Organic Letters
Letter
3
the anticipated difluoromethylthiolation products 2 in 33−78%
yields. There are some merits that need to be highlighted. (1)
Both acyclic and cyclic N-fluorotosylamides 1 bearing a
reactive C−H group (secondary, tertiary, as well as benzylic) at
the δ-position gave the corresponding difluoromethylthiolation
product 2l−al in 33−78% yield. (2) Introducing substituents
of either an alkyl or a phenyl at different sites (α-, β-, or γ-
position) of 1 had no influence on the regioselectivity, enabling
us to isolate the anticipated products 2p−v in 62−75% yields,
albeit with almost no control of the diastereoselectivity. To
further test the stereoselectivity of the protocol, we tested a
selection of nonactivated, five-, six-, or seven-membered ring-
substituted substrates 1w−z, and the monocyclic products 2w
Scheme 3. Scope of the C(sp )−H
a
Difluoromethylselenation
(
75%, dr 5:1), 2x (66%, dr 3:2), 2y (42%, dr 3:2), and 2z
(
72%, dr 1:1) were delivered, albeit with moderate
3
diastereoselectivity. (3) The primary C(sp )−H bonds of N-
fluorotosylamide 1ak worked well in the reaction, delivering
the product 2ak in 33% yield. (4) The protocol had a very
good functional group tolerance. For instance, substrates 1aa−
a
reaction mechanism is provided (Figure 2). At the beginning,
af, containing OMe, ester, amide, Br, N , and allyl groups also
3
proceeded well, giving rise to the desired products 2aa−af in
4
6−67% yields. These examples provided the opportunity for
further modification and highlighted the mildness of the
reaction conditions.
The site selectivity of the C−H difluoromethylthiolation
with substrates bearing different reactive sites was also tested.
For 1al, bearing both secondary and competitive benzylic C−
H bonds at the δ and ε positions, the generation of
regioselective difluoromethylthiolation side products was
isolated at the ε position, in addition to the desired δ-
difluoromethylthiolation product 2al (78%, rr = 2:1). To
further test the functional-group tolerance as well as the
potential application of our method, the functionalization of
both medicinal and natural product derivatives at a late stage
was tested. The transformation of both celecoxib- and
pregabalin-derived 1am and 1an proceeded smoothly under
our optimal conditions, affording difluoromethylthiolation
products 2am and 2an in 66 and 45% yield, respectively.
The 1ao derivatived from the natural product leelamine also
gave the desired product 2ao in 51% yield with complete
diastereocontrol.
Figure 2. Plausible reaction mechanism.
via the reduction of the ligand-coordinated Fe(III)(acac)
3
2
2
upon heating. Subsequently, N-fluorotosylamide 1 was
reduced by this Fe(II)L complex A to produce FFe(III)L
n
n
14
We then questioned whether the congener of PhSO SCF H,
C as well as amidyl radical D. The latter radical went through
an intramolecular 1,5-HAT to form the radical E, which could
2
2
7
d
PhSO SeCF H, also worked under our reaction conditions
2
2
3
to realize the unprecedented difluoromethylselenation of δ-
be trapped by PhSO SCF H to provide the observed C(sp )−
2
2
3
C(sp )−H bonds. To our delight, the difluoromethylselenation
H difluoromethylthiolation product 2 and benzenesulfonyl
radical F at the same time. Meanwhile, as reported by
reaction of N-protected pentyl-, hexyl-, and heptylamine
proceeded with excellent regiocontrol in 67−72% yield to
give 3a−c (Scheme 3). The substrate 1o bearing sterically
bulky adamantyl also took part in remote C−H difluorome-
thylselenation to deliver the product 3d in good yield (61%).
The secondary benzylic position was difluoromethylselenated
to give 3e in a lower yield (40%). Compound 1al, containing a
tertiary C−H bond, also worked well, and the corresponding
product 3f was isolated in 64% yield. The stereoselectivity of
this reaction was also tested, and for substrates 1r, 1x, and 1z,
bearing chain or cyclic systems, although the yield was
moderate to good (59−71%), no stereoselectivity was
observed (dr = 1:1 for all three cases). Moreover, substrates
bearing functional groups including amide (3j), Br (3k), and
azido (3l) were tolerated.
20
Terent’ev and coworkers, the interaction of benzenesulfonyl
radical F with B under the promotion of FFe(III)L C gives
rise to 1-(phenylsulfonyl)propan-2-one 6 and reforms the
Fe(II)Ln.
n
In summary, we have developed an unprecedented iron-
3
catalyzed δ-C(sp )−H bond difluoromethylthiolation or
difluoromethylselenation of aliphatic amides with site
3
selectivity, enabling the preparation of versatile C(sp )−
3
SCF H or C(sp )−SeCF H compounds bearing versatile
2
2
functional groups under mild conditions. The findings
3
3
represent the first time that C(sp )−SCF H or C(sp )−
2
3
SeCF H bonds have been constructed using inert C(sp )−H
2
bond activation and demonstrate that the approach can be
applied for the derivation of pharmaceutical and natural
product derivatives at a late stage. Further studies on other
To study the reaction mechanism, we conducted a couple of
control experiments. (For details, see the SI.) On the basis of
3
useful transformations of inert C(sp )−H bonds are ongoing in
1
4,21
related reports
and these preliminary results, a proposed
our laboratories.
4
723
Org. Lett. 2021, 23, 4721−4725
Zhang, Hongwei
