Catalytic amide formation with α′-hydroxyenones as acylating reagents

Article abstract of DOI:10.1039/b909360e

α′-Hydroxyenones undergo clean, catalytic amidations with amines promoted by the combination of an N-heterocyclic carbene and 1,2,4-triazole. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b909360e

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Catalytic amide formation with a0-hydroxyenones as acylating
reagentswz
Pei-Chen Chiang, Yoonjoo Kim and Jeffrey W. Bode*
Received (in College Park, MD, USA) 14th May 2009, Accepted 17th June 2009
First published as an Advance Article on the web 6th July 2009
DOI: 10.1039/b909360e
a0-Hydroxyenones undergo clean, catalytic amidations with
amines promoted by the combination of an N-heterocyclic
carbene and 1,2,4-triazole.
The use of a0-hydroxyenones as substrates for
NHC-catalyzed reactions stems from our recent studies on
their use as surrogates for a,b-unsaturated aldehydes.13 These
starting materials are attractive due to their facile, one-step
preparation from widely available starting materials,14 their
stability towards long-term storage, and their tendency to be
crystalline products. In contrast, the corresponding
a,b-unsaturated aldehydes often require multi-step syntheses
employing expensive and wasteful reagents.15 We also recognized
The ubiquity of amide-containing organic compounds coupled
with the generally expensive and wasteful methods for their
formation have engendered intense, recent efforts in the
identification and development of catalytic methods for
amide-bond formation.1 The most attractive approach, the
direct catalytic coupling of carboxylic acids and amines,2 can
be achieved with certain boronic acids as catalysts under
conditions involving high temperatures2a,b or the use of molecular
sieves.2c Elegant work with transition metal catalysts has made
possible the formation of amides from amines and alcohols,
with the formation of H2 as the only stoichiometric
byproduct.3 Chemoselective, reagentless amide formations
are an exciting area for the synthesis of peptides and bio-
molecules,4 but the need for specialized starting materials
limits the utility of these processes for the synthesis of simple
amides.5
In seeking to develop simple, waste-free methods for the
synthesis of carboxylic acid derivatives, we have advanced the
concept of redox esterifications and amidations.6 These reac-
tions, promoted by N-heterocyclic carbenes,7 proceed via
transient activated carboxylates catalytically generated by
internal redox reactions of a-functionalized aldehydes including
epoxyaldehydes,8 a-haloaldehydes,9 formyl cyclopropanes,10
and a,b-unsaturated aldehydes.11 Such esterifications proceed
smoothly in high yield without stoichiometric amounts of
reagents or byproducts. The amidations, however, are often
complicated by competing imine formation and proceed only
in the presence of a suitable additive such as imidazole or
HOAt.12 Thus, while feasible, this redox amidation requires
further refinement to improve the yields, catalyst loadings, and
scope to impact the need for simple amidation reactions. In
this communication, we report such an advance in the form of
catalytic amidations of a0-hydroxyenones in the presence of a
triazolium precatalyst and 1,2,4-triazole as a co-catalyst.
Roy and Diana Vagelos Laboratories, Department of Chemistry,
University of Pennsylvania, Philadelphia, USA.
E-mail: bode@sas.upenn.edu; Tel: +1 215 573 1953
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
procedures, reaction optimization and characterization data for all
new compounds. See DOI: 10.1039/b909360e
Fig. 1 NHC-catalyzed amidations of primary amines.
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This journal is The Royal Society of Chemistry 2009
4566 | Chem. Commun., 2009, 4566–4568

