Defluorination-silylation of alkyl trifluoroacetates to 2,2-difluoro-2-(trimethylsilyl)acetates by copper-deposited magnesium and trimethylsilyl chloride

Article abstract of DOI:10.1016/j.tet.2011.10.109

Reductive defluorination-silylation of alkyl trifluoroacetates with copper-deposited magnesium and trimethylsilyl chloride (TMS-Cl) gave 2,2-difluoro-2-(trimethylsilyl)acetates, potential difluoromethylene building blocks, in 60-68% yields.

Full text of DOI:10.1016/j.tet.2011.10.109

Tetrahedron 68 (2012) 580e583
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Tetrahedron
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Defluorinationesilylation of alkyl trifluoroacetates to 2,2-difluoro-2-
(trimethylsilyl)acetates by copper-deposited magnesium and trimethylsilyl
chloride
*
Shinya Utsumi, Toshimasa Katagiri , Kenji Uneyama
Department of Applied Chemistry, Faculty of Engineering, Okayama University, 3-1-1, Tsushimanaka, Kita-ku, Okayama, 700-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 October 2011
Received in revised form 30 October 2011
Accepted 31 October 2011
Available online 6 November 2011
Reductive defluorinationesilylation of alkyl trifluoroacetates with copper-deposited magnesium and
trimethylsilyl chloride (TMS-Cl) gave 2,2-difluoro-2-(trimethylsilyl)acetates, potential difluoromethylene
building blocks, in 60e68% yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Difluoromethylene building block
Reductive defluorinationesilylation reaction
from trifluoroaceates
Electron transfer
Reduction by magnesium metal
Copper-deposited magnesium
1. Introduction
the reductive defluorinationesilylation of various alkyl tri-
fluoroacetates, are potential building blocks for difluoromethylene
Reductive defluorinationesilylation of trifluoromethyl com-
pounds into difluoroorganic compounds using magnesium metal
and trimethylsilyl chloride (TMS-Cl) has become a popular syn-
thetic method in organofluorine chemistry.1 The magnesium
method is easier to use than electrolysis, which requires an electric
power supply unit, electrodes, and a specialized reaction cell.1,2
However, the magnesium method is sometimes less powerful
than electrolysis. Electrolysis has been shown to reduce alkyl (ethyl,
tert-butyl, and n-hexyl) trifluoroacetates into the corresponding
2,2-difluoro-2-(trimethylsilyl)acetates,2a while only the alkyl tri-
fluoroacetates were recovered using the magnesium method
(Scheme 1).3 A successful metal-reduction method requires an al-
teration of the acetate structure, i.e., an alkyloxycarbonyl moiety to
an aryloxycarbonyl moiety3 or a trifluoromethyl group to a bromo-
difluoromethyl group via reduction by Zn.4 Here, we describe a de-
vice with a stronger reducing ability than the magnesium metal,
which requires the deposition of copper metal on the surface of
magnesium metal powder. The copper-deposited magnesium
powder could reduce commercially available alkyl trifluoroacetates.
Alkyl 2,2-difluoro-2-(trimethylsilyl)acetates 2aed, the products of
compounds.2b,c,5
Mg (8 eq.)
O
O
TMS-Cl (16 eq.)
(recovery of 1)
TMS-F2C OR
2
F3C OR
1
DMI,
rt (25 °C), 24 h
R = Et
0%
n-C6H13
t-Bu
Scheme 1.
2. Results and discussion
Optimization of the reductive defluorination of ethyl tri-
fluoroacetate (1a) by copper-deposited magnesium (MgeCu)7 in
N,N-dimethylimidazolidinone (DMI) with LiCl as an additive gave
ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (2a) in 62% isolated
yield (Scheme 2). The MgeCu was prepared by mixing 4 molar
equiv of Mg powder and 0.5 molar equiv of CuCl in a solution of LiCl
in DMI just prior to the reaction. The silyl ketal byproduct, 3a, was
difficult to separate from 2a by distillation because of a small dif-
ference in boiling points.6 However, decomposing 3a by adding
* Correspondingauthor. Tel.: þ8186 2518605; e-mail address: tkata@cc.okayama-
u.ac.jp (T. Katagiri).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.109

S. Utsumi et al. / Tetrahedron 68 (2012) 580e583
581
anhydrous HCl/EtOH (prepared from TMS-Cl and EtOH) enabled the
isolation of 2a by distillation. Details on the optimization of the
reaction conditions are described below.
