Multicomponent reactions of diazoamides: Diastereoselective synthesis of mono- and bis-spirofurooxindoles

Article abstract of DOI:10.1021/jo0493119

This paper describes the intermolecular generation of carbonyl ylides by dirhodium(II) tetraacetatecatalyzed reaction of 3-diazoindol-2-ones in the presence of aryl aldehydes and heteroaryl aldehydes. These carbonyl ylides were subsequently trapped with dipolarophiles such as dimethyl acetylene- dicarboxylate, maleic anhydride, and ethyl acrylate to afford spirofurooxindoles. Consequently, diastereoselective synthesis of spirodihydrofurooxindoles through the multicomponent reactions of cyclic diazoamides was successfully achieved for the first time. The stereochemistry of the spirofurooxindole is unequivocally corroborated by the single-crystal X-ray analysis of the representative product 4o. Interestingly, these reactions were extended to double multicomponent reactions of bis-cyclic diazoamides to afford the respective complex polycycles in a tandem manner, which led to the construction of four carbon-carbon bonds, two carbon-oxygen bonds, and four chiral centers in a single synthetic step.

Full text of DOI:10.1021/jo0493119

Mu lticom p on en t Rea ction s of Dia zoa m id es: Dia ster eoselective
Syn th esis of Mon o- a n d Bis-sp ir ofu r ooxin d oles
Sengodagounder Muthusamy,*,† Chidambaram Gunanathan,† and Munirathinam Nethaji‡
Central Salt & Marine Chemicals Research Institute, Bhavnagar 364 002, India, and Department of
Inorganic & Physical Chemistry, Indian Institute of Science, Bangalore 560 012, India
salt@csir.res.in
Received April 25, 2004
This paper describes the intermolecular generation of carbonyl ylides by dirhodium(II) tetraacetate-
catalyzed reaction of 3-diazoindol-2-ones in the presence of aryl aldehydes and heteroaryl aldehydes.
These carbonyl ylides were subsequently trapped with dipolarophiles such as dimethyl acetylene-
dicarboxylate, maleic anhydride, and ethyl acrylate to afford spirofurooxindoles. Consequently,
diastereoselective synthesis of spirodihydrofurooxindoles through the multicomponent reactions
of cyclic diazoamides was successfully achieved for the first time. The stereochemistry of the
spirofurooxindole is unequivocally corroborated by the single-crystal X-ray analysis of the
representative product 4o. Interestingly, these reactions were extended to double multicomponent
reactions of bis-cyclic diazoamides to afford the respective complex polycycles in a tandem manner,
which led to the construction of four carbon-carbon bonds, two carbon-oxygen bonds, and four
chiral centers in a single synthetic step.
In tr od u ction
and natural product synthesis.4,5 Metallocarbenoids can
be generated from diazo carbonyl compounds that react
with a series of functional groups, whereby further
subsequent reactions can occur. Curtius synthesized the
diazo carbonyl compounds in 1883 for the first time.6
Despite the century-old invention and its synthetic
significance, examples of participation of diazo carbonyl
compounds in the MCRs is scarce.7-11 The intramolecular
generation of carbonyl ylides and their subsequent reac-
tions are studied well, which constituted an important
method for tetrahydrofuran systems and also applied for
the synthesis of many natural products.5 Contrarily, the
intermolecular formation of carbonyl ylides are always
considered to be synthetically unsuitable compared to
their intramolecular counterparts because of their low
selectivity and competitive reactions.5a The intermolecu-
lar carbonyl ylide formation was first reported7 by
Huisgen and de March in the reaction between diazo
The discovery of new reactions is a pivotal focal point
of research activity in organic chemistry. The continual
upsurge in molecular complexity and diversity in the
natural product systems urges chemist to increase tools
of their arsenal. Tandem1 and multicomponent reactions
are appropriate potential tools for synthetic chemists to
increase the efficacy, atom economy, selectivity, and
complexity in a particular process. The Strecker synthe-
sis2 of R-amino cyanides reported in 1850 was generally
construed as the first multicomponent reaction (MCR).
Multicomponent reactions3 are highly convergent reac-
tions that display enormous advantages over divergent
synthesis in terms of time, yield, and reproducibility.
R-Diazo carbonyl compounds find widespread applica-
tions in organic chemistry especially in tandem processes
* To whom correspondence should be addressed. Phone: +91-278-
2567760. Fax: +91-278-2567562.
† Central Salt & Marine Chemicals Research Institute.
(4) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds. From Cyclopropanes to
Ylides; Wiley-Interscience: New York, 1998.
(5) (a) Mehta, G.; Muthusamy, S. Tetrahedron 2002, 58, 9477-9504.
(b) Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Chem. Soc.
Rev. 2001, 30, 50-61. (c) Padwa, A.; Weingarten, M. D. Chem. Rev.
1996, 96, 223-269.
(6) (a) Curtius, T. Berichte 1883, 16, 2230-2231. (b) Curtius, T. J .
Prakt. Chem. 1888, 38, 396-440.
(7) (a) Huisgen, R.; de March, P. J . Am. Chem. Soc. 1982, 104, 4952.
(b) Huisgen, R.; de March, P. J . Am. Chem. Soc. 1982, 104, 4953-
4954.
(8) Alt, M.; Maas, G. Tetrahedron 1994, 50, 7435-7444.
(9) Doyle, M. P.; Forbes, D. C.; Protopopova, M. N.; Stanley, S. A.;
Vasbinder, M. M.; Xavier, K. R. J . Org. Chem. 1997, 62, 7210-7215.
