Highly enantioselective Pd-catalyzed allylic alkylation of indoles using sulfur-MOP ligand

Article abstract of DOI:10.1021/ol102977b

The preparation of various (R)-Sulfur-MOP ligands with aryl and alkyl substituents on sulfur, and the application of these ligands to Pd-catalyzed asymmetric allylic alkylation of indoles is reported. The sulfur substituent served as an effective stereoco

Full text of DOI:10.1021/ol102977b

ORGANIC
LETTERS
2011
Vol. 13, No. 5
932–935
Highly Enantioselective Pd-Catalyzed
Allylic Alkylation of Indoles Using
Sulfur-MOP Ligand
Takashi Hoshi,*,† Koji Sasaki,‡ Shun Sato,‡ Yuichi Ishii,‡ Toshio Suzuki,† and
Hisahiro Hagiwara*,‡
Faculty of Engineering and Graduate School of Science and Technology,
Niigata University, 8050, 2-Nocho, Ikarashi, Nishi-ku, Niigata 950-2181, Japan
hoshi@gs.niigata-u.ac.jp; hagiwara@gs.niigata-u.ac.jp
Received December 9, 2010
ABSTRACT
The preparation of various (R)-Sulfur-MOP ligands with aryl and alkyl substituents on sulfur, and the application of these ligands to Pd-catalyzed
asymmetric allylic alkylation of indoles is reported. The sulfur substituent served as an effective stereocontrol element, and in the case of the 2-i-PrPh
substituent on sulfur, the allylation products from an array of simple and substituted indoles were obtained with high enantioselectivity (up to 95% ee).
Chiral bidentate ligands containing strong and weak
donor heteroatom pairs have emerged as an important
class of chiral ligands for transition metal-catalyzed en-
antioselective processes, because the different intensity of
the trans effects of the two heteroatoms on metal-bound
substrates is a powerful control element in the stereochem-
istry-determining step of the catalytic cycle. Among such
ligands, thioether-containing phosphine ligands (P,S-
ligands) have recently attracted much attention because,
adjacent to the metal-bound substrate, extra chirality on
sulfur is generated by coordination to the metal (sulfur
chirality), thus providing an additional stereocontrol
element.1 We have previously reported the synthesis of
Sulfur-MOP (L1), a P,S-ligand that is an analogue of
BINAP. Ligand L1isthe first MOP-type ligand containing
an aryl thioether group, rather than an alkyl one.2,3 In this
letter, we report the Pd-catalyzed asymmetric allylic alky-
lation of indoles with aryl thioether-containing Sulfur-
MOP ligands L1-L4 and their alkyl counterpart L5.
Because optically active indoles and their derivatives are
† Faculty of Engineering.
‡ Graduate School of Science and Technology.
(1) For some recent examples of chiral mixed phosphorus/sulfur
(2) Hoshi, T.; Hayakawa, T.; Suzuki, T.; Hagiwara, H. J. Org. Chem.
2005, 70, 9085.
(3) Sulfur-MOP ligands containing alkyl sulfur substituents, see:
(a) Zhang, W.; Shi, M. Tetrahedron: Asymmetry 2004, 15, 3467.
(b) Gladiali, S.; Medici, S.; Pirri, G.; Pulacchini, S.; Fabbri, D. Can. J.
Chem. 2001, 79, 670. (c) Gladiali, S.; Dore, A.; Fabbri, D. Tetrahedron:
Asymmetry 1994, 5, 1143.
(4) For some recent reviews of biologically active indoles and deriv-
atives, see: (a) Kochanowska-Karamyan, A.; Hamann, M. T. Chem.
Rev. 2010, 110, 4489. (b) O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep.
2006, 23, 532. (c) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73.
ligands, see: (a) Oura, I.; Shimizu, K.; Ogata, K.; Fukuzawa, S.-i. Org.
ꢀ
ꢀ
Lett. 2010, 12, 1752. (b) Hernanadez-Toribio, J.; Arrayas, R. G.;
Martın-Matute, B.; Carretero, J. C. Org. Lett. 2009, 11, 393.
ꢀ
ꢀ
ꢀ
(c) Hernanadez-Toribio, J.; Arrayas, R. G.; Carretero, J. C. J. Am.
ꢀ
Chem. Soc. 2008, 130, 16150. (d) Lopez-Perez, A.; Adrio, J.; Carretero,
ꢀ
ꢀ
J. C. J. Am. Chem. Soc. 2008, 130, 10084. (e) Gonzalez, A. S.; Arrayas,
R. G.; Rivero, M. R.; Carretero, J. C. Org. Lett. 2008, 10, 4335. (f) Lam,
F. L.; Au-Yeung, T. T.-L.; Kwong, F. Y.; Zhou, Z.; Wong, K. Y.; Chan,
A. S. C. Angew. Chem., Int. Ed. 2008, 47, 1280. (g) Cheung, H. Y.; Yu,
W.-Y.; Lam, F. L.; Au-Yeung, T. T.-L.; Zhou, Z.; Chan, T. H.; Chan,
A. S. C. Org. Lett. 2007, 9, 4295.
r
10.1021/ol102977b
Published on Web 01/24/2011
2011 American Chemical Society

