Reaction of difluorocarbene with propargyl esters and efficient synthesis of difluorocyclopropyl ketones

Article abstract of DOI:10.1016/j.tet.2009.06.019

Difluorocarbene generated from FSO₂CF₂CO₂SiMe₃ (TFDA) at 120 °C could reacted with terminal alkynes having an ester group at the α position to the triple bond. Difluorocyclopropenes were further converted to difluorocyclopropyl ketones under alkaline condition. Mechanism for the conversion was studied.

Full text of DOI:10.1016/j.tet.2009.06.019

Tetrahedron 65 (2009) 6320–6324
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Tetrahedron
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Reaction of difluorocarbene with propargyl esters and efficient
synthesis of difluorocyclopropyl ketones
*
Xiao-Chun Hang, Wei-Peng Gu, Qing-Yun Chen, Ji-Chang Xiao
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Difluorocarbene generated from FSO2CF2CO2SiMe3 (TFDA) at 120 ꢀC could reacted with terminal alkynes
Article history:
Received 29 April 2009
Received in revised form 3 June 2009
Accepted 5 June 2009
having an ester group at the
to difluorocyclopropyl ketones under alkaline condition. Mechanism for the conversion was studied.
a position to the triple bond. Difluorocyclopropenes were further converted
Ó 2009 Elsevier Ltd. All rights reserved.
Available online 10 June 2009
Keywords:
Difluorocyclopropane
Difluorocyclopropene
Difluorocyclopropyl ketone
Difluorocarbene
1. Introduction
2. Results and discussion
Three-membered carbocycles are versatile building blocks in
organic synthesis, which are extremely important and in-
teresting for their unique structural and electronic properties.1
Although the introduction of fluorine atoms into these com-
pounds could significantly alter their chemical properties,2 the
fluorinated analogues such as difluorocyclopropenes and
difluorocyclopropanes have been less studied. This might be due
to the shortage of efficient and convenient synthetic methods for
these compounds. The most possible and direct route to these
fluorinated analogues might be through the addition of difluoro-
carbene to double or triple bonds.3 Recently, we found that
difluoro(methylene)cyclopropanes can be readily prepared from
Trimethylsilyl fluorosulfonyldifluoroacetate (TFDA) was found
to be an efficient difluorocarbene precursor, which can be used to
Table 1
Reaction of alkynes with difluorocarbene
R
TFDA / NaF
R
120 °C
F
F
1a-c
2a-c
Entry
1
Alkyne
Product
Yield (%)
65a
F
the direct difluorocyclopropanation of allenes, using FSO2CF2
F
-
CO2Si(CH3)3 (TFDA) as the difluorocarbene precursor.3f The
difluorocarbene addition to phenylacetylene did give the corre-
sponding difluorocyclopropene structure.3a–e However, the ter-
minal difluorocyclopropene was not stable and decomposed
readily on standing even at room temperature. As an extension
of our studies on highly strained three-membered ring com-
pounds and our interest in difluorocarbene chemistry,4 we in-
vestigated the synthesis of terminal difluorocyclopropenes and
their chemical conversions.
1a
2a
2
3
db
db
1b
OAc
OAc
45
F
2c
F
1c
4c
1c
2a was unstable, see Ref. 3a.
No addition product was detected and the alkyne kept inert in the reaction.
ClCF2COONa (10 equiv) was used as the difluorocarbene reagent and no addition
d
d
a
b
c
* Corresponding author. Tel.: þ86 2154925340; fax: þ86 2164166128.
E-mail address: jchxiao@mail.sioc.ac.cn (J.-C. Xiao).
product was detected.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.019

X.-C. Hang et al. / Tetrahedron 65 (2009) 6320–6324
6321
construct the highly strained ring compounds.3,5 We reexamined
the addition reaction of difluorocarbene derived from TFDA with
terminal alkynes (Table 1). Although the product 2a was not stable,
the addition of difluorocarbene with phenylacetylene did occur
under this condition (entry 1). In the case of ‘normal’ terminal al-
kyne like 1b, no reaction happened (entry 2). Much to our surprise,
the addition of difluorocarbene to alkyne 1c with an acetoxy group
Table 2
Reaction of terminal alkynes with different
a substituents
OR
OR
TFDA (2eq)
NaF(10%), xylene
N2, 120 °C
F
F
1d-j
2d-j
at the
a position to the triple bond could proceed smoothly to give
2c as a stable compound in 45% yield (entry 3). However, no desired
addition product could be detected when ClCF2COONa was used as
the difluorocarbene precursor (entry 4).3i Having the desired
product, the next step was to screen the reaction condition for
optimized yield of the addition. It was found that 2c could be iso-
lated in 59% when xylene was used as the solvent at 120 ꢀC for
35 min (See Supplementary data).