(10) Skaggs, A. J .; Lin, E. Y.; J amison, T. F. Org. Lett. 2002, 4,
2277-2280.
(11) (a) Nair, V.; Mathai, S.; Nair, S. M.; Rath, N. P. Tetrahedron
Lett. 2003, 44, 8407-8409. (b) Nair, V.; Mathai, S.; Varma, R. L. J .
Org. Chem. 2004, 69, 1413-1414.
‡ Indian Institute of Science.
(1) (a) Ho, T. L. Tandem Organic Reactions; Wiley: New York, 1992.
(b) Nicolaou, K. C.; Montagnon, T.; Snyder, S. C. J . Chem. Soc., Chem.
Commun. 2003, 551-564. (c) Waldmann, H. Domino Reaction in
Organic Synthesis Highlight II; VCH: Weinheim, 1995; pp 193-202.
(d) Wender, P. A.; Eds.; Chem. Rev. 1996, 96, 1-600. (e) Tietze, L. F.;
Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131-163.
(2) Strecker, A. Liebigs Ann. Chem. 1850, 75, 27. However, Laurent
and Gerhardt isolated the poorly soluble “benzoyl azotide” from the
reaction of bitter almond oil and ammonia which is the result of a
multicomponent reaction. Laurent, A.; Gerhardt, G. F. Ann. Chim.
Phys. 1838, 66, 181.
(3) For reviews on multicomponent reactions, see: (a) Nair, V.;
Rajesh, R.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathen, J . S.;
Balagopal, L. Acc. Chem. Res. 2003, 36, 899-907. (b) Orru, R. V. A.;
de Greef, M. Synthesis 2003, 1471-1499. (c) Do¨mling, A.; Ugi, I. Angew.
Chem., Int. Ed. 2000, 39, 3168-3210. (d) Bienayme´, H.; Hukme, C.;
Oddon, G.; Schmitt, P. Chem. Eur. J . 2000, 6, 3321-3329. (e) Weber,
L.; Illgen, K.; Almstetter, M. Synlett 1999, 366-374.
10.1021/jo0493119 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/23/2004
J . Org. Chem. 2004, 69, 5631-5637
5631

Muthusamy et al.
SCHEME 1. Syn th esis of Di-/Tetr a h yd r ofu r a n s fr om Dia zo Com p ou n d s, Ald eh yd es, a n d Dip ola r op h iles
In volvin g th e In ter m olecu la r F or m a tion of Ca r bon yl Ylid es
70-80% yields) was substituted later by NaH/DMF,
which gives a better yield (method B, 80-95%). We
succeeded in the investigation of the reaction 3-diazo-1-
methyl-1,3-dihydro-2H-indol-2-one with benzaldehyde
and dimethyl acetylenedicarboxylate (DMAD) in the
presence of 0.5 mol % of rhodium(II) acetate at room
temperature. Diazoamide disappeared in just 30 min and
followed by the chromatographic purification of the
reaction mixture furnished the compound 4a in 62% yield
as single diastereomer.14 The FT-IR spectrum of com-
pound 4a exhibited a characteristic bands at 1663 and
1728 cm-1 indicating the presence of amide and ester
carbonyl functional groups, respectively. The 1H NMR
spectrum of product 4a exhibited three characteristic
singlets at δ 3.19, 3.61, and 3.68 for methyl groups and
a singlet resonance at δ 6.49 for the OCH proton. 13C
NMR and DEPT-135 spectral analyses of product 4a
showed peaks for two CH3 carbons, eight CH carbons,
and nine quaternary carbons. The characteristic spectral
data obviously confirmed the proposed structure of
compound 4a . The stereochemistry is tentatively as-
signed on the basis of the X-ray single-crystal analyses
of product 4o. Stimulated by this result, we ventured to
explore the reactions of several diazoamides that enabled
us to generalize this three-component synthesis of dihy-
drofurooxindoles 4b-k (Scheme 1). The unsubstituted
diazooxindole 1f exhibits a very slow reaction when
compared with substituted diazooxindoles resulting in
the product in low yield (entry 6, Table 1). The reason
may be the result of poisoning the catalyst by unsubsti-
tuted amide functionality.15,16 The presence of an electron-
donating group on aryl aldehydes enhances the yield of
spirodihydrofurooxindoles (entries 7-11, Table 1) when
compared to the unsubstituted aldehyde (entries 1-6,
Table 1). The substitution at the spirodihydrofurooxin-
doles 4 can widely be varied by employing the range of
diazoamides, aldehydes, and dipolarophiles.
F IGURE 1. Structure of cyclic diazoamides.
compound and benzaldehyde to undergo cycloaddition
with another benzaldehyde molecule (to produce diox-
olane) or an electron-deficient alkene (to produce a
tetrahydrofuran). The reported literature examples7-10
involving intermolecular formation of carbonyl ylides
generated usually from acyclic diazo acetates are il-
lustrated in Scheme 1. In this line, a synthesis of spiro-
dioxolanes and tetrahydrofurans has also recently ap-
peared.11 Occasionally, these reactions involving inter-
molecular carbonyl ylide formation are known to yield
dioxolane systems, which reduce the scope of this method.
The transition-metal-mediated multicomponent synthesis
of functionalized heterocyclic systems is rarely en-
countered.3b With a view to unveil the chemistry of diazo
carbonyl compounds12 particularly involving cyclic rhod-
ium carbenoids13 herein, we delineate the results of the
first multicomponent reactions of cyclic diazoamides
catalyzed by rhodium(II) acetate in a tandem manner.
