Free-Radical Azidation with γ-¹⁵N-Labeled Phenylsulfonyl Azide

Abstract

The g-nitrogen of phenylsulfonyl azide can be readily labeled with 15 N by treating benzenesulfonyl hydrazide with Na 15 NO 2 . The resulting g-15 N-labeled sulfonyl azide reacts with carbon-centered free radicals to produce alkyl azides exclusively containing a C-15 N bond. This chemistry provides valuable insight into the free-radical azidation mechanism as well as providing a mild method for the production of 15 N-amines.Free-radical azidation has been used successfully to form carbon-nitrogen bonds under relatively mild reaction conditions. 1-7 The reaction has been shown to proceed smoothly using both phenylsulfonyl azide (1) and ethanesulfonyl azide (2) with great success. Free-radical azidation has also been explored in systems where diastereocontrol was at issue. 8,9 The early reports by Renaud et al. suggested that radical addition to the sulfonyl azide could occur at either the a-nitrogen or the g-nitrogen of the sulfonyl azide (Scheme 1) and that nucleophilic radicals produced the best yields. 2 Scheme 1 Mechanistic possibilities for radical addition to sulfonyl azide 2We devised an experiment aimed at determining which nitrogen of the sulfonyl azide functions as the radical trap. We selectively introduced a 15 N atom in the g-position of phenylsulfonyl azide as illustrated in Scheme 2. 10 Commercially available benzenesulfonyl hydrazide was dissolved in 1.2 M HCl and placed in an ice bath. One equivalent of Na 15 NO 2 was then added slowly as a solid over 15 minutes. The resulting solution was allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was worked up in the normal manner by extraction providing a 96% yield of g-15 N phenylsulfonyl azide (Scheme 2). (1) Free-radical azidation was performed using a variety of substrates in order to determine the generality of the reaction mechanism. A free-radical azidation reaction was performed by slow infusion of Barton ester 3 into a solution of 1 under photolysis conditions. 9 The azide product 4 was isolated by preparative TLC and 4 (60% yield by 1 H NMR of crude mixture) was characterized by 1 H NMR and 13 C NMR. The NMR spectra of compound 4 showed exclusive C-15 N bond formation as evidenced by the observed 1 H-15 N coupling observed in the 1 H NMR spectrum (Scheme 3). Scheme 2 Preparation of g-15 N-labeled phenyl sulfonyl azide Scheme 3 Free-radical azidation with 1The result illustrated in Scheme 3 suggests that the freeradical addition occurs exclusively at the g-nitrogen atom of the phenylsulfonyl azide. Substrate 3 is relatively bulky and we could not rule out that we were simply observing addition to the g-nitrogen atom due to steric considerations. In order to address the steric issue we decided to try substrates with varying steric requirements (i.e. 2° and 3° radical centers).It is well known that electrophilic radicals do not undergo radical addition to sulfonyl azides and that 1° free radicals react with sulfonyl azides in poor yield. 2,3 We decided that we would generate electrophilic radicals that ...

Carboazidation of Chiral Allylsilanes: Experimental and Theoretical Investigations

“…Increasing the size of the aryl (or alkyl) sulfonyl group led to no improvement of the diastereocontrol (entry 13). The absence of a steric effect of the R' sulfonyl group may be explained in the light of recent work by Masterson et al [28] who demonstrated that the linear azide reacts with the carbon radical center, Scheme 7. Carboazidation of OH-protected chiral allylsilanes.…”

“…The moderate yields were generally ascribed to the tedious purification of the products, from excess sulfonyl azide. The diastereomer ratio was estimated from 1 H and 28 Si NMR studies after removal of tin residues through a short pad of silica, and the relative configuration of the major isomer was obtained by treating the isolated pure diastereomers with tetrabutyl ammonium fluoride (TBAF). Under these conditions, the syn and anti-b-azidosilanes led to the corresponding Z-and E-olefins, respectively, in high yield through an anti-stereospecific b-elimination.…”

“…Concerning the azide addition, we considered only an attack at the terminal nitrogen center of the azide. [28] PhSO 2 N 3 may then approach radicals I syn or anti relative to the SiMe 2 Ph group. The syn approach led to much higher energetic transition states (TS) with major rearrangement of the radicals in a conformation in which the silicon group is orthogonal to the radical orbital.…”

From Azides to Nitrogen‐Centered Radicals: Applications of Azide Radical Chemistry to Organic Synthesis

“…[32,33] This peculiar reactivity of sulfonyl azides was originally disclosed by some reactions with alkyl radicals at elevated temperatures [34] and it was then substantiated by Roberts in a study of their radical-chain reactions with allylstannanes in refluxing benzene. [35] Under the latter reaction conditions, arene-as well as alkane-sulfonyl azides afforded N-allylsulfonamides accompanied by significant amounts of allylsulfones and stannyl azides, clearly due to tin radical addition at the terminal nitrogen followed by release of an arene-or alkane-sulfonyl radical (Scheme 17).…”

Radical azidation reactions and their application in the synthesis of alkaloids

“…In this reaction, the alkyl radical adds to the N-terminal position of the azide moiety to give a 1,3-triazenyl radical [11], which fragments to liberate the corresponding alkyl azide and arenesulfonyl radical. Polar effects are believed to play an important role in this addition.…”