resulted in the effective formation of the difluoroacetate 2a in a 50%
yield (entry 2). The use of a similar cyclic amidic solvent, N-meth-
ylpyrrolidone (NMP), resulted in the formation of 2a in only a 14%
yield (entry 3). The use of THF resulted in the formation of the
difluoroacetate 2a in only a 2% yield (entry 4). Using DMI resulted in
the highest yields for the solvents examined.
Mg-Cu
TMS-Cl (8 eq.)
O
OTMS
OEt
O
LiCl (8 eq.)
Table 2
TMS-F2C OEt
F3C
F3C OEt
1a
TMS
Solvent effect on defluorinationesilylation of 1a
DMI,
2a
3a
rt (25 °C), 4 h
Mg-Cua
69%
22%
O
OTMS
OEt
O
TMS-Cl (8 eq.)
62% isolated yield
TMS-F2C OEt
F3C
F3C OEt
1a
TMS
solvent,
5 h
Scheme 2.
2a
3a
The effects of the transition metal deposits and the shape of the
magnesium metal are summarized in Table 1. The reaction without
the addition of any transition metals resulted in the recovery of
ethyl trifluoroacetate, as was previously reported (entry 1).3 Mag-
nesium powder activated by FeCl3 and NiCl2 led to the de-
composition of 1a and gave the target compound 2a in 1% and 2%
yield, respectively (entry 3 and 4). Magnesium powder activated by
0.25 molar equiv of CuCl gave 2a in 25% yield, and 48% of 1a was
recovered (entry 2). The use of 4 molar equiv of the Mg powder
activated by 0.5 molar equiv of CuCl resulted in the complete con-
sumption of 1a.7 The reaction gave compounds 2a and 3a in a 50%
and 45% yield, respectively (entry 5). The use of 4 molar equiv of
magnesium powder activated by 1.0 molar equiv of CuCl resulted in
the formation of the compound 2a in a 26% yield, and recovery of 1a
in 39% (entry 6). A mixture of Cu(0) and Mg powder reduced 1a to 2a
in a 3% yield (entry 7). These results suggest that ‘the Cu(0) attached
on magnesium surface’ is essential for efficient reduction of 1a. The
use of powdered magnesium metal was also found to be essential.
Magnesium turnings and magnesium ribbon resulted in a lower
conversion of the substrate (entries 8, 9, and 10). Use of commer-
cially available Zn dust or ZneCu dust resulted in complete recovery
of the substrate 1a (entry 11 and 12). Mg with a large surface area
was necessary for the complete consumption of 1a in the reaction.
Entry
Solvent
Temp [ꢀC]
Recov. of 1ab [%]
Yieldsb [%]
2a
3a
1
2
3
4
DMF
DMI
NMP
THF
25
25
25
50
70
0
36
76
(8)
(5)
(50)
(14)
(2)
(45)
(14)
(0)
aMgeCu was in situ prepared from Mg powder (4 equiv) and CuCl (0.5 equiv).
b
Yields in parentheses and recoveries of 1a were determined by 19F NMR with
4-(trifluoromethyl)anisole as an internal standard.
