Multicomponent reaction discovery: Three-component synthesis of spirooxindoles

Article abstract of DOI:10.1021/ol902764k

[Chemical equation presented] The Lewis acid-catalyzed, three-component reaction of isatin and two 1,3-dicarbonyl compounds is reported. Reactions proceed with high efficiency under mild reaction conditions and with good functional group tolerance to affo

Full text of DOI:10.1021/ol902764k

ORGANIC
LETTERS
2010
Vol. 12, No. 3
572-575
Multicomponent Reaction Discovery:
Three-Component Synthesis of
Spirooxindoles
Bo Liang, Srinivas Kalidindi, John A. Porco, Jr., and Corey R. J. Stephenson*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment (CMLD-BU), Boston UniVersity, Boston, Massachusetts 02215
crjsteph@bu.edu
Received November 30, 2009
ABSTRACT
The Lewis acid-catalyzed, three-component reaction of isatin and two 1,3-dicarbonyl compounds is reported. Reactions proceed with high
efficiency under mild reaction conditions and with good functional group tolerance to afford spirooxindole pyranochromenedione derivatives.
High-throughput screening is an efficient method for dis-
covery of new reactions and synthesis of complex chemo-
Scheme 1
.
Reactions of N-Methylisatin and Various
types.1 We have recently reported several novel Rh(I)-
catalyzed transformations identified using reaction screening
in which 1,3-dicarbonyl substrates exhibited diversified
reactivities as nucleophiles with electrophiles derived from
o-alkynylbenzaldehydes.2 To further explore modes of
reactivity of 1,3-dicarbonyl compounds under Rh(I) catalysis,
we have screened their reactions with a diverse set of
electrophiles. Our analysis led to the discovery of the
selective, catalyzed condensation of N-methylisatin 1 with
two molecules of 1,3-cyclohexanedione 2 to give spiroox-
indole3-5 pyranochromenedione 3 in 46% yield (Scheme 1).
1,3-Dicarbonyls
(1) For examples of new reaction development using high-throughput
screening, see: (a) Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 366.
(b) Kana, W. M.; Rosenman, M. M.; Sakurai, K.; Snyder, T. M.; Liu, D. R.
Nature 2004, 431, 545. (c) Miller, S. J. Nat. Biotechnol. 2004, 22, 1378.
(d) Ganem, B. Acc. Chem. Res. 2009, 42, 463.
Similarly, reaction of 4-hydroxy-6-methyl-2-pyrone 4 with
N-methylisatin 1 resulted in the production of condensation
product 5 in 36% yield (dr ) 5:1). The structure of 5 (major
(2) Beeler, A. B.; Su, S.; Singleton, C. A.; Porco, J. A., Jr. J. Am. Chem.
Soc. 2007, 129, 1413.
(3) For selected recent examples, see: (a) Castaldi, M. P.; Troast, D. M.;
Porco, J. A., Jr. Org. Lett. 2009, 11, 3362. (b) Zhang, Y.; Panek, J. S. Org.
Lett. 2009, 11, 3366. (c) Shintani, R.; Hayashi, S.-y.; Murakami, M.; Takeda,
M.; Hayashi, T. Org. Lett. 2009, 11, 3754.
(4) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
8748.
10.1021/ol902764k  2010 American Chemical Society
Published on Web 01/05/2010

