Phosphine/Lewis acid mediated Reformatsky-type reaction of α-bromoketone or -thioester derivatives

Article abstract of DOI:10.1246/cl.2002.126

The combination of (?-tolyl)₃P/TiCl₄ effectively promoted the Reformatsky-type reaction of α-bromoketone or -thioester derivatives with various aldehydes, and the corresponding β-hydroxy carbonyl compounds were obtained in good yield

Full text of DOI:10.1246/cl.2002.126

126
Chemistry Letters 2002
Phosphine/Lewis Acid Mediated Reformatsky-type Reaction of
ꢀ-Bromoketone or -Thioester Derivatives
Yukihiko Hashimotoꢀ and Satoshi Kikuchi
Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8656
(Received October 29, 2001; CL-011066)
The combination of (o-tolyl)3P/TiCl4 effectively promoted
the Reformatsky-type reaction of ꢀ–bromoketone or -thioester
derivatives with various aldehydes, and the corresponding ꢁ–
hydroxy carbonyl compounds were obtained in good yield with
high diastereoselectivity.
mediated by Lewis acid and phosphine combination.
Initially, we examined the Reformatsky-type reaction of 2-
bromopropiophenone by using Lewis acid/Ph3P at room
temperature. Although Lewis acid, such as MeAlCl2, BF3ꢁOEt2,
Sc(OTf)3, or TiCl4 promoted the reaction, prolonged reaction
time caused the lowering of the yield and the stereoselectivity
because of the retro-aldol type reaction. It was found that this
undesired degradation could be prevented when the reaction was
carried out at ꢂ78 ꢃC. After reinvestigation of Lewis acids at this
temperature, the combination of TiCl4/Ph3P was found to be the
best promoter with regard to both yield and stereoselectivity
(Table 1, Entry 1). Next we tried screening of phosphines, such as
n-Bu3P, (PhO)3P, (mesityl)3P, and (o-tolyl)3P at ꢂ78 ꢃC using
TiCl4 as Lewis acid. Among the phosphines examined, only (o-
tolyl)3P gave better result than Ph3P (Table 1, Entry 2).
Under the optimized conditions, the Reformatsky-type
reaction of 2-bromoketones with various aldehydes was effec-
tively carried out in good yield with high syn-diastereoselectivity
(Table 1, Entries 3–6).6
In recent years, we have been focused on the study of
composite reagents, combination of Lewis acid and phosphine,
which showed characteristic reducing ability. We have already
reported the reduction of various 2-bromocarboxylic acid
derivatives proceeded in good yield under mild conditions.1 In
addition, we reported that the Reformatsky-type reaction of N,N-
diphenyl-2-bromopropionamide was promoted by this combina-
tion in good yield with high diastereoselectivity.2
Although the Reformatsky reaction3 is one of the most useful
methods for the carbon-carbon bond formation as well as aldol
reaction,4 it has been little worth using because of low
stereoselectivity. To overcome this problem, the metallic
reductive species has been widely investigated,3b) and we have
also reported germanium metal mediated Reformatsky reaction
as one of the efficient methodologies for the stereoselective and
asymmetric synthesis.5
Table 1. The Reformatsky-type reaction of ꢀ-bromoketone
derivatives 3 with aldehydes 4a
OH
O
O
On the other hand, the Reformatsky-type reaction mediated
by phosphine/Lewis acid combination was the first example
based on the non-metallic reductive species.2 The mechanism of
this reaction is illustrated in Scheme 1. As can be seen from
Scheme 1, it is not necessary that the center metal of enolate 2 has
reducing ability. Therefore, it was expected to exhibit distinctive
selectivity that was different from the conventional method.
However, until now, since the substrate was limited to diphenyl
amide 1, wide applicability to the various ꢀ–bromocarbonyl
compounds was strongly desired.
Phosphine/TiCl4
R2CHO
R2
R1
R1
CH2Cl2, 78
, 24 h
Br
3
4
syn: antic
3(R1=) 4(R2=)
Entry
Phosphine
P h
P h
P h
P h
P h
Et
P h
84
91
75
82
78
55
93 : 7d
Ph3P
1
2
3
4
5
6
(o-tolyl)3P
(o-tolyl)3P
(o-tolyl)3P
(o-tolyl)3P
(o-tolyl)3P
96 :
98 :
96 :
99 :
4
2
4
1
P h
n- Pr
i- Pr
t- Bu
P h
O
OH
O
>
Ph3P/Sc(OTf )3
CH2Cl2, r t
NPh2
RCHO
R
NPh2
90 : 10
Br
1
aMolar ratio of 3:4:Phosphine:TiCl4=1.4:1.0:1.4:1.4. bIsolated yield.
cDetermined by HPLC,7 unless otherwise stated. dDetermined by 300
MHz 1H NMR.
Sc(OTf)3
O
OSc(OTf)2
NPh2
NPh2