Resu lts a n d Discu ssion
We planned in this study to utilize the cyclic diazoa-
mides 1, which are depicted in Figure 1. Two methods
were developed for the preparation of substituted 3-diazo-
1,3-dihydro-2H-indol-2-ones (1a -e). The initially adapted
method using 10% ethanolic KOH solution (method A,
(12) (a) Muthusamy, S.; Gunanathan. C. J . Chem. Soc., Chem.
Commun. 2003, 440-441. (b) Muthusamy, S.; Babu, S. A.; Gunan-
athan, C.; Ganguly, B.; Suresh, E.; Dastidar, P. J . Org. Chem. 2002,
67, 8019-8033. (c) Muthusamy, S.; Babu, S. A.; Gunanathan, C.;
Suresh, E.; Dastidar, P. Bull. Chem. Soc. J pn. 2002, 75, 801-811.
(13) (a) Muthusamy, S.; Gunanathan, C. Synlett 2003, 1559-1602.
(b) Muthusamy, S.; Gunanathan, C.; Babu, S. A.; Suresh, E.; Dastidar,
P. J . Chem. Soc., Chem. Commun. 2002, 824-825. (c) Muthusamy,
S.; Gunanathan. C. Synlett 2002, 1783-1786.
(14) No other isomeric products were detected by 1H and 13C NMR
analyses of the crude reaction mixture.
(15) Doyle, M. P. Chem. Rev. 1986, 86, 919-939.
(16) Similar trend was observed in our earlier studies of cyclopro-
panation and C-H insertion reactions using these cyclic diazoamides.
See ref 13.
5632 J . Org. Chem., Vol. 69, No. 17, 2004

Diastereoselective Synthesis of Spirofurooxindoles
TABLE 1. Syn th esis of Sp ir ofu r ooxin d oles fr om th e
Th r ee-Com p on en t Rea ction of Cyclic Dia zoa m id es,
Ald eh yd es, a n d DMAD
F IGURE 2. ORTEP diagram for the compound 4o. The ester
group methyl had a statistical disorder and was assigned 0.5
occupancy factor and refined. Thermal ellipsoids are drawn
at 50% probability.
entry
R1
CH3
Bn
p-xylenyl
allyl
propargyl
H
CH3
Bn
p-xylenyl
allyl
R2
reaction time product yield,a %
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
30 min
25 min
20 min
25 min
25 min
5 h
4a
4b
4c
4d
4e
4f
62
64
50
55
58
25
83
96
87
94
91
maiden study that utilizes the heteroaryl aldehyde for
the generation of intermolecular carbonyl ylides. The
reaction was also stretched to the indole-3-carbaldehyde19
(entries 5 and 6, Table 3) that led to the synthesis of
indole substituted dihydrofuran systems. The results of
these studies are illustrated in Table 3. The effort is also
invested to examine the course of the reaction with other
heterocyclic aldehydes such as 2-thiophenecarbaldehyde
and 3-pyridinecarbaldehyde, which failed to produce the
dihydrofurans in the presence of DMAD under identical
experimental conditions. The aliphatic aldehydes such
as n-butyraldehyde also failed to participate in this
multicomponent process.
OCH3
OCH3
OCH3
OCH3
10 min
15 min
10 min
20 min
25 min
4g
4h
4i
4j
4k
10
11
propargyl OCH3
a
Yields (unoptimized) refer to isolated and chromatographically
pure compounds.
The scope of this novel multicomponent reaction was
further enlarged employing different aromatic aldehydes
with multiple functionalities. Insertion with the O-H
functionality is a potentially competitive well-known
reaction17 in carbenoid chemistry. Notably, the hydroxy
functionality on aromatic aldehydes did not interfere with
the generated rhodium(II)-carbenoid intermediate in
these reactions. The potential applicability of this novel
three-component process is readily seen from the selected
examples of compounds 4l-q. The results of this study
are described in Table 2.
The stereochemistry at 2- and 5-positions of furan ring
system is obviously corroborated by performing the
single-crystal X-ray analysis18 of the representative
product 4o (Figure 2), which confirms the diastereo-
selectivity. The same stereochemistry is tentatively as-
signed for all other products. The presence of allyl,
propargyl, free amide, and hydroxyl functionalities in the
spirofurooxindoles should, in principle, allow us to further
functionalize these products by following the standard
procedures.
The multicomponent reaction of diazoamides can easily
be extended using electron deficient alkenes instead of
alkyne as dipolarophiles in the above process. Thus, the
reaction of diazoamide 1c and p-anisaldehyde in the
presence of maleic anhydride underwent [3 + 2]-cyclo-
addition with the transient intermolecular carbonyl ylide
dipoles to furnish the furofuran system 11 as single
isomer (Scheme 2). Interestingly, these furofuran systems
are present in a number of natural products such as
xanthoxylol, epipinoresinol, and epieudesmin, which
exhibit broad-ranging biological activities.20 Similarly, the
use of an unsymmetrical dipolarophile was also explored.
For example, the presence of ethyl acrylate in this process
afforded dihydrofurooxindoles 12 and 13 as a mixture of
regioisomers (Table 4). Elucidation of the structure of
isomers 12a ,b and 13a ,b was carried out on the basis of
the coupling constants of key proton signals in the 1H
NMR spectra.
The rapid generation of molecular complexity in a
controlled and predictable manner from simple and
readily available starting materials is a contemporary
theme in the practice of modern organic synthesis.
