Table 1. Effect of Catalystsa
Table 2. InBr3-Catalyzed Reaction of Alkyl Halides with Silyl
Enolatesa
entry
catalyst
yield (%)
1
2
3
4
5
6
7
8
9
none
InBr3
InCl3
ZnBr2
ZnCl2
BF3‚OEt2
AlCl3
0
99
9
39
6
0
0
0
0
TiCl4
BiBr3
a Alkyl chloride 1a (1 mmol), silyl enolate 2a (1.5 mmol), catalyst (0.05
mmol), and CH2Cl2 (1 mL).
reported as a moderate Lewis acid, however, showed no
effect (entry 9).5
Second, various alkyl chlorides and silyl enolates were
treated, and the results are summarized in Table 2. Unacti-
vated aliphatic chlorides 1b and 1c effectively produced the
coupling products 3ba and 3ca, respectively (entries 1 and
2). It is an advantage of the indium catalyst that oxygen-
containing functionalities are applicable (entries 3-5). The
coupling with allylic chloride 1g produced the corresponding
ester 3ga in high yield (entry 6). Both benzyl chlorides,
bearing an electron-withdrawing or -donating group, gave
satisfactory yields (entries 7 and 8). Silyl enolates 2b and
2c, derived from ketones, reacted with 1-chloro-1-phenyl-
ethane 1j to yield the desired substituted ketones in high
yields (entries 9 and 10). Interestingly, thioester and amide
enolates 2d and 2e furnished the substituted thioester 3kd
and amide 3ke, respectively (entries 11 and 12). This is the
first example of coupling of alkyl chlorides with silyl enolates
derived from thioesters and amides.
a Alkyl chloride 1 (1 mmol), silyl enolate 2 (1.5 mmol), InBr3 (0.05
mmol), and CH2Cl2 (1 mL). b Silyl enolate 2 (3 mmol). c InCl3 (0.05 mmol)
was added instead of InBr3. d Silyl enolate 2 (2 mmol). e Diastereomer ratio:
52:48.
The alkyl chloride 1l having a bromo moiety selectively
provided the chloro-coupling product 3la in 82% yield
(Scheme 1). On the contrary, employment of Hiyama-
coupling conditions using a palladium catalyst promoted an
alternate coupling at the bromo moiety to furnish the
dehydrochlorinated products 4 and 5.6
Most studies have focused on enolates derived from esters
and ketones, while a few have been done using silyl enolates
derived from aldehydes, in part due to a lower nucleophi-
licity.7,8 In addition, the expected end products have a formyl
moiety which reacts easily with the starting enolates and
leads to a complicated mixture. However, once the desired
aldehyde products are effectively in hand, they make good
synthetic building blocks. Our study examined various types
of aldehyde enolates (Table 3). The reactions of enolate 2f
with unactivated alkyl chloride 1b and benzylic chlorides
1a and 1j resulted in the corresponding aldehydes 3 (entries
1-5). Silyl enolates 2g and 2h, derived from butanal and
acetaldehyde, were not applied to this reaction system (entries
6 and 7) because these enolates were decomposed by the
indium(III) halide.9 Silyl enolates derived from more hin-
dered aldehydes 2i and 2j gave the desired aldehydes 3ji
and 3jj, respectively.
(5) De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46, 8345-8350.
(6) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 11176-11177.
(7) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66-
77.
In our study, a tentative mechanism in which alkyl chloride
was activated by InBr3 to produce a carbocation was
(8) (a) Reetz, M. T.; Maier, W. F. Angew. Chem., Int. Ed. 1978, 17,
48-49. (b) Sasaki, T.; Usuki, A.; Ohno, M. J. Org. Chem. 1980, 45, 3559-
3564. (c) Mayr, H.; Hellmann, W.; Lammers, R. Tetrahedron 1986, 42,
6663-6668. (d) Bentley, T. W.; Irrgang, B.; Mayr, H.; Schleyer, P. v. R.
J. Org. Chem. 1988, 53, 3492-3498.
(9) When InBr3 and an aldehyde enolate were mixed, the formation of
a complicated mixture was observed. Probably the enolate easily changed
to R-silyl aldehyde under the conditions, and the enolate reacted with the
formed R-silyl aldehyde.
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Org. Lett., Vol. 9, No. 24, 2007