Asymmetric indium-mediated Barbier-type allylation reactions with ketones to form homoallylic alcohol products

Article abstract of DOI:10.1016/j.tetlet.2007.11.089

We report a general method for the enantioselective allylation of both aromatic and aliphatic ketones under indium-mediated Barbier-type conditions. Using 2 equiv of a commercially available amino alcohol, either (1S,2R)-(+)-2-amino-1,2-diphenylethanol ((

Full text of DOI:10.1016/j.tetlet.2007.11.089

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 508–511
Asymmetric indium-mediated Barbier-type allylation reactions
with ketones to form homoallylic alcohol products
Terra D. Haddad, Lacie C. Hirayama, Philip Taynton, Bakthan Singaram *
Department of Chemistry and Biochemistry, University of California at Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, United States
Received 30 October 2007; revised 14 November 2007; accepted 15 November 2007
Available online 22 November 2007
Abstract
We report a general method for the enantioselective allylation of both aromatic and aliphatic ketones under indium-mediated Barbier-
type conditions. Using 2 equiv of a commercially available amino alcohol, either (1S,2R)-(+)-2-amino-1,2-diphenylethanol ((+)-1) or
(
1R,2S)-(À)-2-amino-1,2-diphenylethanol ((À)-1) as the chiral auxiliary, good yields and enantioselectivities were achieved. To our
knowledge, the enantioselectivities reported herein are the highest obtained for the indium-mediated allylations of ketones, specifically
the homoallylic alcohol product obtained from the addition to a,a,a-trifluoroacetophenone provided 80% enantiomeric excess.
ꢀ
2007 Elsevier Ltd. All rights reserved.
The asymmetric allylation of carbonyls, such as alde-
(79–93%) using 2 equiv of allyl bromide, (+)-1, pyridine
and indium powder. Also, we have achieved the synthesis
9
hydes and ketones, remains one of the most useful methods
1
a,2
for carbon–carbon bond-formation.
In addition, the
of homopropargylic alcohols in good yield (53–99%) and
1
0
metal-mediated allylation of carbonyls continue to be a
valuable method for the formation of chiral homoallylic
enantiomeric excess (75–95%) using propargyl bromide.
We envisioned that this methodology could be applied to
the allylation of ketones (Scheme 1).
3
alcohols, as they are often used as building blocks in the
1
b,4
synthesis of larger complex molecules.
In particular,
Using indium metal, allyl bromide and (+)-1 in the pres-
ence of pyridine at À78 ꢁC, acetophenone was not con-
verted to the corresponding homoallylic alcohol (<5%)
even after 2 h (Table 1, entry 1). Consequently, we focused
our efforts on optimizing the reaction conditions to
increase the product formation, as ketones are less reactive
than aldehydes. We began by increasing the reaction time
methods for the asymmetric allylation of ketones are desir-
5
able due to the formation of chiral tertiary alcohols.
Although numerous methods exist for the asymmetric
6
allylation of aldehydes, far fewer are known to employ
7
ketones. In recent years, indium-promoted reactions have
gained appeal due to the lack of air- and moisture-sensitiv-
8
ity, toxicity, and ability to tolerate functionality. Herein,
we report a method for the synthesis of enantiomerically
enriched tertiary homoallylic alcohols from ketones using
indium.
Recently, our group has shown (+)-1 to be an effective
chiral promoter for asymmetric indium-mediated reac-
tions. Various aldehydes were converted to the correspond-
ing homoallylic alcohols in excellent enantiomeric excess
Br
py, THF, 25 °C, 24 h
L*,
O
HO R2
R1
+
In°
*
R1
R2
HO
Ph
NH2
Ph
HO
Ph
NH2
Ph
(+)-1
(−)-1
*
Corresponding author. Tel.: +1 831 459 3154; fax: +1 831 459 2935.
E-mail address: singaram@chemistry.ucsc.edu (B. Singaram).
Scheme 1. Asymmetric indium-mediated allylation of ketones.
