Enantioselective allylation of ketones catalyzed by N,N′-dioxide and indium(III) complex

Article abstract of DOI:10.1021/jo0706325

(Chemical Equation Presented) Complexes of (S)-pipecolic acid-, L-proline-, and other amino acid-derived N,N′-dioxides coordinated with different metal ions have been investigated in the enantioselective allylation of ketones. A variety of aromatic ketone

Full text of DOI:10.1021/jo0706325

Enantioselective Allylation of Ketones Catalyzed by N,N′-Dioxide
and Indium(III) Complex
Xin Zhang,† Donghui Chen,† Xiaohua Liu,† and Xiaoming Feng*,†,‡
Key Laboratory of Green Chemistry & Technology (Sichuan UniVersity), Ministry of Education,
College of Chemistry, Sichuan UniVersity, Chengdu 610064, China, and State Key Laboratory of
Applied Organic Chemistry, Lanzhou 730000, China
xmfeng@scu.edu.cn
ReceiVed March 27, 2007
Complexes of (S)-pipecolic acid-, L-proline-, and other amino acid-derived N,N′-dioxides coordinated
with different metal ions have been investigated in the enantioselective allylation of ketones. A variety
of aromatic ketones were found to be suitable substrates in the presence of the L1-In(III) complex, and
afforded the corresponding homoallylic alcohols with good enantioselectivites (up to 83% ee) and moderate
to high yields (up to 94%). On the basis of the experimental results, a possible catalytic cycle including
a transition state has been proposed to explain the origin of the reactivity and asymmetric inductivity,
and a bifunctional catalyst was described with Lewis base N-oxide activating tetraallyltin and Lewis acid
indium activating ketone.
Introduction
recent years, several new procedures with either metal com-
plexes2 or organocatalysts3 have been developed for the ally-
lation of aldehydes. However, allylation of ketones is still
challenging, due to their reduced reactivities and lower binding
The enantioselective allylation of carbonyl compouds is one
of the most valuable methods to furnish chiral homoallylic
alcohols, which are widely used in the syntheses of many natural
products and biologically active compounds.1,2 The development
of efficient synthetic methods for the preparation of chiral
homoallylic alcohols has attracted considerable attention. In
(3) For representative examples, see: (a) Denmark, S. E.; Coe, D. M.;
Pratt, N. E.; Griedel, B. D. J. Org. Chem. 1994, 59, 6161-6163. (b)
Denmark, S. E; Fu, J. J. Am. Chem. Soc. 2000, 122, 12021-12022. (c)
Denmark, S. E.; Fu, J.; Coe, D. M.; Su, X.; Pratt, N. E.; Griedel, B. D. J.
Org. Chem. 2006, 71, 1513-1522. (d) Denmark, S. E.; Fu, J.; Lawler, M.
J. J. Org. Chem. 2006, 71, 1523-1536. (e) Nakajima, M.; Saito, M.; Shiro,
M.; Hashimoto, S. J. Am. Chem. Soc. 1998, 120, 6419-6420. (f) Malkov,
A. V.; Orsini, M.; Pernazza, D.; Muir, K. W.; Langer, V.; Meghani, P.;
Kocˇovsky´, P. Org. Lett. 2002, 4, 1047-1049. (g) Malkov, A. V.; Bell, M.;
Castelluzzo, F.; Kocˇovsky´, P. Org. Lett. 2005, 7, 3219-3222. (h) Shimada,
T.; Kina, A.; Ikeda, S.; Hayashi, T. Org. Lett. 2002, 4, 2799-2801. (i)
Kina, A.; Shimada, T.; Hayashi, T. AdV. Synth. Catal. 2004, 346, 1169-
1174. (j) Pignataro, L.; Benaglia, M.; Annunziata, R.; Cinquini, M.; Cozzi,
F. J. Org. Chem. 2006, 71, 1458-1463. (k) Traverse, J. F.; Zhao, Y.;
Hoveyda, A. H.; Snapper, M. L. Org. Lett. 2005, 7, 3151-3154. (l) Rabbat,
P. M. A.; Valdez, S. C.; Leighton, J. L. Org. Lett. 2006, 8, 6119-6121.
(m) Teo, Y. C.; Tan, K. T.; Loh, T. P. Chem. Commun. 2005, 1318-1320.
† Sichuan University.
‡ State Key Laboratory of Applied Organic Chemistry.
(1) For reviews, see: (a) Marshall, J. A. Chem. ReV. 1996, 96, 31-48.
