Facile denitrosation of Cyclic N-nitrosamines with hydrazoic acid

Article abstract of DOI:10.1080/00397911.2015.1063654

A simple and facile method for the denitrosation of cyclic N-nitrosamines using HN₃ (concentrated H₂SO₄+NaN₃) is reported. In this method, limited usage of this reagent does not affect the carbonyl group.

Full text of DOI:10.1080/00397911.2015.1063654

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Facile Denitrosation of Cyclic N-Nitrosamines with
Hydrazoic Acid
S. Ponnuswamya, A. Akilaa & D. Kiruthiga Devia
a P. G. & Research Department of Chemistry, Government Arts College (Autonomous),
Coimbatore, Tamil Nadu, India
Accepted author version posted online: 26 Jun 2015.
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To cite this article: S. Ponnuswamy, A. Akila & D. Kiruthiga Devi (2015): Facile Denitrosation of Cyclic N-Nitrosamines with
Hydrazoic Acid, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI: 10.1080/00397911.2015.1063654
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Facile Denitrosation of cyclic N-Nitrosamines with Hydrazoic acid
S. Ponnuswamy1, A. Akila1, D. Kiruthiga Devi1
1P. G. & Research Department of Chemistry, Government Arts College (Autonomous),
Coimbatore, Tamil Nadu, India
Corresponding author to S. Ponnuswamy, E-mail: kspons2001@gmail.com
Abstract
A simple and facile method for the denitrosation of cyclic N-nitrosamines using HN3
(Conc.H2SO4 + NaN3) is reported. In this method limited usage of this reagent does not
affect the carbonyl group.
KEYWORDS: Denitrosation, Hydrazoic acid, Schimdt rearrangement, Piperidin-4-one,
1,4-diazepan-5-one
INTRODUCTION
Gaseous HCl and other reagents such as TiCl2-NaBH4, NiCl2-NaBH4 and
chlorosulphonyl isocyanate were used earlier, as denitrosating agents.[1] The use of
metallating agents such as LDA followed by alkylation and denitrosation would lead to
α-alkylated amines.[2] The denitrosation can also be carried out by treatment with LAH
followed by Raney Ni.[3] However, all these processes involve either strong acidic
conditions or conditions in which some functional groups would be reduced.
1

Comparatively a better method involving BF3 with furan/thiophene/THF in presence of
NaHCO3 was also reported.[4a] Furthermore, the denitrosation of N-nitrosoamines have
also been successfully accomplished using HBr/CH3COOH system[4b,c] and others[4d,e] as
well as enzymatically.[4f]
The reagents reported herein, namely Conc.H2SO4 + NaN3 and CH2Cl2 (DCM) as solvent
are mild, cheaper and do not involve tedious reaction conditions, workup procedure and
purification of the product.
RESULTS AND DISCUSSION
As part of our ongoing research on the synthesis of substituted N-nitroso-1,4-diazepan-5-
ones, we attempted the synthesis of N-nitroso-3,3-dimethyl-2, 7-diphenyl-1,4-diazepan-5-
one (2) by employing the nitrosation of 3, 3-dimethyl-2, 7-diphenyl-1,4-diazepan-5-one
(1, Scheme-1). However, we encountered a difficulty in this usual route.[5] Hence an
attempt has been made to synthesize N-nitroso-3,3-dimethyl-2,7-diphenyl-1,4-diazepan-
5-one (2) from N-nitroso-3,3-dimethyl-2,6-diphenylpiperidin-4-one (7) using the Schmidt
rearrangement (Scheme-2). Interestingly, it resulted in denitrosation and rearrangement.
Instead of the expected N-nitroso-3,3-dimethyl-2,7-diphenyl-1,4-diazepan-5-one (2), we
isolated the 3,3-dimethyl-2,7-diphenyl-1,4-diazepan-5-one (1) as an exclusive product.
Furthermore, we tested the same experimental condition with several N-nitroso-2,6-
diarylpiperidin-4-ones using excess reagent and in all the cases, denitrosation followed by
the Schmidt rearangement to 1,4-diazepan-5-one was observed (Representative examples
are given in Scheme-2). However, a controlled reaction involving the catalytic amount
of the reagent (0.4m.mol + 2.5 m.mol compound) results in only denitrosation and the
2

