The von Braun Reaction Applied to Azetidines

Abstract

The von Braun reaction (the reaction of cyanogen bromide with tertiary amines) was applied to a series of functionalized N‐alkyl‐substituted azetidines. This reaction mainly led to the cleavage of the strained four‐membered ring to produce 3‐bromo N‐alkyl cyanamides in good yields with variable regioselectivity. The resulting cyanamide products were then employed as original building blocks for the synthesis of nitrogen heterocycles.

3‐Bromo N‐Alkyl Cyanamides as Versatile Building Blocks

“…Finally, the scope of the reacting 3‐bromocyanamide was briefly examined. Thus the 3‐bromo cyanamides substituted at C‐1 18 and 19 gave good yields of substituted guanidines 21 and 22 . Notably, no competing reactivity of the cyano group in 19 was observed, but t ‐butyl ester 20 behaved differently, since only low yields of the expected guanidine 23 could be isolated under conditions A.…”

“…We first focused on the synthesis of six‐membered cyclic guanidines through the reaction of a 3‐bromo N ‐cyanamide 4 , easily prepared from commercially available N ‐benzhydryl azetidine, with primary amines (Scheme , Table ). Such reactions were first described by Hageman in the early fifties and by us in a single example, but its scope remained to be established.…”

“…We first focused on the synthesis of six‐membered cyclic guanidines through the reaction of a 3‐bromo N ‐cyanamide 4 , easily prepared from commercially available N ‐benzhydryl azetidine, with primary amines (Scheme , Table ). Such reactions were first described by Hageman in the early fifties and by us in a single example, but its scope remained to be established. Interest in guanidines has recently been growing, especially in the field of organocatalysis, and the combination of these simple reactions, together with the potential structural diversity brought by the two reaction partners, would represent a convenient entry to these heterocycles.…”

“…Azetidines, as reactive yet available and bench‐stable nitrogen heterocycles, have emerged as promising candidates to generate new libraries with high levels of structural diversity, from which new drug candidates have emerged . We recently reported that N ‐alkyl azetidines 1 efficiently react with cyanogen bromide, leading to regioisomeric 3‐bromo N ‐alkyl cyanamides 2–3 through the von Braun reaction . These compounds are produced with predictable and usually high regioselectivity in the ring‐opening step, and they can be decorated with diverse substituents or functional groups starting from the required azetidines, which are very easy to prepare (Scheme ).…”

Ring-opening functionalizations of unstrained cyclic amines enabled by difluorocarbene transfer

“…The increased bond polarity ameliorates the leaving group ability of amino moiety, ultimately allowing the C-N bond cleavage by means of elimination 34 or nucleophilic substitution reactions [35][36][37] . This chemistry has been widely utilized in the ringopening reaction of strained rings [38][39][40][41][42] , however, its use in unstrained cyclic systems is somewhat thwarted by the stability of the involved salts. Of a great potential for further development is the von Braun reaction, which employs cyanogen bromide (CNBr) in ring-opening bromination of azacyclic compounds 43,44 .…”