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Angewandte
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Scheme 2. Dehydrogenative cross-coupling of aldehydes and alcohols.
Conditions: 1 (0.5 mmol), 2 (0.5 mmol), 0.2m, 8 h. Yields of isolated
products are given. [a] Reactions performed using 10 mol% of the
catalyst. Cy=cyclohexyl.
oxidant 3d, with no observation of dimer 5a. Related
oxidations typically require excess alcohol,[12] or alcohol as
the solvent.[13]
Under our optimized conditions, aromatic aldehydes
could be coupled with primary (4b, 97%), secondary (4c,
98%) and tertiary (4d, 79%) alcohols at 308C (Scheme 2).
Our method is the first intermolecular oxidative esterification
to achieve high yields using only one equivalent of the tertiary
alcohol nucleophile.[14] Comparatively less nucleophilic part-
ners such as benzyl alcohol also worked well (4e, 96%). Both
electron-rich (4 f, 97%) and electron-deficient (4g, 72%)
aromatic aldehydes can be transformed into esters. Whereas
many NHC-catalyzed esterification reactions are limited to
aromatic aldehyde substrates,[15] we found that aliphatic
aldehydes undergo oxidative functionalization with Ni catal-
ysis. Citronellal, a natural product, can be readily converted
into hindered ester 4h (83%), or methyl ester 4i (97%).
Hindered a-branched aldehydes are also well tolerated (4j,
91%).
In principle, couplings with amines should present
a greater challenge owing to the possibility of condensation
or catalyst inhibition. However, when using the same method
at slightly elevated temperatures (408C), amide bond for-
mation was observed using aniline nucleophiles (Scheme 3).
Thus, we can convert aldehydes into amides using base-metal
catalysis without relying on highly reactive reagents, such as
peroxides[8] or aryl azides.[16] Under these conditions, alde-
hydes containing electron-donating (7b, 93%) or -withdraw-
ing (7c, 97%) groups reacted efficiently, as well as aldehydes
that would be sensitive to peroxide oxidants (7d, 91%).[17]
Aniline nucleophiles with electron-withdrawing (7e, 93%)
and electron-donating (7 f, 90%) groups underwent the
coupling with similar efficiency. Hindered anilines are suit-
able partners, including those with ortho substituents (7 f,
90%) or substituents on the nitrogen atom (7g, 83%). Very
few side products were observed in these transformations,
even in the presence of an aryl chloride (7h, 62%).
Scheme 3. Dehydrogenative cross-coupling of aldehydes and amines.
Conditions: 1 (0.5 mmol), 6 (0.5 mmol), 0.2m, 8 h. Yields of isolated
products are given. [a] At 408C using IPr as the ligand and 3d as the
hydrogen acceptor. [b] At 308C using IPr as the ligand and 3d as the
hydrogen acceptor. [c] At 408C using ItBu as the ligand and an extra
equivalent of the aldehyde as the hydride acceptor. [d] Using 1a
instead of cyclohexanecarboxaldehyde as the hydrogen acceptor.
ItBu=1,3-di-tert-butylimidazole-2-ylidene.
Aliphatic aldehydes are excellent coupling partners for
amide synthesis (Scheme 3). At 308C, the reaction proceeded
to full conversion with cyclopropyl carboxaldehyde without
any ring opening (7i, 96%). b-Branching (7j, 81%) is well
tolerated, even though pivaldehyde only provided the
N-phenyl amide in 36% yield (not shown). An aniline with
a ketone in the para position gives the desired amide (7l) in
78% yield, illustrating that ketone functional groups are
tolerated despite the transfer hydrogenation nature of this
reaction. The syntheses of hindered amide 7m (72%) and
tertiary amides 7k (78%) and 7n (83%) highlight the
efficiency of this transformation.
In preliminary studies that focused on amine nucleophiles,
the reactions were plagued by condensation side products. To
avoid condensation with ketone 3d, we used a second
equivalent of the aldehyde as the oxidant. We were also
able to suppress [Ni(cod)2] catalyzed condensation between
the amine and the aldehyde by using ItBu as the ligand and
a Ni/ligand ratio of 1:1.1 (Scheme 3).[11] Under these con-
ditions, the dehydrogenative coupling proceeded with pri-
mary alkyl amines (7o, 87%), hindered amines (7p, 60%),
benzylic amines (7q, 91%), or even cyclic amines (7r, 97%).
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Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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