2-Chloro-2,2-difluoroacetophenone: A non-ODS-based difluorocarbene precursor and its use in the difluoromethylation of phenol derivatives

Article abstract of DOI:10.1021/jo061799l

A novel and non-ODS-based (ODS = ozone-depleting substance) preparation of 2-chloro-2,2-difluoroacetophenone (1) was achieved in high yield by using 2,2,2-trifluoroacetophenone as the starting material. Compound 1 was found to act as a good difluorocarbene reagent, which readily reacts with a variety of structurally diverse phenol derivatives 4 in the presence of potassium hydroxide or potassium carbonate to produce aryl difluoromethyl ethers 5 in good yields. This new and easy-to-handle synthetic methodology offers an environmentally friendly alternative to other Freon- or Halon-based difluoromethylating approaches.

Full text of DOI:10.1021/jo061799l

aryl difluoromethyl ethers.1-9 Many aryl difluoromethyl ethers
have found applications such as enzyme inhibitors,2 anti-HIV
agents,3 antimicrobial agents,4 potassium channel activators,5
fungicides,6 pestcides,7 herbcides,8 and smectic phase liquid
crystals.9
2-Chloro-2,2-difluoroacetophenone: A
Non-ODS-Based Difluorocarbene Precursor and
Its Use in the Difluoromethylation of Phenol
Derivatives
Despite the fact that numerous structurally diverse aryl
difluoromethyl ethers were synthesized during the past half
century, efficient synthetic methods are few.1 The most com-
monly used method is the reaction between chlorodifluo-
romethane (CHClF2, Freon-22) and phenols in the presence of
a base.10 Chlorodifluoroacetates (ClCF2COONa or ClCF2-
COOMe) are also useful reagents for the preparation of aryl
difluoromethyl ethers from phenols.11 Other reported methods,
such as using CF2Br2,12 CF3COONa,13 FSO2CF2COOH,14 CF3-
ZnBr,15 CHF2I,16 CHF2Br,17 and XeF2,18 are scarcely used due
to the low product yields of aryl difluoromethyl ethers and/or
the difficulty in preparing the reagents themselves. On the other
hand, chlorodifluoromethane (Freon-22) itself is a ozone-
depleting substance (ODS), and chlorodifluoroacetic acid de-
rivatives are commonly prepared directly or indirectly from
ozone-depleting precursors.19 The Montreal protocol has regu-
lated the use of ODS (such as CFCs, HCFCs, and other
halogenated ozone-depleting substances); thus, the development
of alternative non-ODS-based reagents and synthetic methods
for the synthesis of aryl difluoromethyl ethers is highly desired.
We have been interested in developing efficient and environ-
mentally benign difluoromethylation methods to synthesize aryl
difluoromethyl ethers, with the expectation that the new dif-
luoromethylating agents and the intermediates in their prepara-
tion should not be Freon- or Halon-based. Herein, we wish to
Laijun Zhang, Ji Zheng, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 354
Fenglin Road, Shanghai 200032, China
jinbohu@mail.sioc.ac.cn
ReceiVed August 31, 2006
A novel and non-ODS-based (ODS ) ozone-depleting
substance) preparation of 2-chloro-2,2-difluoroacetophenone
(1) was achieved in high yield by using 2,2,2-trifluoroac-
etophenone as the starting material. Compound 1 was found
to act as a good difluorocarbene reagent, which readily reacts
with a variety of structurally diverse phenol derivatives 4 in
the presence of potassium hydroxide or potassium carbonate
to produce aryl difluoromethyl ethers 5 in good yields. This
new and easy-to-handle synthetic methodology offers an
environmentally friendly alternative to other Freon- or Halon-
based difluoromethylating approaches.
(7) Whitney, W. K.; Wettstein, K. In Proc. Brit. Crop Protect. Conf.-
Pests Dis. 1979, 387.
(8) Fowler, J. S. In Organofluorine Compounds in Medicinal Chemistry
and Biomedical Applications; Filler, R., Kobayashi, Y., Yagupolskii, L.
M., Eds.; Elsevier: Amsterdam, 1993.
(9) Tasaka, T.; Takenaka, S.; Kabu, K.; Morita, Y.; Okamoto, H.
Ferroelectronics 2002, 276, 83.
(10) (a) Miller, T. G.; Thanassi, J. W. J. Org. Chem. 1960, 25, 2009.
(b) Shen, T. Y.; Lucas, S.; Sarett, L. H. Tetrahedron Lett. 1961, 2, 43. (c)
Langlois, B. J. Fluorine Chem. 1988, 41, 247. (d) Morimota, K.; Makino,
K.; Sakata, G. J. Fluorine Chem. 1992, 59, 417.