Sulfur-MOP ligands L1-L5 could be prepared in en-
antiomerically pure form via the sulfenylation of (R)-
dibromobinaphthyl (1),9 followed by the phosphination
of the resulting bromosulfide (2) (Scheme 1). Here, the
order of the substitution sequence is opposite that of our
previous route because the phosphination product of 1 is
easily racemized during lithiation in the subsequent sulfe-
nylation step.2,10 As expected, the reversed substitution
sequence allowed the axial chirality to be completely retai-
ned over the course of the entire ligand synthesis without
any special precautions in the experimental procedure. To
prevent the oxidation of the phosphine during workup, the
substitution product was isolated as the BH3-protected
phosphine 3. Deprotection using morpholine as the BH3
scavenger provided the corresponding Sulfur-MOP ligand
in almost quantitative yield.
Scheme 1. Stereoretentive Preparation of Sulfur-MOP Ligand
In the initial study, we examined the catalyst generated
from [Pd(C3H5)Cl]2 and Sulfur-MOP ligand L1, which
contains a Ph group as the sulfur substituent, in the
reaction of dimethyl malonate with 1,3-diphenylpropenyl
acetate (eq 1). After the conditions were optimized, the
product was obtained in 90% yield and 95% ee.
common in biologically active natural products and
pharmaceuticals,4 chiral catalysts for the synthesis of these
compounds are of great importance.5 Recently, remark-
able progress has been made in the development of cata-
lytic asymmetric. Friedel-Crafts alkylation of indole,
benefiting from its nucleophilicity.6 In contrast, indole
nucleophiles are rarely used in metal-catalyzed asymmetric
allylic alkylations.1g,7 In light of the excellent versatility of
Pd-catalyzed allylic alkylation as an enantioselective C-C
bond-forming process,8 we focused on this reaction for
the synthesis of optically active indoles using Sulfur-
MOP ligands. As expected, the steric and electronic
properties of sulfur chirality had a strong effect on en-
antioselectivity; the ligand L2, which contains a 2-i-PrPh
group as the sulfur substituent, was found to be the best
Sulfur-MOP ligand, providing the allylation products in
high enantioselectivity (up to 95% ee). Also, to ensure the
availability of the required sulfur substituents, we devel-
oped a more robust synthetic route to the Sulfur-MOP
ligands, because our previous route included a step in
which axial chirality was lost due to racemization.2
This high catalytic performance encouraged us to ex-
amine the Pd-catalyzed allylic alkylation of indoles using
Sulfur-MOP ligands (Table 1). Because Chan and co-
workers obtained the best result when the reaction was
conducted at 40 °C in CH3CN with two equivalents of
K2CO3 as base,1g we began to examine catalysis based on
L1 under the same conditions. We found that the reaction
occurred smoothly, even at room temperature, to give the
allylation product in 56% yield and 82% ee in 8 h (entry 1).
Fortunately, the undesired N-allylation did not occur.11
Table 1. Pd-Catalyzed Asymmetric Allylic Alkylation of Indole
Using Sulfur-MOP Ligand L1
(5) For a review, see:Bandini, M.; Eichholzer, A. Angew. Chem., Int.
Ed. 2009, 48, 9608.
(6) For recent reviews of catalytic asymmetric Friedel-Crafts alkyl-
ations of indoles, see: (a) Zeng, M.; You, S.-L. Synlett 2010, 1289.
(b) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 2190.
(c) Poulsen, T. B.; Jørgensen, K. A. Chem. Rev. 2008, 108, 2903.
(d) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int.
Ed. 2004, 43, 550.
entry
R
carbonate
yield (%)a
% eeb
(7) (a) Wu, Q.-F.; He, H.; Liu, W.-B.; You, S.-L. J. Am. Chem. Soc.
2010, 132, 11418. (b) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed.
2009, 48, 9553. (c) Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L Synthesis
2009, 2076. (d) Onitsuka, K.; Kameyama, C.; Sasai, H. Chem. Lett. 2009,
38, 444. (e) Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L. Org. Lett. 2008, 10,
1815. (f) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314.
(g) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi, S.;
Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424.
1
2
3
4
5
6
H
K2CO3, 2 equiv
K2CO3, 3 equiv
K2CO3, 5 equiv
K3PO4, 3 equiv
-
56
77
69
44
14
0
82
86
82
80
17
-
H
H
H
H
Me
K2CO3, 3 equiv
(8) For some reviews, see: (a) Trost, B. M.; Crawley, M. L. Chem.
Rev. 2003, 103, 2921. (b) Helmchen, G. J. Organomet. Chem. 1999, 567,
203. (c) Trost, B. M.; Vranken, D. L. V. Chem. Rev. 1996, 96, 395.
a Isolated yield. b Determined by chiral HPLC analysis.
Org. Lett., Vol. 13, No. 5, 2011
933

