Zinc-catalyzed reduction of amides: Unprecedented selectivity and functional group tolerance

Article abstract of DOI:10.1021/ja910083q

(Chemical Equation Presented) A novel zinc-catalyzed reduction of tertiary amides was developed. This system shows remarkable chemoselectivity and substrate scope tolerating ester, ether, nitro, cyano, azo, and keto substituents. Copyright

Full text of DOI:10.1021/ja910083q

Published on Web 01/27/2010
Zinc-Catalyzed Reduction of Amides: Unprecedented Selectivity and
Functional Group Tolerance
Shoubhik Das, Daniele Addis, Shaolin Zhou, Kathrin Junge, and Matthias Beller*
Leibniz-Institut fu¨r Katalyse e.V. an der UniVersita¨t Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
Received November 30, 2009; E-mail: matthias.beller@catalysis.de
Table 1. Zinc Acetate-Catalyzed Reduction of Tertiary Amides
The catalytic reduction of amides to amines under mild conditions
constitutes a highly desired transformation for organic synthesis
and the pharmaceutical as well as agrochemical industry.1 In this
respect, high selectivity and broad tolerance toward functional
groups are key factors for the acceptance and application of a given
methodology. Most of the known reductive transformations of
amides to amines make use of stoichiometric amounts of traditional
aluminum and boron hydrides.2,3 In spite of their utility, clear
drawbacks of these reagents are air and moisture sensitivity as well
as the resulting costly purification of the products and concomitant
formation of environmentally hazardous waste materials. Due to
these problems, the development of catalytic reductions of amides
is of high actual interest.4 Unfortunately, the direct hydrogenation
is still in its infancy.5 On the other hand, the catalytic hydrosilylation
of carboxamides applying precious metal catalysts like Rh,6a-c
Ru,6c-g Pt,6c,h Pd,6c Ir,6c and others6c,i-k has been more intensively
investigated. Most recently, also Fe-based catalysts have been
successfully applied for this purpose at higher temperature.6l,m
Nevertheless, until today a general methodology for the reduction
of amides under mild conditions with inexpensive and environ-
mentally friendly catalysts is not available.
Herein, we report for the first time the efficient reduction of
tertiary amides using convenient zinc catalysts with excellent
chemoselectivity and unique functional group tolerance. Parallel
to this work, Nishiyama and co-workers used a similar catalyst
system for the hydrosilylation of ketones.7 At the start of our project,
the reaction of N,N-dimethylbenzamide with (EtO)3SiH8 was
investigated as a model system to identify and optimize potential
catalysts and the critical reaction parameters. Summarizing these
experiments we observed that in the presence of 10 mol % zinc
acetate and 3 equiv of triethoxysilane reduction took place at room
temperature leading to the corresponding amine in 97% yield! As
expected, the reaction did not occur in the absence of any zinc
catalyst. Nevertheless, other zinc salts such as ZnX2 (X ) F, Cl,
Br, OTf) and hydrated complexes ZnX2 ·6H2O (X ) ClO4, NO3)
showed some activity but gave significantly lower yields, and other
sources of metal acetate (Cu, Fe) were completely inactive in this
reaction.9,10
Next, we investigated the influence of different silanes in more
detail. Noteworthy, other silanes did not react at room temperature,
however PhSiH3, Ph2SiH2, and (EtO)2MeSiH gave excellent yields
(>90%) toward N,N-dimethylbenzylamine at 65 °C. Applying
triethoxysilane to the reaction worked also well at room temperature
in solvents like dichloromethane, toluene, diglyme, 1,2-dimethoxy-
ethane, 1,4-dioxane, and di-n-butylether. To exclude the influence
of potential metal contaminants in the catalyst precursor, we used
zinc acetate from different suppliers (ABCR, Acros, Sigma Aldrich)
giving similar product yields. We were also pleased to find that
the reaction is easily performed on a multigram scale without special
precautions. After surveying the reaction conditions we started to
investigate the scope and limitations of this first zinc-catalyzed
a Reported yields are isolated yields except entries 1 and 12. b All
reactions were performed with 1 mmol of amide except entries 3 and 10
(3 mmol). c Products of entries 4 and 13 were purified by column
chromatography, and products of entries 3 and 10 were purified by
distillation.
reduction of amides. As shown in Table 1 aromatic, aliphatic,
alicyclic, and heterocyclic amides are smoothly reduced under the
optimized reaction conditions with triethoxysilane. Comparing
differently substituted benzamides, we observed that the introduction
of electron-withdrawing groups at the para-position of the benzene
ring (Table 1, entries 6-8) resulted in faster reduction than in the
case of those bearing electron-donating groups (Table 1, entry 4).
Indeed, when a 1:1 mixture of N-(4-methoxy-benzoyl)piperidine
(1f) and N-(4-fluorobenzoyl)piperidine (1d) was subjected to the
standard hydrosilylation conditions, the mixture contained 23% 2f
and 8% 2d, respectively, after 10 h. It should be noted that in a
few cases a slightly higher temperature (40 °C) was needed to
achieve full conversion (Table 1, entries 4, 6, 8-11).
After demonstrating the general applicability of our procedure,
we were interested in the functional group tolerance of the catalytic
system. Hereby, we studied especially challenging substrates, which
might undergo additional reductive transformations. As summarized
in Table 2 the amide is reduced in the presence of ester, ether,
nitro, cyano, and azo substituents as well as isolated and conjugated
double bonds! To our delight none of the functional groups are
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1770 J. AM. CHEM. SOC. 2010, 132, 1770–1771
10.1021/ja910083q  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Functional Group Tolerance
the iminium ion to the product and the siloxane. This mechanistic
proposal is in agreement with the reaction of 1a with Ph2SiD2 where
both deuterium atoms are incorporated on the carbonyl carbon.
In conclusion, we have established for the first time a highly
chemoselective reduction of amides to the corresponding amines
with silanes in the presence of inexpensive zinc catalysts under
mild conditions. We expect our system will be useful for organic
synthesis allowing amide reduction without using protecting groups
and deprotection steps. Further studies on the application of primary
and secondary amides as well ester are ongoing in our laboratory
and will be reported in due course.
Acknowledgment. The authors thank Dr. W. Baumann, Dr. C.
Fischer, S. Buchholz, S. Schareina, A. Krammer, A. Koch, K.
Mevius, and S. Rossmeisl (all at the Leibniz-Institut fu¨r Katalyse
e.V. an der Universita¨t Rostock) for excellent analytical and
technical support.
a All reactions were performed on 1 mmol scale of the respective
amide. b Entries 4-7 were purified by column chromatography.
Scheme 1. Proposed Mechanism
Supporting Information Available: Experimental details and
spectroscopic and analytical data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
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Based on these observations, we propose the reaction mechanism
shown in Scheme 1. Zinc acetate reacts with triethoxysilane at room
temperature and forms an activated species A. Next, the amide is
coordinated to the metal center in A and generates the corresponding
N,O-acetal C via B. Release of the anionic zinc ether D led to the
iminium species E. Finally, another equivalent of the silane converts
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