(11) (a) Christensen, S. B. IV; Dabbs, H. E.; Karpinski, J. M. PCT
International Application, WO 96/23754, 1996. (b) Ho, J. Z.; Elmore, C.
S.; Wallace, M. A.; Yao, D.; Braun, M. P.; Dean, D. C.; Melillo, D. G.;
Chen, C.-Y. HelV. Chim. Acta 2005, 88, 1040. (c) O’shea, P. D.; Chen,
C.-Y.; Chen, W.; Dagneau, P.; Frey, L. F.; Grabowski, E. J. J.; Marcantonio,
K. M.; Reamer, R. A.; Tan, L.; Tillyer, R. D.; Roy, A.; Wang, X.; Zhao,
D. J. Org. Chem. 2005, 70, 3021.
Difluoromethoxy (OCF2H) functionality plays an important
role in many bioactive organic molecules and in liquid crystal
materials for display applications.1 Although aliphatic difluo-
romethoxy-containing compounds have important applications
such as anesthetics, recently, more attention has been paid to
the compounds bearing an aromatic difluoromethoxy group, i.e.,
(12) Rico, I.; Wakselhan, C. Tetrahedron Lett. 1981, 22, 323.
(13) Poludnenko, V. G.; Didinskaya, O. B.; Pozharskii, A. F. Zh. Org.
Khim. 1984, 20, 2483.
(14) Chen, Q.-Y.; Wu, S.-W. J. Fluorine Chem. 1989, 44, 433.
(15) Pasenok, S. V.; Yagupolskii, Y. L.; Tyrra, W.; Naumann, D. Z.
Anorg. Allg. Chem. 1999, 625, 831.
(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, ReactiV-
ity, Applications; Wiley-VCH: Weinheim, 2004. (b) Organofluorine
Compounds: Chemistry and Applications; Hiyama, T., Ed.; Springer: New
York, 2000. (c) Kirsch, P.; Bremer, B. Angew. Chem., Int. Ed. 2000, 39,
4216.
(2) Chauret, N.; Guay, D.; Li, C.; Day, S.; Silva, J.; Blouin, M.;
Ducharme, Y.; Yergey, J. A.; Nicoll-Griffith, D. A. Bioorg. Med. Chem.
Lett. 2002, 12, 2149.
(3) Ohmine, T.; Katsube, T.; Tsuzaki, Y.; Kazui, M.; Kobayashi, N.;
Komai, T.; Hagihara, M.; Nishigaki, T.; Iwamoto, A.; Kimura, T.;
Kashiwase, H.; Yamashita, M. Bioorg. Med. Chem. Lett. 2002, 12, 739.
(4) Takahata, M.; Mitsuyama, J.; Yamashiro, Y.; Yonezawa, M.; Araki,
H.; Todo, Y.; Minami, S.; Watanabe, Y.; Narita, H. Antimirob. Agents
Chemother. 1999, 43, 1077.
(5) Yagupol’skii, L. M.; Petko, K. I.; Tarasova, Y. V. Zh. Org. Farm
Khim. 2004, 2, 11; Chem. Abstr. 2004, 143, 326060.
(6) Ichiba, T.; Murashi, T.; Suzuki, S.; Ohtsuka, T.; Masuko, M. Nippon
Noyaku Gakkaishi 2002, 27, 223; Chem. Abstr. 2002, 138, 51312.
(16) Akritopoulou-Zanze, I.; Patel, J. R.; Hartandi, K.; Brenneman, J.;
Winn, M.; Pratt, J. K.; Grynfarb, M.; Goos-Nisson, A.; von Geldern, T.
W.; Kym, P. R. Bioorg. Med. Chem. Lett. 2004, 14, 2079.
(17) Kym, P. R.; Kort, M. E.; Coghlan, M. J.; Moore, J. L.; Tang, R.;
Ratajczyk, J. D.; Larson, D. P.; Elmore, S. W.; Pratt, J. K.; Stashko, M.
A.; Falls, H. D.; Lin, C. W.; Nakane, M.; Miller, L.; Tyree, C. M.; Miner,
J. N.; Jacobson, P. B.; Wilcox, D. M.; Nguyen, P.; Lane, B. C. J. Med.
Chem. 2003, 46, 1016.
(18) Stavber, S.; Koren, Z.; Zupan, M. Synlett 1994, 265.
