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