Nitriles 1.3- oxazines, 5,6-dihydro

The sulfuric acid-catalyzed condensation of oxetanes with nitriles gives dihydro-1,3-oxazines (45). This reaction has been reported for a wide variety of 2,2-disubstituted oxetanes and nitriles, generally giving fair yields (74ZOR95, 82ZOR181). The nitrogen atom of the nitrile always bonds to the more substituted a-carbon of the oxetane. 

Meyers reported a new method of forming 5,6-dihydro-1,3-4H-oxazine derivatives (37) by reacting chloroolefins with nitriles in an acidic medium. 

Accordingly, cyclic nitronates can be a useful synthetic equivalent of functionalized nitrile oxides, while reaction examples are quite limited. Thus, 2-isoxazoline N-oxide and 5,6-dihydro-4H-l,2-oxazine N-oxide, as five- and six-membered cyclic nitronates, were generated in-situ by dehydroiodination of 3-iodo-l-nitropropane and 4-iodo-l-nitrobutane with triethylamine and trapped with monosubstituted alkenes to give 5-substituted 3-(2-hydroxyethyl)isoxazolines and 2-phenylperhydro-l,2-oxazino[2,3-fe]isoxazole, respectively (Scheme 7.26) [72b]. Upon treatment with a catalytic amount of trifluoroacetic acid, the perhydro-l,2-oxazino[2,3-fe]isoxazole was quantitatively converted into the corresponding 2-isoxazoline. Since a method for catalyzed enantioselective nitrone cycloadditions was established and cyclic nitronates should behave like cyclic nitrones in reactivity, there would be a good chance to attain catalyzed enantioselective formation of 2-isoxazolines via nitronate cycloadditions. 

Es kann ferner von Phenyl-acetonitril, Cyanessigsaure-athylester und Acrylsaure-nitril ausgegangen werden. lm letzteren Fall wird die Homologisierung durch Michael-Addition eincr C—H-aciden Verbindung an das erhal-tene 4,4,6-Trimethyl-2-vinyl-5,6-dihydro-4H-l,3-oxazin durchgefiihrt1. 

ALDEHYDES FROM ALLYLIC ALCOHOLS AND PHENYLPALLADIUM ACETATE 2-METHYL- 3-PHENYLPROPIONAL-DEHYDE, 51, 17 ALDEHYDES FROM AROMATIC NITRILES p-FORMYLBENZENE-SULFONAMIDE, 51, 20 ALDEHYDES FROM 2-BENZYL-4,4,6-TRIMETHYL—5,6-DIHYDRO-l, 3-(4H)-OXAZINE 1-PHENYLCYCLO-PENTANECARBOXYALDEHYDE, 51,... 

The cyclocondensation of l,3-amino alcohols with carboxylic acid derivatives is a method often applied for the synthesis of 5,6-dihydro-4/7-l,3-oxazines <1996CHEC-II(6)301 >. Ebsorb-4, a weakly acidic zeolite-type adsorbent with 4 A pore size, proved an efficient catalyst of the cyclization of benzoic acid and 3-aminopropanol <2002TL3985>. In the presence of zinc chloride as a catalyst, the expulsion of ammonia drove the reactions of 3-aminopropanol with nitriles to completion, affording 2-substituted 5,6-dihydro-47f-l,3-oxazines in good yields... 

However, the most important approach to 2-substituted dihydro-1,3-oxazines involves the acid-promoted condensation of alkyl nitriles and propane-1,3-diols, carbonium species (200) are assumed to be intermediates in this reaction, being formed preferentially from the more highly substituted position of the diol (Scheme 87) (57JOC11). 

Acrylonitrile took part in the cyclization to form 36 (R = CH=CH2), which could be polymerized.141 Cyano- and chlorocyanoacetylene were also used in the modified Ritter nitrile cycloaddition to produce 2-ethynyl- and 2-chloroethynyl-5,6-dihydro-4//-l,3-oxazines.142... 

Meyers et a/.144 gave an ingenious method of forming a 5,6-dihydro-4//-l,3-oxazine with the ultimate aim of producing azasteroids nitriles react with cyclopentenyl-t-butanol (41) in the presence of sulfuric acid... 

One of the earliest heterocyclic applications of the Ritter reaction was to the synthesis of dihydro-1,3-oxazines.9 It was found that the reaction of the dialcohol (1) with nitriles leads to the oxazines (2) rather than the expected bis-amides (Table I). The yields are only fair... 

The use of haloalkenes or halohydrins in Ritter-type reactions has resulted in the development of an oxazoline (105) synthesis85 yields are 60-70%. The formation of 2-ethyl-4,4-dimethyl-5,6-dihydro-4Zf-1.3-oxazine (106)55 from 1-chloro-3-methyl-2-butene and propio-nitrile in the presence of sulfuric acid has a similar basis. 

