C O M M U N I C A T I O N S
alcohol and benzyl amine (entry 5) in a lower yield (57%), probably
because of steric reasons. Significantly, the aliphatic nonactivated amides,
N-ethylacetamide and N-methylpropionamide, also underwent hydrogena-
tion to yield the corresponding alcohols and amines (71% of ethanol and
ethylamine for entry 6 and 68% of n-propanol and methylamine for entry
In conclusion, amides can be selectively and directly hydroge-
nated to alcohols and amines (including under anhydrous conditions)
for the first time. The reaction proceeds under mild pressure and
neutral, homogeneous conditions using a BPy-PNN-Ru(II) hydride
pincer catalyst and dihydrogen by a mechanism involving
metal-ligand cooperation. This new catalytic protocol exhibits a
broad substrate scope providing a variety of amines and alcohols
7). The product gaseous amines were characterized by GC-MS of the gas
phase and not quantified. Anilide derivatives were converted into their
corresponding alcohols and aniline in excellent yields (91-95%; entries
1
7
in good to excellent yields. The analogous Py-PNN complex 1
9-12) along with trace amounts of the secondary amines (detected by
is less efficient. The reasons for this are being explored.
GC-MS) under similar conditions. The reaction is also effective for bis-
amides. Thus, N,N′-(ethane-1,2-diyl)bis(2-methoxyacetamide) (0.5 mmol)
was hydrogenated selectively to diamine (77%) and alcohol (78%) using
catalyst 3 without formation of monoamine-monoamide (entry 13).
Noteworthy, tert-amides also underwent hydrogenation almost quantita-
Acknowledgment. This research was supported by the European
Research Council under the FP7 framework (ERC No 246837), by
the Israel Science Foundation, and by the Helen and Martin Kimmel
Center for Molecular Design. D.M. is the holder of the Israel Matz
Professorial Chair of Organic Chemistry.
15
tively to yield alcohols and secondary amines in equivalent amounts
(
entries 14-16). Gratifyingly, heating a solution of N-formymorpholine
Supporting Information Available: Experimental procedures and
X-ray data for complex 4 in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
(1 mmol) and complex 3 in THF at 110 °C yielded after 32 h 97% of
methanol and 98% of morpholine, formyl decarbonylation not being
observed. These results highlight the substantial scope of the selective
hydrogenation of amides catalyzed by 3, or by the air-stable 4 with an
equivalent of base (which generates 3 in situ).
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6) Catalytic hydrogenation of amides to amines (Via C-O cleavage, generating
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Figure 3. Postulated mechanism for hydrogenation of amides to amines
and alcohols catalyzed by complex 3.
7
Ed. 2010, 49, 1468. (g) Schwartsburd, L.; Iron, M. A.; Konstantinovski, Y.;
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8
,10
(9) (a) Gunanathan, C.; Shimon, L. J. W.; Milstein, D. J. Am. Chem. Soc. 2009,
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pincer complexes 1 and 2
Figure 3. Initially, dihydrogen addition by metal-ligand cooperation
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we propose the mechanism depicted in
1
8,10,16
47, 8661. (c) Gunanathan, C.; Gnanaprakasam, B.; Iron, M. A.; Shimon,
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(
8c
saturated, trans dihydride complex A, as reported for complex 1.
Decoordination of the pyridyl “arm” can provide a site for amide
coordination, to give the intermediate B. Subsequent hydride transfer
to the carbonyl group of the amide ligand leads to a hemiaminoxy
intermediate C, with no formation of free hemiaminal. Deprotonation
of the benzylic arm by the adjacent NH group leads to the amine
product and a dearomatized intermediate D, bearing a coordinated
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L. J. W.; Ben-David, Y.; Iron, M. A.; Milstein, D. Science 2009, 324, 74.
(
12) See SI for full details.
2
(13) Coupling of alcohols with amines to form amides and H reported after
our publication (ref 8e): (a) Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am.
Chem. Soc. 2008, 130, 17672. (b) Zhang, Y.; Chen, C.; Ghosh, S. C.; Li,
Y.; Hong, S. H. Organometallics 2010, 29, 1374.
(
14) Coupling of alcohols with amines to form amides using hydrogen
acceptors: (a) Zweifel, T.; Naubron, J. V.; Gr u¨ tzmacher, H. Angew. Chem.,
Int. Ed. 2009, 48, 559. (b) Watson, A. J. A.; Maxwell, A. C.; Williams,
J. M. J. Org. Lett. 2009, 11, 2667.
2
aldehyde. H addition to D forms the aromatic dihydride E, followed
by hydride transfer to the aldehyde to generate the alkoxy intermediate
F. Deprotonation of the benzylic arm by the alkoxy ligand generates
the product alcohol and regenerates catalyst 3. The overall process
does not involve a change in the metal oxidation state. We postulate
that key to the success of this process is that it does not involve
intermediacy of free hemiaminal, avoiding water elimination to give
an imine and, subsequently, a secondary amine.
(
15) The fact that the monoamine-monoamide was not observed, while some
starting diamide was still present, suggests that it reacts faster than the
diamide, perhaps as a result of coordination of the amine group.
16) (a) Gr u¨ tzmacher, H. Angew. Chem., Int. Ed. 2008, 47, 1814. (b) van der
Vlugt, J. I.; Reek, J. N. H. Angew. Chem., Int. Ed. 2009, 48, 8832.
(
(17) Complex 3 catalyzes also amide formation by dehydrogenative coupling
of alcohols with amines: Balarman, E.; Milstein D. to be published.
JA1080019
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6758 J. AM. CHEM. SOC. 9 VOL. 132, NO. 47, 2010