Oxazinone derivatives

Chiral oxazinone-derived nitrone (16), being of particular interest as a prototype for the synthesis of y-oxygenated a-amino acids, reacts with alkenes (D2) efficiently and with high stereoselectivity, to give cycloadducts (489) (Scheme 2.239) (73). 

Synthesis of (—)-monatin (524), a high-intensity sweetening agent, was achieved by chelation-controlled cycloaddition of chiral oxazinone-derived nitrone (16 ) to allyl alcohol (520) in the presence of MgBr2 OEt2 (Scheme 2.248) (746). 

There are several reports dealing with the use of tetrahydropyrrolo[l,4]oxazinones derived from natural proline or prolinol as chiral auxiliaries for the synthesis of enantiomerically pure compounds. The preparation of the heterocycle is described in Scheme 33 (Section 11.11.7.4). The presence of a rigid bicyclic skeleton allows stereoselective introduction of different substituents. The final ring opening of the system (generally by hydrolysis) provides enantiomerically pure compounds with the possibility of recycling the starting chiral auxiliary. 

FIGURE 10.5 A -Acryloyl oxazinones derived from L-gulose and D-fmctose Ref. [72,73],... 

The intermediary synthesis of oxazinones derivatives is the key for the N-hydroxypropylation of substituted anilines used as components in hair dyes (Ref. 245, 246). One example is given in scheme 193. 

New oxazinone derivatives as chiral reagents for the asymmetric synthesis of a-amino acids 00JHC467. 

Primary amine partners having a terminal unsaturation can be employed fruitfully, therefore allowing further condensations. For instance, in the cases where both the aldehyde and amine pairs were specifically selected to enter in a subsequent intramolecular Diels—Alder reaction, the stereoselective synthesis of the pentacychc oxazinone derivatives 496a and 496b were achieved (Scheme 159) (20090L5706). 

The a-oxoketene 180, generated on heating a mixture of the precursor and phenyl isothiocyanate at 120 °C, is intercepted by the isothiocyanate to give the oxazinone derivative 181 in 29% yield... 

Oxazinones derived from chiral 1,2-amino alcohols and glycine have been demonstrated to function as effective chiral glycine anion equivalents in dia-stereoselective alkylations [20, 21, 57, 58). Williams landmark investigations have established the versatility of this auxiliary, which is conveniently excised by hydrogenolytic cleavage subsequent to the asymmetric step. A particularly noteworthy feature of 54 as an auxiliary is its use in consecutive alkylations to construct a,a-disubstituted amino acids such as 57 (Scheme 10.7) [58]. In the conversion of 54 into 57, both alkylations preferentially occur from the face opposite to the phenyl substituents, thus furnishing the disubstituted amino acid 57 in 93 % yield and > 99 % ee. 

Reacting hydroxylamine with the corresponding trichloro derivative (462) under acidic conditions gave an oxazinone (463) while under basic conditions the 2-isoxazoline (464) was produced (80ZC19). 

In a departure from the prototype molecule, the benzylpiperi-done is first converted to the corresponding aminonitrile (a derivative closely akin to a cyanohydrin) by treatment with aniline hydrochloride and potassium cyanide (126). Acid hydrolysis of the nitrile affords the corresponding amide (127). Treatment with formamide followed by reduction affords the spiro oxazinone... 

A recent variation of these reactions uses 6/f-l, 3-oxazin-6-ones as the electron-deficient heterodiene in place of the triazine.113114 With cyclopropene at — 35 C oxazinone 45 furnishes the 4//-azepine 46 in excellent yield. Likewise, with 3-methylcyclopropene the 4-methyl derivative 46 (R = Me) is formed. Cycloaddition with 1-methylcyclopropene, however, generates a mixture of 7-tert-butyl, 2-methyl 3-methyl- and 5-methyl-4//-azepine-2,7-dicarboxylate in a 2 1 ratio and a 97 % overall yield. 

Oligomers Oppolzer s camphor sultam (see also camphor derivatives) Organometallics Organosilicon Organosulfur Organozirconocenes Orthoquinodimethanes Oxabutadienes Oxanorbornadiene(s) Oxazinolactams Oxazinones Oxazoles... 

This homoenolate methodology has been extended to the use of nitrones 170 as electrophiles [72]. Scheldt and co-workers have shown that enantiomerically enriched y-amino esters 172 can be prepared with excellent levels of stereocontrol from an enal 27 and a nitrone 170 using the NHC derived from triazolium salt 164 (Scheme 12.37). The oxazinone product 171, formally a result of a [3-1-3] cycloaddition, is cleaved to afford the y-amino ester product 172. The reaction shows broad substrate scope, as a range of substituted aryl nitrones containing electron donating and withdrawing substituents are tolerated, while the enal component is tolerant of both alkyl and aryl substituents. 

