Asymmetric synthesis of indolines bearing a benzylic quaternary stereocenter through intramolecular arylcyanation of alkenes

Article abstract of DOI:10.1055/s-0029-1219964

Enantioselective intramolecular arylcyanation of olefins is achieved by a Ni(cod)₂/chiral phosphinoxazoline/AlMe₂Cl catalyst to give chiral, substituted indoline derivatives bearing a benzylic quaternary stereocenter in high yields with good to excellent enantioselectivities. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219964

CLUSTER
1709
Asymmetric Synthesis of Indolines Bearing a Benzylic Quaternary
Stereocenter through Intramolecular Arylcyanation of Alkenes
A
symmetr
e
ic Synthesi
n
s
of Indoline
-
s
Chieh Hsieh, Shiro Ebata, Yoshiaki Nakao,* Tamejiro Hiyama*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
Fax +81(75)3832445; E-mail: yoshiakinakao@npc05.mbox.media.kyoto-u.ac.jp; E-mail: thiyama@z06.mbox.media.kyoto-u.ac.jp
Received 1 April 2010
from readily available nitriles. Our preliminary result for
the enantioselective cyclization of 1a was successfully ap-
plied to the total synthesis of (–)-esermethole, which is a
pyrroloindoline that serves as a synthetic precursor of po-
tent acetylcholinesterase inhibitors such as (–)-physostig-
mine and (–)-phenserine (Scheme 1).8 This scheme
prompted us to examine the generality of the transforma-
tion and thus gain access to a variety of enantiomerically
enriched 3,3-disubstituted indoline derivatives. The re-
sults are reported herein.
Abstract: Enantioselective intramolecular arylcyanation of olefins
is achieved by a Ni(cod)2/chiral phosphinoxazoline/AlMe2Cl cata-
lyst to give chiral, substituted indoline derivatives bearing a benzyl-
ic quaternary stereocenter in high yields with good to excellent
enantioselectivities.
Key words: asymmetric synthesis, carbocyanation, C–C bond acti-
vation, nickel, indoline
An indoline substructure bearing substituents at its 3-po-
sition is frequently found in alkaloids having significant
biological activities.1 To access this structural motif, in-
tramolecular addition of arylpalladium species across ole-
fins tethered by an ortho-amino group has often been a
choice of strategy for synthetic organic chemists. This el-
emental step is followed either by b-hydride elimination2,3
(the Mizoroki–Heck reaction) or reactions with
nucleophiles4,5 to achieve catalytic synthesis of 3,3-disub-
situted indolines starting from relatively simple aromatic
compounds. These strategies have also been successfully
extended to catalytic asymmetric transformations.6,7 In
the former case, however, preinstallation of functional
groups into an olefinic substituent is necessary to further
elaborate complex indoline derivatives, and a stoichio-
metric amount of a waste is generated from the halogen
and nucleophile during the transformations. On the other
hand, we8 and others9 have recently disclosed that catalyt-
ic intramolecular insertion of olefins into C–CN bonds of
nitriles is an atom-economical alternative that can facili-
tate access to 3,3-disubstituted indolines and oxindoles
The conditions previously optimized for the enantioselec-
tive cyclization of 1a using commercially available (S,S)-
i-Pr-Foxap10 were, this time, simply applied to the reac-
tions of a range of 2-aminobenzonitriles bearing an olefin-
ic moiety tethered by an amino group (Equation 1 and
Table 1).11 When halides were present on the benzene
ring, the yield and enantioselectivities were slightly lower
than those achieved with 1a (entries 1–3). Thus, the ben-
zonitrile derivative with a chloro group meta to the cyano
group 1b underwent the asymmetric arylcyanation with
only 39% ee (entry 1). The use of (S)-i-Pr-Phox,12 on the
other hand, increased the ee of 2b to 88% with a slightly
lowered chemical yield. The absolute configuration of 2b
was assigned as R by comparing its data (including HPLC
analyses and optical rotations) with that obtained for 2a.13
Nitrile 1c, having a chloro group para to the cyano group,
underwent the reaction under the original conditions to
give 2c in 93% ee and 56% yield (entry 2). Fluorine-sub-
stituted indoline 2d (90% ee) was also obtained in 72%
yield (entry 3). These results showed that the electron den-
Ni(cod)2 (10 mol%)
(R,R)-i-Pr-Foxap
CN
MeO
MeO
MeO
CN
(20 mol%)
NMe
AlMe2Cl (40 mol%)
N
H
N
3 steps
DME, 100 °C, 10 h
N
Me
(–)-esermethole
Me
Me
2a
1a
88%, 96% ee
O
N
Ph2P
Fe
(R,R)-i-Pr-Foxap
Scheme 1 Asymmetric total synthesis of (–)-esermethole through enantioselective intramolecular arylcyanation of alkenes
SYNLETT 2010, No. 11, pp 1709–1711
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x
.x
x
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0
1
0
Advanced online publication: 10.06.2010
DOI: 10.1055/s-0029-1219964; Art ID: Y00410ST
© Georg Thieme Verlag Stuttgart · New York

