Enantioselective synthesis of 2-methyl indolines by palladium catalysed asymmetric C(sp3)-H activation/cyclisation

Article abstract of DOI:10.1039/c1cc14292e

The first example of the enantioselective methyl C-H activation by an intramolecular ArPdX species and subsequent cyclisation was developed. Palladium catalysts using commercially available chiral diphosphines yield good ee's (up to 93% ee) in the synthesis of 2-methyl indolines from 2-halo N-isopropyl anilides. This approach was also employed for the synthesis of enantioenriched cyclohexyl fused indolines with moderate enantioselectivities.

Full text of DOI:10.1039/c1cc14292e

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COMMUNICATION
Enantioselective synthesis of 2-methyl indolines by palladium catalysed
asymmetric C(sp3)–H activation/cyclisationw
a
Saithalavi Anas,z Alex Cordib and Henri B. Kagan*a
Received 16th July 2011, Accepted 3rd September 2011
DOI: 10.1039/c1cc14292e
The first example of the enantioselective methyl C–H activation
by an intramolecular ArPdX species and subsequent cyclisation
was developed. Palladium catalysts using commercially available
chiral diphosphines yield good ee’s (up to 93% ee) in the synthesis
of 2-methyl indolines from 2-halo N-isopropyl anilides. This
approach was also employed for the synthesis of enantioenriched
cyclohexyl fused indolines with moderate enantioselectivities.
Chiral 2-substituted indolines are common structural subunits
found in numerous natural products and biologically active
Scheme 1 Enantioselective intermolecular methyl C–H activation.
compounds.1 The various routes for the synthesis of this class
of compounds have been recently summarized.2 The general
The enantioselective version of such palladium catalysed
alkyl C–H activation processes was unknown when we started
our investigation. However, the asymmetric transformations
involving the insertion of metal bound carbenes/nitrenes into
C(sp3)–H bonds have been well documented.10 In 2008, Yu
et al. described the first example of the palladium catalysed
asymmetric C(sp3)–H activation involving the methyl group of
2-propylpyridine to yield the butylated product in 37% ee
(Scheme 1, eqn (1)).11 Recently, Baudoin and co-workers
reported a Pd(0) catalysed asymmetric b-arylation of methyl
C–H bonds of carboxylic esters with aryl halides in the
presence of a chiral ligand related to davephos (Scheme 1,
eqn (2)).12
and effective methods for the catalytic asymmetric synthesis of
2-substituted indolines are rare, and mainly used the asymmetric
hydrogenation of 2-alkyl indoles3 as well as the intramolecular
amination reactions.4 We wish to describe a new approach
where a chiral palladium catalyst controls the enantioselective
C(sp3)–H activation of a methyl group and a subsequent aryl
cyclisation.
Among the various classes of palladium catalysed C–H
activation reactions,5 the transformation of C(sp3)–H bonds
has received significant attention in past several years.6 In this
context, Ohno et al. recently described an interesting strategy
towards the synthesis of an indoline skeleton via a palladium
catalysed C(sp3)–H bond activation and subsequent cyclisation
in the presence of caesium carbonate as a base and pivalic acid
as an additive.7 It was discussed earlier by Fagnou et al. who
proposed that coordinated pivalic acid is involved in the key
step for the removal of hydrogen from the methyl group in a
similar class of reactions.8 More studies were reported on
related processes depicting various kinds of intramolecular
cyclisation reactions on substrates devoid of nitrogen in the
absence of pivalic acid.9
To the best of our knowledge, there are no reports available on
the enantioselective methyl C–H activation by an intramolecular
ArPdX species. While preparing this manuscript, Kundig et al.
reported an interesting palladium catalysed asymmetric
activation of methylene C(sp3)–H bonds for the synthesis of
fused indolines by using chiral NHC ligands.13 The main
hurdle associated with palladium catalysed C(sp3)–H activation
processes is the relatively high reaction temperature under
which most of the chiral ligands fail to promote the favored
reaction pathway.6b Herein we report a palladium catalysed
intramolecular enantioselective activation of methyl C–H
bonds using commercially available chiral diphosphines leading
to the synthesis of chiral 2-methyl indolines (Scheme 2).
We started our experiments with the synthesis of rac-2-methyl
indoline 2a from 1a as described by Ohno et al. using PCyꢀ
HBF4 as the achiral ligand.7 Then the attempts for asymmetric
cyclisations were performed using a number of chiral ligands
and the initial trials delivered slight enantioselectivities.14 We
were delighted to observe a significant enantiomeric excess in
some cyclisations using chiral diphosphines (S,S)-DIOP and
a
´
´
Institut de Chimie Moleculaire et des Materiaux d’Orsay
´
´
(UMR 8182, CNRS), Laboratoire de Catalyse Moleculaire, Universite
Paris-Sud, 91405 Orsay, France. E-mail: henri.kagan@u-psud.fr;
Fax: +33 169154680; Tel: +33 169157895
b COrdi CONseils sprl, 8 bis rue Ledru Rollin, 92150 Suresnes, France.
E-mail: alex.cordi@sfr.fr
w Electronic supplementary information (ESI) available: Experimental
details, optimization studies and characterization of all new
compounds. See DOI: 10.1039/c1cc14292e
z Present address: School of Chemical Sciences, Mahatma Gandhi
University, Kottayam, Kerala, India. Tel: +91 4812731036; E-mail:
anastvr@gmail.com.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11483–11485 11483

