A practical and highly efficient synthesis of α-(trimethylsilyl)-difluoro-acetates

Article abstract of DOI:10.1055/s-2000-8718

An efficient method for the gram scale preparation of α-(trimethylsilyl)difluoroacetates is described. The key step involves Mg(0)-promoted selective C-F bond cleavage of readily available trifluoroacetates.

Full text of DOI:10.1055/s-2000-8718

SHORT PAPER
2001
A Practical and Highly Efficient Synthesis of a-(Trimethylsilyl)-difluoro-
acetates
Hideki Amii, Takeshi Kobayashi, Kenji Uneyama*
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Tsushimanaka 3-1-1, Okayama 700-8530, Japan
Fax +81(86)2518075; E-mail: uneyamak@cc.okayama-u.ac.jp
Received 4 August 2000; revised 4 September 2000
O
O
R2 OH O
O
C
Abstract: An efficient method for the gram scale preparation of a-
trimethylsilyl)difluoroacetates is described. The key step involves
1
2
R R C=O
X
Cl
X
(
R1
OR
OR
OR
O
F
F
Mg(0)-promoted selective C-F bond cleavage of readily available
trifluoroacetates.
F
F
4c
4a
Me3Si
OR
(X = Ph, OEt)
Key words: magnesium, fluorine, silicon, esters, electron transfer
F
F
O
NHPh O
3
a (R = C6H13)
R3
NPh
3
Ph
R -X
OR
Ph
C H
F
F
d
F
4b
F
4
Difluoroketene silyl acetals 1 are synthetic equivalents of
enolates of difluoroacetates 2 which serve as a difluorin-
ated building block for the synthesis of a variety of
biologically active difluoromethylene compounds
(
R3 = Bn, H2C=CH-CH2-)
Scheme 2
1
-4
(
Scheme 1). However, despite a growing interest, there
are some problems in the practical use of 1; one is the in-
stability of 1 under both chromatographic and distillative
O
O
Mg / Me3SiCl
C-F Bond Cleavage
Me3Si
4
a,b
CF3
OR
OR
conditions, another is the high cost of the starting ha-
lodifluoroacetates XCF CO R (X = Br, I) for the prepara-
F
F
3
5
2
2
tion of 1 (through Reformatsky-type reaction).
Scheme 3
O
OSiMe3
O
of trifluoroacetates 5 in the presence of chlorotrimethylsi-
lane (Scheme 3).
Me3Si
F
OR
CF2
OR
OR
F
F
F
Mg metal-promoted defluorinative silylation of hexyl tri-
fluoroacetate (5a) was studied first (Table, Entry 1). Sev-
eral attempts to convert 5a into a-silyldifluoroacetate 3a
were unsuccessful, resulting in the complete recovery of
the starting material 5a (r.t., 24 h) or the formation of a
complex mixture of decomposition products (50 °C, 24
h), whereas the electrochemical version gave 3a in 68%
1
2
3
Scheme 1
a-Silyldifluoroacetates 3 are interesting alternative sourc-
es of the enolate 2 which are stable enough to be stored for
a long time. Recently, our group developed a selective
formation of C-silylated compounds 3 by means of elec-
troreductive defluorinative silylation of trifluoroacetates 5
and the subsequent thermal 1,3-silyl migration (1 Æ 3).
We have also demonstrated the synthetic utility of silyldi-
fluoroacetates 3 which act as an attractive CF building
5a
yield. From the viewpoint of reduction potential, phenyl
trifluoroacetate (5b) is expected to act as an electron ac-
ceptor better than aliphatic 5a due to an enhanced elec-
tronegativity of the phenoxy group. Therefore, we
examined Mg(0)-promoted reductive defluorination of ar-
omatic esters 5b-e. When phenyl ester 5b was treated
with Mg (8 equiv) and chlorotrimethylsilane (16 equiv) in
distilled DMF at room temperature for 2.5 hours, the de-
sired a-silyldifluoroacetate 3b was obtained in 66% yield
5,6
2
block. In the presence of fluoride anion (TBAF or KF/
CuI), a-silyldifluoroacetate 3a underwent C-C bond
forming reactions with electrophiles such as aldehydes,
ketones, acyl halides, imines, benzyl and allyl halides to
afford the C-alkylated products 4 in good yields (Scheme
(
Entry 2). Interestingly, no thorough drying technique for
the materials was required (Entry 3); the use of commer-
cially available DMF (dried over molecular sieves 3Å)
5
b
2
).
Quite recently, we have reported that Mg(0) metal, which and Me SiCl (without distillation) did not crucially affect
3
serves as a more convenient electron source, proves useful the yield of 3b (63% isolated yield).
for the C-F bond breaking process of trifluoromethyl ke-
As shown in the Table, the same procedure for the selec-
tones to provide a practical route to 2,2-difluoroenol silyl
tive formation of 3 on a gram scale works well for p-tolyl,
7
ethers. Herein, we describe a facile and efficient proce-
p-methoxyphenyl and p-chlorophenyl trifluoroacetates
dure for the preparation of a-silyldifluoroacetates 3 which
(
Entries 4-6), and neither the overreduction products (for
involves Mg(0)-promoted selective monodefluorination
Synthesis 2000, No. 14, 2001–2003 ISSN 0039-7881 © Thieme Stuttgart · New York

