Isocyanide-based multicomponent reactions: Catalyst-free stereoselective construction of polycyclic spiroindolines

Article abstract of DOI:10.1021/ol400606c

A novel catalyst-free one-pot tandem reaction for the stereoselective construction of polycyclic spiroindolines was developed. This method offers a straightforward access to structurally diverse polycyclic spiroindoline derivatives in high yields (up to 90%) with excellent levels of diastereoselectivity.

Full text of DOI:10.1021/ol400606c

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Isocyanide-Based Multicomponent
Reactions: Catalyst-Free Stereoselective
Construction of Polycyclic Spiroindolines
Xiang Wang, Shun-Yi Wang,* and Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
China
shunyi@suda.edu.cn; shunjun@suda.edu.cn
Received March 7, 2013
ABSTRACT
A novel catalyst-free one-pot tandem reaction for the stereoselective construction of polycyclic spiroindolines was developed. This method offers
a straightforward access to structurally diverse polycyclic spiroindoline derivatives in high yields (up to 90%) with excellent levels of
diastereoselectivity.
The development of efficient approaches to chemically
and biologically important products from common start-
ing materials, while combining economic and environmen-
tal aspects, has been an active topic in modern organic
chemistry.1,2 An increasing number of multicomponent
reactions involving cascade processes have been reported,
which provide powerful strategies for the total synthesis of
natural products and synthetic building blocks.3ꢀ5 In these
reactions, multiple stereocenters could be generated with
step economy, without further purification of various
precursors, and tedious steps of protection and deprotec-
tion of functional groups.6ꢀ8
(1) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115–136. (b) Tietze, L. F.;
Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis; Wiley-
VCH: Weinheim, 2006. (c) Rosamilia, A. E.; Strauss, C. R.; Scott, J. L. Pure
Appl. Chem. 2007, 79, 1869–1877.
(2) (a) Chen, C.; Li, X.; Neumann, C. S.; Lo, M. M. C.; Schreiber,
S. L. Angew. Chem., Int. Ed. 2005, 44, 2249–2252. (b) Mitchell, J. M.;
Shaw, J. T. Angew. Chem., Int. Ed. 2006, 45, 1722–1726. (c) Kumagai,
N.; Muncipinto, G.; Schreiber, S. L. Angew. Chem., Int. Ed. 2006, 45,
3635–3638. (d) Thomas, G. L.; Spandl, R. J.; Glansdorp, F. G.; Welch,
M.; Bender, A.; Cockfield, J.; Lindsay, J. A.; Bryant, C.; Brown, D. F. J.;
Loiseleur, O.; Rudyk, H.; Ladlow, M.; Spring, D. R. Angew. Chem., Int.
Ed. 2008, 47, 2808–2812.
(6) (a) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raab, G. Nature
2006, 441, 861–863. (b) Andrey, S. I. Chem. Soc. Rev. 2008, 37, 789–811.
(c) de Meijere, A.; von Zezschwitz, P.; Brase, S. Acc. Chem. Res. 2005, 38,
413–422.
(7) (a) Huang, Y.; Waljji, A. M.; Larsen, C. H.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2005, 127, 15051–15053. (b) Yang, J. W.; Fonseca,
H. M. T.; List, B. J. Am. Chem. Soc. 2005, 127, 15036–15037.
(8) (a) Barluenga, J.; Jimenez-Aquino, A.; Valdes, C.; Aznar, F.
Angew. Chem., Int. Ed. 2007, 46, 15292–15293. (b) Alex, K.; Tillack,
A.; Schwarz, N.; Beller, M. Angew. Chem., Int. Ed. 2008, 47, 2304–2307.
(c) Lu, M.; Zhu, D.; Lu, Y.; Hou, B.; Tan, B.; Zhong, G. Angew. Chem.,
Int. Ed. 2008, 47, 10187–10191. (d) Wang, J.; Xie, H.; Li, H.; Zu, L.;
Wang, W. Angew. Chem., Int. Ed. 2008, 47, 4177–4179.