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Scheme 3 Synthesis of (S)-2-methyl indolines.16
Table 2 Asymmetric cyclisation of various substratesa
Scheme 2 Enantioselective intramolecular methyl C–H activation.
Table 1 Screening studies on 1a as a substrate with various Pd
catalysts/ligands/basesa
Time/
h
Entry Substrate
Product
Yield%b eec (%)
Entry Catalyst Ligand (L*)
Base
Yield%b eeb (%)
1
2
3
4
1a XQBr, RQCO2Me
1b XQl, RQCO2Me
1c XQCI, RQCO2Me 16
2
4
(S)-2a
(S)-2a
(S)-2a
(S)-2b
97
82
nrd
80
93
90
—
55
1
2
3
4
5
6
7
8
9
10
Pd2(dba)3 (R,R)-DIOP
Pd2(dba)3 (S,S)-Me-DUPHOS Cs2CO3 80
Pd(OAc)2 (S,S)-DIOP
Pd(OAc)2 (R,R)-DIOP
Pd(OAc)2 (R,R)-Me-DUPHOS Cs2CO3 4 99
Pd(OAc)2 (S,S)-Me-DUPHOS Cs2CO3 4 99
Pd(Oac)2 (R,R)-Me-DUPHOS Et3N
Pd(OAc)2 (R,R)-Me-DUPHOS K2CO3 61
Cs2CO3 4 99
47
84
48
44c
93
93c
80
58
i
1d XQBr, RQCO2 Bu
2
Cs2CO3 4 99
Cs2CO3 97
5
6
3
65
23
6
Pd(OAc)2 (R,R)-Me-DUPHOS Na2CO3 No reaction
6
Pd(OAc)2 (R,R)-Me-DUPHOS Cs2CO3
90d
3
84
85
—
a
b
Procedure: ref. 15 Determined by HPLC analysis. Enantioselectivity
c
d
reversed. ln toluene at 100 1C.
7
16
nrd
(R,R)-Me-DUPHOS. However the lack of reproducibility of
these results prompted us for further optimization studies with
Pd(OAc)2/DIOP or Me-DUPHOS combination. After a series
of experiments14 we found effective conditions for the
enantioselective methyl C–H activation and cyclisation.
During our studies, it was observed that argon is not necessary
for this reaction. Using this modified procedure,15 the reaction
of 1a was repeated with various catalysts, ligands and bases.
These results are summarized in Table 1. Best results were
obtained with Pd(OAc)2/Me-DUPHOS/Cs2CO3 combinations
(entries 5 and 6). The effort to lower the reaction temperature
by carrying out the reaction in toluene (100 1C) resulted in poor
yield (entry 10). The scale up reaction using 1 g of the substrate
1a and (S,S)-DIOP as a ligand also gave substantially good
results.14
a
b
Under optimized conditions (ref. 15). Isolated yields. Determined
c
d
by HPLC analysis. No reaction, starting material recovered.
while the reaction of chloro substrate 1c resulted in complete
recovery of the starting material (entry 3). The isobutylcarbamate
1d and the fluoroaniline derivative 1f also afforded the expected
products (S)-2b and (S)-2d, respectively, with good yields and
reasonable enantioselectivities (entries 4 and 6). Interestingly,
the C–H activation of the N-sec-butylaniline derivative
(rac)-1e regioselectively proceeded at the methyl group to
afford 2-ethylindoline (S)-2c with 23% ee (entry 5). The
unreactivity of N-propyl substrate 1g (entry 7) to afford
3-methyl indoline 2e via C(sp3)–H activation at the secondary
carbon was correlating with Fagnou’s observations for a
similar kind of reaction.8b
The absolute configuration of the product 2a was assigned
by correlation with the known compound (S)-4. The
compound (S)-4 was prepared by Beak’s procedure of
asymmetric deprotonation/methylation of N-Boc indoline 3
in the presence of s-BuLi/Sparteine.16 The original procedure
was slightly modified by replacing cumene by diethyl ether as
solvent and dimethyl sulfate by methyl iodide. Hydrolysis of
(S)-4 followed by treatment with methyl chloroformate gave
(S)-2a (Scheme 3).
We have also examined the possibility of the palladium
catalysed C(sp3)H–activation/cyclisation reaction involving a
methylene group leading towards the synthesis of fused
indolines. Upon treatment of N-cyclohexyl derived substrates
1h and 1i under similar reaction conditions,15 the expected
C–H activation/cyclization proceeded smoothly to yield the
corresponding trans-fused products 2f and 2g in moderate ee’s
(Scheme 4).
We briefly investigated the scope of the palladium catalysed
methyl C–H activation/cyclisation reaction with various
2-halo-N-alkyl anilide derivatives (Table 2). The iodide 1b
delivered the indoline 2a in 82% yield and 90% ee (entry 2),
In conclusion, we have developed a novel methodology for
palladium catalysed asymmetric activation of methyl C–H
c
11484 Chem. Commun., 2011, 47, 11483–11485
This journal is The Royal Society of Chemistry 2011

