A NHC-Involved, cascade, metal-free, and three-component synthesis of 2,3-diarylated fully substituted furans under solvent-free conditions

Article abstract of DOI:10.1055/s-0030-1261229

An efficient synthesis of 2,3-diarylated fully substituted furans was performed through the sequential reactions of Knoevenagel reaction, Stetter reaction catalyzed by NHC, and intramolecular cyclization under solvent-free conditions. The protocol has the

Full text of DOI:10.1055/s-0030-1261229

2420
LETTER
A NHC-Involved, Cascade, Metal-Free, and Three-Component Synthesis of
2,3-Diarylated Fully Substituted Furans under Solvent-Free Conditions
N
HC-Involved S
h
F
e
ully Substit
n
uted Furansxia Yu,a Jun Lu,a Tuanjie Li,a Donglin Wang,a Binbin Qin,a Honghong Zhang,a Changsheng Yao*b
a
School of Chemistry and Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials,
Xuzhou Normal University, Xuzhou, Jiangsu 221116, P. R. of China
b
School of Chemistry and Engineering, Key Laboratory of Biotechnology for Medicial Plant,
Xuzhou Normal University, Xuzhou, Jiangsu 221116, P. R. of China
Fax +86(516)83500365; E-mail: csyao@xznu.edu.cn
Received 14 July 2011
the starting material, such as crossed benzoin, a-bromodi-
arylethanone, and deoxybenzoin, makes these methods
not suitable for the diversity-oriented synthesis of 2,3-di-
arylated fully substituted furans. Therefore, a strong de-
Abstract: An efficient synthesis of 2,3-diarylated fully substituted
furans was performed through the sequential reactions of Knoeve-
nagel reaction, Stetter reaction catalyzed by NHC, and intramolec-
ular cyclization under solvent-free conditions. The protocol has the
advantages of easy workup, high yields, and an environmental be- mand remains to develop an efficient approach to
nign procedure compared with the reported methods.
synthesize these important fully substituted furans.
Key words: NHC, fully substituted furans, umpolung, solvent-free
synthesis, multicomponent reaction
In the recent years there have been a continuously grow-
ing number of successful and novel applications of N-het-
erocyclic carbenes (NHC) as organocatalysts and reagents
for an expanding set of reactions.15,16 Knoevenagel con-
Multisubstituted furans are one of the most important
classes of heterocyclic compounds. They not only have
great significance in medicinal, agricultural, and material
chemistry, but also act as useful and versatile building
blocks in organic synthesis.1–4 Therefore, the develop-
ment of new synthetic approaches to synthesize multisub-
stituted furans represents an important area of research in
organic chemistry.5–7 The direct construction of the furan
ring system using some specific substrates have been de-
signed and well applied,8 such as cyclocondensation of
1,4-dicarbonyl compounds (Paal–Knorr synthesis),9
Feist–Bénary synthesis10 and transition-metal-catalyzed
cycloisomerization of alkynyl or allenyl substrates.11 In
addition, transition-metal-catalyzed coupling reactions
and related transformations are also effective methods to
yield highly functionalized furans.12 However, most of the
synthetic protocols reported have many drawbacks, in-
cluding prolonged reaction time, drastic reaction condi-
tions, tedious workup, low yields, poor tolerance of
functional groups, and the use of organic solvent or ex-
pensive catalysts. Interestingly, because furans of the type
5 are key synthetic intermediates,13 the synthesis of these
furan derivatives has attracted considerable attention. So
far, there are a few reports on the syntheses of tetrasubsti-
tuted furans with two aryl groups and an amino, a cyano,
or an ester,14 for example, the direct conversion from b,b-
dicyanoketone, the transformation from benzoin (or a-
bromodiarylethanone) and malononitrile, the cascade
Stetter–g-ketonitrile cyclization reaction of aromatic alde-
hydes with acylidenemalononitriles, the multistep synthe-
sis from deoxybenzoin. However, the difficulty to prepare
densation between aryl aldehyde and malononitrile may
afford arylmethylidenemalononitriles efficiently.17 We
envisioned that the umpolung addition between aryl alde-
hyde and arylmethylidenemalononitriles catalyzed by
NHC (Stetter reaction) could give the key intermediate
b,b-dicyanoketone to synthesize the furans of the type 5.
