Oxazines, preparation

A fluorinated oxazine, prepared fromfluoroacetonitrile and 2 methyl-1,3-pen-tanediol, is alkylated at low temperature The resulting products furnish a fluoro aldehydes after botohydride reduction and hydrolysis [JJ4] (equation 99)... 

The ring opening of tetrahydro-l,3-oxazines to aldehydes has recently found wide application through the work of Meyers.2-3 2-Alkylidene-tetrahydro-l,3-oxazines, prepared from the readily available 5,6-dihydro-4//-1,3-oxazines, possess strong nucleophilic properties and can react with alkyl halides and carbonyl compounds. The derivatives so obtained can be reduced to tetrahydro-l,3-oxazines, and through ring opening the latter can furnish acyclic, alicyclic, and a,jS-unsaturated aldehydes and their C-l deuterated derivatives.221-223 228... 

It is used for the preparation of azines and oxazines by condensation with w-diamines and phenols. 

Photochemical decomposition of riboflavin in neutral or acid solution gives lumichrome (3), 7,8-dimethyl all oxazine, which was synthesized and characterized by Karrer and his co-workers in 1934 (11). In alkaline solution, the irradiation product is lumiflavin (4), 7,8,10-trimethyhsoalloxazine its uv—vis absorption spectmm resembles that of riboflavin. It was prepared and characterized in 1933 (5). Another photodecomposition product of riboflavin is 7,8-dimethy1-10-foTmylmethy1isoa11oxazine (12). 

Pyrido[2,3-rf]-[l,3]-oxazin-4-oiies were first prepared by Dornow et but were not converted into pyiidopyrimidines by these... 

One of the most extensively investigated groups of 1,3-oxazine derivatives is the 5-nitro derivatives of tetrahydro-l,3-oxazine. They were first prepared from 1-nitropropane, aqueous formaldehyde, and ammonia by Hirst et and independently by Senkus from other primary nitroparaffins, formaldehyde, and primary amines. Numerous compounds of the general formula (6) were later prepared from primary nitroparaffins. " ... 

It has been found that the simplest method of preparing 5-nitro-tetrahydro-l,3-oxazine derivatives consists in warming 2-alkyl-2-nitropropane-l,3-diol with formaldehyde and ammonia or primary amines ... 

All attempts failed to prepare 5-nitrotetrahydro-l,3-oxazine derivatives irom nitromethane, ammonia and formaldehyde, acetaldehyde, or isovaleraldehyde. ... 

A new method of preparing tetrahydro-1,3-oxazine derivatives (13 and 14) consists in reacting olefins with formaldehyde and ammonium chloride or hydrochlorides of primary amines. ... 

An interesting method for preparing 2,6-dioxo-l,3-oxazine derivatives was described by Wasserman and Koch who stated that the five-membered ring of an a-keto-lactam could be transformed into the 1,3-oxazine (22) by ozone followed by reduction with zinc. 

Gabriel and Lauer first prepared a 2-iminotetrahydro-l,3-oxazine (28a) as early as 1890 by reacting y-bromopropylamine hydrobromide and potassium cyanate ... 

An interesting method of preparing 2-iminotetrahydro-l,3-oxazine derivatives (30) consists in cyclizing A -butyl-A -(y-bromopropyl)-cyanamide. ... 

Dihydro-l,3-4//-oxazines (32) are among the best known 1,3-oxazines. Their preparation was first described by Gabriel and Elfeldt in 1891. The reaction consisted in benzoylation of y-bromopropyl-amine in the presence of sodium hydroxide by an intermediate formation of A"-benzoyl-y-bromopropylamine (31). The cyclization of the... 

A number of 2-aryl and 2-alkyl derivatives of 5,6-dihydro-l,3-4i/-oxazine have been prepared in a similar An analogous re-... 

The only known derivative of this class was prepared from ethyl 8-anilinecrotonate, ethyl acetoacetate, and benzaldehyde. In the first instance, a pyrimidine derivative is formed, this is then subjected to partial hydrolysis to form the 3,4-dihydro-l,3-2H-oxazine derivative (42). 

When an S-alkyl-A A -disubstituted isothiourea reacts with diketene in a boiling solvent, 2-imino-4-keto-3,4-dihydro-l,3-2i/-oxazine derivatives (45) are formed. Analogous compounds can be prepared from dialkylcarbodiimides and diketene. ... 

