Highly chemoselective metal-free reduction of tertiary amides

Article abstract of DOI:10.1021/ja077463q

This communication describes the chemoselective metal-free reduction of tertiary amides to the corresponding amines. Hantzsch ester is used as a mild reducing agent for the reduction of trifluoromethanesulfonic anhydride activated amides providing the tertiary amines with high functional group tolerance. Copyright

Full text of DOI:10.1021/ja077463q

Published on Web 12/13/2007
Highly Chemoselective Metal-Free Reduction of Tertiary Amides
Guillaume Barbe and Andre´ B. Charette*
De´partement de chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Quebec, Canada H3C 3J7
Received September 27, 2007; E-mail: andre.charette@umontreal.ca
Table 1. Metal-Free Reduction of Tertiary Amidesa
The reduction of amides to amines is a well-documented process
for which a large number of reaction conditions have been reported
in the literature. They include the use of highly reactive reagents
such as aluminum and boron hydrides as the most frequently
encountered hydrogen sources.1 These methods are usually high
yielding and have been efficiently applied to the synthesis of a wide
array of biologically active alkaloids. However, the low functional-
group tolerance and tedious purification procedures often associated
with such reaction conditions still represent a major drawback.
Over the past decade, silanes have emerged as an alternative
hydrogen source in the transition-metal-catalyzed reduction of
amides. For example, Rh,2a,b Ru,2c,d Pt,2e Mo,2f and Ti2g complexes
have been shown to exhibit catalytic activity in the hydrosilylation
of carboxamides. Although improvements in terms of byproduct
removal have been described, the high costs associated with
catalysts and/or silane reagents along with the moderate chemose-
lectivity observed in most of these reduction reactions still impaired
their generality. Herein, we describe a highly chemoselective metal-
free reduction process for the reduction of tertiary amides.
a All reactions were performed on 1 mmol of amide. b Reaction was
performed on 1 g scale. c No column chromatography required.
clever applications in organocatalytic enantioselective hydrogen
transfer reactions.6
After surveying the reaction conditions, we were pleased to find
that submitting N,N-dibenzylbenzamide to triflic anhydride7 and
HEH8,9 in DCM10 at room temperature led to the formation of
tribenzylamine in 70% isolated yield after 1 h (Table 1, entries 1
and 2).9 We then investigated the electronic and steric effects of
the reaction. By substituting the benzamide with electron-withdraw-
ing (entry 3) and -donating (entry 4) groups at the para position of
the benzoyl moiety, similar yields could be obtained. Moreover,
N-aryl- (entries 5-8) and N-allylbenzamides (entry 9) were also
found to be reduced under these conditions, albeit in slightly lower
yields. Interestingly, these classes of substrates are known to
produce considerable amounts of the corresponding primary alco-
hols and secondary amines when reduced with LiAlH4.11 However,
under our reaction conditions, the sequestration of the oxygen atom
by the electrophilic triflyl moiety completely prevented the forma-
tion of such byproducts.
It is noteworthy that the reaction can also be performed on 1 g
scale without affecting the yield (entries 2 and 6). As shown in
entries 10 and 11, amides bearing aliphatic substituents on either
the nitrogen or the carbonyl unit were also found to be suitable
substrates for the reaction. However, increasing the steric demand
on either side of the amide moiety drastically impairs the reduction
step (entries 13 and 14).
We previously reported that amides can be selectively trans-
formed into a variety of carboxylic acid derivatives3a and chiral
piperidines3b via an electrophilic activation with trifluoromethane-
sulfonic anhydride (Tf2O) in the presence of pyridine and a suitable
nucleophile. More recently, Movassaghi reported the synthesis of
polysubstituted pyridines and pyrimidines from amides using Tf2O
and 2-chloropyridine as activating agents and alkynes/alkenes or
nitriles as respective nucleophiles.4 In an effort to find mild and
chemoselective reaction conditions for the reduction of carboxa-