diastereoisomer shown) was confirmed by X-ray crystal
structure analysis.6 Unexpectedly, when 1, 2, and 4 were
added in a ∼1:1:1 ratio in the presence of 10 mol % of
Rh(cod)2BF4 in Cl(CH2)2Cl at 60 °C, the three-component
coupling product 6 was obtained in 32% after 24 h.7 Only
trace amounts of 3 and 5 were detected along with recovered
starting materials. While we were delighted by the selectivity
of this three-component reaction, the reaction proceeded very
slowly. The isatin was only fully consumed after prolonged
reaction time (3 days) affording spirooxindole 6 in 78% yield.
To accelerate the three-component reaction, we next
examined additives including Ag(I) salts and observed a
significant rate acceleration. Upon further examination, we
discovered that the Rh(I) catalyst was not required when
AgBF4 was employed as the catalyst, the yield of 6 was
improved to 62% (Table 1, entry 2). Consequently, we
spirooxindoles using microwave irradiation. In the event,
irradiation of 1, 2, and 4 in DCE at 80 °C with 10 mol % of
SnCl4•5H2O as catalyst afforded an 80% yield of 6 in only 80
min (Table 2, entry 2). As a result of these studies, we examined
Table 2. Three-Component Reaction with Different Isatins
entry
R
R′ protocola
time
16 h
product yield (%)b
63
A
1
2
H
H
H
H
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
80 min
12 h
80 min
20 h
80 min
18 h
80 min
18 h
80 min
18 h
80 min
24 h
80 min
18 h
80 min
18 h
7
78
75
80
81
56
81
65
89
77
62
85
75c
52d
90
80
93
84
65
67
Me
Ph
6
3
8
Table 1. Optimization of Reaction Conditions for the Formation
of 6 from 1, 2, and 4
4
5-OMe Me
5-Me Me
5-NO2 Me
9
entrya
catalystb
time (h)
yield (%)c
5
10
11
12
13
14
15
1
2
3
4
5
6
Rh(cod)2BF4 (10 mol %)
AgBF4 (10 mol %)
(CuOTf)•C6H6 (10 mol %)
BF3•OEt2 (10 mol %)
TiCl4 (10 mol %)
24
24
24
24
24
12
32
62
38
65
61
76
6
7
4-Br
5-Br
6-Br
7-Br
Me
Me
Me
Me
SnCl4 (10 mol %)
8
a Conditions for formation: Cl(CH2)2Cl, 60 °C; 1 (1.0 equiv), 2 (1.1
equiv), 4 (1.1 equiv). b Three-component product is not observed in the
absence of catalyst, only 27 (Vide infra) is observed. c Yield (UPLC analysis)
using biphenyl as an internal standard.
9
80 min
18 h
80 min
10
a Protocol A: SnCl4 (10 mol %), Cl(CH2)2Cl, 60 °C. Protocol B:
SnCl4•5H2O (10 mol %), Cl(CH2)2Cl, µW, 80 °C. b Isolated yields of
compounds purified by chromatography on SiO2. c 20 mol % SnCl4 at 80
°C. d 20 mol % SnCl4•5H2O.
suspected that the reaction was operating under Lewis acid
catalysis. After screening numerous Lewis acids, we found
that SnCl4 provided the three-component product in good
8
yield after 12 h (Table 1, entry 6), while other catalysts
including CuOTf, BF3•Et2O, and TiCl4 gave low to moderate
yields (Table 1, entries 3-5).9 Other Sn(IV) catalysts and
desiccants (4 Å molecular sieves and MgSO4) did not
improve the overall efficiency of the transformation.
Subsequent experiments led to the finding that we could
further accelerate the three-component reaction to produce
the reaction with a broad range of substrates to determine the
reaction specificity and scope. Various substituted isatins were
reacted with 1,3-cyclohexanedione 2 and 4-hydroxy-6-methyl-
2-pyrone 4 under both thermal and microwave conditions (Table
2). From the results, it is evident that most of the reactions
provided the desired spirooxindole products in good to excellent
yields employing both electron-deficient (Table 2, entry 6) and
electron-rich (Table 2, entry 4) isatins as substrates. Bromo-
substitution on the isatin was tolerated including the sterically
demanding 4-bromo derivative. In addition, unprotected isatins
also participated in the reaction affording the desired coupling
product 7 in moderate yield (Table 2, entry 1).
We next examined a number of 1,3-dicarbonyl compounds
in the three-component reaction with N-methylisatin 1 and
4-hydroxy-6-methyl-2-pyrone 4. The results listed in Table 3
show that good to excellent yields of coupling products were
obtained under the optimized conditions using dimedone,
1,3-cyclopentanedione, 1,3-indanedione, and 1-oxaspiro[5.5]-
undecane-2,4-dione as coupling partners (Table 3, entries 1-5).
In addition, different 1,3-dicarbonyl reagents, a substituted
hydroxypyrone, and 4-hydroxycoumarin were reacted with
N-methylisatin 1 and 1,3-cyclohexanedione 2. Cyclic sub-
(5) Numerous biologically active natural products contain the spiroox-
indole moiety. For selected recent examples in total synthesis, see: (a)
Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc.
1998, 120, 6477. (b) Matsuura, T.; Overman, L. E.; Poon, D. J. J. Am.
Chem. Soc. 1998, 120, 6500. (c) Edmondson, S.; Danishefsky, S. J.; Sepp-
Lorenzinol, L.; Rosen, N. J. Am. Chem. Soc. 1999, 121, 2147. (d) Alper,
P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira, E. M. Angew. Chem.,
Int. Ed. 1999, 38, 3186. (e) Sebahar, P. R.; Williams, R. M. J. Am. Chem.
Soc. 2000, 122, 5666. (f) Onishi, T.; Sebahar, P. R.; Williams, R. M. Org.
Lett. 2003, 5, 3135. (g) Onishi, T.; Sebahar, P. R.; Williams, R. M.
Tetrahedron 2004, 60, 9503.
(6) See the Supporting Information for complete details.
(7) For the synthesis of spirooxindoles via three-component reactions,
see: (a) Zhu, S.; Ji, S.; Zhang, Y. Tetrahedron 2007, 63, 9365. (b) Elinson,
M. N.; Ilovaisky, A. I.; Dorofeev, A. S.; Merkulova, V. M.; Stepanov, N. O.;
Miloserdov, F. M.; Ogibin, Y. N.; Nikishin, G. I. Tetrahedron 2007, 63,
10543. (c) Jadidi, K.; Ghahremanzadeh, R.; Bazgir, A. J. Comb. Chem.
2009, 11, 341.
(8) Franz, A. K.; Dreyfuss, P. D.; Schreiber, S. L. J. Am. Chem. Soc.
2007, 129, 1020.
(9) We also examined a number of alternative solvents, however no
improvement over Cl(CH2)2Cl was observed.
Org. Lett., Vol. 12, No. 3, 2010
573

