N-Heterocyclic Carbene-catalyzed Difluorocarbene Generationand its Application to Aryl Difluoromethyl Ether Synthesis
Kohei Fuchibe, Yuta Koseki, Hisashi Sasagawa, and Junji Ichikawa*
Department of Chemistry, Graduate School of Pure and Applied Sciences,
University of Tsukuba, Tsukuba, Ibaraki 305-8571(Received July 25, 2011; CL-110621; E-mail: junji@chem.tsukuba.ac.jp)

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2011 p.1189–1191
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October 5, 2011

The Chemical Society of Japan
Published on the web October 1, 2011; doi:10.1246/cl.2011.1189

doi:10.1246/cl.2011.1189
Published on the web October 1, 2011

1189

N-Heterocyclic Carbene-catalyzed Difluorocarbene Generationand its Application to Aryl Difluoromethyl Ether Synthesis
Kohei Fuchibe, Yuta Koseki, Hisashi Sasagawa, and Junji Ichikawa*
Department of Chemistry, Graduate School of Pure and Applied Sciences,
University of Tsukuba, Tsukuba, Ibaraki 305-8571(Received July 25, 2011; CL-110621; E-mail: junji@chem.tsukuba.ac.jp)
NHC-catalyzed generation of diﬂuorocarbene from trimethylsilyl 2,2-diﬂuoro-2-(ﬂuorosulfonyl)acetate (TFDA) enables
the synthesis of enol diﬂuoromethyl ethers starting from
cyclohexenones and tetralones. The resultant enol diﬂuoromethyl ethers were successively dehydrogenated with DDQ tofurnish aryl diﬂuoromethyl ethers in good to high yield.
Aryl diﬂuoromethyl ether units are often found in the
structures of pharmaceuticals and agrochemicals.1 One conventional synthesis of aryl diﬂuoromethyl ethers is an electrophilic
diﬂuoromethylation of phenols.2 Phenoxides are diﬂuoromethylenated with diﬂuorocarbene, generated by ¡-eliminationof chlorodiﬂuoromethane, to give aryl diﬂuoromethyl ethers
after protonation.3,4 However, this process requires the preparation of the starting phenols and strongly basic conditions.5
Thus, we envisaged developing a new synthetic method foraryl diﬂuoromethyl ethers starting from six-membered cyclicketones. Diﬂuoromethylation of the ketones would begin withtreatment with diﬂuorocarbene. The resultant six-membered
enol diﬂuoromethyl ethers might be readily dehydrogenated toconstruct a benzene ring, thus targeting aryl diﬂuoromethyl
ethers (Scheme 1). Commercial and synthetic availability of thecyclohexanone derivatives makes this a practical approach forthe synthesis of aryl diﬂuoromethyl ethers.
To this end, generation of diﬂuorocarbene was studied
because the reported methods in general require harsh conditions.6 For example, the strongly basic conditions for thegeneration of diﬂuorocarbene from chloro- and bromodiﬂuoromethane7 might cause an aldol-type condensation of ketones.
Similarly, the high reaction temperature required to generatediﬂuorocarbene from ClF2CCO2Na8 might give rise to undesired
diﬂuorocyclopropanation of the resultant enol diﬂuoromethyl
ethers.9
Trimethylsilyl 2,2-diﬂuoro-2-(ﬂuorosulfonyl)acetate (TFDA)
reportedly releases diﬂuorocarbene in the presence of a catalytic
amount of ﬂuoride ion, which attacks the Si atom of TFDA topromote its decomposition.10 However, the treatment of indanones under the TFDA/F¹ system did not give indenyl
diﬂuoromethyl ethers, but instead yielded 2-ﬂuoronaphthols
via overreaction, diﬂuorocyclopropanation.11 We then focusedon using N-heterocyclic carbene (NHC)12 as an activator of
TFDA. We expected that NHC might allow the decomposition
of TFDA under more controlled conditions.13

