1.4- Benzoxazines, condensed

The 3,4-dihydro-277,6/7,ll 7/-[l,3]oxazino[3,2-f][l,3]benzoxazine 403 was formed by condensation of fV-(2-hydroxy-benzylidene)-3-aminopropanol 402 with formaldehyde and two subsequent cyclizations (Equation 47) <2002CHE1434>. 

Condensation of [3- or "y-amino alcohols with aldehydes or ketones RR CO gives the product 27. In solution the position of the equilibrium varies with R and R, and with the solvent (73). When the carbonyl reactant is a substituted benzaldehyde, the solid is found (IR, KBr) to comprise molecules of the open-chain structure 27a, whereas aliphatic aldehydes and ketones give crystals of dihydro- 1,3-benzoxazines, 27b. An interesting case is that of the condensation product of o-hydroxybenzylamine with cyclopentanone, for which McDonagh and Smith (73) suggest that ring and chain tautomers coexist in the solid. 

Reduction of cycloalkane-condensed 2-phenyl-5,6-dihydro-4//-l,3-benzoxazines 144 with lithium aluminium hydride (LAH) afforded A -benzyl-substituted 2-(aminomethyl)cycloalkanols 145 in a reductive ring opening via the ring-chain tautomeric tetrahydro-l,3-oxazine intermediates. Catalytic reduction of 1,3-oxazines 144 under mild conditions in the presence of palladium-on-carbon catalyst similarly resulted in formation of the A -benzyl-1,3-amino alcohols 145. When the catalytic reduction was performed at elevated temperature at hydrogen pressure of 7.1 MPa, the N-unsubstituted 2-(aminomethyl)cycloalkanols 146 were formed in good yields (Scheme 22) <1998SC2303>. 

In the condensations of o-aminohenzyl alcohol 376 or anthranilic acid 401 with 4,5-dichloro-l,2,3-dithiazolium chloride (Appel s salt) 402, imino-l,2,3-dithiazoles 403 were formed. Heating of the imino alcohol 403 (X = H2) in THE in the presence of NaH afforded an 11 1 mixture of 3,1-benzoxazine 404 and 3,1-benzothiazine 405 in moderate yield. Thermal cyclization of imino acid 403 (X = 0) resulted nearly quantitatively in formation of 3,1-henzoxazin-4-one 406 (Scheme 76) <1995CC1419, 1995J(P 1)2097, 1997SL704>. 

The gallium(lll) triflate-mediated condensation of anthranilic acid with fluorinated ketones gave the corresponding 2,2-disubstituted l,2-dihydro-4//-3,l-benzoxazin-4-ones in high yields <20070L179>. 

The cyclizations of /3-hydroxycarboxamides with aldehydes, ketones, or their equivalents results in l,3-oxazin-4-one derivatives <1996CPB734, 2006BMC584, 2006BMC1978>. In the acid-catalyzed condensation of salicylamide 422 with (—)-menthone, a 2 1 mixture of C-2-epimeric 27/-l,3-benzoxazin-4(37r)-ones 202 and 423 was formed, the equilibrium of which could be shifted toward the (23 )-enantiomer 202 by base-catalyzed isomerization with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in A -methyl-2-pyrrolidone (NMP) to yield a 14 1 mixture of 202 and 423 (Equation 44) <1996TL3129>. 

The condensation of 2-(5-bromo-4-chloro-2-hydroxybenzoyl)pyridine 506 in a sealed tube with ammonia and acetone proved a convenient route to 2//-l,3-benzoxazine derivative 225 via the imine intermediate 507 <1996CPB734>. The yield was improved considerably and a closed vessel was not required for the reaction when the ammonia was prepared in situ from NH4I and piperidine, and 2,2-dimethoxypropane was used instead of acetone (Scheme 95). The improved method was extended to the preparation of other 2,2-disubstituted-2//-l,3-benzoxazine derivatives <2001T7501>. 

