Sc(OTf)3-catalyzed or t-BuOK promoted tandem reaction of 2-(2-(alkynyl)benzylidene)malonate with indole

Article abstract of DOI:10.1021/ol800664z

(Chemical Equation Presented) Tandem reaction of 2-(2-(alkynyl)benzylidene) malonate with indole was investigated. (Z)-1-Benzylidene-3-(1H-indol-1-yl)-1H- indene-2,2(3H)-dicarboxylate was generated in the presence of t-BuOK at room temperature; whereas 3-((1H-indol-3-yl)(2-(alkynyl)aryl)methyl)-1H-indole was obtained when Sc(OTf)₃ was utilized as catalyst at 50°C.

Full text of DOI:10.1021/ol800664z

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2251-2254
Sc(OTf)3-Catalyzed or t-BuOK Promoted
Tandem Reaction of
2-(2-(Alkynyl)benzylidene)malonate with
Indole
Ke Gao† and Jie Wu*,†,‡
Department of Chemistry, Fudan UniVersity, 220 Handan Road, Shanghai 200433,
China, and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, China
jie_wu@fudan.edu.cn
Received March 24, 2008
ABSTRACT
Tandem reaction of 2-(2-(alkynyl)benzylidene)malonate with indole was investigated. (Z)-1-Benzylidene-3-(1H-indol-1-yl)-1H-indene-2,2(3H)-
dicarboxylate was generated in the presence of t-BuOK at room temperature; whereas 3-((1H-indol-3-yl)(2-(alkynyl)aryl)methyl)-1H-indole was
obtained when Sc(OTf)3 was utilized as catalyst at 50 °C.
Diversity-oriented chemical synthesis has been used as an
engine to efficiently synthesize complex and diverse small
molecules in the field of chemical genetics.1 Among the
strategies used in diversity-oriented synthesis, design and
synthesis of natural products and complex compounds via
tandem reactions has attracted much attention, and the
development of tandem reactions has been a fertile area in
organic synthesis.2
alkynyl)benzaldehydes, amines, and various nucleophiles.3
The key intermediate in the reaction process was believed
to be 2-(1-alkynyl)arylaldimine 1. Prompted by these results,
we envisioned that 2-(2-(alkynyl)benzylidene)malonate 2
might be utilized in similar tandem reactions because of the
structural similarity of 2-(1-alkynyl)arylaldimine 1 (Figure
1). Herein, we disclose that 2-(2-(alkynyl)benzylidene)ma-
lonate 2 undergoes a tandem reaction with indole under acid-
Recently, we have described efficient synthesis of 1,2-
dihydroisoquinolines via multicomponent reactions of 2-(1-
(2) For selected examples, see: (a) Denmark, S. E.; Thorarensen, A.
Chem. ReV. 1996, 96, 137–166. (b) Porco, J. A., Jr.; Schoenen, F. J.; Stout,
T. J.; Clardy, J.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 7410–7411.
(c) Molander, G. A.; Harris, C. R. J. Am. Chem. Soc. 1996, 118, 4059–
4071. (d) Chen, C.; Layton, M. E.; Sheehan, S. M.; Shair, M. D. J. Am.
Chem. Soc. 2000, 122, 7424–7425. (e) Shi, F.; Li, X.; Xia, Y.; Zhang, L.;
Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 15503–15504.
† Fudan University.
‡ Chinese Academy of Sciences.
(1) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Schreiber, S. L.
Chem. Eng. News 2003, 81 (9), 51.
10.1021/ol800664z CCC: $40.75
Published on Web 05/02/2008
2008 American Chemical Society