1710
J.-C. Hsieh et al.
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Table 1 Nickel/AlMe2Cl-Catalyzed Asymmetric Intramolecular
sity on the benzene ring slightly affected the enantioselec-
tivity, possibly through altering the ability of the nitrogen
and/or olefin to coordinate to nickel. It is worth noting that
aryl–halogen bonds, which are normally labile to nick-
el(0) species, were tolerated, and that the C–CN bonds
were activated exclusively by the nickel/AlMe2Cl cooper-
ative catalyst.14 Nevertheless, the observed decrease in the
reaction rate and yield could be ascribed to some compet-
itive side reactions occurring through activation of the
aryl–halogen bonds. The size of the N-substituents affect-
ed both chemical yield and enantioselectivity significant-
ly (entries 4–7). Bulkier substituents might retard
oxidative addition of the Ar–CN bond as well as coordi-
nation of the double bond to nickel. A range of alkyl sub-
stituents, on the other hand, could be introduced to the
olefin moiety to give the corresponding 3,3-disubstituted
indolines with good to excellent enantioselectivities (en-
tries 8–12). An internal double bond and a protected hy-
droxy group were tolerated (entries 11 and 12), although
the latter affected the enantioselectivity to some extent.
Prenylated indoline 2l may be transformed into natural
products such as pseudophrynamine A,15 deoxy-
pseudophrynaminol,16 and debromoflustramine B.17 Ni-
triles having phenyl and 4-chlorophenyl groups on the
double bond afforded 3-arylindolines 2n and 2o with high
enantioselectivities (entries 13 and 14).
Arylcyanation of Alkenesa (continued)
Entry Products
Time (h) Yield (%)b ee (%)c
CN
N
R2
4
5
6
7
2e (R2 = Me)
2f (R2 = Et)
2g (R2 = Pr)
2h (R2 = Bn)
40
40
87
54
41
20d
93
81
69
61d
40
120
CN
8
9
40
40
87
93
93
96
N
Me
2i
CN
CN
N
Me
2j
Ph
10
11
160
120
88
46
95
93
Ni(cod)2 (10 mol%)
R3
CN
ligand (20 mol%)
N
CN
Me
AlMe2Cl (40 mol%)
R1
R1
2k
N
DME, 100 °C
R2
N
R3
R2
1
2
O
O
CN
N
PPh2
N
Fe
N
PPh2
Me
(S,S)-i-Pr-Foxap
(S)-i-Pr-Phox
2l
TBSO
Equation 1
CN
CN
12
13
80
40
91d
73d
Table 1 Nickel/AlMe2Cl-Catalyzed Asymmetric Intramolecular
N
Arylcyanation of Alkenesa
Me
2m
Entry Products
Time (h) Yield (%)b ee (%)c
Ph
CN
CN
55
97
Cl
82 (67)d
39 (88)d
N
1
180
140
Me
N
Me
2n
2b
Cl
2
56
93
14
160
56d
92d
N
CN
Cl
Me
2c
N
F
Me
CN
2o
3
80
72
90
a Reactions were carried out on a 0.50 mmol scale.
b Isolated yield.
N
Me
c Determined by HPLC analysis.
d Run with (S)-i-Pr-Phox.
2d
Synlett 2010, No. 11, 1709–1711 © Thieme Stuttgart · New York

