Diethyl 3-bromo-3,3-difluoropropyl acetal: Preparation and SnCl4-promoted cross-coupling reaction with trimethylsilyl enol ethers

Article abstract of DOI:10.1016/S0022-1139(99)00294-8

The radical addition of dibromodifluoromethane to ethyl vinyl ether in ethanol under Na₂S₂O₄ initiation affords diethyl 3-bromo-3,3-difluoropropyl acetal (1) in high yield. SnCl₄-promoted cross-coupling reaction of 1 with trimethylsilyl enol ethers (2) yield γ-bromodifluoromethyl-β-ethoxy ketones (3).

Full text of DOI:10.1016/S0022-1139(99)00294-8

Journal of Fluorine Chemistry 103 (2000) 135±137
Diethyl 3-bromo-3,3-di¯uoropropyl acetal: preparation and
SnCl -promoted cross-coupling reaction with trimethylsilyl enol ethers
4
*
Sheng Peng, Feng-Ling Qing
Laboratory of Organo¯uorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 9 August 1999; received in revised form 7 October 1999; accepted 5 November 1999
Abstract
The radical addition of dibromodi¯uoromethane to ethyl vinyl ether in ethanol under Na
di¯uoropropyl acetal (1) in high yield. SnCl -promoted cross-coupling reaction of 1 with trimethylsilyl enol ethers (2) yield
2 2 4
S O initiation affords diethyl 3-bromo-3,3-
4
g-bromodi¯uoromethyl-b-ethoxy ketones (3). # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Di¯uoromethylene; Trimethylsilyl enol ethers; Cross-coupling
1
. Introduction
2. Results and discussions
The incorporation of di¯uoromethylene (CF ) into an
2
Wakselman reported [9,10] the preparation of diethyl 3-
bromo-3,3-di¯uoropropyl acetal (1) through the condensa-
tion of dibromodi¯uoromethane and ethyl vinyl ether under
UV irradiation, followed by the treatment with ethanol.
However, the overall yield (two steps) is 65% and the ®rst
step is not convenient due to the dif®culty in handing
reactive and volatile substrates (the boiling points of dibro-
modi¯uoromethane and ethyl vinyl ether are 22 and 238C,
respectively). We developed a convenient and practical
synthesis of 1 in 81% yield from the radical addition of
dibromodi¯uoromethane to ethyl vinyl ether under Na S O
2 4
organic molecule has been receiving considerable attention
due to the well-known feature that ¯uorine may confer
biological active nature to molecules [1±3]. Many CF2-
containing molecules have been reported to have biological
activities [4±6], and great efforts have been made for the
exploration of practical and effective methods to synthesize
organic compounds containing di¯uoromethylene group.
Fluorinating reagents have been widely used for incorpor-
ating CF unit into a molecule [7], however, most of such
2
reagents are not only expensive and dif®cult to be prepared,
but also are limited to functional groups compatible with the
reactive reagents. Another approach is to synthesize inter-
2
initiation (Scheme 1) [11±14]. Ethanol was used as a solvent
and the reaction was accomplished in 5 h.
mediates containing CF group and use them as the synthons
2
With a convenient route to diethyl 3-bromo-3,3-di¯uor-
opropyl acetal (1) in hand and based on the extensively
studied reactivities of acetals [15], we attempted the reaction
of 1 with trimethylsilyl enol ethers in the presence of SnCl4
to prepare g-bromodi¯uoromethyl-b-ethoxy ketones which
are a kind of highly functionalized molecules containing a
[
of the CF -containing compound, because it usually
8], which is becoming the main tendency for construction
2
accesses the target molecule under mild condition. There-
fore, the development of an ef®cient and convenient method
for the synthesis of CF -containing building block is highly
2
desirable. Herein, an ef®cient general route to 3-bromo-3,3-
di¯uoropropyl acetal (1) and SnCl -promoted cross-cou-
pling reaction of 1 with trimethylsilyl enol ethers (2) were
described.
