Facile Denitrosation of Cyclic N-Nitrosamines with Hydrazoic Acid

Abstract 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. GRAPHICAL ABSTRACT


INTRODUCTION
Gaseous HCl and other reagents such as TiCl 2 -NaBH 4 , NiCl 2 -NaBH 4 , and chlorosulfonyl isocyanate have been used earlier as denitrosating agents. [1] The use of metallating agents such as lithium diisopropylamide (LDA), followed by alkylation and denitrosation, would lead to a-alkylated amines. [2] The denitrosation can also be carried out by treatment with lithium aluminium hydride (LAH) followed by Raney nickel. [3] However, all these processes involve either strong acidic conditions or conditions in which some functional groups would be reduced. A better method involving BF 3 with furan = thiophene = tetrahydrofuran (THF) in the presence of NaHCO 3 was also reported. [4a] Furthermore, the denitrosation of N-nitrosoamines has also been successfully accomplished using an HBr=CH 3 COOH system [4b,c] and others, [4d,e] as well as enzymatically. [4f] The reagents reported herein, namely concentrated H 2 SO 4 þ NaN 3 and CH 2 Cl 2 (DCM) as solvent, are mild and inexpensive and do not involve tedious reaction conditions, workup procedure, or purification of the product.

FACILE DENITROSATION USING HYDRAZOIC ACID
we tested the same experimental condition with several N-nitroso-2,6diarylpiperidin-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 a catalytic amount of the reagent (0.4 mmol þ 2.5 mmol compound) results in only denitrosation and the 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.

2032
S. PONNUSWAMY, A. AKILA, AND D. KIRUTHIGA DEVI reactions was checked with the reported melting point and infrared (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 NaN 3 or concentrated H 2 SO 4 alone. Hence HN 3 is the reagent involved in denitrosation. In the absence of a carbonyl group, HN 3 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 faster in the presence of a carbonyl group; that is, denitrosation is faster in 2-8 and 32-36 when compared to 20-25.

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 on a Bucker FT-IR a-model spectrometer using KBr pellets. The 1 H and 13 C NMR spectra were recorded in a CDCl 3 solution using tetramethylsilane (TMS) as the internal standard on 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.

SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher's website.