Tetrahydro-1,2-oxazines derivatives

Alkoxy-3-(4-biphenyl)perhydropyrido[], 2-c][], 4]oxazines were obtained from 3-hydroxy derivative with PrOH and Br(CH2)30H in a boiling acidified medium (00JMC609, 00MIP13). Spontaneous dehydration of b-hydroxy-1,3,4,6,7,1 lZ -hexahydro[l,4]oxazino[3,4-n]isoquinolin-4-one 258 in CHCI3 gave 3,4,6,7-tetrahydro derivative 259 (97JOC2080). 

Although direct oxidation is sometimes possible (54CCC282), N- or S-oxides and dioxides are normally prepared by indirect routes. 3,6-Dihydro-l,2-oxazines can be reduced catalyti-cally to their tetrahydro derivatives, but zinc and acetic acid cause ring fission to 4-aminobut-3-enols which cyclize to dihydropyrroles (54MI22700). 

Sodium borohydride is an effective reductant for the imine bond of dihydro-1,3-oxazines affording tetrahydro derivatives, but predictably where lactam or sultam functions form part of the heterocycle, treatment with lithium aluminum hydride is necessary. Dihydro-1,3-benzothiazinones for instance are reduced by this reagent to the corresponding dihydroben-zothiazines (Scheme 29) <77ACH(92)317). 

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... 

Kato et al.186 reported that the reaction of valerolactim ether and diketene gave rise to a pyrido[2,l-b](l,3)oxazine (126), which was converted with concentrated aqueous ammonia to the 6,7,8,9-tetrahydro derivative of 37. 

R,9aR)-7-Azido-9a-methyl-4-phenyl-3,4,9,9a-tetrahydro-lH,6H-pyr-ido[2,l-c][l,4-oxazine-l,6-dione was obtained from (4R,9aR)-9a-methyl-4-phenyl-3,4,9,9a-tetrahydro derivative by addition of Br2 in boiling CCI4 for 2 h, then by stirring with saturated aqueous Na3S03 solution at room temperature, followed by the reaction with NaN3 in DMF at ambient temperature for 3 h and 70 °C for 4 h (09JOC4429). 

The dihydro-1,3-oxazine route has been extensively investigated by Meyers. Controlled reduction to the tetrahydro derivative (53), followed by hydrolysis, gave good yields of the corresponding aldehyde or deuteriated aldehyde, R—CDO (Scheme 22). ° Further development of this concept has subsequently given rise to convenient routes to acyclic, a,3-unsaturated, ° alicyclic, y-hydroxy and y-oxo aldehydes. Full synthetic details of these and other variants of the Meyers aldehyde synthesis have been published. ... 

The formation of 1,3-oxazine derivatives was reported for the first time by Kohn. It consisted in cyclizing 3-aminopropan-l-ol derivatives with aldehydes to yield tetrahydro-1,3-oxazine derivatives (1). 

It was recently shown that the formation of a Schiff s base is the first step of the reaction between 3-aminopropan-l-ol and an aldehyde. The action of acid chlorides, such as tosyl chloride, on the SchifTs base forms the W-acyl derivative of tetrahydro-1,3-oxazine. 

Among various other ways of cyclizing 3-aminopropan-l-ol to a tetrahydro-1,3-oxazine derivative, an interesting reagent is acetylene under pressure ... 

An interesting formation of a tetrahydro-l,3-oxazine derivative (5) occurs on reacting the vinyl ether of 3-aminopropan-l-ol with A jA-dimethylcarbamyl chloride/... 

One of the most extensively investigated groups of 1,3-oxazine derivatives is the 5-nitro derivatives of tetrahydro-l,3-oxazine. They were first prepared from 1-nitropropane, aqueous formaldehyde, and ammonia by Hirst et and independently by Senkus from other primary nitroparaffins, formaldehyde, and primary amines. Numerous compounds of the general formula (6) were later prepared from primary nitroparaffins. " ... 

It has been found that the simplest method of preparing 5-nitro-tetrahydro-l,3-oxazine derivatives consists in warming 2-alkyl-2-nitropropane-l,3-diol with formaldehyde and ammonia or primary amines ... 