A novel heterocyclic system has been achieved from methyl 3-aminopyra-zine-2-carboxylate and several aroyl chlorides, leading to 3-aroylamino derivatives the latter are cyclized with dibromotriphenylphosphorane to 2-arylpyrazino[2,3-rf][3,l]oxazin-4-one (94S405). Furthermore, vinylimino-phosphoranes and diphenylketene react (Scheme 87) to give nonisolable vinylketenimines (233) which afford, with a second equivalent of ketene in a [4 + 2]-cycloaddition, 1,3-oxazinones (234) [89JCS(P1)2140]. 

From the readily available benzotriazole derivative 76, Katritzky and Harris (90T987) prepared a diastereomeric mixture of the /3-amino ketone 77 with the lithium enolate of cyclohexanone. In the reduction of 77 with lithium aluminium hydride, a reductive cyclization took place, resulting in the two diastereomeric oxazinones 78 in a ratio of 5 2. This cyclization can be regarded as a variation of the chloroformate cyclization under alkaline conditions. 

The observation that fram-2-hydroxy-l-cyclopentanecarboxamide does not react with aldehydes or ketones was used in the synthesis of stereohomo-geneous cis cyclopentane-fused oxazinones and c -2-aminomethyl-l-cyclo-pentanol derivatives. The cumbersome separation of the cis- and tram-2-hydroxy-l-cyclopentanecarboxamides can be avoided, because only the cis isomer forms the oxazinone ring (81S628 83T1829). 

Two types of dihydro-l,3-oxazinones are relevant to the discussed topic the e -fused hexahydro-2//-l,3-benzoxazin-4-ones and their homologs, and the d -fused hexahydro-2//-3,l-benzoxazin-4-ones and their homologs. For the synthesis of these derivatives, just two methods are known. 

Methylene-l,3-benzoxazin-2-ones 194 were found to be susceptible to addition to the exocyclic double bond. On heating under reflux in ethanol, oxazinones 194 were transformed to the 4-ethoxy derivatives 195. Treatment of 194 with l-chloromethyl-4-fluoro-l,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (F-TEDA-BF4), an electrophilic fluorinating reagent, in the presence of methanol, led to the 4-fluoromethyl-4-methoxy-substituted compounds 196 (Scheme 34) <2003T8163>. 

The asymmetric alcoholytic ring opening of 4-substituted-2-phenyl-4,5-dihydro-l,3-oxazin-6-ones proved to be a efficient method for the preparation of enatiomerically pure /3-amino acid derivatives <2005AGE7466>. Treatment of 2,4-diphenyl-4,5-dihydro-l,3-oxazin-6-one 208 in the presence of the bifunctional chiral thiourea catalyst 211 resulted in formation of an enantiomerically enriched mixture of the unchanged oxazinone (iJ)-208 and allyl (4)-3-benzoyl-amino-3-phenylpropanoate 209. The resolved material (iJ)-208 and the product 209 could easily be separated by a selective hydrolytic procedure that converted oxazinone (iJ)-208 quantitatively into the insoluble iV-benzoyl /3-amino acid 210 (Scheme 37). 

Harwood and co-workers (105) utihzed a phenyloxazine-3-one as a chiral derived template for cycloaddition (Scheme 4.50). An oxazinone template can be formed from phenylglycinol as the template precursor. The diazoamide needed for cycloaddition was generated by addition of diazomalonyl chloride, trimethyl-dioxane-4-one, or succinimidyl diazoacetate, providing the ester, acetyl, or hydrogen R group of the diazoamide 198. After addition of rhodium acetate, A-methylmaleimide was used as the dipolarophile to provide a product that predominantly adds from the less hindered a-face of the template in an endo fashion. The cycloaddition also provided some of the adduct that approaches from the p-face as well. p-Face addition also occurred with complete exo-selectivity. Mono- and disubstituted acetylenic compounds were added as well, providing similar cycloadducts. 

Thieno[3,4- ] and [3,4-f]pyridine derivatives can be generated from a cycloaddition reaction of oxazinones with l,4-dichloro-2-butyne to afford polyhalogenated pyridine products which cyclize to thienopyridines (Scheme 39) <2001T4203>. In a similar reaction, pyrazinones, 122, containing alkynyl substituents cyclize to form thieno[3,4-3] and [3,4-i ]pyridine derivatives <2002TL799, 2004T429>. 

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