Sodium bromodifluoroacetate: A difluorocarbene source for the synthesis of gem -difluorocyclopropanes

Article abstract of DOI:10.1055/s-0029-1218754

As a new difluorocarbene source, sodium bromodifluoroacetate (BrCF ₂CO₂Na) was found to be effective for high-yielding synthesis of gem-difluorocyclopropanes and gem-difluorocyclopropenes under mild conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218754

2080
PAPER
Sodium Bromodifluoroacetate: A Difluorocarbene Source for the Synthesis of
gem-Difluorocyclopropanes
S
odium Bromodifl
o
uoroacetate
as
D
iflu
u
orocarbene
Source Oshiro, Yoshimichi Morimoto, Hideki Amii*
Department of Chemistry, Graduate School of Science, Kobe University, Nada-ku 1-1, Kobe 657-8510, Japan
Fax +81(78)8035799; E-mail: amii@kobe-u.ac.jp
Received 24 February 2010; revised 23 March 2010
cent, therefore it is difficult to handle. In order to over-
Abstract: As a new difluorocarbene source, sodium bromodifluo-
roacetate (BrCF2CO2Na) was found to be effective for high-
yielding synthesis of gem-difluorocyclopropanes and gem-difluoro-
cyclopropenes under mild conditions.
come these technical issues, herein we report a highly
efficient route to gem-difluorocyclopropanes and difluo-
rocyclopropenes using sodium bromodifluoroacetate
(BrCF2CO2Na) as a new precursor of difluorocarbene
(Scheme 1).
Key words: fluorine, carbenes, cycloaddition, cyclopropanes,
cyclopropenes
F
F
R1
R2
R3
R4
BrCF2CO2Na
diglyme, heat
R1
R2
R3
R4
Organofluorine compounds find diverse applications in
scientific and industrial fields.1 In particular, fluorine-
containing cyclopropanes have received a great deal of at-
tention due to their biological activities.2,3 Actually, cer-
1
2
Scheme 1
tain
gem-difluorocyclopropanes
show
potential
bioactivities such as inhibition of P-glycoproteins,4 degra-
dation of oncogenic proteins,5 DNA alkylation,6,7 and in-
secticidal properties.8 In recent years, introducing gem-
difluorocyclopropyl moieties into biomolecules such as
nucleosides9,10 and amino acids11 have been topics of con-
siderable interest. Beside biological utilities, gem-difluo-
rocyclopropanes exhibit unique physical properties as
liquid crystalline12 and polymer materials.13 Furthermore,
the transformations involving regioselective ring-opening
of gem-difluorocyclopropanes provides a variety of useful
fluoroorganic compounds.14,15 Therefore, the develop-
ment of effective synthetic methods for gem-difluorocy-
clopropanes are of significant importance. To date,
several synthetic methods for gem-difluorocyclopropanes
have been developed.16 Among them, addition of difluo-
rocarbene (:CF2) to alkenes is one of the most versatile
methods for constructing gem-difluorocyclopropanes in a
stereospecific manner; the starting alkenes undergo
[2+1]-cycloaddition reactions to afford the corresponding
difluorocyclopropanes with stereochemical fidelity.17,18
Sodium chlorodifluoroacetate (ClCF2CO2Na) is a conve-
nient reagent to generate difluorocarbene via thermoly-
sis.17 However, despite its usefulness, there exist several
problems while using ClCF2CO2Na as a difluorocarbene
source: (i) pyrolysis of ClCF2CO2Na needs high tempera-
ture condition (usually, 180–190 °C); (ii) slow addition
technique is required to improve the yields of difluorocy-
clopropanes in some cases;4b (iii) an excess amount of so-
dium chlorodifluoroacetate is used to complete the [2+1]
cycloaddition (generally, 8 equiv to the substrate alkenes),
and (iv) ClCF2CO2Na is highly hygroscopic and deliques-
Initially, we evaluated sodium halodifluoroacetates
XCF2CO2Na (X = Cl, Br) for difluorocyclopropanation of
1,1-diphenylethene (1a) in diglyme under heating condi-
tions. The results of these experiments are summarized in
Table 1. When 1a was treated with sodium chlorodifluo-
roacetate (8 equiv to 1a) at 180 °C for 20 minutes, cy-
cloaddition of difluorocarbene to 1a took place to afford
the difluorocyclopropane 2a in 96% GC yield (entry 1).
