α-arylation of 3-aryloxindoles

Article abstract of DOI:10.1021/ol100666v

A versatile method for the synthesis of 3,3-diaryloxindoles via Pd-catalyzed α-arylations or an S_NAr reaction is described. The reaction proceeds using mild base, is tolerant of a variety of functional groups, and is capable of preparing hinder

Full text of DOI:10.1021/ol100666v

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2306-2309
r-Arylation of 3-Aryloxindoles
Cheng-Kang Mai, Matthew F. Sammons, and Tarek Sammakia*
Department of Chemistry and Biochemistry, UniVersity of Colorado,
Boulder, Colorado 80309-0215
sammakia@colorado.edu
Received March 20, 2010
ABSTRACT
A versatile method for the synthesis of 3,3-diaryloxindoles via Pd-catalyzed r-arylations or an SNAr reaction is described. The reaction proceeds
using mild base, is tolerant of a variety of functional groups, and is capable of preparing hindered all-carbon quaternary centers.
The efficient construction of quaternary carbon centers
remains an important challenge for organic chemists,1 and
3,3-disubstitued oxindoles represent a structural motif found
in numerous biologically active natural products and a series
of pharmaceutically active compounds.2,3 Recently, several
methods for the synthesis of 3,3-disubstituted oxindoles have
been described;4 however, reports on the preparation of 3,3-
diaryloxindoles are rare. 3,3-Diaryloxindoles have been
prepared and studied as mineralocortocoid receptor
antagonists3a and anticancer agents,3b yet the structural
diversity of these compounds was limited by the available
methods for their synthesis (Scheme 1). Symmetrical 3,3-
Scheme 1. Friedel-Crafts Approach to 3,3-Diaryloxindoles
(1) Quaternary Stereocenters-Challenges and Solutions for Organic
Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, 2005.
(2) For current reviews of 3,3-disubstituted oxindole related natural
products, see : (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209–
2219. (b) May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262–5271. (c)
Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748–
8758. (d) Siengalewicz, P.; Gaich, T.; Mulzer, J. Angew. Chem., Int. Ed.
2008, 47, 8170–8176
.
diaryloxindoles were first prepared in 1885 by Baeyer and
Lazarus via the double electrophilic aromatic substitution of
isatin using electron-rich arenes and sulfuric acid.5 In 1998,
Olah and co-workers refined this method by using a
superacid, triflic acid, to synthesize symmetrical 3,3-diary-
loxindoles.6 Nicolaou used a related method to prepare
unsymmetrical 3,3-diaryloxindoles by subjecting 3-hydroxyl-
3-aryloxindoles to strong acids and N-protected tyrosine
derivatives.11a,b No other method for the synthesis of
unsymmetrical diaryloxindole derivatives has been disclosed,
and given that these are Friedel-Crafts alkylation reactions,
harsh conditions and electron-rich aromatic substrates are
(3) For biological active 3,3-diaryloxindoles, see: (a) Neel, D. A.; Brown,
M. L.; Lander, P. A.; Grese, T. A.; Defauw, J. M.; Doti, R. A.; Fields, T.;
Kelley, S. A.; Smith, S.; Zimmerman, K. M.; Steinberg, M. I.; Jadhav, P. K.
Bioorg. Med. Chem. Lett. 2005, 15, 2553–2557. (b) Uddin, M. K.; Reignier,
S. G.; Coulter, T.; Montalbetti, C.; Gra˚na¨s, C.; Butcher, S.; Krog-Jensen,
C.; Felding, J. Bioorg. Med. Chem. Lett. 2007, 17, 2854–2857
.
(4) For selected recent examples of the synthesis of 3,3-disubstitued
oxindoles, see : (a) Ku¨ndig, E. P.; Seidel, T. M.; Jia, Y.-X.; Bernardinelli,
G. Angew. Chem., Int. Ed. 2007, 46, 8484–8487. (b) Trost, B. M.; Zhang,
Y. J. Am. Chem. Soc. 2007, 129, 14548–14549. (c) Yasui, Y.; Kamisaki,
H.; Takemoto, Y. Org. Lett. 2008, 10, 3303–3306. (d) Tian, X.; Jiang, K.;
Peng, J.; Du, W.; Chen, Y.-C. Org. Lett. 2008, 10, 3583–3586. (e) Luan,
X.; Mariz, R.; Robert, C.; Gatti, M.; Blumentritt, S.; Linden, A.; Dorta, R.
Org. Lett. 2008, 10, 5569–5572. (f) Linton, E. C.; Kozlowski, M. C. J. Am.
Chem. Soc. 2008, 130, 16162–16163. (g) Duffey, T. A.; Shaw, S. A.; Vedejs,
E. J. Am. Chem. Soc. 2009, 131, 14–15. (h) Jia, Y.-X.; Ku¨ndig, E. P. Angew.
Chem., Int. Ed. 2009, 48, 1636–1639. (i) Chen, X.-H.; Wei, Q.; Luo, S.-
W.; Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 13819–13825. (j)
Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stoltz, B. M. Angew. Chem.,
Int. Ed. 2009, 48, 8037–8041. (k) Ackermann, L.; Vicente, R.; Hofmann,
N. Org. Lett. 2009, 11, 4274–4276.
(5) Baeyer, A.; Lazarus, M. J. Chem. Ber. 1885, 18, 2637–2643.
(6) Klumpp, D. A.; Yeung, K.; Prakash, G. K. S.; Olah, G. A. J. Org.
Chem. 1998, 63, 4481–4484.
10.1021/ol100666v  2010 American Chemical Society
Published on Web 04/28/2010