The diversity of products could be adjusted effectively by
varying the types of aryl aldehyde used. The diversity-
generating potential of multicomponent reactions (MCR)
has been recognized, and their utility in preparing libraries
to screen for functional molecules is well appreciated.18
Besides, progress in the field of solvent-free reactions is
gaining more and more significance because of their high
efficiency, operational simplicity, and environmentally
benign processes. So far, many organic reactions have
been reported to proceed under solvent-free conditions.19
As a continuation of our work on the multicomponent
synthesis of a heterocyclic-compound library with high
diversity,20 we herein shall report that a N-heterocyclic
carbenes (NHC) involved, highly efficient, multicompo-
nent synthesis of 2,3-diarylated fully substituted furans 5
from aromatic aldehydes 1, 3 and malononitrile (or ethyl
cyanoacetate) 2 (Scheme 1).
In order to determine the optimal reaction conditions, the
multicomponent reaction was first studied with benzalde-
hyde and malononitrile as model reactants. Firstly, the
solvent effect on the reaction was investigated using
EtOH, THF, and DMF at room temperature (Table 1, en-
tries 1–3). In EtOH as well as in THF, only 68% of prod-
uct 521 could be isolated (entries 1 and 2), whereas a yield
of 57% could be obtained in DMF (Table 1, entry 3).
Thus, the results showed that reaction under solvent-free
conditions gave the expected product in the highest yield
(Table 1, entry 4). So we used solvent-free conditions to
SYNLETT 2011, No. 16, pp 2420–2424
x
x
.x
x
.2
0
1
1
Advanced online publication: 08.09.2011
DOI: 10.1055/s-0030-1261229; Art ID: W15411ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
NHC-Involved Synthesis of Fully Substituted Furans
2421
Ar1
8). Therefore, the temperature of 55 °C was chosen to syn-
thesize the substitued furans.
O
O
R
R
+
+
4
Ar1
H
Ar2
H
CN
Ar2
To further examine the practical base for the synthesis, the
effect of base was investigated under solvent-free condi-
tions at 55 °C (Table 1, entries 9 and 10). To our delight,
the precatalyst 4a with DBU gave the desired product in
the yield of 90% (Table 1, entry 7). Further study showed
that the optimal loading for the precatalyst 4a was 15
mol%. Besides, other types of NHC precursors, such as
4b–e were applied to the three-component reaction at the
loading of 15 mol%, and 4a was found to be most effec-
tive. Therefore, all of the following experiments were
conducted in the presence of 15 mol% of the precatalyst
4a and 35 mol% of DBU.
base
NH2
O
R = CN, COOEt
1
3
2
5
Bn
H3C
CH3
H3C
N
N
HO
HO
S
Cl–
S
I–
4b
CH3
I–
N
N
N
+
N
N
Mes
Mes
N
N
CH3
I–
H3C
Cl–
CH3
In order to study the substrate scope and general validity
of the protocol, the reactions of other substrates were next
investigated (Table 2). When 1 and 3 were the same aro-
matic aldehydes, the yield of furans were found to be good
to excellent, and the highest yield of 5 was 90% (Table 2,
5a). The similar result was obtained when the different ar-
omatic aldehydes were added. The effect of electronic na-
ture of substituents on the aromatic ring did not show
strongly obvious difference in terms of yields. This proto-
col can be applied not only to aromatic aldehydes either
with electron-withdrawing groups (such as a halogen) or
electron-donating groups (such as a methyl group) but
also heteroaromatic aldehydes with moderate to excellent
yields under the same conditions, which highlighted the
wide scope of this condensation. However, when the ali-
phatic aldehyde was applied to this reaction, no expected
product was obtained. In order to check the versatility of
the methodology, another active methylene compound
such as ethyl cyanoacetate was used instead of malononi-
trile. To our delight, the reaction under the above-opti-
mized conditions gave the corresponding products in
moderate to good yields (Table 2, entries 14 and 15).