The results of our research on the activators for TFDA aresummarized in Table 1. Indan-1-one (1a) was treated withTFDA (2 equiv) in the presence of 1 to 10 mol % of theactivators, and the yield of the desired enol ether 2a wasdetermined by 19F NMR spectroscopy. Fluoride ion, the activator
originally adopted by Dolbier and utilized typically at 105 °C,10
gave only a 14% yield of 2a at 80 °C (Entry 1). Other reagents
such as DABCO14 or pyridine N-oxide,15 which can activate Sicontaining reagents, were found to be ineﬀective (Entries 2 andTable 1. NHC-catalyzed generation of diﬂuorocarbene andselective formation of enol diﬂuoromethyl ethers

Entry Activator
Time/h 2a/%a 3/%a1 NaF (1 mol %)414®
2 DABCO (2 mol %)140<1
3 Pyridine N-oxide (10 mol %)
1
trace
®
0.5
70
®
4 IMes¢Cl (1 mol %)Na2CO3 (10 mol %)5 IMes¢Cl (2 mol %)0.5
74, 72b trace
Na2CO3 (20 mol %)6c IMes¢Cl (2 mol %)0.5
61
7Na2CO3 (20 mol %)137
2
7 IMes¢Cl (2 mol %)K2CO3 (20 mol %)8 IMes¢Cl (2 mol %)0.5
15®
DBU (2 mol %)9 IMes¢Cl (2 mol %)0.5
20®
t-BuOK (20 mol %)10 IMes (1 mol %)
0.5
52
17
0.5
54
26
11 SIMes¢Cl (2 mol %)Na2CO3 (20 mol %)1
4630
12 4¢Br (2 mol %)Na2CO3 (20 mol %)134
17
13 5¢I (2 mol %)Na2CO3 (20 mol %)a 19c

F NMR yield based on (CF3)2C(p-Tol)2. bIsolated yield.
TFDA 1.2 equiv.

Scheme 1. Synthetic strategy for aryl diﬂuoromethyl ethers.
Chem. Lett. 2011, 40, 1189­1191© 2011 The Chemical Society of Japanwww.csj.jp/journals/chem-lett/1190
Table 2. Synthesis of aryl diﬂuoromethyl ethers

Entry

1

6

TFDA
/equiv

Temp
/°C

Yield
a
/%

1

1b

6b

2.0

80

78

2
3
4

1c (R = H)
1d (R = Br)
1e (R = Cl)

6c
6d
6e

2.0
1.6
1.6

100
100
80

81
75
77

5

1f

6f

2.0

100

79

6

1g

6g

1.2

80

91

7

1h

6h

1.2

80

86

8b

1i

6i

1.6

100

90

9

1j

6j

1.6

100

63

a
Yield in two steps. bThe corresponding enol ether 2i was obtained as a regioisomeric mixture (conjugated:nonconjugated = 88:12, 19F NMR).

3). Note that the diﬂuorocarbene generation proceeded smoothlywith the use of NHC as a catalyst. 1,3-Dimesitylimidazolylidene(IMes), generated in situ from 1,3-dimesitylimidazolium chloride (IMes¢Cl, 1 and 2 mol %) and sodium carbonate, gave 2a in
70% and 74% yield, respectively (Entries 4 and 5). Reducing theloadings of TFDA from 2 to 1.2 equiv resulted in a diminishedyield of 2a (Entry 6). The use of potassium carbonate, DBU, andpotassium tert-butoxide in place of sodium carbonate, gave
inferior results (Entries 7­9). Note that isolated IMes gave adecreased yield of 2a (52%) along with a 17% yield of 3
(Entry 10). This suggests that considerably rapid generation of
diﬂuorocarbene leads to undesired diﬂuorocyclopropanation.
Use of imidazolinium and related salts also resulted in theformation of considerable amounts of diﬂuorocyclopropane 3,
making the reaction less selective (Entries 11­13).
Various aryl diﬂuoromethyl ethers were successfully synthesized from six-membered ketones via the diﬂuoromethylation­dehydrogenation sequence (Table 2).16 Enol diﬂuoromethyl
ether 2b was formed from 3-phenylcyclohexenone (1b) under
the TFDA/NHC system (Entry 1). The resulting mixture wastreated with DDQ (2 equiv) under reﬂux. Standard chromatographic separation of the products gave biphenyl-3-yl diﬂuoromethyl ether (6b) in 78% yield.
This method was successfully applied to tetralone derivatives, which produced diﬂuoromethyl naphthyl ethers. Not only
did parent 1c give 1-naphthyl ethers 6c in 81% yield, but also
Chem. Lett. 2011, 40, 1189­1191