The condensation of 4-oxo-47f-3,l-benzothiazine-2-carbonitriles 572 with 1,2-dimethylhydrazine under micro-wave irradiation resulted in formation of 2-hydrazino-4/7-3,l-benzoxazine-4-thiones 573 and 5-oxo-4,5-dihydro-377-l,3,4-benzotriazepine-2-carbonitriles 574 (Equation 68). The ratio of 573 and 574 was strongly influenced by the substituents R -R methoxy substituents facilitated the formation of 574, while in their absence l,3-benzoxazine-4-thiones 573 were formed as the exclusive products <2005T8288>. 

Condensation of anthranilic acid or its methyl ester with the 2,3-benzoxazine imidoyl chloride or imidate ester (569) gave the 5H, H-quinazo ino[3,2-c]2,3-benzoxazin-9-one (570) [74CI(M)492]. 

The title compounds (584) were synthesized from 1,4-benzoxazine precursors carrying a good leaving group at position 3 (583, LG = Cl or SMe) by condensation with anthranilic acids [79IJC(B)107 88S336]. 

Benzoxazine-2,4-diones (43) (isatoic anhydrides) have proved useful synthons for various new heterocycles. For example, a base-catalyzed condensation with the oxindole (44) affords tetracycles (45) (80JHC1785), whereas the parent compound (43 R = H) and 3-hydroxyisothiazole give the quinazolinone (46) (69AJC2497). 

Other routes to 1,3-oxazines employ condensation reactions between /3-chloroketones and nitriles or between chloroalkyl amides and alkynes <69LA(723)ill) (Scheme 62). Thiazines are available through similar condensations between thioamides, aldehydes and acetylenes (74G849), and AH- 1,3-benzoxazines may be prepared from 2-hydroxybenzyl alcohols and nitriles in the presence of either perchloric or sulfuric acids (Schemes 63 and 64) (68MIP22700). 

Such compounds are unstable unless the double bond is held in conjugation with other systems as, for example, when it is part of an aryl ring. Indeed, dihydro-3,1-benzoxazines are readily accessible from 2-aminobenzyl alcohols by condensation with aldehydes or ketones (Scheme 84) (75AP622). Oxacephems (199) also contain the 3,6-dihydro-2//-l,3-oxazine unit and they are formed for instance, on cyclization of chlorolactams (198) by the action of stannic chloride (B-80MI22701). 

Dihydro-l,4-benzoxazin-3-ones and -benzothiazin-3-ones are synthesized by the reductive cyclodehydration of 2-nitrophenoxyacetic acids or their thioxy equivalents and as these heterocycles have an active methylene group it is a simple matter to prepare 2-substituted derivatives by condensation reactions with aldehydes and other carbonyl compounds (Scheme 123) (79AP302). 

Tetracyclic compound 197 was obtained when 4,4,4-trifluoroacetate and 3-amino-6,6a,7,8,9,10-hexahydropyrido[2,l-c][l,4]benzoxazine 195 was heated in benzene, then the condensation product 196 was cyclized by heating in PPA (07JMC2486). 

As shown in Scheme 8, a common ketone precursor led to the pyrazolo[4,3- ]- and thiazolo[5,4- ]-fused 1,4-benzoxazines (96) and (97) <87JMC580>. For the synthesis of compound (96) the ketone was condensed with HC02Et and subsequently cyclized with hydrazine. For the synthesis of the thiazole (97) a-bromination of the ketone was followed by condensation with thiourea. The linear tricyclic structures (96) and (97) were supported by H and 13C NMR spectroscopic analyses. 

Condensation of anthranilic acid with various ort/zo-esters and reaction of semicarbazides, gave 2-substituted benzoxazin-4-ones and also by the reaction of hydrazones with aryl-/alkyl-ureas and by salicylaldehyde or 2-hydroxyacetophenones with 4-aryl-/alkyl-semicarbazides. Hydrolysis of o-aminoesters and subsequent treatment with phosgene gave 40. Fused oxazine with bridge head nitrogen 41 and triazolo[3,4-Z>]thiazines 42 were also prepared . The 2,3-dihydrobenzoxazine 43, thiomorpholines 44 and phenothiazines 45 were prepared. ... 

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