Copper catalyzed oxidative coupling of amines with formamides: A new approach for the synthesis of unsymmetrical urea derivatives

Article abstract of DOI:10.1039/c3cc42381f

Direct access to unsymmetrical urea derivatives via copper catalysed C-H/N-H coupling of formamides with amines has been developed at room temperature. This protocol is also applied to the synthesis of chiral urea derivatives.

Full text of DOI:10.1039/c3cc42381f

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Copper catalyzed oxidative coupling of amines with
formamides: a new approach for the synthesis of
unsymmetrical urea derivatives†
G. Sathish Kumar,a R. Arun Kumar,a P. Santhosh Kumar,a N. Veera Reddy,a
K. Vijaya Kumar,a M. Lakshmi Kantam,a S. Prabhakarb and K. Rajender Reddy*a
Cite this: DOI: 10.1039/c3cc42381f
Received 3rd April 2013,
Accepted 4th June 2013
DOI: 10.1039/c3cc42381f
www.rsc.org/chemcomm
Direct access to unsymmetrical urea derivatives via copper catalysed over the past several years. However, most of these methods rely
C–H/N–H coupling of formamides with amines has been developed on the use of phosgene, isocyanate, azide, carbamate and carbonyl-
at room temperature. This protocol is also applied to the synthesis of imidazole derivatives, which are highly toxic, unstable and
chiral urea derivatives.
expensive to handle.6 Although alternative routes particularly
oxidative carbonylation of amines with CO7 and direct carbonyla-
The unsymmetrical urea derivatives are found in a large number tion of amines with carbon dioxide8 have been reported, the use
of molecules having applications in the fields of medicine, of expensive metal catalysts and high pressure conditions are
biology, chemistry and material science.1–3 For example, simple some of the issues to be addressed. Moreover these methods have
urea with morpholine ring A (Fig. 1) is effective for the treatment limitations particularly in the synthesis of unsymmetrical urea
of chronic myelogenous leukemia.2d Similarly diethylcarbama- derivatives. Therefore, the discovery of new synthetic protocols to
zine B, a synthetic derivative of piperazine, is used as an prepare unsymmetrical urea derivatives through non-toxic routes
anthelmintic drug in the treatment of filariasis and compound under mild conditions is highly desirable.
C (cycluron) is used as a herbicide. The other derivatives D and E
In recent years cross coupling chemistry via C–H bond activation
are found to be active as an HIV-1 protease inhibitor2e and an has emerged as one of the potential alternatives to the traditional
NK1 selective antagonist respectively.2b Moreover, these units cross coupling methods.9 The attractive feature of the new approach
also serve as important intermediates4 and bifunctional organo- is that it avoids the use of pre-functionalized substrates, which
catalysts5 in organic synthesis.
makes the method more straightforward, atom-economical and
Due to the broad applications of these compounds several environmentally benign. The synthetic importance of these
methods have been developed for the synthesis of urea derivatives approaches involving both intermolecular10 and intramolecular11
couplings has been documented in several recent works under the
headings of cross-dehydrogenative couplings (CDC) or oxidative
cross couplings. Among them activation of formamides under
oxidative conditions has received special attention (Scheme 1).12 It
has been shown that formamide can act as a source of amide or
Fig. 1 Examples of bio-active unsymmetrical urea derivatives.
a Inorganic and Physical Chemistry Division, Indian Institute of Chemical
Technology (CSIR-IICT), Tarnaka, Hyderabad-500 607, India.
E-mail: rajender@iict.res.in, rajenderkallu@yahoo.com; Fax: +91-040-27160921
b National Centre for Mass Spectrometry, Indian Institute of Chemical Technology,
Tarnaka, Hyderabad-500607, India
† Electronic supplementary information (ESI) available: Detailed experimental
Scheme 1 Synthetic application of formamides under oxidative conditions.
procedures and analytical data. See DOI: 10.1039/c3cc42381f
c
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amine in amidation reactions (Path A), which were achieved under
metal or metal-free conditions.12a–c Similarly, direct synthesis of
a-ketoamides was achieved from methyl ketones and dialkylforma-
mides using tert-butylhydroperoxide (TBHP) as an oxidant and
nBu4NI as a catalyst (Path B).12d In some cases formamide is also
used as a CN source in the presence of ammonia (Path C).12e–h
Our group has been working on oxidative couplings using metal
and non-metal catalysts for the last several years.13 Recently we have
shown the synthetic utility of formamides by coupling them with
2-carbonyl substituted phenols and b-keto esters to provide the
phenol and enol carbamates under oxidative conditions (Path
D).14a Similarly, we have also shown the oxidative coupling of
carboxylic acids with formamides to obtain amides (Path A).14b In
general experimental evidence along with the previous results from
other groups clearly show that formamide can be a good source of
amide or amine radical under oxidative conditions, providing
different coupled products. Based on this hypothesis, we envisaged
that direct coupling of formamides with amines could generate
