An easy access to tertiary amides from aldehydes
and N,N-dialkylchlorothiophosphoramidates†
Uma Pathak,
*
a
Shubhankar Bhattacharyya,
a
Lokesh kumar Pandey,‡
a
Sweta Mathur‡
a
and Rajeev Jain
b
A mechanistically unprecedented approach for the formation of
tertiary amides from N,N-dialkylchlorothiophosphoramidates and
aldehydes has been developed. The reaction occurred via the activa-
tion of aldehydes with N,N-dialkylchlorothiophosphoramidates fol-
lowed by amidation with dialkylamine pendent of the same
phosphoramidate.
The construction of amide functionalities is of great impor-
tance due to their wide applications in organic and pharma-
ceutical chemistry.
1
Among the various strategies available for
amide formation;
2
oxidative addition of amines to aldehydes
3
has extensively being pursued in recent years as it has the
potential to enable highly efficient and/or unprecedented
transformations. Accordingly, various procedures have been
reported to accomplish this reaction. Most of the reported
procedures utilize various transition metals such as Fe, Cu, Rh,
Ru, Pd, Ni, Sm, La and Au etc. to assist the reaction.
4
Simul-
taneously, successful attempts have also been made to develop
the metal free oxidative amidation of aldehydes.
5
Recently, we
reported a straightforward aqueous H
2
O
2
mediated amidation
of aldehydes,
6
which was applicable to amines with reduced
steric demands (cyclic and N-methyl amines). Similar ndings
have also been reported by Liu and Jensen, and they success-
fully carried out the reaction in a micro reactor system.
7
In
spite of the availability of these excellent methods oxidative
addition of acyclic secondary amines (bulkier than ethyl) to
aromatic aldehydes to produce tertiary amides is still a
synthetic challenge.
5b,4h,4j
In this work, an innovative approach
for the construction of tertiary amides through O-
phosphorylation of aromatic aldehydes by dialkyl-
chlorothiophosphoramidate followed by amidation with the
dialkylamine moiety of the same phosphoramidate has been
described.
To uncover new opportunities for this reaction; consid-
ering the mechanistic aspect, we wished to explore the
potential of phosphorus compounds as a promoter. Phos-
phorus compounds are abundantly used as reagents and
ligands in organic transformations. Though, in metal cata-
lyzed oxidative amidation, organophosphorus compounds
have occasionally been used as ligands,
8,4c
but there is no
precedence in the literature where a phosphorus compound
by itself (without any metal catalyst) has been utilized to
assist this reaction. This is more surprising in view of the
oxophilic nature of phosphorus compounds. The rationale of
our proposed hypothesis is as follows: Lewis acidity and
oxophilicity of the phosphorus reagent
9
would enable it to
form an activated complex 3 with the aldehyde 1 (Scheme 1).
The activated complex 3, having an electron decient
carbonyl carbon and a good leaving group (phosphorus
moiety), may then undergo a facile oxidative addition of
amine 4 to yield the amide 5.
To test our hypothesis, we investigated the reaction of
p-chlorobenzaldehyde with dibutylamine in the presence of
O,O-diethylchlorophosphate. 50% aqueous H
2
O
2
was used as an
oxidant. The reaction was studied under different reaction
conditions, but, no desired conversion was observed, mainly
due to the incompatibility of diethylchlorophosphate with the
oxidant.
Scheme 1 Rationale for phosphorus reagent assisted oxidative
amidation.
a
Synthetic Chemistry Division, Defence R & D Establishment, Jhansi Road,
Gwalior-474002, India. E-mail: sc_drde@rediffmail.com; Fax: +91-0751-2341148;
Tel: +91-0751-2390189
b
School of Studies in Chemistry, Jiwaji University, Gwalior-474002, India. E-mail:
rajeevjain54@yahoo.co.in; Fax: +91-0751-2346209; Tel: +91-0751-2346209
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra45781h
‡ These authors contributed equally.
Cite this: RSC Adv. , 2014, 4, 3900
Received 12th October 2013
Accepted 24th October 2013
DOI: 10.1039/c3ra45781h
www.rsc.org/advances
3900 | RSC Adv., 2014, 4, 3900–3903 This journal is © The Royal Society of Chemistry 2014
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