corresponding piperidin-4-ones 14-19 were isolated as an exclusive product in all the
cases studied (Scheme-2). Hence, in this method, limited use of the reagent has not
affected the carbonyl group.
In order to check the denitrosation reaction in the absence of a carbonyl group, we
employed several N-nitroso-2,6-diarylpiperidines 20-25[6] (Scheme-3). In all these cases
the denitrosated product was isolated as an exclusive product. Representative examples
are given in Scheme- 3. Furthermore, the denitrosation has also been tested with N-
nitroso-2,7-diphenyl-1,4-diazepan-5-ones 2, 32-36[5] and the denitrosated product has
been isolated as an exclusive product (Scheme-3). In both the cases only a catalytic
amount of the reagent was used. The identity of the product in all these reactions has
checked with the reported melting point, IR and NMR spectra (Tables S1-S3, Figures S1-
S23, available online in the Supplemental Material).
This is a new reagent and the method is also a synthetically useful one. Denitrosation
does not occur with either NaN3 (or) Con. H2SO4 alone. Hence HN3 is the reagent
involved in denitrosation. In the absence of a carbonyl group, HN3 behaves as a
denitrosating agent. However, in the presence of a carbonyl group, by controlling the
usage of the reagent, we can carry out either chemoselective denitrosation alone or both
denitrosation and Schmidt rearrangement. Furthermore, the rate of the reaction is found
to be faster in presence of a carbonyl group ie. denitrosation is fast in 3-8 and 2, 32-36
when compared to 20-25.
3

EXPERIMENTAL
Thin-layer chromatography (TLC) was carried out to monitor the course of the reaction.
All the reported melting points were recorded in open capillaries and are uncorrected. IR
spectra were recorded in BRUCKER FT-IR α-model spectrometer using KBr pellets.
The 1H and 13C NMR spectra were recorded in a CDCl3 solution using TMS as the
internal standard in Bruker AMX 400 and 100 MHz NMR spectrometers, respectively.
Unless otherwise stated, all the reagents and solvents used were of high grade and
purchased from Aldrich and Merck. All the solvents were distilled prior to use.
All the parent N-nitroso-r-2,c-6-diphenylpiperidin-4-ones 3-8, N-nitroso-r-2,c-6-
diphenylpiperidines 20-25 and N-nitroso-2,7-diphenyl-1,4-diazepan-5-ones 2, 32-36 were
prepared by following the literature methods.[5-9]
PROCEDURE FOR DENITROSATION
In a typical reaction dry, powdered N-nitroso-r-2,c-6-diphenylpiperidin-4-one (5 mmol)
was added, in portions, to cold Con. H2SO4 (5 ml) and CH2Cl2 (DCM) (10 ml) in a round
bottomed flask equipped with a magnetic stirrer. Then, NaN3 (0.4 mmol) was added in
small portions with vigorous stirring. After the addition was over, the reaction mixture
was stirred for 2 hours. Then the solution was poured into crushed ice and neutralised
with ammonia solution. Similar procedure was followed for nitroso piperidines and
nitroso diazepines. For the conversion of 3-8 to 1, 9-13, for 5 mmol of 3-8, 6 mmol of
HN3 was added. The yield of the product varies between 50 and 90%. Analytical data
4

for denitrosated compounds are presented in supplementary data (Table-S1). The
compounds 26-31 and 37-41 have been synthesized similarly.
ACKNOWLEDGMENT
SP thanks UGC, New Delhi, for financial assistance in the form of a Major Research
Project. No. [F. 39-724/2010 (SR)].
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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Scheme 1. Nitrosation of 3,3-dimethyl-2,7-diphenyl-1,4-diazepan-5-one
7

Scheme 2. Denitrosation of N-nitroso-3,3-dimethyl-2,6-diphenyl-piperidin-4-one
8

Scheme 3. Denitrosation of N-nitroso-3,3-dimethyl-2,6-diphenyl-piperidines & N-
nitroso-2,7-diphenyl-1,4-diazepan-5-ones
9