(b) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207-2293. For
representative examples, see: (c) Felpin, F. X.; Lebreton, J. J. Org. Chem.
2002, 67, 9192-9199. (d) Nicolaou, K. C.; Kim, D. W.; Baati, R. Angew.
Chem. 2002, 114, 3853-3856; Angew. Chem., Int. Ed. 2002, 41, 3701-
3704. (e) Hoveyda, A. H.; Morken, J. P. Angew. Chem. 1996, 108, 1378-
1401; Angew. Chem., Int. Ed. 1996, 35, 1262-1284. (f) Leighton, J. L.;
Hornberger, K. R.; Hamblett, C. L. J. Am. Chem. Soc. 2000, 122, 12894-
12895.
(2) For reviews, see: Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103,
2763-2794.
10.1021/jo0706325 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/09/2007
J. Org. Chem. 2007, 72, 5227-5233
5227

Zhang et al.
FIGURE 1. Ligands evaluated in this study.
affinity to metals.4 Over the past decade, many efforts have been
devoted in this area.5-11 Typically, Yamamoto et al. reported
the Ag-catalyzed asymmetric Sakurai-Hosomi allylation of
ketones in which the (R)-DIFLUORPHOS was used as the chiral
ligand.6 Loh and co-workers developed two novel In-complex
catalysts in which the BINOL or PYBOX and InBr3 promoted
the asymmetric addition of allyltributylstannane to aromatic and
aliphatic ketones.7-8 Tagliavini et al. and Walsh et al. outlined
a method for the addition of allylic group to ketones using
BINOL and Ti(Oi-Pr)4,9 in which 2-propanol played a key role
in the catalytic system. Shibasaki and co-workers reported the
new approaches to asymmetric allylation of ketones and other
broad rangesof substrates by Cu(I)-tol-BINAP10 and Cu(II)-
(R,R)-iPr-DUPHOS11 catalysts. Despite the progress achieved,
the development of new approaches for the enantioselective
allylation of ketones is still highly desirable.
N-Oxides, a series of strong electron donors, have long been
recognized as suitable entities for ligand design.12 As a coin,
the application of chiral N-oxides has two sides. One is metal-
free catalytic transformations, and the other is as ligands in
transition metal catalysts.12b In our previous studies, continuing
attention has been paid to the synthesis and application of the
achiral and chiral N-oxide library.13 Very recently, N,N′-dioxides
as a highly efficient organocatalyst have been successfully used
in the cyanosilylation of aldehydes,14 aldimines,15 ketones,16 and
ketoimines.17 However, use of N-oxides in metal-mediated
asymmetric synthesis has been limited. We reported successful
attempts in the cyanosilylation of ketones dually catalyzed by
proline-based N,N′-dioxides and Ti(Oi-Pr)4 complexes,18,19 in
which N-oxide as the Lewis base activated the TMSCN. Herein,
we wish to report the enantioselective allylation of ketones
catalyzed by (S)-pipecolic acid-derived N,N′-dioxides and in-
dium(III) bromide complexes, which delivered good yields and
enantioselectivities.
(4) Walsh, P. J.; Kim, J. G.; Camp, E. H. Org. Lett. 2006, 8, 4413-
4416.
(5) For representative examples of enantioselective allylation of ketones,
see: (a) Leighton, J. L.; Burns, N. Z.; Hackman, B. M.; Ng, P. Y.; Powelson,
I. A. Angew. Chem. 2006, 118, 3895-3897; Angew. Chem., Int. Ed. 2006,
45, 3811-3813. (b) Schaus, S. E.; Lou, S.; Moquist, P. N. J. Am. Chem.
Soc. 2006, 128, 12660-12661. (c) Soderquist, J. A.; Canales, E.; Prasad,
K. G. J. Am. Chem. Soc. 2005, 127, 11572-11573. (d) Soderquist, J. A.;
Burgos, C. H.; Canales, E.; Matos, K. J. Am. Chem. Soc. 2005, 127, 8044-
8049. (e) Chong, J. M.; Wu, T. R.; Shen, L. Org. Lett. 2004, 6, 2701-
2704. (f) Woodward, S.; Cunningham, A. Synlett 2002, 43-44. (g)
Woodward, S.; Prieto, O. J. Organomet. Chem. 2006, 691, 1515-1519.
(h) Woodward, S.; Cunningham, A.; Mokalparekh, V.; Wilson, C. Org.
Biomol. Chem. 2004, 2, 741-748. (i) Tietze, L. F.; Kinzel, T.; Schmatz, S.
