Synthesis of (Z)-1-benzylidene-3-(1H-indol-1-yl)-1H-indene-2,2(3H)- dicarbonitriles via three-component reaction of 2-alkynylbenzaldehyde, malononitrile, and indole

Article abstract of DOI:10.1016/j.tetlet.2010.06.065

Three-component reaction of 2-alkynylbenzaldehyde, malononitrile, and indole under mild conditions is described, which generates the desired (Z)-1-benzylidene-3-(1H-indol-1-yl)-1H-indene-2,2(3H)-dicarbonitriles in moderate to good yields. This reaction pr

Full text of DOI:10.1016/j.tetlet.2010.06.065

Tetrahedron Letters 51 (2010) 4391–4394
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of (Z)-1-benzylidene-3-(1H-indol-1-yl)-1H-indene-2,2(3H)-
dicarbonitriles via three-component reaction
of 2-alkynylbenzaldehyde, malononitrile, and indole
b,
Guanyinsheng Qiu a, Qiuping Ding a, Yiyuan Peng a, , Jie Wu
*
*
a Key Laboratory of Green Chemistry of Jiangxi Province, College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330027, China
b Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Three-component reaction of 2-alkynylbenzaldehyde, malononitrile, and indole under mild conditions is
described, which generates the desired (Z)-1-benzylidene-3-(1H-indol-1-yl)-1H-indene-2,2(3H)-dicarbo-
nitriles in moderate to good yields. This reaction proceeds smoothly with high selectivity. The tandem
condensation, nucleophilic addition, and 5-exo-cyclization may be involved in the process.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 13 May 2010
Revised 8 June 2010
Accepted 12 June 2010
Available online 17 June 2010
Keywords:
2-Alkynylbenzaldehyde
Malononitrile
Indole
Three-component reaction
As we know, the indene core is regarded as a privileged scaffold
which can be found in many natural products and drug candidates
with remarkable biological activities.1 Furthermore, in the filed of
materials science many applications have been demonstrated con-
cerning about the function of indene-related compounds.2 There-
fore, new approaches continue to be appearing for the synthesis of
indene-related compounds.3–6 With an expectation for the con-
struction of diverse indene-related compounds for our specific bio-
logical assays, the development of novel method for efficient
assembly of indenes is of high demand. Recently, we reported an
unprecedented route for the generation of (Z)-1-benzylidene-3-
(1H-indol-1-yl)-1H-indene-2,2(3H)-dicarboxylates via t-BuOK-pro-
moted tandem addition–cyclization reaction of 2-(2-(alkynyl)ben-
zylidene)malonate with indole (Scheme 1, Eq. 1).7 This reaction
worked efficiently with high selectivity. Since cyano is an important
group for further functionalization, reaction of 2-benzylidenemal-
ononitrile was tested (Scheme 1, Eq. 2). However, the reaction was
complicated under the standard conditions, and only 20% isolated
yield of the corresponding product was obtained. In order to find a
more efficient way to generate this kind of molecules, we thus
started to re-explore the possibility of this transformation.
with an optimal number of new bonds and functionalities.8 Since
2-benzylidenemalononitrile could be traced back to 2-alkynylbenz-
aldehyde and malononitrile, we considered that three-component
reaction of 2-alkynylbenzaldehyde 1, malononitrile, and indole 2
might be occurring under suitable conditions (Scheme 1, Eq. 3). Re-
cently, 2-alkynylbenzaldehyde was discovered as a useful building
block for the construction of carbo- and heterocycles.9 We also dem-
onstrate its utility in tandem reactions for heterocycles construc-
tion.10 Encouraged by these results, we conceived that after
condensation of 2-alkynylbenzaldehyde 1 with malononitrile, the
subsequent nucleophilic addition of indole and intramolecular 5-
exo-cyclization would occur to afford the desired product 3.
With these considerations in mind, the initial studies were per-
formed for the reaction of 2-alkynylbenzaldehyde 1a (Scheme 1,
Eq. 3: R1 = H, R2 = Ph), malononitrile, and indole 2a (R3 = H) in the
presence of different bases and solvents. No desired product 3a
was detected when t-BuOK was utilized as a base in MeCN. To
our delight, compound 3a was afforded in 18% yield when Cs2CO3
(1.0 equiv) was used as a base replacement in the reaction. Inferior
results were observed when other bases were screened. Further
investigation revealed that lower yield of compound 3a was fur-
nished when the reaction occurred in THF, EtOH, DCE, or toluene
in the presence of Cs2CO3. Fortunately, the yield could be increased
to 49% when the solvent was changed to pyridine. The presence of
Cs2CO3 was essential since blank experiment indicated that no
reaction took place in pyridine without the addition of Cs2CO3.
Reactions with additives (Na2SO4, PdCl2, CuI, AgOTf, etc.) were
It is well recognized that multi-component reaction is an attrac-
tive process since the strategy pushes the limits of synthetic effi-
ciency by using more than two reactants to create novel products
* Corresponding authors. Tel.: +86 21 65102412; fax: +86 21 65641740.
E-mail addresses: yypeng@jxnu.edu.cn (Y. Peng), jie_wu@fudan.edu.cn (J. Wu).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.065