Complexity and brevity mostly rely on the coupling of
individual transformation into one synthetic process. In
this line, we speculated the use of appropriate bis-
diazoamide or bis-aldehyde would result in the creation
of complex molecules by doubling the efficiency the above
After performing the generation of intermolecular
carbonyl ylides with diverse aryl aldehydes, we decided
to extend this multicomponent reaction to the heteroaryl
aldehydes. The 2-furaldehyde was chosen as a benchmark
substrate for this study, which led to the concomitant
construction of the furofuranyl system, incorporating the
spirodihydrofuran ring. Significantly, this becomes the
(19) Kurihara, T.; Fujimoto, T.; Harusawa, S.; Yoneda, R. Synthesis
1987, 396-397.
(20) (a) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75-96. (b) Ward, R.
S. Nat. Prod. Rep. 1997, 14, 43-74. (c) Ward, R. S. Nat. Prod. Rep.
1995, 12, 183-205.
(17) Miller, D. J .; Moody, C. J . Tetrahedron 1995, 51, 10811-10843.
(18) Crystallographic data have been deposited with the Cambridge
Cryatallographic Data Center (CCDC-215094).
J . Org. Chem, Vol. 69, No. 17, 2004 5633

Muthusamy et al.
TABLE 2. Th r ee-Com p on en t Rea ction of Cyclic Dia zoa m id es w ith Va r iou s Ald eh yd es a n d DMAD
a
Yields (unoptimized) refer to isolated and chromatographically pure compounds.
process. The efficiency of this process is further extended
to demonstrate the double multicomponent process by
utilizing the bis-diazoamide 14 in a tandem manner. The
required 1,3-di[(3-diazo-1,3-dihydro-2H-indol-2-on-1-yl)-
methyl]benzene (14) was synthesized by the dialkylation
of 1,3-bis(bromomethyl)benzene with 3-diazo-1,3-dihydro-
2H-indol-2-one (1f). The bis-diazoamide 14 was reacted
with p-anisaldehyde or 1-pyrenecarbaldehyde to furnish
the respective interesting bis-spirocyclic system 15,16 in
the presence of an excess amount of DMAD and 1 mol %
of rhodium(II) acetate catalyst (Scheme 3). This reaction
efficiently resulted in formation of six chemical bonds and
two spiro-dihydrofuran units in a single operation. The
complex spiro-polycyclic systems are skillfully and pro-
ficiently synthesized from simple, readily available start-
ing materials in brevity.
(3-diazo-1,3-dihydro-2H-indol-2-on-1-yl)propane (17) was
subjected to the double multicomponent reaction with
1-allyl indol-3-carbaldehyde in the presence of DMAD to
afford the corresponding bis-spirofurooxindole 18 in 57%
yield (Scheme 4).
After exploring the double multicomponent reaction of
bis-diazoamides, we were interested in exploring the use
of bis-aryl aldehydes in this process. For this purpose,
bis-aldehydes 19a ,b with alkyl spacers were synthesized
from the reaction of corresponding dihaloalkanes with
4-hydroxybenzaldehyde. The reaction of bis-aldehydes
with an excess of diazoamide and DMAD in the presence
of a catalytic amount of Rh2(OAc)4 afforded the bis-
spirooxindoles 20-23 in good yields (Table 5). These
processes demonstrated prime examples for the multi-
step, one-pot operation of cyclic diazoamides and in turn
are equivalent to a five-component21 reaction.
The bis-diazoamide 17 with alkyl spacer was also
synthesized by the alkylation of 3-diazo-1,3-dihydroindol-
2-one with 1,3-dibromopropane in K2CO3/DMF. 1,3-Di-
In this operationally simple three-component process,
mechanistically, the rhodium(II) acetate catalyst reacted
5634 J . Org. Chem., Vol. 69, No. 17, 2004

Diastereoselective Synthesis of Spirofurooxindoles
TABLE 3. Mu lticom p on en t Rea ction s of Cyclic
Dia zoa m id es w ith Heter oa r yl Ald eh yd es a n d DMAD
in a diasteroselective manner. Moreover, similar types
of cyclic metallo-carbenoid intermediates always have a
propensity to undergo 1,3-dipolar cycloaddition reac-
tions,22,23 cyclopropanation,13a and C-H insertion13b,c
reactions. No formation of dioxolane compounds was
noticed in the above reactions with an excess amount of
aldehyde. Interestingly, these cyclic diazoamides have
recently been discovered24 to afford stereoselective ep-
oxide ring formation. Thus, the clean reaction obtained
is remarkable. To the best of our knowledge, this repre-
sents the first paradigm in which the cyclic rhodium
carbenoid generates the carbonyl ylides in an inter-
molecular fashion.
yield,a
%
Con clu sion
entry diazoamide
R1
CH3
Bn
allyl
propargyl furan-2-yl
CH3
allyl
Ar
product
1
2
3
4
5
6
1a
1b
1d
1e
1a
1d
furan-2-yl
furan-2-yl
furan-2-yl
5
6
7
8
9
10
68
81
80
57
68
75
In conclusion, the three-component reactions of cyclic
diazoamides involving rhodium(II) acetate catalyst are
described for the spirofuran synthesis incorporating the
oxindole unit. This method constitutes a distinct example
in which the cyclic diazoamides participate in the multi-
component reactions. The processes involving bis-diazo-
amides and bis-aldehydes lead to the simultaneous
creation of four carbon-carbon bonds, two carbon-
oxygen bonds, and four chiral centers in a single synthetic
step. The operational simplicity and high yields with
diastereoselectivity are salient features of this multistep,
one-pot process to synthesize the novel functionalized
heterocyclic compounds.