J. Am. Chem. Soc. 2006, 128, 11483-11495. (j) Tietze, L. F.; Vo¨lkel, L.;
Wulff, C.; Weigand, B.; Bittner, C.; McGrath, P.; Johnson, K.; Scha¨fer,
M. Chem. Eur. J. 2001, 7, 1304-1308. (k) Tietze, L. F.; Weigand, B.;
Vo¨lkel, L.; Wulff, C.; Bittner, C. Chem. Eur. J. 2001, 7, 161-168. (l) Tietze,
L. F.; Schiemann, K.; Wegner, C.; Wulff, C. Chem. Eur. J. 1998, 4, 1862-
1869. (m) Tietze, L. F.; Wegner, C.; Wulff, C. Eur. J. Org. Chem. 1998,
1639-1644. (n) Tietze, L. F.; Wegner, C.; Wulff, C. Synlett 1996, 471-
472. (o) Baba, A.; Yasuda, M.; Kitahara, N.; Fujibayashi, T. Chem. Lett.
1998, 8, 743-744. (p) Miller, J. J.; Sigman, M. S. J. Am. Chem. Soc. 2007,
129, 2752-2753.
(6) Wadamoto, M.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 14556-
14557.
(7) Loh, T. P.; Lu, J.; Hong, M. L.; Ji, S. J.; Teo, Y. C. Chem. Commun.
2005, 4217-4218.
(8) Loh, T. P.; Teo, Y. C.; Goh, J. D. Org. Lett. 2005, 7, 2743-2745.
(9) For representative examples, see: (a) Wooten, A. J.; Kim, J. G.;
Walsh, P. J. Org. Lett. 2007, 9, 381-384. (b) Walsh, P. J.; Kim, J. G.;
Waltz, K. M.; Garcia, L. F.; Kwiatkowski, D. J. Am. Chem. Soc. 2004,
126, 12580-12585. (c) Walsh, P. J.; Waltz, K. M.; Gavenonis, J. Angew.
Chem. 2002, 114, 3849-3852; Angew. Chem., Int. Ed. 2002, 41, 3697-
3699. (d) Tagliavini, E.; Casolari, S.; D’Addario, D. Org. Lett. 1999, 1,
1061-1063. (e) Maruoka, K.; Kii, S. Chirality 2003, 15, 68-70. (f)
Maruoka, K.; Hanawa, H.; Kii, S. AdV. Synth. Catal. 2001, 343, 57-60.
(10) Shibasaki, M.; Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M. J. Am.
Chem. Soc. 2002, 124, 6536-6537.
Results and Discussion
In the preliminary study, (S)-pipecolic acid-derived N,N′-
dioxide L1 (Figure 1) was employed as an organocatalyst
for the enantioselective allylation of acetophenone with tetraal-
lyltin. Unfortunately, no homoallylic alcohol was obtained
(12) For review, see: (a) Chelucci, G.; Murineddu, G.; Pinna, A. G.
Tetrahedron: Asymmetry 2004, 15, 1373-1389. (b) Kocˇovsky´, P.; Malkov,
A. Eur. J. Org. Chem. 2007, 29-36.
(11) Shibasaki, M.; Wada, R.; Oisak, K.; Kanai, M. J. Am. Chem. Soc.
2004, 126, 8910-8911.
5228 J. Org. Chem., Vol. 72, No. 14, 2007

EnantioselectiVe Allylation of Ketones
TABLE 1. Effect of Indium Reagents in Enantioselective
Allylation of Acetophenone with L1a
SCHEME 1. Allylation of Acetophenone with Tetraallyltin
Promoted by L1
entry
indium reagentb
yield (%)c
ee (%)d
(Scheme 1), which showed that only N-oxide activating the
tetraallyltin could not overcome the activation energy barrier
of the reaction.
1
2
3
4
InBr3
In(OTf)3
InCl3
8
74e
21e
25
ndf
ndf
In(OCOCH3)3
Following the concept of bifunctional catalysis, and to
compensate for the low reactivity of ketones, several indium-
(III) reagents were screened, which had proved to be efficient
in allylation of the carbonyl compouds3m,7,8 as Lewis acids to
activate acetophenone (Table 1). The results indicated that InBr3
coordinated with L1 in the ratio of 1:2 as the catalyst could
catalyze the enantioselective allylation of acetophenone with
74% enantiomeric excess and 8% yield (Table 1, entry 1). In-
(OTf)3 produced the homoallylic alcohol with 21% ee and 25%
yield (Table 1, entry 2). When InCl3 and In(OCOCH3)3 were
examined, no allylic product was detected (Table 1, entries 3
and 4). Therefore, we chose InBr3 combined with L1 as a
catalyst to optimize other parameters.
