1-Azirines

1-Azirines constitute another class of neutral, electon-rich imines which will undergo [4 + 2] cycloadditions with certain types of dienes. As can be seen in the following discussion, the initial adducts of these reactions are often not isolable and that a Diels-Alder reaction has, in fact, occurred is sometimes inferred by mechanistic reasoning. 

Several examples have been published of thermal cycloadditions of aryl- and alkyl-substituted 1-azirines to symmetrically substituted cyclo-pentadienones, as outlined in [Eq. (19)].  

1-Azirines add stereoselectively to diphenylisobenzofuran to afford exo bicyclic adducts [Eq. (20)].  

The exo selectivity of this process was explained on the basis of unfavorable secondary orbital interactions that destabilize the endo transition state. Some of the products of this cycloaddition tend to rearrange to benzazepine derivatives.  

1-Azirines bearing alkyl or aryl substituents apparently do not add to simple aliphatic 1,3-dienes. However, it has been reported that a benzoy-lazirine does combine rapidly with cyclopentadiene, affording an endo Diels-Alder adduct [Eq. (21)].  

The chemistry of azirines and diazirines has been reported as part of a general review of three-, four-, and seven-membered aza-heterocycles. Recent aspects 

Gelas-Mialhe, and R. Vessiere, Chem. Lett., 1979, 1095. 

A study of the effect of substituents on the cycloaddition of arylazirines (255) to diphenylketen showed that bicyclic adducts (256) or pyrrolidones (257) were the major products isolated. Azirinium ion intermediates were postulated to explain the formation of (256).  

The first isolation of a heterocyclic bicyclobutane (258) has been achieved by the reaction of 2-phenylazirine with dimethylsulphonium methylide. 

This reaction was extended to the synthesis of substituted azabicyclobutanes, all of which underwent acid-catalysed reaction with water or methanol to form azetidines.  

The reduction of azirines with sodium borohydride to give the corresponding aziridines has been applied to a series of aziridine-2-carboxamides (259). The well established synthetic route of lithium aluminium hydride 

Although the 1-azirine ring system is well known, to date, there are no authentic examples of 2-azirines in spite of several attempts directed toward their synthesis. 

The 2-azirine ring system is of theoretical interest since it is a cyclic conjugated structure containing 47t electrons and is predicted by Hiickel s rule not to be stabilized by cyclic delocalization. Electronically it is analogous to cyclobutadiene. 

The decomposition of a i ic-triazole would appear to oifer a direct route to the 2-azirine ring system. However, photolysis of triazole (3) does not give the 2-azirine (4) but indole (5) and ketenimine (6).  

Treatment of triazole (7) with acetic anhydride was reported to give the 2-azirine (8), but further investigation of this reaction by Rees et al. has shown that the correct structure is the oxazole (9).  

The addition of a nitrene to an acetylene would appear to be another direct route to 2-azirines. The reaction of ethyl azidoformate (12) with either diphenyl- or diethylacetylene (15) produces mainly the oxazole (16).  

Preparation. - The reaction of (292) with HN3 in 95% acetic acid at room temperature gave a mixture of cis- and trans- 296) in the ratio 40 60. Heating cis-(296) to 45-50°C gave the azirine (297). The amidoxime (298 R = 2,4,6-Cl3C6H2NHCO, = H), prepared from the corresponding nitrile, 

4-MeC6H4S02) and treated with base to yield (299) as the sole product. This new variant of the Neber rearrangement provides the first synthesis of unsubstituted amino-azirines and has also been shown to proceed for the formation of (299 = PhS02). 

A theoretical approach to the photochemical ring-opening reactions of azirines has been published. 

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Apart from the azirine pathway, a vinylnitrene 526 was postulated as a possible intermediate in the reaction (Scheme 14). The nitrene may be formed by a base-promoted elimination of the leaving group on the nitrogen and gives rise to the 277-azirine by electrocyclization (nitrene insertion) and, in view of current data, this pathway cannot be excluded. 

The use of compounds with activated methylene protons (doubly activated) enables the use of a mild base during the Neber reaction to 277-azirines. Using ketoxime 4-toluenesulfonates of 3-oxocarboxylic esters 539 as starting materials and a catalytic quantity of chiral tertiary base for the reaction, moderate to high enantioselectivity (44-82% ee) was achieved (equation 240). This asymmetric conversion was observed for the three pairs of Cinchona alkaloids (Cinchonine/Cinchonidine, Quinine/Quinidine and Dihydro-quinine/Dihydroquinidine). When the pseudoenantiomers of the alkaloid bases were used, opposite enantioselectivity was observed in the reaction. This fact shows that the absolute configuration of the predominant azirine can be controlled by base selection. 

The 5,7-diaryl-2-fluoro-4/7-l,3-diazepines have been synthesized from 3-aryl-substituted 277-azirines and difluoro-carbene (Scheme 13). The reaction involves isomerization of azirinium ylide into a 2-aza-l,3-diene, which undergoes [4+2] cycloaddition with the starting azirine, followed by ring expansion and dehydrofluorination <2006TL639>. 

The electrophilic carbene CF2 forms donor-acceptor complexes with 277-azirines.104 The resulting complexes rearrange to form oxazines and 4/7-1,3-diazepines. The rearrangements are of general mechanistic interest, but the reactions are not synthetically useful due to very low yields. 

A simple and efficient stereoselective synthesis of aziridine-2-phosphonate 781 and phosphine oxide 782 was achieved by diastereoselective addition of Grignard reagents to 277-azirine phosphonate 779 and phosphine oxide 780. Addition of benzenethiol and heterocyclic amines proceeded in an analogous manner to yield functionalized aziridines 783 and 784 (Scheme 188). 

In contrast, treatment of the related 277-azirine-3-methylacrylate 785 with imidazoles and pyrazoles gave 2-aza-l,3-dienes 786 derived from a transient addition product (Scheme 189) <1999JOC49>. These dienes are useful in hetero-Diels-Alder reactions with electron-deficient dienophiles. 

The chiral enriched ethyl 3-methyl-277-azirine-2-carboxylate 787 was found to act as an efficient alkylating agent for the preparation of a variety of five-memhered aromatic nitrogen heterocycles 788 (Scheme 190) <2003TL6277>. 

The reaction of simple 277-azirines with heterocumulenes proceeds to give a wide range of heterocyclic adducts. For example, treating 277-azirine-3-methylacrylate 794 with diphenylketene afforded 5-pyrrolin-2-one 795 in 70% yield (Scheme 193) <1997T7089>. A related reaction occurred using A -sulfonylimines to give 1,2,5-thiodiazoles <1996J(P1)1629>. 

The vinyl azide method has been employed to prepare heterospirocyclic 3-amino-277-azirines, which represent useful synthons for heterocyclic amino acids <1997HCA1528>. Diphenyl phosphorazidate (DPPA) was used as the azide... 

Thermal or photochemical treatment of isoxazoies 851 has been found to result in a ring-contraction reaction to produce acyl 277-azirines 852, which sometimes rearrange to form other heterocycles like oxazoles 853. This ring-contraction reaction can also be promoted by iron(ii) catalysts. Thus, 5-alkoxy- and 5-aminoisoxazoles isomerize to 27/-azirine-2-carboxylic esters and 2/7-azirine-2-carboxamides, respectively, in nearly quantitative yield by reaction with catalytic FeCb (Scheme 212) <1997T10911>. 

Methyl-3-phenyl-277-azirine (21, R = Me) and ethyl glycinate hydrochloride... 

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