Increasing the amount of K2CO3 from 2 equiv to 3 equiv
favorably affected the yield, likely because of the more
effective deprotonation of indole to generate the amide
anion nucleophile (entry 2). However, the further addition
of K2CO3 resulted in decreased yield (entry 3). The use of
the stronger base K3PO4 was also ineffective at promoting
the reaction (entry 4). It is noteworthy that not only the
yield (14%) but also the enantioselectivity (17% ee) was
reduced when the reaction was carried out without base
(entry 5). The marked decrease in enantioselectivity in this
case indicates that the base plays an important role, not
only promoting the reaction but also inducing the enan-
tioselectivity. The lack of reactivity of N-methylindole is
consistent with our speculation that the amide anion,
rather than indole, is the effective nucleophile that attacks
the palladium π-allyl intermediate in the catalytic cycle
(entry 6).
Because of the practical advantages of EtOAc, namely,
safety and low cost, it was selected as the solvent for the
optimized catalytic system. In contrast to the high solvent
tolerance, the catalytic performance was highly dependent
on the identity of the base (entries 7-13).12 Because potas-
sium carbonate was found to give better results than
potassium phosphate in the initial study, we surveyed
carbonates of alkali metals, alkaline earth metals, yttrium,
and cerium in an attempt to optimize the base further.
Unfortunately, none of these metal carbonates further
enhanced the activity and selectivity of the catalyst; ac-
cordingly, K2CO3 was used as the base for the optimized
catalytic system. The catalyst exhibited the best perfor-
mance at room temperature. The reaction at 0 °C resulted
in considerably lower yield, while the enantioselectivity
remained invariant (entry 14). Conducting the reaction at
40 °C resulted in both lower yield and lower enantioselec-
tivity (entry 15). The replacement of allyl acetate by allyl
carbonate led to lower enantioselectivity due mainly to
the influence of in situ-generated methoxide base on the
stereochemistry-determining step (entry 16). In fact, in
contrast to allyl acetate, the reaction with allyl carbonate
smoothly proceeded even in the absence of basic additive,
but gave the almost racemic product (entry 17). Conse-
quently, we selected allyl acetate, EtOAc, K2CO3, and
room temperature as the allylation reagent, the solvent,
the base, and the reaction temperature.
Table 2. Optimization of Reaction Conditions
Having found the optimized conditions, we next exam-
ined Sulfur-MOP ligands containing 2-i-PrPh, 2-naphthyl
(2-Np), 3,5-xylyl (3,5-Xyl), and cyclohexyl (Cy) groups as
sulfur substituents to evaluate the importance of sulfur
chirality as a stereocontrol element of the ligand architec-
ture. We also expected that tuning sulfur chirality by
changing the sulfur substituent would produce further
enhancement in the catalyst’s enantioselectivity. As shown
in Table 3, all three aryl substituents on sulfur served as
effective stereocontrol elements, as did the Ph sulfur sub-
stituent (entries 1-3). Among them, 2-i-PrPh induced the
highest enantioselectivity, providing the allylation product
in 92% ee and 83% yield (entry 1). The replacement of the
aryl substituents on sulfur by their alkyl counterpart, Cy,
more clearly exhibited the influence of the sulfur chirality
on the enantioselectivity of the catalyst, which was drama-
tically changed to give the opposite absolute configuration
of the product (entry 4). To gain additional insight into the
effects of sulfur chirality, we also examined (R)-MeO-
MOP13 and (R)-BINAP,14 the binaphthyl-based P,X-li-
gands containing oxygen and phosphorus instead of sulfur
as the heteroatom X, respectively. The catalyst based on
(R)-MeO-MOP exhibited comparable enantioselectivity,
but moderate yield (entry 5). The use of (R)-BINAP, which
can be regarded as the complete phosphorus counterpart
of Sulfur-MOP ligand L1, led to a significant loss in the
entry
X
carbonate solvent temp (°C) yielda (%) % eeb
1
2
3
4
5
6
7
8
9
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Li2CO3
Na2CO3
Cs2CO3
CaCO3
SrCO3
EtOAc
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
86
89
74
83
86
77
0
83
81
81
81
69
86
-
71
82
-
DME
toluene
CH2Cl2
CH3CN
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
41
62
0
10 OAc
11 OAc
12 OAc
13 OAc
14 OAc
15 OAc
32
0
23
Y2(CO3)2 EtOAc
Ce2(CO3)2 EtOAc
-
-
0
K2CO3
K2CO3
EtOAc
EtOAc
EtOAc
EtOAc
0
57
57
87
69
84
71
71
8
40
rt
16 OCO2CH3 K2CO3
17 OCO2CH3
-
rt
a Isolated yield. b Determined by chiral HPLC analysis.
Having verified the efficiency of the catalytic system
based on Sulfur-MOP ligand L1, we pursued further opti-
mization of the reaction conditions (Table 2). The cata-
lyst worked well in various polar and nonpolar solvents
(entries 1-6). Among them, EtOAc was the second best
solvent in terms of both yield and enantioselectivity.
(9) (a) Hoshi, T.; Shionoiri, H.; Suzuki, T.; Ando, M.; Hagiwara, H.
Chem. Lett. 1999, 28, 1245. (b) Brown, K. J.; Berry, M. S.; Murdoch,
J. R. J. Org. Chem. 1985, 50, 4345.
(10) Shimada, T.; Kurushima, H.; Cho, Y.-H.; Hayashi, T. J. Org.
Chem. 2001, 66, 8854.
(12) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089.
Chan and co-workers also reported the significant effect of base on the
enantioselectivity of Pd-catalyzed asymmetric allylic alkylations of
indole. See ref 1g.
(13) Hayashi, T. Acc. Chem. Res. 2000, 33, 354.
(14) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345.
(11) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Org. Lett. 2004, 6,
3199.
934
Org. Lett., Vol. 13, No. 5, 2011