a All reactions were carried out under nitrogen at 0 °C, 0.2 mmol of
ketone, 1.1 equiv of tetraallyltin, and L1-indium reagent complex (2:1, 10
mol %) in CH3CN for 24 h. b The catalyst loading was calculated according
to the center metal. c Isolated yield. d Determined by chiral HPLC on a
Chiralcel OJ-H column. e The absolute configuration of the major product
was R, which was determined by comparison with the reported value of
optical rotation, see ref 7. f Not detected.
TABLE 2. Solvent Effect in the Enantioselective Allylation of
Acetophenone with InBr3 and L1a
The enantioselectivity and reactivity were largely dependent
on solvent. As shown in Table 2, in hexane, THF, or toluene,
the desired products were not detected (Table 2, entries 1-3).
The desired product was obtained in CH2Cl2 with 44% ee and
18% yield (Table 2, entry 4). To improve the yield and the
enantioselectivity, we investigated other solvents with greater
polarity, such as CH3CN (Table 2, entry 5). Fortunately, the
homoallylic alcohol was isolated in 25% yield and 75% ee in
DMF (Table 2, entry 6). In HMPA, the enantioselectivity of
product was 23% ee with 18% yield (Table 2, entry 7). In terms
of enantioselectivity, DMF was a better choice over the other
solvents for exploring the other conditions.
These results prompted us to screen other N,N′-dioxides
(Figure 1). Other (S)-pipecolic acid-derived N,N′-dioxides and
L-proline-based N,N′-dioxides were prepared and evaluated, with
the results listed in Table 3. When the R1 group of the (S)-
pipecolic acid-derived N,N′-dioxides (L2) was a methyl group,
the ee value was lower, which was probably due to the steric
effect (Table 3, entry 2). When the R2 group was a methyl group
(L3), the yield of the homoallylic alcohol was dramatically
decreased to 13% with the enantioselectivity slightly increased
entry
solvent
yield (%)b
ee (%)c
1
2
3
4
5
6
7
hexane
toluene
THF
CH2Cl2
CH3CN
DMF
nd.d
ndd
ndd
18
8
25
44e
74e
75e
23e
HMPA
18
a All reactions were carried out under nitrogen at 0 °C, 0.2 mmol of
ketone, 1.1 equiv of tetraallyltin for 24 h. b Isolated yield. c Determined by
chiral HPLC on a Chiralcel OJ-H column. d Not detected. e The absolute
configuration of the major product was R, which was determined by
comparison with the reported value of optical rotation, see ref 7.
TABLE 3. The Enantioselective Allylation of Acetophenone
Catalyzed by InBr3 and Different N,N′-Dioxide Complexesa
entry
N,N′-dioxides
yield (%)b
ee (%)c,d
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
25
14
13
22
20
18
25
17
11
trace
21
75 (R)
16 (R)
76 (R)
9 (S)
16 (S)
15 (S)
13 (S)
8 (R)
5 (S)
(13) For achiral and chiral N-oxides acting as Lewis base or organo-
catalysts catalytic systems. See: (a) He, B.; Chen, F. X.; Feng, X. M.; Zhang,
G. L. Tetrahedron Lett. 2004, 45, 5465-5467. (b) Li, Y.; He, B.; Feng, X.
M.; Zhang, G. L. Synlett 2004, 1598-1600. (c) Zhou, H.; Chen, F. X.;
Qin, B.; Feng, X. M.; Zhang, G. L. Synlett 2004, 1077-1079. (d) Chen, F.
X.; Feng, X. M.; Qin, B.; Zhang, G. L.; Jiang, Y. Z. Org. Lett. 2003, 5,
949-952. (e) Shen, Y. C.; Feng, X. M.; Zhang, G. L.; Jiang, Y. Z. Synlett
2002, 1353-1355. (f) Liu, B.; Feng, X. M.; Chen, F. X.; Zhang, G. L.;
Cui, X.; Jiang, Y. Z. Synlett 2001, 1551-1554.
10
11
0
(14) Wen, Y. H.; Huang, X.; Huang, J. L.; Xiong, Y.; Qin, B.; Feng, X.
