Angewandte
Chemie
(2b, 2d, 2k, 2m, 2t) but also alkoxy and aryloxy (2c, 2j, 2l,
2o, 2s, 2v), carbalkoxy (2i, 2n), silyl (2g), and even formyl
(2e, 2q) groups. (Note that previous attempts to trifluoro-
methylate aryl boronic acids bearing an aldehyde function
have been unsuccessful.[7]) Also important is the fact that like
the para and meta isomers, ortho-substituted ArB(OH)2 are
smoothly trifluoromethylated in good (74%, 2q) to excellent
(90%, 2u) yield. On the whole, the yields (Scheme 3) are
noticeably higher than those previously reported[5,7–10] for
oxidative trifluoromethylation of aryl boronic acids and
boronate esters. For some substrates it was beneficial to
perform the reaction at 08C rather than at room temperature.
Thus, at 08C, 2e, 2r, 2s, 2t, 2u, and 2y were formed in
noticeably higher yield and the side formation of the
corresponding deborylation product was minimized. This
effect was particularly well-pronounced for the trifluorome-
thylation of 1y. At 258C, the yield of 2y was 77% and
considerable quantities (up to 15–20%) of benzothiophene
side product were produced, whereas at 08C the reaction
furnished 2y in 88% yield and only about 3% of benzothio-
phene. Overall, the trifluoromethylation reaction exhibits
excellent selectivity, as manifested by the yields of around
90% and higher for over two-thirds of the substrates explored
(Scheme 3).
- The lack of necessity to use costly Ruppertꢀs reagent as the
CF3 source, especially in excess (see above and Ref. [17]) by
far overwhelms the issue of employing Cu in stoichiometric
amounts. Note that all of the reported oxidative trifluoro-
methylation methods also use copper in stoichiometric[7–9]
or at best semicatalytic (20–60%)[5,10] quantities.
- Ligands such as phen are conventionally used in large
amounts[5,7,9,10] for the reported oxidative trifluoromethy-
lation reactions, thus adding considerably to the cost and
lowering the overall atom economy of the reaction. In
contrast, the reactions employing fluoroform-derived
CuCF3 smoothly occur in the absence of any extra
ligands/additives.
Although the mechanism of the Chan–Lam reaction is not
fully understood,[6,22] evidence has been presented for its non-
radical character.[6] This conclusion accords with the lack of
signs of involvement of free radicals in our reaction (see
above). The trifluoromethylation is most likely initiated by air
oxidation of the air-sensitive[18] CuICF3 reagent to a CuIICF3
species that, being much more electrophilic, undergoes
transmetalation with ArB(OH)2, as shown in the simplified
mechanism presented in Scheme 4. Reductive elimination of
The reactions listed in Scheme 3 were run on a 0.5 mmol
scale for yield determination by 19F NMR spectroscopy with
an internal standard and on a 1.0 mmol scale for isolation that
was performed for less volatile products 2b, 2g, 2h, 2i, 2k, 2l,
2v, 2w, and 2y. To demonstrate further scalability, the
synthesis of 2w was carried out with 10 mmols of 2-
naphthylboronic acid 1w. In this experiment, 2-trifluorome-
thylnaphthalene (2w) was successfully prepared and isolated
in an amount of 1.85 g (91% yield).
Scheme 4. Proposed simplified mechanism for trifluoromethylation of
aryl boronic acids with fluoroform-derived CuCF3.
Other salient features of the method are as follows:
- The reaction employs aryl boronic acids that are more
atom-economical and readily available than the corre-
sponding boronate esters. However, aryl boronic acids are
prone to undergo facile protodeborylation under the
reaction conditions used in the previously reported proce-
dures.[5,7,8] This highly undesired side-process could be
reduced by using dry O2 in the presence of molecular
sieves[7] or by diverting to pinacol boronate esters as the
substrate.[8] In favorable contrast, our method, despite
employing aryl boronic acids and non-dried air as the
oxidant, does not suffer significantly from the protodebor-
ylation. With a handful of exceptions, only small quantities
(< 5%, if any) of the corresponding arenes were observed
(GC-MS) in all of the reactions carried out at room
temperature.[21] For the trifluoromethylation of 1e, 1r, 1s,
1t, 1u, and 1y that proceeds less selectively at ambient
temperature, the side deborylation process can be largely
minimized by performing the reaction at 08C (see above).
Indeed, the isolated trifluoromethylated products 2b, 2g,
2h, 2i, 2k, 2l, 2v, 2w, and 2y were all found to be 95–99%
ArCF3 from the resultant CuII(Ar)CF3 intermediate would
complete the transformation, although involvement of CuIII
and polynuclear species should not be ruled out.[6,22] Signifi-
cantly however, the transmetalation, which is possibly[22a] the
rate-limiting step of the entire process, might be facilitated by
the CF3 ligand. The latter has been shown to promote
nucleophile-aided transmetalation reactions, likely because of
its stabilization of the d orbitals on the metal in addition to
strong electron donation.[3a,23]
In conclusion, we have demonstrated, for the first time,
that low-cost fluoroform-derived CuCF3 reagents[18] readily
trifluoromethylate aryl boronic acids. The reaction smoothly
occurs at room temperature (and even below) and 1 atm of air
as the oxidant to give the corresponding benzotrifluorides in
excellent yield (up to 99%) and with high selectivity. The
method exhibits unprecedentedly high functional-group tol-
erance for a variety of substrates bearing substituents in the
ortho, meta, and para positions; even aryl boronic acids with
formyl groups on the ring have been successfully trifluoro-
methylated in 74–82% yield. Importantly, use of additional
ligands, costly oxidants (AgI), drying agents, and pure O2 is
not needed, which makes the reaction not only synthetically
useful and inexpensive, but also advantageously simple and
safe to run.
1
pure by H and 19F NMR spectroscopy and GC-MS data.
- Importantly, no tert-butoxylation of ArB(OH)2 was
observed in the reaction, despite the fact that the CuCF3
reagent solutions always contain tBuOH from the prepa-
ration step.[18]
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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