Table 3. Ligand Effect
Table 4. Scope of Indoles
entry
R
Sulfur-MOP
yield (%)a
% eeb
1
5-Br
L2
L2
L2
L2
L2
L2
L1
L1
L1
L1
L1
L1
67
88
85
84
76
66
80
76
75
87
60
54
78
83
95
93
90
66
68
58
83
81
79
52
2
5-Cl
3
5-Me
5-MeO
7-Me
2-Ph
5-Br
4
5
6
entry
ligand
yield (%)a
% eeb
7
8
5-Cl
1
2
3
4
5
6
7
L2
83
58
89
68
45
32
6
92
82
9
5-Me
5-MeO
7-Me
2-Ph
L3
10
11
12
L4
78
L5
-48
-85
44
(R)-MeO-MOP
(R)-BINAP
Trost ligand
a Isolated yield. b Determined by chiral HPLC analysis.
<1
a Isolated yield. b Determined by chiral HPLC analysis.
improvement was seenfor thereactionofthe simpleindole.
These results demonstrate the importance of sulfur chir-
ality as the stereocontrol element in our catalytic system.
In summary, we have developed a method for highly
enantioselective Pd-catalyzed allylic alkylation of indoles,
using Sulfur-MOP ligands. Tuning of the sulfur chirality
by changing the structural properties of the sulfur sub-
stituent was an effective stereocontrol tactic. The allylation
products derived from an array of the simple and sub-
stituted indoles could be obtained with high enantioselec-
tivity (up to 95% ee) in the case of ligand L2. The catalytic
performance was also strongly dependent on the identity
and amount of added base. In contrast, the catalyst system
exhibited broad solvent tolerance. To prepare ligands with
a structurally diverse array of sulfur substituents, we also
developed a racemization-free route to Sulfur-MOP li-
gands. Further exploration of the potential of Sulfur-
MOP ligands is underway in our laboratory.
activity and selectivity (entry 6). The Trost ligand,15 which
has also found widespread use as a chiral C2-symmetric P,
P-ligand, gave only the racemic product in low yield (entry 7).
Although the mechanism of the enhancement of the
catalytic activity and selectivity remains unknown, the
difficulty in achieving high catalytic performance even
through the use of these outstanding chiral ligands also
exhibits the exceptional efficiency of Sulfur-MOP ligand
L2 in this asymmetric reaction.
The catalyst based on ligand L2 also worked well in the
reactions of substituted indoles to afford the correspond-
ing products in up to 95% ee (Table 4, entries 1-6). The
enantioselectivity was highly dependent on the electronic
properties of the substituents at the 5- and 7-positions: the
enantioselectivity for electron-donating groups was higher
than that for electron-withdrawing groups (entries 1-5).
Because of unfavorable steric interactions, a bulky sub-
stituent on the pyrrole ring led to deterioration in both the
yield and enantioselectivity (entry 6). The use of ligand L2
in the reactions of these substituted indoles resulted in ee
values 10-25% higher than those in the case of the parent
ligand L1 (entries 1-6 vs entries 7-12). A similar degree of
Acknowledgment. This work was supported financially
by Grant-in-Aids for Scientific Research (No. 21550100
for T.H.) from MEXT.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc.
1992, 114, 9327.
Org. Lett., Vol. 13, No. 5, 2011
935