Dihydro-(8//)-5,6-pyridazino[4,5-rf][l,3]oxazin-4-one (153) was prepared from the enamino aldehyde 4-methoxycarbonyl-5-formyl-2,3-dihydro(6//)-1,3-oxazine (152) with hydrazine hydrate in methanol (Equation (20)) <87CCC1773, 87CCC2953). Using the nitrile (154) the resulting pyr-idazinooxazine (155) carries an amino group at position 7 (Equation (21)). 

Various heterocycles, such as 4,5-dihydrooxazoles, 4,5-dihydro-4Jf-oxazines and tetra-zoles, can be readily metallated and condensed with a variety of organic nitriles to afford heterocyclic enamines such as 128 and 129 (R = Me, Et, Pr, t-Bu, Ph)532. 

In 1957 Tillmanns and Ritter report that reaction of diol (51) with nitriles led to dihydro-1,3-oxazine products (52) instead of yielding bisamides (Scheme 21). In this process the tertiary alcohol group... 

The reaction of epoxides, nitriles and sulfuric acid results in generally poor yields of oxazoline derivatives, and mixtures of isomers may also result (Scheme 28)." These difficulties are overcome by the use of epoxy ethers (equation 35). As shown in equation (36), oxetanes undergo analogous reactions to afford dihydro-1,3-oxazines in excellent quantities. ... 

It is known that nitrilium salts can be prepared by alkylation of nitriles , via the reaction of imidoyl chlorides with Lewis acids as well as by Beckmann rearrangement of oximes . The application of nitrilium salts in organic synthesis is summarized in a number of reviews " . In this connection it is appropriate to mention another three-component one-pot synthesis of 5,6-dihydro-4. -l,3-oxazines 40 based on the reaction of aldehydes with iV-tcr/-butylnitrilium salt 41 which, however, proceeds without the participation of Af-acyliminium ions . The reaction is carried out by mixing the aliphatic or aromatic aldehyde, tcrt-butyl chloride and Lewis acid (SbCljjSnC ) in benzonitrile solution (equations 16 and 17). 

Synthesis of carboxylic acids. Dihydro-1,3-oxazines are hydrolyzed by aqueous hydrobromic acid to carboxylic acids.6 This fact, coupled with the fact that this ring system is completely inert to Grignard derivatives, forms the basis for a new synthesis of carboxylic acids.7 Thus 2,4,4,6-tetramethyl-5,6-dihydro-1,3-(4H)-oxazine (1) is alkylated with 1,5-dibromopentane to produce (2). This is converted into the nitrile (3), then the phenyl ketone (4) finally acid hydrolysis gives 7-benzoylheptanoic acid (5). 

Most interest in this area centers around 5,6-dihydro-4//-l,3-oxazines. These compounds can be prepared in a variety of ways, for example, by the addition of nitriles to oxetanes (presumably the latter ring-open by 5n1 cleavage, prior to reaction with the nitrile (Equation (13)) <8iTL34l, 82ZOR178), or through the interaction of -hydroxyalkenes with nitriles in the presence of concentrated sulfuric acid (Equation (14)) <79URP649713>. 

Dihydro-4/7-l,3-oxazines (269) can be prepared in two steps first the addition of allenyl nitriles and 3-aminopropanol to give enamino nitriles (268), and then treatment of these products with a catalytic amount of sodium ethoxide at 200-250°C (Scheme 77) <81H(16)1889>. 

This process is similar to the Ritter reaction for the preparation of amines from nitriles and olefins. The first step is the regioselective formation of a carbenium ion from the diol 13 followed by addition to the nitrile. The resulting nitrilium ion 15, following attack on the remaining OH group, cyclizes and gives dihydro-1,3-oxazine 14. 

Therefore, the incorporation of a nitrile into a dihydro-1,3-oxazine leads to its a-functionalization and conversion into an aldehyde (RCH2C=N RR CHCH=0) [128]. 

Thermal decarboxylation (at 150 °C) of 3-carboxy-5,6-dihydro-4/f-l,2-oxazines (376) proceeds with concomitant ring-opening to give y-hydroxy-nitriles (377) in excellent yields. 4-Aryl-benzo[ (][l,2]oxazin-l-ones (378) have been prepared by treatment of monosubstituted benzenes with N-hydroxyphthalimide under Friedel-Crafts conditions (AICI3, heat for 15 min) reaction occurs para to the substituent. ... 

Acetonitrile added dropwise with stirring at 3-8 to 92%-H.2SO y then 3-methyl-3-buten-l-oI added slowly at 8-10°, and stirred ca. 25 min. while allowed to warm to room temp. 2,4,4-trimethyl-5,6-dihydro-4H-l,3-oxazine. Y 48%. F. e. s. S. P. McManus and J. T. Carroll, Org. Prep. Procedures 2, 71 (1970) from nitriles, ethylene derivs., and formaldehyde cf. C. Giordano, G. Ribaldone, and G. Borsotti, Synthesis 1971, 92. 

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