4392
G. Qiu et al. / Tetrahedron Letters 51 (2010) 4391–4394
R4
CO2R3
N
R1
t-BuOK (1 equiv)
CO2R3
R4
CO2R3
R2
+
(1)
MeCN, 25 oC
ref. 1
R1
N
CO2R3
R2
H
CN
+
N
t-BuOK
CN
CN
(2)
N
CN
CH3CN, rt
20% yield
N
H
Ph
Ph
R3
(3)
CHO
CN
CN
R1
base
solvent
R3
+
+
CN
R1
N
H
CN
R2
R2
3
1
2
Scheme 1.
examined as well. Finally, we realized that the reaction worked
most efficiently in the presence of Cs2CO3 and Na2SO4 in pyri-
dine/MeCN (v/v 1:2) at room temperature, which generated the
desired product 3a in 66% yield.
Table 1
Three-component reaction of 2-alkynylbenzaldehyde 1, malononitrile, and indole 211
R3
CHO
CN
N
R1
Cs2CO3, Na2SO4
R3
+
+
CN
Pyridine, CH3CN
R1
N
CN
H
R2
CN
1
2
3
R2
Entry
R1, R2
R3
Product/yielda
N
CN
1
H, C6H5 (1a)
H (2a)
CN
Ph
3a: 66%
N
CN
CN
2
3
4
H, C6H5 (1a)
5-Me (2b)
Ph
3b: 77%
OMe
N
N
H, C6H5 (1a)
4-OMe (2c)
CN
CN
Ph
3c: 70%
OMe
CN
CN
H, C6H5 (1a)
6-OMe (2d)
Ph
3d: 74%

G. Qiu et al. / Tetrahedron Letters 51 (2010) 4391–4394
4393
Table 1 (continued)
Entry
R1, R2
R3
Product/yielda
Cl
N
CN
5
H, C6H5 (1a)
5-Cl (2e)
CN
Ph
3e: 35%
3f: 40%
N
CN
CN
6
H, p-MeC6H4 (1b)
5-Me (2b)
C6H4p-Me
7
8
H, n-Bu (1c)
H, cyclopropyl (1d)
5-Me (2b)
5-Me (2b)
—
—
N
CN
9
4-F, C6H5 (1e)
5-Me (2b)
CN
Ph
F
3g: 52%
N
MeO
MeO
CN
10
11
4,5-(OMe)2, C6H5 (1f)
H (2a)
CN
Ph
3h: 50%
N
MeO
MeO
CN
4,5-(OMe)2, C6H5 (1f)
5-Me (2b)
CN
Ph
3i: 70%
OMe
N
N
12
4,5-(OMe)2, C6H5 (1f)
4-OMe (2c)
MeO
MeO
CN
CN
Ph
3j: 60%
Br
MeO
MeO
CN
CN
13
4,5-(OMe)2, C6H5 (1f)
5-Br (2f)
Ph
3k: 41%
a
Isolated yield based on 2-alkynylbenzaldehyde 1.
Based on the above results, we started to explore the scope of
this three-component reaction under the preliminary optimized
conditions [Cs2CO3 (1.0 equiv), Na2SO4 (2.0 equiv), pyridine/MeCN
(v/v 1:2)], and the results are summarized in Table 1. From Table 1,
we noticed that, for most cases, the base-promoted three-compo-
nent reaction of 2-alkynylbenzaldehyde 1, malononitrile, and in-
of 2-alkynylbenzaldehyde 1a, malononitrile, and 5-methylindole
2b gave rise to the desired product 3b in 77% yield (entry 2). Sim-
ilar yield was generated when 4-methoxyindole 2c or 6-methoxy-
indole 2d was used as a partner in the reaction (entries 3 and 4).
However, the yield decreased dramatically when 5-chloroindole
2e was employed as a substrate (35% yield, entry 5). With respect
to the R2 group attached on the triple bond in substrate 1, it
seemed that the alkyl group was not suitable in this transforma-
tion. For example, compound 3f was afforded in 40% yield when
dole
2 proceeded smoothly leading to the corresponding
products 3 in moderate to good yields. Usually, 24–30 h were
needed for completion of the reaction. As expected, the reaction