BrCF group. The reaction succeeds in a series of trimethyl-
2
silyl enol ethers (Scheme 2), and g-bromodi¯uoromethyl-b-
ethoxy ketones (3) are obtained in good yields. The results
are listed in Table 1.
4
*
Corresponding author. Tel.: ‡86-2164163300; fax: ‡86-2164166128.
E-mail address: flq@pub.sioc.ac.cn (F.-L. Qing).
Scheme 1
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 2 9 4 - 8

1
36
S. Peng, F.-L. Qing / Journal of Fluorine Chemistry 103 (2000) 135±137
Scheme 2
Table 1
Reactions of diethyl 3-bromo-3,3-difluoropropyl acetal with trimethylsilyl
enol ethers in the presence of SnCl
colorless liquid; bp 648C/4 mm Hg; d (CCl , 60 MHz) 4.8
H
4
(
4
1H, t, J ˆ 4.0 Hz), 3.4±3.5 (4H, m), 2.7 (2H, d-t, J ˆ 14.0,
4
.0 Hz), 1.2 (3H, t, J ˆ 7.0 Hz); dF (CCl ) � 35.6 (t,
4
a
Entry
R
1
R
2
R
3
Product
Yield (%)
J ˆ 14.0 Hz).
1
2
3
4
5
6
7
Ph
H
H
3a
3b
3c
3d
3e
3f
91
94
88
90
87
94
83
t-Bu
i-Pr
Et
H
H
3.2. General procedure for SnCl -promoted reaction of
4
Me
H
Me
Me
H
diethyl 3-bromo-3,3-difluoropropyl acetal (1) with
trimethylsilyl enol ethers (2)
(CH
(CH
(CH
2
)
4
)
5
)
7
2
2
H
Stannic chloride (1.1 g, 1.2 mmol) was added to a well
stirred solution of acetal 1 (1.0 g, 4 mmol) and trimethylsilyl
enol ether (5 mmol) in anhydrous CH Cl (15 ml) at � 788C.
H
3g
a
Isolated yield based on acetal.
2
2
After 4 h, the reaction was quenched by addition of satu-
rated aqueous NaHCO (10 ml) and extracted with CH Cl
2
In conclusion, we have developed a convenient prepara-
tion of diethyl 3-bromo-3,3-di¯uoropropyl acetal (1) and
studied the SnCl -promoted cross-coupling reaction of
4
3
2
(3 Â 20 ml). The combined extracts were washed with brine
(50 ml), dried (Na SO ) and concentrated. The residue was
4
2
diethyl 3-bromo-3,3-di¯uoropropyl acetal with trimethylsi-
lyl enol ethers, giving g-bromodi¯uoromethyl-b-ethoxy
ketones (3). Work continues in exploring further the use
of 1 and 3 in the construction of various functionalized CF2-
containing compounds.
puri®ed by column chromatography on silica gel.
3.3. Spectroscopic data for 3a
Oil, IR (liquid ®lm): 2980, 2687, 1598, 1450, 1374,
�
1
1
203 cm ; dH (CDCl , 300 MHz) 7.97±7.94 (2H, m),
3
7
.62±7.56 (1H, m), 7.51±7.46 (2H, m), 4.39±4.32 (1H,
3
. Experimental
m), 3.58 (2H, q, J ˆ 7.0 Hz), 3.40 (1H, d-d, J ˆ 16.8,
6
.7 Hz), 3.08 (1H, d-d, J ˆ 16.8, 5.7 Hz), 2.80±2.69 (2H,
1
H NMR spectra were recorded on a 300, 90 or 60 MHz
m), 1.13 (t, 3H, J ˆ 7.0 Hz); d (CCl ) � 36.0 (t,
F
4
1
spectrometer with Me Si as internal standard. F NMR
9
‡
J ˆ 14.0 Hz); m/z (EI) 322/320 (M , 44.73%), 292
4
spectra were obtained on a 56.4 MHz spectrometer using
tri¯uoroacetic acid as external standard, down®eld shifts
being designated as negative. All chemical shifts (d) are
expressed in ppm, coupling constants (J) are given in Hz.
Mass spectra were obtained using EI ionization at 70 eV.