4c
Mes = 2,4,6-trimethylphenyl
4d
4e
Scheme 1 Synthesis of substituted furans 5 catalyzed by different
N-heterocyclic carbenes
Table 1 Optimization of Reaction Conditions for the Formation of
Representative Compound 5aa,b
CN
Ph
O
O
CN
CN
4 (15 mol%)
+
+
base (35 mol%)
Ph
H
Ph
1a
H
NH2
Ph
O
3a
2
5a
Entry
Base
Solvent
Temp (°C) Yield (%)c
1
2
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
Et3N
EtOH
r.t.
r.t.
r.t.
r.t.
40
50
55
60
55
55
68
68
57
72
75
82
90
84
75
65
THF
3
DMF
4
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
5
6
According to the literature, the detailed mechanism of the
multicomponent reactions is still unclear, so we propose a
plausible reaction mechanism, which is illustrated in
Scheme 2. In the initial step, Knoevenagel condensation
between aryl aldehyde and malononitrile under basic con-
ditions gave intermediate 6. Intermolecular Stetter reac-
tions between aryl aldehyde 3 and 6 catalyzed by NHC
then furnished the intermediate 8, followed by intramolec-
ular cyclization to give 5 under the effect of base. To con-
firm that this is a NHC-involved reaction some control
reactions were performed. When DBU was used as the
single catalyst, the reaction gave the intermediate (arylm-
ethylidenemalononitriles) only. If the NHC precursor was
applied to the reaction merely, trace amount of the same
intermediate was also obtained. The facts provided the ev-
idence in support of the proposed pathway.
7
8
9
10
Cs2CO3
a For the experimental procedure, see ref. 21.
b All entries were performed in 1 h.
c Isolated yield.
synthesize the target compound throughout the present
study.
Next, in order to accelerate the reaction rate and enhance
the yield, the aforementioned reaction was carried out un-
der solvent-free conditions from room temperature to 55
°C (Table 1, entries 4–7). The yield of 5a22 was improved
from 72% to 90%. However, when the temperature
reached 60 °C, the reaction became complex, and the de-
sired product was isolated in lower yield (Table 1, entry
In summary, we have provided a NHC-involved, efficient,
and three-component route using inexpensive starting ma-
terials to the synthesis of a series of 2,3-diarylated fully
substituted furans under solvent-free conditions. The ex-
perimental simplicity, high yields, short reaction time,
Synlett 2011, No. 16, 2420–2424 © Thieme Stuttgart · New York

2422
C. Yu et al.
LETTER
Table 2 Multicomponent Reactions of Aryl Aldehydes and Propanedinitrile for the Synthesis of Substituted Furans 5a–oa
Entry
1
Ar1
Ar2
R
Time (h)
Product
5a
Yield (%)b
Ph
Ph
CN
1
90
78
87
81
85
84
82
80
79
78
86
82
84
82
74
2
3-MeOC6H4
4-FC6H4
3,4-Cl2C6H3
3-ClC6H4
4-ClC6H4
4-MeC6H4
3,4-Cl2C6H3
2-FC6H4
Ph
Ph
CN
2.5
2
5b
5c
3
4-FC6H4
Ph
CN
4
CN
2.5
3
5d
5e
5
3-ClC6H4
4-ClC6H4
4-ClC6H4
3,4-Cl2C6H3
2-FC6H4
3-FC6H4
3-FC6H4
3-MeOC6H4
4-BrC6H4
4-BrC6H4
thiophene-2-yl
CN
6
CN
2
5f
7
CN
2.5
3
5g
8
CN
5h
5i
9
CN
2.5
4
10
11
12
13
14
15
CN
5j
3-FC6H4
3-MeOC6H4
4-BrC6H4
4-ClC6H4
4-ClC6H4
CN
3
5k
5l
CN
5
CN
3.5
3.5
5
5m
5n
5o
COOEt
COOEt
a All products have been characterized by HRMS spectrometry, 1H NMR, 13C NMR, and IR spectroscopy.
b Isolated yield.