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G. Qiu et al. / Tetrahedron Letters 51 (2010) 4391–4394
7. Gao, K.; Wu, J. Org. Lett. 2008, 10, 2251.
2-alkynylbenzaldehyde 1b was utilized as a replacement (entry 6).
However, no reactions occurred when 2-alkynylbenzaldehyde 1c
or 1d was used in the reaction of malononitrile with 5-methylin-
dole 2b (entries 7 and 8). Fluoro- or methoxy-substituted 2-alky-
nylbenzaldehydes 1e and 1f were examined meanwhile. It
seemed that the electron effect on the aromatic backbone of the
substrates was invisible, and all reactions worked well to afford
the desired products in moderate to good yields (entries 9–13).
In summary, we have described a three-component reaction of
2-alkynylbenzaldehyde, malononitrile, and indole promoted by
Cs2CO3. The reaction might proceed through tandem condensation,
nucleophilic addition, and intramolecular 5-exo-cyclization, giving
rise to the corresponding (Z)-1-benzylidene-3-(1H-indol-1-yl)-1H-
indene-2,2(3H)-dicarbonitriles in moderate to good yields.
8. (a)For selected examples of multi-component reactions, see: Multicomponent
Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005;
(b) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602; (c) Nair, V.;
Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekenth, A. R.; Balagopal, L. Acc. Chem. Res.
2003, 36, 899; (d) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471; (e) Balme,
G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003, 4101; (f) Dömling, A.; Ugi,
I. Angew. Chem., Int. Ed. 2000, 39, 3168; (g) Bienaymé, H.; Hulme, C.; Oddon, G.;
Schmitt, P. Chem. Eur. J. 2000, 6, 3321; (h) Weber, L.; Illgen, K.; Almstetter, M.
Synlett 1999, 366; (i) Ugi, I.; Domling, A.; Werner, B. J. Heterocycl. Chem. 2000,
37, 647; (j) Zhu, J. Eur. J. Org. Chem. 2003, 1133; (k) Hulme, C.; Gore, V. Curr.
Med. Chem. 2003, 10, 51; (l) Weber, L. Curr. Med. Chem. 2002, 9, 1241.
9. Selected examples for metal-catalyzed cyclization of 2-alkynylbenzaldehyde:
(a) Beeler, A. B.; Su, S.; Singleton, C. A.; Porco, J. A., Jr. J. Am. Chem. Soc. 2007, 129,
1413. and references cited therein; (b) Asao, N. Synlett 2006, 1645; (c)
Nakamura, I.; Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc.
2005, 127, 9844; (d) Kim, N.; Kim, Y.; Park, W.; Sung, D.; Gupta, A.-K.; Oh, C.-H.
Org. Lett. 2005, 7, 5289; (e) Sato, K.; Asao, N.; Yamamoto, Y. J. Org. Chem. 2005,
70, 8977; (f) Asao, N.; Sato, K.; Menggenbateer; Yamamoto, Y. J. Org. Chem.
2005, 70, 3682; (g) Kusama, H.; Funami, H.; Takaya, J.; Iwasawa, N. Org. Lett.
2004, 6, 605; (h) Asao, N.; Aikawa, H.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126,
7458.
Acknowledgments
10. For selected examples, see: (a) Yu, X.; Wu, J. J. Comb. Chem. 2010, 12, 238; (b)
Ye, S.; Wu, J. Tetrahedron Lett. 2009, 50, 6273; (c) Yu, X.; Ding, Q.; Wang, W.;
Wu, J. Tetrahedron Lett. 2008, 49, 4390; (d) Ding, Q.; Wu, J. Org. Lett. 2007, 9,
4959; (e) Gao, K.; Wu, J. J. Org. Chem. 2007, 72, 8611; (f) Sun, W.; Ding, Q.; Sun,
X.; Fan, R.; Wu, J. J. Comb. Chem. 2007, 9, 690; (g) Ding, Q.; Wang, B.; Wu, J.
Tetrahedron 2007, 63, 12166.
Financial support from the National Natural Science Foundation
of China (No. 20972030) and the Science & Technology Commission
of Shanghai Municipality (09JC14049) is gratefully acknowledged.
References and notes
11. General experimental procedure for the three-component reaction of 2-
alkynylbenzaldehyde 1, malononitrile, and indole 2: malononitrile (0.4 mmol)