0
040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.089

T. D. Haddad et al. / Tetrahedron Letters 49 (2008) 508–511
509
Table 1
Gratified by these initial results, we investigated various
temperatures at longer reaction times. We found that by
cooling the reaction flask to both À40 and À15 ꢁC and
allowing the mixture to warm to room temperature over-
night increased the enantiomeric excess slightly to 50%
and 56%, respectively (Table 1, entries 3 and 4). Appar-
ently, the reaction is not taking place at À78 ꢁC but occurs
during the warm up. By conducting the reaction at room
temperature overnight, 86% of the homoallylic alcohol
was isolated in 58% ee (Table 1, entry 5). However, reflux-
ing the reaction mixture did not increase conversion or ee,
therefore the optimal conditions were identified as those
shown in entry 5.
We then investigated the effect of excess allyl bromide on
the allylation reaction. Initially, we used 2 equiv of allyl
bromide in our reaction (Table 2, entry 1). We found that
the use of 3 equiv of allyl bromide decreased the conversion
of acetophenone to the corresponding homoallylic alcohol
to 50% (Table 2, entry 2). In addition, we observed an over-
all reduction in the allylation of acetophenone with increas-
ing equivalents of allyl bromide providing only 43%
Temperature and time optimization for the enantioselective allylation of
acetophenone with allyl bromide
a
O
HO
NH2
Ph
Ph
Me
HO Me
Ph
+
In°
+ Br
py, THF
Ph
b
c
Entry
Temperature (ꢁC)
Time (h)
% Conversion
% ee
1
2
3
4
5
6
a
À78
2
24
24
24
24
24
<5
85
97
87
86
79
—
48
50
56
58
56
À78 to 25
À40 to 25
À15 to 25
25
65
o
Reactions run with In (0.5 mmol), (+)-1(0.5 mmol), pyridine
(
0.5 mmol), allyl bromide (0.5 mmol) and ketone (0.25 mmol) in THF.
b
1
Determined by H NMR analysis.
c
Determined by chiral GC analysis.
and temperature by allowing the reaction to warm slowly
from À78 ꢁC to room temperature overnight. This resulted
in an 85% conversion of the acetophenone to the homoal-
lylic alcohol in 48% enantiomeric excess (Table 1, entry 2).
Table 3
Screening of chiral auxiliaries for the enantioselective allylation of
a
acetophenone with allyl bromide
Table 2
Optimization for the enantioselective allylation of acetophenone with allyl
bromide
O
a
Ph
Me
HO Me
Ph
In° + Br
Ligand*
+
O
py, THF, 25 °C, 24 h
Ph
Me
HO Me
In° + Br
(
+)-1
+
Entry
Ligand*
% Conversion
b
% ee
c
py, THF, 25 °C, 24 h Ph
1
2
3
4
5
6
7
(+)-1
87
0
0
78
47
44
81
58
0
0
0
0
ob
b
Entry In
(+)-
1
Pyridine Allyl
bromide
%
%
ee
2
3
4
5
6
7
b
b
c
d
Conversion
1
2
3
4
2
2
2
2
2
2
2
2
2
2
2
2
2
87
50
43
55
58
53
54
56
3
4
6
0
0
a
b
c
a
Reactions run with In (0.5 mmol), Ligand* (0.5 mmol), pyridine
o
Reactions run with acetophenone (0.25 mmol) as the limiting reactant.
Refers to number of equivalents.
Determined by H NMR analysis.
(0.5 mmol), allyl bromide (0.5 mmol) and ketone (0.25 mmol) in THF.
b
1
1
Determined by H NMR analysis.
Determined by chiral GC analysis for the acetylated homoallylic
d
c
Determined by chiral GC analysis of the acetylated homoallylic alco-
hol product.
alcohol product.
H
HO
HO
HO
O
H
H
N
S
N
N
O
H
N
2: (−)-cinchonidine
3
4
OH
O
HO
OH
N
H N
NH
Me
2
5
6
7
Figure 1. Ligands used in the indium-mediated allylation of acetophenone with allyl bromide.