However, the use of the reduced amount of ClCF2CO2Na
(2 equiv) at lower temperature (150 °C) resulted in the
formation of 2a in poor yield (entry 2). Under the same re-
action condition (150 °C, 20 min), the cycloaddition pro-
ceeded smoothly to give the desired cyclopropane 2a in
99% GC yield (99% isolated yield) upon treatment with
sodium bromodifluoroacetate (2 equiv to 1a) (entry 3).
Moreover, even at 120 °C, using BrCF2CO2Na as a car-
bene source afforded 2a in 76% yield (entry 4). Due to the
smaller bond dissociation energy (BDE) of a C–Br bond
Table 1 Difluorocyclopropanation of 1,1-Diphenylethene (1a)
F
Ph
F
XCF2CO2Na (X = Cl, Br)
diglyme, heat
Ph
Ph
Ph
1a
2a
Entry XCF2CO2Na
Conditions
Yield (%)a
1
2
3
4
ClCF2CO2Na (8 equiv)
180 °C, 20 min
150 °C, 20 min
150 °C, 20 min
120 °C, 20 min
96
ClCF2CO2Na (2 equiv)
BrCF2CO2Na (2 equiv)
BrCF2CO2Na (2 equiv)
64
99 (99)b
76
SYNTHESIS 2010, No. 12, pp 2080–2084
x
x.
x
x
.
2
0
1
0
a Determined by GC analysis using biphenyl as an internal standard.
b Isolated yield in parenthesis.
Advanced online publication: 23.04.2010
DOI: 10.1055/s-0029-1218754; Art ID: F04010SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Sodium Bromodifluoroacetate as Difluorocarbene Source
2081
than that of a C–Cl bond, thermolysis of BrCF2CO2Na oc- BrCF2CO2Na (entries 1, 2, 4, and 7–10). In each case,
curred readily to generate difluorocarbene effectively un- slow addition technique for BrCF2CO2Na was not re-
der the lower temperature conditions.19
quired. Notably, the presence of electron-withdrawing
groups had little effect on the chemical yields of 2 (entries
9 and 10).
Other examples of the selective synthesis of gem-difluo-
rocyclopropanes 2 by the use of BrCF2CO2Na are given in
Table 2. A wide repertoire of alkenes 1 possessing aryl or The present protocol is applicable to the preparation of
aliphatic substituents underwent [2+1] cycloaddition to 1,1-difluoro-2-siloxycyclopropanes, which would act as
provide the corresponding gem-difluorocyclopropanes 2 homoenolate anion precursors. The reactions of silyl enol
in high yields. The use of BrCF2CO2Na for difluorocyclo- ethers with difluorocarbene are anticipated to deliver sil-
propanation was much more effective than that of oxydifluorocyclopropanes. However, it is known that the
ClCF2CO2Na (entry 2 vs. entry 3, and entry 5 vs. entry 6). thermal stabilities of siloxydifluorocyclopropanes are too
Generally, difluorocyclopropanation of alkenes proceed- low to obtain the desired adducts selectively under high
ed smoothly without using a large excess amount of temperature conditions.20 Actually, heating the silyl enol
Table 2 Synthesis of gem-Difluorocyclopropanes 2
F
R1
XCF2CO2Na
(X = Br or Cl)
R1
R2
F
R3
R2
diglyme, heat
R3
R4
R4
1
2
Entry
1
1
XCF2CO2Na
Conditions
2
Yield (%)a,b
99 (99)
F
Ph
F
Ph
BrCF2CO2Na (2 equiv)
150 °C, 20 min
Ph
Ph
1a
2a
F
F
2
3
BrCF2CO2Na (4 equiv)
ClCF2CO2Na (4 equiv)
150 °C, 15 min
150 °C, 15 min
99 (76)
61
t-Bu
1b
t-Bu
2b
F
F
4
BrCF2CO2Na (4 equiv)
180 °C, 15 min
99 (79)
Cl
Cl
1c
2c
F
5
6
7
BrCF2CO2Na (8 equiv)
ClCF2CO2Na (8 equiv)
BrCF2CO2Na (2 equiv)
150 °C, 15 min
150 °C, 15 min
180 °C, 15 min
93 (73)
35
61
F
Ph
OAc
Ph
OAc
1d
2d
F
F
Ph
Ph
8
BrCF2CO2Na (3 equiv)
150 °C, 15 min
99 (80)
1e
2e
F
Ph
F
Ph
9
BrCF2CO2Na (4 equiv)
BrCF2CO2Na (2 equiv)
150 °C, 15 min
150 °C, 15 min
95 (67)
99 (84)
(pin)B
1fc
(pin)B
2fc
F
F
10
BnO2C
BnO2C
1g
2g
a Determined by GC analysis using biphenyl as an internal standard.