M. Synlett 2005, 2445-2448.
72 (R)
a All reactions were carried out under nitrogen at 0 °C, 0.2 mmol of
ketone, 1.1 equiv of tetraallyltin in DMF for 24 h. b Isolated yield.
c Determined by chiral HPLC on a Chiralcel OJ-H column. d The absolute
configuration of the major product was determined by comparison with
the reported value of optical rotation, see ref 7.
(15) Jiao, Z. G.; Feng, X. M.; Liu, B.; Chen, F. X.; Zhang, G. L.; Jiang,
Y. Z. Eur. J. Org. Chem. 2003, 3818-3826.
(16) (a) Huang, J. L.; Liu, X. H.; Wen, Y. H.; Qin, B.; Feng, X. M. J.
Org. Chem. 2007, 72, 204-208. (b) Huang, X.; Huang, J. L.; Wen, Y. H.;
Feng, X. M. AdV. Synth. Catal. 2006, 348, 2579-2584.
(17) Qin, B.; Liu, X. H.; Shi, J.; Zheng, K.; Zhao, H. T.; Feng, X. M. J.
Org. Chem. 2007, 72, 2374-2378.
(18) Li, Q. H.; Chang, L.; Liu, X. H.; Feng, X. M. Synlett 2006, 1675-
1678.
to 76% ee (Table 3, entry 3). No better result was provided
when the phenyl group (L1) was replaced by the (S)-1-
phenylethanamine-based aliphatic group (L4) (Table 3, entry
4). When the amide portion of the N,N′-dioxides was the same
(19) (a) Li, Q. H.; Liu, X. H; Wang, J.; Shen, K.; Feng, X. M.
Tetrahedron Lett. 2006, 47, 4011-4014. (b) Shen, Y. C.; Feng, X. M.; Li,
Y.; Zhang, G. L.; Jiang, Y. Z. Eur. J. Org. Chem. 2004, 129-137.
J. Org. Chem, Vol. 72, No. 14, 2007 5229

Zhang et al.
TABLE 4. Effect of Temperature for the Enantioselective
Allylation of Acetophenone Catalyzed by L1-In(III) Complexa
TABLE 7. Effect of Different Catalyst Loading for the
Enantioselective Allylation of Acetophenone Catalyzed by L1-In(III)
Complexa
catalyst loading
entry
(mol %)
yield (%)b
ee (%)c,d
1
2
3
4
5
10
20
30
17
48
49
60
85
80
79
76
entry
temp (°C)
yield (%)b
ee (%)c,d
1
2
23
0
-20
-45
72
66
48
nd
70
77
80
a All reactions were carried out under nitrogen at -20 °C, 0.2 mmol of
ketone, 1.1 equiv of tetraallyltin in DMF for 72 h. b Isolated yield.
c Determined by chiral HPLC on a Chiralcel OJ-H column. d The absolute
configuration of the major product was R, which was determined by
comparison with the reported value of optical rotation, see ref 7.
3
4e
a All reactions were carried out under nitrogen, 0.2 mmol of ketone, 1.1
equiv of tetraallyltin in DMF for 72 h. b Isolated yield. c Determined by
chiral HPLC on a Chiralcel OJ-H column. d The absolute configuration of
the major product was R, which was determined by comparison with the
reported value of optical rotation, see ref 7. e Reacted for 120 h.
TABLE 8. Effect of the Amount of Tetraallyltin for the
Enantioselective Allylation of Acetophenone Catalyzed by Chiral
L1-In(III) Complexa
TABLE 5. Effect of the Molar Ratios between InBr3 and L1a
amount of
tetraallyltin (equiv)
yield (%)b
ee (%)c,d
entry
ratio (InBr3:L1)
yield (%)b
ee (%)c,d
entry
1
2
3
1.1
2
3
60
63
72
76
76
80
1
2
3
4
5
2:1
1:1
1:1.5
1:2
1:3
44
43
46
48
44
47
70
76
80
80
a All reactions were carried out under nitrogen at -20 °C, 0.2 mmol of
ketone, 30 mol % of InBr3, and 60 mol % of L1 in DMF for 72 h. b Isolated
yield. c Determined by chiral HPLC on a Chiralcel OJ-H column. d The
absolute configuration of the major product was R, which was determined
by comparison with the reported value of optical rotation, see ref 7.
a All reactions were carried out under nitrogen at -20 °C, 0.2 mmol of
ketone, 1.1 equiv of tetraallyltin in DMF for 72 h. b Isolated yield.
c Determined by chiral HPLC on a Chiralcel OJ-H column. d The absolute
configuration of the major product was R, which was determined by
comparison with the reported value of optical rotation, see ref 7.
