The Reformatsky reaction is an excellent synthetic tool
for site-selective formation and subsequent elaboration of
an enolate.8 Many metals such as magnesium, chromium,
and zinc can be used to promote this transformation.
Nevertheless, only a few examples of such reactions involv-
ing quaternary substitution adjacent to the R-bromoketone
have been described. Dubois has reported the use of
chromium(II) chloride to promote the Reformatsky-type
coupling of pinacolone-type R-bromoketones with alde-
hydes;9 however, to date, this coupling has found limited
utility. Other metallic species, namely magnesium10 and
diethylzinc,11 have been used to promote the pinacolone-
type Reformatsky-type coupling, but the low degree of
functional group compatibility of these reagents places
significant restrictions on these methods.12
1-bromopinacolone derivatives were also effective; coupling
reactions of 3-bromo-2,2-dimethyl-3-butanone with the same
series of aldehydes proceeded in good yields and excellent
diastereoselectivities, favoring, as determined by H NMR,
the syn diastereomer (entries 5-8).16
The remarkably high reactivity observed in the aldehyde
couplings led us to also consider ketones as electrophiles
(Table 2). The intermolecular Reformatsky-type coupling of
1
Table 2. R-Bromoketone-Ketone Couplings Promoted by
a
SmI2
Since the advent of diiodosamarium as a reagent in organic
synthesis, it has been extensively employed in intramolecular
Reformatsky-type reactions.13 In contrast, this reagent has
found little use in intermolecular Reformatsky-type coupling
reactions, presumably due to the numerous side reactions
that can occur.14 Our recent total synthesis of (+)-acutiphycin
demonstrated the first use of diiodosamarium to promote a
chemoselective Reformatsky-type fragment coupling of a
pinacolone-like R-bromoketone.15 On the basis of this work,
we hypothesized that an R′-quaternary group on the R-bro-
moketone would reduce the likelihood of side reactions of
the ketone. Herein, the generality of this method is described.
The coupling of 1-bromopinacolone proved general across
a range of aldehyde electrophiles (Table 1). Aldehydes
entry
R1
R2
yield (%)
1
2
3
4
5
Me
Et
Et
t-Bu
t-Bu
Me
Me
Et
Me
Et
77
63
75
98
51
a Standard procedure: See Table 1, footnote a.
R-haloketones with ketones traditionally requires harsh Lewis
acids or elevated temperatures to obtain a serviceable yield
of the desired product.17,18 Using the diiodosamarium method,
however, simple ketones coupled efficiently (entries 1-3),
and remarkably, even pinacolone (entry 4) served as an
effective electrophile. Despite the less electrophilic nature
of ketones, the reaction proceeded efficiently at -78 °C,
without significant alterations to the procedure.
Table 1. R-Bromoketone-Aldehyde Couplings Promoted by
a
SmI2
(6) Examples involving the synthesis of R,â-unsaturated ketones derived
from 1-bromopinacolone: Oare, D. A.; Henderson, M. A.; Sanner, M. A.;
Heathcock, C. H. J. Org. Chem. 1990, 55, 132.
(7) Examples involving the synthesis of R-aryl ketones derived from
pinacolone under SRN1 conditions: (a) Carver, D. R.; Greenwood, T. D.;
Hubbard, J. S.; Komin, A. P.; Sachdeva, Y. P.; Wolfe, J. F. J. Org. Chem.
1983, 48, 1180. (b) Layman, W. J., Jr.; Greenwood, T. D.; Downey, A. L.;
Wolfe, J. M. J. Org. Chem. 2005, 70, 9147.
(8) Reviews of the Reformatsky reaction: (a) Ocampo, R.; Dolbier, W.
R., Jr. Tetrahedron 2004, 60, 9325. (b) Fu¨rstner, A. Synthesis 1989, 571.
(9) Dubois, J.-E.; Axiotis, G.; Bertounesque, E. Tetrahedron Lett. 1985,
26, 4371.
(10) Fellmann, P.; Dubois, J.-E. Tetrahedron 1978, 34, 1349.
(11) Hansen, M. M.; Bartlett, P. A.; Heathcock, C. H. Organometallics
1987, 6, 2069.
(12) The use of magnesium requires refluxing the R-bromoketone with
magnesium in benzene prior to introduction of the aldehyde, whereas the
diethylzinc reaction must be concentrated in vacuo prior to introduction of
the aldehyde substrate.
(13) Reviews: (a) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96,
307. (b) Kagan, H. B. Tetrahedron 2003, 59, 10351. (c) Edmonds, D. J.;
Johnston, D.; Procter, D. J. Chem. ReV. 2004, 104, 3371.
(14) R-Bromoesters often “self-couple” to form products of reductive
dimerization, among others. Moreover, SmI2 promotes numerous reactions
of aldehydes themselves. For further examples see ref 13 and Krief, A.;
Laval, A.-M. Chem. ReV. 1999, 99, 745.
(15) (a) Moslin, R. M.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128,
15106. (b) Moslin, R. M.; Jamison, T. F. J. Org. Chem. 2007, 72, 9736.
(16) (a) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M.
C.; Sohn, J. E.; Lampe, J. J. Org. Chem. 1980, 45, 1066. (b) Ando, A.;
Shioiri, T. Tetrahedron 1989, 45, 4969.
entry
R1
R2
yield (%)
syn:anti
1
2
3
4
5
6
7
8
H
H
H
H
Me
Me
Me
Me
n-Bu
Cy
t-Bu
Ph
n-Bu
Cy
t-Bu
Ph
60b
94b
85
72
85
80
84
70
na
na
na
na
95:5
93:7
>98:2
94:6
a
Standard procedure: A THF solution of the R-bromoketone (1 equiv)
and the aldehyde (1 equiv) was prepared and added dropwise over 25 min
to a THF solution of SmI2 (5 equiv) at -78 °C, and the reaction was stirred
1 h. Air was bubbled through the solution for 5 min before a sodium
thiosulfate workup. Compounds were isolated using standard column
chromatography. See Supporting Information for details. b A minor product
was also isolated and is tentatively assigned as an Evans-Tischenko-type18
monoprotected diol, formed from the addition a second equivalent of the
aldehyde to the Reformatsky-type coupling product.
(17) Aoyagi, Y.; Yoshimura, M.; Tsuda, M.; Tsuchibuchi, T.; Kawamata,
S.; Tateno, H.; Asano, K.; Nakamura, H.; Obokata, M.; Ohta, A.; Kodama,
Y. J. Chem. Soc., Perkin Trans. 1 1995, 689.
containing secondary (entry 1), tertiary (entry 2), quaternary
(entry 3), and aromatic (entry 4) R-substitution performed
well in the coupling reaction. More sterically demanding
(18) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447.
1292
Org. Lett., Vol. 10, No. 6, 2008