N-heterocyclic carbene-catalyzed redox amidations of α-functionalized aldehydes with amines

Article abstract of DOI:10.1021/ja0768136

A catalytic method for the direct synthesis of carboxylic acid amides from amines and α-functionalized aldehydes is possible through the synergistic role of a N-heterocyclic carbene catalyst and imidazole, affording amides via activated carboxylates catalytically generated via an internal redox reaction of the aldehyde substrates. The use of imidazole or other N-heterocycles as an additive is essential to overcoming imine formation and serves as a uniquely reactive substrate for the generation of an acyl imidazolium intermediate that is converted to the final amide product. Copyright

Full text of DOI:10.1021/ja0768136

Published on Web 10/23/2007
N-Heterocyclic Carbene-Catalyzed Redox Amidations of r-Functionalized
Aldehydes with Amines
Jeffrey W. Bode*,† and Stephanie S. Sohn
Department of Chemistry and Biochemistry, UniVersity of California at Santa Barbara,
Santa Barbara, California 93106-9510
Received September 9, 2007; E-mail: bode@sas.upenn.edu
Table 1. NHC-Catalyzed Amidations of Formyl Cyclopropanesa
Despite the quintessential importance of carboxylic acid amides
in organic chemistry, there are few catalytic methods for their pre-
paration from simple starting materials.1 Established approaches
for amide synthesis continue to rely on the stoichiometric generation
of an activated carboxylate via the reaction of a carboxylic acid
and a coupling reagent, a process that not only generates copious
byproducts but also requires extensive protection of other functional
groups.2
As part of a program aimed at developing new reactions for
amide bond formation, we have pioneered isohypsic approaches
to carboxylic acid derivatives that obviate the need for stoichio-
metric reagents or reaction byproducts. For example, we have
disclosed that R-ketoacids and various hydroxylamines undergo
reagentless, chemoselective couplings to afford amides.3 In parallel,
we have developed a method for the catalytic generation of activated
carboxylates via N-heterocyclic carbene-catalyzed internal redox
reactions of R-functionalized aldehydes.4 These developments have
allowed us and others to identify conditions for the synthesis of
esters and thioesters from R,â-epoxy aldehydes,5 R-haloaldehydes,6
R,â-unsaturated aldehydes,7 ynals,8 formyl cyclopropanes,9 and
formyl â-lactams10 without the need for stoichiometric reagents or
the production of byproducts.
Despite these impressive and rapid advances in catalytic,
stereoselective approaches to carboxylic acid derivatives, reliable
protocols for the synthesis of the corresponding amides have re-
mained elusive.11 This difficulty stems from the unsurprising finding
that the combination of aldehyde substrates and amine nucleophiles
results in rapid formation of carbonyl imines, leading to extensive
inhibition of the desired catalytic amidation reactions. We now
report an effective and general solution via the unexpected role of
imidazole as promoter that makes possible catalytic amidations of
a wide range of R-functionalized aldehydes (eq 1).12
a Conditions A: 1 equiv of aldehyde, 1.1 equiv of imidazole, 5 mol %
of 1, 20 mol % of DBU at 40 °C for 20 min prior to addition of 1.2 equiv
of amine at rt, 15 h. Conditions B: 1.5 equiv of aldehyde, 1 equiv of amine,
1.1 equiv of imidazole, 40 °C, 15 h. b Isolated yield after chromatography.
c With 3 equiv of aldehyde.
For reaction development, we considered the redox amidation
of a formyl cyclopropane 2 with benzyl amine, catalyzed by a
combination of triazolium precatalyst 1 and DBU. In the absence
of a suitable promoter, less than 5% of the desired amide was
isolated, and NMR analyses revealed that the bulk of the aldehyde
starting material was converted to the corresponding imine (4).
Cognizant of our studies suggesting a key role for a suitable proton
source in accelerating the NHC-catalyzed generation of the activated
carboxylate, we screened a number of suitable additives. While a
number of nucleophilic co-catalysts (0.2 equiv) commonly em-
ployed in acylation reactions, including HOBt, DMAP, pentafluo-
rophenol, and ortho-nitrophenol, offered little or no improvement
in the amidation reaction, we were pleased to find that protic
N-heterocycles greatly benefited the amidation reaction (see the
Supporting Information).
Useful yields of the desired amide were obtained using 20 mol
% of imidazole as an additive, and employing 1.1 equiv of imidazole
completely suppressed imine formation and led to amide formation
in excellent yield. A wide range of amines, including primary,
secondary, aniline, and hydroxylamines, were viable reaction
partners for catalytic amidations (Table 1, entries 1-7). Likewise,
a range of substituted formyl cyclopropanes served as efficient acyl
donors in catalytic amidation reactions with benzyl amine (entries
8-11). R-Chloroaldehydes, which are exceptionally reactive toward
† Present address: Department of Chemistry, University of Pennsylvania.
9
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J. AM. CHEM. SOC. 2007, 129, 13798-13799
10.1021/ja0768136 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Redox Amidations of Enals
forming a known, metastable hemiaminal 3 that acts as an in situ
protecting group;15 (2) a role in promoting the decomposition of
the imine to the aldehyde and amine substrates;16 and (3) a tandem
catalysis approach via chemoselective reaction of the acyl triazolium
activated carboxylate with imidazole, leading to an acyl imidazolium
species that is eventually converted to the desired amide product.
Given the previous failures of nitrogen-based nucleophiles to
participate in these redox-type reactions,17 we initially favored for
imidazole a role as a transient aldehyde-protecting group. However,
exposure of formyl cyclopropane 1 to imidazole, without precatalyst
1, in either the presence or absence of DBU led to no observable
reactions by NMR analysis (Scheme 1). Upon addition of benzyl
amine, in the absence of 1, imine formation occurred readily,
discounting a role for imidazole in suppressing or reversing imine
formation. In contrast, when 2, imidazole, precatalyst 1, and DBU
were combined in the absence of benzyl amine, the aldehyde was
quickly consumed and new product formed. Analysis by 1H NMR
(see Supporting Information) identified this species as the acyl
imidazole 5. Treatment of this intermediate with amines or alcohols
leads cleanly to amide or esters products, respectively.
In summary, we have documented a straightforward solution to
the seemingly intractable problem of competing imine formation
in the NHC-catalyzed redox amidation of R-functionalized alde-
hydes. These studies provide a valuable addition to ongoing efforts
on developing catalytic, stereoselective, and atom-economical
approaches to carboxylic acid derivatives.
a Conditions: 1 equiv of aldehyde, 1.1 equiv of imidazole, 5 mol % of
1 and 20 mol % of DIPEA amine at 40 °C for 20 min prior to addition of
1.2 equiv of amine at rt, 15 h. b Amine added after 15 h, and rxn stirred at
rt for 1 h. c With 1 equiv of DIPEA employed. d Isolated yield after
chromatography.
Acknowledgment. Support for this work was provided by the
National Science Foundation (CHE-0449587). Unrestricted support
from Amgen, AstraZeneca, Eli Lilly, Boehringer Ingelheim, and
Bristol Myers Squibb is gratefully acknowledged. J.W.B. is a fellow
of the Packard Foundation, the Beckman Foundation, the Sloan
Foundation, and a Cottrell Scholar. We thank Justin Struble for
catalyst preparation. We thank Prof. Tomislav Rovis for a personal
communication of related results.
Scheme 1. Consideration of Reaction Pathways in Imidazole-
Promoted Redox Amidation of R-Functionalized Aldehydes
Supporting Information Available: Experimental procedures and
characterization data for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
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