Electrochemical reduction of 1a gave compound 2a in a 68%
yield by 19F NMR analysis of the crude mixture,2a which was higher
than the best reaction by conditions present in Table 2 (entry 2,
50%). In order to determine if the electrolyte present in the elec-
trochemical reaction was the reason for the higher yields, we de-
cided to add ‘supporting electrolyte’ to the magnesium metal
reaction. The results are summarized in Table 3. The reaction with
Et4NCl added resulted in a lower conversion of 1a. The reaction
with an 8 equiv amount of LiCl additive resulted in a 62% isolated
yield (69% by 19F NMR analysis, entry 4).8 The reaction with
a 12 equiv amount of LiCl resulted in the formation of 2a in the
same yield with the ketal 3a in lower yield (20%; entry 5). Reactions
with other lithium salt (LiBr, LiClO4, Li(OTf)) additives resulted in
Table 1
Table 3
Effects of metals on defluorinationesilylation of ethyl trifluoroacetate (1a)
Effects of additives on the defluorinationesilylation reaction of 1a
Metal (4 eq.)
O
OTMS
OEt
Mg-Cua
TMS-Cl
O
TMS-Cl (8 eq.)
TMS-F2C OEt
F3C
F3C OEt
1a
TMS
DMI
O
OTMS
OEt
O
2a
3a
additive
25 °C, 5 h
TMS-F2C OEt
F3C
F3C OEt
1a
TMS
DMI,
Entry
Metal reducing
Activation
Recov. of
Yieldsa (%)
2a
3a
25 °C, 5 h
agent
of Mg (equiv)
1aa [%]
2a
3a
Entry
Additive (equiv)
Recov. of 1ab (%)
Yieldsc [%]
1b
2
3
4
5
6
7
8
9
Mg powder
Mg powder
Mg powder
Mg powder
Mg powder
Mg powder
Mg powder
Mg turnings
Mg turningsd
Mg ribbon
Zn dust
d
100
48
84
38
0
39
93
70
44
45
100
100
0
0
CuCl (0.25)
FeCl3 (0.25)
NiCl2 (0.25)
CuCl (0.5)
CuCl (1.0)
Cu(0) (0.5)c
CuCl (0.5)
CuCl (0.5)
CuCl (0.5)
d
(25)
(1)
(2)
(50)
(26)
(3)
(9)
(24)
(25)
0
(23)
(0)
(1)
(45)
(15)
(2)
(9)
(18)
(23)
0
2a
3a
1
2
d
0
68
0
0
2
56
100
100
95
20
100
59
(50)
(18)
(62)
62d (69)
(69)
(25)
(0)
(45)
(14)
(26)
(22)
(20)
(11)
(0)
(0)
(0)
(34)
(0)
(15)
Et4NCl (16)
LiCl (4.0)
LiCl (8.0)
LiCl (12)
LiBr (4.0)
3
4e
5
6
7
8
9
10
11
12
LiBr (8.0)
10
11
12
Li(ClO4) (4.0)f
Li(OTf) (4.0)f
MgBr2$OEt2 (0.5)
MgBr2$OEt2 (2.0)f
KCl (4)
(0)
(4)
(43)
(0)
(19)
ZneCu dust
d
0
0
Yields in parentheses and recoveries of 1a were determined by 19F NMR with 4-
(trifluoromethyl)anisole as an internal standard.
a
b
Reaction time is 24 h.
Cu(0) powder was added to the suspension of Mg powder.
Mg (12 equiv) turnings were used.
aMgeCu was in situ prepared from Mg powder (4 equiv) and CuCl (0.5 equiv).
c
b
Values were determined by 19F NMR of crude mixture containing solvent with
d
4-(trifluoromethyl)anisole as an internal standard.
c
Values in parentheses were yields determined by 19F NMR of crude mixture after
Results for the optimization of reaction conditions by changing
the solvent are summarized in Table 2. The use of the highly polar
solvent DMF resulted in the formation of 2a in 8% yield (entry 1).
The use of DMI, whose dielectric constant is similar to that of DMF,
extractions with benzotrifluoride as an internal standard.
d
The yield is the isolated yield.
Reaction time is 4 h.
The additives were not completely dissolved.
e
f

582
S. Utsumi et al. / Tetrahedron 68 (2012) 580e583
lower conversions of the substrate 1a than that with LiCl (entry 4),
although these additives suppressed the formation of the ketal 3a
(entries 6e9). Other metal salt additives (MgBr2$OEt2 and KCl) did
not suppress the formation of 3a (entry 10e12). Thus, the reaction
in DMI with an 8 equiv amount of LiCl was found to be the best
conditions for the preparation of 2a, which is shown in Scheme 2.
