of simple nonchelating R,â-unsaturated carbonyl compounds
as electrophiles represents a considerable synthetic challenge
and has been less studied. MacMillan et al. have reported
an organocatalytic alkylation of indole with R,â-unsaturated
Table 1. Ligand Evaluation and Optimization of the
Enantioselective Friedel-Crafts Reaction of 1a with 2a
a
time
(h)
yield
(%)b
ee
11
aldehydes. Umani-Ronchi et al. have described the addition
of indoles to R,â-unsaturated ketones using salen-Al com-
plexes obtaining enantiomeric excesses in the 80% range for
entry
solvent
catalyst
(%)c
1
2
3
4
5
6
7
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH Cl
L1-Sc(OTf)3
6
21
1
1
3
22
96
46
71
60
85
84
87
41
trace
21
2
25
74
74
97
75
i
12
L1-Ti(O Pr)4
most of the reported substrates. Recently an enantioselective
Friedel-Crafts reaction of indole with electron-rich alkenes
activated by a chiral Brønsted acid catalyst has been
t
L1-Zr(O Bu)4
t
L2-Zr(O Bu)4
t
L3-Zr(O Bu)4
13
described. Finally, two organocatalytic examples of asym-
t
L4-Zr(O Bu)4
metric Friedel-Crafts alkylation of indoles with enones via
L5-Zr(OtBu)
2
2
4
1
4
d
t
ketiminine salts have been reported very recently. The
purpose of this Letter is to describe the enantioselective
Friedel-Crafts reactions of R,â-unsaturated ketones 2 with
indoles 1 catalyzed by a chiral BINOL-type-zirconium(IV)
tert-butoxide complex.15
8
CH2Cl2
L3-Zr(O Bu)4
78
a
0 mol % of (R)-ligand and 20 mol % of metal salt. b Isolated yield of
2
3aa. c Determined by chiral HPLC analysis. (R) configuration assigned by
d
comparison of the optical rotation sign with literature data (ref 12). 10
mol % catalyst was used in this run.
The reaction of indole (1a) with enone 2a was chosen to
optimize the reaction conditions. Several chiral Lewis acid
catalysts generated in situ from metal salts and the ligand
t
presence of Zr(O Bu)
4
indole 1a reacted fast (within 1 h)
with enone 2a, giving 3-(1-methyl-3-phenyl-3-propanone)-
1H-indole (3aa) in good yield (85%) and enantioselectivity
(74%) (entry 3). We further screened different solvents,
temperature, and catalyst loading. With 1,2-dichloroethane
the results were practically the same, but other solvents
(R)-BINOL (L1) were evaluated as shown in the illustrated
reaction (Scheme 1), and the results are summarized in Table
(
3
CHCl , acetonitrile, ether, THF, toluene) had a negative
Scheme 1. Friedel-Crafts Reaction of Indole 1a with Enone
influence on the catalytic activity. Increasing or diminishing
the reaction temperature as well as the catalyst loading also
had a negative effect on the enantioselectivity. Our efforts
2
a and Structure of BINOL-Type Ligands Used in This Study
to optimize the reaction conditions were also aimed at
t
exploring the effectiveness of Zr(O Bu)
4
with other BINOL-
type ligands (L2-L5) which contain electron-withdrawing
groups at the 3,3′ and 6,6′ positions as well as a tetrahydro-
genated ring. Ligand L3 led to the best result (87% yield,
9
7% ee) (entry 5). A reduction of the catalyst load to 10
mol % had a deleterious effect on the reaction, compound
3
aa being obtained in 21% yield and 78% ee (entry 8)
To demonstrate the scope and potential of this reaction,
we next examined a series of indole derivatives 1 and enones
. Enones with a sterically demanding aromatic group bound
2
to the carbonyl group and an aliphatic chain linked to the
C-C double bond produced alkylated indoles in excellent
yields and very high enantioselectivities, above 95% ee in
most of the cases (Table 2). The size of the alkyl group at
the â-position (Me, Et, Pr) did not seem to influence the
reaction (entries 1-3) although in the case of chalcone
i
1
. With use of 20 mol % of Sc(OTf)
3
or Ti(O Pr)
3
and 20
at room
mol % of ligand L1 (entries 1 and 2) in CH
2
Cl
2
temperature the reaction took place slowly, and the enan-
tiomeric excess of the product was zero or low, while in the
(phenyl group at the â-position) a diminished reactivity was
observed (entry 4). The reaction with enones containing an
electron-donating group on the phenyl group had a slightly
lower reaction rate than that with enones containing an
(
8) Evans, D. A.; Fandrick, K. R.; Song, H. J. J. Am. Chem. Soc. 2005,
27, 8942-8943.
9) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. HelV.
Chim. Acta 2003, 86, 3753-3763.
10) (a) Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Org. Biomol. Chem.
1
(
(
2
005, 3, 2566-2571. (b) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci,
(14) (a) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.;
Melchiorre, P. Org. Lett. 2007, 9, 1403-1405. (b) Chen, W.; Du, W.; Yue,
L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Org. Biomol. Chem. 2007, 5,
816-821.
(15) For reviews on asymmetric catalysis with BINOL: (a) Shibasaki,
M.; Matsunaga, S. Chem. Soc. ReV. 2006, 35, 269-279. (b) Brunel, J. M.
Chem. ReV. 2005, 105, 857-898. (c) Shibasaki, M.; Yoshikawa, N. Chem.
ReV. 2002, 102, 2187-2210. For examples of BINOL-Zr complexes: (d)
Saruhashi, K.; Shibashaki, S. J. Am. Chem. Soc. 2006, 128, 11232-11235.
(e) Ihori, Y.; Yamashita, I.; Ishitani, H.; Kobayashi, H. J. Am. Chem. Soc.
2005, 127, 15528-15532. (f) Kobayashi, S,; Kobayashi, J.; Ishani, H.; Ueno,
M. Chem., Eur. J. 2002, 8, 4185-4190.
A. Angew. Chem., Int. Ed. 2005, 44, 6576-6579. (c) Jia, Y. X.; Zhu, S. F.;
Yang, Y.; Zhou, Q. L. J. Org. Chem. 2006, 71, 75-80.
(11) (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001,
1
23, 4370-4371. (b) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 1172-1173. (c) Paras, N. A.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 7894-7895.
(12) (a) Bandini, M.; Fagioli, M.; Garavelli, M.; Melloni, A.; Trigari,
V.; Umani-Ronchi, A. J. Org. Chem. 2004, 69, 7511-7518. (b) Bandini,
M.; Fagioli, M.; Melchiorre, P.; Melloni, A.; Umani-Ronchi, A. Tetrahedron
Lett. 2003, 44, 5843-5846.
(13) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292-293.
2602
Org. Lett., Vol. 9, No. 13, 2007