Table 1. Screening Conditions for Reaction of 2a with Indole
3aa
Figure 1. Structure of 2-(1-alkynyl)arylaldimine 1 and 2-(2-
(alkynyl)benzylidene)malonate 2.
or base-controlled conditions, thus offering an unprecedented
and straightforward route for the synthesis of (Z)-1-ben-
zylidene-3-(1H-indol-1-yl)-1H-indene-2,2(3H)-dicarboxy-
late or 3-((1H-indol-3-yl)(2-(alkynyl) aryl)methyl)-1H-indole.
Because the indole skeleton is an important substructure
in both natural products and therapeutic agents,4 at the
beginning a set of experiments was carried out using diethyl
2-(2-(2-phenylethynyl)benzylidene)malonate 2a and indole
3a as model substrates. This preliminary survey, carried out
in the presence of a Lewis acid as the catalyst, allowed us
to evaluate and optimize the most efficient catalytic system.
In an initial experiment, the reaction was performed in
acetonitrile at room temperature catalyzed by Yb(OTf)3
(Table 1, entry 1). The generated product was the normal
Michael addition adduct 4a (53% yield). A similar result
was obtained when the catalyst was replaced by Dy(OTf)3
or Sc(OTf)3 (Table 1, entries 2 and 8). This normal Michael
addtion reaction is well-established in the literature.5 No
reaction occurred or only a trace amount of product was
detected when other Lewis acids (LiClO4, Mg(ClO4)2, ZnCl2,
YbCl3, CAN) were utilized as catalyst (Table 1, entries 3-7).
Interestingly, compound 5a was formed when the reaction
was performed at 50 or 70 °C catalyzed by Sc(OTf)3 or
Yb(OTf)3 (Table 1, entries 9 and 10). The alkynyl group in
the substrate is not a specific factor for the outcome of double
addition. The same outcome was observed with the parent
benzylidenemalonate. It seems that the difference for genera-
tion of compound 4a or 5a depends on the temperature
employed. Further investigation revealed that the tandem
addition-cyclization could occur via 5-exo-cyclization6 when
t-BuOK was added as a base in the Yb(OTf)3-catalyzed
reaction (Table 1, entry 11). The corresponding product was
afforded in 77% yield, and the structure was verified as 6a
by 1H and 13C NMR, mass spectroscopy, and X-ray diffrac-
tion analysis (see Supporting Information). The yield could
temp time
yield
(%)b
entry Lewis acid
base
solvent
(°C)
(h)
1
2
3
Yb(OTf)3
Dy(OTf)3
LiClO4
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
25
25
25
25
25
25
25
25
50
70
25
25
60
25
25
25
25
25
25
25
25
25
25
25
25
25
25
70
72
24
24
24
24
24
24
5
48
20
24
48
24
24
24
24
7
53 (4a)
71 (4a)
NR
NR
NR
4
5
Mg(ClO4)2
ZnCl2
6
YbCl3
trace
trace
7
CAN
8
9
Sc(OTf)3
Sc(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
AgOTf
87 (4a)
99 (5a)
80 (5a)
77 (6a)
NR
85 (6a)
NR
NR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27c
tBuOK
K2CO3
Cs2CO3 MeCN
NaH
Et3N
iPr2NEt MeCN
tBuOK
tBuOK
tBuOK
MeCN
MeCN
NR
MeCN
MeCN
MeCN
MeCN
MeCN
tBuOH
DCE
THF
toluene
DMF
61 (6a)
63 (6a)
63 (6a)
85 (6a)
76 (6a)
17 (6a)
trace
trace
trace
70 (6a)
97 (6a)
CuI
FeCl3
Mg(ClO4)2 tBuOK
tBuOK
7
7
24
24
48
48
48
24
9
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
MeCN
a Reaction conditions: 2-(2-(alkynyl)benzylidene)malonate 2a (0.3
mmol), indole 3a (0.33 mmol, 1.1 equiv), Lewis acid (10 mol %), base
(1.0 equiv). b Isolated yield based on 2-(2-(alkynyl)benzylidene)malonate
2a. c Reaction conditions: 2-(2-(alkynyl)benzylidene)malonate 2a (0.3
mmol), indole 3a (0.25 mmol), base (1.0 equiv). Isolated yield based on
indole 3a.
(3) (a) Ding, Q.; Wu, J. Org. Lett. 2007, 9, 4959–4962. (b) Gao, K.;
Wu, J. J. Org. Chem. 2007, 72, 8611–8613. (c) Sun, W.; Ding, Q.; Sun,
X.; Fan, R.; Wu, J. J. Comb. Chem. 2007, 9, 690–694.
be increased to 85% when the base was changed to Cs2CO3,
although prolonged reaction time was needed (48 h, Table
1, entry 13). However, no product was detected when other
(4) (a) Saxton, J. E. Nat. Prod. Rep. 1997, 14, 559–590. (b) Toyota,
M.; Ihara, N. Nat. Prod. Rep. 1998, 15, 327–340.
(5) (a) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu,
J. J. Am. Chem. Soc. 2003, 125, 10780–10781. (b) Lewis Acids in Organic
Synthesis; Yamamoto, H., Ed.; Wiley-VCH Verlag GmbH: Weinheim, 2000.
(6) For selected examples, see: (a) Martinez, I.; Alford, P. E.; Ovaska,
T. V. Org. Lett. 2005, 7, 1133–1135. (b) Bailey, W. F.; Longstaff, S. C. J.
Org. Chem. 1998, 63, 432–433. (c) Duan, X.-H.; Guo, L.-N.; Bi, H.-P.;
Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2006, 8, 5777–5780. (d) Bi, H.-P.; Guo,
L.-N.; Duan, X.-H.; Gou, F.-R.; Huang, S.-H.; Liu, X.-Y.; Liang, Y.-M.
Org. Lett. 2007, 9, 397–400. (e) Guo, L.-N.; Duan, X.-H.; Bi, H.-P.; Liu,
X.-Y.; Liang, Y.-M. J. Org. Chem. 2007, 72, 1538–1540. (f) Guo, L.-N.;
Duan, X.-H.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2006, 71,
3325–3327. (g) Bi, H.-P.; Liu, X.-Y.; Gou, F.-R.; Guo, L.-N.; Duan, X.-
H.; Liang, Y.-M. Org. Lett. 2007, 9, 3527–3529.
i
bases (K2CO3, NaH, Et3N, Pr2NEt) were employed (Table
1, entries 12, 14-16). Other Lewis acids (AgOTf, CuI, FeCl3,
Mg(ClO4)2) were also screened in the presence of t-BuOK,
and the desired product 6a was generated in moderate to
good yield (Table 1, entries 17-20). From these results, the
role of the Lewis acid in the reaction was doubted. Thus,
the reaction without adding Lewis acid in the presence of
t-BuOK was examined at room temperature. Surprisingly,
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Org. Lett., Vol. 10, No. 11, 2008