510
T. D. Haddad et al. / Tetrahedron Letters 49 (2008) 508–511
conversion for 4 equiv and 55% conversion for 6 equiv
Table 2, entries 3 and 4). The enantiomeric excess for
the corresponding homoallylic alcohol product remained
essentially constant with increasing concentration of allyl
bromide (Table 2, entries 2–4). Therefore, we used 2 equiv
of allyl bromide in our subsequent reactions.
Although we had found that the chiral auxiliary (+)-1
was the most effective for aldehydes, we screened other
chiral amino alcohols for their efficiency in the allylation
of ketones (Fig. 1). Under our reaction conditions, we did
not observe the conversion of acetophenone to the corre-
sponding homoallylic alcohol when using (À)-cinchonidine
as the chiral director (Table 3, entry 2). We evaluated
various b-amino alcohols derived from terpenes that were
1
1
(
available in our lab and found that one did not promote
the conversion of acetophenone (Table 3, entry 3), while
the other two provided the homoallylic alcohol product
in 78% and 81%, respectively (Table 2, entries 4 and 7).
However, 4 and 7 were inefficient chiral promoters and
no enantiomeric excess was obtained (Table 3, entries 4
and 7). Ligands 5 and 6 provided moderate conversion of
acetophenone, 47% and 44%, but the product was racemic
(Table 3, entries 5 and 6). Since none of these other chiral
amino alcohols gave better results, we used the commer-
cially available (1S,2R)-(+)-2-amino-1,2-diphenylethanol
for further study (Table 3, entry 1).
Table 4
a
Enantioselective indium-mediated allylation of ketones
Br
py, THF, 25 °C, 24 h
L*,
O
HO R2
R1
*
+
In°
R1
R2
b,c
d,e
Entry
Ketone
Product
L*
% Yield
% ee
O
OH
1
2
(+)-1
(À)-1
87
72
58 (S)
57 (R)
O
O
OH
OH
3
4
(+)-1
(+)-1
92
74
48 (S)
NC
O
NC
OH
f
48 (S)
MeO C
MeO2C
2
f
5
(+)-1
77
41 (S)
HO
HO
O
O
OH
g
6
7
O
(+)-1
>99
77
44 (S)
45 (S)
O
OH
(À)-1
O
OH
8
(À)-1
(À)-1
46
81
42 (S)
64 (S)
O
OH
1
3
9
O
F3C OH
1
3
1
1
0
1
(+)-1
(À)-1
94
>99
80 (S)
78 (R)
CF3
g
a
o
Reactions run with In (1.0 mmol), 2-amino-1,2-diphenylethanol (1.0 mmol), pyridine (1.0 mmol), allyl bromide (1.0 mmol) and ketone (0.5 mmol) in
13
THF at room temperature for 24 h.
b
1
Isolated yield of analytically pure product all products greater than 90% by H NMR.
Based on unreacted starting material.
Determined by chiral GC analysis.
Absolute configuration determined by comparison of the optical rotation with literature value, all others were assigned by analogy.
Determined by chiral RP-HPLC analysis.
Reactions run with recovered and purified ligand.
c
d
e
f
14
g

T. D. Haddad et al. / Tetrahedron Letters 49 (2008) 508–511
3. Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207–2293.
511
To evaluate the generality of this reaction, we screened
4
. Nicolaou, K. C.; Kim, D. W.; Baati, R. Angew. Chem., Int. Ed. 2002,
several ketones under the optimized reaction conditions.
In addition to using (+)-1 as the chiral director for the ally-
lation of ketones, the enantiomer, (À)-1, was employed for
several ketone substrates providing the opposite enantio-
mer of the homoallylic alcohol products. We investigated
4
1, 3701–3704.
5
6
. Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873–888.
. (a) Xia, G.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 2554–2555;
(b) Burgos, C. H.; Canales, E.; Matos, K.; Soderquist, J. A. J. Am.
