Dual behavior of isatin-based cyclic ketimines with dicarbomethoxy carbene: Expedient synthesis of highly functionalized spirooxindolyl oxazolidines and pyrrolines

Article abstract of DOI:10.1021/ol400287q

A highly stereo-, regio-, and chemoselective method has been devised for the synthesis of a wide range of spirooxindolyl oxazolidines via an intermolecular 1,3-dipolar cycloaddition of carbonyl ylides generated from dimethyl diazomalonate and aromatic aldehydes, with cyclic ketimines using 5 mol % of Rh₂(OAc)₄ under mild conditions. Similarly, highly functionalized spirooxindolyl pyrrolines have also been prepared through 1,3-dipolar cycloaddition of azomethine ylides generated from dimethyl diazomalonate and cyclic ketimines, with dimethyl acetylenedicarboxylate.

Full text of DOI:10.1021/ol400287q

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1512–1515
Dual Behavior of Isatin-Based Cyclic
Ketimines with Dicarbomethoxy Carbene:
Expedient Synthesis of Highly
Functionalized Spirooxindolyl
Oxazolidines and Pyrrolines
T. Rajasekaran,† G. Karthik,† B. Sridhar,‡ and B. V. Subba Reddy*,†
Natural Product Chemistry, Laboratory of X-ray Crystallography, CSIR-Indian
Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, 500 007, India
basireddy@iict.res.in
Received January 31, 2013
ABSTRACT
A highly stereo-, regio-, and chemoselective method has been devised for the synthesis of a wide range of spirooxindolyl oxazolidines via an
intermolecular 1,3-dipolar cycloaddition of carbonyl ylides generated from dimethyl diazomalonate and aromatic aldehydes, with cyclic ketimines
using 5 mol % of Rh2(OAc)4 under mild conditions. Similarly, highly functionalized spirooxindolyl pyrrolines have also been prepared through
1,3-dipolar cycloaddition of azomethine ylides generated from dimethyl diazomalonate and cyclic ketimines, with dimethyl acetylenedicarboxylate.
Over the last few decades, great efforts have been
focused on catalytic multicomponent reactions (CMCRs)
as they offer rapid access to biologically relevant complex
molecules with wide structural diversity, high atom econ-
omy, and excellent bond-forming efficiency in a single-step
process.1 A multicomponent reaction of R-diazocarbonyl
compounds is one of the attractive methods for the rapid
production of the highly functionalized five-membered
heterocycles.2 Notably, a 1,3-dipolar cycloaddition of car-
bonyl ylides and azomethine ylides generated from R-diazo-
carbonyl compounds with dipolarophiles has been em-
ployed for the stereoselective synthesis of oxygen- and
(3) (i) For oxygen heterocycles, see: (a) de March, P.; Huisgen, R.
J. Am. Chem. Soc. 1982, 104, 4952. (b) Huisgen, R.; de March, P. J. Am.
Chem. Soc. 1982, 104, 4953. (c) Alt, M.; Maas, G. Tetrahedron 1994, 50,
7435. (d) Doyle, M. P.; Forbes, D. C.; Protopopova, M. N.; Stanley,
S. A.; Vasbinder, M. M.; Xavier, K. R. J. Org. Chem. 1997, 62, 7210. (e)
Hamaguchi, M.; Matsubara, H.; Nagai, T. J. Org. Chem. 2001, 66, 5395.
(f) Johnson, T.; Cheshire, D. R.; Stocks, M. J.; Thurston, V. T. Synlett
2001, 646. (g) Skaggs, A. J.; Lin, E. Y.; Jamison, T. F. Org. Lett. 2002, 4,
2277. (h) Jiang, B.; Zhang, X.; Luo, Z. Org. Lett. 2002, 4, 2453. (i) Nair,
V.; Mathai, S.; Nair, S. M.; Rath, N. P. Tetrahedron Lett. 2003, 44, 8407.
(j) Nair, V.; Mathai, S.; Varma, L. R. J. Org. Chem. 2004, 69, 1413. (k)
Russell, A. E.; Brekan, J.; Gronenberg, L.; Doyle, M. P. J. Org. Chem.
2004, 69, 5269. (l) DeAngelis, A.; Panne, P.; Yap, G. P. A.; Fox, J. M.
J. Org. Chem. 2008, 73, 1435. (m) DeAngelis, A.; Taylor, M. T.; Fox,
J. M. J. Am. Chem. Soc. 2009, 131, 1101and references therein. (ii) For
nitrogen heterocycles, see: (a) Bartnik, R.; Mloston, G. Tetrahedron
1984, 40, 2569. (b) Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 1995, 34, 676. (c) Doyle, M. P.; Hu, W.; Timmons,
D. J. R. Org. Lett. 2001, 3, 933. (d) Padwa, A.; Pearson, W. H. Synthetic
Application of 1,3-Dipolar Cycloaddition Chemistry Heterocycles and
Natural Products; Wiley-Interscience: New York, 2002.