The defluorinationesilylation reaction with another silylating
agent, TES-Cl, resulted in a low yield of difluoroacetate (a 5% yield
determined by 19F NMR of the crude mixture, Scheme 3).
3. Conclusions
In summary, alkyl 2,2-difluoro-2-(trimethylsilyl)acetates 2aed
were produced by the reduction of alkyl trifluoroacetates 1 by
copper-deposited magnesium, which can be easily prepared by the
mixing of magnesium powder and CuCl in DMI with LiCl additive
solution just prior to the reaction. Alkyl 2,2-difluoro-2-(trime-
thylsilyl)acetates 2 were isolated by distillation after the de-
composition of byproducts 3 under acidic conditions. Detailed
mechanisms and the scope of the reduction ability of copper-
deposited magnesium are now under investigation.
Mg
TES-Cl
4. Experimental
4.1. General
LiCl 8 eq.
O
O
others
11%
TES-F2C OEt
F3C OEt
1a
DMI
25 °C, 5 h
5%
All NMR spectra were recorded as CDCl3 solutions. 1H NMR
(600 MHz) was recorded with Varian Unity INOVA AS600. 1H NMR
(400 MHz), 13C NMR (100 MHz), 19F NMR (376 MHz) spectra were
recorded with Varian VNMRS-400 instrument. The chemical shifts
are reported in Ô (ppm) related to the CHCl3 (7.26 ppm for 1H
NMR), CDCl3 (77 ppm for 13C NMR), and C6F6 (0 ppm for 19F NMR:
the relative chemical shift of C6F6 to CFCl3 is ꢁ162.2 ppm). Coupling
constants (J) are reported in hertz (Hz). Infrared spectra were
recorded on a Hitachi 270-30 spectrometer. Only selected absor-
(1a (48%) was recovered )
Scheme 3.
While variation in the silyl moiety led to reduced yields, varia-
tion in the alkyl moiety was successful; two primary (R¼Et, n-
C6H13) and two secondary (R¼i-Pr, Cy) 2,2-difluoro-2-(trime-
thylsilyl)acetates 2aed were similarly produced from the corre-
sponding trifluoroacetate under the optimized conditions (Table 4).
The i-propyl 2,2-difluoro-2-(trimethylsilyl)acetate 2c was produced
in a 65% isolated yield using a similar procedure as that for 2a (entry
3). The n-hexyl and the cyclohexyl 2,2-difluoro-2-(trimethylsilyl)
acetates were isolated in a 60% and 68% yield, respectively, by dis-
tillation followed after the decomposition of the silyl ketals 3b and
3d by reacting them with TFA (entries 2, 4). The yields for products
2aed were comparable to those of electrochemical reductions.
bances are reported (n
in cmꢁ1). MS analyses were performed on
a Shimadzu GCMS-QP5050A. Elemental analyses were performed
on a PerkineElmer series II CHNS/O Analyzer 2400.
4.2. Procedures for reductions of alkyl trifluoroacetates (1) by
Cu-deposited Mg and trimethylsilyl chloride
4.2.1. Synthesis of ethyl 2,2-difluoro-2-(trimethylsilyl)acetate
(2a). Mg powder (0.486 g, 20 mmol), copper(I) chloride (0.248 g,
2.5 mmol), and lithium chloride (1.7 g, 40 mmol) were stirred in
DMI (10.0 ml) and TMS-Cl (5.0 ml, 40 mmol) for 15 min under an
argon atmosphere at room temperature. Ethyl trifluoroacetate
(5 mmol, 0.71 g) was added dropwise into the stirred suspension.
The suspension was stirred for additional 4 h at room temperature.
After removal of MgeCu by decantation, the DMI solution was
extracted with Et2O. The Et2O layer was washed with 10% HCl aq
and brine, dried over MgSO4. Then, solvent was removed under
a reduced pressure. The mixture of difluoro-compound 2a and silyl
ketal 3a was obtained.