H3C
Ar2CHO
3
CH3
N
O–
N
S
R2
CH2
H3C
H
H3C
Ar1CHO +
Ar2
N
R1
HO
N
S
R1
DBU
R2
S
CN
9
4
Ar2
S
R1
1
2
DBU
R1
O
9'
4'
R2
Ar2
CN
Ar1
CH3
CN
H3C
Ar1
8
O–
HO
N
6
N
Ar2
Ar1
DBU
Ar2
Ar1
S
CN
R1
S
CN
R1
R1 = CH2CH2OH
5
R2 = CN, COOEt
7'
R2
7
R2
Scheme 2 A plausible mechanism for multicomponent catalyzed by 4a
eco-friendly, and the simple workup procedure make the Acknowledgment
procedure attractive to synthesize a variety of 2,3-diary-
lated fully substituted furans.
We are grateful for financial support by the Major Basic Research
Project of the Natural Science Foundation of the Jiangsu Higher
Education Institutions (09KJA430003), Natural Science Foundati-
on of Xuzhou City (XM09B016), Graduate Foundation of Xuzhou
Normal University (2010YLB029), and Qing Lan Project
(08QLT001).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
References and Notes
Primary Data for this article are available online at http://
www.thieme-connect.com/ejournals/toc/synlett and can be cited
using the following DOI: 10.4125/pd0016th.
(1) (a) Hou, X. L.; Yang, Z.; Wong, H. N. C. In Progress in
Heterocyclic Chemistry, Vol. 15; Gribble, G.-W.; Joule, J.
A., Eds.; Pergamon: Oxford, 2008, 176. (b) Keay, B. A.;
Dibble, P. W. In Comprehensive Heterocyclic Chemistry II,
Synlett 2011, No. 16, 2420–2424 © Thieme Stuttgart · New York

LETTER
Vol. 2; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
NHC-Involved Synthesis of Fully Substituted Furans
2423
Chem. 2009, 17, 4406.
Elsevier: Oxford, 1997, 395. (c) Hou, X. L.; Cheung, H. Y.;
Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y. T.; Wong,
H. N. C. Tetrahedron 1998, 54, 1955. (d) Keay, B. A.
Chem. Soc. Rev. 1999, 28, 209.
(14) (a) Kim, S. Y.; Kim, D. J. Bull. Korean Chem. Soc. 2007, 28,
1114. (b) Watanuki, S.; Sakamoto, S. Heterocycles 2004,
62, 127. (c) Selivanov, S. I. Zh. Org. Khim. 1981, 17, 666.
(d) Prousek, J. Collect. Czech. Chem. Commun. 1983, 48,
3140. (e) Aran, V.-J.; Perez, M.-A. J. Chem. Soc., Perkin
Trans. 1 1984, 2009. (f) Liu, P.; Lei, M.; Ma, L.; Hu, L.
Synlett 2011, 1133.
(15) (a) Maki, B. E.; Chan, A.; Scheidt, K. A. Synthesis 2008,
1306. (b) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev.
2007, 107, 5606. (c) Marion, N.; Díez-González, S.; Nolan,
I. P. Angew. Chem. Int. Ed. 2007, 46, 2988. (d) Zeitler, K.
Angew. Chem. Int. Ed. 2005, 44, 7506.
(16) (a) Wu, K. J.; Li, G. Q.; Li, Y.; Dai, L. X.; You, S. L. Chem.
