.
Angewandte
Communications
DOI: 10.1002/anie.201207410
Homogeneous Catalysis
Sustainable Synthesis of Diverse Privileged Heterocycles by Palladium-
Catalyzed Aerobic Oxidative Isocyanide Insertion**
Tjøstil Vlaar, Razvan C. Cioc, Pieter Mampuys, Bert U. W. Maes,* Romano V. A. Orru,* and
Eelco Ruijter*
Heterocycles containing a guanidine moiety are of great
importance in medicinal chemistry (Scheme 1).[1] As a result,
several methods for the synthesis of these “privileged
scaffolds” have been reported.[2,3] Classical approaches, such
suffer from poor atom and/or step efficiency, thus making
them unattractive from a sustainability point of view.
We envisioned the aerobic oxidative coupling of diamines
and isocyanides using palladium catalysis could provide
access to a wide range of guanidine-containing heterocycles
in a single step with water as the sole byproduct. The
oxidation sensitivity of, for example o-phenylenediamines—
which form the basis for most permanent hair dyes—makes
this approach particularly challenging. Oxidative palladium
catalysis has drawn considerable attention because of its mild
and environmentally benign character, especially when
molecular oxygen is used as the terminal oxidant.[5] Isocya-
nides have emerged as valuable C1 building blocks in
palladium catalysis that readily undergo similar transforma-
tions as carbon monoxide. Isocyanides are more easily
handled than carbon monoxide and contain a diversity
point. It is therefore not surprising that there has been
a recent surge of interest in palladium-catalyzed processes
that involve isocyanide insertion.[6] However, only two
oxidative processes utilizing molecular oxygen have been
reported.[7] In light of our interest in Pd-catalyzed cascade
reactions[8] involving isocyanide insertion, we report herein
the atom-efficient synthesis of diverse cyclic guanidines from
diamines and isocyanides by using aerobic oxidative palla-
dium catalysis.[9]
Scheme 1. Clinically used guanidine-containing heterocycles.
as the addition of diamines to isothiocyanates followed by
condensation and the coupling of diamines with cyanogen
bromide,[2,4] have some clear limitations, such as the avail-
ability and toxicity of reagents. Moreover, these procedures
We started our investigations with the benchmark reac-
tion between o-phenylenediamine (1a) and tert-butyl isocy-
anide (2a) to give 2-aminobenzimidazole (3a). After opti-
mization of the conditions (see the Supporting Information
for details) we found that the reaction proceeds quantitatively
in the presence of Pd(OAc)2 (1 mol%) in the absence of an
external ligand or base in an atmosphere of molecular oxygen
(1 atm) in the renewable solvent 2-methyltetrahydrofuran
(MeTHF)[10] at 758C.
[*] T. Vlaar, R. C. Cioc, Prof. Dr. R. V. A. Orru, Dr. E. Ruijter
Department of Chemistry & Pharmaceutical Sciences and
Amsterdam Institute for Molecules
To evaluate the reaction scope, we first tested a range of
electronically diverse o-phenylenediamines (Table 1,
entries 1–11). Pleasingly, all examined substrates underwent
clean conversion to the desired 2-aminobenzimidazoles 3a–k
in excellent yields (83–99%), and the only noticeable differ-
ence was observed in the reaction rate. Electron-donating
groups (OMe, Me) and weak or moderately electron-with-
drawing groups (F, Cl, COOMe) gave full conversion under
the standard conditions, whereas strong electron-withdrawing
groups (CN, CF3, NO2) required more catalyst and longer
reaction times. 4-Bromo-o-phenylenediamine curiously also
reacts slower, although the product 3g was obtained in good
yield (83%, Table 1, entry 7). Aza analogue 1l also under-
went clean, albeit slower, conversion to product 3l in 65%
yield (Table 1, entry 12). Finally, an interesting theophylline
Medicines and Systems (AIMMS), VU University Amsterdam
De Boelelaan 1083, 1081 HV Amsterdam (The Netherlands)
E-mail: r.v.a.orru@vu.nl
P. Mampuys, Prof. Dr. B. U. W. Maes
Organic Synthesis, Department of Chemistry, University of Antwerp
Groenenborgerlaan 171, 2020 Antwerp (Belgium)
E-mail: bert.maes@ua.ac.be
[**] This work was financially supported by The Netherlands Organ-
ization for Scientific Research (NWO) by means of a TOP grant to
R.V.A.O, and by the Hercules Foundation. We thank Elwin Janssen
for technical assistance, Sanne Bouwman for HRMS measure-
ments, and Dr. Andreas W. Ehlers for NMR spectroscopic
measurements.
Supporting information for this article is available on the WWW
13058
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 13058 –13061