1.3- Oxazines tetrahydro-, preparation

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. ... 

Reaction of tetrahydropyridin-4-one 119 and l,r-carbonyldiimidazole furnished l,3,4,4n,5,6-hexahydropyrido[l,2-c][l,3]oxazine-l,6-dione 120 (99JA2651). Similarly, pyrido[l,2-c][l,3]oxazine-l-one 121 and [1,3] oxazino[4,3-n]isoquinoline-4-one 122 were prepared from the respective 2-(2-hydroxypropyl)piperidine and l-(2-hydroxypropyl)-1,2,3,4-tetrahy-droisoquinoline (99JOC3790). Reaction of a 2 1 diastereomeric mixture of l-(l,2-dihydroxyethyl)-6,7-dihydroxy-l,2,3,4-dihydroisoquinolines 123 and 124 with l,l -carbonyldiimidazole gave a 2.7 1 mixture of 1,9,10-trihy-droxy-l,6,7,ll/)-tetrahydro-2//,4//-[l,3]oxazino[4,3-n]isoquinoline-4-ones 125 and 126, which were separated on preparative TLC plate (99BMC2525). 

The tetrahydro-[l,3]oxazino[3,4-b][l,2]oxazin-8-one 389 was prepared by cycloaddition reaction of the C-nitroso derivative 408 (Scheme 65) <1999TL4391>. 

A series of enantiomerically pure tetrahydro-l//-pyrrolo[2,l-c][l,4]oxazine-l,4(3//)-diones 86a-d have been prepared by bromolactonization of acrylamides derived from proline mediated by NBS (Equation 5). These compounds... 

The simplest and most commonly used method for the synthesis of tetrahydro-l,3-oxazines is the ring closure of the corresponding 1,3-amino alcohols with oxo compounds [80H(14)1333]. The parent ring system is known merely in the case of 3,1-perhydrobenzoxazines 18 cis or trans R = H, Ph) it was prepared from cis- and rrans-2-hydroxymethyl-l-cyclohex-... 

To increase the yields of the ring closure reactions, a new method was developed that was successfully applied for the synthesis of alicyclic fused systems of both the parent oxazolidine-2-thione and tetrahydro-1,3-oxazine-2-thione (85S1149). As an example, the synthesis of 2-thioxoperhydro-l,3-benzoxazine 103 is described. The dithiocarbamate 101, prepared from the amino alcohol 100, carbon disulfide and triethylamine, was treated with ethyl chloroformate in the presence of triethylamine, to give the thioxo derivative 103 via the transition state 102 (85S1149). In this way, the fused-skeleton thioxooxazines (91, X = S, 92) can be prepared with considerably higher yields (50-70%) than by the earlier methods (85S1149). 

New types of fluorinated cyclopent[d]-3,l-oxazines and tetrahydro-4//-3,l-benzoxazines 180 and 181 were prepared (88IZV132 89TL-1987 91IZV1130, 91T5577). Cyclopentene, 1-methylcyclopentene, or 1,3-cyclohexadiene was reacted with a mixture of acetyl boron trifluoride and acetonitrile, resulting in the oxazines 180 and 181 regio- and stereospecifi-cally via acylamidation. 

A convenient, one-pot procedure devised for the preparation of 2-phenyl-5,6-dihydro-4//-l,3-oxazine 373 was based on the A -bromosuccinimide oxidation of tetrahydro-l,3-oxazine 372, formed in situ from 3-aminopropanol 371 and benzaldehyde (Scheme 69) <2006S2996>. 

Azomethine ylides derived from (55,6/ )-2,3,5,6-tetrahydro-5,6-diphenyl-1,4-oxazin-2-one (53) and various aldehydes have been prepared by Williams and co-workers (87,88) (Scheme 12.19). In a recent communication they reported the application of the azomethine ylide 54 in the asymmetric total synthesis of spirotryprostatin B 56 (88). The azomethine ylide 54 is preferentially formed with ( )-geometry due to the buLkiness of the aldehyde substituent. The in situ formed azomethine ylide 54 reacted with ethyl oxindolylidene acetate to give the 1,3-dipolar cycloaddition adduct 55 in 82% yield as the sole isomer. This reaction, which sets four contiguous stereogenic centers, constmcts the entire prenylated tryprophyl moiety of spirotryprostatin B (56), in a single step. 