Commun. 2011, 493. (b) Yadav, L. D. S.; Singh, S.; Rai,
V. K. Synlett 2010, 240. (c) Yadav, L.; Singh, S.; Rai, V.
Synlett 2010, 240. (d) Biju, A. T.; Wurz, N. E.; Glorius, F.
J. Am. Chem. Soc. 2010, 132, 5970. (e) Ryan, S. J.;
Candish, L.; Lupton, D. W. J. Am. Chem. Soc. 2009, 131,
14176. (f) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem.
Soc. 2006, 128, 8418. (g) Nair, V.; Vellalath, S.; Poonoth,
M.; Suresh, E. J. Am. Chem. Soc. 2006, 128, 8736.
(17) (a) Inokuma, T.; Sakamoto, S.; Takemoto, Y. Synlett 2009,
1627. (b) Polonka-Balint, A.; Saraceno, C.; Ludanyi, K.
Synlett 2008, 2846. (c) Wang, X.-S.; Wu, J.-R.; Li, Q.; Yao,
C.-S.; Tu, S.-J. Synlett 2008, 1185. (d) McNab, H.; Nelson,
D. J.; Rozgowska, E. J. Synthesis 2009, 2171. (e) Xu, C.;
Bartley, J. K.; Enache, D. I. Synthesis 2005, 3468. (f) Su,
C.; Chen, Z.-C.; Zheng, Q.-G. Synthesis 2003, 555.
(18) (a) Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem. Rev.
1997, 97, 449. (b) Zhang, W. Chem. Rev. 2004, 104, 2531.
(c) Dömling, A. Chem. Rev. 2006, 106, 17. (d)Toure, B. B.;
Hall, D. G. Chem. Rev. 2009, 109, 4439. (e) Zhang, W.
Green Chem. 2009, 11, 911. (f) Sunderhaus, J.; Martin, S. F.
Chem. Eur. J. 2009, 15, 1300. (g) Ganem, B. Acc. Chem.
Res. 2009, 42, 463.
(2) (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (b) Wong, H.
N. C.; Yu, P.; Yick, C.-Y. Pure Appl. Chem. 1999, 71, 1041.
(c) Lee, H.-K.; Chan, K.-F.; Hui, C.-W.; Yim, H.-K.; Wu,
X.-W.; Wong, H. N. C. Pure Appl. Chem. 2005, 77, 139.
(3) (a) Selvaraj, C. M. ChemMedChem 2010, 5, 255. (b) Ajit,
A. J. Med. Chem. 2010, 53, 37. (c) Hayato, T. Adv. Mater.
2009, 21, 3776. (d) Kufareva, I. J. Med. Chem. 2008, 51,
7921. (e) Flynn, B. L. J. Med. Chem. 2002, 45, 2670.
(f) Simone, B.; Maria, K. J. Chem. Inf. Model. 2009, 49,
2489. (g) Jochen, Z.; Erwin, V. A. J. Steroid Biochem. Mol.
Biol. 2007, 104, 259.
(4) (a) Taylor, E. C.; Patel, H. H.; Jun, J.-G. J. Org. Chem. 1995,
60, 6684. (b) Eger, K.; Folkers, G.; Frey, M.; Zimmermann,
W.; Koop-Kirfel, G. Synthesis 1988, 632. (c) Briel, D.;
Rybak, A.; Kronbach, C. Eur. J. Med. Chem. 2010, 69.
(d) Carlsson, L.; Helgee, E. A. J. Chem. Inf. Model. 2009,
49, 2551. (e) Lee, D. Electrophoresis 2000, 21, 2405.
(f) Iris, F.; Wilson, W. D. J. Med. Chem. 1999, 42, 2260.
(5) (a) Marshall, J. A.; Wang, X. J. J. Org. Chem. 1991, 56, 960.
(b) Trost, B. M.; McIntosh, M. C. J. Am. Chem. Soc. 1995,
117, 7255. (c) Marshall, J. A.; Robinson, E. D. J. Org.
Chem. 1990, 55, 3450. (d) Marshall, J. A.; Wang, X. J. Org.
