Rhodium-catalyzed Reformatsky-type reaction of ethyl bromodifluoroacetate

Article abstract of DOI:10.1016/j.tetlet.2004.05.099

Treatment of a variety of carbonyl compounds with ethyl bromodifluoroacetate and Et₂Zn in the presence of RhCl(PPh ₃)₃ in CH₃CN afforded Reformatsky-type products in good to excellent yields in a mild reaction c

Full text of DOI:10.1016/j.tetlet.2004.05.099

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5735–5737
Rhodium-catalyzed Reformatsky-type reaction of ethyl
bromodifluoroacetate
Kazuyuki Sato, Atsushi Tarui, Tetsuya Kita, Yoshitaka Ishida, Hanae Tamura,
Masaaki Omote, Akira Ando and Itsumaro Kumadaki*
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
Received 11 March 2004; revised 17 May 2004; accepted 17 May 2004
Abstract—Treatment of a variety of carbonyl compounds with ethyl bromodifluoroacetate and Et2Zn in the presence of
RhCl(PPh3)3 in CH3CN afforded Reformatsky-type products in good to excellent yields in a mild reaction condition. This is a good
method to obtain a b-hydroxy-a,a-difluoro carboxylic acid ethyl ester and especially to improve the poor reactivity of ketones.
Ó 2004 Elsevier Ltd. All rights reserved.
The Reformatsky reaction of ethyl bromodifluoroace-
tate (1) with various carbonyl compounds (2) is one of
the most useful methods to give a b-hydroxy-a,a-diflu-
oro carboxylic acid ethyl esters (3) (Scheme 1). This
reaction was first reported by Hallinan and Fried in
1984.1 Usually, zinc powder and 1 reacted to form an
organozinc reagent, which reacted with 2 to give the
corresponding esters 3. Since this was one of the most
effective methods to introduce a CF2 group to organic
compounds, many chemists have challenged to improve
this reaction.2 However, a few problems are still left for
this reaction: it needs to reflux the mixture to complete
the reaction, 3 are not obtained in satisfactory yields
with ketones even at a high temperature, and the trou-
blesome activation of zinc is required.
problems have been solved by addition of TMS-X,3
TDAE4 or CeCl3.5 However, the problem of trouble-
some activation of zinc has not been solved yet.
Honda et al. reported a Reformatsky-type reaction
using ethyl bromoacetate and Et2Zn catalyzed by Wil-
kinson’s catalyst, RhCl(PPh3)3.6 Recently, Fujii and
co-workers reported that the rhodium-catalyzed Refor-
matsky-type reaction using ethyl bromodifluoroacetate
(1) with imines gave a,a-difluoro-b-amino acid deriva-
tives, independently from us.7
Here, we would like to report the results of this rho-
dium-catalyzed Reformatsky-type reaction of 1 with
various carbonyl compounds.
Generally, 1 reacts easily with aldehydes in good to
excellent yields, but the yields from ketones are low,
even if the mixture is refluxed for a long time. These
First, we applied Honda’s methodology to the reaction
of 1 with 2-cyclohexen-1-one (2a). As we expected, the
Reformatsky-type product (3a) was obtained, but it was
a minor product. When THF was used as a solvent, an
abnormal product (4a), where 1 was trapped at a-posi-
tion of 2a, was obtained as a main product (Scheme 2).
O
HO CF2COOEt
Zn
BrCF2COOEt
+
R
R'
3
R
R'
1
To improve the yield of 3a, we examined the reaction
conditions (Table 1).
2
Scheme 1.
Et2Zn
O
O
HO CF2COOEt
Rh Cat.
CF2COOEt
BrCF COOEt
+
2
+
Solv.
Keywords: Reformatsky reaction; Fluorine; Difluoroacetate; Rho-
dium.
1
2a
Scheme 2.
3a
4a
* Corresponding author. Tel.: +81-72-866-3140; fax: +81-70-850-7020;
e-mail: kumadaki@pharm.setsunan.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.099

