Reaction of halothane with carbonyl compounds in the presence of bases

Article abstract of DOI:10.1016/S0022-1139(03)00148-9

The reaction of halothane, 2-bromo-2-chloro-1,1,1-trifluoroethane (1), with aldehydes and ketones in the presence of bases was found to give 1-alkyl- or 1-aryl-2-bromo-2-chloro-3,3, 3-trifluoropropanols (2) or 2-chloro-3,3-difluoro-2-propenols (3) selecti

Full text of DOI:10.1016/S0022-1139(03)00148-9

Journal of Fluorine Chemistry 123 (2003) 283–285
Short communication
Reaction of halothane with carbonyl compounds in the presence of bases
Akira Ando*, Junko Takahashi, Yuki Nakamura, Naoki Maruyama, Masakazu Nishihara,
Kaori Fukushima, Jin Moronaga, Mayumi Inoue, Kazuyuki Sato, Masaaki Omote,
Itsumaro Kumadaki*
Faculty of Pharmaceutical Sciences, Setsunan University, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
Received 17 March 2003; received in revised form 9 April 2003; accepted 26 May 2003
Abstract
The reaction of halothane, 2-bromo-2-chloro-1,1,1-trifluoroethane (1), with aldehydes and ketones in the presence of bases was found to
give 1-alkyl- or 1-aryl-2-bromo-2-chloro-3,3,3-trifluoropropanols (2) or 2-chloro-3,3-difluoro-2-propenols (3) selectively in good to
moderate yields depending on the bases and reaction conditions.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Halothane; Fluorine; Butyllithium; Carbonyl compounds
1. Introduction
exchange reaction of 1-bromo-1-chloro-2,2-difluoroethene
to give 1-chloro-2,2-difluorovinyllithium (5), which reacted
with zinc chloride to produce the zinc reagent. We expected
that 3 would be obtained selectively, if 5 was allowed to react
with carbonyl compounds. Further, if some bases gave 4, but
not 5, 2 would be obtained selectively. When two equivalent
of BuLi was used, compounds 3 were obtained selectively.
On the other hand, when LHMDS was used, 2 were obtained
in much better yields than when LDA was used (Scheme 2).
In this paper, we would like to describe these reactions for
selective synthesis of 2 and 3.
Organofluorine compounds have attracted much attention
in the various fields, such as medicinal or agricultural che-
micals and liquid crystal, based on their interesting proper-
ties. Therefore, various researches are going on searching for
new synthetic methods for fluorine compounds. We have
reported some reactions of halothane, 2-bromo-2-chloro-
1,1,1-trifluoroethane (1), as a building block for the syntheses
of fluorine compounds. Halothane, an anesthetic agent, has
bromine, chlorine and trifluoromethyl groups on a carbon
atom. Therefore, we expected 1 would work as a valuable
synthone for various fluorine compounds. We have already
reported that the reaction of 1 with Mg or Zn in the presence
of carbonyl compounds gave 1-alkyl- or 1-aryl-2-bromo-2-
chloro-3,3,3-trifluoropropanols (2) and/or 2-chloro-3,3-
difluoro-2-propenols (3) [1–3]. Further, we reported that 1
afforded 2 when it was allowed to react with LDA in the
presence of the carbonyl compounds [4] (Scheme 1).
2. Results and discussion
We examined BuLi in the place of sec-BuLi for the
reaction of 1, since the former was available more easily
than the latter. We expected that if 1 was treated with two
equivalent of BuLi, 1-chloro-2,2-difluorovinyllithium would
be formed as the reaction described above and that this
would react with a carbonyl compound in situ to give
compounds 3. In fact, addition of benzaldehyde to the
reaction mixture of 1 and two equivalents of BuLi gave
2-chloro-3,3-difluoro-1-phenyl-2-propenol (3a). This result
shows that 5 might be formed and have reacted with
benzaldehyde to give 3a (Scheme 3).