Dioxanes (337) are also conveniently obtained by acid-catalyzed condensation of oxiranes with glycols, while use of ethanolamine gives morpholine (338). Base-catalyzed reaction of oxiranes with a-amino acids and esters gives tetrahydro-l,4-oxazin-2-ones, e.g. propene oxide + RNHCH2C02H — (339). 1,4-Dithianes have been prepared by the dimerization of thiiranes either in the vapor phase or in the presence of acid catalysts. 

Racemic morpholine-3-carboxylic acid (4-oxapipecolic acid, 18) is prepared by a multistep synthesis, starting from 3-methoxymorpholine 205 It can, however, be obtained as optically pure (3S)-morpholine-3-carboxylic acid (l-4-oxapipecolic acid) by base-mediated cyclization of 0(2-chloroethyl)-L-serine.[253] Similarly, (4S)-tetrahydro-2//-1, 3-oxazine-4-carboxylic acid (L-5-oxapipecolic acid, 19) is obtained from L-homoserine by reaction with aqueous formaldehyde under alkaline conditions 173 ... 

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). 

Both tetrahydro-l,4-oxazine (morpholine) and its thia analogue (thiomorpholine) find application as solvents and bases, morpholine having particular value in synthesis as it is often used to prepare enamines from ketones with a free a-hydrogen atom. TV-Acylation and -alkylation are readily accomplished and a great diversity of TV-substituted morpholines and thiomorpholines are encountered in the patent literature, some having biological activity. 

Tetrahydro-l,4-oxazines are normally prepared by the cyclization of diethanolamines in the presence of acids, although an alternative route employs the reaction of di(/3-chloroethyl) ethers with ammonia or amines (Scheme 124) (12JCS1788). Similar procedures can be adapted to the syntheses of tetrahydro-l,4-thiazines, their 1-oxides and 1,1-dioxides (25JA282). 

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... 

A number of diastereoisomeric pairs of quaternary salts of 5-nitro-tetrahydro-l,3-oxazine derivatives (11a and lib) were prepared by the action of n-alkyl bromides or iodides on 5-nitrotetrahydro-1,3-oxazines.61 The products contained at the 3-equatorial position the n-alkyl derived from the alkyl bromide (or iodide), 6a and 6b [Eqs. (4) and (5)]. 

A few perchlorates of quaternary tetrahydro-l,3-oxazines were also described.82 Quaternary chlorides were prepared by direct cyclization of 3-dimethylaminopropanols with formaldehyde in hydrochloric acid.23... 

A number of A-oxides have been obtained by oxidizing 5-nitrotetra-hydro-l,3-oxazines (6) with peracetic acid.63 Rassat and Rey34 prepared nitroxides (12) from tetrahydro-l,3-oxazines with an NH group and m-chloroperbenzoic acid [Eq. (6)]. 

The most general method of preparing 2-carbonyl derivatives is to react 3-aminopropanols with difunctional derivatives of carbonic acid.1 2-Oxo derivatives of tetrahydro-1,3-oxazine being both 8-lactams and 8-lactones differ in their chemical properties from those of tetra-hydro-1,3-oxazines. 

Amino acids and phosgene were used, as previously reported,1 for the preparation of 2,6-dioxo derivatives.114 Reaction of dialkylmalonyl chloride with A-methylisobutyramide to yield 27 [Eq. (17)] is a general method of forming 4,6-dioxo derivatives of tetrahydro-1,3-oxazine, as reported by Martin et al.115... 

The ring opening of tetrahydro-l,3-oxazines to aldehydes has recently found wide application through the work of Meyers.2-3 2-Alkylidene-tetrahydro-l,3-oxazines, prepared from the readily available 5,6-dihydro-4//-1,3-oxazines, possess strong nucleophilic properties and can react with alkyl halides and carbonyl compounds. The derivatives so obtained can be reduced to tetrahydro-l,3-oxazines, and through ring opening the latter can furnish acyclic, alicyclic, and a,jS-unsaturated aldehydes and their C-l deuterated derivatives.221-223 228... 

Preparative details for passing from dihydro- to tetrahydro-1,3-oxazines followed by ring opening have been given.241,242 The methods have been used to synthesize systems related to natural products243 including those with a pyrrole ring.244-248... 

Conjugat addition of dipentylcuprate, prepared from pentylmagne-sium bromide and Cul, to 3,4,4a,5-tetrahydro-lH,6H-pyrido[l,2-c][l,3] oxazin-6-one 65 afforded nearly complete facial selectivity (96%) providing 8-pentylperhydropyrido[l,2-c][l,3]oxazin-6-one 66 (05OL5227). 

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