2
002
H. Amii et al.
SHORT PAPER
-
1
Table Mg(0)-Promoted Defluorinative Silylation of Trifluoroace-
tates (5)
IR (KBr): n = 1770 cm .
1
a
H NMR (200 MHz, CDCl ): d = 0.34 (s, 9 H), and 7.1-7.4 (m, 5
3
Mg (8 eq)
H).
19
O
O
Me3SiCl (16 eq)
Me3Si
F NMR (188 MHz, CDCl , C F as internal standard): d = 38.5 (s,
3
6 6
OR
CF3
OR
DMF
2 F).
F
F
3
+
5
GC/MS: m/z (%) = 244 (1) [M ], 167 (5), 151 (29), 77 (61), 73
100).
(
Entry
R
Conditions Product 3
Yieldc
Anal. calcd for C H F O Si: C, 54.08; H, 5.78. Found: C, 53.77;
1
1
14
2
2
(
%)
H, 6.01.
1
C H
r.t., 24 h
r.t., 2.5 h
r.t., 2.5 h
r.t., 6.5 h
r.t., 4.5 h
r.t., 1.5 h
3a
3b
3b
3c
3d
3e
0d
6
13
3c (R = 4-MeOC H )
6
4
Pale yellow oil; bp 100 °C/1.2 Torr.
2
Ph
Ph
66
63
64
56
55
-
1
IR (neat): n = 1774 cm .
3b
4
1
H NMR (200 MHz, CDCl ): d = 0.32 (s, 9 H), 3.8 (s, 3 H), 6.91 (d,
3
4-MeOC H5
J = 9.2 Hz, 2 H), 7.06 (d, J = 9.2 Hz, 2 H).
6
1
9
F NMR (188 MHz, CDCl ): d = 38.5 (s, 2 F).
3
5
4-MeC H5
6
+
GC/MS: m/z (%) = 274 (4) [M ], 167 (17), 123 (44), 73 (100).
6
4-ClC H5
6
Anal. calcd for C H F O Si: C, 52.54; H, 5.88. Found: C, 52.16;
1
2
16
2
3
a
Unless otherwise stated, the reactions were performed on a 20 mmol
H, 6.27.
scale in freshly distilled DMF and Me SiCl.
Commercially available DMF (dried over molecular sieves 3Å) and
3
3
d (R = 4-MeC H )
b
6
4
Pale yellow solid; mp 46 °C, bp 80 °C/1.2 Torr.
IR (KBr): n = 1776 cm-1.
Me SiCl (without distillation) were used.
3
c
Isolated yield.
d
Complete recovery of the starting material 5a.
1
H NMR (200 MHz, CDCl ): d = 0.33 (s, 9 H), 2.36 (s, 3 H), 7.02
3
(
d, J = 9.2 Hz, 2 H), 7.20 (d, J = 9.2 Hz, 2 H).
1
9
F NMR (188 MHz, CDCl ): d = 38.7 (s, 2 F).
3
instance, mono- and non-fluorinated derivatives) nor self-
condensation products were detected in each case. Nota-
bly, Cl-arene functionality was compatible with the
present reaction conditions; the reductive cleavage of the
aromatic C-Cl bond did not occur (Entry 6).
+
8
GC/MS: m/z (%) = 258 (5) [M ], 167 (56), 91 (93), 73 (100).
Anal. calcd for C H F O Si: C, 55.79; H, 6.24. Found: C, 55.71;
12 16
2
2
H, 6.58.
3e (R = 4-ClC
H )
4
6
Colorless oil; bp 70 °C/0.5 Torr.
Key features of the Mg-Me SiCl system for selective C-
3
-
1
F bond cleavage are (i) the starting trifluoroacetates are IR (neat): n = 1772 cm .
readily available, (ii) Mg as a reducing agent is inexpen-
1
H NMR (200 MHz, CDCl ): d = 0.32 (s, 9 H), 7.10 (d, J = 8.9 Hz,
3
9
sive and easily handled, and (iii) selective formation of 2 H), 7.38 (d, J = 8.9 Hz, 2 H).
C-silylated difluoroacetates 3 without formation of labile
O-silylated derivatives 1 probably due to the nature of
magnesium enolates is achieved under mild conditions
and it makes the purification procedure very simple.
19
F NMR (188 MHz, CDCl ): d = 38.5 (s, 2 F).
3
+
GC/MS: m/z (%) = 278 (2) [M ], 111 (20), 73 (100).
1
0
Anal. calcd for C H ClF O Si: C, 47.70; H, 4.70. Found: C, 47.70;
H, 5.06.
11 13
2
2
In conclusion, we have disclosed a practical synthesis of
a-silyl difluoroacetates. In light of its operational simplic-
ity and high efficiency, this reliable method is expected to
have broad utility, especially in the synthesis of difluo-
romethylene compounds,
applications.
Acknowledgement
This work has been supported by Mitsubishi Chemical Corporation
for biological and chemical Fund and Ministry of Education, Science, Sports and Culture of Ja-
pan (Scientific Research (B), No. 12450356). We also thank SC-
1
1,12
1
19
NMR Laboratory of Okayama University for H and F NMR ana-
lyses.
Phenyl 2,2-Difluoro-2-trimethylsilylacetate (3b); Typical Pro-
cedure
References
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(
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(
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(
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Synthesis 2000, No. 14, 2001–2003 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
A Practical and Highly Efficient Synthesis of a-(Trimethylsilyl)difluoroacetates
2003
(
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(
(
(
(
(
(
(
(
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Et O or THF.
2
Article Identifier:
1437-210X,E;2000,0,14,2001,2003,ftx,en;F04800SS.pdf
Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757, and
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Synthesis 2000, No. 14, 2001–2003 ISSN 0039-7881 © Thieme Stuttgart · New York