Chem. Soc. 2005, 127, 8044–8049; (c) Nokami, J.; Nomiyama, K.;
Shafi, S. M.; Kataoka, K. Org. Lett. 2004, 6, 1261–1264; (d) Loh, T.-
P.; Yin, Z.; Song, H.-Y.; Tan, K.-L. Tetrahedron Lett. 2003, 44, 911–
(
À)-1 with acetophenone and were pleased to see that (R)
homoallylic alcohol was obtained in good yield and in
9
14; (e) Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.; Shibasaki, M.
1
2
5
7% ee (Table 4, entry 2). Although the enantioselectivity
J. Am. Chem. Soc. 2002, 124, 6536–6537; (f) Kirihara, M.; Takuwa,
T.; Takizawa, S.; Momose, T.; Nemoto, H. Tetrahedron 2000, 56,
8250–8275.
was only moderate for 4-acetylbenzonitrile, methyl-4-acet-
ylbenzoate, 4-hydroxyacetophenone (41–48% ee), these
substrates demonstrated that various functionalities were
tolerated under our reaction conditions and provided good
to excellent yield (74–92%) of the corresponding homoal-
lylic alcohols (Table 4, entries 3–5). In addition, 2-acetylfu-
ran afforded the corresponding homoallylic alcohol in
quantitative yield and moderate enantiomeric excess, 44%
7
. (a) Wooten, A. J.; Kim, J. G.; Walsh, P. J. Org. Lett. 2007, 9, 381–
3
84; for an asymmetric Reformatsky reaction, see: (b) Cozzi, P. G.
Angew. Chem., Int. Ed. 2006, 45, 2951–2954; (c) Teo, Y.-C.; Goh, J.-
D.; Loh, T.-P. Org. Lett. 2005, 7, 2743–2745; (d) Lu, J.; Ji, S.-J.; Teo,
Y.-C.; Loh, T.-P. Tetrahedron Lett. 2005, 46, 7435–7437; (e) Wu, T.
R.; Shen, L.; Chong, J. M. Org. Lett. 2004, 6, 2701–2704; (f)
Cunningham, A.; Woodward, S. Synlett 2002, 43–44; (g) Yasuda, M.;
Kitahara, N.; Fujibayashi, T.; Baba, A. Chem. Lett. 1998, 27, 743–
(
Table 4, entry 6). Aliphatic ketones provided the corre-
7
3
44; (h) Soai, K.; Ishizaki, M.; Yokoyama, S. Chem. Lett. 1987, 2,
41–344.
sponding homoallylic alcohols in good yields and enantio-
meric excesses. The homoallylic alcohols from 2-hexanone
and cyclohexylmethyl ketone were obtained in moderate to
high yields and enantiomeric excesses of 45% and 42%,
respectively (Table 4, entries 7 and 8). We found that the
reaction with the more sterically demanding pinacolone
afforded the product in a higher enantiomeric excess of
8. (a) Lee, P. H. Bull. Korean Chem. Soc. 2007, 28, 17–28; (b) Loh, T.-P.;
Chau, G.-L. Chem. Commun. 2006, 26, 2739–2749; (c) K a¨ llstr o¨ m, S.;
Jagt, R. B. C.; Sillanp a¨ a¨ , R.; Feringa, B. L.; Minnaard, A. J.; Leino,
R. Eur. J. Org. Chem. 2006, 3826–3833; (d) Ritson, D. J.; Cox, R. J.;
Berge, J. Org. Biomol. Chem. 2004, 2, 1921–1933; (e) Paquette, L. A.
Synthesis 2003, 765–774; (f) Podlech, J.; Maier, T. C. Synthesis 2003,
5, 633–655; (g) Lee, W.; Kim, K.-H.; Surman, M. D.; Miller, M. J.
Org. Chem. 2003, 68, 139–149; (h) Lu, W.; Chan, T. K. J. Org. Chem.
6
4% (Table 4, entry 9). Similarly, a,a,a-trifluoroacetophe-
none produced the corresponding homoallylic alcohol in
2
000, 65, 8589–8594.
9
. Hirayama, L. C.; Gamsey, S.; Knueppel, D.; DeLaTorre, K.; Steiner,
8
0% ee, the highest observed for this ketone under
D.; Singaram, B. Tetrahedron Lett. 2005, 46, 2315–2318.