The IR spectra were recorded on a Shimadzu IR-440
spectrometer. All reactions were routinely monitored with
(53.08), 290 (55.23), 276 (23.47), 275 (49.90), 105 (100);
79
HRMS for C H F O Br : Calculated 320.0224; Found
320.0234.
13 15 2 2
3.4. Spectroscopic data for 3b
Oil, IR (liquid ®lm): 2979, 1708, 1480, 1371, 1205,
� 1
1
9
the aid of TLC or F NMR spectroscopy. Dichloromethane
was freshly distilled from calcium hydride.
1132 cm ; dH (CDCl , 300 MHz) 4.20±4.16 (1H, m),
3
2.93 (1H, d-d, J ˆ 17.2, 7.1 Hz), 2.69±2.49 (3H, m),
1
.19±1.13 (12H, m); dF (CCl ) � 36.6 (t, J ˆ 14.0 Hz);
4
‡
3
.1. Diethyl 3-bromo-3,3-difluoropropanal diethyl acetal
m/z (EI) 302/300 (M , 20.82%), 273 (11.89), 203
(85.43), 173 (26.85), 85 (23.75), 57 (100.00). Anal. Calc.
for C H F O Br: C, 43.85; H, 6.31; F, 12.62. Found: C,
(
1)
11 19 2 2
A mixture of CF Br (31.5 g, 0.15 mol), ethyl vinyl ether
2
43.91; H, 6.57; F, 12.61%.
2
(
7.2 g, 0.1 mol), Na S O (26.1 g, 0.15 mol) and NaHCO
2 2 4 3
(
5
25.2 g, 0.3 mol) in ethanol (40 ml) was stirred at 608C for
h. The reaction mixture was poured into water, and
3.5. Spectroscopic data for 3c
extracted with diethyl ether (3 Â 20 ml). The combined
extracts were washed with water, brine and dried over
Na SO . After evaporation of the solvent, the residue was
Oil, IR (liquid ®lm): 2978, 1702, 1472, 1207, 1108,
�
1
1006 cm ; dH (CDCl , 300 MHz) 3.93±3.90 (1H, m),
3
3.72±3.67 (1H, m), 3.47±3.44 (1H, m), 3.13±3.08 (1H,
m), 2.53±2.41 (2H, m), 1.27±1.00 (15H, m); d (CCl )
2
4
distilled under reduced pressure to give 1 (20.0 g, 81%) as a
F
4

S. Peng, F.-L. Qing / Journal of Fluorine Chemistry 103 (2000) 135±137
137
‡
�
36.0 (t, J ˆ 14.0 Hz); m/z (EI) 316/314 (M , 14.67%),
3.9. Spectroscopic data for 3g
Oil, IR (liquid ®lm): 2932, 1699, 1456, 1375, 1191,
2
03 (22.90), 201 (24.22), 71 (100.00), 69 (10.00), 43
79
(
3
57.95); HRMS for C H F O Br : Calculated
12 21 2 2
�
1
14.0694; Found 314.0708.
.6. Spectroscopic data for 3d
Oil, IR (liquid ®lm): 2980, 1716, 1461, 1377, 1192,
1106 cm ; d (CCl , 90 MHz) 4.16±3.90 (1H, m), 3.80±
H
4
3
.60 (2H, q, J ˆ 7.0 Hz), 2.80±2.20 (3H, m), 2.15±1.30
3
(10H, m), 1.26±1.03 (3H, m); d (CCl ) � 37.3 (t,
F 4
‡
J ˆ 14.0 Hz); m/z (EI) 313 (M , 93.26%), 269 (73.88),
203 (74.05), 121 (100), 112 (81.42), 95 (90.18). Anal. Calc.
for C H F O Br: C, 46.01; H, 6.07. Found: C, 45.97; H,
�
1
1
3
021 cm ; dH (CDCl , 300 MHz) 3.89±3.84 (1H, m),
.59±3.53 (1H, m), 3.47±3.42 (1H, m), 2.89±2.85 (1H,
3
12 19 2 2
6.17%.
m), 2.63±2.49 (4H, m), 1.27±1.00 (9H, m); dF (CCl4)
‡
(
(
(
5
� 35.3 (t, J ˆ 14.0 Hz); m/z (EI) 286 (M , 29.84%), 203
25.85), 201 (26.75), 143 (11.97), 121 (9.61), 103 (13.50),
57, 100.00). Anal. Calc. for C H F O Br: C, 41.81; H,
Acknowledgements
We thank the National Science Foundation of China for
funding this work.