To demonstrate generality of this method, we started to
investigate the scope of this tandem addition-cyclization
reaction under the optimized reaction conditions (t-BuOK,
MeCN, room temperature), and the results are shown in
Table 2. From Table 2, it was found that for most cases this
base-promoted tandem reaction of 2-(2-(alkynyl)benzyliden-
e)malonate 2 and indole 3 furnished the corresponding (Z)-
1-benzylidene-3-(1H-indol-1-yl)-1H-indene-2,2(3H)-dicar-
boxylate 6 in good to excellent yields. A better result was
observed when an indole with an electron-donating group
attached on the aromatic ring was employed. For example,
98% or 94% yield of corresponding product 6c or 6d was
obtained, respectively, when 2-(2-(alkynyl)benzylidene)ma-
lonate 2a reacted with methoxy-substituted indole 3c or 3d
(Table 2, entries 3 and 4). However, only moderate yield
was observed when 5-bromoindole was utilized in the
reaction of 2-(2-(alkynyl)benzylidene)malonate 2a (50%
yield, Table 2, entry 2). Substrate 2b reacted with indole
3a, leading to the formation of compound 6e in 89% yield
(Table 2, entry 5). A similar result was obtained when indole
3c or 3d was used as a replacement (Table 2, entries 6 and
7). Reaction of compound 2c with indole 3a or 3d also
proceeded smoothly and gave rise to the desired product 6h
or 6i in 99% or 88% yield, respectively (Table 2, entry 8).
We also tested the reactions of indole 3a with other
substrates, such as 2d and 2e. Interestingly, only normal
Michael addition product 7 was furnished when substrate
2d was employed (63% yield, Scheme 1, eq 1). Reaction of
Table 2. Reaction of Compound 2 with Indole 3 in the Presence
of t-BuOK (1.0 equiv) at Room Temperature
Scheme 1. Reaction of 2-(2-(Alkynyl)benzylidene)malonate 2d
and 2e with Indole 3a Promoted by t-BuOK
a Isolated yield based on indole 3. The Z/E ratio was determined by 1H
NMR.
compound 2e with indole 3a generated the desilylated
product 6j in 80% yield (Scheme 1, eq 2).
Other nucleophiles were also examined in the reaction of
compound 2b under the conditions shown in Table 2. As
presented in Scheme 2, imidazole 8 was also a good partner
for the reaction of 2-(2-(alkynyl)benzylidene)malonate 2b,
which gave rise to the desired product 6k in 93% yield.
However, only a trace amount of product was detected when
pyrrole 9 was utilized. No reaction occurred when diisopro-
pylamine 10, p-anisidine 11, or phenylacetylene 12 was
employed as nucleophile. A complex mixture was observed
for reaction of 2b with pentane-2,4-dione 13.
the reaction also proceeded smoothly to give rise to the
desired product 6a in 76% yield (24 h, Table 1, entry 21).
The presence of Lewis acid may accelerate the reaction. For
instance, the reaction was complete in 7 h when Mg(ClO4)2
was added (Table 1, entry 20). Solvent effect was also inves-
tigated, and acetonitrile was demonstrated as the best choice
for this transformation (Table 1, entries 21-26). The yield
could be dramatically improved when the ratio of substrates
was changed to 1.2:1 (97% yield, Table 1, entry 27).
Org. Lett., Vol. 10, No. 11, 2008
2253