required. In addition, the regiochemical outcome is dictated
by the substrate, providing ortho-, para-products, and thereby
narrowing the scope of this method. These limitations as well
as our interest in the preparation of 3,3-diarlyoxidnole
substrates for the synthesis of natural products prompted us
to pursue a milder and more versatile method.
Table 1. Reaction Optimization
The transition-metal-catalyzed R-arylation of carbonyl
compounds has emerged as a powerful and versatile method.7
In 2007, Willis reported the first Pd-catalyzed R-arylation
of oxindoles.8 In 2008, Buchwald reported the Pd-catalyzed
R-arylation of 3-alkyloxindoles9 and, more recently, the
asymmetric version of this reaction.10 Herein, we describe
a general approach to the preparation of 3,3-diaryloxindoles
via R-arylation of 3-aryloxindoles under mild conditions with
or without Pd catalysis.
entry
1
conditions
R
yield (%)a
95
Pd(OAc)2, t-Bu3PHBF4,
Cs2CO3, toluene, 30 min
Pd(dba)2, t-Bu3PHBF4,
Cs2CO3, toluene, 30 min
Pd(dba)2, XPhos, Cs2CO3,
toluene, 3 h
Pd(dba)2, RuPhos, Cs2CO3,
toluene, 3 h
Pd(OAc)2, t-Bu3PHBF4,
K2CO3, toluene, 5 h
Pd(OAc)2, t-Bu3PHBF4,
Cs2CO3, DMF, 120 °C, 3 h
Pd(OAc)2, t-Bu3PHBF4,
Cs2CO3, toluene, 3.5 h
Pd(OAc)2, t-Bu3PHBF4,
Cs2CO3, dioxane, 18 h
Pd(OAc)2, t-Bu3PHBF4,
Cs2CO3, t-BuOH, 12 h
H
2
3
4
5
6
7
8
9
H
93
0
H
H
93
92
0
H
In the course of our studies on the synthesis of diazona-
mide A,11 we wished to examine the two disconnections
shown in Figure 1 (A and B) wherein the quaternary carbon
H
Me
Me
Me
80
10
0
a Isolated yield after flash chromatography.
to be superior to other solvents, such as DMF, 1,4-dioxane,
or tert-butanol (entries 6, 8, and 9).
With optimized conditions in hand, we studied the
substrate scope using compound 2 (Table 2). We find that
the reaction is compatible with a variety of substitution
Figure 1. Structure of diazonamide A and key disconnections.
Table 2. Arylation of N-Benzyl-3-phenyloxindole (2)
is prepared by the R-arylation of an oxindole enolate. These
disconnections require a method for the synthesis of 3,3-
diaryloxindoles, and given the facility of Pd-catalyzed
R-arylations, we expected this to be a viable method for this
transformation. We began with the R-arylation of N-benzyl-
3-phenyloxindole (2) with either bromobenzene or o-bro-
motoluene in order to study the viability and optimization
of this reaction (Table 1). We found using bromobenzene
that the best conditions were Pd(OAc)2 (5 mol %),
t-Bu3PHBF412 (10 mol %), and Cs2CO3 (3.0 equiv) in toluene
at reflux (entry 1).13 These are related to the conditions of
Hartwig, who has formed quaternary centers via the R-ary-
lation of dialkyl esters.14 Using these conditions o-bromo-
toluene also reacts to provide the product in 80% yield (entry
7). Pd(dba)2 can also be used and provides comparable yields
(entry 2); however, in later studies we found that the
dibenzylideneacetone byproduct at times co-elutes with our
product, thereby complicating purification. Other ligands
were less satisfactory; for example, XPhos (2-dicyclohexy-
lphosphino-2′,4′,6′-tri-isopropylbiphenyl) provides recovered
starting material (entry 3), while RuPhos (2-dicyclohexy-
lphosphino-2′,6′-diisopropoxybiphenyl) provides good yields
but is significantly slower (entry 4).15 Other carbonate bases,
such as K2CO3, also provide high yields but are slower (entry
5). A solvent survey was conducted, and toluene was found
a Isolated yield after flash chromatography. b After 2 h. c Pd(dba)2 was
used instead of Pd(OAc)2, which provided lower yield (53%). d After 20 h.
Org. Lett., Vol. 12, No. 10, 2010
2307