† Natural Product Chemistry.
‡ Laboratory of X-ray Crystallography.
(1) (a) For reviews on MCRs, see: (a) Domling, A.; Wang, W.; Wang,
€
K. Chem. Rev. 2012, 112, 3083. (b) Orru, R. V. A.; de Greef, M. Synthesis
2003, 1471. (c) Nair, V.; Rajesh, R.; Vinod, A. U.; Bindu, S.; Sreekanth,
A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899. (d)
Bienayme, H.; Hukme, C.; Oddon, G.; Schmitt, P. Chem.;Eur. J. 2000,
6, 3321. (e) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (f)
Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 366. (g) Armstrong,
R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc.
Chem. Res. 1996, 3, 123.
(2) Reviews and books: (a) Doyle, M. P. Chem. Rev. 1986, 86, 919. (b)
Padwa, A.; Hornbuckle, S. Chem. Rev. 1991, 91, 263. (c) Padwa, A.;
Weingarten, M. D. Chem. Rev. 1996, 96, 223. (d) Hodgson, D. M.;
Pierad, F. Y. T. M.; Stupple, P. A. Chem. Soc. Rev. 2001, 30, 50. (e)
Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; Wiley-Interscience: New
York, 1984. (f) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley & Sons:
New York, 1998.
r
10.1021/ol400287q
Published on Web 03/11/2013
2013 American Chemical Society

nitrogen-containing heterocycles.3 However, an intermo-
lecular cycloaddition of ylides with dipolarophiles is
known to be synthetically unsuitable in CMCRs because
of their low selectivity and the competitive side reactions
such as epoxidation, dioxolane formation. Further-
more, the cycloaddition of carbonyl ylides with imines
to produce oxazolidines has received limited attention
because of their low dipolarophilicity. Recently, an elegant
approach has been reported by Somfai et al. for the
cycloaddition of a carbonyl ylide generated from ethyl
diazoacetate and aromatic aldehyde with aldimine.4 How-
ever, this method suffers from low conversion and moderate
diastereoselectivity with respect to substrate. Competitive
dioxolane formation reduces the efficiency of this method
(Scheme 1).
ylides from carbenoids. Therefore, the cyclic ketimines
could be used to produce the spirooxindolyl-1,3-oxazoli-
dines and spirooxindolyl-1,3-pyrrolidines. Such spiroox-
indoles, oxazolidines, and pyrrolidines have emerged as
attractive synthetic targets because of their prevalence in
biologically active natural products and drugs7 (Figure 1).
Herein, we report a novel approach for the construction
of spirooxindolyl-1,3-oxazolidines and spirooxindolyl-1,3-
pyrrolines via the coupling of diazomalonate and ketimine
with aldehyde or with dimethyl acetylenedicarboxylate,
respectively.
Accordingly, the three-component coupling (3CC) of
dimethyl diazomalonate with benzaldehyde and N-methyl-
isatin-3-arylimine in the presence of 5 mol % of Rh2(OAc)4
afforded the spirooxindolyl-1,3-oxazolidine 4a in 86%
yield (entry a, Table 1). The 1H NMR analysis of a crude
sample indicates the exclusive formation of cycloadduct 4a
as a single diastereomer. The product was purified by flash
column chromatography on silica gel and characterized by
spectroscopic analysis.
Scheme 1
The spectral data evidently confirm the proposed struc-
ture for 4a. The relative stereochemistry of spirooxindolyl-
1,3-oxazolidine 4q was determined on the basis of X-ray
crystallography (see the Supporting Information).
Like carbonyl ylide, the generation of azomethine ylide
from N-benzylideneaniline and diazo compound has also
been reported to facilitate cycloaddition with diplorophiles
to produce the pyrrolidines and pyrroles.5 But N-benzyli-
deneaniline fails to undergo cycloaddition with carbonyl
ylide (Scheme 1). Therefore, there is still a need to find a
suitable imine that can trap the carbonyl ylide effectively
without the formation of any epoxide and dioxolane and
also to generate the azomethine ylide.
As a part of our research program on diazocarbonyl
compounds, we recently reported the synthesis of spiroox-
indolyl lactams and oxazinones through the trapping of
acylketeneswithisatin-based cyclicketimines.6 Weinitially
envisaged that the cyclic ketimines derived from isatin
could be interesting if they act as good dipolarophiles to
trap the carbonyl ylides and also to generate azomethine
Figure 1. Biologically active spirooxindolyl oxazole and pyrro-
line derivatives.
