Oxazines, dihydro hydrogenation

Reduction of the Oximino Fragment in Substituted 5,6-Dihydro-4H-Oxazines Catalytic hydrogenation of substituted dihydro-477-oxazines (552), as well as their reduction with sodium cyanoborohydride (553), were studied in sufficient detail and were used in several total syntheses. However, the use of silylation of six-membered cyclic nitronates enables the synthesis of previously unknown dihydrooxazines containing functionalized substituents at the C-3 and C-4 atoms from easily available precursors. 

Some rather unexpected formations of 5,6-dihydro-l,3-4i/-oxazines have also been noted, e.g., reaction of y-bromopropyl iminobenzoate with hydrogen sulfide, which yielded in addition to the main product (thiobenzoate) small amounts of (35) ... 

Tetrahydropyrido[2,1 -HI 1,4 oxazinc-7,9-dicarboxylate 278 was obtained from the 1,8-dihydro derivative 277 by hydrogenation over a Pd/C catalyst (Equation 51) <1997CAP2188071 >. Catalytic hydrogenation of an epimeric mixture of (4.S, 9a.S )-l -trimcthylsilyloxy-4-phenyl-3,4,6,7-tetrahydro-l//-pyrido[2,1 -HIl,4]oxazine over Raney-Ni afforded perhydro derivatives <2000SC2565>. 

Methyl-8-(2-chlorophenyl)-3,4-dihydro-177,877-pyrido[2,l-f][l,4]oxazine-7,9-carboxylate was obtained by cyclization of l,4-dihydropyridine-3,5-dicarboxylate 338 in the presence of 3M HC1 <1997CAP2188071>. Mild catalytic hydrogenation of oxazinone 339 over 5% Pd/C catalyst afforded 3,4-diphenyl-9-hydroxyperhydropyrido[2,l-f][l,4]oxazin-l-one via sequential iV-carbobenzyloxy (fV-Cbz) deprotection and reductive amination <1998TL3659>. 

The catalytic hydrogenation of dihydro-1,3-oxazine 118 afforded the tetrahydro-l,3-oxazine derivative 119 as a single diastereomer, in excellent yield. Hydroboration of the double bond in dihydro-1,3-oxazine 120 yielded the acetate 121 as a single regio- and stereoisomer. The configurations of the products indicated that both the hydrogenation of... 

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>. 

The synthesis of l,3-oxazin-4-ones of type 464 is the first example of the formation of a C-O bond in the course of the Norrish-Yang reaction. Upon treatment with 1-hydroxy-l-phenyl-A -iodanyl mesylate, /3-keto amide 460 was converted to the corresponding a-mesyloxy-/3-keto amide 461 in excellent yield. On ultraviolet (UV) irradiation (A>300nm) of 461, 5-hydrogen transfer to the excited carbonyl group occurred and the diradical 462 thus formed underwent MsOH elimination to enolate diradical 463, cyclization of which resulted in formation of 3-methyl-6-phenyl-3,4-dihydro-277-l,3-oxazin-4-one 464 (Scheme 89) <2001S1258>. 

Aminopropanols, when reacted with cyanogen bromide, also afford 2-amino-(or imino)-dihydro-1,3-oxazines (Scheme 90) (64ZOB3427), and related thiazines are formed when allylic isothiouronium salts (207) are cyclized with trifluoroacetic acid and stannic chloride. The necessary starting materials are synthesized from aldehydes or ketones by the action of vinylmagnesium chloride and subsequent treatment of the product allyl alcohols (206) first with hydrogen chloride and then with a thiourea (Scheme 91) (77JHC717). 

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... 

Dihydro-l,3-oxazines are usually reduced by borohydrides2,3 reasons for some failures have been discussed.229 Catalytic hydrogenation led to ring opening.58... 

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. 

On the other hand, when a methyl substituent is present at C-4, i.e., 5b, low asymmetric induction is observed and only a 64 36 diastereomeric mixture of the bicyclic cis- and trans-dihydro-1,2-oxazine lactams 6 is recovered. The relative stereochemistry of the c/s-product is assigned by NOE measurements in the spectra of the compound obtained by hydrogenation. The major adduct constitutes the key intermediate in the synthesis of the alkaloid (+)-monomorine. 

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-... 

The synthesis of 5,6-dihydro-1,3-oxazines in the androstane series as analogues of steroidal alkaloids has been reported. Treatment of the acetal (12a) with HN3-BF3 etherate gave the dihydro-1,3-oxazine (13) as major product and (14) as minor product. Catalytic hydrogenation, in neutral medium, of (13) led to the tetrahydro-... 

Electron Transfer Processes - A study of the benzophenone/acetonitrile/t-butylamine system has shown that electron transfer occurs from the amine to the excited state benzophenone. Hydrogen abstraction processes within this system ultimately yield the CH2CN radical. When this species is generated in the presence of a diarylethene such as that shown in Scheme 1 then addition affords reasonable yields of the adducts (16). The mode of addition is dictated by the stability of the radical formed on addition to the ethene bond. Addition can also occur to alkenes such as (17) when the adduct (18) is obtained. SET processes also provide a novel synthetic path to 5,6-dihydro-4/f-l,2-oxazines. These reactions involve the DCA-sensitized transformations of the y,5-unsaturated oximes (19). The reactions are carried out in acetonitrile solution with irradiation through Pyrex for no longer than 30 min. This treatment yields the products (20) in reasonable yields. The likely mechanism for the process involves the formation of the intermediate (21) which cyclizes to yield the final products. The reaction is to some extent substituent dependent and when the oxime (19, R = H, R = R = R = Me) is irradiated under the same conditions for 3 h no reaction is... 

The nomenclature used in this chapter follows lUPAC rules as laid down in the lUPAC Nomenclature of Organic Compounds, 1979 edition. Thus the parent compounds and the dihydro-1,3-oxazines have the names indicated in Figure 1, where the locant for H (the indicated hydrogen) is always given the lowest number. 

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