patterns and functional groups on the aryl bromide, including
electron-donating (methoxy, hydroxy, and amino groups) and
electron-withdrawing substituents (chloro, formyl, keto, and
trifluoromethyl groups). All are good partners in this reaction
and provide the products in excellent yields (entries 1-9).
In addition, due to the enhanced acidity of the oxindole, no
ketone arylation16 is observed with substrate 3 (entry 6).
Further, the use of the mild, reversible carbonate base renders
the reaction compatible with protic substituents, such as
phenol (entry 7) and aniline (entry 8) groups. The reaction
is also remarkably tolerant of steric hindrance in the aryl
bromide component; in addition to o-bromotoluene (Table
1, entry 7) and o-bromoanisole (entry 3), the highly hindered
di-ortho-substituted aryl bromide 4 also reacted cleanly to
provide the product in 64% yield (entry 10). This is in
contrast to other Pd-catalyzed enolate arylations wherein low
yields have been reported with ortho-substituted aryl ha-
lides.10,17
For highly electron-deficient aryl halides, arylations can
proceed without Pd catalysts via an SNAr mechanism (Table
4). Common SNAr substrates, such as 2,4-dinitrochloroben-
Table 4. Arylations without Pd-Catalyst
We then studied the effects of sterics in the enolate
component using the 3-ortho-substitued phenyloxindole
substrates 5 and 6 (Table 3). Both substrates were competent
Table 3. Arylation of 3-ortho-Substitued Pheyloxindoles (5 and
6)
a Isolated yield after flash chromatography. b Obtained as an ap-
proximately 1:1 mixture of diastereomers.
zene (entry 1) and p-nitrochlorobenzene (entry 2) react with
3-phenyloxindole (7)18 to cleanly provide the R-arylation
(7) For recent reviews of R-arylations, see: (a) Bellina, F.; Rossi, R.
Chem. ReV. 2010, 110, 1082–1146. (b) Johansson, C. C. C.; Colacot, T. J.
Angew. Chem., Int. Ed. 2010, 49, 676–707.
(8) Durbin, M. J.; Willis, M. C. Org. Lett. 2008, 10, 1413–1415.
(9) Altman, R. A.; Hyde, A. M.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 9613–9620.
(10) Taylor, A. M.; Altman, R. A.; Buchwald, S. L. J. Am, Chem. Soc.
2009, 131, 9900–9901.
(11) For the synthesis of diazonamide A, see: (a) Nicolaou, K. C.; Bella,
M.; Chen, D. Y.-K.; Huang, X.; Ling, T.; Snyder, S. A. Angew. Chem.,
Int. Ed. 2002, 41, 3495–3499. (b) Nicolaou, K. C.; Chen, D. Y.-K.; Huang,
X.; Ling, T.; Bella, M.; Snyder, S. A. J. Am. Chem. Soc. 2004, 126, 12888–
12896. (c) Nicolaou, K. C.; Rao, P. B.; Hao, J.; Reddy, M. V.; Rassias, G.;
Huang, X.; Chen, D. Y.-K.; Snyder, S. A. Angew. Chem., Int. Ed. 2003,
42, 1753–1758. (d) Nicolaou, K. C.; Hao, J.; Reddy, M. V.; Rao, P. B.;
Rassias, G.; Snyder, S. A.; Huang, X.; Chen, D. Y.-K.; Brenzovich, W. E.;
Giuseppone, N.; Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2004,
126, 12897–12906. (e) Burgett, A. W. G.; Li, Q.; Wei, Q.; Harran, P. G.
Angew. Chem., Int. Ed. 2003, 42, 4961–4966. (f) Cheung, C.-M.; Goldberg,
F. W.; Magnus, P.; Russell, C. J.; Turnbull, R.; Lynch, V. J. Am. Chem.
Soc. 2007, 129, 12320–12327. (g) Mai, C.-K.; Sammons, M. F.; Sammakia,
T. Angew. Chem., Int. Ed. 2010, 49, 2397–2400.
a Isolated yield after flash chromatography. b Pd(dba)2 (10 mol %),
t-Bu3PHBF4 (20 mol %), Cs2CO3 (3.0 equiv), toluene, sealed tube, 120 °C,
2 d. c 52% yield after 3 d when the title conditions were used. d 50% yield
after 3 d when the title conditions were used.
with meta- and para-substituted aryl bromides, providing the
products in good yields (entries 1-3, 5, and 6), although
long reaction times were required. No arylation products were
observed in the case of o-bromoanisole due to the extreme
steric hindrance at the transition state (entry 4).
(12) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295–4298.
2308
Org. Lett., Vol. 12, No. 10, 2010