Entry
Alkyne
R
Product
Yield (%)
dc
dc
49,a dd
67,a 49b
53,a 50b
66,a 65b
78,a 61b
1
2
3
4
5
6
7
1d
1e
1f
1g
1h
1i
Diethoxyphosphoryl
4-Chlorophenyl
Benzoyl
Cyclohenxanecarbonyl
Ethylsuccinyl
Phenylacetyl
2d
2e
2f
2g
2h
2i
1j
Pivaloyl
2j
The above results have shown that an
a substituted acetoxy
Determinated by 19F NMR.
Isolated yield.
No adduct was detected.
The adduct decomposed readily after the reaction.
group in alkynes is necessary for the reaction. With the optimized
reaction conditions in hand, we further investigated the reaction of
a
b
c
other
a
substituted alkynes. As shown in Table 2, no addition
d
Table 3
Addition of difluorocarbene to propargyl esters
G
O
G
O
TFDA (2eq)
NaF(10%), xylene
N2, 120 °C
G = acetyl, pivaloyl (Pv)
or phenylacetyl
R
R = aryl, alkyl
R
or hydrogen
F
F
3a-r
4a-r
OAc
F
OPv
F
Cl OAc
OAc
F
OAc
F
Cl
F
F
F
F
F
F
Cl
F
F
4a
4b
4c
4e
44%a/33%b
4d
57%a/46%b
63%a/54%b
51%a/46%b
63%a/52%b
OPv
OPv
OAc
F
OPv
MeO
OPv
MeO
t-Bu
Br
F
F
F
4g
F
F
F
F
MeO
MeO
F
F
Br
4f
4j
4h
4i
73%a/37%b
53%a/48%b
73%a/55%b
60%a/55%b
54%a/35%b
OPv
F
OAc
F
OAc
OAc
OAc
PhO
F
F
F
F
F
F
Me
F
F
t-Bu
MeO
4n
4m
4k
4l
4o
74%a/43%b
60%a/51%b
64%a/53%b
51%a/45%b
61%a/58%b
O
O
Br OPv
OPv
MeO
OPv
F
OAc
n-C7H15
F
F
MeO
F
F
F
F
F
MeO
4p
4q
F
F
4r
4t
c
4s
57%a/30%b
45%a/39%b
62%a/60%b
65%a/29%b
45%a/35%b
Determined by 19F NMR.
Isolated yield.
a
b
c
5 equiv TFDA was used.

6322
X.-C. Hang et al. / Tetrahedron 65 (2009) 6320–6324
a position of the triple bond was
NaOH (1 equiv.)
NaOH (2 equiv.)
reaction happened when the
F
F
F
O
AcO
HO
substituted with phosphoryloxy (entry 1) or aryloxy (entry 2) group.
The reaction with alkyne containing a benzoyloxy substitutent was
similar to that with phenylacetylene. The easy decomposition of the
adduct made the isolation difficult (entry 3). As for other carboxy
substituted alkynes, the reaction could proceed very well to give the
adducts 2g–j with satisfied yields (entries 4–7), which indicated the
strong neighboring group effect existed in the difluorocarbene ad-
dition to terminal alkynes. Further evidence is needed to elucidate
the underlying mechanism for this inherent effect.
CH3OH / H2O
0 °C, 30 min
CH3OH (dried)
3h
F
F
F
R
R
R
6a
5l
4l
F
F
(92 %)
(95 %)
F
F
D
D
NaOH (2 equiv.)
NaOH (2 equiv.)
(71 %)
D
H
CD3OD (dried)
5h
O
CD3OD (dried)
5h
O
D
H
(71 %)
R
R
8
7
R = -C H C H
5 6 4.
p
6
Scheme 1. Deuterium-labeling experiment.