(Table 4, entry 4). To provide good levels of enantioselectivity,
the appropriate reaction temperature was -20 °C.
TABLE 6. Effect of the Concentration of Acetophenone for the
Enantioselective Allylation Catalyzed by L1-In(III) Complexa
The molar ratio of InBr3 to L1 was found to be another
important factor for the enantioselectivity. When the ratio (InBr3/
L1) was 2:1, low enantioselectivity (47% ee) and yield (44%)
was obtained (Table 5, entry 1). Decreasing the molar ratio
(InBr3/L1) from 2:1 to 1:2, enantiomeric excesss increased to
80% ee (Table 5, entries 1-4). However, when the molar ratio
was decreased to 1:3, a similar enantioselectivity was maintained
(Table 5, entry 5). The molar ratio of InBr3 to L1 was seen to
be most efficient at 1:2.
The effect of the concentration of substrate was also
investigated (Table 6). A moderate result was observed when
the reaction was carried out at 0.5 M (Table 6, entry 3). When
the concentration of acetophenone was diminished from 0.5 to
0.1 M, the reactivity was decreased remarkably (Table 6, entries
1 and 2). When the concentration of acetophenone was increased
to 1.0 M, both the reactivity and the enantioselectivity were
decreased (Table 6, entry 4).
To improve the reactivity, the effect of the catalyst loading
was examined (Table 7). By increasing of the catalyst loading
from 5 mol % to 30 mol %, the yield was sharply enhanced
from 17% to 60% with the ee value slightly dropped from 85%
to 76%. To hold the moderate yield, 30 mol % catalyst loading
had to be employed (Table 7, entry 4).
The amount of tetraallyltin was also studied (Table 8). There
was a tendency that the higher amount of tetraallyltin resulted
in higher yields. When the amount of tetraallyltin was increased
from 1.1 to 2.0 equiv, the reactivity increased slightly (yield
from 60% to 63%) and enantioselectivity was maintained (Table
8, entries 1 and 2). When 3.0 equiv of tetraallyltin was used,
the reaction led to an increase in both yield and enantioselectivity
(Table 8, entry 3).
concn of
acetophenone (M)
entry
yield (%)b
ee (%)c,d
1
2
3
4
0.1
0.2
0.5
1.0
37
48
56
55
82
80
79
77
a All reactions were carried out under nitrogen at -20 °C, 0.2 mmol of
ketone, 1.1 equiv of tetraallyltin, 10 mol % of InBr3, and 20 mol % of L1
in DMF for 72 h. b Isolated yield. c Determined by chiral HPLC on a
Chiralcel OJ-H column. d The absolute configuration of the major product
was R, which dwas etermined by comparison with the reported value of
optical rotation, see ref 7.
phenyl group as L1, L-proline-derived N,N′-dioxide (L5) (Table
3, entry 5) only gave 16% ee and 20% yield. No more than
15% ee was afforded when substituted phenyl groups in the
amide portion of the L-proline-derived N,N′-dioxides (L6-L9)
were investigated (Table 3, entries 6-9). It was notable that
when the piperidinamide (L10) was studied as a ligand, trace
racemic product was obtained (Table 3, entry 10), which proved
that the N-oxide was essential to activate the allylic tin reagent.
Interestingly, the (S)-pipecolic acid-derived single N-oxide (L11)
also gave 72% ee (Table 3, entry 11). The (S)-pipecolic acid-
derived N,N′-dioxide L1 was found be a more efficient ligand
to possess good enantioselectivity for the enantioselective
allylation of ketones.
