DOI: 10.1002/chem.201304978
Communication
&
Organic Synthesis
Palladium(II)-Catalyzed ortho-CÀH Arylation/Alkylation of
N-Benzoyl a-Amino Ester Derivatives
Luis C. Misal Castro and Naoto Chatani*[a]
reach the biological target.[10] In addition, bi(hetero)aryl com-
Abstract: The palladium-catalyzed arylation/alkylation of
ortho-CÀH bonds in N-benzoyl a-amino ester derivatives is
described. In such a system both the NH-amido and the
CO2R groups in the a-amino ester moieties play a role in
successful CÀH activation/CÀC bond formation using iodo-
aryl coupling partners. A wide variety of functional groups
and electron-rich/deficient iodoarenes are tolerated. The
yields obtained range from 20 to 95%.
pounds containing peptides are widespread and structurally
diverse in natural products.[11] A survey of the literature indi-
cates that studies of these types of molecules that present im-
portant biological activities have been reported (Figure 1).[12,13]
The development of straightforward synthetic methodologies
for the efficient and selective preparation of bioactive mole-
cules is an important goal in drug discovery and in the produc-
tion of pharmaceutical and agrochemical compounds.[1] In the
last decades, transition-metal catalysis has become a powerful
tool for the synthesis of a myriad of organic functionalities.[2]
Among these catalytic reactions, direct regioselective
C(sp2,sp3)ÀH activation/functionalization is a practical strategy
for linking different building blocks in a one-step reaction in
a cleaner fashion.[3] To achieve such selectivity, in most cases,
the coordinating group must be associated with the substrate
in a configuration that permits the metal centre to approach
a specific CÀH bond, and is subsequently removed after the
target reaction.[4] In the last few years, we developed several
chelation-assisted catalytic systems that led to excellent CÀH
bond activation and selective CÀC and/or CÀN bond formation
by using commercially available but costly (Pd),[5] less costly
(Ru),[6] and much less costly (Ni)[7] metal complexes. In our con-
tinuing pursuit of identifying new and more efficient directing-
group moieties based on the regioselective arylation[8] and al-
kylation[6a,7a,9] of benzamides using well established reactions
catalyzed by transition-metal catalysts, we hypothesized that
an a-amino ester group might participate in the ortho-CÀH
activation/CÀC coupling of carboxylic acid derivatives.
Figure 1. Bioactive ortho-substituted N-benzoyl a-amino acid compounds.
The ortho-functionalization of N-benzoyl a-amino esters
through transition-metal catalysis might led to the synthesis of
a great variety of potentially active molecules in which the
amino ester arm plays, not only the role of a coordinating
group, but also is an indispensable part of the reaction inter-
mediate (functioning as the active region for further modifica-
tions) and the final product.
Our preliminary studies were focused on the reaction of the
simple N-(2-methyl)benzoyl-glycine ester 1a and iodobenzene
using commercially available palladium(II) complexes in t-
Amyl-OH as a solvent at 1008C for 24 h (Table 1). All of the pal-
ladium complexes showed catalytic activity (I–V, entries 1–5).
Among them, complexes IV and V resulted in better yields
(70%). Several solvents were also evaluated for use (toluene,
1,2-DCE, and neat, Table 1, entries 6–8) in a search for a higher
conversion using complex V, and only 0.1 mL of toluene
showed a similar activity to that for t-Amyl-OH. When the reac-
tion was carried out under atmospheric conditions the yield
was slightly improved and better reproducibility was obtained
(76%, entry 9). Other attempts to improve the conversion such
as a higher temperature (1108C, entry 10), more catalyst load-
ing (15 mol%, entry 11), and more AgOAc (3 equiv, entry 12)
failed to result in an improvement. In fact, under previous con-
ditions, lower conversions were observed (entry 9 vs. 10–12).
The use of larger amounts of PhI (2–4 equiv, entries 13 and 14)
resulted in only a minor increase in yield (entry 9 vs. entries 13
and 14). Reducing the catalyst loading or the use of AgOAc
Functionalized molecules bearing amino acid moieties are of
interest as potential bioactive substrates, because an amino
acid can facilitate the diffusion of compounds through the wall
of adnormal cells or bacterial cells, thus allowing them to
[a] Dr. L. C. Misal Castro, Prof. N. Chatani
Department of Applied Chemistry
Faculty of Engineering, Osaka University
Suita, Osaka 565-0871 (Japan)
Fax: (+81)6-6879-7396
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304978.
Chem. Eur. J. 2014, 20, 4548 – 4553
4548
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