Esters from oxazines

Amino-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]oxazine-6-carbox-ylic acids were obtained from 8-(4-methoxyphenyl)amino derivatives by treatment with TFA at room temperature in CH2CI2, and 8-amino-3-esters from 8-benzylamino- and 8-nitro-3-ester derivatives by catalytic hydrogenation over Pd/C catalyst in acidified EtOH and DMF in 60% and 87% yields, respectively (07WOP2007/106537). The nitro group of 8-nitro-9,10-difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]oxazine-6-carboxylic amide was reduced with Na2S204 in a suspension in boiling aqueous EtOH for 5-8 h. 

Keten 55-acetals are obtained from thioamides that have at least one hydrogen atom a- to the thiocarbonyl group by 5-methylation and treatment of the imidium ester with propane-1,3-dithiol. Treatment of the imidium esters from NN-disubstituted thioamides with 4-amino-4-methylpentan-2-ol gives 2-substituted 4,6,6-trimethyl-5,6-dihydro-l,3-oxazines, and with sodium azide they give alkylidenetriazenes (1,2,3-triazabutadienes) (77), not dihydrothia(5 )triazoles (78), as previously claimed (see Vol. 3, p. 399). Structure (77) was demonstrated by Z-ray studies. 

A number of 5-hydroxy-2-oxotetrahydro-l,3-oxazine derivatives can also be formed from glycide esters of carbamic acid ... 

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. 

The syntheses of simple 1,3-oxazines (74AG596 86G361) from acylated amino acids (86G361) by treatment with dihalotriphenylphosphorane and of heterocondensed l,3-oxazin-4-ones from several N-acylated heterocyclic /3-enamino esters (81CB3188) have been implemented by aza-Wittig reactions of heterocyclic 2-(triphenylphosphoranylidenamino)esters with acid halides. 

Hydrolytic reactions can also be applied in the synthesis of aldehydes or ketones via the corresponding 1,3-oxazine derivatives. The anion formed from 3-methyl-2-(4-pyridyl)tetrahydro-l,3-oxazine 155 on treatment with BuLi proved to react with various electrophiles (alkyl halides, carboxylic esters, acid chlorides, or aldehydes) exclusively at position 2 of the 1,3-oxazine ring and not at the pyridine nitrogen atom. The readily formed 2,2-disubstituted-l,3-oxazine... 

The acetic anhydride-induced cyclodehydration of the symmetrical diamide 411, derived from the tetrahydro-benzothiophene / -amino ester 410 and diethyl malonate, afforded the thieno[2,3-r7 [h3]oxazine derivative 413 rather than the expected bis-oxazine 412 (Scheme 78). The reaction probably takes place through sequential cyclizations, in which the pyridine ring of 413 is produced by condensation of the exocyclic double bond of the enamine tautomeric form of the 1,3-oxazine moiety and the mixed anhydride formed by the carboxylic group and acetic anhydride <2003PS245>. 

As mentioned in Section 8.06.9.3, a 2-chloro ester can be used instead of an acid chloride <1986FES229>. Equation (52) <1983EPP80115, 1983USP4420480> shows a different order to perform the general steps discussed above. Using a dihalide or equivalent gives the oxazine product 367 from 366 without the need for LAH reduction (Equation 53) <1983EPP80115>. 

The 2//-l,3-oxazine ring was first described by King and Durst202 who revised earlier work of Kohler and Blatt203 and established that the anhydro compounds formed by the action of alkalis on isoxazolium salts are 2H-1,3-oxazines (66) [Eq. (52)]. The same ring system is obtained from an a-cyano-a-bromo ester with triisopropyl phosphite through an... 

The formyloxy group of cis-8,9a-H-8-formyloxyperhydropyrido[2,l-c][l,4]-thiazin-4-one was hydrolyzed to a hydroxy group and the hydroxy group was oxidized to an oxo group with fluorenone in the presence of ferf-BuOK in benzene at ambient temperature (81EUP34015). 6-Oxoperhydropyrido[2,l-c][l,4]oxazine-4-carboxylic acid was obtained by hydrolysis of the ethyl ester in the presence of LiOH in aqueous THF at 0°C (96MIP8). An amide was prepared from 4-carboxylic acid. 

Dioxanes are produced in excellent yields from oxiranes and dilute sulfuric acid. 1,4-Dioxanes are also conveniently obtained by acid-catalyzed condensation of oxiranes with glycols, while the reaction of oxirane with ethanolamine gives morpholine 482. Base-catalyzed reaction of oxiranes with -amino acids and esters gives tetrahy-dro-l,4-oxazin-2-ones, e.g., propene oxide + RNHCH2C02H 483. 1,4-Dithianes have been prepared by the dimerization of thiiranes either in the vapor phase or in the presence of acid catalysts. 

Dihydro- 1,3-oxazines (398) are cyclic intermediates in the synthesis of a-amino-y-oxo acid esters by reaction of acyliminoacetates with enamines derived from six-membered ketones240. Sulfur-containing heterocycloadducts 399 and 400 have been prepared by [4 + 2] cycloaddition of enamines to heterocumulenes like thioacyl isocyanates and acyl isothiocyanates241. 

---