Recently, we found that the reaction of 1 with two
equivalents of sec-BuLi in the presence of ZnCl2 afforded
bis(1-chloro-2,2-difluorovinyl)zinc [5]. In this reaction, one
equivalent of the base was used for the dehydrofluorination
of 1 to give 1-bromo-1-chloro-2,2,2-trifluoroethyllithium
(4), and another equivalent was used for halogen–lithium
However, the vinyllithium 5 is too unstable to give a
satisfactory yield of 3. To solve this problem, we reexamined
the reaction: 1 was treated with BuLi in the presence of a
carbonyl compound, expecting that 5 would react with the
* Corresponding authors. Tel.: þ81-72-866-3141;
fax: þ81-72-850-7020.
E-mail addresses: aando@pharm.setsunan.ac.jp (A. Ando),
kumadaki@pharm.setsunan.ac.jp (I. Kumadaki).
0022-1139/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00148-9

284
A. Ando et al. / Journal of Fluorine Chemistry 123 (2003) 283–285
F Cl
OH
R
−F−
R' Cl
R C C CF3
HO Br
F
F
Cl
Br
BuLi
Cl
Zn or Mg
LDA
C
F
F
CF3CHBrCl
F C C Br
C C
F
CF CHBrCl
RCOR'
+
+
3
R'
Cl
C C
Li+
1
4 F
1
2
3
Cl
F
BuLi
C6H5CHO
C C
C C
Li
F
C6H5 CH
OH
F
3a
Scheme 1.
5
Scheme 3.
F Cl
−F−
F
Cl
Br
F
F
Cl
Li
BuLi or
LHMS
BuLi
CF3CHBrCl
F C C Br
C C
C C
Li+
F
1
4
BuLia
THF
−85 ˚C
F
5
1
+
RCOR'
3
RCOR'
(LHMS)
RCOR'
OH
R
R' Cl
R C C CF3
HO Br
yield (%)b
C
F
3
R
R'
R'
Cl
C C
C6H5-
4-CH OC H -
3a 70
-
H-
F
2
3
3b
3c
3d 77
-
81
H-
H-
H-
(88)
(92)
-
3
6 4
C H CH=CH-
Scheme 2.
6
5
4-ClC6H4-
C6H5- CH3-
3e
3f
3g
-
-
69
67
82
carbonyl compound as soon as it was formed. As expected,
the reaction of 1 with two equivalents of BuLi in the
presence of carbonyl compounds gave 3 selectively in good
yields (78–92% based on the carbonyl compounds)
(Scheme 4). This reaction proceeded with both ketones
and aldehydes, and gave much better yields of 3 than the
reaction of 1 in the presence of magnesium.1
C7H15
C8H17
-
H-
CH3-
(84)
(66)
-
-(CH2)5-
61
3h
a. 1 : BuLi : RCOR' = 2.2-2.4 : 4.4 : 1
b. Isolated yield. ( ) estimated by 19F-NMR.
Scheme 4.
To compare the above results with that of the reaction of 1
with LDA in the presence of carbonyl compounds [4], the
reaction of 1 with lithium and/or sodium hexamethyldisi-
lazide (MHMDS) was examined. As shown in Scheme 5,
compounds 2 were obtained selectively in moderate to good
yields (54–96%).2 In these reactions, 3 were not obtained.
MNMDSa
THF −56 ˚C
+
RCOR'
1
2
2 yield (%)b
R
R' MHMDS
C6H5-
4-CH OC H -
NaN(SiMe3)2
H-
H- LiN(SiMe3)2 2b
6 4
2a
78
65
3
NaN(SiMe3)2
4-CH OC H -
2b 83
H-
3
6 4
LiN(SiMe )
C6H5-
CH3-
-(CH2)5-
2e
2h
54
96
3 2
1 Typical procedure of the reaction of halothane (1) with BuLi in the
presence of carbonyl compound is as follows: To a solution of 1
(1.53 g, 7.7 mmol) and benzaldehyde (0.424 g, 4.0 mmol) in THF
(20 ml), BuLi (1.56 M in hexane, 11.1 ml, 17.3 mmol) was added at
À84 8C for 2 h, and the mixture was stirred for 1 h at the same
temperature. The reaction mixture was poured into ice and 10% HCl.
