Tetrahedron Letters
Bis-morpholinophosphorylchloride, a novel reagent for the conversion
of primary amides into nitriles
P. Purnachandra Rao a,b, Shaik Nowshuddin a, Anjali Jha b, B. Leela Maheswara Rao a,
Murali K. Divi a, M.N.A. Rao a,
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a Divis Research Center, Divis Laboratories Limited, B-34, Industrial Estate, Sanathnagar, Hyderabad, Telangana 500018, India
b Department of Chemistry, GIS, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh 530 045, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Bis-morpholinophosphorylchloride (Bmpc), in the presence of a base, is an efficient dehydrating agent for
both aromatic and aliphatic primary amides, and gives corresponding nitriles under mild conditions in
god yields and purity. During the reaction the enantiomeric integrity remains intact.
Ó 2020 Elsevier Ltd. All rights reserved.
Received 2 November 2020
Revised 4 December 2020
Accepted 6 December 2020
Available online 29 December 2020
Keywords:
Bis-morpholinophosphorylchloride
Dehydration
Primary amide
Nitrile
Nitrile is an important pharmacophore which is present in a
large number of drug substances that are in the market and many
are under clinical development [1]. It is a good bioisostere and acts
as surrogate for the hydroxyl and carboxyl groups. Several cardio-
vascular drugs such as milrinone, olprinone; CNS drugs such as
escitalopram, vilazodone; and anti-HIV drugs such as etravirine,
dapivirine are all nitrile derivatives. Dipeptidyl peptidase IV (DPP
IV) inhibitors, such as vildagliptin, saxagliptin, which are used as
antidiabetic agents, are the derivatives of pyrrolidine-2 nitriles [2].
Various methods for the synthesis of nitrile have been reviewed
[3]. One of the convenient methods for the preparation of aromatic
and aliphatic nitriles is by dehydration of the corresponding pri-
mary amides. N-protected asparagine and glutamine were dehy-
drated to their corresponding nitriles using dicyclohexyl
carbodiimide (DCC) in pyridine [4]. Campagna et al used trifluo-
racetic anhydride for the dehydration of primary amides to obtain
nitriles [5]. Olah et al reported dehydration of amide using cyanuric
chloride in N,N-Dimethylformamide, a reaction which is highly
exothermic [6]. Chun-Wei Kuo et al reported ethyl dichlorophos-
phate (EtOPOCl2) or phenyl dichlorophosphate (C6H5OPOCl2), in
the presence of a base such as 1,8-diazabicyclo [5.4.0]undec-7-
ene (DBU) as a convenient system for converting primary amides
into nitriles [7]. They also studied other dichlorophosphates such
as phenyl dichlorophosphate. Both ethyl dichlorophosphate and
phenyl dichlorophosphate are liquid and cause irritation to nose,
eye and skin. Besides, the reactions involving these reagents are
highly exothermic in nature.
Herein, we report bis morpholinophosphorylchloride (Bmpc) as
a more convenient reagent for the preparation of nitriles from pri-
mary amides. Bmpc has been used as phosphorylating agent, for
both N-phosphorylation and O-phosphorylation [8–10]. The Bmpc
is a non-irritating, colorless solid. It is stable under dry conditions.
It reacts with both aromatic and aliphatic primary amides at room
temperature in dichloromethane (DCM), in the presence of a base
to give corresponding nitriles in good yields and purity (Scheme 1).
During the reaction, chiral integrity is also maintained.
As a model reaction, phenyl-2-acetamide (Table 1, entry-7) was
reacted with 2 equivalents each of Bmpc and triethylamine in
toluene at reflux temperature up to 5 h and there was no reaction.
Similar result was obtained in tetrahydrofuran as solvent. When
the reaction was conducted in acetonitrile, at 40–45 °C for 5 h,
nitrile was obtained in about 80% yield. However, when dichloro-
methane was used as the solvent, reaction took place at room tem-
perature and nitrile was obtained in about 90% yield within two
hours. DBU and N,N-Diisopropylethylamine were less effective as
base compared to triethylamine. No reaction was observed when
inorganic bases such as NaOH, Na2CO3, NaHCO3, NH4OAc and
Potassium tert-butoxide were used in place of triethylamine. Using
dichloromethane as solvent and triethylamine as base, conversion
of various amides into nitrile were studied (Table 1).
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Corresponding author.
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