b The values in parentheses indicate the isolated yields of 2.
c pin = OCMe2CMe2O.
Synthesis 2010, No. 12, 2080–2084 © Thieme Stuttgart · New York

2082
K. Oshiro et al.
PAPER
ether 3a with ClCF2CO2Na (6 equiv to 3) at 180 °C af- In summary, we have described a convenient synthesis of
forded not only the desired siloxydifluorocyclopropane fluorinated cyclopropanes and cyclopropenes by the use
4a in only 23% yield, but also a mixture of enone 5 and of BrCF2CO2Na as
a
difluorocarbene source.
trifluorocyclopropane 6 (Scheme 2). The formation could BrCF2CO2Na is stable (not deliquescent) at room temper-
be explained via thermal ring-opening reaction of 4a and ature and is easy to handle. In light of its operational sim-
the subsequent addition of difluorocarbene.21 In order to plicity and high efficiency, this reliable protocol is
prevent thermal decomposition of 4a, a reaction tempera- expected to have broad utility in the synthesis of difluo-
ture of less than 160 °C is required. When the silyl enol romethylene compounds for biological and chemical ap-
ether 3a was treated with BrCF2CO2Na (1.5 equiv to 3a) plications.
at 150 °C, the desired adduct 4a was obtained in 69% GC
yield (54% isolated yield) as the sole product. The difluo-
rocyclopropanation of cyclic silyl enol ether 3b gave the
corresponding siloxycyclopropane 4b in high yield. Thus,
the use of BrCF2CO2Na was found to be effective for se-
lective formation of siloxydifluorocyclopropanes.
1H and 19F NMR spectra were recorded at 400 and 376 MHz, re-
spectively, using CDCl3 as a solvent. The chemical shifts are report-
ed in d (ppm) values relative to Me4Si (d = 0 for 1H NMR) and C6F6
(d = 0 for 19F NMR). Coupling constants are reported in hertz (Hz).
All air and/or water sensitive reactions were carried out under argon
atmosphere with anhyd solvents using standard syringe-cannula/
septa techniques. Anhyd diglyme was purchased from Sigma-
Aldrich Chemicals. Sodium bromodifluoroacetate was prepared by
the reaction of BrCF2CO2H23 with NaOH (1 equiv) in MeOH at r.t.
for 4 h (88% yield). The spectral data of compounds 2a,24 2c,18e
2d,14c 2f,25 4a and 4b,20 8a,22a and 8b26 were comparable with those
reported.