that the use of a0-hydroxyenones could overcome the imine
formation that complicates the use of aldehydes in catalytic
amidation reactions.
The interaction of an N-heterocyclic carbene with the
a0-hydroxyenone leads to the conjugated Breslow intermediate
via a retro-benzoin reaction that expels acetone. This inter-
mediate must be protonated in order to form the key acyl
azolium intermediate that serves as the catalytically generated
activated carboxylate.11b We were pleased to see that ester-
ifications from alcohols and the a0-hydroxyenones proceeded
smoothly, but initial attempts to extend this to amidations
gave rise to only small amounts of the desired products.
Reasoning that the use of a suitable co-catalyst was essential
for the success of the amidation, we screened a number of
additives and found that imidazole and related heterocycles
were effective at promoting the amidation (see ESIw).16 From a
number of active co-catalysts, we selected 1,2,4-triazole17 for
further development. Additional optimization identified the
conditions showed in Fig. 1 as preferred. A screen of alter-
native azolium precatalysts confirmed the unique reactivity of
N-mesityl substituted triazolium salt 1.18
Fig. 1 shows the scope of the amidation reaction with
primary amines and the phenyl substituted a0-hydroxyenone
2 (Fig. 1). The products are the corresponding hydrocinnamyl
amides. Excellent results were obtained for most substrates,
with only the sterically demanding tert-butyl amine giving
lower yields. Chemoselective amidation of the primary amine
occurs with tryptamine. Anilines, despite being less reactive,
turned out to be excellent substrates if the reactions were
performed at lower concentration for 12 h.
Fig. 3 Variation of the a0-hydroxyenone in catalytic amidations.
aldehydes, under conditions that readily tolerate diverse
functionalities including heterocycles. We were pleased to find
that these substrates participated in the amidation reactions
without modification of the reaction conditions. An initial
attempt with an aliphatic substituted hydroxyenone gave the
expected amide 30 in inferior yield. We anticipate that further
substrate dependent optimization will be possible.
The amidation reaction also works well for secondary
amines (Fig. 2). For the preparation of Weinreb amide 19,
we found it necessary to first form the free base the hydroxyl-
amine prior to the amidation. For reasons that we do currently
understand, simply using the hydrochloride salt and an
additional equivalent of base did not allow for amidation
under these conditions.
We also examined the use of various a0-hydroxyenones in
the amidation reaction (Fig. 3). The advantage of these
substrates is that they are easily prepared from aromatic
An intriguing feature of NHC-catalyzed redox reactions is
that while esterification processes generally work extremely
well without the need for any additive, amidations reactions in
the absence of a suitable co-catalyst generally fail. We were
therefore interested in the chemoselectivity of the amidation
reaction when amino alcohols were used as substrates.19 Fig. 4
shows our preliminary investigations on NHC-catalyzed
amidations of various amino alcohols in the presence of
1,2,4-triazole as a co-catalyst. In the absence of the co-catalyst,
NHC-catalyzed acylations of the amino alcohols usually gave
mixtures of the amide and ester products, including bis-acylated
Fig. 2 Catalytic amidations of secondary amines.
Fig. 4 Chemoselective amidations of aminoalcohols.a
Chem. Commun., 2009, 4566–4568 | 4567
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This journal is The Royal Society of Chemistry 2009