Chem. 1992, 57, 3387. (e) Marshall, J. A.; DuBay, W. J.
J. Org. Chem. 1993, 58, 3602.
(6) Donnelly, D. M. X.; Meegan, M. J. In Comprehensive
Heterocyclic Chemistry, Vol. 4; Bird, C. W.; Cheeseman,
G. W. H., Eds.; Pergamon: Oxford, 1984, 657.
(7) (a) Kreiser, W. Nachr. Chem. Tech. Lab. 1981, 29, 118.
(b) Lipshutz, B. H. Chem. Rev. 1986, 86, 795.
(8) (a) Chen, K. W.; Syu, S.-E.; Jang, Y. J. Org. Biomol. Chem.
2011, 9, 2098. (b) Melzig, L.; Rauhut, C. B.; Knochel, P.
Chem. Commun. 2009, 3536. (c) Ila, H.; Baron, O.; Wagner,
A. J.; Knochel, P. Chem. Commun. 2006, 583.
(9) (a) Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J.
Org. Chem. 2005, 5277. (b) Mattson, A. E.; Bharadwaj,
A. R.; Zuhl, A. M.; Scheidt, K. A. J. Org. Chem. 2006, 71,
5715.
(19) (a) Walsh, P. J.; Li, H. M. Chem. Rev. 2007, 107, 2503.
(b) Hobbs, H. R.; Thomas, N. R. Chem. Rev. 2007, 107,
2786. (c) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025.
(d) Sheldon, R. A. Green Chem. 2005, 7, 267.
(20) (a) Jiang, B.; Tu, S. J.; Kaur, P.; Wever, W.; Li, G. G. J. Am.
Chem. Soc. 2009, 131, 11660. (b) Yao, C. S.; Wang, C. H.;
Jiang, B.; Feng, X. D.; Yu, C. X.; Li, T. J.; Tu, S. J. Bioorg.
Med. Chem. Lett. 2010, 20, 2884. (c) Yao, C. S.; Lei, S.;
Wang, C. H.; Yu, C. X.; Tu, S. J. J. Heterocycl. Chem. 2008,
45, 1609. (d) Yao, C. S.; Lei, S.; Wang, C. H.; Yu, C. X.;
Shao, Q. Q.; Tu, S. J. Chin. J. Chem. 2008, 26, 2107.
(e) Wei, P.; Zhang, X. H.; Tu, S. J.; Yan, S.; Ying, H. J.;
Ouyang, P. K. Bioorg. Med. Chem. Lett. 2009, 19, 828.
(f) Shi, F.; Li, C. M.; Xia, M.; Miao, K. J.; Zhao, Y. X.; Tu,
S. J.; Zheng, W. F.; Zhang, G.; Ma, N. Bioorg. Med. Chem.
Lett. 2009, 19, 5565. (g) Tu, S. J.; Zhu, X. T.; Zhang, J. P.;
Xu, J. N.; Zhang, Y.; Wang, Q.; Jia, R. H.; Jiang, B.; Zhang,
J. Y.; Yao, C. S. Bioorg. Med. Chem. Lett. 2006, 16, 2925.
(h) Tu, S. J.; Zhang, J. P.; Zhu, X. T.; Xu, J. N.; Zhang, Y.;
Wang, Q.; Jia, R. H.; Jiang, B.; Zhang, J. Y. Bioorg. Med.
Chem. Lett. 2006, 16, 3578. (i) Tu, S. J.; Miao, C. M.; Fang,
F.; Feng, Y. J.; Li, T. J.; Zhuang, Q. Y.; Zhang, X. J.; Zhu,
S. L.; Shi, D. Q. Bioorg. Med. Chem. Lett. 2004, 14, 1533.
(j) Han, Z. G.; Zhang, G.; Jiang, B.; Ma, N.; Shi, F.; Tu, S. J.