(3) (a) Domling, A. Chem. Rev. 2006, 106, 17–89. (b) Zhu, J.;
Bienayme, H., Eds. Multicomponent Reactions; Wiley-VCH: Weinheim,
Germany, 2005. (c) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439–
4486. (d) Ganem, B. Acc. Chem. Res. 2009, 42, 463–472.
(9) (a) Bonjoch, J.; Sole, D. Chem. Rev. 2000, 100, 3455–3482.
(b) Sirasani, G.; Paul, T.; Dougherty, W.; Kassel, S.; Andrade, R. B.
J. Org. Chem. 2010, 75, 3529–3532.
(10) (a) Martin, D. B. C.; Vanderwal, C. D. Chem. Sci. 2011, 2, 649–
651. (b) Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D.W.
C. Nature 2011, 475, 183–188.
(11) (a) Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007,
129, 13794–13795. (b) Zuo, Z.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2010,
132, 13226–13228. (c) Zuo, Z.; Ma, D. Isr. J. Chem. 2011, 51, 434–441.
(d) Zhang, D.; Song, H.; Qin, Y. Acc. Chem. Res. 2011, 44, 447–457.
(4) (a) Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, V.; Zografos,
S. L. J. Am. Chem. Soc. 2009, 131, 1753–1765. (b) Muller, F. L.;
Constantieux, T.; Rodriguez, J. J. Am. Chem. Soc. 2005, 127, 17176–
17177.
(5) (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134–7186. (b) Diguez-Vzquez, A.; Tzschucke, C. C.;
Lam, W. Y.; Ley, S. V. Angew. Chem., Int. Ed. 2008, 47, 209–212.
(c) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
(d) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602–1634.
Santra, S.; Andreana, P. R. Angew. Chem., Int. Ed. 2011, 50, 9418–9422.
r
10.1021/ol400606c
XXXX American Chemical Society

Polycyclic spiroindoline is a complex molecular skeleton
that often exists in both natural products and pharmaceu-
tical molecules with important biological activities.9ꢀ12
could be synthesized via a one-pot procedure combining
an Ugi coupling and a copper-catalyzed oxidative process
at a peptidyl position (Scheme 1, eq 1). Ma et al.17 reported
a protocol for assembling a polycyclic spiroindoline
scaffold involving an intramolecular oxidative cou-
pling of dianions derived from indole-embodied
β-ketoamides using iodine as the oxidant, and the
subsequent addition of the oxygen anion to the resultant
imine moiety (Scheme 1, eq 2).
Figure 1. Structures of polycyclic spiroindoline alkaloids.
Scheme 2. Construction of Polycyclic Pyrrole Skeletons Based
on Functionalized Isocyanide
For example, tabersonine I and akuammicine II are char-
acteristic members of the alkaloid family that continue to
capture the imagination of organic chemists (Figure 1).13ꢀ15
Polycyclic spiroindoline frameworks possessing quatern-
ary carbon centers that assemble in a regio- and stereo-
specific manner from simple substrates have attracted
attention over the past decades.
Wu et al.18 reported a base-promoted cascade reaction
of (E)-2-alkynylphenylchalcone with 2-isocyanoacetate
providing a novel and efficient route for the construction
of tetrahydroindeno[2,1-b]pyrroles (Scheme 2, eq 3). They
also developed a novel and efficient route for the construc-
tion of isoquinolines via a silver triflate catalyzed reaction
of 2-alkynylbenzaldehyde with 2-isocyanoacetate.
Scheme 1. Construction of Polycyclic Spiroindoline Skeletons
Despite impressive advances in the construction of
polycyclic spiroindolines, the most popular strategy for
this transformation relies on transition-metal catalysts.
These procedures have some drawbacks: the catalysts are
expensive, high temperatures are required, and the reac-
tions are characterized by low selectivity. Herein, we
present a novel one-pot catalyst-free multicomponent
reaction to construct polycyclic spiroindolines from simple
and readily available 2-isocyanoethylindole,19 aromatic
aldehydes, and malononitrile. This transformation pro-
ceeds smoothly under mild conditions to afford the desired
polycyclic spiroindolines in good to excellent yields with
high diastereoselectivities (Scheme 2, eq 4).