OSiMe3
ClCF2CO2Na (6 equiv)
Ph
diglyme, 180 °C, 1 h
3a
O
F
F
O
F
F
F
OSiMe3
Ph
+
+
Ph
Ph
4a (23%)a
1,1-Difluoro-2,2-diphenylcyclopropane (2a);24 Typical Proce-
dure 1 (Table 2, Entry 1)
F
5 (5%)a
6 (20%)a
To a solution of 1a (181.32 mg, 1.0 mmol) in diglyme (5 mL) was
added a diglyme solution (10 mL) of BrCF2CO2Na (78 mg, 0.40
mmol) dropwise for 10 min at 150 °C. Then, the reaction mixture
was stirred for 5 min at 150 °C. After cooling to r.t., the reaction was
quenched with ice water (30 mL). The organic materials were ex-
tracted with hexane (4 × 50 mL) and the combined organic layers
were washed with brine (200 mL) and dried (Na2SO4). After remov-
al of the solvent under reduced pressure, the residue was purified by
silica gel column chromatography (hexane–EtOAc, 100:1) to give
2a (231.6 mg, 99%) as a colorless solid; mp 50–51 °C.
1H NMR (400 MHz, CDCl3): d = 2.08 (t, JH,F = 8.6 Hz, 2 H), 7.24
(t, J = 7.6 Hz, 2 H), 7.32 (t, J = 7.6 Hz, 4 H), 7.41 (d, J = 7.6 Hz, 4
H).
19F NMR (376 MHz, CDCl3): d = 31.8 (d, JH,F = 8.6 Hz, 2 F).
F
OSiMe3
F
OSiMe3
Ph
BrCF2CO2Na (1.5 equiv)
Ph
diglyme, 150 °C, 15 min
4a
3a
69%a (54%)b
F
F
OSiMe3
OSiMe3
BrCF2CO2Na (1.2 equiv)
diglyme, 150 °C, 15 min
3b
4b
96%a
a Determined by GC analysis using biphenyl as an internal standard.
b Isolated yield.
GC-MS: m/z (%) = 230 (M+, 80), 210 (80), 178 (39), 165 (100), 77
Scheme 2
(16).
Furthermore, the use of sodium bromodifluoroacetate
2-[1-(tert-Butyl)phenyl]-1,1-difluorocyclopropane (2b); Typical
Procedure 2 (Table 2, Entry 2)
worked well for the synthesis of gem-difluorocycloprop-
enes.22 As shown in Scheme 3, terminal and internal To a solution of 1b (16 mg, 0.10 mmol) in diglyme (0.5 mL) was
added a diglyme solution (1.0 mL) of BrCF2CO2Na (78 mg, 0.40
mmol) dropwise for 10 min at 150 °C. Then, the reaction mixture
was stirred for 5 min at 150 °C. After cooling to r.t., the reaction was
quenched with ice water (5 mL). The organic materials were ex-
tracted with hexane (4 × 20 mL) and the combined organic layers
were washed with brine (70 mL) and dried (Na2SO4). After removal
of the solvent under reduced pressure, the residue was purified by
silica gel column chromatography (hexane–EtOAc, 50:1) to give 2b
(16.0 mg, 76%) as a colorless oil.
alkynes 7a and 7b were converted into the corresponding
gem-difluorocyclopropenes 8 in high yields.
F
F
BrCF2CO2Na (4 equiv)
C8H17
C8H17
diglyme
150 °C, 15 min
7a
8a
99%a
1H NMR (400 MHz, CDCl3): d = 1.31 (s, 9 H), 1.60 (dddd,
JH,F = 12.8, 3.8 Hz, JH,H = 8.0, 7.0 Hz, 1 H), 1.79 (dddd, JH,F = 12.6,
5.0 Hz, JH,H = 12.0, 7.7 Hz, 1 H), 2.72 (ddd, JH,F = 13.2 Hz,
JH,H = 12.0, 8.0 Hz, 1 H), 7.16 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4
Hz, 2 H).
19F NMR (376 MHz, CDCl3): d = 19.3 (dd, JF,F = 152 Hz,
JH,F = 12.8 Hz, 1 F), 35.8 (ddd, JF,F = 152 Hz, JH,F = 13.2, 12.6 Hz,
1 F).
F
F
BrCF2CO2Na (4 equiv)
Ph
Ph
diglyme
7b
Ph
99%a (80%)b
Ph
180 °C, 15 min
8b
a Determined by GC analysis using biphenyl as an internal standard.
b The value in parenthesis indicates the isolated yield after recrystallization.