Encouraged by the initial results, we further examined
the reactivity of ketimines with various carbonyl ylides
generated from diazomalonate and electron-rich as well as
electron-deficient aryl aldehydes (Table 1). In order to
investigate the competitive side reactions such as epoxida-
tion and 1,3-dioxolane formation, we performed the 3CC
reaction with electron-deficient aryl aldehydes which
usually serve as dipolarophiles in the formation of dioxo-
lanes. Surprisingly, no such formation of dioxolane was
observed with p-nitrobenzaldehyde under the present re-
action conditions. Inspired by this observation, we extended
its effectiveness to the preparation of spirooxazolidine with
a highly electron-deficient substrate, i.e., 2,4-dinitrobenzal-
dehyde. Remarkably, the corresponding oxazolidine was
obtained in good yield under the present reaction conditions
without the formation of dioxolane (entries d and r, Table 1)
although 2,4-dinitrobenzaldehyde is known to act as an
excellent dipolarophile in carbonyl ylide cycloadditions.
(4) (a) Torssell, S.; Kienle, M.; Somfai, P. Angew. Chem., Int. Ed.
2005, 44, 3096. (b) Torssell, S.; Somfai, P. Adv. Synth. Catal. 2006, 348,
24214.
(5) (a) Li, G. Y.; Chen, J.; Yu, W. Y.; Hong, W.; Che, C. M. Org. Lett.
2003, 5, 2153. (b) Galliford, C. V.; Scheidt, K. A. J. Org. Chem. 2007, 72,
1811.
(6) Reddy, B. V. S.; Karthik, G.; Rajasekaran, T.; Antony, A.;
Sridhar, B. Tetrahedron Lett. 2012, 53, 2396.
(7) (a) Badillo, J. J.; Hanhan, N. V.; Franz, A. K. Curr. Opin. Drug
Discovery Dev. 2010, 13, 758. (b) Galliford, C. V.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 8748. (c) Yeung, B. K. S.; Zou, B.; Rottmann,
M.; Lakshminarayana, S. B.; Ang, S. H.; Leong, S. Y.; Tan, J.; Wong, J.;
Keller-Maerki, S.; Fischli, C.; Goh, A.; Schmitt, E. K.; Krastel,
P.; Francotte, E.; Kuhen, K.; Plouffe, D.; Henson, K.; Wagner, T.;
Winzeler, E. A.; Petersen, F.; Brun, R.; Dartois, V.; Diagana, T. T.;
Keller, T. H. J. Med. Chem. 2010, 53, 5155. (d) Vintonyak, V.; Warburg,
K.; Kruse, H.; Grimme, S.; Hubel, K.; Rauh, D.; Waldmann, H. Angew.
Chem., Int. Ed. 2010, 49, 5902. (e) Jiang, X.; Cao, Y.; Wang, Y.; Liu, L.;
Shen, F.; Wang, R. J. Am. Chem. Soc. 2010, 132, 15328. (f) Bhaskar, G.;
Arun, Y.; Balachandran, C.; Saikumar, C.; Perumal, P. T. Eur. J. Med.
Chem. 2012, 51, 79.
Org. Lett., Vol. 15, No. 7, 2013
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Table 1. Three-Component Synthesis of Spirooxindolyl
Oxazolidinesa
Scheme 2. Formation of Bis-spirooxindolyl Oxazolidine
yieldb (%)
entry
R1
CH3
R2
R3
Ar
of 4aÀx
a
b
c
d
e
f
H
H
H
H
H
H
H
H
H
Ph
86
82
84
78
86
90
88
88
84
86
88
86
84
84
85
86
85
76
82
90
86
85
88
88
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
allyl
allyl
allyl
allyl
allyl
allyl
allyl
allyl
allyl
propargyl
Bn
H
p-NO2C6H4
p-CNC6H4
o,p-(NO2)2C6H3
Ph
ketimine. Isatin-based ketimine, being a very good dipo-
larophile, can trap the carbonyl ylide effectively via endo
attack (Scheme 4). The reaction does not proceed through
the formation of epoxide from diazomalonate and aro-
matic aldehyde as this was confirmed by reacting the
ketimine with epoxide which was prepared independently
from diazomalonate and anisaldehyde. With this evidence,
we excluded the possibility of involving a stepwise mechan-
ism (Scheme 3).