Table 4
Defluorinationesilylation of alkyl trifluoroacetates (1)
Mg-Cua
TMS-Cl
OTMS
O
TMS-F2C OR
2
LiCl
O
F3C OR
1
OEt
F3C
TMS
3
DMI
Entry
R
Temp (ꢀC)
Time (h)
Yieldsc (%)
Ref. 2a
2b
3
(2)d
1
2
3
4
Et (a)
rt (25)
rt (25)
rt (29)
rt (23)
4
4
3.5
4
62 (69)
60 (68)
65 (77)
68 (73)
(22)
(24)
(11)
(18)
[47]
[62]
d
Procedure for removal of 3a from the mixture of 2a and 3a. An-
hydrous HCl/EtOH was prepared from TMS-Cl (3.0 ml, 25 mmol)
and ethanol (2 ml, 34 mmol). The prepared anhydrous HCl/EtOH
was added dropwise into the mixture of difluoro-compound 2a and
silyl ketal 3a. After stirring 90 min at room temperature, the solu-
tion was extracted with ether (5 mlꢂ4). The combined organic layer
was washed with brine. Organic layer was dried over MgSO4, then,
was concentrated under a reduced pressure. Kugelrohr distillation
(100 ꢀC/32 mmHg, bath temperature) of the crude product gave
ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (2a) in 62% (0.602 g) of
isolated yield. Colorless oil. Bp¼70 ꢀC/20 mmHg (bath tempera-
n-C6H13 (b)
i-Pr (c)
Cy (d)
d
aMgeCu was in situ prepared from Mg powder (4 equiv) and CuCl (0.5 equiv).
b
Isolated yields by distillation after decomposition of silyl ketals 3 under acidic
conditions (on 5 mmol scale).
c
Values in parentheses are yields in crude product mixture determined by 19F
NMR with benzotrifluoride as an internal standard.
d
Reported isolated yields by electrochemical reductions [Ref. 2a].
A plausible mechanism is illustrated in Scheme 4. Initial electron
transfer(s) from magnesium to the trifluoroacetates would give
some anion species, followed by defluorinationesilylation or dou-
ble silylations.2e The enolate form of the product would be ther-
mally rearranged to the ester 2.2b
ture). IR nmax (neat) 2980, 1760 cmꢁ1 1H NMR (400 MHz, CDCl3)
.
d
0.23 (s, 9H), 1.34 (t, J¼7 Hz, 3H), 4.31 (q, J¼7 Hz, 2H) ppm. [
d 0.16
(s, 9H), 1.27 (t, J¼7 Hz, 3H), 4.24 (q, J¼7 Hz 2H) ppm. (Ref. 2c)] 13C
NMR (100 MHz, CDCl3)
d
ꢁ5.2 (s), 13.9 (s), 62.2 (s), 121.0 (t,
OTMS
OR
J¼268 Hz), 166.3 (t, J¼26 Hz) ppm. 19F NMR (376 MHz, CDCl3)
d 38.4
F3C
TMS-Cl
TMS
3
(s, 2F) ppm. [d 38.7 (s, 2F) ppm. (Ref. 2c)] EI-MS m/z (% relative
ET
O
F3C OR
1
intensity) 181 ([M]þꢁCH3, 1), 153 (4), 117 (5), 73 (100).
O
F3C OR
OTMS
OR
O
F
F
TMS-F2C OR
4.2.2. Ethyl silyl ketal (3a). Compound 3a was isolated from the
reaction mixture with 2a by column chromatography on silica gel
(hexane eluent). Colorless oil. Bp¼80 ꢀC/20 mmHg (bath
defluorination
(ref. 2b)
2
Scheme 4.