synthetically highly useful urea products. However, during these
investigations, very recently we have come across two examples,
where formamides have been coupled with N-alkoxy amides and
N-pyridyl amides using copper catalysts resulting in urea derivatives
(Path E).12i,j However, both these methods have limited substrate
scope. Here we wish to report the direct oxidative cross coupling of
formamides with amines resulting in unsymmetrical urea deriva-
tives, which to the best of our knowledge has not been reported
previously (Path F). Moreover, we have demonstrated the general
applicability of this method to different amines (primary, secondary
Scheme 2 Oxidative coupling of amines with formamides.
Since the aromatic urea derivatives also have potential applica-
and substituted aromatic amine) and formamides (both mono- and tions in chemistry and biology,1c we looked at the possibility of
di-substituted) for the synthesis of urea derivatives. extending the above methodology to aromatic amines also. Our
For the initial studies 4-phenyl piperidine was chosen as a model initial attempts with anilines were not successful. However, the
substrate and treated with 2 mL of DMF, using 5 mol% of CuI as a desired product was isolated (20%) with 2-acyl aniline in the
catalyst and 1.5 mmol of TBHP (5–6 M solution of tert- butylhydro- presence of 5 mol% of Cu(OAc)2 and TBHP. During the screening,
peroxide in decane) as the external oxidant. We observed the we observed that Cu(OTf)2, which provided 31% of the urea product,
anticipated urea product in 48% yield which was confirmed further could be a better catalyst. Further substrates were screened with
by NMR and mass analysis. Further optimizations with respect to Cu(OTf)2 and the results are summarized in Scheme 3. In all the
various copper salts, oxidants, solvents, temperature and reaction cases we observed the formation of aromatic urea derivatives in
times were investigated (see ESI†). It was found that 5 mol% of CuBr2 moderate yield within 3 hours (Scheme 3, 5a–d). Our attempts to
in the presence of 1.5 equivalents of TBHP in 2 mL of DMF at room
temperature were the best conditions for the conversion of 1a to 3a.
Under the optimized reaction conditions, various amines are coupled
with different formamides to afford urea derivatives and the results
are summarized in Scheme 2. In general the desired urea derivatives
are obtained in moderate to good yields. Various secondary amine
derivatives were treated with DMF to provide the urea products
in good yields (Scheme 2, 3a–3g). Other formamide sources viz.,
N,N-diethylformamide and N-formylmorpholine also provided the
urea products in good yields (Scheme 2, 3h–3l). Although most of
the earlier works reported the use of the secondary amines, under
the present conditions even the primary amines worked very
well resulting in corresponding urea products (Scheme 2, 3m–3q)
including the cycluron (3o), which is used as a herbicide. To our
delight even the chiral aminoacids L-phenyl alanine methyl ester and
L-valine methyl ester provided the ureido derivatives (3r and 3s), with
the retention of stereochemistry. It should be noted that even
N-methyl formamide, which has been rarely reported,12b worked well
Scheme 3 Oxidative coupling of 2-carbonyl substituted aromatic/hetero aro-
to provide the corresponding urea products (Scheme 2, 3t–3v).
matic amines with DMF.
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increase the yields by running the reactions for a longer time
resulted in the formation of unidentified side products. The
reaction also worked well for the 2-substituted pyrrole and
indole derivatives (Scheme 3, 5e–f). This clearly shows that
substitution of 2-carbonyl functionality adjacent to the amine
group might help in product formation via assisting the metal-
chelation pathway. A similar observation was also made in
our previous work on copper catalysed oxidative coupling of
2-carbonyl phenols with formamides.
Regarding the mechanism, it is generally believed that these
reactions involve a radical pathway and the formation of a
formamide radical is proposed to be one of the key steps.12c,d,15
Moreover, there is no product formation in the presence of
TEMPO. These lines of evidence favor the mechanism involving
the direct coupling of a formamide radical with the coordinated
amine complex, which is similar to the synthesis of urea
derivatives via coupling of N-alkoxy amides with formamides.12i
In summary, we have developed a copper catalyzed oxidative
cross coupling of formamides with amines for the preparation
of unsymmetrical urea derivatives. Noteworthy features of the
present work are direct coupling of formamides with simple
aliphatic amines, utilization of N-methylformamide as a for-
mamide source and also application towards the synthesis of
chiral urea derivatives. Further studies on the application of
oxidative couplings, particularly with chiral aminoacids, are
under investigation.
G. S. K, R. A. K, and N. V. R. acknowledge Council of
Scientific and Industrial Research (CSIR) and P. S. K. acknowl-
edges University Grants Commission (UGC) for fellowship.
K. R. R. thanks CSIR, India, for financial support under network
project CSC-0125.
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c
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Chem. Commun.