The whole mixture was extracted with Et2O. The Et2O layer was
washed with saturated NaCl, and dried over MgSO4. After evapora-
tion of the solvent, purification of the residue by column chromato-
graphy (SiO2, 15% Et2O in hexane) gave 3a (R ¼ C6H5–, R0 ¼ H,
0.570 mg, 70%). MS m/z: 204 (Mþ). HRMS calcd. for C9H7ClF2O
(Mþ): 204.015. Found: 204.015. 1H NMR (CDCl3) d: 7.27 (5H, bs), 5.6
(1H, m), 3.1 (1H, d, J ¼ 5 Hz). 19F NMR (CDCl3) d: 23.25 (1F), 26.82
(1F). 3b: MS m/z: 234 (Mþ). HRMS calcd. for C10H9ClF2O2 (Mþ):
LiN(SiMe3)2
a. molar ratio: 1 : MHMDS : RCOR'
= 1.9-2.1 : 1.7-2.2 : 1
b. Isolated yield.
Scheme 5.
Our working hypothesis for synthesis of 3 using BuLi was
that this reaction would proceed through the vinyllithium 5,
but we could not eliminate the possibility that 3 were
formed through 2, which had been formed by the reaction
of 1-bromo-1-chloro-2,2,2-trifluoroethyllithium (4) with
carbonyl compounds. Therefore, we examined the reaction
of 1 with one equivalent of BuLi in the presence of carbonyl
compounds, and confirmed by 19F NMR that mixtures of
CF3CBrCl- and CF2¼CCl–alcohols (2 and 3) were formed
(Scheme 6).3
234.026. Found: 234.025. 1H NMR (CDCl3) d:
7 .35 (2H, d,
J ¼ 8:8 Hz), 6.94 (2H, d, J ¼ 8:8 Hz), 5.73 (1H, bs), 3.84 (3H, s),
2.37(1H, d, J ¼ 5:2 Hz). 19F NMR (CDCl3) d: 22.52 (1F, d,
J ¼ 36:6 Hz), 26.26 (1F, dd, J ¼ 36:6, 2.8 Hz). 3d: MS m/z: 238
(Mþ). HRMS calcd. for C9H6Cl2F2O (Mþ): 237.976. Found: 237.977.
1H NMR (CDCl3) d: 7.12 (4H, bs), 5.55 (1H, bs), 4.03 (1H, br). 19F
NMR (CDCl3) d: 22.63 (1F, d, J ¼ 41:02 Hz), 26.39 (1F, d,
J ¼ 41:02 Hz). All the other products were identified by comparison
of spectral data with those reported before [1,2].
2 Typical procedure for using lithium hexamethyldisiliylamide. To a
solution of 1 (0.681 g, 3.80 mmol) and cyclohexanone (0.178 g,
1.82 mmol) in THF (7.5 ml), LiN(TMS)2 (1.0 M in THF, 3.96 ml,
3.96 mmol) was added at À58 8C for 1 h, and the mixture was stirred for
1 h at the same temperature. The reaction mixture was poured into ice
and 10% aqueous HCl. The whole mixture was extracted with Et2O. The
Et2O layer was washed with saturated NaCl, and dried over MgSO4.
After evaporation of the solvent, the residue was purified by column
chromatography (SiO2, 15% Et2O in hexane) to give 2 h (514 mg, 96%).
3 Typical procedure for using one equivalent of BuLi. To a solution of 1
(0.710 g, 3.96 mmol) and cyclohexanone (0.214 g, 1.98 mmol) in THF
(7.5 ml), BuLi (1.56 M in hexane, 2.54 ml, 3.96 mmol) was added at
À53 8C for 1 h, and the mixture was stirred for 1 h at the same
temperature. The reaction mixture was poured into ice and 10%
aqueous HCl. The whole mixture was extracted with Et2O. The Et2O
layer was washed with saturated NaCl, and dried over MgSO4. After
evaporation of the solvent, the residue was separated by column
chromatography (SiO2, Et2O:hexane ¼ 1:4) to give 2 h (122.6 mg,
20%) and 3 h (178.8 mg, 46%), both of which were identified with the
authentic samples [1].

