.
Angewandte
Communications
Table 1: Electrophilic (phenylsulfonyl)difluoromethylation of 2a with the
salts 1.[a]
achieve
the
previously
unsuccessful
selective
Csp3 difluoromethylation of b-ketoesters, difluoromethylation
should take place under a more electrophilic pathway rather
than that of radical or carbene, and the reactive species for the
difluoromethylation should be softer. Incidentally, Hu and co-
workers developed a hypervalent-iodine-type reagent for
electrophilic (phenylsulfonyl)difluoromethylation of thiols.[8a]
This reagent is also applicable for the allylic (phenylsulfo-
Entry
1
Base
Solvent
T [8C]
Yield [%][b]
1
2
3
1a
1b
1a
1a
1a
1a
DBU
DBU
DBU
DBU
P1
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
À78
À78
À40
À78
À78
À78
99
87
83
83
74
14
nyl)difluoromethylation under copper catalysis to provide
[7q]
À
Csp3 CF2SO2Ph products (Scheme 1b). Since Huꢀs reagent
4[c]
5
has a somewhat radical-type character because of the hyper-
valent iodine structure, it required modification to be more
electrophilic for the selective Csp3 difluoromethylation of b-
ketoesters. We disclose herein the novel electrophilic
reagents, S-(phenylsulfonyldifluoromethyl)thiophenium salts
(1), for this purpose. With the reagents 1, b-ketoesters and 1,3-
diketones 2 are selectively functionalized with a difluoro-
methyl group at the Csp3 centers in high to excellent yields
under mild reaction conditions, thus providing 3 which has
6
K2CO3
[a] The reaction was carried out with 0.1 mmol of substrate 2a. For
detailed reaction conditions, see the Supporting Information. [b] Yields
of isolated products. [c] Used 1.2 equivalents of 1a. DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene, P1 =phosphazene base P1-tert-butyl-
tris(tetramethylene).
alents of 1a or 1b in the presence of 1.5 equivalents of DBU
in dichloromethane at À788C (entries 1 and 2). As expected,
À
a quaternary carbon center. None of the undesired O
CF2SO2Ph products were isolated. Allylic (phenylsulfonyl)di-
fluoromethylation of dicyanoalkylidenes 4 was also achieved
with 1 to provide the allylic Csp3 CF2SO2Ph products 5
À
1a gave only the Csp3 CF2SO2Ph product 3a in 99% yield
À
without any undesired O CF2SO2Ph product. The phenyl
À
reagent 1b also proceeded nicely to afford 3a in 87% yield.
We next examined the effects of temperature and solvent. The
yield decreased to 83% in acetonitrile at À408C (entry 3).
When 1.2 equivalents of DBU were used, the yield decreased
slightly to 83% (entry 4). The base was also screened, and
when P1 was used instead of DBU it gave a lower yield of
74% (entry 5), whereas the inorganic base K2CO3 provided
3a in only 14% yield (entry 6). The complete carbon
selectivity could be explained in terms of the electrophilic
softness of difluoromethyl cation increase caused by the
phenylsulfonyl moiety.
(Scheme 1c). The CF2SO2Ph group can be readily trans-
formed into CF2H under mild reaction conditions. Prelimi-
nary results for asymmetric variant of this reaction are also
discussed (up to 55% ee).
The reagents 1 were synthesized by the procedure shown
in Scheme 2. The difluoromethyl sulfone 7 was prepared from
benzenethiol (6) in two steps, and reacted with 8 to furnish the
aniline 9. After treatment of 9 with NaNO2 and NaI under
acidic conditions, 9 was converted into the iodide 10, and
subsequent Sonogashira cross-coupling afforded the alkyne
11. Finally, the target S-(phenylsulfonyldifluoromethyl)thio-
phenium salts 1 were successfully prepared in excellent yields
by cyclization of 11 in the presence of triflic acid.
Under the optimum reaction conditions, we explored the
substrate scope (2b–r; Table 2). A wide range of both
indanone carboxylates and tetralone carboxylates were
À
The potential for electrophilic (phenylsulfonyl)difluoro-
methylation of the b-ketoesters 2 by 1 was next examined. We
began our investigation with methyl indanone-2-carboxylate
(2a) as a model substrate for (phenylsulfonyl)difluoromethy-
lation (Table 1). The reaction was carried out with 1.5 equiv-
evaluated and furnished the corresponding Csp3 CF2SO2Ph
products 3b–p, having a quaternary carbon center. Methyl
indanone carboxylates with both an electron-donating group
(2b–d) and an electron-withdrawing group (2e,f) on the
benzene ring reacted smoothly with 1a to provide the
corresponding products 3b–d and 3e,f in good to excellent
yields. A variety of alkyl indanone carboxylates 2g–i were
efficiently transformed into the desired products 3g–i in high
to excellent yields. The allyl indanone carboxylate 2j
proceeded well to give 3j in 77% yield. Benzyl indanone
carboxylate without a substituent (2k) or with electron-
withdrawing and electron-donating groups on benzene ring
(2l,m) were good substrates for difuoromethylation with 1a,
thus affording 3k–m in excellent yield. Tetralone carboxylates
2n–p were also found to be good substrates for (phenyl-
sulfonyl)difluoromethylation and furnished the products 3n–
p in good to excellent yields. It is noteworthy that even the
less reactive acyclic b-ketoester 2q afforded the correspond-
ing difluoromethylated compound in moderate yield. We next
examined the difluoromethylation of 1,3-diketones which, is
À
more challenging since they selectively afford O CF2H
products. Interestingly, the 1,3-diketone 2r was selectively
Scheme 2. Synthesis of S-(phenylsulfonyldifluoromethyl)thiophenium
salts (1). See details in the Supporting Information.
À
converted into the corresponding Csp3 CF2SO2Ph product 3r
1828
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1827 –1831