Palladium-catalyzed tandem heck reaction/C-H functionalization - Preparation of spiro-indane-oxindoles

Article abstract of DOI:10.1002/anie.200800549

(Chemical Equation Presented) Tied up nicely: A novel tandem reaction involving an intramolecular Heck reaction with subsequent functionalization of an unactivated C-H bond to generate spiro-fused indane-oxindoles is described (see scheme; PMB = p-methoxybenzyl).

Full text of DOI:10.1002/anie.200800549

Angewandte
Chemie
DOI: 10.1002/anie.200800549
Synthetic Methods
À
Palladium-Catalyzed Tandem Heck Reaction/C H
Functionalization—Preparation of Spiro-Indane-Oxindoles
Rebecca T. Ruck,* Mark A. Huffman, Mary M. Kim, Michael Shevlin, Wynne V. Kandur, and
Ian W. Davies
The oxindole framework is a motif common to natural
products[1] and pharmaceutically active compounds.[2] In
particular, 3,3-disubstituted oxindoles have shown promising
biological activity.[1a,e] Considerable efforts have been dedi-
cated to developing new methods for the preparation of these
pharmacaphores, especially spiro-oxindoles: functionaliza-
tion of heterocycles,[3] variations of the Stolle reaction,[4]
À
Scheme 1. Heck/C H functionalization tandem reaction. PMB=p-
methoxybenzyl.
epoxide rearrangement,[5] Lewis acid promoted cyclization,[6]
Pummerer rearrangement,[7] and various palladium-catalyzed
methodologies.[8] Within that last category, the intramolecular
Heck reaction is of particular relevance here.[8e]
Although tremendous efforts have been invested in the
discovery of new palladium-catalyzed processes, there
remains limited overlap between two key transformations,
namely the Heck reaction[9] and the direct arylation reac-
tion,[10] which appear to be orthogonal methodologies. Most
relevant examples of reaction commonality entail carbopal-
ladation to form a vinylpalladium intermediate and subse-
[11]
À
quent C H functionalization.
The two examples that
proceed by olefin insertion to form an alkylpalladium
À
intermediate undergo C H insertion to form a cyclobutane
product after reductive elimination.[12] Of particular relevance
to this work is the report from Grigg et al. on a Heck reaction
that forms an alkylpalladium complex and then undergoes a
heteroatom-directed arylation reaction to make a five-
membered ring.[13] Herein we report an efficient preparation
of spiro-fused indane-oxindoles by carbopalladation to form
an alkylpalladium intermediate and subsequent functionali-
À
zation of an unactivated aryl C H bond. (Scheme 1).
To investigate the viability of a tandem Heck/arylation
reaction sequence, we prepared N-(2-bromophenyl)acryla-
mides (5a–h) in a five-step sequence from 2-bromoaniline (1)
(Scheme 2). Reductive amination between p-anisaldehyde
Scheme 2. N-(2-bromophenyl)acrylamide synthesis. TFA=trifluoroace-
tic acid; MSA=methanesulfonic acid.
and 2-bromoaniline afforded PMB-protected aniline
2
(PMB = p-methoxybenzyl).[14] Amide bond formation
between compound 2 and potassium mono-methyl malonate
provided malonamic acid methyl ester 3, which was alkylated
with the requisite substituted benzyl bromide to afford
alkylation products 4a–h. Hydrolysis of the methyl ester,
and treatment of the liberated carboxylic acid with diethyl-
amine and paraformaldehyde, furnished acrylamides 5a–h in
good yields.
Initial efforts to effect the desired transformation from
compound 5a to 6a employed the catalytic system reported
by Fagnou and co-workers: Pd(OAc)2 (10 mol%), PtBu3-
HBF4 (20 mol%), and K2CO3 in DMA at 1308C.[15,17] Gratify-
ingly, spiro-fused indane-oxindole 6a was observed under
these conditions. A second product (7; see Scheme 4),
assigned as the product formed by a reductive Heck reaction,
was also observed in the complex reaction mixture.[16] A series
of palladium sources and ligands was screened in an effort to
develop a cleaner reaction. Decreasing the catalyst loading in
[*] Dr. R. T. Ruck, Dr. M. A. Huffman, M. M. Kim, M. Shevlin,
W. V. Kandur, Dr. I. W. Davies
Department of Process Research
Merck Research Laboratories
Merck & Co., Inc.
