Whereas
the metal-catalyzed C(sp2)–N cross-coupling
of cyclopropylamine with aryl electrophiles represents an attractive
route to pharmaceutically relevant N-arylcyclopropylamines,
few catalysts that are capable of effecting such transformations have
been identified. Herein, the nickel-catalyzed C(sp2)–N
cross-coupling of cyclopropylamine and related nucleophiles, including
ammonium salts, with (hetero)aryl (pseudo)halides is reported for
the first time, with the demonstrated scope of reactivity exceeding
that displayed by all previously reported catalysts (Pd, Cu, or other).
Our preliminary efforts to effect the N-arylation
of cyclopropylamine with (hetero)aryl chlorides at room temperature
by use of (L)NiCl(o-tolyl) precatalysts
(L = PAd-DalPhos, C1; L = JosiPhos
CyPF-Cy, C2) were unsuccessful, despite the established
efficacy of C1 and C2 in transformations
of other primary alkylamines. However, systematic modification of
the ancillary ligand (L) structure enabled success in
such transformations, with crystallographically characterized (L)NiCl(o-tolyl) precatalysts incorporating o-phenylene-bridged bisphosphines featuring phosphatrioxaadamantane
and PCy2 (L = L3, CyPAd-DalPhos; C3), P(o-tolyl)2 and P(t-Bu)2 (L = L4; C4), or PCy2 and P(t-Bu)2 (L = L5; C5) donor pairings
proving to be particularly effective. In employing the air-stable
precatalyst C3 in cross-couplings of cyclopropylamine,
substituted electrophiles encompassing an unprecedentedly broad range
of heteroaryl (pyridine, isoquinoline, quinoline, quinoxaline, pyrimidine,
purine, benzothiophene, and benzothiazole) and (pseudo)halide (chloride,
bromide, mesylate, tosylate, triflate, sulfamate, and carbamate) structures
were employed successfully, in the majority of cases under mild conditions
(3 mol % of Ni, 25 °C). Preliminary studies also confirmed the
ability of C3 to effect the N-arylation
of cyclopropanemethylamine hydrochloride and cyclobutylamine hydrochloride
under similar conditions. A notable exception in this chemistry was
observed specifically in the case of electron-rich aryl chlorides,
where the use of C4 in place of C3 proved
more effective. In keeping with this observation, catalyst inhibition
by 4-chloroanisole was observed in the otherwise efficient cross-coupling
of cyclopropylamine and 3-chloropyridine when using C3. Competition studies involving C3 revealed a (pseudo)halide
reactivity preference (Cl > Br, OTs).