Organic Letters
aromatic ring had a negative impact on the reaction probably
by making the arylcyclopropanes more difficult to oxidize. To
overcome this limitation, we switched NFSI to its p-
14
trifluoromethylated derivative. We were delighted to find
that the same substrate 3t now delivered the desired products
4
u in a much higher (48%) yield in comparison with 4t (12%
yield). Similarly, the reaction of (m-methoxycarbonylphenyl)-
cyclopropane (3m) with (p-CF -C H SO ) NF provided 4v in
3
6
4
2 2
a higher (58%) yield compared to its reaction with NFSI (to
give 4m in 40% yield). The protocol could be further extended
to heteroarylcyclopropanes. For example, thiophenylcyclopro-
pane 3w furnished the expected product 4w in 76% yield on
reaction with (p-CF -C H SO ) NF. The above experiments
3
6
4
2 2
clearly demonstrated that the p-CF substitution increased the
3
Figure 1. Proposed mechanism.
reaction efficiency. Presumably, the p-CF -substitution renders
3
the N−F reagent a stronger oxidant than NFSI, thus facilitating
the oxidative ring opening of electron-deficient arylcyclopro-
panes. This assumption was further supported by our
15
give the CuIII intermediate A. The oxidation of arylcyclo-
propanes by A generates arylcyclopropanes radical cation B,
observation that a much weaker oxidant, (PhSO )EtN-F,
2
failed to give the desired product 4x.
−
II
(
(
PhSO ) N anion, and Cu −CF complex. The interaction of
2
2
3
In addition to being general, the 1,3-aminotrifluoromethy-
lation was highly regioselective in that the trifluoromethyl
group was always attached to the benzylic carbon. Moreover,
the reaction could be easily scaled up without an obvious
decrease in product yield, as exemplified by the gram-scale
synthesis of 4i (Scheme 3). One of the sulfonyl groups in 4i
−
PhSO ) N anion with radical cation B results in the ring-
2
2
opening of the latter, and the corresponding benzyl radical C is
produced. Finally, the CF group transfer from the Cu −CF
complex to radical C furnishes the 1,3-aminotrifluoromethy-
II
3
3
I
lation product and regenerates the Cu catalyst.
In conclusion, we have successfully developed the
unprecedented protocol for the 1,3-aminotrifluoromethylation
of arylcyclopropanes, providing a convenient entry to γ-
trifluoromethylated amines. As the procedure is catalytic in
copper, broad in scope, and operationally simple, the method
should find important applications in the synthesis of
trifluoromethylated molecules of biological interests.
Scheme 3. Gram-Scale Synthesis and Derivatization of 4i
ASSOCIATED CONTENT
sı Supporting Information
■
*
Full experimental details, characterizations of new
1
13
19
was readily removed by acid hydrolysis at rt to give
sulfonamide 5 in almost quantitative yield. Further treatment
of 5 with Mg/MeOH at rt furnished the corresponding free
amines under mild conditions, which could be easily converted
to amides such as 6 according to the conventional methods. In
another case, the palladium-catalyzed Heck coupling of 4i with
ethyl acrylate led to the easy synthesis of alkene 7. These
experiments further demonstrated the potential of 1,3-
aminotrifluoromethylation products in the synthesis of
structurally complex trifluoromethylated compounds.
■
Corresponding Authors
Lin Zhu − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Chaozhong Li − School of Physical Science and Technology,
ShanghaiTech University, Shanghai 201210, China; Key
Laboratory of Organofluorine Chemistry, Center for
Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai
200032, China; School of Materials and Chemical
A mechanism involving the trifluoromethylation of benzyl
radicals could be inferred from the above experiments. Indeed,
the reaction was completely inhibited by the addition of a
stoichiometric amount of TEMPO (2,2,6,6-tetramethylpiper-
idin-N-oxyl) or BHT (2,6-di-tert-butyl-4-methylphenol), thus
providing additional evidence for the radical intermediacy.
A plausible mechanism can thus be proposed based on the
above results and literature reports, as depicted in Figure 1.
I
Transmetalation of CF anion from (bpy)Zn(CF ) to Cu
3
3 2
I
forms the Cu −CF species that is then captured by NFSI to
3
2
270
Org. Lett. 2021, 23, 2268−2272