New 2,3‐dihalopyridines. Potential precursors for 2,3‐dehydropyridine

Abstract

One of the most desirable methods for the generation of the highly labile dehydrobenzerie (benzyne) involves the action of an appropriate dehalogenating agent on air ortho-dihalobenzene (5). This procedure has been corroborated in the heterocyclic series by the successful generation of 3,4-dehydropyridine (3,4-pyridyne) (6) and 2,3-dehydropyridinc (2,3-pyridyne) (7) by the respective treatment of 3-bromo-4-chloropyridine and 3-bromo-2chloropyridine with lithium amalgam at 20" (8). However, the low yield of products resulting from the trapping of these highly reactive dehydropyridines as opposed to the high yield of analogous products formed from dehydrobenzene generated from the action of lithium amalgam on o-bromofluorobenzene is noteworthy. These facts suggest that an appropriate bromofluoropyridine or even a fluorochloropyridine might conceivably serve as a more desirable precursor for either a 3,4or a 2,3-dehydropyridine. We wish to report the preparation of some new 2,3-dihalopyridines which could serve in the latter capacity.Bromination of 2-amino-5-methylpyridine (I) in acetic acid at 90" proceeded rapidly to yield a single product, (68%) characterized as 2-amino-3-bromo-5-methylpyridine (11) (9). The absence of n.m.r. absorption assignable to the proton in position 3 (7 = 3.74) in 11 as compared to the appearance of this signal in the spectrum of I confirmed that bromination occurred in the 3-position.Diazotization of I1 directly in 40% fluoboric acid (Method A) by the Schiemann method (10) yielded the hitherto unknown 3-bromo-2-fluoro-5-methylpyridine (111) and 3-bromo-5-methyl-2(1H)pyridone (IV) in 40% and 31% yields respectively. That the formation of IV may be attributed to the hydrolysis of initially formed 111 was established by independent experiment. Treatment of pure 111 with 40% fluoboric acid under the conditions described for Method A resulted in the formation of IV in 38% yield (11). If diazotization of I1 is carried out directly in hexafluorophosphoric acid (12) by a modified Schiemann method (Method B) the fluorobromopyridine I11 is obtained in slightly better (45%) yield together with only trace amounts of the pyridone IV.3-Bromo-2-chloro-5-methylpyridine (V) was conveniently prepared in 46% yield by diazotization of I1 in hydrochloric acid at 0". We observed that careful temperature control is of utmost importance in this reaction since significant amounts of IV are formed also if the diazotization temperature is allowed to rise above 5" (13). However, the steam volatility of V permits its separation from any pyridone contamination.Our route to the previously unreported 2-chloro-3fluoropyridine (VI) involved initial tin and hydrochloric acid reduction of commercially available 2-chloro-3nitropyridinc to 3-amino-2-chloropyridine in 55% yield (14). Subsequent diazotization of the aminopyridine in hydrochloric acid followed by addition of hexafluorophosphoric acid, (12) yielded the stable solid diazonium hexafluorophosphate (VII) in 86% yield. Decomposition of VII in preheated mineral oil pr...

2,5- and 5,6-Dihalonicotinic acids and their precursors

“…2-Amino-5-bromo-3-methylpyr¡dine (Ie). Bromination of 2-amino-3-methylpyridine at 80-90°in acetic acid was carried out by a procedure identical with that described for the preparation of la from 2-amino-5-methylpyridine (2). 5-Bromo-2-chloro-3-methylpyridine (If).…”

“…5-Bromo-2-chloro-3-methylpyridine (If). Diazotization of Ie in concentrated hydrochloric acid was done in a fashion analogous to the preparation of lb from la (2), except that the crude product was isolated by steam distillation. (We have subsequently found that steam distillation also is the preferred method of isolating lb.)…”