A. Ando et al. / Journal of Fluorine Chemistry 123 (2003) 283–285
285
BuLia
THF
−55 ˚C>
not reactive enough to abstract the bromine atom. In other
words, steps c and/or e in Scheme 7 did not proceed with
these nitrogen bases and only compounds 2 were obtained,
while those steps did proceed with BuLi to give considerable
amounts of 3 with 2. Namely, more soft carbon bases can
abstract a bromine atom.
1
3
+ RCOR'
R
2
+
yield (%)b
R'
3
2
4-CH3OC6H4-
C6H5CH=CH-
16
40
5
47
37
34
46
H- (b)
H- (c)
H- (f)
C7H15
-
-(CH2)5-
20
(h)
a. 1 : BuLi : RCOR' = 2.2-2.5 : 2.2: 1
b. Estimated by 19F-NMR.
3. Conclusion
Scheme 6.
The reaction of 1 with carbonyl compounds in the
presence of two equivalents of BuLi gave 1-aryl- or 1-
alkyl-2-chloro-3,3-difluoropropenols (3) selectively, and in
the presence of LDA or MHMDS, 1-aryl- or 1-alkyl-2-
bromo-2-chloro-3,3,3-propanols (2) were obtained selec-
tively. Compounds 2 and 3 were converted to several types
of fluorine compounds [6]. Therefore, above reaction would
be used for syntheses of these compounds. Study on detailed
mechanism for 3 is now going on.
F Cl
−F−
b
F
F
Cl
Br
F
F
Cl
Li
RLi
a
RLi
c
CF3CHBrCl
F C C Br
C C
C C
Li+
1
4
F
5
f
RCOR'
RCOR'
d
OH
R
R' Cl
C
F
RLi
R C C CF3
R'
Cl
C C
e
LiO Br
F
2
3
Scheme 7.
References
Thus, the mechanisms for 2 and 3 were reconsidered.
Since two equivalents of BuLi gave only 3, some 3 must be
formed through 2 (steps d and e in Scheme 7), but if steps b
and c in Scheme 7 proceed as fast as step d, some 3 might be
formed directly by the reaction of the vinyllithium (step f).
As shown in the first part of this section, the reaction of 1
with two equivalents of sec-BuLi gave 5 and this reacted
actually with a carbonyl compound to produce 3. At this
stage, we cannot say through which route 3 were formed
mainly.
[1] T. Takagi, A. Takesue, M. Koyama, A. Ando, T. Miki, I. Kumadaki, J.
Org. Chem. 57 (1992) 3921–3923.
[2] T. Takagi, A. Takesue, A. Isowaki, M. Koyama, A. Ando, I.
Kumadaki, Chem. Pharm. Bull. 43 (1995) 1071–1075.
[3] T. Takagi, A. Takesue, J. Takahashi, H. Nakatsuka, M. Koyama, A.
Ando, I. Kumadaki, Chem. Pharm. Bull. 44 (1996) 280–283.
[4] T. Takagi, A.K. Kanai, M. Omote, A. Ando, I. Kumadaki, J. Fluorine
Chem. 89 (1998) 233–234.
[5] M. Nishihara, Y. Nakamura, N. Maruyama, K. Sato, M. Omote, A.
Ando, I. Kumadaki, J. Fluorine Chem., in press.
On the other hand, the results in Scheme 5 suggest that
LDA or MHMDS, nitrogen bases, can abstract proton but are
[6] T. Takagi, N. Okikawa, S. Johnoshita, M. Koyama, A. Ando, I.
Kumadaki, Synlett (1996) 82–84, and references therein.