Then a variety of propargyl esters with
a substituted carboxy
groups were applied to the reaction (Table 3). Both aryl and alkyl
propargyl esters could be converted to the corresponding difluoro-
cyclopropenes in moderate yields. The carboxy group of the alkyne
had some influence on the reaction. Increasing the hindrance of the
ester group would depress the addition of difluorocarbene to the
triple bond. Compared with 4h, the yield of 4t decreased signifi-
cantly when the acetyl was substituted by pivaloyl. However, as it
might be seen from the yield of 4q and 4r, bulky ester group on
alkyl propargyl esters would favor the difluorocarbene addition. It
should be noted that all of these terminal difluorocyclopropenes
are stable at room temperature when exposed to air for long time.
An ester functionality is most commonly used to protect the
hydroxyl group. We carried out the deprotection by hydrolysis with
NaOH in anhydrous methanol. To our surprise, the deprotected
product rearranged readily to give the gem-difluorocyclopropyl
ketone under the alkaline reaction condition (Table 4). However,
this reaction only worked well for the aryl-substituted difluoro-
cyclopropenes, while not for the alkyl-substituted ones (entry 10).
Longer reaction time and more amounts of NaOH were necessary to
complete the reaction for those difluorocyclopropenes with sub-
stituents at the ortho position of the aryl ring (entries 2, 5). The
reaction was not affected by the electronic properties of the sub-
stituents on the aryl ring, giving the corresponding difluoro-
cyclopropyl ketones6 in moderate to good yields.
5l under the same reaction condition as that in Table 4. The a-hy-
drogen of 5l was deuterated quite easily under basic condition to give
8, while the methylene hydrogens of the cyclopropane ring remained
inert. However, when the reaction was performed in CD3OD, the
cyclopropane ring hydrogens of the product were mostly deuterated,
affording difluorocyclopropyl ketone 7 with a deuterium content of
71% as determined by 1H NMR.
Based on the above results, a plausible reaction mechanism was
proposed similar to a propargylic alcohol rearrangement under the
alkaline condition.7 Deacetylation of 4l under basic condition first
led to the formation of the intermediate 9 (Scheme 2), which could
either abstract a proton to give 6b or convert to 10 through proton
transfer from carbon to oxygen. Allylic rearrangement of 10 would
give 11. Subsequent deuteration of active allylic hydrogens could
afford the final product.
F
F
F
CD3OD
base
base
(D)HO
AcO
-O
F
F
F
R
R
R
R
9
6b
4l
H
NaOH
(2 equiv.)
F
F
(D)HO
5h
(H)DO
base
CD3OD
(dried)
F
F
R
11
10
Table 4
CD3OD
Conversion of difluorocyclopropenes to difluorocyclopropyl ketones
F
(92 %D)
F
O
(D)H D(H)
F
D(71 %)
(H)DO
O
O
O
G
D
NaOH (2 eq)
(71 %)
R
F
F
R
12
7
R
R
MeOH
Time
F
R = p-C6H5C6H4.
F
F
Scheme 2. Proposed mechanism for the formation of difluorocyclopropyl ketones.
4
5
Entry
R
G
Time (h)
Product
Yielda (%)
3. Conclusion
1
2
3
4
5
6
7
8
9
10
p-F–Ph–
o-Cl–Ph–
p-Cl–Ph–
m-Cl–Ph–
o-CH3O–Ph–
p-CH3O–Ph–
m-CH3O–Ph–
p-CH3–Ph
Acetyl, 4b
Acetyl, 4c
Acetyl, 4d
Pivaloyl, 4e
Acetyl, 4h
Pivaloyl, 4i
Pivaloyl, 4j
Acetyl, 4k
Acetyl, 4l
Acetyl, 4q
5
72b
5
5b
5c
5d
5e
5h
5i
85
75
99
71
66
89
94
72
82
dc
In conclusion, the difluorocarbene addition to terminal alkynes
was realized through the introduction of a carboxy group at the
5
101b
5
a
-position to the triple bond. The corresponding difluoro-
cyclopropenes were further converted to difluorocyclopropyl ke-
tones under alkaline condition. A deuterium-labeling technique
was adopted to elucidate the mechanism for this conversion.