(19) (a) Hu, C.-M.; Qing, F.-L.; Zhang, H.-G. J. Fluorine Chem. 1990,
49, 275. (b) Kumai, S.; Seki, T. Japanese Patent JP 06239792, 1994. (c)
Henne, A. L.; Alderson, T.; Newman, M. S. J. Am. Chem. Soc. 1945, 67,
919. (d) Swarts, F. Chem. Zentr. II 1903, 709.
10.1021/jo061799l CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/24/2006
J. Org. Chem. 2006, 71, 9845-9848
9845

TABLE 1. Survey of Reaction Conditions
SCHEME 1
reactant ratiob
(4a/1/KOH)
entrya
solventc
T (°C)
yieldd (%)
1
2
3
4
5
6
7
8
9
1:2:21
1:2:21
1:2:21
1:3:21
1:4:21
1:5:21
1:2:21
1:2:21
1:2:21
1:3:21
1:4:21
1:5:21
MeCN-H2O
MeCN-H2O
MeCN-H2O
MeCN-H2O
MeCN-H2O
MeCN-H2O
dioxane-H2O
diglyme-H2O
DME-H2O
0
rt
28
30
34
45
56
63
25
40
32
45
49
53
80
80
80
80
80
80
80
80
80
80
disclose the non-ODS-based preparation of 2-chloro-2,2-dif-
luoroacetophenone 1 (PhCOCF2Cl) and the use of 1 as a novel
and convenient difluoromethylating agent for phenol derivatives.
2-Chloro-2,2-difluoroacetophenone 1 is a commercially avail-
able compound, and it has been used to synthesize 2,2-difluoro
enol silyl ethers,20 2,2-difluoro enol phosphates,21 and other
chlorodifluoromethyl-containing compounds.22-24 However,
compound 1 has never been used as a difluorocarbene reagent
to prepare difluoromethyl ethers. Currently, the preparation of
1 is mainly based on the reaction between phenyl Grignard
reagents (PhMgX) and chlorodifluoroacetic acid.25 In order to
avoid the use of chlorodifluoroacetic acid, we decided to develop
a Freon- and Halon-free new synthetic method for the prepara-
tion of 1. Since the commercially available 2,2,2-trifluoroac-
etophenone 2 is derived from trifluoroacetic acid, a compound
commercially produced by the electrochemical fluorination of
acetyl fluoride by HF-KHF2,26,27 we chose compound 2 as the
Freon- and Halon-free precursor to prepare 1 via 2,2-difluoro
enol silyl ether intermediates 3 (see Scheme 1). By using
Uneyama’s magnesium metal-mediated reductive defluorination
procedure,28 trifluoroacetophenone 2 was readily transformed
to 2,2-difluoro enol silyl ether 3 in excellent yield (91%). The
initial chlorination of 3 with N-chlorosuccinimide (NCS) in the
presence of tetrabutylammonium fluoride (TBAF) at room
temperature was successful, but with only moderate yield (68%
isolated) of 2-chloro-2,2-difluoroacetophenone 1 (Scheme 1,
method A). When we used the elemental chlorine (Cl2) as the
chlorinating agent to react with 3 in CH2Cl2 at -78 °C, the
yield of 3 was remarkably improved (87% isolated; Scheme 1,
method B). This simple and facile preparation of chlorodifluo-
roacetophenone 1 from trifluorocetophenone 2 (via both method
A and B) was previously never reported, and we found that the
reactions with method B are easy to scale up with reproducible
chemical yields.
10
11
12
diglyme-H2O
diglyme-H2O
diglyme-H2O
a Reaction conditions: 4a (1 mmol), KOH (30 wt % in H2O, 4 mL, ca.
21 mmol) and 1 were mixed in a pressure tube at -78 °C, and the tube
was sealed. The reaction mixture was heated to desired temperature for 4
h. b Molar ratio. c Organic solvent/water (v/v) ) 1:1. d Determined by 19F
NMR spectroscopy using PhCF3 as internal standard.
difluorocarbene source. First of all, phenol 4a was chosen as a
model compound to optimize the reaction conditions. As shown
in Table 1, increasing the reaction temperature (80 °C) is helpful
for the reaction, and acetonitrile-water solvent mixture gave the
best yield (entry 6) when 5 equiv of 1 was applied as the
difluorocarbene reagent. Although 1,4-dioxane, diglyme, and
dimethoxyethane (DME) can be also used as cosolvent for the
reaction, the yields were somewhat lower (entries 7-12).