1-allylindol-3-yl
1-allylindol-3-yl
a
Yields (unoptimized) refer to isolated and chromatographically
pure compounds.
SCHEME 2. Mu lticom p on en t Rea ction s of 1c w ith
Ald eh yd e a n d Ma leic An h yd r id e
Exp er im en ta l Section
Due to a very long relaxation time, the resonance for the
carbon atom adjacent to the diazo functional group was usually
not detected in the 13C NMR analysis for the diazo compounds
prepared in this study.
Dim et h yl 1′-Met h yl-5-p h en yl-2′-oxo-1′,2′-d ih yd r o-5H -
sp ir o(fu r a n -2,3′-in d ole)-3,4-d ica r boxyla te (4a ). To a dry
CH2Cl2 (20 mL) solution of 3-diazo-1-methyl-1,3-dihydro-2H-
indol-2-one (1a , 250 mg, 1.45 mmol), benzaldehyde (306 mg,
2.89 mmol), and dimethyl acetylenedicarboxylate (246 mg, 1.73
mmol) was added rhodium(II) acetate dimer (3.2 mg, 0.5 mol
%) catalyst. The reaction mixture was stirred for 30 min, and
the chromatographic purification (hexane/EtOAc, 65:35) of the
residue afforded 352 mg (62%) of 4a as a yellow solid: mp
140-142 °C (hexane/EtOAc); IR (KBr) 3057, 2956, 1728, 1663,
1615, 1494, 1471, 1438, 1265, 1159, 1090, 1024, 738 cm-1; 1H
NMR (200 MHz, CDCl3) δ 3.19 (s, 3H), 3.57 (s, 3H), 3.68 (s,
3H), 6.49 (s, 1H), 6.82 (d, 1H, J ) 7.7 Hz), 7.08 (t, 1H, J ) 7.5
Hz), 7.30-7.48 (m, 7H); 13C NMR (50.3 MHz, CDCl3) δ 26.9
(CH3), 53.0 (CH3), 89.2 (CH), 90.6 (quat-C), 109.2 (CH), 123.7
(CH), 125.5 (CH), 127.2 (quat-C), 128.0 (CH), 129.3 (CH), 129.8
(CH), 131.6 (CH), 134.7 (quat-C), 137.8 (quat-C), 145.1 (quat-
C), 145.5 (quat-C), 161.6 (quat-C), 163.1 (quat-C), 174.0 (quat-
C); EIMS m/z 393 (M+, 36), 361 (53), 334 (38), 290 (16), 275
(23), 246 (16), 121 (18), 105 (100), 77 (30). Anal. Calcd for
with cyclic diazoamides to produce the respective cyclic
rhodium carbenoids, which underwent the intermolecular
reaction with an appropriate aldehyde to produce the
respective carbonyl ylide intermediates. From the ob-
served stereochemistry of the products, we propose the
selective formation of carbonyl ylide 24a rather than 24b
(Figure 3). The symbiotic steric interactions between the
amide oxygen and Ar group may shun the formation of
24b. Further, the rotamer (180° rotation around indolyl
carbon/carbonyl oxygen bond of aldehyde) that can arise
from the ylide 24a experiences the electrostatic repulsion
between the 4H-proton (indole numbering) of indole
moiety and aldehyde proton. Similarly, the rotamer of
the ylide 24b suffers from Ar-Ar steric hindrance. Thus,
the most favorable transient intermediate 24a stereo-
selectively underwent 1,3-dipolar cycloaddition reactions
with alkyne or alkenes to furnish the spiro-furooxindoles
C
22H19NO6: C, 67.17; H, 4.87; N, 3.56. Found: C, 67.36; H,
4.79; N, 3.49.
Com p ou n d 11. A mixture of 3-diazo-1-(4-methylbenzyl)-
1,3-dihydro-2H-indol-2-one (1c, 200 mg, 0.76 mmol), 4-meth-
oxybenzaldehyde (124 mg, 0.91 mmol), and maleic anhydride
(97 mg, 0.99 mmol) was allowed to react with rhodium(II)
(22) Pirrung, M. C.; Blume, F. J . Org. Chem. 1999, 64, 3642-3649.
(23) (a) Pirrung, M. C.; Lee, Y. R. J . Am. Chem. Soc. 1995, 117,
4814-4821. (b) Pirrung, M. C.; Lee, Y. R. J . Chem. Soc., Chem.
Commun. 1995, 673-674. (c) Pirrung, M. C.; Lackey, K.; Zhang, J .;
Sternbach, D. D.; Brown, F. J . Org. Chem. 1995, 60, 2112-2124.
(24) Muthusamy, S.; Gunanathan, C.; Nethaji, M. Synlett 2004,
639-642.
(21) For other five-components reactions, see: (a) J anvier, P.;
Bienayme´, H.; Zhu, J . Angew. Chem., Int. Ed. 2002, 41, 4291-4294.
(b) Ugi, I.; Steinbru¨ckner, C. Chem. Ber. 1961, 94, 2802-2814.
J . Org. Chem, Vol. 69, No. 17, 2004 5635

Muthusamy et al.
TABLE 4. Mu lticom p on en t Rea ction s of 1 w ith Ald eh yd es a n d Eth yl Acr yla te
ratio,b %
a /b
entry
diazoamide
aldehyde
R1
product
yield,a %
1
2
1c
1e
2-furaldehyde
4-CH3OC6H4CHO
p-xylenyl
propargyl
12
13
33
67
51:49
59:41
a
b
Yields (unoptimized) refer to isolated and chromatographically pure compounds. Determined from 1H NMR spectrum of the crude
reaction mixture.
