In this article, comprehensive studies
on the nucleophilic chlorination
and bromination of readily available six-membered cyclic nitronates
(1,2-oxazine-N-oxides) are reported. Under optimized
conditions (POCl3 or (COBr)2 with Hünig’s
base), 3-halo-substituted 1,2-oxazines, which are difficult to access
by other routes, were obtained in good to high yields. The latter
were shown to be convenient precursors to other 3-substituted 1,2-oxazine
derivatives using Lewis/Brønsted acid-assisted substitution of
the halide atom for C-, S-, and N-nucleophiles.
The review summarizes recent advances in the synthesis of C2‐halogenated nitrogen heterocycles via nucleophilic halogenation of corresponding N‐oxides as well as application of this methodology in the synthesis of pharmaceuticals. Both scientific and patent literature is reviewed mostly over the period of the last ten years. The review contains a practical guide (typical procedures and infographic based on extensive literature analysis), which can help practitioners in choosing optimal reagents/conditions for nucleophilic halogenation of N‐heterocycles of different types. The bibliography contains 199 references.
Reaction
of six-membered cyclic nitronates with disubstituted ketenes
affords hitherto unknown saturated oxazolo[3,2-b][1,2]oxazines
possessing up to four contiguous stereogenic centers. The process
involves a tandem of [3+2]-cycloaddition across the CO bond
of ketene, followed by a spontaneous [1,3]-rearrangement of transient
vinylidene-substituted bicyclic nitrosoacetals. DFT calculations of
the mechanism suggest that the [1,3]-O,C-shift proceeds through a
recyclization of a biradical intermediate formed by an unusually mild
homolytic cleavage of the N–O bond. The resulting products
can be utilized as precursors of other fused 1,2-oxazines derivatives,
in particular 1,2-oxazino-1,2,4-triazin-3-ones.
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