the reactions of (Z)-ethyl 2-cyano-3-phenylacrylate with
EtSH catalyzed by AkX3 (X ) Br, Cl).7 In the reactions,
double bonds activated by electron-withdrawing groups were
cleaved on treatment with a hard Lewis acid and EtSH. For
the results shown in Table 3, we reasoned that the formation
of unexpected product 5 could be explained in a similar
manner.7 Initially, Michael addition of indole takes place to
afford the normal adduct 4, which is converted into the
benzylidene-3H-indole species by the loss of the active
methylene moiety in the presence of Lewis acid at higher
temperature. Addition of another molecule of indole com-
pletes the overall transformation.
Scheme 2
.
Reaction of 2-(2-(Alkynyl)benzylidene)malonate 2b
with Other Nucleophiles
In conclusion, we have described an unprecedented and
straightforward route for the synthesis of (Z)-1-benzylidene-
3-(1H-indol-1-yl)-1H-indene-2,2(3H)-dicarboxylate via a
tandem addition-cyclization reaction of 2-(2-(alkynyl)ben-
zylidene)malonate with indole under base conditions. We
also discover that 3-((1H-indol-3-yl)(2-(alkynyl)aryl)methyl)-
1H-indole may be formed in the presence of Lewis acid via
double sequential addition of indole to 2-(2-(alkynyl)ben-
zylidene)malonate.
In a second set of experiments, the Lewis acid catalyzed
reaction of 2-(2-(alkynyl)benzylidene)malonate 2 with indole
3 was examined (Table 3). This transformation was highly
Table 3. Reaction of Compound 2 with Indole 3 Catalyzed by
Sc(OTf)3 (10 mol %) at 50 °C
Figure 2. X-ray structure of compound 6a.
Acknowledgment. We thank Dr. Renhua Fan (Fudan
University) for his invaluable advice during the course of
this research. We also thank Dr. Jason Wong (Roche R&D
Center, China) for English polishing. Financial support from
National Natural Science Foundation of China (20772018),
Shanghai Pujiang Program, and Program for New Century
Excellent Talents in University (NCET-07-0208) is gratefully
acknowledged.
Supporting Information Available: Experimental pro-
cedures, characterization data including X-ray diffraction
analysis data of compound 6a in CIF format, and copies of
1H and 13C NMR of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
a Isolated yield based on 2-(2-(alkynyl)benzylidene)malonate 2.
OL800664Z
effective and gave rise to the 3-((1H-indol-3-yl)(2-(alkyny-
l)aryl)methyl)-1H-indole 5 in excellent yield. Although the
mechanism is not clear, our finding is similar to a report on
(7) Fuji, K.; Kawabata, T.; Node, M.; Fujita, E. Tetrahedron Lett. 1981,
22, 875–878.
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Org. Lett., Vol. 10, No. 11, 2008