Recently, Van der Eycken et al.16a reported a post-Ugi
Au-catalyzed domino cyclization method to generate spiro-
indolines. Miranda et al.16b reported that spiroindolines
(12) (a) Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem., Int. Ed.
2010, 49, 2000–2003. (b) Zuo, Z.; Ma, D. Angew. Chem., Int. Ed. 2011,
50, 12008–12011. (c) Siengalewicz, P.; Gaich, T.; Mulzer, J. Angew.
Chem., Int. Ed. 2008, 47, 8170–8176.
We initiated our studies with the three-component reac-
tion of 2-isocyanoethylindole 1a (1 mmol), malononitrile
2a (1 mmol), and 4-bromobenzaldehyde 3l (1 mmol) in
MeCN at room temperature for 5 h without any addi-
tive. To our delight, it afforded 4-bromophenyl-2,3,5a,
6-tetrahydropyrrolo[30,20:2,3]cyclopenta[1,2-b]indole-
5,5(1H)-dicarbonitrile 4l in 90% LC-yield. The polycyclic
(13) (a) Sundberg, R. J. Indoles; Academic Press: London, 1996.
(b) Gribble, G. W. Heterocyclic Scaffolds II: Reactions and Applications
of Indoles; Springer-Verlag: Berlin, Heidelberg, 2010; Vol. 26.
(14) (a) Saxton, J. E. Indoles, Part 4: The Monoterpenoid Indole
Alkaloids; Wiley: Chichester, U.K., 1983. (b) Herbert, R. B. In The
Monoterpenoid Indole Alkaloids; supplement to Vol. 25, part 4, of The
Chemistry of Heterocyclic Compounds; Saxton, J. E., Ed.; Wiley: Chichester,
U.K., 1994; Chapter 1. (c) Saxton, J. E. The Monoterpenoid Indole
Alkaloids; supplement to Vol. 25, part 4, of The Chemistry of Heterocyclic
Compounds; Saxton, J. E., Ed.; Wiley: Chichester, U.K., 1994; Chapter 8. (d)
Saxton, J. E. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New
York, 1998; Vol. 50. (e) Saxton, J. E. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: New York, 1998; Vol. 51, Chapter 1.
(15) (a) Toyota, M.; Ihara, M. Nat. Prod. Rep. 1998, 327. (b) Janot,
M.-M.; Pourrat, H.; Le Men, J. Bull. Soc. Chim. Fr. 1954, 707–708.
(c) Wenkert, E. J. Am. Chem. Soc. 1962, 84, 98–102.
(16) (a) Modha, S. G.; Kumar, A.; Vachhani, D. D.; Jacobs, J.;
Sharma, S. K.; Parmar, V. S.; Van Meervelt, L.; Van der Eycken, E. V.
Angew. Chem., Int. Ed. 2012, 57, 9572–9575. (b) Kaim, L. E.; Grimaud,
L.; Goff, X. L.; Menes-Arzate, M.; Miranda, L. D. Chem. Commun.
2011, 47, 8145–8147.
1
spiroindoline 4l was fully characterized by H and 13C
NMR and IR spectra. Only a single diastereoisomer of
polycyclic spiroindoline product 4l was detected by NMR
(17) Fan, F.; Xie, W.; Ma, D. Org. Lett. 2012, 14, 1405–1407.
(18) (a) Zheng, D.; Li, S.; Luo, Y.; Wu, J. Org. Lett. 2011, 13, 6402–
6405. (b) Zheng, D.; Li, S.; Wu, J. Org. Lett. 2012, 14, 2655–2657.
(19) (a) Liu, H.; Domling, A. J. Org. Chem. 2009, 74, 6895–6898.
(b) Wang, W.; Herdtweck, E.; Domling, A. Chem. Commun. 2010, 46,
770–772.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of Reaction Conditions for the
Multicomponent Reactions
Scheme 3. Reaction of 2-Isocyanoethylindole and
Malononitrile with Aromatic Aldehydes
entry
solvent
yield (%)a
1
2
3
4
5
MeOH
CHCl3
MeCN
CH2Cl2
EtOH
98
87
90
90
99 (89b)
a The yields were determined by LC analysis using biphenyl as the
internal standard. b Isolated yield.
analysis. To identify an ideal solvent for the transforma-
tion, the model reaction was investigated in different
solvents. The results were summarized in Table 1. To our
delight, the desired product 4l could be obtained in good to
excellent LC-yields in different solvents, and EtOH gave
the best result. The desired product 4l could be obtained in
89% isolated yield (Table 1, entry 5).
