Angewandte
Communications
Chemie
[Cu(CH3CN)4](PF6) (abbreviated CuPF6) showed that this
oxidation of cyclopropyl amine afforded nitrile 2x without the
catalyst system is more active than the CuI system (Fig-
ure 1a), thus suggesting that selectivity for 3a arises from its
high Lewis acidity. Therefore, to augment Lewis acidity, we
examined more polar solvents that would favor a more
dissociated ion pair. Whereas coordinating solvents, such as
dimethylformamide (DMF), dimethyl sulfoxide (DMSO),
and acetone, inhibited catalysis (Table 1, entries 9–11), the
use of CH3CN, in concert with a lower-surface-area molecular
sieve in pellet form, led to our optimized conditions for the
formation of imine 3a in 71% yield (entry 12).
These results demonstrate that potent catalysts for
selective amine oxidation can be generated from simple Cu
salts, whereby the counterion plays a critical role in control-
ling selectivity. To evaluate their generality, we surveyed
a range of amines for the selective synthesis of either nitriles
or imines. In the case of nitriles, a broad range of ortho-, meta-
, and para-substituted benzylic amines were tolerated,
including those bearing halogens (products 2d–f), electron-
donating groups (products 2j,n), and electron-withdrawing
groups (products 2i,m). A thiophene moiety was also
tolerated (product 2p), as was allyl amine, which provided
acrylonitrile (2q). A number of the reactions included in
Scheme 2 were complete within 1 h at room temperature, thus
showing the exceptional efficiency of these conditions for the
copper-catalyzed synthesis of aromatic nitriles.[12–15] Besides
facilitating product isolation, the simplicity of this catalyst
system makes scale-up straightforward, as illustrated by the
synthesis of nitrile 2k on a 10 mmol scale in 82% yield.[20] The
oxidation of less-activated aliphatic amines proceeded within
standard reaction times and maintained excellent selectivity
to provide valuable aliphatic nitriles possessing a- or b-
branching (products 2w,y), heteroatom substitution (products
observation of ring-opened products.[21]
The CuPF6-catalyzed synthesis of imines tolerated com-
parably diverse functionality, including benzylic hydrogen
atoms (product 3c), electron-donating groups, and electron-
withdrawing groups para to the benzylic amine and halogen
substituents traditionally employed in cross-coupling reac-
tions (products 3e,g) or fluorine (product 3 f). Substitution at
the meta position was also tolerated (products 3g,h), as was
substitution at the ortho position (product 3i). However, in
contrast to the synthesis of nitriles, aliphatic amines were not
compatible, and returned unreacted starting material.
A series of isotope-labeling and control experiments
provided preliminary insight into the mechanism of amine
oxidation with these catalysts (Scheme 3). Kinetic analysis
showed a rate dependence on the amine for both CuI- and
CuPF6-mediated oxidation (see Figures S7 and S9 in the
Supporting Information), but there was an absence of a kinetic
isotope effect (KIE) in the relative rates of oxidation for 1a-
CH2 and 1a-CD2 (Scheme 3, entries 1 and 2). Together, these
À
results suggest that substrate coordination, rather than C H
bond cleavage, is rate-determining during catalysis. An
intermolecular competition isotope effect between 1a-CH2
and 1a-CD2 of 2.6 and 1.9 was observed for the CuI- and
CuPF6-catalyzed oxidation, respectively (entries 1 and 2),
thus implying that the active oxidant has the opportunity to
oxidize either amine substrate after rate-determining coordi-
nation (see below). We also observed an inverse secondary
KIE of 0.8 in the independent rates of oxidation for 1a-ND2
and 1a-NH2 with both the CuI and the CuPF6 catalyst
(entries 3 and 4).[22] Neither hydroxylamine 4, nor oxime 5
were converted into the expected products (entries 6 and 7),
À
thus disfavoring a mechanism of oxidation involving N O
bond formation.
À
2s,u), and readily oxidized C H bonds (product 2y). The
Scheme 2. Investigation of the scope of the reaction. Reaction conditions for the synthesis of nitriles: amine (0.5 mmol), CuI (4.8 mg,
0.05 mmol), 3 ꢀ powdered sieves (250 mg), CH2Cl2 (1 mL), O2 (1 atm), 6 h. Reaction conditions for the synthesis of imines: amine (0.5 mmol),
[Cu(CH3CN)4](PF6) (0.025 mmol), 3 ꢀ MS pellets (100 mg), CH3CN (1 mL), O2 (1 atm), 24 h. Yields were determined by 1H NMR spectroscopy
unless otherwise indicated. [a] Reaction time: 2 h. [b] Yield of the isolated product. [c] The reaction was carried out on a 10 mmol scale.
[d] Reaction time: 1 h. [e] Reaction time: 40 h.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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