Further investigation into the reaction of difluorocyclopropenes
and difluorocyclopropyl ketones is currently under way in our
laboratory.
5
5
5
5
5j
5k
5l
p-Ph–Ph–
CH3(CH2)6–
dc
a
Isolated yield.
4 equiv of NaOH was used in the reaction.
No desired product detected.
b
c
4. Experimental section
4.1. General information
In order to gain insights into the mechanism for the conversion of
difluorocyclopropenes to difluorocyclopropyl ketones,6 a series of
conditional experiments were conducted (Scheme 1). In wet meth-
anol, deacetylation of 4l occurred rapidly to give the unstable
hydroxyl difluorocyclopropene 6a, which subsequenty rearranged to
a
-
1H NMR spectra were recorded on a Bruker AM 300 (300 MHz)
spectrometer with TMS as an internal standard (negative for

X.-C. Hang et al. / Tetrahedron 65 (2009) 6320–6324
6323
upfield). 19F NMR spectra were recorded on a Bruker AM 300
(282 MHz) with CFCl3 as an external standard (negative for upfield).
13C NMR spectra were recorded on a Bruker AM 400 (100 MHz)
spectrometer with CDCl3 as an internal standard (negative for up-
field). The solvent for NMR measurement was CDCl3, which were
purchased from Cambridge Isotope Laboratories, Aldrich or Acros.
MS and HRMS were recorded on a Hewlett–Packard HP-5989A
spectrometer and a Finnigan MAT-8483 mass spectrometer. Ele-
mentary analyses were obtained on a Perkin–Elmer 2400 Series II
Elemental Analyzer. Infrared spectra were measured with a Perkin–
Elmer 983 spectrometer. TLC analysis was performed on silica gel
plates, column chromatography over silica gel (mesh 300–400). All
solvents were purified by standard methods. FSO2CF2COOSiMe3
(TFDA),5 propargyl compounds 1d,8 1e9 were prepared as described
in the literature.10
699 cmꢁ1
.
MS (ESI): m/z: 247.0 [MþNaþ]. Anal. Calcd for
C12H10F2O2: C, 64.28; H, 4.50. Found: C, 64.20; H, 4.61.
4.4. Typical procedure for the synthesis of 2,2-
difluorocyclopropyl ketones (5)
To a stirred solution of 4b (49 mg, 0.2 mmol) in MeOH (1.5 mL)
was added NaOH (16 mg, 0.4 mmol). The reaction process was
monitored by TLC. After complete conversion it was directly puri-
fied by flash chromatography on silica gel column. Compound 5b
was obtained as red oil, 42 mg, 85% yield. 1H NMR (300 MHz,
CDCl3):
d
¼1.67–1.81 (m, 1H), 2.27–2.41 (m, 1H), 3.20–3.38 (m, 1H),
7.05–7.15 (m, 2H), 7.92–8.00 (m, 2H) ppm. 19F NMR (282 MHz,
CDCl3):
d
¼ꢁ103.9 (s, 1F), ꢁ124.2 (dt, J1¼148.2 Hz, J2¼12.4 Hz, 1F),
ꢁ140.1 (dt, J1¼148.2 Hz, J2¼16.7 Hz, 1F) ppm. 13C NMR (100 MHz,
CDCl3)
d¼15.63 (t, JFC¼10.9 Hz), 29.60 (t, JFC¼11.7 Hz), 111.45 (t,
4.2. Synthesis of propargylic ester substrates
JFC¼286.2 Hz), 114.31, 116.07, 131.02, 131.12, 127.64–137.84 (m),
166.12 (d, JFC¼25.5 Hz), 188.88. IR (film): 3113, 3076, 2965, 1685,
1600, 1509, 1454, 1413, 1374, 1326, 1255, 1206, 1159, 1051, 1004, 959,
916, 854, 784 cmꢁ1. MS (EI): m/z: 200, 180, 151, 133, 123, 95, 75.
HRMS (EI) calcd for C10H7F3Oþ: 200.0449; found: 200.0452.
