Tetrahydro-1,3-oxazin-4-ones, preparation

Conventional methods have been used to prepare ribonucleoside analogues from 2-(l//)pyrazinone, 3,5-disubstituted pyridines (including a-anomers), 6-methyl-l,3-oxazine-2,4-dione and 6-methyluracil, 2-alkyl-4,5-dicarboxamido-imidazoles, 7-membered ring analogues (4) and (5) of uracil and tetrahydro-uracil [one diastereomer of (4) being the most potent inhibitor of cytidine deaminase yet discovered], 2-alkylthioadenine, 8-aza-3-deaza-guanine/ ... 

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. " ... 

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). 

The tetrahydro-[l,3]oxazino[3,4-b][l,2]oxazin-8-one 389 was prepared by cycloaddition reaction of the C-nitroso derivative 408 (Scheme 65) <1999TL4391>. 

A convenient, one-pot procedure devised for the preparation of 2-phenyl-5,6-dihydro-4//-l,3-oxazine 373 was based on the A -bromosuccinimide oxidation of tetrahydro-l,3-oxazine 372, formed in situ from 3-aminopropanol 371 and benzaldehyde (Scheme 69) <2006S2996>. 

Azomethine ylides derived from (55,6/ )-2,3,5,6-tetrahydro-5,6-diphenyl-1,4-oxazin-2-one (53) and various aldehydes have been prepared by Williams and co-workers (87,88) (Scheme 12.19). In a recent communication they reported the application of the azomethine ylide 54 in the asymmetric total synthesis of spirotryprostatin B 56 (88). The azomethine ylide 54 is preferentially formed with ( )-geometry due to the buLkiness of the aldehyde substituent. The in situ formed azomethine ylide 54 reacted with ethyl oxindolylidene acetate to give the 1,3-dipolar cycloaddition adduct 55 in 82% yield as the sole isomer. This reaction, which sets four contiguous stereogenic centers, constmcts the entire prenylated tryprophyl moiety of spirotryprostatin B (56), in a single step. 

Dioxanes (337) are also conveniently obtained by acid-catalyzed condensation of oxiranes with glycols, while use of ethanolamine gives morpholine (338). Base-catalyzed reaction of oxiranes with a-amino acids and esters gives tetrahydro-l,4-oxazin-2-ones, e.g. propene oxide + RNHCH2C02H — (339). 1,4-Dithianes have been prepared by the dimerization of thiiranes either in the vapor phase or in the presence of acid catalysts. 

Numerous tetrahydro- 1,3-oxazines have been prepared by Meyers et al.2-3 by reducing 5,6-dihydro-4//-l, 3-oxazines with sodium borohy-dride. Catalytic hydrogenation of 5,6-dihydrooxazine-6-one failed to produce the tetrahydro derivative, as ring opening occurred.58... 

Conjugat addition of dipentylcuprate, prepared from pentylmagne-sium bromide and Cul, to 3,4,4a,5-tetrahydro-lH,6H-pyrido[l,2-c][l,3] oxazin-6-one 65 afforded nearly complete facial selectivity (96%) providing 8-pentylperhydropyrido[l,2-c][l,3]oxazin-6-one 66 (05OL5227). 

Benzyl-6-oxoperhydropyrido[2,l-c][l,4]oxazine-4-carboxylic acid was prepared from the 7-unsubstituted derivative by alkylation with PhCH2Br in the presence of lithium bis(trimethylsilyl)amide in THF at -78°C (96MIP8). The reaction of 1,3, 4,6,7,116-hexahydro[l,4]thiazino[3,4-a]-isoquinolin-4-one (45) with a Vielsmeier-Haack reagent afforded 3-formyl-4-chloro-l,6,7,llh-tetrahydro[l,4]thiazino[3,4-a]isoquinoIine (111) (81CP 1101857). 

Heating ethyl 6-methylpicolinate and ethylene oxide in methanol in a pressure bottle afforded 6-methylperhydropyrido[2,l-c][l,4]oxazin-l-one (66JMC311 68USP3388128). Similarly, l,3,4,6-tetrahydro[l,4]oxazino[4,3- >]isoquinolin-l-ones were prepared in the reactions of ethyl 1,2,3,4-tetrahy-droisoquinoline-3-carboxylates and ethylene oxide (85MI2). 

In a similar way, 2-oxazolidinones and tetrahydro-2//-l, 3-oxazin-2-ones have been prepared by the reaction of primary allyl amines and homoallyl amines10, respectively, with carbon dioxide and iodine in methanol via an intramolecular cyclization. Prolonged reaction for a week in the presence of cesium carbonate increases the yield to 70-90%. This reaction has a large applicability and the ease of the method makes it useful in organic synthesis. 

Tetrahydro-l,3-oxazin-2-ones can be used to prepare enantiomerically pure amino alcohols. The starting materials can be prepared through the nonselective iodocyclization of homoallylic... 

Tetrahydro-l,3-oxazin-2-ones may be obtained through the palladium-catalyzed carbonylation of 3-aminopropanols <86JOC2977>, but despite these innovations more traditional methods for the syntheses of perhydro-1,3-oxazines are still used for example, the cyclization of 3-aminopropanols with ethyl chloroformate, phosgene, or similar reagents <76BAP447>. The preparation of the cor-... 

The tetrahydro-l,3-oxazin-2-one (372) is prepared through the cyclization of the threo form of hydroxycarbamate (371) in contact with mesyl chloride, conversely the erythro isomer is O-sulfinated without undergoing cyclization. The removal of an A-Boc group under basic conditions is unusual, and it is proposed that the selective cyclization of the threo isomer occurs because, in its lowest energy conformation, the proximity of the ethoxycarbonyl group and the mesyloxy unit potentiates the ionization of the latter. Once formed, the mesyloxy anion assists deprotonation of the Boc group and hence the cyclization to the oxazine (Scheme 100) <87H(26)64i, 88H(27)667>. 

A -Benzoyloxypyridinium chloride (72), prepared from pyridine oxide and benzoyl chloride, reacts with silver phenylacetylide selectively at position 2 to afford 2-(phenylethynyl)pyridine (73). The bromine atom of the tetrahydro-l,4-oxazin-2-one 74 is replaced by an alkynyl group on treatment with stannanes 75 (R = hexyl or Ph) the products 76 are transformed into ( S)-amino acids 77 by catalytic hydrogenation. ... 

Aminocyclopropane-l-carboxylic acids. These cyclopropyl amino acids can be obtained in high chemical and optical yield by reaction of this ylide with the a, -dehydro lactones (3) prepared from (5S,6R)-4-r-butoxycarbonyl-5,6-diphenyl-2,3,5,6-tetrahydro-4/f-l,4-oxazin-2-one (2, 14,58-59). The reaction of 3 with the ylide derived from... 

Typical examples of oxazoline monomers to be polymerized via CROP mode are shown in Scheme 3. Not only five-mem-bered monomers of ROZO and 5-oxazolones (4,5-dihydro-l,3-oxazol-5-one, ROZLO) but also six-membered analogs (5,6-dihydro-4H-l,3-oxazines, ROZI) and seven-membered ones (4,5,6,7-tetrahydro-4H-l,3-oxazepine, ROXP) have been polymerized. 2-Iminotetrahydrofurans (ITHFs) are known as an exo-cydic imino ether derivative of ROZO. CROP of ITHF was reported in 1963, which was preceded by the studies on the CROP of OZOs. Preparations of these monomers have been well known and documented. ... 

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