and Na2SO4 (0.8 mmol, 2.0 equiv) were added to
a solution of 2-
1. (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.
2. For selected examples, see: (a) Yang, J.; Lakshmikantham, M. V.; Cava, M. P. J.
Org. Chem. 2000, 65, 6739; (b) Barbera, J.; Rakitin, O. A.; Ros, M. B.; Torroba, T.
Angew. Chem., Int. Ed. 1998, 37, 296; (c) Akbulut, U.; Khurshid, A.; Hacioglu, B.;
Toppare, L. Polymer 1990, 31, 1343.
3. (a) Gassman, P. G.; Ray, J. A.; Wenthold, P. G.; Mickelson, J. W. J. Org. Chem.
1991, 56, 5143; (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; (d) Singh, G.; Ila, H.; Junjappa, H.
Synthesis 1986, 744; (e) Kimiaki, Y.; Hideyoshi, M.; Akira, S. Bull. Chem. Soc.
Jpn. 1986, 59, 3699; (f) Yoshida, H.; Kato, M.; Ogata, T. J. Org. Chem. 1985, 50,
1145.
4. (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.
alkynylbenzaldehyde (0.4 mmol, 1.0 equiv) in pyridine:CH3CN (v/v 1:2). The
mixture was then stirred at 60 °C for 4 h. Subsequently, indole (0.4 mmol,
1.0 equiv) and Cs2CO3 (0.4 mmol, 1.0 equiv) were added, then the reaction
mixture was stirred at room temperature for 24–30 h. After the completion of
reaction as indicated by TLC, the reaction was quenched with aqueous HCl
(1.0 M), extracted with EtOAc (2 Â 10 mL), and dried by anhydrous Na2SO4.
Evaporation of the solvent followed by purification on silica gel provided the
product 3. Data of selected examples: (Z)-1-benzylidene-3-(1H-indol-1-yl)-1H-
indene-2,2(3H)-dicarbonitrile (3a). 1H NMR (400 MHz, CDCl3)
d 6.64 (d,
J = 3.2 Hz, 1H), 6.87 (s, 1H), 6.95 (d, J = 3.2 Hz, 1H), 7.22–7.28 (m, 2H), 7.33–
7.37 (m, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.45–7.49 (m, 3H), 7.54 (s, 1H), 7.60–7.61
(m, 3H), 7.68–7.72 (m, 2H), 7.77 (d, J = 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
44.1, 69.0, 104.3, 109.7, 111.7, 113.9, 121.2, 121.4, 121.5, 122.8, 124.8, 125.9,
128.8, 129.1, 129.2, 129.3, 129.4, 130.1, 131.1, 131.4, 133.2, 136.0, 137.0,
138.2; HRMS (ESI) calcd for C26H17N3Na (M+Na+) 394.1320, found 394.1323.
(Z)-1-Benzylidene-3-(5-methyl-1H-indol-1-yl)-1H-indene-2,2(3H)-
dicarbonitrile (3b). 1H NMR (400 MHz, CDCl3) d 2.46 (s, 3H), 6.51 (d, J = 3.6 Hz,
1H), 6.80 (s, 1H), 6.87 (d, J = 3.2 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H),
7.35–7.39 (m, 1H), 7.42–7.45 (m, 4H), 7.50 (s, 1H), 7.54–7.58 (m, 4H), 7.73 (d,
J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 21.3, 44.3, 69.1, 104.1, 109.0,
111.7, 113.9, 121.1, 121.5, 124.3, 124.8, 126.0, 128.7, 128.9, 129.1, 129.3, 129.4,
130.5, 130.7, 131.0, 131.2, 133.1, 135.3, 136.0, 138.1; HRMS (ESI) calcd for
C
27H19N3Na (M+Na+) 408.1477, found 408.1498. (Z)-1-Benzylidene-3-(4-
methoxy-1H-indol-1-yl)-1H-indene-2,2(3H)-dicarbonitrile (3c). 1H NMR
(400 MHz, CDCl3) d 3.97 (s, 3H), 6.63 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 3.6 Hz,
1H), 6.81–6.82 (m, 2H), 7.24–7.32 (m, 3H), 7.37–7.40 (m, 1H), 7.44–7.50 (m,
3H), 7.53 (s, 1H), 7.58–7.60 (m, 3H), 7.75 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 44.1, 55.3, 69.2, 101.1, 101.9, 102.6, 111.6, 113.9, 119.6, 121.5, 123.3,
123.8, 126.0, 128.7, 128.8, 129.3, 129.4, 130.8, 131.1, 131.5, 133.2, 136.0, 138.1,
138.4, 153.6; HRMS (ESI) calcd for C27H19N3NaO (M+Na+) 424.1426, found
426.1428.
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Tulinsky, J.; Judge, T. M.; Gammill, R. B. J. Org. Chem. 1999, 64, 1733.
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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.