mides, we hypothesized that treating an amide with Tf2O would
generate a highly electrophilic iminium derivative that could
subsequently be reduced to the corresponding amine using a mild
reducing agent.
Over the past century, 1,4-dihydropyridines have been widely
studied as hydrogen transfer agents for the reduction of unsaturated
organic compounds.5 More specifically, the Hantzsch ester (HEH)
has been shown to reduce a wide variety of ketiminium and
aldiminium species even at low temperature. This has recently found
We evaluated the chemoselectivity of the reduction process by
grafting different functionalities on N-benzoylpiperidine (Table 2).
By positioning these functionalities at the 4-position of the
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10.1021/ja077463q CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reduction of Functionalized Amidesa
In conclusion, a highly chemoselective metal-free reduction of
tertiary amides has been developed. As was demonstrated in the
chemoselective synthesis of donepezil, we believe this could find
great interest in the synthesis of highly functionalized molecules
and especially in the synthesis of natural products. Efforts are
actually directed toward the extension of this methodology to
secondary amides, and the results will be reported in due course.
Acknowledgment. This work was supported by NSERC
(Canada), the Canada Research Chairs Program, the Canadian
Foundation for Innovation, and the Universite´ de Montre´al. G.B.
thanks NSERC (ES D) and Boehringer Ingelheim (Canada) Ltd.
for postgraduate fellowships.
Supporting Information Available: Experimental details and
spectroscopic data (PDF). This material is available free of charge via
the internet at http://pubs.acs.org.
References
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Synthesis, 2nd ed.; Wiley: New York, 1997.
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a All reactions were performed on 1 mmol of amide. b No column
chromatography required.
Scheme 1. Chemoselective Synthesis of Donepezil
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piperidine moiety, we minimized both the steric and electronic
influence of the functional group on the reaction. We were delighted
to find that, under our reaction conditions, a ketone (entry 1), esters
(entries 2-4), an R,â-unsaturated ester (entry 4), a nitrile (entry
5), an epoxide (entry 6), an alkyne (entry 7), and ethers (entries
5-7) were all tolerated, providing the corresponding amines in
moderate to excellent yields. It should be noted that, in all of these
cases, none of the reduced functionalities could be observed, thereby
demonstrating the high chemoselectivity of the reduction process.
A demonstration of the synthetic potential is shown in Scheme
1. Donepezil (5), an acetylcholine esterase inhibitor used for the
management of Alzheimer’s disease, was marketed in the U.S. as
Aricept (donepezil hydrochloride) in 1996.12 It was originally
synthesized from 4 via a debenzoylation/benzylation sequence.13
This two-step process can now be reduced to a single step of amide
reduction, providing donepezil (5) in 49% yield without the
necessity of a flash chromatography. It is also noteworthy that the
presence of the amide functionality results in crystalline material
for all of the donepezil synthetic intermediates.
(7) Unlike other reagents that were screened (e.g., POCl3, (COCl)2, Et3+OBF4-),
Tf2O reacts rapidly (<5 min) and is not substrate-dependent.
(8) A small excess is necessary due to some HEH decomposition in the
reaction conditions: (a) van Bergen, T. J.; Mulder, T.; Kellogg, R. M. J.
Am. Chem. Soc. 1976, 98, 1960-1962. (b) van Bergen, T. J.; Kellogg, R.
M. J. Am. Chem. Soc. 1976, 98, 1962-1964.
(9) See Supporting Information for more details.
(10) Other solvents such as MTBE, Et2O, THF, or toluene led to low conversion
due to low solubility of the iminium triflate and HEH.
(11) Akamatsu, H.; Kusumoto, S.; Fukase, K. Tetrahedron Lett. 2002, 43,
8867-8869 and references therein.
(12) (a) Roberson, E. D.; Mucke, L. Science 2006, 781-784. (b) Melnikova,
I. Nat. ReV. Drug DiscoVery 2007, 6, 341-342.
(13) Sugimoto, H.; Iimura, Y.; Yamanishi, Y.; Yamatsu, K. J. Med. Chem.
1995, 38, 4821-4829.
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