5736
K. Sato et al. / Tetrahedron Letters 45 (2004) 5735–5737
Table 1. Examination of reaction conditions
Entry
Catalyst (mol %)
Temp (°C)
1.500
Time (h)
THF
Et2Zn (equiv)
Solv.
Yielda of 3a (%)
Yielda of 4a (%)
1
2
3
4
5
6
7
8
RhCl(PP.h5 )3 (1)
3
4
71
RhCl(PPh3)3 (1)
RhCl(PPh3)3 (1)
RhCl(PPh3)3 (1)
None
03
03
01
05
06
0
1.5
Et
2O
Trace
37
44
1.5
1.5
1.5
1.5
DME
CH
CH
CH
1.5
Trace
3CN
800
61
3CN
3CN
0
0
0
[RhCl(cod)]2 (1)
PPh3 (100)
RhCl(PPh3)3 (1)
67
48
25
CH
CH3CN
3CN
066
0
00
a Isolated yield.
First, we examined the solvent effect (entries 1–4). When
ethers were used, the main product was 4a. We found
that CH3CN was the best solvent to obtain 3a. The
complex products were formed in toluene or DMF, al-
though not shown in Table 1. Next, we examined the
effect of catalysts. The reaction time must be prolonged
and the yield of 3a was decreased to about 60% in the
absence of RhCl(PPh3)3. RhCl(PPh3)3 was very useful to
shorten the reaction time and to improve the yield, but
other rhodium catalysts were not effective (entries 4–6).
To eliminate the possibility that triphenylphosphine
(PPh3) released from RhCl(PPh3)3 activated the zinc
reagent directly, we examined the reaction only in
the presence of PPh3 (entry 7), but the reaction time
was prolonged and the yield of 3a was much
decreased. Further, the Reformatsky-type product was
not obtained in the absence of Et2Zn as shown in
entry 8.
Based on the above results, we examined the Refor-
matsky-type reaction of various carbonyl compounds
using the reaction condition in entry 4 (Table 2).8
With aromatic aldehydes, the reaction proceeded
smoothly to give the desired products in good to excel-
lent yields (entries 1–4). The corresponding Reformat-
sky-type products were also obtained in good yields
from hetero aromatic aldehydes and aliphatic aldehydes
(entries 5–7). With the aromatic, aliphatic or a,b-
unsaturated ketones, the corresponding products were
obtained in good to excellent yields, too (entries 7–11).
In conclusion, this reaction in CH3CN could be applied
to improve the yield of Reformatsky-type reaction of 1
with ketones and eliminate the troublesome activation
of zinc. The reaction could be applied to the synthesis of
various CF2 compounds. Further, 4a, where 1 was
Table 2. Reaction of 1 with various carbonyl compounds
Et2Zn
Rh Cat.
CH3CN
O
HO CF2COOEt
BrCF2COOEt
+
R
R'
3
R
R'
1
2
Entry
2
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
Ph–CHO
04.5
05
86
93
4-MeO–C6H4–CHO
4-Cl–C6H4–CHO
4-MeOOC–C6H4–CHO
0to rt
0to rt
0.5
1
94
81
O
CHO
5
0to rt
0.5
72
6
7
C7H15–CHO
Ph–CH2CH2–CHO
0to rt
0to rt
0.5
1
82
82
80
8
9
0
1
1
O
0to rt
78
O
O
b
10
0to rt
0to rt
0.5
7
91
Ph
Ph
Ph
O
11
85
CH3
a Isolated yield.
b 1 and Et2Zn were used 3 equiv.

K. Sato et al. / Tetrahedron Letters 45 (2004) 5735–5737
5737
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sphere, 1 (0.19 mL, 1.5 mmol) and benzaldehyde (0.10 mL,
1 mmol) were added to the solution of RhCl(PPh3)3 (9 mg,
0.01 mmol) in CH3CN (8 mL) at 0 °C and the mixture was
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stirred for 30min. Then, 1.0M Et Zn in hexane (1.5 mL,
2
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whole mixture was stirred at same temperature for 4.5 h.
The mixture was worked-up as usual, followed by column
chromatographic purification over silica gel (AcOEt–hex-
ane ¼ 1:4) to give the corresponding product1 (197 mg,
86%).
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