products in excellent yields. Protection of the oxindole
nitrogen is not required for this reaction,19 and no N-arylation
is observed.20 More relevant to the synthesis of natural
products, such as diazonamide A, electron-deficient 5-ha-
looxazoles21 also provide the desired products in good yields
under these conditions (entries 3-7).
In conclusion, we have developed a versatile method to
prepare 3,3-diaryloxindoles via Pd-catalyzed R-arylation of
3-aryloxindoles or via nucleophilic aromatic substitution with
electron deficient aryl halides. The reaction proceeds using
mild base, is tolerant of a variety of functional groups, and
is capable of preparing hindered all-carbon quaternary
centers. The broad substrate scope and ability to form highly
hindered carbon-carbon bonds should render this method
applicable to the synthesis of natural products and other
biologically active compounds.
(13) The use of chlorobenzene in place of bromobenzene in our
optimized conditions provided the desired product in less than 5% yield.
The use of LHMDS in place of Cs2CO3 was not beneficial, even after 5 h.
In both these reactions, Pd black was observed, suggesting that no active
catalyst remained in solution.
(14) Jørgensen, M.; Lee, S.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F.
J. Am. Chem. Soc. 2002, 124, 12557–12565.
(15) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653–6655.
(16) For examples of R-arylations of ketones, see ref 7.
Acknowledgment. This work was supported by a gener-
ous grant from the National Institutes of Health (GM 48498).
(17) (a) Chieffi, A.; Kamikawa, K.; Åhman, J.; Fox, J. M.; Buchwald,
S. L. Org. Lett. 2001, 3, 1897–1900. (b) Hamada, T.; Chieffi, A.; Åhman,
J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261–1268. (c) Liao, X.;
Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195–200.
(18) For alkylation and acylation of 3-phenyloxindole (7), see: Bruce,
J. M.; Sutcliffe, F. K. J. Chem. Soc. 1957, 4789–4798.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) This reaction also proceeds with protected oxindoles. For an
example, see ref 11g.
OL100666V
(20) The Pd-catalyzed arylation of 7, the unprotected variant of 2, was
studied using bromobenzene (1.2 equiv) under our standard conditions
(Pd(OAc)2, 5 mol %; t-Bu3PHBF4, 10 mol %; Cs2CO3, 3.0 equiv; toluene
at reflux for 24 h; however, no product was observed and only recovered
7 was isolated. On the other hand, by using LHMDS (3.2 equiv) in place
of Cs2CO3 we were able to obtain the desired product in 61% yield along
with 31% recovered 7 after 12 h at reflux.
(21) For SNAr reactions of halo-oxazoles, see: Palmer, D. C.; Venkatra-
man, S. In The Chemistry of Heterocyclic Compounds, Oxazoles: Synthesis,
Reactions, and Spectroscopy: Part A.; Palmer, D. C., Ed.; John Wiley &
Sons, Inc.: Hoboken, NJ, 2003; Vol. 60, pp 138-149.
Org. Lett., Vol. 12, No. 10, 2010
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