N-heterocyclic carbene-catalyzed difluorocarbene generation and its application to aryl difluoromethyl ether synthesis

Article abstract of DOI:10.1246/cl.2011.1189

NHC-catalyzed generation of difluorocarbene from trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFD(A) enables the synthesis of enol difluoromethyl ethers starting from cyclohexenones and tetralones. The resultant enol difluoromethyl ethers were successively dehydrogenated with DDQ to furnish aryl difluoromethyl ethers in good to high yield.

Full text of 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 Generation
and 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 trimeth-
ylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA) enables
the synthesis of enol difluoromethyl ethers starting from
cyclohexenones and tetralones. The resultant enol difluoro-
methyl ethers were successively dehydrogenated with DDQ to
furnish aryl difluoromethyl ethers in good to high yield.
The results of our research on the activators for TFDA are
summarized in Table 1. Indan-1-one (1a) was treated with
TFDA (2 equiv) in the presence of 1 to 10 mol % of the
activators, and the yield of the desired enol ether 2a was
determined 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 Si-
containing reagents, were found to be ineffective (Entries 2 and
Aryl difluoromethyl ether units are often found in the
structures of pharmaceuticals and agrochemicals.1 One conven-
tional synthesis of aryl difluoromethyl ethers is an electrophilic
difluoromethylation of phenols.2 Phenoxides are difluoro-
methylenated with difluorocarbene, generated by ¡-elimination
of chlorodifluoromethane, to give aryl difluoromethyl ethers
after protonation.3,4 However, this process requires the prepara-
tion of the starting phenols and strongly basic conditions.5
Thus, we envisaged developing a new synthetic method for
aryl difluoromethyl ethers starting from six-membered cyclic
ketones. Difluoromethylation of the ketones would begin with
treatment with difluorocarbene. The resultant six-membered
enol difluoromethyl ethers might be readily dehydrogenated to
construct a benzene ring, thus targeting aryl difluoromethyl
ethers (Scheme 1). Commercial and synthetic availability of the
cyclohexanone derivatives makes this a practical approach for
the synthesis of aryl difluoromethyl ethers.
Table 1. NHC-catalyzed generation of difluorocarbene and
selective formation of enol difluoromethyl ethers
Entry Activator
Time/h 2a/%a 3/%a
1
2
3
4
NaF (1 mol %)
4
1
1
0.5
14
40
trace
70
®
<1
®
DABCO (2 mol %)
Pyridine N-oxide (10 mol %)
IMes¢Cl (1 mol %)
®
To this end, generation of difluorocarbene was studied
because the reported methods in general require harsh con-
ditions.6 For example, the strongly basic conditions for the
generation of difluorocarbene from chloro- and bromodifluoro-
methane7 might cause an aldol-type condensation of ketones.
Similarly, the high reaction temperature required to generate
difluorocarbene from ClF2CCO2Na8 might give rise to undesired
difluorocyclopropanation of the resultant enol difluoromethyl
ethers.9
Na2CO3 (10 mol %)
IMes¢Cl (2 mol %)
5
0.5
0.5
1
74, 72b trace
Na2CO3 (20 mol %)
6c IMes¢Cl (2 mol %)
Na2CO3 (20 mol %)
61
37
15
20
7
2
7
8
9
IMes¢Cl (2 mol %)
K2CO3 (20 mol %)
IMes¢Cl (2 mol %)
DBU (2 mol %)
IMes¢Cl (2 mol %)
t-BuOK (20 mol %)
0.5
0.5
®
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 to
promote its decomposition.10 However, the treatment of inda-
®
10 IMes (1 mol %)
11 SIMes¢Cl (2 mol %)
Na2CO3 (20 mol %)
12 4¢Br (2 mol %)
Na2CO3 (20 mol %)
13 5¢I (2 mol %)
Na2CO3 (20 mol %)
0.5
0.5
52
54
17
26
¹
nones under the TFDA/F system did not give indenyl
difluoromethyl ethers, but instead yielded 2-fluoronaphthols
via overreaction, difluorocyclopropanation.11 We then focused
on 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
1
1
46
34
30
17
a 19F NMR yield based on (CF3)2C(p-Tol)2. bIsolated yield.
cTFDA 1.2 equiv.
Scheme 1. Synthetic strategy for aryl difluoromethyl ethers.
Chem. Lett. 2011, 40, 1189-1191
© 2011 The Chemical Society of Japan
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1190
Table 2. Synthesis of aryl difluoromethyl ethers
Yield
/%a
TFDA
/equiv
Temp
Entry
1
1
6
/°C
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
6
1f
6f
2.0
1.2
100
80
79
91
1g
6g
7
1h
1i
6h
6i
1.2
1.6
1.6
80
100
100
86
90
63
8b
9
1j
6j
aYield in two steps. bThe corresponding enol ether 2i was obtained as a regioisomeric mixture (conjugated:nonconju-
gated = 88:12, 19F NMR).
3). Note that the difluorocarbene generation proceeded smoothly
with the use of NHC as a catalyst. 1,3-Dimesitylimidazolylidene
(IMes), generated in situ from 1,3-dimesitylimidazolium chlo-
ride (IMes¢Cl, 1 and 2 mol %) and sodium carbonate, gave 2a in
70% and 74% yield, respectively (Entries 4 and 5). Reducing the
loadings of TFDA from 2 to 1.2 equiv resulted in a diminished
yield of 2a (Entry 6). The use of potassium carbonate, DBU, and
potassium tert-butoxide in place of sodium carbonate, gave
inferior results (Entries 7-9). Note that isolated IMes gave a
decreased 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 the
formation of considerable amounts of difluorocyclopropane 3,
making the reaction less selective (Entries 11-13).
Various aryl difluoromethyl ethers were successfully syn-
thesized from six-membered ketones via the difluoromethyla-
tion-dehydrogenation sequence (Table 2).16 Enol difluoromethyl
ether 2b was formed from 3-phenylcyclohexenone (1b) under
the TFDA/NHC system (Entry 1). The resulting mixture was
treated with DDQ (2 equiv) under reflux. Standard chromato-
graphic separation of the products gave biphenyl-3-yl difluoro-
methyl ether (6b) in 78% yield.
bromo- and chlorotetralones 1d and 1e afforded the halogenated
naphthyl ethers 6d and 6e in 75% and 77% yield, respectively
(Entries 2-4). Electron-rich tetralones appeared to be suitable for
this reaction: Methyl- and methoxy-substituted tetralones 1f-1h
afforded the corresponding naphthyl ethers 6f-6h in 79-91%
yield (Entries 5-7). The reaction of ¢-tetralone (1i) allowed the
formation 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 difluoro-
carbene generation and mechanism for the formation of enol
difluoromethyl ethers. IMes, generated in situ from IMes¢Cl and
sodium carbonate, attacks the Si atom of TFDA. The decom-
position 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 difluorocar-
bene 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 dehydro-
genated with DDQ to give aryl difluoromethyl ethers in good to
high yield.19
This method was successfully applied to tetralone deriva-
tives, which produced difluoromethyl naphthyl ethers. Not only
did parent 1c give 1-naphthyl ethers 6c in 81% yield, but also
Chem. Lett. 2011, 40, 1189-1191
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1191
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Scheme 2. Proposed catalytic cycle for :CF2 generation and
mechanism 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 the
resulting 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 ¡-difluoromethoxy-
styrene in 57% yield (19F NMR) in the presence of 3 mol % of
SIMes¢Cl catalyst.
5
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6
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ethylene is generated in the reaction medium.
19 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2011, 40, 1189-1191
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/