10 17 2 2
.92; F, 13.24. Found: C, 41.83; H, 6.06; F, 13.58%.
3
.7. Spectroscopic data for 3e
References
Oil, IR (liquid ®lm): 2976, 1455, 1375, 1204, 1157,
[
1] R. Filler, Y. Kobayashi (Eds.), Biomedicinal Aspects of Fluorine
Chemistry, Elsevier, Amsterdam, 1982.
�
126 cm ; dH (CCl , 90 MHz) 4.10 (1H, m), 3.70±3.20
4
1
1
(
(
2H, m), 2.80±1.60 (9H, m), 1.10 (3H, t, J ˆ 7.0 Hz); d
[2] J.T. Welch, S. Eswarakrishnan, Fluorine Bioorganic Chemistry,
Wiley, New York, 1990.
F
‡
CCl ) � 35.6 (t, J ˆ 14.0 Hz); m/z (EI) 284 (M , 39.76%),
4
[
3] R. Filler, Y. Kobayashi, L.M.Yagupolski (Eds.), Organofluorine
Compounds in Medicinal Chemistry and Biomedical Applications,
Elsevier, Amsterdam, 1993.
2
39 (87.99), 201 (38.04), 159 (45.23), 141 (100.00), 121
44.05). Anal. Calc. for C H F O Br: C, 42.11; H, 5.26.
(
Found: C, 42.41; H, 5.40%.
10 15 2 2
[
4] T.S. Chou, P.C. Heath, L.E. Patterson, L.M. Poteet, R.E. Lalin, A.H.
Hunt, Synthesis (1992) 565.
[
[
5] D.B. Berkowits, D.G. Sloss, J. Org. Chem. 60 (1995) 7047.
6] D. Schirlin, S. Baltzer, J.M. Altenburger, C. Tarnus, J.M. Remy,
Tetrahedron 52 (1996) 305.
3
.8. Spectroscopic data for 3f
Oil, IR (liquid ®lm): 2939, 1711, 1451, 1374, 1202,
[7] J.S. Wilkinson, Chem. Rev. 92 (1992) 505.
[8] M.J. Tozer, T.F. Herpin, Tetrahedron 52 (1996) 8619.
�
1
129 cm ; dH (CDCl3, 300 MHz) 4.12 (1H, d-t,
1
J ˆ 11.3, 5.3 Hz), 3.64±3.50 (2H, m), 2.67±1.60 (11H,
[9] J. Leroy, H. Molines, C. Wakselman, J. Org. Chem. 52 (1987) 290.
10] H. Molines, C. Wakselman, J. Fluorine Chem. 37 (1987) 183.
[
m), 1.13 (3H, t, J ˆ 7.0 Hz); d (CCl ) � 36.6 (t,
F
4
‡
[11] W.-Y. Huang, L. Lu, Chinese J. Chem. 10 (1992) 268.
J ˆ 14.0 Hz); m/z (EI) 299 (M , 100.00%), 203 (68.88),
[
[
12] W.-Y. Huang, H.-Z. Zhang, Chinese J. Chem. 10 (1992) 274.
13] W.-Y. Huang, L. Lu, Y.-F. Zhang, Chinese J. Chem. 1 (1990) 68.
201 (69.55), 155 (94.43), 121 (44.05). Anal. Calc for
C H F O Br: C, 44.15; H, 5.69; F, 12.71. Found: C,
1
1
17
2
2
[14] B.-N. Huang, J.-T. Liu, Chinese J. Chem. 4 (1990) 358.
[15] T. Mukaiyama, M. Murakami, Synthesis (1987) 1043.
4
4.12; H, 5.91; F, 12.83%.