1
5
indium-mediated Barbier reaction (Table 4, entry 11).
1
0. Hirayama, L. C.; Dunham, K. K.; Singaram, B. Tetrahedron Lett.
2006, 47, 5173–5176.
Using (À)-1 we obtained the enantiomeric (R) homoallylic
alcohol in 78% ee in excellent yield (Table 4, entry 10). As
ketone substrates are more sterically hindered and less elec-
trophilic than aldehydes, diminished yields were not sur-
prising. Nevertheless, this demonstrates an effective
method for the enantioselective indium-mediated allylation
of ketones, both aromatic and aliphatic, using a chiral
amino alcohol (see Table 4).
In summary, we have demonstrated a general method
for the indium-promoted enantioselective allylation of both
aromatic and aliphatic ketones using both enantiomers of a
commercially available chiral auxiliary, (+) or (À)-2-
amino-1,2-diphenylethanol. The chiral ligand is recover-
able in high yield and purity from the reaction mixture.
Although the enantioselectivities reported herein are mod-
erate, they are the highest for the indium-mediated allyl-
ations of trifluoroketone.
11. Chrisman, W.; Camara, J. N.; Marcellini, K.; Singaram, B.; Goralski,
C. T.; Hasha, D. L.; Rudolf, P. R.; Nicholson, L. W.; Borodychuk, K.
K. Tetrahedron Lett. 2001, 42, 5805–5807.
1
2. Representative procedure: An oven-dried 25-mL round bottom flask
with stirbar was cooled under argon and charged with (1S,2R)-(À)-2-
amino-1,2-diphenylethanol (0.213 g, 1 mmol), indium powder
(0.115 g, 1 mmol) and anhydrous THF (14 mL). The flask was
vacuum purged with argon (5X), at which time anhydrous pyridine
(
0.08 mL, 1 mmol) and allyl bromide (0.09 mL, 1 mmol) were added
and the mixture was stirred vigorously at 25 ꢁC. After 30 min at
5 ꢁC, acetophenone (0.06 mL, 0.5 mmol) was added dropwise. After
2
24 h the reaction was quenched with saturated ammonium chloride
(6 mL), and the mixture was transferred to a separatory funnel with
hexanes (5 mL). The aqueous layer was removed and the organic layer
was washed with dilute hydrochloric acid (HCl, 2 · 8 mL), brine
(
4
1 · 8 mL), dried with magnesium sulfate (MgSO ), filtered through a
silica plug, and evaporated to give 2-phenylpent-4-en-2-ol as a clear,
yellow oil (0.058 g, 72% yield). Enantiomeric excess was determined to
be 57% by chiral GC analysis. GC conditions: 121 ꢁC isothermal, t
for the (R)-alcohol = 29.14 min, and for the (S)-alcohol =
9.41 min.
13. For entries 9 and 10, the reaction conditions were as follows: In
4.0 mmol), 2-amino-1,2-diphenylethanol (4.0 mmol), pyridine
R
t
R
2
o
References and notes
(
1
. (a) Denmark, S. E.; Almstead, N. G. Allylation of Carbonyls:
Methodology and Stereochemistry. In Modern Carbonyl Chemistry;
Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; pp 299–401; (b)
Chemler, S. R.; Roush, W. R. Recent Applications of the Allylation
Reaction to the Synthesis of Natural Products. In Modern Carbonyl
Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; pp 403–490.
. Demark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763–2793.
(1.0 mmol), allyl bromide (4.0 mmol) and ketone (2.0 mmol) in
THF (24 mL) at room temperature for 24 h.
14. (a) Canales, E.; Prasad, K. G.; Soderquist, J. A. J. Am. Chem. Soc.
2005, 127, 11572–11573; (b) Wu, T. R.; Shen, L.; Chong, J. M. Org.
Lett. 2004, 6, 2701–2704.
15. Loh, T.-P.; Zhou, J.-R.; Li, X.-R. Tetrahedron Lett. 1999, 40, 9333–
9336.
2