SCHEME 3. Syn th esis of Bis-sp ir op olycyclic
System s via Dou ble Th r ee-Com p on en t Rea ction
SCHEME 4. Dou ble Th r ee-Com p on en t Rea ction of
Bis-d ia zoa m id e
TABLE 5. Dou ble Th r ee-Com p on en t Rea ction s Usin g
Bis-Ald eh yd es
acetate dimer (1.7 mg, 0.5 mol %) in dry CH2Cl2 for 30 min
under an argon atmosphere. Chromatographic purification
(hexane/EtOAc, 70:30) of the residue afforded 132 mg (37%)
of yellow solid: mp 172-174 °C (hexane/EtOAc); IR (KBr)
2940, 1782, 1704, 1615, 1516, 1490, 1468, 1375, 1255, 1176,
1045, 943, 914, 759 cm-1; H NMR (200 MHz, CDCl3) δ 2.31
1
entry
diazoamide
R1
n
product
yield, %
(s, 3H), 3.82 (s, 3H), 3.90 (d, 1H, J ) 8.6 Hz), 4.28 (t, 1H, J )
8.5 Hz), 4.78 (d, B part of AB system, 1H, J ) 15.6 Hz), 4.91
(d, A part of AB system, 1H, J ) 15.6 Hz), 6.29 (d, 1H, J ) 8.1
Hz), 6.79 (d, 1H, J ) 8.4 Hz), 6.93 (d, 2H, J ) 8.7 Hz), 7.10-
7.20 (m, 5H), 7.28-7.36 (m, 4H); 13C NMR (50.3 MHz, CDCl3)
δ 21.7 (CH3), 44.3 (CH2), 52.9 (CH), 55.9 (CH3), 82.0 (CH), 84.7
(quat-C), 110.6 (CH), 114.8 (CH), 122.8 (quat-C), 124.1 (CH),
127.2 (CH), 127.9 (CH), 128.2 (CH), 130.4 (CH), 130.9 (quat-
C), 132.2 (CH), 132.4 (quat-C), 138.5 (quat-C), 144.1 (quat-C),
160.8 (quat-C), 168.5 (quat-C), 168.9 (quat-C), 175.4 (quat-C);
MS (EI) m/z 470 (M+1, 4), 469 (M+, 11), 451 (11), 233 (19),
146 (21), 135 (100); HRMS (FAB) calcd for C28H24NO6 (MH+)
470.1604, found 470.1611.
1
2
3
4
1b
1d
1c
1d
Bn
0
0
1
1
20
21
22
23
72
83
76
75
allyl
p-xylenyl
allyl
mg, 0.57 mmol), 2-furaldehyde (109 mg, 1.14 mmol) and ethyl
acrylate (89 mg, 0.85 mmol) was allowed to react with
rhodium(II) acetate dimer (1.3 mg, 0.5 mol %) in dry CH2Cl2
for 45 min under an argon atmosphere. After removal of
solvent, the residue was purified by column chromatography
(hexane/EtOAc, 80:20) to give 42 mg (17%) of 12a and 39 mg
(16%) of 12b.
Syn th esis of com p ou n d s 12a a n d 12b. A mixture of
3-diazo-1-(4-methylbenzyl)-1,3-dihydro-2H-indol-2-one (1c, 150
5636 J . Org. Chem., Vol. 69, No. 17, 2004

Diastereoselective Synthesis of Spirofurooxindoles
solution of bis-diazoamide (14, 100 mg, 0.14 mmol), 4-meth-
oxybenzaldehyde (130 mg, 0.95 mmol), and dimethyl acetylene-
dicarboxylate (81 mg, 0.57 mmol) was added rhodium(II)
acetate dimer (1.1 mg, 1.0 mmol) catalyst. The reaction
mixture was stirred for 35 min, and the column chromato-
graphic (hexane/EtOAc, 50:50) purification of the residue
afforded 136 mg (62%) of 15 as an orange solid: mp 106-108
°C (hexane/CHCl3); IR (KBr) 3056, 2957, 1729, 1663, 1614,
1
1514, 1489, 1467, 1438, 1265, 1179, 1026, 906, 739 cm-1; H
F IGURE 3. Intermolecularly generated possible carbonyl
NMR (200 MHz, CDCl3) δ 3.53 (s, 6H), 3.72 (s, 6H), 3.81 (s,
6H), 4.68 (d, 1H, B part of AB system, J ) 15.7 Hz), 4.72 (d,
1H, B part of AB system, J ) 15.7 Hz), 5.06 (d, 1H, A part of
AB system, J ) 15.7 Hz), 5.10 (d, 1H, A part of AB system, J
) 15.7 Hz), 6.48 (s, 2H), 6.58 (t, 2H, J ) 7.0 Hz), 6.91-7.14
(m, 6H), 7.26-7.47 (m, 12H); 13C NMR (50.3 MHz, CDCl3) δ
44.5 (CH2), 53.1 (CH3), 53.2 (CH3), 55.9 (CH3), 89.0 (CH), 90.4
(quat-C), 110.4 (CH), 114.8 (CH), 123.9 (CH), 125.7 (CH), 127.3
(CH), 127.5 (quat-C), 129.7 (CH), 130.0 (CH), 130.3 (CH), 131.6
(CH), 134.5 (quat-C), 136.6 (quat-C), 138.9 (quat-C), 144.2
(quat-C), 146.0 (quat-C), 161.1 (quat-C), 161.8 (quat-C), 163.3
(quat-C), 174.4 (quat-C); HRMS (FAB) calcd for C52H45N2O14
(MH+) 921.2871, found 921.2859.
ylide intermediates.