Scheme 3
Synthesis 2010, No. 12, 2080–2084 © Thieme Stuttgart · New York

PAPER
Sodium Bromodifluoroacetate as Difluorocarbene Source
2083
GC-MS: m/z (%) = 210 (1, [M+]), 195 (22), 145 (17), 77 (20), 57
(100).
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7.66.
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362.
rac-(1S,6R)-7,7-Difluoro-1-phenylbicyclo[4.1.0]heptane (2e)
(Table 2, Entry 8)
Colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.28–1.52 (m, 4 H), 1.72–1.88 (m,
3 H), 1.94–2.06 (m, 1 H), 2.10–2.22 (m, 1 H), 7.21–7.36 (m, 5 H).
19F NMR (376 MHz, CDCl3): d = 18.7 (d, JF,F = 149.5 Hz, 1 F), 33.9
(dd, JF,F = 149.5 Hz, JH,F = 15.0 Hz, 1 F).
GC-MS: m/z (%) = 208 (100, [M+]), 77 (20).
Anal. Calcd for C13H14F2: C, 74.98; H, 6.78. Found: C, 74.97; H,
6.92.
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Benzyl 2,2-Difluoro-1-methylcyclopropanecarboxylate (2g)
(Table 2, Entry 10)
Colorless oil.
IR (neat): 1734 cm–1.
3
1H NMR (400 MHz, CDCl3): d = 1.34 (ddd, JH,F = 11.4 Hz,
4JH,F = 5.0 Hz, JH,H = 7.6 Hz, 1 H), 1.46 (s, 3 H), 2.2–2.3 (m, 1 H),
5.1–5.2 (m, 2 H), 7.3–7.4 (m, 5 H).
19F NMR (376 MHz, CDCl3): d = 25.1 (dd, JF,F = 150 Hz,
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5.44.
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Acknowledgment
The financial support of the Ministry of Education, Culture, Sports,
Science and Technology of Japan (Grant-in-Aid for Scientific Re-
search (B), No. 18350054 and Grant-in-Aid for Scientific Research
on Priority Areas ‘Chemistry of Concerto Catalysis’, No.
20037050) is acknowledged. We would like to thank Prof. Masahiko
Hayashi (Kobe University) for his useful suggestions. We are
grateful to Central Glass Co., Ltd. for a gift of bromodifluoroacetic
acid.
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F
SiMe3
F
OSiMe3
F
F
CF2
OSiMe3
Ph
>160 °C
O
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Ph
Ph
3a
4a
O
F
O
F
CF2
Ph
Ph
– Me3SiF
F
F
5
6
Scheme 4
(22) (a) Bessard, Y.; Schlosser, M. Tetrahedron 1991, 47, 7323.
(b) Xu, W.; Chen, Q.-Y. J. Org. Chem. 2002, 67, 9421.
(23) Bromodifluoroacetic acid is available from SynQuest
Laboratories, Inc. (www. synquestlabs.com).
(24) (a) Weyerstahl, P.; Schwartzkopff, U.; Nerdel, F. Liebigs
Ann. Chem. 1973, 2100. (b) Kamel, M.; Kimpenhaus, W.;
Buddrus, J. Chem. Ber. 1976, 109, 2351.
(19) Tissot, P.; Waefler, J. P. Thermochim. Acta 1983, 66, 315.
(20) Wu, S.-H.; Yu, Q. Acta Chim. Sinica 1989, 253.
(21) The formation of 5 and 6 can be explained by assuming the
following pathway (Scheme 4).
(25) Fujioka, Y.; Amii, H. Org. Lett. 2008, 10, 769.
(26) Eujen, R.; Hoge, B. J. Organomet. Chem. 1995, 503, C51.
Synthesis 2010, No. 12, 2080–2084 © Thieme Stuttgart · New York