1.2- Oxazine ring opening reductive

Another interesting reaction of benzoxazines 114 (115) is the reductive opening of the oxazine ring with simultaneous dehydrogenation of the pyrazoline moiety [170]. This process is carried out in a KOH suspension of a mixture of dimethyl sulfoxide and dimethylformamide. For instance, this treatment involving 2,5-diary l-l,10b-dihydro-177-pyrazolo[l,5-c]benzo[e]-l,3-oxazines 116 leads to the formation of pyrazoles 117 (Scheme 2.32). Similar disproportionation reactions have also been described for some bezopiranes, for example, pyrazole derivative 118 [91, 170]. 

Platinum oxide/hydrogen chloride Reductive tetrahydro-l,2-oxazine ring opening... 

Reductive N-O bond cleavage of perhydropyrido[l,2-6][l,2]oxazine 10 with Zn dust furnished 2-(3-hydroxypentyl)piperidine 11 (96JCS(P1)1113). Similarly, 2/S,4u S,5Q ,7/0,8yS-H-5-benzyloxy-7-(tert-butyldiphenylsilyloxy)-2-[2-(methoxymethoxy)ethyl]-8-methylperhydropyrido[l,2-6][l,2]oxazine gave the respective ring-opened piperidine (OOOL2955, 01JOC3338). 

Treatment of perhydropyrido[2,l-c][l,4]oxazine-3,6-dione 232 with B2H6 yielded (—)-(2i )-[(2S)-hydroxymethyl)piperldin-1 -yl]-2-phenylethanol (233) (00T233). Reduction of ( )-(3i ,4i ,9aS)-4-methyl-3-phenylperhydropyr-ido[2,l-c][l,4]oxazin-3-ol (234) with NaBH4 yielded ring-opened product 235 (97JHC1813). 

Enantiomerically pure tetrahydro-l//-pyrrolo[2, l -acrylamides derived from proline (see Section 11.11.7.4), are versatile intermediates for the synthesis of natural products or drugs. Compound 86a was submitted to debromination with Bu3SnH followed by ring opening in KOH and further reduction with BHj to give diol 89 that was then easily transformed into (A)-4-(2,2,4-trimethyl-l,3-dioxolan-4-yl)-lT>utanol 90, a key intermediate for )-frontalin, <2002TA155>,... 

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>. 

Meyers et al.221-222 showed that tetrahydro-l,3-oxazines exist in tautomeric ring-chain forms [Eq. (62)]. When a 5,6-dihydro-l,3-oxazine is reduced to a tetrahydro-l,3-oxazine, some 3-aminoalcohol can also be formed through the reduction of the open-chain imino form [cf. Eq. (62)]. To avoid this the reduction should be carried out with sodium borohydride at - 40°C. 

Reduction of perhydropyrido[l,2-c][l,3]oxazin-l-ones with Zn in AcOH yielded ring-opened products (06OBC1587). 

The treatment of a 5-oxoperhydropyrido[l,2-c][l,3]oxazine derivative with NaBH4 in MeOH afforded ds-4aH,5H-5-hydroxy derivative (06JOC8481, 06TL7923). Reduction of (3S,4 R)-(+)-3-phenyl-4,4fl,7,8-tetra-hydro-lH,3H-pyrido[l,2-c][l,3]oxazin-l-one with LAH gave ring-opened l-methyl-2-(2-phenyl-2-hydroxyethyl)-l,2,5,6-tetrahydropyridine (08S1033). 

Treatment of 6-methylperhydropyrido[2,l-h][l,4]oxazin-l-one with lithium aluminum hydride (LAH) in Et20 gave the ring-opened l-(2-hydroxyethyl)-2-hydroxymethyl-6-methylpiperidine (66JMC311 68USP 3388128). 2-Hydroxymethyl-l-(2-aryl-2-hydroxyethyl)piperidines were obtained from 3-aryl-3-hydroxyperhydropyrido[2,l-h][l,4]oxazines by catalytic reduction over Pd-C or Pd(OH)2-C, or by treatment with NaBH4... 

Several related reactions involve reduction of cyclic carboxylic acid derivatives to masked aldehydes which resist further reduction but can be converted into the required aldehydes by acid hydrolysis. In a series of papers, it was established that carboxylic acids could be converted into dihydro-1,3-thiazines or dihydro-1,3-oxazines which could be reduced by NaBH4 in weakly acidic ethanol. Thus, as shown in Scheme 20, dihydro-1,3-thiazines (41) were reduced to tetrahydro-1,3-thiazines (42) in yields of 66-84%. The resulting tetrahydro compounds could be hydrolyzed to aldehydes by aqueous acid. - In a later publication, these workers showed that there was little evidence for ring opening during reduction and that other methods of reduction e.g. hydrogenation over Pt, Pd or Rh or use of dissolving metals such as Zn, Sn or Na) were totally unsuccessful. In closely similar work, reduction of 5,6-dihydro-4W-... 

Much interest lies in the use of dihydro-1,3-oxazines (190) as enolate equivalents, since, if an alkyl group is carried at C-2, these compounds may be deprotonated and the anions formed reacted with numerous types of electrophiles. Reduction of the imine bond of the products (191), is then conveniently effected by treatment with sodium borohydride. The tetrahydrooxazines (192) which are formed may then be ring opened by hydrolysis with aqueous acid (Scheme 15). This topic and its utility in synthesis has been well reviewed. - ... 

Reductive ring opening of N-beteroeycles s. 18, 531 Diolamines from 5,6-dihydro-l,4-oxazin-2-ones via 2-morpholones s. 18, 74 G... 

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