P.O. Box 2000, Rahway, NJ 07065 (USA)
Fax : (+1)732-594-5170
E-mail: rebecca_ruck@merck.com
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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the original Pd(OAc)2/PtBu3 system led to incomplete reac-
functionalization of the less sterically hindered para-C H
bond (with respect to the methyl group) was preferred over
tion. Pd(OAc)2 alone was sufficient to catalyze the trans-
formation, but reaction progress again stalled at less than
100% conversion of the starting material. Catalysis by
PdCl2(dppf) (dppf = 1,1’-bis(diphenylphosphanyl)ferrocene)
increased the reaction rate, but led to the formation of
more reductive Heck product 7. [Pd(PPh3)2Cl2] emerged as
the catalyst that offered the optimal balance of reaction rate
À
the ortho-C H bond by a ratio of 3:1 (Table 1, entry 3). When
the steric bulk of the 3-substituent was increased by using a
tert-butoxy group, C H functionalization occurred almost
À
exclusively at the para position (Table 1, entry 5).
À
A proposed catalytic cycle for the tandem Heck/C H
functionalization reaction is shown in Scheme 3. In this
mechanism, the palladium–ligand complex undergoes oxida-
À
and selectivity for C H functionalization over a reductive
Heck reaction. As a base, Cs2CO3 provided a cleaner reaction
profile than K2CO3 or K3PO4. The reaction in DMF at 1108C
was equivalent to that in DMA, and superior to the reaction
in less polar solvents. The optimal reaction conditions were
determined to be [Pd(PPh3)2Cl2] (2 mol%) and Cs2CO3
(2.5 equiv) in DMF at 1108C.
À
The tandem Heck/C H functionalization reaction
afforded spiro-fused indane-oxindoles 6a–i in excellent
yields, ranging from 64 to 91%. The transformation was
effective over a range of electronic properties on the phenyl
À
ring to be C H functionalized, from electron-donating
(Table 1, entries 4 and 5) to electron-deficient (Table 1,
À
Table 1: Substrate scope of tandem Heck/C H functionalization.
Entry SMX (SM)
Y
Product
X (Product)
Yield [%]
1
2
3
4
5
6
7
8
9
5a 4-CH3
H
H
H
H
H
H
H
H
6a
6b
4-CH3
2-CH3
90
91
5b 2-CH3
5c 3-CH3
5d 4-OCH3
5e 3-OtBu
6a and 6b 4-CH3:2-CH3
6d 4-OCH3
6e and 6e’ 4-OtBu: 2-OtBu 80 (>50:1)[b]
6 f
6g
6h
75 (3:1)[a]
À
Scheme 3. Proposed Heck/C H functionalization catalytic cycle.
87
5 f
H
H
4-F
4-Cl
4-CH3
65
84
64
82
tive addition to the carbon–bromine bond of acrylamide 5a to
form intermediate 8. The intramolecular Heck insertion
proceeds by a 5-exo-trig cyclization to form primary alkyl-
5g 4-F
5h 4-Cl
5i 4-CH3
CH3 6i
À
palladium species 9. Reaction at the highlighted C H bond
[a] Combined yield for 6a and 6b. Ratio in parentheses represents the
ratio of 6a:6b. [b]The yield is for the major regioisomer 6e; 6e’ was
assigned based on LC/MS analysis. SM=starting material.
affords six-membered palladacycle 10,[18] and subsequent
reductive elimination provides spiro-fused indane-oxindole
6a.
Overman and others have reported many examples of
asymmetric Heck reactions to generate 3,3-disubstituted
oxindoles in moderate to high enantioselectivities.[19]
Unfortunately, considerable ligand screening has failed to
identify an enantioselective variant of our tandem trans-
formation, a reaction sequence with an analogous enantio-
determining step. These negative results may be explained by
entries 7 and 8).[17] Substitution at the 2-, 3-, and 4-positions
of the phenyl ring in the starting material was tolerated in this
system, and afforded products that have been defined as 2- or
4-substituted in the product. The reaction rate was fastest in
the case of ortho substitution (Table 1, entry 2), a surprising
observation given that this substrate has the kinetic disad-
À
vantage of only one ortho-C H bond that may be function-
alized, whereas the 3- and 4-substituted substrates have two
two proposals. First, there is a fast and reversible olefin
[20]
À
insertion with a subsequent, slow C H insertion. In this
À
available ortho-C H bonds. In the case of the 3-substituted
starting material, functionalization can occur at either of the
way, facial selectivity may exist for the initial insertion to
generate intermediate 9, but, in a Curtin–Hammett situation,
À
À
two ortho-C H bonds to give two distinct products; these
there is a minimal preference for C H functionalization to
products correspond to the products obtained from the 4-
substituted or the 2-substituted starting material. The ratio of
these two products was governed by the size of the 3-
substituent. In the case of the relatively small methyl group,
occur from either of the two diastereomers of 9.[21] Olefin
insertion was shown to be fast by running the reaction under
reductive Heck conditions,[22] with 100% conversion into
compound 7 achieved in less than one hour (Scheme 4). If b-
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1994, 50, 359.
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[15] For a recent report on intramolecular alkane activation, see: M.