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Asymmetric Synthesis of Indolines
1711
(5) For a review, see: Grigg, R.; Sridharan, V. J. Organomet.
Chem. 1999, 576, 65.
In summary, we have demonstrated an enantioselective
intramolecular arylcyanation that provides a variety of
3,3-disubstituted indolines bearing a benzylic quaternary
carbon. The approach uses chiral nickel/Lewis acid coop-
erative catalysis with phosphinoxazoline ligands. This re-
action may be used to access biologically active natural
products and pharmaceuticals containing the indoline
structural core. Current efforts are directed towards the
enantioselective construction of oxindoles by this meth-
odology.18
(6) For reviews of the enantioselective intramolecular
Mizoroki–Heck reaction, see: (a) Dounay, A. B.; Overman,
L. E. Chem. Rev. 2003, 103, 2945. (b) Shibasaki, M.; Vogl,
E. M.; Ohshima, T. Adv. Synth. Catal. 2004, 346, 1533.
(7) Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem. Eur. J. 2007,
13, 961.
(8) Nakao, Y.; Ebata, S.; Yada, A.; Hiyama, T.; Ikawa, M.;
Ogoshi, S. J. Am. Chem. Soc. 2008, 130, 12874.
(9) (a) Kobayashi, Y.; Kamisaki, H.; Takeda, H.; Yasui, Y.;
Yanada, R.; Takemoto, Y. Tetrahedron 2007, 63, 2978.
(b) Watson, M. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2008,
130, 12594. (c) Yasui, Y.; Kinugawa, T.; Takemoto, Y.
Chem. Commun. 2009, 4275. (d) Reddy, V. J.; Douglas,
C. J. Org. Lett. 2010, 12, 952. (e) Yasui, Y.; Kamisaki, H.;
Ishida, T.; Takemoto, Y. Tetrahedron 2010, 66, 1980.
(10) Miyake, Y.; Nishibayashi, Y.; Uemura, S. Synlett 2008,
1747.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(11) General Experimental Procedure: An aryl cyanide (0.50
mmol) and a solution of AlMe2Cl (1.04 M in hexane, 0.20
mL, 0.20 mmol) were added sequentially to a solution of
Ni(cod)2 (13.8 mg, 50 mmol) and a ligand (50 mmol) in 1,2-
dimethoxyethane (0.50 mL) prepared in a 3 mL vial under an
argon atmosphere in a dry-box. The vial was sealed with a
screw-cap, taken outside the dry-box and heated at 100 °C
for the time specified Table 1. The resulting mixture was
filtered through a silica gel pad, concentrated in vacuo, and
purified by flash column chromatography on silica gel to
give the corresponding arylcyanation products in the yields
listed in Table 1
(12) Helmchen, G.; Praltz, A. Acc. Chem. Res. 2000, 33, 336.
(13) See Supporting Information for details
(14) Nakao, Y.; Yada, A.; Ebata, S.; Hiyama, T. J. Am. Chem.
Soc. 2007, 129, 2428.
(15) Mitchel, M. O.; Le Quesne, P. W. Tetrahedron Lett. 1990,
31, 2681.
This work was supported financially by a Grant-in-Aid for Scienti-
fic Research (S) and Young Scientists (A) from MEXT. J.C.H.
acknowledges JSPS for a postdoctoral fellowship.
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Synlett 2010, No. 11, 1709–1711 © Thieme Stuttgart · New York