S. Utsumi et al. / Tetrahedron 68 (2012) 580e583
583
temperature). IR nmax (neat) 2990, 2910 cmꢁ1. 1H NMR (400 MHz,
CDCl3)
0.16 (q, J¼1 Hz, 9H), 0.17 (s, 9H), 1.19 (t, J¼7 Hz, 3H), 3.66
(m, 2H) ppm. [
0.18 (s, 9H), 0.19 (s, 9H), 1.21 (t, J¼7.0 Hz, 3H), 3.68
(m, 2H) (Ref. 6)] 19F NMR (376 MHz, CDCl3)
86.5 (s, 3F) ppm. [
86.7 (s, 3F) ppm. (Ref. 6)] EI-MS m/z (% relative intensity) 259
([M]þꢁC2H5, 6), 73 (100).
1H NMR (400 MHz, CDCl3)
d
0.13 (s, 9H), 0.18 (s, 9H), 1.13 (dd, J¼16,
d
6 Hz, 6H), 4.19 (sep(q), J¼6 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3)
d
d
ꢁ3.2 (s),1.8 (s), 23.3(s), 24.7 (s), 66.4 (s), 97.7 (q, J¼34 Hz),125.1 (q,
d
d
J¼289 Hz) ppm. 19F NMR (376 MHz, CDCl3)
d 87.4 (s, 3F). EI-MS m/z
(% relative intensity) 259 ([M]þꢁC3H7, 7), 73 (100). Elemental Anal.
Calcd for C11H25F3O2Si2: C, 43.68; H, 8.33. Found: C, 43.59; H, 8.28.
4.2.3. Synthesis of n-hexyl 2,2-difluoro-2-(trimethylsilyl)acetate
(2b). The procedure to obtain the mixture of difluoro-compound
2b and silyl ketal 3b was similar to that of the mixture of 2a and 3a.
TFA (20 mmol, 2 ml) was added to the mixture of difluoro-
compound 2b and silyl ketal 3b, and stirred additional 60 min at
room temperature. The TFA solution of the crude mixture was
extracted with n-hexane. The combined n-hexane solution was
washed with 10% HCl aq and brine. The n-hexane solution was
dried over MgSO4. After removal of the solvent under a reduced
pressure, Kugelrohr distillation afforded n-hexyl 2,2-difluoro-2-
trimethylsilylacetate (2b) in 60% (0.757 g) of isolated yield, re-
spectively. Colorless oil. Bp¼90 ꢀC/2 mmHg (bath temperature). IR
4.2.7. Synthesis of cyclohexyl 2,2-difluoro-2-(trimethylsilyl)acetate
(2d). The procedure to obtain the mixture of difluoro-compound
2d and silyl ketal 3d is similar to that of the mixture of 2a and 3a.
Procedure to remove 3d from the mixture of 2d and 3d is the
same to that of n-hexyl acetate 2b. Yield (68%). Colorless oil.
Bp¼90 ꢀC/2 mmHg (bath temperature). IR nmax (neat) 2950,
1750 cmꢁ1. 1H NMR (600 MHz, CDCl3)
d
0.23 (s, 9H), 1.29 (dtt, J¼13,
10, 4 Hz, 1H), 1.39 (dtt, J¼14, 10, 4 Hz, 2H), 1.48e1.52 (m, 2H), 1.55
(dtt, J¼13, 8, 4 Hz,1H),1.74e1.78 (m, 2H),1.88e1.91 (m, 2H), 4.92 (tt,
J¼4, 10 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3)
d
ꢁ5.0(s), 23.5 (s),
25.1 (s), 31.3 (s), 74.8 (s), 120.8 (t, J¼267 Hz), 165.6 (t, J¼25 Hz) ppm.
19F NMR (376 MHz, CDCl3)
d 38.6 (s, 2F) ppm. EI-MS m/z (% relative
nmax (neat) 2970, 1760 cmꢁ1
.
1H NMR (600 MHz, CDCl3)
d
0.23 (s,
intensity) 168 ([M]þeC6H10, 14), 152 (19), 83 (74), 77 (31), 73 (57),
55 (100). Elemental Anal. Calcd for C11H20F2O2Si: C, 52.77; H, 8.05.
Found: C, 52.49; H, 8.31.