By using the optimized reaction condition, we studied the
scope of this new type of difluoromethylation chemistry with
reagent 1. The results are summarized in Table 2. A variety of
structurally diverse phenol derivatives 4a-k were difluorom-
ethylated by 1 in the presence of KOH in acetonitrile-water
solvent mixture to give the corresponding products 5a-k in
moderate to good yields. The reaction was compatible with
bromo- and iodo-substituted phenols (entries 7-11) to give
products 5g-k, which are possible for further elaboration
through transition metal-catalyzed cross-coupling reaction.
We also applied the present non-ODS-based difluoromethy-
lation methodology in the synthesis of key intermediate 9 for
the antimicrobial agent garenoxacin mesylate 10.29 As shown
in Scheme 2, the precursor compound 8 was prepared from 2,6-
difluorophenol (6) by using the known procedures.29 Difluo-
romethylation of 8 by using PhCOCF2Cl (1) in the presence of
potassium carbonate (not KOH) in CH3CN-H2O solvents at
80 °C was proved to be successful, and the desired product 9
was obtained in 60% isolated yield. Intermediate 9 can be further
transformed to the target drug garenoxacin mesylate 10 through
known procedures.29
With the chlorodifluoroacetophenone 1 in hand, we carried
out the difluoromethylation of phenol derivatives using 1 as a
(20) Yamana, M.; Ishihara, T.; Ando, T. Tetrahedron Lett. 1983, 24,
507.
(21) Ishihara, T.; Yamana, M.; Ando, T. Tetrahedron Lett. 1983, 24,
5657.
(22) (a) Reddy, M. V. R.; Rudd, M. T.; Ramachandran, P. V. J. Org.
Chem. 2002, 67, 5382.
(23) Dubbaka, S. R.; Vogel, P. Tetrahedron 2005, 61, 1523.
(24) Sevenard, D. V. Tetrahedron Lett. 2003, 44, 7119.
(25) (a) Shah, N. V.; Cama, L. D. Heterocycles 1987, 25, 221. (b) Qiu,
Z.-M.; Burton, D. J. J. Org. Chem. 1995, 60, 5570.
(26) McGrath, T. F.; Levine, R. J. Am. Chem. Soc. 1955, 77, 3656.
(27) Fluorine Chemistry: A ComprehensiVe Treatment; Howe-Grant, M.,
Ed.; Wiley: New York, 1995.
The plausible reaction mechanism was proposed as shown
in Scheme 3. Chlorodifluoroacetophenone 1 reacts with hy-
droxide (OH-) to give chlorodifluoromethyl anion species 11
that readily undergoes R-elimination of a chloride ion to afford
difluorocarbene intermediate (:CF2). The phenoxide (ArO-)
(28) Amii, H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K. Chem.
Commun. 1999, 1323.
(29) Todo, Y.; Hayashi, K.; Takahata, M.; Watanabe, Y.; Narita, H. EP
882725, WO 9729102, 1997.
9846 J. Org. Chem., Vol. 71, No. 26, 2006

SCHEME 2 a
TABLE 2. Difluoromethylation of Phenyl Derivatives 4 with
Reagent 1
a Conditions: (a) (1) CH3I, K2CO3, 50 °C, DMF, (2) n-BuLi, THF, -78
°C, then add CO2, 51% yield; (b) (1) CH3I, KOH, K2CO3, DMSO, rt, (2)
BBr3, CH2Cl2, -30-0 °C, 57% yield; (c) compound 1, K2CO3, CH3CN-
H2O, 80 °C, 4 h, 60% yield.
SCHEME 3
handle synthetic methodology offers an environmentally friendly
alternative to other Freon- or Halon-based difluoromethylating
approaches. The present difluorocarbene chemistry promises to
find many applications in the fields of pharmaceutical, agro-
chemical chemistry, and materials science.
Experimental Section
Preparation of Chlorodifluoroacetophenone (1). Method A.
Into a mixture of 2,2-difluoro-1-phenyl-1-trimethylsiloxyethene 3
(5.70 g, 25 mmol), CH2Cl2 (60 mL), and N-chlorosuccinimide (3.99
g, 30 mmol) was added TBAF (2.0 mL, 1 M in THF). Then the
mixture was stirred for 4 h at rt. The completion of the reaction
was monitored by 19F NMR. After the removal of solvent under
vacuum, the crude product was further purified by silica gel column
chromatography to give product 1 as a colorless liquid: yield 68%
(3.22 g).