H
H
CH3
Br
Cl
NO2
H
Ph
g
h
i
Ph
Ph
m-Cl
H
Ph
j
H
p-CH3C6H4
p-BrC6H4
p-FC6H4
p-CNC6H4
p-NO2C6H4
m-NO2C6H4
p-NO2C6H4
k
l
H
H
H
H
m
n
o
p
q
r
H
H
H
H
H
H
Scheme 3. Reaction of Isatin-3-arylimine with Epoxide
H
p-Br
H
p-CH3 p-NO2C6H4
H
H
H
H
H
H
o,p-(NO2)2C6H3
s
H
p-NO2C6H4
Ph
t
H
u
v
w
x
Bn
H
p-CNC6H4
p-NO2C6H4
Bn
H
Bn
H
p-CH3 p-NO2C6H4
p-Br p-NO2C6H4
Bn
H
a Unless otherwise noted, all reactions were performed using Rh2(OAc)4
(5 mol %), imine 1 (1.2 equiv), dimethyl diazomalonate 2 (1 equiv), and
aromatic aldehydes 3 (1 equiv) in dry benzene at 80 °C. b Yield refers to
pure products after column chromatography.
Scheme 4. Plausible Reaction Pathway for the Formation of
Spirooxindolyl Oxazolines
This is due to high dipolarophilicity of ketimines over
nitrobenzaldehydes. Furthermore, it is inevitable to note
that no oxazole (which is known to form from diazoma-
lonate and cyano group) or dioxolane was formed with
p-cyanobenzaldehyde (entries c, m, and u, Table 1). Further,
the bond-forming efficiency of this method is exemplified
by making six bonds (two CÀC bonds, two CÀO bonds,
and two CÀN bonds) with bis-aldehyde 5 in a single-step
process (Scheme 2).
To study the electronic effect of substituents on the
aromatic ring, we prepared several ketimines with both
electron-rich and electron-deficient substrates. Remark-
ably, N-substituted isatin-3-arylimines such as allyl, pro-
pargyl, and benzyl are well tolerated without participating
in side reactions such as cyclopropanation, furan forma-
tion, and CÀH insertion, respectively, which shows the
high chemoselectivity of this protocol.
To the best of our knowledge, there is no report on the
generation of azomethine ylide from diazomalonate and
imine. Therefore, we were curious to extend our approach
to azomethine ylides generated from diazomalonate
and ketimines. Accordingly, treatment of azomethine
ylides with dimethyl acetylenedicarboxylate afforded a
highly substituted spirooxindolyl dihydropyrroline in
Mechanistically, the reaction was proposed to proceed
via Huisgen’s cycloaddition of carbonyl ylide, formed in
situ from diazomalonate and aromatic aldehyde, with
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Org. Lett., Vol. 15, No. 7, 2013

Table 2. Three-Component Synthesis of Spirooxindolyl
Pyrrolinesa
Scheme 5. Plausible Reaction Pathway for the Formation of
Spirooxindolyl Pyrroline
In conclusion, we have developed a highly efficient ap-
proach for the synthesis of a novel class of highly substituted
spirooxindolyl oxazolidines via a 1,3-dipolar cycloaddition
of carbonyl ylides with ketimines and also spirooxindolyl
pyrrolines through the cycloaddition of dimethyl acety-
lenedicarboxylate with azomethine ylides generated from
ketimines and diazomalonate. These spirocycles may find
significant application in medicinal chemistry since the
concept of hybrid drugs is gaining popularity in medicine.
The bond-forming efficiency of this method is exempli-
fied by making six bonds (two CÀC bonds, two CÀO
bonds, and two CÀN bonds) with bis-aldehyde in a
single-step operation.
entry
R1
R2
yieldb (%) of 10aÀk
a
b
c
d
e
f
CH3
CH3
CH3
CH3
Bn
H
80
84
82
80
85
86
85
80
85
84
86
CH3
Br
OCH3
H
Bn
CH3
OCH3
H
g
h
i
Bn
allyl
allyl
allyl
allyl
CH3
OCH3
Cl
j
k
a Unless otherwise noted, all reactions were performed using
Rh2(OAc)4 (5 mol %), imine 1 (1.2 equiv), dimethyl diazomalonate 2
(1 equiv), and dimethyl acetylenedicarboxylate 9 (1.2 equiv) in dry benzene
at 80 °C. b Yield refers to pure products after column chromatography.
Acknowledgment. T.R.S. thanks UGC and G.K.
thanks CSIR, New Delhi, for the award of fellowships.
good to excellent yields without the formation of azir-
idines (Table 2).
Supporting Information Available. Experimental de-
tails, characterization data of the products, copies of
1H and 13C NMR spectra of the products, and X-ray
crystallography data of 4q and 10e (CIF). This material
is available free of charge via the Internet at http://pubs.
acs.org
The structure of 10e was unambiguously determined
by single-crystal X-ray analysis (see the Supporting Infor-
mation). The reaction was assumed to proceed via forma-
tion of azomethine ylide from diazomalonate and ketimine.
The ylide is trapped with dimethyl acetylenedicarboxylate
via the Huisgen’s cycloaddition to produce the desired
spirooxindolyl pyrroline (Scheme 5).
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
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