Next we applied (o-tolyl)3P/TiCl4 system to the reaction of
ꢀ–bromoester or -thioester derivatives with benzaldehyde. As a
result, S-phenyl ꢀ–bromothioester gave the best yield with
moderate stereoselectivity (Table 2, Entry 1). In this case, the
reaction could be performed at room temperature without any
retro-aldol type reaction. In order to improve the stereoselectivity,
we next examined the sulfenyl group in the thioester (Table 2,
Entries 1–3). Consequently, it was found that the bulkier
substituent gave better selectivity, and the corresponding ꢁ–
Br
2
Ph3P
Ph3PBr OTf
Scheme 1.
In this manuscript, we would like to describe the Reforma-
tsky-type reaction of ꢀ–bromoketone or -thioester derivatives
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
127
hydroxy thioester was obtained with high syn-diastereoselectivity
using the newly developed thioester derived from 2,4,6-
triisopropylbenzenethiol (Entry 3).8
Then the Reformatsky-type reaction of this bulky thioester
with various aldehydes was carried out under the optimized
conditions and the results were summarized in Table 2 (Entries
3–6), and the desired adduct was obtained stereoselectively in
each entry.
Sports, Science and Technology, Japan.
Dedicated to Professor Teruaki Mukaiyama on the occasion
of his 75th birthday.
References and Notes
1
2
3
H. Kagoshima, Y. Hashimoto, D. Oguro, T. Kutsuna, and K.
Saigo, Tetrahedron Lett., 39, 1203 (1998).
H. Kagoshima, Y. Hashimoto, and K. Saigo, Tetrahedron
Lett., 39, 8465 (1998).
a) M. W. Rathke and P. Weipert, in ‘‘Comprehensive Organic
Synthesis,’’ Pergamon Press, Oxford (1991), Vol. 2, p 277
Table 2. The Reformatsky-type reaction of ꢀ-bromothioester
derivatives with aldehydes in the presence of the (o-tolyl)3P/
TiCl4 combinationa
and references therein. b) A. Furstner, Synthesis, 1989, 571
and references therein.
¨
OH
O
O
(o-tolyl)3P/TiCl4
CH2Cl2, rt
R
SAr
SAr
RCHO
4
a) C. H. Heathcock, in ‘‘Comprehensive Organic Synthesis,’’
Pergamon Press, Oxford (1991), Vol. 2, p 181. b) B. M. Kim,
S. F. Williams, and S. Masamune, in ‘‘Comprehensive
Organic Synthesis,’’ Pergamon Press, Oxford (1991),
Vol. 2, p 239.
Br
5
6
b
Entry
1
syn : anti
6(R=)
Ar
P h
Time/h
c
P h
5
12
5
81
86
94
91
89
77
75 : 25
5
6
H. Kagoshima, Y, Hashimoto, D. Oguro, and K. Saigo, J. Org.
Chem., 63, 691 (1998).
c
2
2,4,6- MeC6H2
P h
89 : 11
Typical procedure for the Reformatsky-type reaction
(Table 1, Entry 2): Under an argon atmosphere, to a solution
of 2-bromo-1-phenyl-1-propanone (140.0 mg, 0.66 mmol)
and TiCl4 (3.3 mol/L, 0.2 ml, 0.66 mmol) in CH2Cl2
(3.0 mL), which was stirred for 20–30 min, was added a
solution of (o-tolyl)3P (198.2 mg, 0.65 mmol) in
CH2Cl2(1.5 mL). After cooling to ꢂ78 ꢃC, PhCHO
(50.5 mg, 0.48 mmol) was added dropwise and stirred for
24 h with keeping at ꢂ78 ꢃC. The reaction was quenched with
phosphate buffer (pH 7) and the mixture was extracted with
CH2Cl2(3 ꢄ 10 mL). The combined CH2Cl2 layers were
washed with brine (1 ꢄ 10 mL) and dried over Na2SO4. This
organic layer was filtered and evaporated under reduced
pressure, and then the crude product was purified by PTLC
(SiO2, Hexane/Ethyl Acetate ¼ 1=3) to give 3-hydroxy-2-
iPr
3
P h
95 :
92 :
91 :
5
8
9
4d
5d
6d
e
n- P r
i- P r
t- Bu
5
iPr
iPr
5
5
85 : 15
aMolar ratio of 5:6:(o-tolyl)3P:TiCl4=1.4:1.0:1.4:1.4. bIsolated yield.
eDetermined by GC.
In summary, the (o-tolyl)3P/TiCl4 combination was found to
be an efficient mediator having a high generality for the
Reformatsky-type reaction of ꢀ–bromoketone or -thioester
derivatives. And the range of ꢀ–bromocarbonyl compounds
was much extended as compared with that of the original
Reformatsky reaction. Now the investigation of the asymmetric
Reformatsky-type reaction using phosphine/Lewis acid combi-
nation is in progress.
methyl-1,3-diphenyl-1-propanone
(104.8 mg,
91%,
syn : anti ¼ 96 : 4).
7
8
S. S. Labadie and J. K. Stille, Tetrahedron, 40, 2329 (1984).
2,4,6-Triisopropylbenzenethiol was prepared by the reduc-
tion of 2,4,6-triisopropylbenzenesulfonyl chloride with
Ph3P.9
This work was financially supported by a Grant-in-Aid for
Scientific Research (C) from the Ministry of Education, Culture,
9
S. Oae and H. Togo, Bull. Chem. Soc. Jpn., 56, 3802 (1983).