An examination of the temperature effect revealed that the
temperature affected both the yield and the enantioselectivity
(Table 4). A higher ee value was achieved at lower temperature
but the yield decreased significantly. When the reaction was
carried out at -20 °C, allylic product was obtained with 80%
ee (Table 4, entry 3). Unfortunately, if the reaction temperature
was decreased to -45 °C, no product was detected for 120 h
With the optimal conditions, the scope of the catalytic
enantioselective allylation of ketones was investigated by
5230 J. Org. Chem., Vol. 72, No. 14, 2007

EnantioselectiVe Allylation of Ketones
TABLE 9. The Scope of Ketones for the Enantioselective Allylation Catalyzed by L1-In(III) Complexa
yield
(%)b
ee
(%)
entry
ketone
product
1
2
3
4
5
6
7
8
9
acetophenone (1a)
3a
3b
3c
3d
3e
3f
3g
3h
3i
72
69
48
85
70
61
86
94
77
89
36
80 (R)c,e
2-methoxyacetophenone (1b)
4-methoxyacetophenone (1c)
3-methoxyacetophenone (1d)
4-methylacetophenone (1e)
4-fluoroacetophenone (1f)
4-chloroacetophenone (1g)
4-bromoacetophenone (1h)
3-chloroacetophenone (1i)
2-acetonaphthone (1j)
3,4-dihydronaphthalen-
1(2H)-one (1k)
2,2,2-trifluoroacetophenone (1l)
4-phenylbutan-2-one (1m)
83d
80 (R)d,e
74d
81 (R)c,f
81c
80c
79d
70d
10
11
3j
3k
73 (R)d,f
75 (R)d,e
12
13
3l
3m
70
49
73d
53 (S)d,g
a All reactions were carried out under nitrogen at -20 °C, 0.2 mmol of ketone, and 0.6 mmol of tetraallyltin in DMF (0.4 mL) for 72 h. b Isolated yield.
c Determined by chiral HPLC on a Chiralcel OJ-H column. d Determined by chiral HPLC on a Chiralcel OD-H column. e The absolute configuration of the
major product was determined by comparison with the reported value of optical rotation, see ref 6. f The absolute configuration of the major product was
determined by comparison with the reported value of optical rotation, see ref 7. g The absolute configuration of the major product was determined by
comparison with the reported value of optical rotation, see ref 8.
treatment of a series of ketones. The results were listed in Table
9. Substituents on the aromatic ring had a slight influence on
the enantioselectivity. For example, 2-methoxyacetophenone
gave the allylic product with highest ee value (83% ee) (Table
9, entry 2), the homoallylic alcohol from 4-methoxyacetophe-
none obtained with 48% yield and 80% ee (Table 9, entry 3),
and 3-methoxyacetophenone only gave 74% ee with the 85%
yield (Table 9, entry 4). 4-Methylacetophenone also produced
good yield (70%) and enantioselectivity (81% ee) (Table 9, entry
5). The halogen-substituted aromatic ketones afforded the
corresponding homoallylic alcohols in moderate to high yields
FIGURE 2. NLE in enanotioselective allylation of acetophenone with
tetraallyltin catalyzed by N,N′-dioxide L1-In(III) complex.
and good enantioselectivities (Table 9, entries 6-9). The
allylation of 2-acetonaphthone under the influence of the chiral
indium catalyst furnished the homoallylic alcohol with 89%
yield and 73% ee (Table 9, entry 10). Both cyclic ketone (3,4-
dihydronaphthalen-1(2H)-one) and 2,2,2-trifluoroacetophenone
underwent the allylation to afford the products in 75% ee (Table
9, entry 11) and 73% ee (Table 9, entry 12). Inspired by the
results from aromatic ketones, aliphatic ketones were surveyed.
However, moderate enantioselectivity (53% ee) was obtained
with 4-phenylbutan-2-one (Table 9, entry 13) under the current
system as well as other aliphatic ketones.
as a Lewis acid and the N-oxide activated tetraallyltin as a Lewis
base. A plausible catalytic cycle of the enantioselective allylation
of aromatic ketones was illustrated in Figure 3. We speculated
that two molecules of N,N′-dioxide L1 were tetradentate
coordinated with InBr3 (complex A).21 The 1H NMR date
(combination of InBr3 and L1 in ratio of 1:2 in d6-DMSO)
indicate that in the generation of the In(III)-L1 complex A, three
molecules HBr were removed (see the Supporting Information
for details). The N-oxide coordinated to the tin atom as a Lewis
base in the presence of tetraallyltin to form a possible hyper-
valent tin species (complex B).22 One of the activated allylic
groups might be transferred from the tin atom to the indium
atom to form an allylic indium complex (complex C).23 It was
notable that the solvent played a key role for the formation of
the allylic indium complex in this step. DMF made this
procedure more effective.23a As a Lewis acid, the indium
activated the ketone. So the allylic group in indium preferred
to attack the activated ketone to afford 2a, and the product was
Mechanisic Consideration
To obtain the information on the mechanism of the allylation
of ketones with the N,N′-dioxide In(III) complex, the relationship
between the enantiopurity of the ligand L1 and the enantiopurity
of the product 3a was studied (Figure 2). The result indicated
a positive nonlinear effect for the reaction. We considered the
ML2 model fit to experimental data described by Kagan and
co-workers.20
On the basis of the experimental investigation and previous
reports,21-23 we considered here that indium activated the ketone
(22) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2003, 125, 2208-2216.