9H), 0.89 (t, J¼7 Hz, 3H), 1.28e1.34 (m, 4H), 1.34e1.40 (m, 2H), 1.69
(quint, J¼7 Hz, 2H), 4.24 (t, J¼7 Hz, 2H) ppm. [(200 MHz, CDCl3)
d
0.23 (s, 9H), 0.89 (t, J¼6.6 Hz, 3H),1.30e1.41 (m, 6H),1.62e1.72 (m,
2H), 4.23 (t, J¼6.8 Hz, 2H) ppm. (Ref. 2a)] 19F NMR (376 MHz, CDCl3)
4.2.8. Cyclohexyl silyl ketal (3d). Compound 3d was isolated from
the reaction mixture by column chromatography on silica gel
(hexane eluent). Yield (18%, determined by 19F NMR). Colorless oil.
Bp¼90 ꢀC/2 mmHg (bath temperature). IR nmax (neat) 2940,
d
38.4 (s, 2F) ppm. [d 38.7 (s, 2F) (Ref. 2a)] EI-MS m/z (% relative
intensity) 168 ([M]þꢁC6H12, 6), 152 (12), 77 (25), 73 (50), 43 (100).
4.2.4. n-Hexyl silyl ketal (3b). Compound 3b was isolated from the
reaction mixture by column chromatography on silica gel (hexane
eluent). Yield (24%, determined by 19F NMR). Colorless oil.
2860 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d 0.13 (br, 9H), 0.17 (s, 9H),
1.20e1.48 (m, 6H), 1.71e1.78 (m, 4H), 3.84e3.89 (m, 1H) ppm. 13C
NMR (100 MHz, CDCl3)
ꢁ3.1 (s), 1.8 (s), 24.0 (s), 24.3 (s), 25.7 (s),
33.3 (s), 34.7 (s), 71.7 (s), 97.7 (q, J¼34 Hz), 125.1 (q, J¼289 Hz) ppm.
d
Bp¼90 ꢀC/2 mmHg (bath temperature). IR nmax (neat) 2970 cmꢁ1
.
1H NMR (400 MHz, CDCl3)
d
0.16 (br, 9H), 0.17 (s, 9H), 0.89 (t,
19F NMR (376 MHz, CDCl3)
d 87.4 (s, 3F) ppm. EI-MS m/z (% relative
J¼7 Hz, 3H), 1.24e1.40 (m, 6H), 1.51e1.59 (m, 2H), 3.54e3.64 (m,
intensity) 259 ([M]þꢁC6H11, 4), 147 (2), 73 (100). Elemental Anal.
2H) ppm. 13C NMR (100 MHz, CDCl3)
d
ꢁ2.5 (s), 1.6 (s), 14.0 (s), 22.6
Calcd for C14H29F3O2Si2: C, 49.09; H, 8.53. Found: C, 48.98; H, 8.52.
(s), 25.7 (s), 30.1 (s), 31.6 (s), 64.8 (s), 98.6 (q, J¼34 Hz), 124.9 (q,
J¼288 Hz) ppm. 19F NMR (376 MHz, CDCl3)
d 86.8 (s, 3F) ppm. EI-MS
Acknowledgements
m/z (% relative intensity) 259 ([M]þꢁC6H13, 13), 73 (100). Elemental
Anal. Calcd for C14H31F3O2Si2: C, 48.80; H, 9.07. Found: C, 48.86; H,
8.96.
We are grateful to the SC-NMR Laboratory of Okayama Univer-
sity for 1H and19F NMR analyses.
4.2.5. Synthesis of i-propyl 2,2-difluoro-2-(trimethylsilyl)acetate
(2c). The procedure to obtain the mixture of difluoro-compound 2c
and silyl ketal 3c was similar to that of the mixture of 2a and 3a.
Anhydrous HCl/i-PrOH was prepared from TMS-Cl (25 mmol)
and H2O (0.18 ml, 10 mmol) and i-PrOH (2.6 ml, 34 mmol). The
lower layer of the acidic mixture (i-PrOH layer) was added to the
mixture of 2c and 3c, and stirred for additional 10 h. The i-PrOH
solution was extracted with Et2O (5 mlꢂ5). The combined organic
layer was washed with diluted HCl aq and brine. Organic layer was
dried over MgSO4, and was concentrated under a reduced pressure.
