Pyridines from oxazoles

Ring opening of the cycloadducts (172) from oxazoles (171) and dienophiles (XCH=CHY) gives dihydropyridines and frequently pyridines (172 — 173 — 174) entities such as XR3, HR3 or XOH can also be lost in the aromatization of intermediate (173). 

Isoxazole (1,2-oxazole) contains a pyridine-like N-atom, but differs from oxazole by the presence of an N-0 bond. The bond energy of such a cr-bond amounts only to 200 kJ mol", much lower than that of N-C or O-C bonds. The univalent radical is known as isoxazolyl. 

Oxazoles readily participate in cycloaddition reactions as dienophiles and as dienes in Diels-Alder reactions, and suitably substituted oxazoles participate in sigmatropic rearrangements (e.g., aza-Claisen rearrangements). In particular, the Diels-Alder reaction of oxazoles is one of the most widely explored and synthetically useful reactions, and as such, it has been used extensively both in natural product syntheses and to convert oxazoles to other heterocyclic ring systems. For example, a partial list of heterocyclic systems readily accessible from oxazoles via Diels-Alder reactions or other cycloadditions include pyridines hydroxy-pyridines isoindoles pyridazines tetrahydronaphthyridines benzo[h]-l,6-naphthyridines benzopyrano[3,4-b]pyridines 2-substituted, 2,4-disubstituted,... 

Tris( 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato )europium Pyridine ring from oxazoles... 

Isoxazole (1,2-oxazole) contains a pyridine-like N-atom, but differs from oxazole by I I... 

The current paradigm for B syntheses came from the first report in 1957 of a synthesis of pyridines by cycloaddition reactions of oxazoles (36) (Fig. 5). This was adapted for production of pyridoxine shordy thereafter. Intensive research by Ajinomoto, BASF, Daiichi, Merck, Roche, Takeda, and other companies has resulted in numerous pubHcations and patents describing variations. These routes are convergent, shorter, and of reasonably high throughput. 

An example of this methodology was its use in the synthesis of vitamin Be, pyridoxine 12. Cycloaddition of oxazole 9, prepared from ethyl A-acetylalanate and P2O5, with maleic anhydride initially gave 10. Upon exposure to acidic ethanol, the oxabicyclooctane system fragments to afford pyridine 11. Reduction of the ester substituents with LiAlIU generated the desired product 12. 

Treatment of a 3-aminotriazolopyridine with acid gave the imidazopyridine 242 (81T1787), also obtained from the 3-nitro derivative by catalytic reduction (83AHC79). Quaternary salts derived from compound 2, when treated with tri-ethylamine and subsequently heated give 2-pyridylcyanamides 243 or 2-(oxazol-l-yl)pyridines 244 depending on the alkyl group (86H(24)2563) the ylides are presumably intermediates (see also Section IV.I). 

As in the synthesis of other bipyridines, several routes to 4,4 -bipyridine have been devised where one of the pyridine rings is built up from simpler components. For example, a dimer of acrolein reacts with ammonia and methanol in the presence of boron phosphate catalyst at 350°C to give a mixture of products including 4,4 -bipyridine (3.4% yield), and in a reaction akin to ones referred to with other bipyridines, 4-vinylpyridine reacts with substituted oxazoles in the presence of acid to give substituted 4,4 -bipyridines. ° ° Condensation of isonicotinaldehyde with acetaldehyde and ammonia at high temperatures in the presence of a catalyst also affords some 4,4 -bipyridine, and related processes give similar results,whereas pyran derivatives can be converted to 4,4 -bipyridine (56% conversion), for example, by reaction with ammonia and air at 350°C with a nickel-alumina catalyst. Likewise, 2,6-diphenyl-4-(4-pyridyl)pyrylium salts afford 2,6-... 

Diels-Alder reactions of oxazoles afford useful syntheses of pyridines (Scheme 53) (74AHC( 17)99). A study of the effect of substituents on the Diels-Alder reactivity of oxazoles has indicated that rates decrease with the following substituents alkoxy > alkyl > acyl >> phenyl. The failure of 2- and 5-phenyl-substituted oxazoles to react with heterodienophiles is probably due to steric crowding. In certain cases, bicyclic adducts of type (359) have been isolated and even studied by an X-ray method (87BCJ432) they can also decompose to yield furans (Scheme 54). With benzyne, generated at 0°C from 1-aminobenzotriazole and lead tetraacetate under dilute conditions, oxazoles form cycloadducts (e.g. 360) in essentially quantitative yield (90JOC929). They can be handled at room temperature and are decomposed at elevated temperatures to isobenzofuran. 

To a soln of Fmoc-TOAC-OH (0.437 g, 1.0 mmol) in CH2C12 at —10 °C were added cyanuric fluoride (0.085 mL, lmmol) and pyridine (0.081 mL, lmmol) under nitrogen. After stirring for lh at 0 °C the mixture was directly applied to a silica gel column and eluted with EtOAc/light petroleum ether (1 5). The product eluted first was identified as the oxazol-5(4T/)-one l 51 (0.110 g, 0.026 mmol yield 26%). The fluoride, which was eluted from the column immediately after the oxazolone, was obtained as a thick, orange oil yield 0.308 g (70%) IR (film) 1839,1715 cmA... 

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