Method B. Compound 3 (22.8 g, 100 mmol) was dissolved in
CH2Cl2 (150 mL) at -78 °C. Then Cl2 was passed through the
mixture for 30 min. The completion of the reaction was monitored
by 19F NMR. After the removal of solvent under vacuum, the crude
product was further purified by silica gel column chromatography
to give product 1 as a colorless liquid: yield 87% (16.53 g). The
characterization data of 1 was consistent with the previous report.25
Typical Procedure for Difluoromethylation of Phenols Using
Compound 1. Into a mixture of 1-naphthol (0.144 g, 1 mmol),
aqueous KOH (30 wt %, 4 mL), and CH3CN (4 mL) at -78 °C
was added chlorodifluoroacetophenone (1). The reaction tube was
sealed, and the mixture was heated to 80 °C and stirred for 4 h.
Then the mixture was extracted with Et2O (25 mL × 3), and the
combined organic phase was dried over MgSO4. After the removal
a Yields were determined by 19F NMR spectroscopy using PhCF3 as
internal standard, and the data in parentheses are isolated yields. The isolated
yields for entries 1 and 4 are not listed due to the high volatility of the
products 5a and 5d.
reacts with difluorocarbene species to give the product 5 via
anionic species ArOCF2-. It is also possible that the ArO- anion
attacks 1 to give chlorodifluoromethyl anion 11 and ester 13.
Species 11 decomposes into difluorocarbene and chloride ion,
while the ester 13 can be transformed back to ArO- by the
nucleophilic attack of hydroxide ion (Scheme 3).
In summary, a novel and non-ODS-based preparation of
2-chloro-2,2-difluoroacetophenone 1 was achieved in high yield
using 2,2,2-trifluoroacetophenone as a starting material. Com-
pound 1 was found to act as a good difluorocarbene reagent,
which readily reacts with a variety of structurally diverse phenol
derivatives 4 in the presence of hydroxide to produce aryl
difluoromethyl ethers 5 in good yields. Since reagent 1 derives
from non-ozone-depleting precursors, this new and easy-to-
J. Org. Chem, Vol. 71, No. 26, 2006 9847

of solvents under vacuum, the crude product was further purified
product was further purified by silica gel column chromatography
to give product 9 as a white solid. Yield: 60% (143 mg). 1H
NMR: δ 7.89 (m, 1H), 7.06 (t, J ) 8.8 Hz, 1H), 6.61 (t, J ) 73
Hz, 1H), 3.95 (s, 3H). 19F NMR: δ -82.6 (dt, J ) 73.5 Hz, 7 Hz,
2F), -116.7 (m, 1F), -120.2 (m, 1F). The characterization data
was consistent with the previous report.4,29
by silica gel column chromatography to give product 5c as a
1
colorless liquid. Yield: 75% (146 mg). H NMR: δ 8.18 (t, J )
5.0 Hz, 1H), 7.85 (t, J ) 4.4 Hz, 1H), 7.69 (d, J ) 8.2 Hz, 1H),
7.54 (t, J ) 4.3 Hz, 2H), 7.40 (t, J ) 7.5 Hz, 1H), 7.18 (d, J ) 7.5
Hz, 1H), 6.65 (t, J ) 73.9 Hz, 1H). 19F NMR: δ -79.8 (d, J )
72.5 Hz, 2F). 13C NMR: δ 147.5, 134.7, 127.8, 126.9, 126.6, 126.5,
125.4, 125.3, 121.6, 116.6 (t, J ) 257.3 Hz), 113.7. MS (EI, m/z):
194 (M+, 79.16), 144 (100.00). IR (film): 3060, 1600, 1582, 1510,
1467, 1375, 1263, 773 cm-1. Anal. Calcd for C11H8F2O: C, 68.04;
H, 4.15; Found: C, 68.18; H, 4.14.
Acknowledgment. We thank the National Natural Science
Foundation of China (20502029), Shanghai Rising-Star Program
(06QA14063), and the Chinese Academy of Sciences (Hundreds-
Talent Program) for funding.
Preparation of Compound 9. Into a mixture of compound 8
(188 mg, 1.0 mmol), K2CO3 (4.968 g, 36.0 mmol), CH3CN (4 mL),
and H2O (4 mL) at rt was added chlorodifluoroacetophenone (950
mg, 5.0 mmol). The reaction tube was sealed, and the mixture was
heated to 80 °C and stirred for 4 h. Then the mixture was extracted
with Et2O (25 mL × 3), and the combined organic phase was dried
over MgSO4. After the removal of solvents under vacuum, the crude
Supporting Information Available: General experimental
information and characterization data of the isolated compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO061799L
9848 J. Org. Chem., Vol. 71, No. 26, 2006