J. Comb. Chem. 2009, 11, 809.
(10) Mross, G.; Holtz, E.; Langer, P. J. Org. Chem. 2006, 71,
8045.
(11) (a) Dudnik, A. S.; Gevorgyan, V. Angew. Chem. Int. Ed.
2007, 46, 5195. (b) Hashmi, A. S. K.; Sinha, P. Adv. Synth.
Catal. 2004, 346, 432. (c) Sniady, A.; Wheeler, K. A.;
Dembinski, R. Org. Lett. 2005, 7, 1769. (d) Liu, Y.; Song,
F.; Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7, 5409.
(e) Zhang, J.; Schmalz, H.-G. Angew. Chem. Int. Ed. 2006,
45, 6704. (f) Peng, L.; Zhang, X.; Ma, M.; Wang, J. Angew.
Chem. Int. Ed. 2007, 46, 1905. (g) Zhang, M.; Jiang, H.-F.;
Neumann, H.; Beller, M.; Dixneuf, P. H. Angew. Chem. Int.
Ed. 2009, 48, 1681.
(12) (a) Snegaroff, K.; Komagawa, S.; Chevallier, F. Chem. Eur.
J. 2010, 16, 8191. (b) Guchhait, S. K.; Kashyap, M.; Saraf,
S. Synthesis 2010, 1166. (c) Snegaroff, K.; L’Helgoual’ch,
J.-M.; Bentabed-Ababsa, G. Chem. Eur. J. 2009, 15, 10280.
(d) Ryabov, A. N.; Izmer, V. V.; Tzarev, A. A.; Uborsky,
D. V. Organometallics 2009, 28, 3614. (e) Denmark, S. E.;
Baird, J. D.; Regens, C. S. J. Org. Chem. 2008, 73, 1440.
(f) L’Helgoual’ch, J. M.; Bentabed-Ababsa, G.; Chevallier,
F.; Yonehara, M.; Uchiyama, M. Chem. Commun. 2008,
5375.
(21) General Procedure for the Synthesis of 5
Aryl aldehyde 1 (1 mmol), DBU (0.35 mmol), and
malononitrile 2 (1 mmol) were triturated together in an agate
mortar with a pestle for 5 min. Then the mixture was kept at
55 °C for a certain time (monitored by TLC). After addition
of another aryl aldehyde (1 mmol), sulfamethiazole salt
(13) (a) Han, Y.; Ebinger, K.; Vandevier, L. E.; Maloney, J. W.
Tetrahedron Lett. 2010, 54, 629. (b) Willemann, C.;
Gruenert, R.; Bednarski, P. J.; Troschuetz, R. Bioorg. Med.
Synlett 2011, No. 16, 2420–2424 © Thieme Stuttgart · New York

2424
C. Yu et al.
LETTER
(0.15 mmol) was added and mixed thoroughly by grinding at
55 °C. The reaction mixture was mixed by grinding every
half an hour with a pestle and mortar during 1–5 h reaction
time (monitored by TLC). The resultant mixture was cooled
to r.t., purified through column chromatography using
acetone and PE (1:5) as the eluent, to give pure product 5a–
o.
206 °C). IR (KBr): nmax = 3467, 3443, 2216, 1653, 1455,
1067, 763, 694 cm–1. 1H NMR (400 MHz, DMSO-d6): d =
7.17–7.27 (m, 5 H, ArH), 7.38–7.47 (m, 5 H, ArH). 7.75 (s,
2 H, NH2) ppm. 13C NMR (100 MHz, DMSO-d6): d = 163.5,
136.6, 131.2, 129.4, 129.0, 128.8, 128.6, 128.3, 126.9,
124.2, 121.8, 115.5, 69.2 ppm. ESI-HRMS: m/z calcd for
C17H11N2O [M – H]–: 259.0871; found: 259.0871.
(22) Characterization Data of Representative Compounds 5a
Yield 90%, white solid, mp 205–206 °C (reported 204–
Synlett 2011, No. 16, 2420–2424 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.