.
Angewandte
Communications
DOI: 10.1002/anie.201205921
Cross-Coupling Reactions
Organocatalytic Amidation and Esterification of Aldehydes with
Activating Reagents by a Cross-Coupling Strategy**
Bin Tan, Narihiro Toda, and Carlos F. Barbas III*
Amide and ester functionalities are inarguably among the
most abundant motifs in natural products, polymers, agro-
chemicals, and pharmaceuticals.[1] The development of syn-
thetic routes to amides and esters have therefore attracted
considerable interest.[2] Acylation of amines and alcohols with
Scheme 1. Comparison of the traditional strategy to synthesize an
active intermediate from an acid verses organocatalytic cross-coupling
using an aldehyde (AG=activating group).
activated carboxylic acids is a common strategy, and the use of
N-hydroxyimide esters as coupling intermediates has become
the standard approach to amidation.[3] The traditional strat-
egy involves direct coupling of carboxylic acids with
N-hydroxyimides using carbodiimide activating reagents.[4]
The by-product ureas formed may be difficult to remove
and the most common coupling agent, N,N’-dicyclohexylcar-
bodiimide, is a potent allergen and sensitizer. Despite the
remarkable generality of this reaction strategy, it suffers from
both the industrial and green chemistry points of view. The
development of effective and environmentally benign meth-
ods for this transformation under mild reaction conditions are
needed.[5]
Cross-coupling amidation and esterification reactions of
aldehydes are economically attractive alternatives to tradi-
tional synthesis.[6] However, the use of transition-metal
catalysts[7] and the need for more than stoichiometric amounts
of a hypervalent iodine (III) reagent[8] limit the practical
application of this strategy. Quite recently, Wan and co-
workers developed an nBu4NI catalyzed amide formation
reaction of aldehydes with N,N-disubstituted formamides.[9,10]
Although only aromatic aldehydes are reactive and the
reaction is limited to the formation of secondary amides
from pre-formed formamides, the generation of an acyl
radical from an aldehyde inspired us to develop an organo-
catalytic[11] approach to access versatile active intermediates
which can be displaced in situ by amines or alcohols
(Scheme 1).
ester 3a was isolated in 35% yield (see Table 1 in the
Supporting Information for optimization details). When the
reaction temperature was increased to 708C, the obtained
yield was 83%. Among the catalysts screened, several were
very effective. The cross-coupling reaction was most effective
in the presence of nBu4NBr, indicating that the iodide was not
essential for the reaction. To the best of our knowledge, this is
the first example of the use of ammonium bromide as
a catalyst for a coupling reaction.[13] The desired product was
not formed in the absence of a catalyst or oxidant. The
presence of water was detrimental, as the yield was signifi-
cantly higher when TBHP in decane was used as an oxidant
rather than when an aqueous solution of TBHP or aqueous
H2O2 was used. Further optimization involved the study of
catalyst loading and a solvent screen. The optimal reaction
conditions found consisted of ammonium iodide or bromide
(10 mol%) and TBHP (2 equiv), with ethyl acetate as the
solvent. NHPI could be replaced with N-hydroxysuccinimide
(NHSI, 2b) under identical conditions to provide the
corresponding active ester 4a in a comparable yield.
To examine the scope of this transformation, the opti-
mized conditions were applied to the reactions of a variety of
aldehydes (1) with 2a. As shown in Scheme 2, the electronic
properties and positions of the aromatic ring substituents had
Our initial studies focused on the model reaction of
4-chlorobenzaldehyde 1a with N-hydroxyphthalimide 2a
(NHPI).[12] With catalytic amounts of simple tetrabutylam-
monium iodide (nBu4NI) as the precatalyst and a solution of
tert-butyl hydrogen peroxide (TBHP) in decane as co-oxidant
at room temperature, the desired active 4-chlorobenzoate
[*] Dr. B. Tan, Dr. N. Toda, Prof. Dr. C. F. Barbas III
The Skaggs Institute for Chemical Biology and the Departments of
Chemistry and Molecular Biology, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: carlos@scripps.edu
[**] Research support from the Skaggs Institute for Chemical Biology is
gratefully acknowledged. N.T. also thanks Daiichi Sankyo Co., Ltd.
for financial support.
Supporting information for this article is available on the WWW
Scheme 2. Scope of the reaction of aldehydes with NHPI (2a) cata-
lyzed by nBu4NBr.
12538
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 12538 –12541