(1H-naphtho[2,3-d]imidazol-1-yl)-
1
1H-indene-2,2(3H)- dicarboxylate 3{6,5}: yellow oil; H NMR
(400 MHz, CDCl3) δ 2. 27 (s, 3H), 2.31 (s, 3H), 3.83 (s, 3H),
7.06-7.07 (m, 3H), 7.32 (d, J = 8.4 Hz, 2H), 7.35-7.45 (m, 6H),
7.52-7.56 (m, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.95-8.03 (m, 3H),
8.20 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.2, 52.1, 53.7, 64.8,
68.9, 106.0, 117.1, 121.0, 123.7, 124.6, 125.8, 127.8, 128.4, 128.6,
128.7, 128.9, 129.8, 130.3, 130.7, 132.6, 134.8, 136.6, 137.9, 142.6,
146.1, 166.7, 169.2; HRMS calcd for C32H27N2O4 (Mþ þ H)
503.1971; found 503.1969.
(Z)-Dimethyl 1-(4-Chlorobenzylidene)-3-(1H-benzo[d]imid-
azol-1-yl)-1H-indene-2,2(3H)-dicarboxylate 3{7,1}: yellow oil; 1H
NMR (400 MHz, CDCl3) δ2.38 (s, 3H), 3.81 (s, 3H), 6.97 (s, 1H),
7.18 (s, 1H), 7.23-7.27 (m, 3H), 7.31 (d, J = 8.4 Hz, 1H), 7.34-
7.37 (m, 4H), 7.40-7.44 (m, 1H), 7.51-7.55 (m, 1H), 7.61 (d, J =
8.4 Hz, 1H), 7.71-7.76 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
52.2, 53.9, 64.6, 69.1, 110.1, 120.2, 120.3, 121.3, 122.7, 123.3, 126.1,
127.5, 128.3, 130.0, 130.3, 130.4, 130.8, 133.8, 134.2, 136.5, 136.9,
142.3, 166.7, 168.9. HRMS calcd for C27H22ClN2O4 (Mþ þ H)
473.1268; found 473.1276.
(7) (a) Zhang, D.; Liu, Z.; Yum, E. K.; Larock, R. C. J. Org. Chem.
2007, 72, 251. (b) Zhang, D.; Yum, E. K.; Liu, Z.; Larock, R. C. Org. Lett.
2005, 7, 4963. (c) Xi, Z.; Guo, R.; Mito, S.; Yan, H.; Kanno, K.;
Nakajima, K.; Takahashi, T. J. Org. Chem. 2003, 68, 1252. (d) Yoshikawa, E.;
Radhakrishnan, K. V.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 7280.
(e) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc.
2006, 128, 202.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures,
b
characterization data, and 1H and 13C NMR spectra of
17
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RESEARCH ARTICLE
(8) Romines, K. R.; Lovasz, K. D.; Mizsak, S. A.; Morris, J. K.; Seest,
E. P.; Han, F.; Tulinsky, J.; Judge, T. M.; Gammill, R. B. J. Org. Chem.
1999, 64, 1733.
(9) (a) Zhou, F.; Yang, M.; Lu, X. Org. Lett. 2009, 11, 1405. (b) Lu,
J.-M.; Zhu, Z.-B.; Shi, M. Chem.;Eur. J. 2009, 15, 963. (c) Ye, S.;
Gao, K.; Zhou, H.; Yang, X.; Wu, J. Chem. Commun. 2009, 5406. (d) Ye,
S.; Yang, X.; Wu, J. Chem. Commun. 2010, 46, 2950. (e) Gao, K.; Wu, J.
Org. Lett. 2008, 10, 2251.
(10) For selected recent examples, see: (a) Yu, X.; Wu, J. J. Comb.
Chem. 2010, 12, 238. (b) Yu, X.; Chen, Z.; Yang, X.; Wu, J. J. Comb.
Chem. 2010, 12, 374. (c) Chen, Z.; Yang, X.; Wu, J. Chem. Commun.
2009, 3469. (d) Chen, Z.; Yu, X.; Su, M.; Yang, X.; Wu, J. Adv. Synth.
Catal. 2009, 351, 2702. (e) Chen, Z.; Ding, Q.; Yu, X.; Wu, J. Adv. Synth.
Catal. 2009, 351, 1692. (f) Ding, Q.; Wang, Z.; Wu, J. J. Org. Chem. 2009,
74, 921. (g) Ding, Q.; He, X.; Wu, J. J. Comb. Chem. 2009, 11, 587.
(h) Yu, X.; Wu, J. J. Comb. Chem. 2009, 11, 895. (i) Ding, Q.; Huang, X.;
Wu, J. J. Comb. Chem. 2009, 11, 1047.
(11) Liu, L.; Zhang, J. Angew. Chem., Int. Ed. 2009, 48, 6093.
18
dx.doi.org/10.1021/co100006g |ACS Comb. Sci. 2011, 13, 13–18