(23) (a) Yasuda, M.; Miyai, T.; Shibata, I.; Baba, A. Tetrahedron Lett.
1995, 36, 9497-9500. (b) Shibata, I.; Kato, H.; Ishida, T.; Yasuda, M.;
Baba, A. Angew. Chem. 2004, 116, 729-732; Angew. Chem., Int. Ed. 2004,
43, 711-714. (c) Takita, R.; Fukuta, Y.; Tsuji, R.; Ohshima, T.; Shibasaki.
M. Org. Lett. 2005, 7, 1363-1366.
(20) Guillaneux, D.; Zhao, S. H.; Samuel, O.; Rainford, D.; Kagan, H.
B. J. Am. Chem. Soc. 1994, 116, 9430-9439.
(21) Delpech, F.; Guzei, I. A.; Jordan, R. F. Organometallics 2005, 21,
1167-1176.
J. Org. Chem, Vol. 72, No. 14, 2007 5231

Zhang et al.
FIGURE 3. Plausible catalytic cycle and transition state.
obtained after general workup. When another tetraallyltin was
coordinated by N-oxides, complex B was regenerated.
possible catalytic cycle including a transition state has been
proposed. Future efforts will be focused on the possibility of
reducing the catalyst loading to obtain maximum levels of
enantioselectivity and yield and examine other silicon allyl
reagents for the enantioselective allylation of ketones.
On the basis of the observed absolute configuration of 3a,6
we proposed a possible transition state I. In transition state I,
the allylic group was much more accessible to attack the Si-
face of the carbonyl of acetophenone than the Re-face, since
the Re-face attack was likely to increase the steric repulsion
between the phenyl group of acetophenone and the phenyl
subunit of the catalyst in proposed transition state II.
Experimental Section
Typical Experimental Procedure for the Enantioselective
Allylation of Ketones. To an oven dried tube equipped with a
magnetic stirring bar were added InBr3 (21.3 mg, 0.06 mmol) and
L1 (57.6 mg, 0.12 mmol) in anhydrous DMF (0.4 mL), and the
solution was allowed to stir at ambient temperature for 2 h under
N2 atmosphere. The tetraallyltin (144 µL, 0.6 mmol) was added at
-20 °C, then acetophenone 1a (24 µL, 0.2 mmol). The reaction
mixture was stirred at -20 °C for 72 h and directly purified by
column chromatography on silica gel eluted with diethyl ether/
petroleum ether (1:10 v/v) to afford product 3a as a colorless oil
in 72% isolated yield with 80% ee [determined with chiral HPLC,
DAICEL CHIRALCEL OJ-H, isopropanol:hexane 2:98, 1.0 mL/
min, λ ) 254 nm, tR(major) ) 12.019 min, tR(minor) ) 15.512
Conclusion
We have developed a novel chiral indium complex prepared
from indium(III) bromide and (S)-pipecolic acid-derived N,N′-
dioxides for the enantioselective allylation of ketones. Under
the optimized conditions, good enantioselectivities (up to 83%
ee) and moderate to high yields were observed for a range of
aromatic ketones. The experimental results showed that it was
feasible for the L1-InBr3 complex to be an efficient catalyst
for the allylation of ketones with good enantioselectivity. A
5232 J. Org. Chem., Vol. 72, No. 14, 2007

EnantioselectiVe Allylation of Ketones
min]; [R]25D +42.6 (c 0.108, CHCl3). 1H NMR (400 MHz, CDCl3)
δ 7.43-7.46 (m, 2H), 7.33-7.37 (m, 2H), 7.24-7.26 (m, 1H),
5.58-5.63 (m, 1H), 5.11-5.17 (m, 2H), 2.69(dd, J ) 13.6, 6.4
Hz, 1H), 2.50 (dd, J ) 13.6, 8.4 Hz , 1H), 2.05 (s, 1H), 1.55 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 146.6, 132.6, 127.2, 125.6,
123.7, 118.5, 72.6, 47.4, 28.9 ppm.
University Analytival and Testing Center for 1H NMR and 13
NMR spectra analysis.
C
Supporting Information Available: Experimental procedures
1
and structural proofs for catalysts and racemates, H NMR, and
13C NMR spectra, and HPLC. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was financially supported by
the National Nature Science Foundation of China (Nos.
20390055, 20372050, and 20602025). We also thank Sichuan
JO0706325
J. Org. Chem, Vol. 72, No. 14, 2007 5233