Nucleophilic carbene and HOAt relay catalysis in an amide bond coupling: An orthogonal peptide bond forming reaction

Article abstract of DOI:10.1021/ja0764052

A catalyzed internal redox process provides a route from α-reducible aldehydes and amines to α-reduced amides. The chemistry is catalyzed by nucleophilic carbenes and common peptide cocatalysts such as HOBt and HOAt in a relay fashion. The transformation proceeds in excellent yields using a variety of primary and secondary alkyl and aryl amines. The aldehyde component may be varied from haloaldehydes to epoxy and aziridino aldehydes as well as enals. The latter three substrates provide for a waste-free amide bond forming reaction. Copyright

Full text of DOI:10.1021/ja0764052

Published on Web 10/11/2007
Nucleophilic Carbene and HOAt Relay Catalysis in an Amide Bond Coupling:
An Orthogonal Peptide Bond Forming Reaction
Harit U. Vora and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
Received August 25, 2007; E-mail: rovis@lamar.colostate.edu
Table 1. Amine Scope
The ubiquity of amides throughout organic, biological, and
materials chemistry mandates the development of more efficient
methods for their synthesis.1 Conventional amide bond formation
utilizes acids and amines as coupling partners and relies on
stoichiometric activating agents for the acid functionality.2,3 A recent
survey of process scale reactions cites a “...pressing need for the
development of catalytic environmentally friendly acylation pro-
cesses”.4,5 We6 and others7 have recently illustrated that nucleophilic
carbenes8 catalyze an internal redox reaction whereby R-reducible
aldehydes provide R-reduced ester derivatives under catalytic
conditions.9 Surprisingly, among the many nucleophiles reported
to participate in this process, there are only two amines: we6a have
shown that aniline participates, and Scheidt7b has shown that a
vinylogous imide could be used.10 Clearly, the salient features of
this redox manifold, a waste free catalyzed acylation, provide a
strong impetus to identify a general solution to the problem of NHC
catalyzed amidation. Herein, we report one such solution relying
on relay catalysis by a nucleophilic carbene and a common peptide
cocatalyst such as 1-hydroxy-7-azabenzotriazole11 (HOAt).
Outside of aniline, our efforts at using amines as nucleophiles
in the R-redox reaction were met with uniform failure. Since we
had established that phenols are competent partners, we hypoth-
esized that the use of a cocatalyst such as HOAt could provide a
relay shuttle.12,13 HOAt should participate in the redox chemistry
to generate activated ester which would undergo the in situ
amidation, thereby regenerating the catalyst. The viability of a
concerted catalytic system using N-heterocyclic carbenes and HOAt
to generate amides was investigated utilizing 2,2-dichloro-3-
phenylpropanal as the redox substrate and benzyl amine as the
nucleophile. The desired chemical transformation took place to
afford the benzyl amide 2a in 93% yield (eq 1). In the absence of
HOAt, only minor amidation product is observed.14 A cocatalyst
screen revealed that 1-hydroxybenzotriazole (HOBt), 4-(dimethy-
lamino)pyridine (DMAP), imidazole, and pentafluorophenol (PF-
POH) are effective at promoting the reaction, affording the desired
amide products.
a Catalyst A (20 mol %), HOAt (20 mol %), Et3N (1.2 equiv), THF (0.5
M), t-BuOH (1.0 equiv), 25 °C, 6 h, unless otherwise noted. b HOBt (20
mol %) and Et3N (2.1 equiv) were used. c Diastereomeric ratio 2:1.
1). Electron-rich and -poor aryl amines 2f-h (entries 6-8, Table
1) also undergo the transformation readily to give the desired
anilides in 82-87% yield. Amino esters are also competent partners
(entry 9, Table 1).
A variety of R-haloaldehydes are suitable partners in the R-redox
amidation. The reaction is tolerant of branching at the R and â
position: R,R-dichloroisovaleraldehyde provides 3 in 72% yield,
and R-bromocyclohexanecarboxaldehyde provides 4 in 80% yield
(Figure 1).
One of the strengths of the redox amidation reaction manifold
is that the appropriate choice of R-reducible aldehyde provides an
opportunity for a waste free amidation. Treatment of R,â-epoxy
and aziridino aldehydes under the redox amidation conditions
affords â-hydroxy and â-amino amides (entries 1-3, Table 2) in
good yields and excellent diastereoselectivities. R,â-Unsaturated
aldehydes provide the alkanamides in good yield (entries 4 and 5,
Experiments that probe the scope of useful amine partners are
summarized in Table 1. A variety of primary and secondary amines
partake in the reaction (entries 1-5, Table 1) to afford the desired
amide in good to excellent yields. Of particular interest is the
generation of the Weinreb amide 2f in 72% yield (entry 5, Table
Figure 1. R-Haloaldehyde substrate scope.
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J. AM. CHEM. SOC. 2007, 129, 13796-13797
10.1021/ja0764052 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Atom-Economical Amidation
Acknowledgment. We thank NIGMS (GM72586), Eli Lilly,
Johnson and Johnson, and Boehringer Ingelheim for support. T.R.
is a fellow of the Sloan Foundation and thanks the Monfort Family
Foundation for a Monfort Professorship.
Note Added after ASAP Publication. Reference 11c was added
on October 12, 2007.
Supporting Information Available: Experimental procedures and
full characterization of all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
a Catalyst A (10 mol %), imidazole (10 mol %), DIPEA (30 mol %),
t-BuOH (0.1 M), 40 °C, 24 h. b Catalyst A (10 mol %), HOAt (10 mol %),
DIPEA (10 mol %), THF (1.0 M), 45 °C.
References
Scheme 1. Proposed Catalytic Cycle
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Table 2). Importantly, in each case, the only stoichiometric waste
generated is derived from solvent; even the base is used in catalytic
amounts.
The catalytic cycle is postulated to initiate upon formation of
carbene I, which undergoes nucleophilic addition to the aldehyde
(Scheme 1). Generation of the acyl azolium intermediate II sets
the stage for an acyl transfer event with cocatalyst III to furnish
the activated carboxylate IV. Nucleophilic attack by the amine
affords the amide and regenerates the cocatalyst.
Experimental support for the proposed mechanism is provided
by the use of chiral carbenes in this process. The use of catalyst B
leads to an asymmetric R-chloroamide synthesis in modest ee (eq
2), validating the role of the carbene in controlling the protonation
event. In contrast, the use of B provides no selectivity in the kinetic
resolution of R-methylbenzyl amine (eq 3). In addition, the use of
stoichiometric HOAt in the absence of amine provides the HOAt
ester IV in 64% yield. Addition of BnNH2 generates the amide
quantitatively.
In summary, we have developed a waste free amide bond forming
reaction using R-reducible aldehydes and amines catalyzed by
carbenes in conjunction with common peptide additives as cocata-
lysts.
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