.
Angewandte
Communications
that one wishes to transfer. Inspiration was thus drawn from
two independent reports, one from the Prakash, Olah, and co-
workers[7] and one from Hu and co-workers.[8] The former
group elegantly demonstrated that Huꢀs reagent (7) could be
efficiently alkylated and cleaved to liberate sodium sulfinate
salts (which were immediately oxidized to sulfonates). This
route was adapted for the scalable preparation[9] of sodium
difluoroethylsulfinate (9, DFES-Na, a new chemical entity),
a stable white solid that is now commercially available
(Sigma–Aldrich).
and xanthines (11, 30, 31) are all amenable to fluoroalkyla-
tion. Out of the 21 examples shown, 18 could potentially
result in mixtures of regioisomers. Remarkably, 12 of these
react with DFES-Na to deliver a single regioisomer, two react
with good regioselectivity (6.4:1 or higher), and four achieve
modest but synthetically useful selectivity (2.3:1 or higher).
Particularly notable examples are 18, 23, and 29, the
À
precursors of which have three or more C H bonds that
could conceivably be substituted. The functional group
tolerance of this reaction, which is conducted with water as
a co-solvent and open to the air if desired, is also notable.
Ketones, esters, nitriles, chlorides, bromides, heterocycles
With a reliable synthesis of the requisite sulfinate salt (9)
À
established, optimization of the C H alkylation was con-
À
ducted as shown in Scheme 2A. Using caffeine (10), in a 2.5:1
mixture of CH2Cl2/H2O with TBHP as oxidant, and in the
absence of any additives, only trace amounts of the desired
product 11 were observed (entry 1). Although Brønsted acids
such as TFA improved the conversion (entry 2), zinc-based
Lewis acids (entries 3–13) dramatically enhanced the reac-
tion. Ultimately, ZnCl2 was identified as the optimal additive
along with TsOH·H2O (entry 13).
containing free N H, and even free carboxylic acids are
tolerated, as well as free amines and alcohols (see above).
These reactions are also scalable, with heterocycle 22 being
difluoroethylated on a gram scale in 89% yield upon
isolation.
Cursory analysis of the patent literature indicates that the
current method can dramatically simplify the way such
fluoroalkylated compounds are prepared. As shown in
Scheme 2C, the known route to pyrazine 21[10] involves
a three-step procedure proceeding in 11% overall yield, all
of which involve laborious functional group manipulations
(and DAST). The known route to 22[11] requires a 5-step
sequence (using DASTand KCN) proceeding in 9.3% overall
yield. In contrast, the one-step routes to 21 and 22 proceed in
Using these optimized conditions, a wide range of hetero-
cycles were examined as depicted in Scheme 2B. The scope,
site selectivity, and functional-group tolerance are notable
aspects of the method. Thus, pyridines (12–17), pyridones
(18), pyrazines (19–21), quinoxalines (22), azabenzimidazoles
(23), indazoles (24), benzimidazoles (25), indoles (26),
pyrimidines (27), benzoquinolines (28), pyridazines (29),
À
Scheme 2. A) Optimization of the reaction. Reactions performed on 0.05 mmol scale. B) Scope of C H difluoroethylation of heteroarene substrates.
Reactions performed on 0.2 mmol scale. Reaction conditions: Heterocycle (1.0 equiv), DFES-Na (3.0 equiv), tert-butyl hydroperoxide (TBHP, 5.0 equiv),
TsOH·H2O (1.0 equiv), ZnCl2 (1.5 equiv), 0 to 238C. C) Comparison to current state-of-the-art methods. Yields of chromatographically pure products are
displayed, unless otherwise noted. [a] Conversion on 0.2 mmol scale, yield 71%. [b] Conversion on 0.2 mmol scale, yield 51%. [c] Reaction showed
incomplete conversion after 12–24 h, and a second addition of DFES-Na (3.0 equiv), ZnCl2 (1.5 equiv), and TBHP (5.0 equiv) was performed. [d] DFES-Na
(2.0 equiv), ZnCl2 (1.0 equiv), TsOH·H2O (1.0 equiv), TBHP (5.0 equiv), 0 to 238C, reaction completed in 10 h. [e] Gram-scale reaction: DFES-Na (2.5 equiv),
ZnCl2 (1.25 equiv), TsOH·H2O (1.0 equiv), TBHP (5.0 equiv), 0 to 238C, 8 h, then 15 h with O2 balloon. TBHP=tert-butyl hydroperoxide, Tf=trifluorome-
thanesulfonyl, TFA=trifluoroacetic acid, Ts=p-toluenesulfonyl.
2
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!