Eth yl 1′-(4-m eth ylben zyl)-5-(fu r a n -2-yl)-2′-oxo-1′,2′-d i-
h yd r o-5H-sp ir o(3,4-d ih yd r ofu r a n -2,3′-in d ole)-4-ca r boxy-
la te (12a ): yellow solid; mp 58-60 °C (hexane/CHCl3); IR
(KBr) 2927, 1727, 1615, 1468, 1372, 1265, 1174, 908, 734 cm-1
;
1H NMR (200 MHz, CDCl3) δ 1.06 (t, 3H, J ) 7.1 Hz), 2.30 (s,
3H), 2.60 (1H, X part of ABX system, dd, J ) 13.2, 7.6 Hz),
3.05 (1H, B part of ABX system, dd, J ) 13.2, 10.4 Hz), 3.96
(q, 2H, J ) 7.2 Hz), 4.26-4.32 (m, 1H), 4.81 (s, 2H), 5.82 (d,
1H, J ) 8.9 Hz), 6.33-6.43 (m, 2H), 6.56-6.68 (m, 2H), 6.83-
6.91 (m, 1H), 7.01-7.25 (m, 4H), 7.45-7.69 (m, 2H); 13C NMR
(50.3 MHz, CDCl3) δ 14.7 (CH3), 21.8 (CH3), 37.7 (CH2), 44.0
(CH2), 48.4 (CH), 61.6 (CH2), 76.8 (CH), 83.9 (quat-C), 109.7
(CH), 110.0 (CH), 111.0 (CH), 124.0 (CH), 125.6 (CH), 127.3
(CH), 127.8 (CH), 128.1 (quat-C), 130.0 (CH), 130.2 (CH), 130.7
(CH), 133.1 (quat-C), 138.1 (quat-C), 143.4 (CH), 152.8 (quat-
C), 171.4 (quat-C), 178.2 (quat-C); HRMS (FAB) calcd for
1,3-Di[(5-(1-allylin dol-3-yl)-2′-oxo-1′,2′-dih ydr o-5H-spir o-
(fu r a n -2,3′-in d ole)-3,4-d ica r boxylic a cid d im eth yl ester )-
1′-yl]p r op a n e (18): brown solid; mp 102-104 °C (hexane/
CHCl3); IR (KBr) 3057, 2955, 1726, 1615, 1550, 1466, 1438,
1266, 1018, 738 cm-1; 1H NMR (200 MHz, CDCl3) δ 2.13 (t,
2H, J ) 6.8 Hz), 3.62 (s, 6H, CH3), 3.68 (s, 6H, CH3), 3.74-
3.81 (overlapping m, 4H), 4.72 (d, 4H, J ) 5.3 Hz), 5.04-5.24
(m, 4H), 5.92-6.06 (m, 2H), 6.85 (s, 2H), 6.87 (s, 2H), 6.97 (t,
2H, J ) 7.3 Hz), 7.13-7.34 (m, 12H), 7.81 (dd, 2H, J ) 6.4,
1.9 Hz); 13C NMR (50.3 MHz, CDCl3) δ 25.8 (CH2), 38.9 (CH2),
49.5 (CH2), 53.2 (CH3), 83.2 (CH), 90.0 (quat-C), 109.4 (CH),
110.6 (CH), 112.5 (quat-C), 118.2 (CH2), 120.1 (CH), 120.7
(CH), 122.9 (CH), 123.7 (CH), 125.9 (CH), 127.4 (quat-C), 128.0
(quat-C), 128.6 (CH), 131.5 (CH), 133.7 (CH), 134.2 (quat-C),
137.4 (quat-C), 144.2 (quat-C), 146.3 (quat-C), 161.8 (quat-C),
163.8 (quat-C), 174.6 (quat-C); HRMS (FAB) calcd for
C
26H26NO5 (MH+) 432.1811, found 432.1819.
Eth yl 1′-(4-m eth ylben zyl)-5-(fu r a n -2-yl)-2′-oxo-1′,2′-d i-
h yd r o-5H-sp ir o(3,4-d ih yd r ofu r a n -2,3′-in d ole)-3-ca r boxy-
la t e (12b): yellow solid; mp 74-76 °C (hexane/CH2Cl2); IR
(KBr) 2926, 1728, 1615, 1469, 1374, 1264, 1181, 1015, 909,
1
733 cm-1; H NMR (200 MHz, CDCl3) δ 0.53 (t, 3H, J ) 7.1
Hz), 2.30 (s, 3H), 2.57-2.69 (m, 1H), 3.10 (dd, 1H, J ) 24.1,
12.5 Hz), 3.59-3.79 (m, 2H), 3.93 (dd, 1H, J ) 12.5, 7.3 Hz),
4.70 (B part of AB system, 1H, J ) 15.5 Hz), 5.01 (A part of
AB system, 1H, J ) 15.5 Hz), 5.54 (dd, 1H, J ) 11.0, 4.9 Hz),
6.35 (dd, 1H, J ) 3.2, 1.8 Hz), 6.45 (d, 1H, J ) 2.9 Hz), 6.64
(d, 1H, J ) 7.6 Hz), 6.98-7.39 (m, 6H), 7.40-7.45 (m, 2H);
13C NMR (50.3 MHz, CDCl3) δ 13.9 (CH3), 21.7 (CH3), 33.9
(CH2), 44.5 (CH2), 53.2 (CH), 61.4 (CH2), 76.1 (CH), 83.9 (quat-
C), 109.8 (CH), 111.0 (CH), 123.7 (CH), 125.7 (CH), 128.0 (CH),
128.2 (quat-C), 130.0 (CH), 130.4 (quat-C), 130.7 (CH), 133.1
(quat-C), 138.0 (quat-C), 143.8 (CH), 152.3 (quat-C), 170.1
(quat-C), 177.3 (quat-C); HRMS (FAB) calcd for C26H26NO5
(MH+) 432.1811, found 432.1816.