Table 3. Reaction of 4 with Different 1,3-Dicarbonyl Reagents
Table 4. Reaction of 2 with Different 1,3-Dicarbonyl Reagents
a Protocol A: SnCl4 (10 mol %), Cl(CH2)2Cl, 60 °C. Protocol B:
SnCl4•5H2O (10 mol %), Cl(CH2)2Cl, µW, 80 °C. b Isolated yields of
compounds purified by chromatography on SiO2. c 1,3-Indanedione (2.0
equiv). d See ref 10.
a Protocol A: SnCl4 (10 mol %), Cl(CH2)2Cl, 60 °C. Protocol B:
SnCl4•5H2O (10 mol %), Cl(CH2)2Cl, µW, 80 °C. b Isolated yields of
compounds purified by chromatography on SiO2. c One and a half
equivalents of each reagent was used. d Two equivalents of 1,3-dicarbonyl
reagent was used. e See ref 10. f Solvent: Cl(CH2)2Cl/1,4-dioxane, 3:1; 2.5
equiv 4-hydroxycoumarin. g Cu(OTf)2 (10 mol %) was used as catalyst.
strates afforded the desired spirooxindole products in moder-
ate to good yields (Table 4, entries 1-5). However, reaction
of 2,4-pentanedione catalyzed by SnCl4 (10 mol %) did not
result in formation of the desired product. When Cu(OTf)2
(10 mol %) was used as catalyst, product 26 was obtained
in 50% yield (Table 4, entry 6). The less reactive 4-hydroxy-
coumarin also gave a good yield of the three component
coupling product (Table 4, entry 5). However, when 5,5-
dimethyl-1,3-cyclohexanedione was reacted with N-meth-
ylisatin and 1,3-cyclohexanedione, the yield of the three-
component product was low (Table 4, entry 3), due to
increased production of the corresponding two-component
reaction product.6 The yield of the three-component product
was diminished when the 1,3-dicarbonyl compounds are
similar in pKa.11
furnish 31 (path A).14 Alternatively, the reaction may be initiated
by aldol reaction of 4 with 1 to afford 28, followed by
dehydration and nucleophilic attack of 2, to afford intermediate
31 (path B). Prior to addition of SnCl4, mixing of 1, 2, and 4
provided an equilibrium mixture of 1:27:28 (5:3:2). In addition,
in the absence of SnCl4, mixing 1 and 2 affords a 1:1
equilibrium mixture (1:27) while mixing 1 and 4 affords only
an 4:1 mixture (1:28).6 The position of the complex equilibrium
during the three-component reaction appears to be related to
the pKa of the corresponding dicarbonyl compounds such that
the aldol adduct of the weaker carbon acid is favored, thereby
biasing the reaction toward path A.15 In combination with the
enhanced nucleophilicity of the more acidic 1,3-dicarbonyl
compound (Vide infra), the three-component reaction pathway
On the basis of these results, we propose two plausible
pathways for the reaction (Scheme 2). N-Methylisatin 1 may
coordinate with SnCl48 and react with 2 to afford the aldol
adduct 27.12 Dehydration of 27 by SnCl4 affords indolenium
intermediate 2913 which may be subsequently attacked by 4 to
(10) Under the reaction conditions, decomposition of 1,3-indanedione is
competitive with the three-component coupling, presumably via self-condensa-
tion. The two-component product is not observed in appreciable quantities.
(11) We have characterized all byproducts for the reactions in Table 3
(entries 2 and 4), and Table 4 (entries 3 and 6). Two-component products
of 1,3-diketones (such as 2) are not observed, while the products incorporat-
ing two molecules of ꢀ-keto esters or hydroxypyrones were found as major
byproducts. See the Supporting Information for further details.
(12) The structure of 7 was confirmed by X-ray analysis of the
corresponding enol mesylate. See the Supporting Information for details.
(13) (a) England, D. B.; Merey, G.; Padwa, A. Org. Lett. 2007, 9, 3805.
(b) England, D. B.; Merey, G.; Padwa, A. Heterocycles 2007, 74, 491.
(14) The product of E1CB elimination of 27 (an isatylidene) cannot be
ruled out as a reaction intermediate. On the basis of non-bonding interactions
and angle strain involved in such an intermediate, we currently favor a
mechanism involving an indolenium intermediate.
574
Org. Lett., Vol. 12, No. 3, 2010