To a solution of ethynylmagnesium bromide (90 mL, 45 mmol,
0.5 M in THF) was added slowly to a solution of benzaldehyde
(3.18 g, 30 mmol) in 10 mL THF at ꢁ20 ꢀC within 30 min. Then the
cold bath was removed. The reaction mixture was stirred for an
additional 4 h at room temperature till TLC showed that benzal-
dehyde was consumed. The reaction was quenched by addition of
10 mL saturated aqueous ammonium chloride, and the viscous
residue was extracted with Et2O. The combined organic layers were
dried with Na2SO4 overnight, and concentrated by rotary evapo-
ration to yield the propargylic alcohol, which was further purified
by chromatography on a silica gel column (ethyl acetate/petroleum
ether¼1:10). Yield 1-phenylprop-2-yn-1-ol as a yellow oil, 3.2 g,
4.5. Hydrolysis of difluorocyclopropenes 4l
To a stirred solution of 4l (30 mg, 0.1 mmol) in wet MeOH (1 mL)
was added NaOH (4 mg, 0.1 mmol). The mixture was kept under
0 ꢀC and monitored by TLC. After complete conversion it was di-
rectly purified by flash chromatography on silica gel column to give
compound 6a as a while solid, 19 mg, 74% yield. 1H NMR (300 MHz,
CDCl3):
NMR (282 MHz, CDCl3):
(100 MHz, CDCl3)
d
¼2.53 (s, 1H), 5.83 (s, 1H), 7.33–7.74 (m, 10H) ppm. 19F
80%. 1H NMR (300 MHz, CDCl3):
5.42 (s, 1H), 7.29–7.42 (m, 3H), 7.49–7.56 (m, 2H).
d
¼2.65 (s, 1H), 2.58–2.86 (br, 1H),
d
¼ꢁ102.6 to 101.5 (m, 2F) ppm. 13C NMR
d
¼69.20, 102.15 (t, JFC¼270.2 Hz), 118.66 (t,
To a solution of 1-phenylprop-2-yn-1-ol (1.32 g, 10 mmol) in
15 mL CH2Cl2 at 0 ꢀC was added DMAP (123 mg, 1 mmol), tri-
ethylamine (2.1 mL, 15 mmol), Ac2O (2.0 mL, 15 mmol), and the re-
action mixture was stirred for 2 h. After addition of an appropriate
volume of aqueous water, the reaction was extracted with CH2Cl2.
The combined organic layer was washed twice with saturated NaCl
aqueous, dried over Na2SO4 and concentrated by rotaryevaporation.
The crude product was purified by flash chromatography on silica
gel (ethyl acetate/petroleum ether¼10:1) to give the desired prop-
argylic acetate 1c in almost quantitative yield as a yellow oil.10a 1H
JFC¼11.9 Hz), 127.21, 127.37, 127.89, 128.01, 129.09, 137.48, 139.23 (t,
JFC¼11.2 Hz), 140.56, 142.19. IR (film): 3386 (br), 3032, 2925, 1947,
1832, 1718, 1488, 1310, 1034, 842, 764, 698 cmꢁ1. MS (EI): m/z: 258,
236, 229, 209,191,181,165, 152, 82. HRMS (EI) calcd for C16H12F2Oþ:
258.0856; found: 258.0852.
Acknowledgements
We thank the Chinese Academy of Sciences (Hundreds of Talents
Program) and the National Natural Science Foundation (20772147)
for financial support.
NMR (300 MHz, CDCl3):
(d, J¼2.0 Hz, 1H), 7.21–7.31 (m, 3H), 7.39–7.46 (m, 2H).
d
¼1.97 (s, 3H), 2.56 (d, J¼2.0 Hz, 1H), 6.35
Supplementary data
4.3. Typical procedure for the synthesis of
difluorocyclopropenes 2c–j and 4a–t
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.06.019.
Alkyne 1-phenylprop-2-ynyl acetate 1c (0.45 g, 2.5 mmol),
NaF (10.5 mg, 10% mol) and xylene (1 mL) were placed in a 30-mL
Schlenk flask fitted with a magnetic stirring bar under N2. After
the mixture was heated to 120 ꢀC (bath temperature), TFDA
(1.25 g, 5 mmol) was added within a period of 30–35 min by
a microinjection pump. The mixture was then stirred for an ad-
ditional 30 min to ensure the substrate was consumed. After
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d
¼2.12
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