C
55H49N4O12 (MH+) 957.3347, found 957.3357.
1,3-Di[4-(3,4-d im eth yl 1′-ben zyl-2′-oxo-1′,2′-d ih yd r o-5H-
sp ir o(fu r a n -2,3′-in d ole)-3,4-d ica r boxyla te)-5-p h en yloxy]-
p r op a n e (20): brown solid; mp 116-118 °C (hexane/CHCl3);
IR (KBr) 2953, 1728, 1613, 1512, 1490, 1467, 1436, 1248, 1176,
1020, 752 cm-1; 1H NMR (200 MHz, CDCl3) δ 2.26 (t, 2H, J )
5.9 Hz), 3.52 (s, 6H), 3.71 (s, 6H), 4.16 (t, 4H, J ) 5.9 Hz),
4.75 (d, B part of AB system, 2H, J ) 15.7 Hz), 5.05 (d, A part
of AB system, 2H, J ) 15.7 Hz), 6.48 (s, 2H), 6.69 (d, 2H, J )
7.7 Hz), 6.94 (d, 4H, J ) 8.5 Hz), 7.04 (t, 2H, J ) 7.5 Hz),
7.18-7.43 (m, 18H); 13C NMR (50.3 MHz, CDCl3) δ 29.9 (CH2),
44.7 (CH2), 53.1 (CH3), 53.2 (CH3), 65.2 (CH2), 89.0 (CH), 90.4
(quat-C), 110.3 (CH), 115.4 (CH), 123.9 (CH), 125.8 (CH), 127.6
(quat-C), 128.0 (CH), 128.3 (CH), 129.4 (CH), 129.8 (CH), 130.2
(quat-C), 131.6 (CH), 134.7 (quat-C), 136.1 (quat-C), 144.4
(quat-C), 146.1 (quat-C), 160.3 (quat-C), 161.7 (quat-C), 163.3
(quat-C), 174.4 (quat-C); HRMS (FAB) calcd for C59H51N2O14
(MH+) 1011.3340, found 1011.3356.
1,3-Di[(3-d ia zo-1,3-d ih yd r o-2H-in d ol-2-on -1-yl)m eth yl]-
ben zen e (14). To a 10% ethanolic KOH solution (20 mL) was
added 3-diazo-1,3-dihydro-2H-indol-2-one (1 g, 6.28 mmol) and
the resulting mixture stirred for 1 h. Then 1,3-bis(bromom-
ethyl)benzene (0.83 g, 3.14 mmol) was added to the above
reaction mixture at 0 °C. The reaction mixture was slowly
brought to the room temperature, a catalytic amount of
tetrabutylammonium iodide was added, and the mixture was
allowed to stir for 3 days. After that, the solvent was removed
under reduced pressure and the resulting residue poured into
ice-water. The aqueous solution was extracted with dichloro-
methane (3 × 30 mL). The combined organic layer was washed
with brine and dried with anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the emerging
residue chromatographed using silica gel column to yield 0.924
g (35%) of red solid: mp 146-148 °C; IR (KBr) 2924, 2096,
Ack n ow led gm en t. This research was supported by
Department of Science and Technology, New Delhi. We
are grateful to Professor W. Sander, Ru¨hr University,
Germany, for providing mass spectral analyses. We
thank Dr. P. K. Ghosh, Director, for his encouragement
of this work. C.G. thanks CSIR, New Delhi, for the
award of a Senior Research Fellowship.
1683, 1610, 1468, 1400, 1343, 1174, 1102, 747 cm-1. H NMR
1
(200 MHz, CDCl3) δ 4.96 (s, 4H), 6.68-6.72 (m, 2H), 7.01-
7.08 (m, 4H), 7.15-7.25 (m, 6H); 13C NMR (50.3 MHz, CDCl3)
δ 44.6 (CH2), 110.1 (CH), 117.2 (quat-C), 118.8 (CH), 122.7
(CH), 126.0 (CH), 126.6 (CH), 127.1 (CH), 129.9 (CH), 134.0
(quat-C), 137.2 (quat-C), 167.4 (quat-C). Anal. Calcd for
Su p p or tin g In for m a tion Ava ila ble: General informa-
tion, experimental procedures, and spectral data for all new
compounds. 1H, 13C, and DEPT-135 spectra of 4a -q, 5-13,
15, 16, 18, and 20-23, and X-ray structural data of compound
4o (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
C
24H16N6O2: C, 68.56; H, 3.84; N, 19.99. Found: C, 68.77; H,
3.91; N, 20.16.
1,3-Di[(5-(4-m et h oxyp h en yl)-2′-oxo-1′,2′-d ih yd r o-5H -
sp ir o(fu r a n -2,3′-in d ole)-3,4-d ica r boxylic a cid d im eth yl
ester )-1′-ylm eth yl]ben zen e (15). To a dry CH2Cl2 (20 mL)
J O0493119
J . Org. Chem, Vol. 69, No. 17, 2004 5637