bromo- and chlorotetralones 1d and 1e aﬀorded the halogenatednaphthyl ethers 6d and 6e in 75% and 77% yield, respectively(Entries 2­4). Electron-rich tetralones appeared to be suitable forthis reaction: Methyl- and methoxy-substituted tetralones 1f­1h
aﬀorded the corresponding naphthyl ethers 6f­6h in 79­91%
yield (Entries 5­7). The reaction of ¢-tetralone (1i) allowed theformation of the corresponding 2-naphthyl ether 6i in 90% yield(Entry 8). A similar treatment of cyclohexanone 1j also
provided the corresponding biphenyl-4-yl diﬂuoromethyl ether(6j) (Entry 9).17
Scheme 2 shows the proposed catalytic cycle for diﬂuorocarbene generation and mechanism for the formation of enol
diﬂuoromethyl ethers. IMes, generated in situ from IMes¢Cl andsodium carbonate, attacks the Si atom of TFDA. The decomposition of TFDA forms the key species, diﬂuorocarbene,18
accompanied by the formation of silylimidazolium salt A, CO2,
SO2, and a ﬂuoride ion. Salt A is desilylated by the released
ﬂuoride ion to regenerate free IMes. The generated diﬂuorocarbene reacts with ketones to aﬀord the corresponding enol ethers,
presumably via oxycarbenium intermediates.11b
In summary, we have developed an NHC-catalyzed method
for the generation of diﬂuorocarbene from TFDA under mild
conditions. Cyclohexenones and tetralones were transformed
into enol diﬂuoromethyl ethers, which were in turn dehydrogenated with DDQ to give aryl diﬂuoromethyl ethers in good tohigh yield.19© 2011 The Chemical Society of Japanwww.csj.jp/journals/chem-lett/1191

Scheme 2. Proposed catalytic cycle for :CF2 generation andmechanism for the formation of CHF2 ethers.
This research was partly supported by Grant-in-Aid for
Exploratory Research from MEXT, Japan, and the Naito
Foundation.
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16 Typical procedure. To a toluene solution (0.4 mL) of IMes¢Cl(2.7 mg, 0.0079 mmol), sodium carbonate (8.5 mg, 0.080 mmol),and 6,7-dimethyl-¡-tetralone (1g) (70 mg, 0.40 mmol) was added
TFDA (100 ¯L, 0.48 mmol) at room temperature. The reaction
mixture was stirred and heated at 80 °C for 1 h. After cooling theresulting mixture to room temperature, DDQ (182 mg, 0.80 mmol)
and toluene (2 mL) was added and the mixture was heated at
100 °C for 2 h. Puriﬁcation by column chromatography (SiO2,
hexane) gave 6g (82 mg, 91% yield) as a colorless liquid.
17 Acetophenone aﬀorded the corresponding ¡-diﬂuoromethoxystyrene in 57% yield (19F NMR) in the presence of 3 mol % ofSIMes¢Cl catalyst.
18 19F NMR analysis of crude mixtures suggested that tetraﬂuoroethylene is generated in the reaction medium.
19 Supporting Information is available electronically on the CSJJournal Web site, http://www.csj.jp/journals/chem-lett/index.html.

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