The mixture of the products was purified by Kugelrohr distillation
(80 ꢀC/20 mmHg, bath temperature), which provided isopropyl
difluoro(trimethylsilyl)acetate 2c in 65% (0.684 g) of isolated yield.
Colorless oil. Bp¼80 ꢀC/20 mmHg (bath temperature). IR nmax (neat)
References and notes
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M.; Frebault, F.; Gobet, M.; Picard, J.-P. Eur. J. Org. Chem. 2006, 4147e4154; (d)
Uneyama, K.; Maeda, K.; Kato, T.; Katagiri, T. Tetrahedron Lett. 1998, 39,
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mun. 1999, 1323e1324.
3. Amii, H.; Kobayashi, T.; Uneyama, K. Synthesis 2000, 2001e2003.
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Tetrahedron 1997, 53, 10271e10280; (b) Igumnov, S. M.; Vyazkov, V. A.; Pro-
khorov, A. V. Russ. Patent RU 2009e121461, (CAN 153:406629), 2010.
5. (a) Kawano, Y.; Kaneko, N.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2006, 79,
1133e1145; (b) Clavel, P.; Biran, C.; Bordeau, M.; Roques, N.; Trevin, S. Tetrahe-
dron Lett. 2000, 41, 8763e8767.
6. Bordeau, M.; Clavel, P.; Barba, A.; Berlande, M.; Biran, C.; Roques, N. Tetrahedron
Lett. 2003, 44, 3741e3744.
7. (a) Hurd, C. D.; Webb, C. N. J. Am. Chem. Soc. 1927, 49, 546e559; (b) Gilman, H.;
Peterson, J. M.; Schulze, F. Rec. Trav. Chim. 1928, 47, 19e27; (c) Gilman, H.; Heck,
L. L. Bull. Soc. Chim. 1929, 45, 250; (d) Kharasch, M. S.; Reimuth, O. Grignard
Reactions of Nonmetallic Substances; Prentice-Hall: New York, 1954, pp 11; (e)
Wakefield, B. J. Organomagnesium Method in Organic Synthesis; Academic Press:
London, 1995, pp 26; (f) Gilman, H.; Heck, L. L. J. Am. Chem. Soc. 1931, 53,
377e378; (g) Gilman, H.; Zoellner, E. A. J. Am. Chem. Soc. 1931, 53, 1581e1583; (h)
Johnson, G.; Adkins, H. J. Am. Chem. Soc. 1931, 53, 1520e1523; (i) Gilman, H.; John,
N. B. S. Rec. Trav. Chim. Pays-Bas 1930, 49, 717e723.
ꢀ
2990, 1760 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d 0.23 (s, 9H), 1.32 (d,
J¼6 Hz, 6H), 5.15 (sep, J¼6 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3)
d
ꢁ5.2 (s), 21.4 (s), 70.1 (s), 120.8 (t, J¼267 Hz), 165.5 (t, J¼25 Hz)
ppm. 19F NMR (376 MHz, CDCl3)
d 38.4 (s, 2F) ppm. EI-MS m/z (%
relative intensity) 168 ([M]þꢁC3H6, 5), 153 (11), 117 (12), 77 (42), 73
(100). Elemental Anal. Calcd for C8H16F2O2Si: C, 45.69; H, 7.67.
Found: C, 45.80; H, 7.85.
8. (a) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Angew. Chem., Int. Ed.
2006, 45, 6040e6044; (b) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm,
M.; Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 6802e6806; (c) Piller, F. M.;
Appukkuttan, P.; Gavryushin, A.; Helm, M.; Knochel, P. Chem. Commun. 2010,
4082e4084.
4.2.6. Isopropyl silyl ketal (3c). Compound 3c was isolated from the
reaction mixture by column chromatography on silica gel (hexane
eluent). Yield (11%, determined by 19F NMR). Colorless oil.
Bp¼85 ꢀC/20 mmHg (bath temperature). IR nmax (neat) 2990 cmꢁ1
.