With the above optimized conditions in hand, the sub-
strate scope was examined by using readily available
starting materials. As presented in Scheme 3, 2-isocyano-
ethylindole1awithmalononitrile2 and varioussubstituted
aromatic aldehydes 3 worked well to afford he desired
products (4a to 4o) in moderate to excellent yields (72% to
90%) with high diastereoselectivities. Notably, polycyclic
spiroindoline 4o was obtained in excellent yield (90%
yield) with 3o bearing a strong electron-withdrawing
group. When 3-methylbenzaldehyde 3d bearing an electron-
donating group was subjected to this reaction, the yield of
the desired product 4d was decreased to 72%. When other
benzaldehyde derivates bearing F, CN, NO2, Br, Cl groups
were applied to the reaction, the desired products (4j to 4n)
could also be obtained in moderate to good yields. The
structure of 4n was further confirmed by single-crystal
X-ray diffraction.
When 2-isocyanoethylindole derivatives 1b to 1d instead
of 1a was subjectd to the reaction with 2 and 3n under
the optimized conditions, the desired polycyclic spiroindo-
line derivatives 4p to 4r were obtained in 54% to 66%
yield (Scheme 4, eq 5). Interestingly, when aliphatic pival-
aldehyde was used instead of aromatic aldehydes, un-
rearranged product 8a was obtained (Scheme 4, eq 6).
However, other aliphatic aldehydes with R-H were em-
ployed in this reaction, and no corresponding polycyclic
spiroindoline was obtained. When 2-(2-oxoindolin-3-
ylidene) malononitrile was subjected to the reaction under
the identical conditions, no polycyclic spiroindoline was
observed (Scheme 4, eq 7). The possible reason is the steric
hindrance of the 2-(2-oxoindolin-3-ylidene)malononitrile
and the low polarity of the activated alkene.
To better understand the mechanism of this reaction, we
carried out the reaction of 1 with 5g under the identical
conditions. The desired product 4l could also be obtained
in similar yield (Scheme 4, eq 8).
Based on the above results, we proposed a plausible
mechanism for this multicomponent reaction.20 First, the
reaction is initiated by Knoevenagel condensation of mal-
ononitrile 2 and the aldehyde 3 to perform the benzylide-
nemalonodinitrile 5. Then, the isocyanide 1 undergoes
nucleophilic addition to intermediate 6 followed by nu-
cleophilic attack by the C3 of indole to afford intermediate
7. Subsequently, intermediate 7 undergoes intramolecular
nucleophilic addition to afford polycyclic spiroindoline
derivatives 4 (Scheme 5).
(20) Mironov, M. A.; Ivantsova, M. N.; Mokrushin, V. S. Synlett
2006, 4, 615–618.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Scope of the Construction of Polycyclic
Spiroindolines
Scheme 5. Proposed Mechanism for the Products 4
synthetic applications and synthesis of natural product
analogs are ongoing in our laboratory.
Acknowledgment. We gratefully acknowledge the
Natural Science Foundation of China (Nos. 21042007,
21172162), the Young National Natural Science Founda-
tion of China (No. 21202111), the Young Natural Science
Foundation of Jiangsu Province (BK2012174), Key Labora-
tory of Organic Synthesis of Jiangsu Province (KJS1211),
PAPD, and Soochow University for financial support.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds and X-ray crystallographic details of 4n (CIF
file; atomic coordinates, displacement parameters, bond
lengths and angles, and torsion angles). This material
is available free of charge via the Internet at http://pubs.
acs.org.
Inconclusion, we have developed a novel catalyst-free
multicomponent reaction for the construction of poly-
cyclic spiroindolines by using 2-isocyanoethylindole
with different types of aromatic aldehydes and malono-
nitrile. The reactions proceed under mild conditions and
performed the products in good to excellent yields with
high diastereoselectivities. Further studies for the
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX