Table 1. Effect of Lewis Acids on Crotylboration of
Benzaldehydea
Table 2. Influence of Electronic Nature of Substituents of
Benzaldehyde on Crotylboration with 1 and 2a
reacn
time
(h)
aldehyde
lactone
yldb
reacn
time
(h)
Lewis
acid
yieldb
(%)
drc
cis:trans
drc
entry boronate
lactone
entry reagent
#
R
#
(%)
cis:trans
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
2
2
2
2
2
Sc(OTf)3
In(OTf)3
Bu2BOTf
ZnCl2
Yb(OTf)3
Et3B
8
6
4a
4a
4a
4a
4a
4a
4a
5a
5a
5a
5a
5a
85
85
90
94
80
88
80
82
91
80
85
83
3:97
2:98
7:93
90:10
92:8
93:7
90:10
2:98
2:98
2:98
95:5
95:5
1
2
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
3b
3c
3d
3e
3f
4-MeO
3-MeO
2-MeO
4-Me
4-Cl
12
8
7
10
7
8
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
5b
5e
5f
85
90
88
95
90
80
85
95
95
96
89
95
90
80
98
80
83
96
95
87
95
5:95
10:90
10:90
3:97
33:67
40:60
55:45
75:25
99:1
92:8
97:3
98:2
95:5
2:98
2:98
31:69
30:70
90:10
98:2
20
36
36
48
36
14
10
36
48
30
3
4
5
6
7
8
9
3g
3h
3i
4-Br
3-Cl
2-Cl
TiCl4
8
8
Sc(OTf)3
In(OTf)3
Bu2BOTf
Et3B
3j
3k
3l
4-NO2
3-NO2
4-CN
18
14
16
16
18
10
10
10
10
16
16
14
18
10
11
12
10
11
12
13
14
15
16
17
18
19
20
21
Yb(OTf)3
3m 4-CF3
a Reaction conditions: crotylboronate 1 or 2 (1 mmol), benzaldehyde
3a (1.5 mmol), and 20% catalyst in toluene at room temperature. Entries 3,
5, 6, 10, 11, and 12 are with 40% catalyst. Entries 3 and 4 are in diethyl
ether and 5 and 12 are in THF. b Isolated yield after chromatography.
3n
3b
3e
3f
F5
4-MeO
4-Me
4-Cl
c Determined by H NMR of the crude reaction mixture.
1
3g
3j
3l
4-Br
4-NO2
4-CN
5g
5j
5l
5m
5n
vided the lactone with the reversed stereochemistry, whereas
weaker Lewis acids showed no influence on the stereo-
outcome (eq 2). Crotylboration of 3a with 1, in the presence
of strong Lewis acids, such as In(OTf)3 and Sc(OTf)3, was
completed within 6-8 h at room temperature (rt), as
compared to 7 d for the uncatalyzed reaction, and provided
trans-4a with very high diastereoselectivity (Table 1,
entries 1 and 2). On the other hand, Lewis acids with
moderate activity, such as ZnCl2, Yb(OTf)3, Et3B, and TiCl4
provided cis-4a in 90-93% diastereoselectivity. Similar
diastereomeric ratios were observed in the case of 2 as
well.
3m 4-CF3
3n F5
95:5
98:2
a Reaction condition: 1 or 2 (1 mmol), 20% In(OTf)3, and aldehyde
3b-n (1.5 mmol) in toluene at room temperature. b Isolated yield
after chromatography. c Determined by 1H NMR of the crude reaction
mixture.
high selectivity, (entry 9-12). Parallel observations were
made with 2 as well.
We then selected In(OTf)3 for the crotylboration of a
series of substituted benzaldehydes and noticed that the
reversal in stereochemistry of the lactone is dependent
on the electronic environment of the aldehydes as well!
While an electron-donating substituent on the benzene ring
inverted the stereochemistry, an electron-withdrawing group
provided the cis-lactone (Table 2). A correlation was also
observed for the rate of the reaction: benzaldehydes with
electron-donating groups reacted faster than those with
electron-withdrawing groups. Thus, the crotylboration of
anisaldehydes (3b-d) and p-tolualdehyde (3e) with 1, in
the presence of catalytic In(OTf)3, provided the correspond-
ing trans-lactones, trans-4b-e (entries 1-4) and the reac-
tion of p- and m-nitro, p-cyano-, p-trifluoromethyl- and
pentafluorobenzaldehydes (3j-n) with 1 provided the
corresponding cis-lactones, cis-4j-n, respectively, with very
Halogen substituents provide a mixture of lactones. In line
with the decreased resonance contribution, 4-bromobenzal-
dehyde (3g) provided increased ratio (40%) of cis-4g (entry
6) as compared to 4-chlorobenzaldehyde (3f), which gave
33% of cis-4f (entry 5). As expected, with an increased polar
effect, 2-chlorobenzaldehyde (3i) provided 75% of cis-4i
(entry 8).
After establishing a trend for the inversion of the lactone
stereochemistry, we set out to trace the occurrence of the
reversal. The crotylboration of 3b with 1 under thermal
condition, in the absence of a catalyst, provided the
intermediate 6b, which upon lactonization using pTSA,
provided cis-4b in 96% de. However, lactonization using
20% In(OTf)3 resulted in the exclusive formation of trans-
4b, revealing that the reversal occurred during lactonization
following crotylboration.
(6) (a) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124,
11586. (b) Ishiyama, T.; Ahiko, T.-a.; Miyaura, N. J. Am. Chem. Soc. 2002,
124, 12414. (c) Kennedy, J. W. J.; Hall, D. G. J. Org. Chem. 2004, 69,
4412.
(7) For a review on the relative strength of Lewis acids, see the
following: (a) Marshman, R. W. Aldrichim. Acta. 1995, 28, 77. (b)
Kobayashi, S.; Manabe, K. Pure Appl. Chem. 2000, 72, 1373.
3878
Org. Lett., Vol. 8, No. 17, 2006