Lafrance, S. I. Gorelsky, K. Fagnou, J. Am. Chem. Soc. 2007, 129,
14570.
hydride elimination is fast and olefin insertion is rate-
determining in a standard Heck reaction, this change in
À
mechanism with reversible C C bond formation would
explain the lack of enantioselectivity.
The olefin substitution pattern for the tandem Heck/C-H
functionalization may also explain the failed asymmetric
variant. The 1,1-disubstituted olefin employed in this chemis-
try cannot participate in the standard enantioselective Heck
reaction, which requires a 1,1,2-trisubstituted olefin. In this
case, the absence of substitution at the b position of the olefin
may prevent enantiofacial discrimination by the catalyst.[23]
Indeed, the reductive Heck reaction above also provided
compound 7 in 0% ee, when the catalyst was modified to
[((S)-binap)PdCl2]
(binap = 2,2’-bis(diphenylphosphanyl)-
1,1’-binaphthyl),[24] a catalyst commonly employed in asym-
metric intramolecular Heck reactions.[19]
In conclusion, we have developed a novel tandem Heck/
À
C H functionalization reaction to generate spiro-fused
indane-oxindoles in high yields. The reaction employs only
2 mol% of a commercially available palladium catalyst to
effect a 5-exo-trig Heck cyclization with subsequent function-
À
alization of an unactivated C H bond. Efforts are ongoing to
discover a chiral ligand that may facilitate the development of
À
an asymmetric variant of the tandem Heck/C H functional-
ization reaction.
Experimental Section
Spiro-fused indane-oxindole 6a: A 10 mL round-bottom flask was
charged with 4-methylacrylamide 5a (450 mg, 1.0 mmol), [Pd-
(PPh3)2Cl2] (14 mg, 0.020 mmol) and Cs2CO3 (815 mg, 2.5 mmol).
The flask was purged with nitrogen. DMF (4 mL) was then added by
syringe and the mixture was sparged with nitrogen. The reaction
mixture was heated in an oil bath at 1108C for 24 h and then cooled to
room temperature. Ethyl acetate (20 mL) and water (12 mL) were
added and the reaction mixture was filtered to remove palladium. The
two layers were separated and the organic layer was washed two times
with water. The ethyl acetate layer was dried over Na2SO4 and
evaporated under reduced pressure. Silica gel chromatography (35%
ethyl acetate/hexane) afforded spiro-fused indane-oxindole 6a
(341 mg, contaminated with 3% reductive Heck byproduct 7,[14]
90% yield corrected for purity). The mixture was recrystallized
from MTBE/heptane (MTBE = methyl tert-butyl ether) to isolate an
analytically pure sample.
[16] Even under optimized conditions, 3–5% of reductive Heck
product was observed. The identity of this product was
confirmed by an independent synthesis.
[17] Acrylamides with 4-NO2 or 4-CN groups were unstable to the
basic conditions at 1108C.
[18] For a recent report on intramolecular alkane activation, see: M.
Lafrance, S. I. Gorelsky, K. Fagnou, J. Am. Chem. Soc. 2007, 129,
14570.
Received: February 1, 2008
Revised: April 7, 2008
Published online: May 19, 2008
À
Keywords: C H activation · Heck reaction · oxindoles ·
palladium
[19] a) P. J. Guiry, D. Kiely, Curr. Org. Chem. 2004, 8, 781; b) A. B.
Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945.
.
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[20] Palladium-catalyzed C C bond cleavage is known: a) S. Matsu-
mura, Y. Maeda, T. Nishimura, S. Uemura, J. Am. Chem. Soc.
2003, 125, 8862; b) X. Wang, S. Z. Stankovich, R. A. Widenhoe-
fer, Organometallics 2002, 21, 901; c) J. Cꢀmpora, E. Gutiꢁrrez-
Puebla, J. A. Lꢂpez, A. Monge, P. Palma, D. del Rꢃo, E.
Carmona, Angew. Chem. 2001, 113, 3753; Angew. Chem. Int.
Ed. 2001, 40, 3641; d) M. Catellani, F. Frignani, A. Rangoni,
Angew. Chem. 1997, 109, 142; Angew. Chem. Int. Ed. Engl. 1997,
36, 119.
[22] Reaction conditions were identical to those employed for the
À
Heck/C H functionalization sequence, except for the addition
of five equivalents of ammonium formate. See the Supporting
Information for more details.
[23] Olefin stereochemistry has been shown to be important in
asymmetric Heck reactions: a) reference [18b]; b) A. B.
Machotta, B. F. Straub, M. Oestreich, J. Am. Chem. Soc. 2007,
129, 13455.
[24] Few asymmetric reductive Heck reactions are known: a) A.
Minatti, X. Zheng, S. L. Buchwald, J. Org. Chem. 2007, 72, 9253;
b) J. C. Namyslo, D. E. Kaufmann, Synlett 1999, 804.
[21] C. R. Landis, J. Halpern, J. Am. Chem. Soc. 1987, 109, 1746.
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