A new method of preparing tetrahydro-1,3-oxazine derivatives (13 and 14) consists in reacting olefins with formaldehyde and ammonium chloride or hydrochlorides of primary amines. ... 

A similar reaction of y-bromopropyl derivatives under the influence of silver nitrate was described by Kohn as early as 1904. The 3-hydroxyketone formed from chloral and acetophenone can react with a chlorocarbamate to yield a pseudourethane which is probably a 4-hydroxy-2-0X0 tetrahydro-l,3-oxazine. ... 

A number of simple reactions are now known which form 2-oxo-tetrahydro-1,3-oxazine (18). Here, also, 3-aminopropanol and some of its derivatives are frequently used, Cyclizing reagents are carbonic acid esters in strongly basic medium, " ethyl chloropropionate, trichloracetic esters, or phenyl isocyanate. An example of the first of these methods is ... 

The thiono derivatives of tetrahydro-1,3-oxazine became a subject matter of some interest since Kjaer and Jensen discovered that products of enzymatic hydrolysis of Malcolma maritima contain 6-methyl- and 6,6-dimethyl-2-thionotetrahydro-l,3-oxazine (26). The authors proved the identity of these compounds with the products of cyclization of 3-hydroxypropyl-isothiocyanate in an alkaline medium. 

By reacting phosphorous pentasulfide with dioxo derivatives of tetrahydro-l,3-oxazine, the oxygen atoms of both carbonyl groups are replaced by sulfur (27) ... 

The tetrahydro-l,3-oxazines which contain a free A -hydrogen atom can be iV-acylated and A -nitrosated. - Certain A-substituted derivatives of tetrahydro-l,3-oxazin s can also react with acetic anhydride to form A -acetyl derivatives. > Most tetrahydro-l,3-oxazines add methyl iodide to form quaternary... 

Ring opening of some derivatives of tetrahydro-1,3-oxazine can also occur when warmed with aqueous sodium hydroxide ... 

The simple ring opening of tetrahydro-1,3-oxazine derivatives is not the only possible reaction of these heterocyclic compounds catalyzed by mineral acids. An interesting rearrangement of 6-aryl-6-alkyltetrahydro-l,3-oxazines when warmed with concentrated hydrochloric acid was found by Schmiedle and Mansfield ... 

Infrared absorption spectra gave more information regarding the structure of 1,3-oxazine derivatives. These studies were mainly concerned with tetrahydro-ljS-oxazine " and dihydro-1,3-oxazine derivatives. - " According to Eckstein et al. a number of bands of frequencies 1150-1050, 955-925, and 855-800 cm characterize the hemiacetal bond C—0—C. Lukes et expressed the view that a triplet of bands at 1143, 1129, and 1083 cm characterized the tetrahydro-1,3-oxazine ring. However, Bergmann and Kaluszyner assigned these bands to the N—C—O system in the tetrahy dro-1,3-oxazines. 

Other functional groups in tetrahydro-1,3-oxazine derivatives, such as N02, qq so,s7,io5 ]s jj (amincs)and NH (amides) give... 

The formation of various tetrahydro-l,3-oxazine derivatives was used to separate diastereo isomers of 3-amino-1,3-diphenylpropanol. 

According to Urbanski et al. biological activity of 1,3-oxazine derivatives is due to the active CH2 group in the 2-position. Tne use of tetrahydro-l,3-oxazines was also suggested against some infections in veterinary service. The suggested use of tetrahydro-l,3-oxa-zines as herbicides did not seem to be a success. 

Another line of approach to the practical application of 1,3-oxazine derivatives was the suggested use of tetrahydro-1,3-oxazine derivatives as detergents for textile industry, as anticorrosion chemicals, and polymers from 2-oxo derivatives as additives to improve the properties of paper and textiles. ... 

Both tetrahydro- and dihydro-1,3-oxazine derivatives have been suggested as passive components of azo dyes. ... 

Reduction of 3-substituted-3,4,7,8-tetrahydro-l//,6//-pyrido[l,2-t][l,3 oxazin-l-ones with NaBHjCN in boiling MeOH, and with NaBH4 in AcOH, afforded 4a-epimeric mixtures of perhydro derivatives <2005T1595>. 

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>. 

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