Journal of the American Chemical Society
Communication
Scheme 3. Isotope Labelling and Control Experiments
via 5-exo-trig or 6-endo-trig cyclizations with 10 as substrate
2
1−23
(
bottom).
On the basis of these results, we believe that
binding of Ni(II) precatalyst to the amide backbone via I
might occur prior to C−C bond-formation under a Ni/Ir
regime whereas a canonical PCET mechanism might take place
with particularly acidic trifluoromethyl-substituted amides
leading to the formation of amidyl radicals II prior to 1,5-
13
HAT. These interpretations gain credence by preliminary
1
UV−vis data, H NMR studies, cyclic voltammetry, luminis-
cence quenching experiments, and the lack of reactivity found
13,24
for tertiary amides 9 (middle).
In summary, we have developed a switchable catalytic
3
defluorinative sp C−H alkylation of secondary amides, thus
allowing us to rapidly and reliably incorporate gem-difluor-
oalkenes into hydrocarbon side chains. Site selectivity can
easily be dictated and modulated by an appropriate selection of
both the catalyst and the amide backbone. The salient features
of our protocol are the experimental ease, wide scope and mild
conditions, thus offering a complementary technique to
incorporate gem-difluoroalkenes at previously unfunctionalized
3
sp sites.
ASSOCIATED CONTENT
sı Supporting Information
■
*
3
). In sharp contrast with the results shown in Table 2, the
inclusion of nickel catalysts was not critical for the reaction to
occur. Importantly, products resulting from α sp C−H
functionalization (7) or via 1,6-HAT at activated benzylic
3
(
6g) or tertiary carbons (6h) could not be observed in the
crude mixtures. As shown, substrates bearing aliphatic alcohols
6b), sulfonates (6c), sulfones (6d), or phthalimides (6e)
Corresponding Author
■
(
Ruben Martin − The Barcelona Institute of Science and
Technology, Institute of Chemical Research of Catalonia
could easily be accommodated. Notably, C−C bond formation
3
at a primary or tertiary sp C−H bonds could be effected under
our protocol (6i, 6l). Interestingly, high diastereoselectivity
was observed for 6k whereas a 1:1 diastereomeric ratio was
18
found in amides possessing enantioenriched α-carbons (6j).
As expected, a wide variety of CF -substituted alkenes could be
employed with equal ease, including those bearing aldehydes
3
Authors
Wen-Jun Yue − The Barcelona Institute of Science and
Technology, Institute of Chemical Research of Catalonia
(
(
6p), ketones (6r), nitriles (6s), aryl halides (6t, 6u), acetals
6v), or heterocyclic motifs (6w−6z). The successful
(
ICIQ), 43007 Tarragona, Spain; Departament de Química
Analítica i Química Organica, Universitat Rovira i Virgili,
3007 Tarragona, Spain
preparation of 6aa−6ad stands as a testament to the impact
̀
3
of our δ sp C−H functionalization with advanced synthetic
4
19
intermediates such as pregabalin, menthol, or lysine, among
others.
Craig S. Day − The Barcelona Institute of Science and
Technology, Institute of Chemical Research of Catalonia
Next, we decided to gather indirect evidence about the
(
ICIQ), 43007 Tarragona, Spain; Departament de Química
3
mechanism of our sp α C−H defluorinative alkylation by
conducting experiments with isotopically labeled substrates
(Scheme 3). A significant kinetic isotope effect was observed in
the competitive reaction of 1a and 1a-d with 2a (k /k =
2
H
D
3
3
.8), suggesting that sp α C−H bond-cleavage might be
13
involved in the rate-determining step. Interestingly, no
deuterium crossover was observed by examining the reactivity
Notes
of 1a-d and 1f (top); under the limits of detection, 3a or 3f-d
2
The authors declare no competing financial interest.
were not detected in the crude reaction mixtures, thus arguing
against the involvement of intermolecular HAT processes.
While the results of Table 2 could also be interpreted on the
basis of an intramolecular 1,5-HAT from an in situ generated
amidyl radical followed by chain walking to locate the nickel
catalyst α to the nitrogen atom prior to C−C bond
ACKNOWLEDGMENTS
■
We thank ICIQ, FEDER/MICIU (AEI/PGC2018-096839-B-
100), and MCI/AIE (Severo Ochoa Excellence Accreditation
2020-2023, CEX2019-000925-S) for financial support. W.-J.Y.
and C.S.D. thank the China Scholarship Council (CSC) and
the European Union’s Horizon 2020 under the Marie Curie
PREBIST grant agreement 754558.
2
0
3
formation, the formation of 8a lacking δ sp C−H bonds
indicates otherwise (middle). The intermediacy of open-shell
species was indirectly corroborated by observing 11a and 11b
6
398
J. Am. Chem. Soc. 2021, 143, 6395−6400