In addition, time course experiments indicate that intermediate
27 is formed as the primary product upon mixing 1, 2, and 4.6
Upon addition of SnCl4, disappearance of 27 corresponds to
the appearance of the three-component product 6. On the basis
of these results, in combination with the indolenium reactivity
profile (Scheme 3), we propose that Path A (Scheme 2) is the
major path for the formation of the three-component reaction
products such as 6. By monitoring the reaction using UPLC,
kinetic profiles of the model reaction were obtained and clearly
demonstrate the predominance of three-component product 6
compared to two-component products 3 and 5 throughout the
reaction (Figure 1).
Scheme 2. Proposed Mechanism
thus predominates. Nucleophilic addition of the hydroxyl group
of 31 to the adjacent carbonyl group, followed by dehydration
cata-
lyzed by SnCl4, would provide the desired coupling product 6.
To gain insight into the reaction pathways, we independently
prepared two of the proposed intermediates along the mecha-
nistic pathway. Intermediates 27 and 32 were independently
prepared and converted to 6 under the three-component coupling
conditions.6 In addition, compound 33, used as a model of 27,
was treated with 4 and 2 respectively under the three-component
reaction conditions (Scheme 3). The products of this reaction
Figure 1. Kinetic plot of the three-component reaction. UPLC yields
with biphenyl as internal standard (λ ) 254 nm).
Scheme 3. Reactions via an Indolenium Intermediate
In summary, using a reaction screening approach we have
identified the Lewis acid-catalyzed, three-component cou-
pling of substituted isatins and two pKa differentiated 1,3-
dicarbonyls to synthesize various spirooxindoles bearing a
pyranochromenedione ring system. Mechanistic studies
indicate the likely involvement of an indolenium ion derived
from the isatin and one 1,3-dicarbonyl component. Further
studies to intercept this intermediate are currently underway
and will be reported in due course.
Acknowledgment. Financial support from the NIGMS
(P50-GM067041) and partial funding from Merck for a post-
doctoral fellowship (S.K.) is gratefully acknowledged. NMR
(CHE-0619339) and MS (CHE-0443618) facilities at Boston
University are supported by the NSF. We thank Professor Aaron
Beeler (Boston University) and Professor Scott Schaus (Boston
University) for helpful discussions and Dr. Emil Lobkovsky
(Cornell University) for X-ray crystallographic analysis.
support the formation of indolenium intermediate 36 (similar
to the proposed intermediate 29 in Scheme 2). The reaction of
pyrone afforded the desired product 34 in good yield, while
cyclohexandione afforded only trace amounts of 35. These
results suggest that hydroxypyrone 4 is a much better nucleo-
phile for indolenium electrophiles such as 36 in comparison to
2. By analogy, indolenium ions formed in our three-component
reaction should react more quickly with 4 than 2.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) The experimentally measured pKa of 2 in DMSO is 10.3 (15a),15a
while the pKa of 4 in 80% DMSO/H2O is 6.83.15b (a) Arnett, E. M.;
Harrelson, J. A. J. Am. Chem. Soc. 1987, 109, 809. (b) Tan, S.-F.; Ang,
K.-P.; Jayachandran, H. J. Chem. Soc., Perkin Trans. 2 1983, 472.
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