Preparation of 1,-Oxazine Derivatives

Schmidt4 systematically classified methods of synthesis of some unsaturated 1,3-oxazines. We use the same system for all 1,3-oxazines. 

The main ring syntheses of tetrahydro-l,3-oxazine derivatives are summarized by diagrams a to d (Fig. 1). Two additional methods comprise the cyclization of six-membered chains, and the hydrogenation or 

A general rule can be suggested for one of the principal ways of forming 1,3-oxazine derivatives. They can be formed from 1,3-sub-stituted propane derivatives of general formula  

These compounds can react with various cycliziug agents, described in the following. 

In addition to the compounds just tabulated, a number of less typical methods can also be used to form 1,3-oxazine rings. 

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). 

The reaction was studied by a number of authors and both aldehydes and ketones were used as cyclizing agents.  

---

Many patents describe the preparation of 1,3-oxazine derivatives as antibacterials and antifungals.21-22-27-69-81-87-89-90-129-300,301 Strong antiprotozoal activity of 5-bromo-5-nitrotetrahydro-l,3-oxazines, e.g., 126, was also registered.302-303 N-Nitroso derivatives were found to be... 

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. " ... 

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 synthesis of aldehydes developed by Meyers begins with the commercially available dihydro-1,3-oxazine derivatives 132 (A = H, Ph, or COOEt). Though the ions (133) prepared from 132 are ambident, they are regioselectively alkylated at... 

An active period of investigation of the positively charged 1,3-oxazine derivatives commenced in the early 1960s. At that time preparative methods... 

Nitrotetrahydro- 1,3-oxazine derivatives show cytotoxic activity in vitro,283,284 and antitumor properties against subcutaneous tumors in mice.84,286 Compound 124 reduced tumors by 70%. The preparation of these compounds is covered by patents.41-46... 

In another modification of this approach (1992CCC2359), the corresponding anilides 100 (R1 — II, R2+R3 = C4H4) are used instead of acids 112. This method was employed to prepare oxazinothienoquinoline 114. However, it should be noted that numerous data suggest that (see Section II.A.3.b) pyrimidine derivatives 96, rather than 1,3-oxazine derivatives, would be expected to be produced under these... 

A number of diastereoisomeric pairs of quaternary salts of 5-nitro-tetrahydro- 1,3-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)]. 

An intramolecular cycloaddition reaction results in the simultaneous formation of two new rings. Examples include the formation of a tetrahydroquinoline derivative (Section 4.4.2.3.4), the asymmetric synthesis of 1,2-oxazine derivatives (Section 4.3.2.4.2), and the preparation of a hcxahydrothiazino 2,3vz]quinolinc (Section 4.6.3.4) by intramolecular... 

Kigoshi and co-workers recently isolated zamamistatin (17) from a sponge Pseudoceratina sp. [42]. In the spectral analysis of 17, they found tW the chemical shift of C6 (5ce 74.3) and C7 (8c 26.7) in 17 were different from those (See 91.5 and 8cy 40.2) of aerothionin (18), which let them reconsider its structure, Fig. (12). Considering the molecular formula of 17, they proposed a structure possessing a dihydro-1,2-oxazine ring for 17. To confirm this, they prepared dihydro-1,2-oxazine derivatives, 17a and 17b, Scheme (6) [42-45] and compared the CNMR data for 17 with those of 17a, 17b and the known 17c [45]. The CNMR data of synthetic 17a and 17b were similar to those of zamamistatin (17) rather than aerothionin-related compounds, Fig (12). Base on these observations it was concluded that the structure of zamamistatin should be revised to an endo-type dimmer. 

As in many other areas of 1,3-oxazine chemistry, ketenes and isocyanates generated in situ are often used to prepare oxazin-6-ones. For example, 2,4-disubstituted l,3-oxazin-6-ones (135) are readily available through the thermolysis of 5-[(A-acylamino)alkylidene]-l,3-dioxane-4,6-diones (134). The latter are generated from the reactions of the appropriate ethyl acylimidate (133) and Meldrum s acid (Scheme 36) <86CPB1980>. Similarly, the bismethylthiomethylene derivative (136) reacts with benzamides in the presence of potassium hydroxide to afford the methyl-thioacylaminomethylene derivatives (137 R = MeS), which can be reacted further with ammonia to give the amino compounds (137 R = NHj). In turn, these products can be thermolyzed to afford the oxazinones (138 R = MeS) or (138 R = NH2), respectively (Scheme 37) <91SC1213>. 

It has been found that the simplest method of preparing 5-nitro-tetrahydro-1,3-oxazine derivatives consists in warming 2-alkyl-2-nitropropane-l,3-diol with formaldehyde and ammonia or primary amines ... 

An interesting method for preparing 2,6-dioxo-l,3-oxazine derivatives was described by Wasserman and Koch who stated that the five-membered ring of an a-keto-lactam could be transformed into the 1,3-oxazine (22) by ozone followed by reduction with zinc. 

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). 

Further stereoisomeric derivatives of the 1,3-oxazines 167 (n = 1, 2 Ph a or j8) (82MI1 90T6859), and of 168-171 (diendo and diexo) (83JHC1181 84JHC1373 87MRC584) and several of their 4-aryl-substituted derivatives, were also prepared by ring closure with imidates (90MRC1045). 

As part of an extensive study of the 1,3-dipolar cycloadditions of cyclic nitrones, Ali et al. (392-397) found that the reaction of the 1,4-oxazine 349 with various dipolarophiles afforded the expected isoxazolidinyloxazine adducts (Scheme 1.78) (398). In line with earlier results (399,400), oxidation of styrene-derived adduct 350 with m-CPBA facilitated N—O cleavage and further oxidation as above to afford a mixture of three compounds, an inseparable mixture of ketonitrone 351 and bicyclic hydroxylamine 352, along with aldonitrone 353 with a solvent-dependent ratio (401). These workers have prepared the analogous nitrones based on the 1,3-oxazine ring by oxidative cleavage of isoxazolidines to afford the hydroxylamine followed by a second oxidation with benzoquinone or Hg(ll) oxide (402-404). These dipoles, along with a more recently reported pyrazine nitrone (405), were aU used in successful cycloaddition reactions with alkenes. Elsewhere, the synthesis and cycloaddition reactions of related pyrazine-3-one nitrone 354 (406,407) or a benzoxazine-3-one dipolarophile 355 (408) have been reported. These workers have also reported the use of isoxazoles with an exocychc alkene in the preparation of spiro[isoxazolidine-5,4 -isoxazolines] (409). 

---