General methods for the preparation of l,3-4/3f-oxazines were given by GabrieH and Karrer and Miyamichi. They consist in reacting... 

Perhydro derivatives of pyrido[l,2-7)][l,2]oxazines are frequently applied in the total synthesis of various alkaloids to control the stereochemistry, and pyrido[l,2-c][l,3]oxazines and [l,3]oxazino[3,4-u]quinolines were also used in the stereoselective syntheses of different alkaloids. Perhydropyrido[l,2-c][l,3]oxazines and their benzologs are formed form 2-(2-hydroxyethyl) piperidines and from their benzologs to justify the stereochemistry of 2-(2-hydroxyethyl) derivatives. Different optically active pipecolic acids can be prepared via 4-phenylperhydropyrido[2,l-c][l,4]oxazin-l-ones. 

Perhydropyrido[l,2-A][l,2]oxazines are applied as key intermediates in a stereospecific total syntheses of (-)-pumiliotoxin C and 5-e/ /-pumiliotoxin C(96JCS(P1)1113), and the marine alkaloid)—)-lepadins A, B, C (OOOL2955). (2-Pyridyl)propionic acids 13 can be regioselectively prepared via 2,3,4, 4fl,7,8-hexahydropyrido[l,2-A][l,2]oxazin-2-ones 12 (00OL4007). 

Reaction of tetrahydropyridin-4-one 119 and l,r-carbonyldiimidazole furnished l,3,4,4n,5,6-hexahydropyrido[l,2-c][l,3]oxazine-l,6-dione 120 (99JA2651). Similarly, pyrido[l,2-c][l,3]oxazine-l-one 121 and [1,3] oxazino[4,3-n]isoquinoline-4-one 122 were prepared from the respective 2-(2-hydroxypropyl)piperidine and l-(2-hydroxypropyl)-1,2,3,4-tetrahy-droisoquinoline (99JOC3790). Reaction of a 2 1 diastereomeric mixture of l-(l,2-dihydroxyethyl)-6,7-dihydroxy-l,2,3,4-dihydroisoquinolines 123 and 124 with l,l -carbonyldiimidazole gave a 2.7 1 mixture of 1,9,10-trihy-droxy-l,6,7,ll/)-tetrahydro-2//,4//-[l,3]oxazino[4,3-n]isoquinoline-4-ones 125 and 126, which were separated on preparative TLC plate (99BMC2525). 

Hyperaspine (1), a perhydropyrido[l,2-c][l,3]oxazine alkaloid was isolated from the ladybird beetle H. campestris (01TL4621). 9-Epi-6-epipinidinol (90), a piperidine alkaloid, was prepared from a perhydropyrido[l,2-c][l,3]oxazin-l-one derivative (98T13505). Perhydropyrido[l,2-c][l,3]oxa-zin-l-ones were used to prepare 2,6-disubstituted piperidines (96CJC2434). 

Phenyl-9-(2-propoxycarbonylamino)perhydropyrido[2,l-c][l,4]oxazin-1-one was prepared from methyl 4 phenyl-l-oxoperhydropyrido[2, l-c][l,4]oxazine-9-carboxylate (98MIP12). First, the methyl ester was hydrolyzed into 9-carboxylic acid by heating in 6N HCl, then the carboxylic acid was reacted with (Ph0)2P(0)N3 in benzene in the presence of NEt3 at 22 °C for 45 min, then at reflux for 50 min. After addition of -PrOH the reaction mixture was boiled for 20 h to yield a 9-(iso-propoxycarbonylamino) derivative. 

Treatment of an epimeric mixture of 4-substituted 2-(trimethylsilyloxy)-5-phenyl-3-phenylthio-l,4-oxazine 264 with ZnBr2 led to the stereoselective formation of perhydropyrido[2,l-c][l,4]oxazine 266 via the iminium ion 265 by the phenyl bearing stereocenter directed addition of the olefinic double bond from the /S-face of the cyclic moiety (97SL799, 98T10309). Similarly, an epimeric mixture of (45,9aS)-l-trimethylsilyloxy-4-phenyl-3,4,6,7-tetra-hydropyrido[2,l-c][l,4]oxazine was prepared by cyclization of (Z)-5(S)-phenyl-3-phenvlsulfanyl-2-trimethylsilyloxy-4-[4-(trimethylsilyl)but-3-enyll morpholine (OOSC2565). 

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