We are grateful to the NIH (GM079339) and the NSF
(CAREER Award to J.W.B.) for support of this research.
P.C.C. received a fellowship from the government of Taiwan.
Unrestricted support from Bristol Myers Squibb and Roche is
gratefully acknowledged.
Notes and references
1 J. W. Bode, Curr. Opin. Drug Discovery Dev., 2006, 9, 765–775.
2 (a) T. Maki, K. Ishihara and H. Yamamoto, Tetrahedron, 2007, 63,
8645–8657; (b) K. Ishihara, S. Ohara and H. Yamamoto, J. Org.
Chem., 1996, 61, 4196–4197; (c) R. M. Al-Zoubi, O. Marion and
D. G. Hall, Angew. Chem., Int. Ed., 2008, 47, 2876–2879.
3 (a) C. Gunanathan, Y. Ben-David and D. Milstein, Science, 2007,
317, 790–792; (b) T. Zweifel, J.-V. Naubron and H. Grutzmacher,
Angew. Chem., Int. Ed., 2009, 48, 559–563; (c) L. U. Nordstrøm,
H. Vogt and R. Madsen, J. Am. Chem. Soc., 2008, 130,
17672–17673.
4 C. P. R. Hackenberger and D. Schwarzer, Angew. Chem., Int. Ed.,
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5 J. W. Bode, R. M. Fox and K. D. Baucom, Angew. Chem., Int. Ed.,
2006, 45, 1248–1252.
6 For a highlight, see: K. Zeitler, Angew. Chem., Int. Ed., 2005,
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7 D. Enders, O. Niemeier and A. Henseler, Chem. Rev., 2007, 107,
5606–5655.
8 K. Y.-K. Chow and J. W. Bode, J. Am. Chem. Soc., 2004, 126,
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Soc., 2004, 126, 9518–9519; (b) N. T. Reynolds and T. Rovis,
J. Am. Chem. Soc., 2005, 127, 16406–16407.
10 S. S. Sohn and J. W. Bode, Angew. Chem., Int. Ed., 2006, 45,
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11 (a) S. S. Sohn, E. L. Rosen and J. W. Bode, J. Am. Chem. Soc.,
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13 P.-C. Chiang, M. Rommel and J. W. Bode, J. Am. Chem. Soc.,
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14 (a) C. Palomo, M. Oiarbide, J. M. Garcıa, A. Gonzalez and
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15 For an improved protocol and a survey of other methods for the
synthesis of a,b-unsaturated aldehydes, see: P. Valenta,
N. A. Drucker, J. W. Bode and P. J. Walsh, Org. Lett., 2009, 11,
2117–2119.
Scheme 1 Postulated tandem catalytic cycles for amide formation
from a0-hydroxyenones.
compounds. With 10 mol% 1,2,4-triazole, however, the
desired amides were chemoselectively formed in moderate to
good yield.
We believe that this NHC-catalyzed redox amidation
proceeds according to the tandem catalytic cycle shown
in Scheme 1. Attack of the NHC-catalyst onto the
a0-hydroxyenone gives I, which expels acetone to generate
Breslow intermediate II. The conjugate acid of the catalytic
base, formed during the deprotonation of the triazolium
precatalyst, protonates the Breslow intermediate, which may be
considered as a formal homoenolate equivalent. Tautomerization
of III affords activated carboxylate IV. This intermediate is a
competent acylating agent for alcohols, but reacts only slowly
with amines and is turned over by the triazole co-catalyst to
regenerate the precatalyst and form acyl triazole V. This is the
active acylating agent with amines.20
16 In some cases, modest yields (5–30%) of amide products could be
obtained without a co-catalyst. For many substrates, however, no
amide products were obtained in the absence of 1,2,4-triazole or
similar promoter.
17 During the course of this work, Birman reported that the combi-
nation of 1,2,4-triazole and base catalyzes the acylations of amines
and esters: X. Yang and V. B. Birman, Org. Lett., 2009, 11,
1499–1502.
In summary, we have documented a new method for
catalytic amide formation. No stoichiometric reagents are
required, the reaction proceeds under mild conditions, and
the only byproduct is one equivalent of acetone. The use of
readily prepared a0-hydroxyenones overcomes the two major
limitations of a,b-unsaturated aldehydes as substrates in
similar amidation reactions: (1) their relative difficulty of
preparation and (2) their tendency to form imines that
complicate the reaction protocols or contaminate the desired
amide product. The two distinct catalytic cycles involved in
this reaction offer the opportunity to develop new chemo- and
stereoselective processes for amine acylation.
18 This triazolium precatalyst is commercially available from Aldrich
(Cat. No. 688487).
19 M. Movassaghi and M. A. Schmidt, Org. Lett., 2005, 7,
2453–2456.
20 We have detected this intermediate during the reaction and studied it
1
by H NMR and 13C NMR. This data supports the regiochemical
assignment shown in Scheme 1.
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This journal is The Royal Society of Chemistry 2009
4568 | Chem. Commun., 2009, 4566–4568