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6 (a) G. Dyker, Angew. Chem., Int. Ed. Engl., 1992, 31, 1023;
(b) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew.
Chem., Int. Ed., 2009, 48, 5094; (c) R. Giri, B.-F. Shi, K. M. Engle,
N. Maugel and J.-Q. Yu, Chem. Soc. Rev., 2009, 38, 3242. For
review on catalytic C(sp3)–H activation, see: (d) R. Jazzar, J. Hitce,
A. Renaudat, J. Sofack-Kreutzer and O. Baudoin, Chem.–Eur. J.,
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Scheme 4 Asymmetric cyclisation towards fused indolines.17
7 T. Watanabe, S. Oishi, N. Fujii and H. Ohno, Org. Lett., 2008,
10, 1759.
bonds by using commercially available chiral diphosphine
ligands and subsequent cyclisation leading to the synthesis of
chiral 2-methyl indolines with ee’s up to 93%. This is the first
example of the enantioselective methyl C–H activation by an
intramolecular ArPdX species. We have also successfully
employed this approach for the synthesis of enantioenriched
cyclohexyl fused indolines with moderate enantioselectivities.
More studies to explore the scope of the reaction over a range
of substrates and the use of chiral carboxylic acids as ligands
and/or additives in this kind of reactions are in progress.18
We are grateful to the Servier Company, Universite Paris-Sud
and CNRS for their financial support. S. A. thanks Servier
Company for a postdoctoral fellowship. We thank Drs J.-L.
Peglion and P. Gloanec for useful discussions.
8 (a) M. Lafrance, S. I. Gorelsky and K. Fagnou, J. Am. Chem. Soc.,
2006, 128, 16496; (b) M. Lafrance, S. I. Gorelsky and K. Fagnou,
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10 For reviews on carbenes, see: (a) P. Muller and C. Friut, Chem.
Rev., 2003, 103, 2905; (b) H. M. L. Davies, Nature, 2008, 451, 417.
For C–H amination review, see: (c) H. M. L. Davies and
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P. Dauban, Chem. Commun., 2009, 5061.
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13 M. Nakanishi, D. Katayev, C. Besnard and E. P. Kundig, Angew.
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14 For more details, see ESIw.
15 Optimized procedure: 0.2 mmol of substrate, 5 mol% catalyst,
10 mol% ligand, 1.4 eq. base and 0.5 eq. tBuCO2H were taken in a
10 mL RB flask equipped with a reflux condenser. To this, xylene
(2.0 mL) was added in an open atmosphere and mixed well under
stirring at room temperature. The reaction mixture was stirred
further for 2 h at 140 1C. After cooling, the reaction mixture was
concentrated in vacuo and crude material was purified by silica gel
chromatography with the pentane/ethyl acetate mixture to afford
the corresponding indolines.
16 K. M. Bertini Gross, Y. M. Jun and P. Beak, J. Org. Chem., 1997,
62, 7679.
17 trans-Stereochemistry assigned by comparing with the compound
in ref. 7.
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18 When the reaction depicted in entry 1 (Table 2) was repeated with
(0.5 eq.) N-Boc-L-Valine instead of pivalic acid, we observed traces
of formation of 2a with 30% ee even in the absence of a phosphine
ligand. This experiment provided further evidence for the
involvement of carboxylic acid additive in the catalytic cycle.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11483–11485 11485