Nitrogen 1-azirines

The main example of a category I indole synthesis is the Hemetsberger procedure for preparation of indole-2-carboxylate esters from ot-azidocinna-mates[l]. The procedure involves condensation of an aromatic aldehyde with an azidoacetate ester, followed by thermolysis of the resulting a-azidocinna-mate. The conditions used for the base-catalysed condensation are critical since the azidoacetate enolate can decompose by elimination of nitrogen. Conditions developed by Moody usually give good yields[2]. This involves slow addition of the aldehyde and 3-5 equiv. of the azide to a cold solution of sodium ethoxide. While the thermolysis might be viewed as a nitrene insertion reaction, it has been demonstrated that azirine intermediates can be isolated at intermediate temperatures[3]. 

The 27T-electrons of the carbon-nitrogen double bond of 1-azirines can participate in thermal symmetry-allowed [4 + 2] cycloadditions with a variety of substrates such as cyclo-pentadienones, isobenzofurans, triazines and tetrazines 71AHC(13)45). Cycloadditions also occur with heterocumulenes such as ketenes, ketenimines, isocyanates and carbon disulfide. It is also possible for the 27r-electrons of 1-azirines to participate in ene reactions 73HCA1351). 

A particularly interesting system where nitrogen is lost cheletropically after formation of the initial [4 + 2] cycloadduct involves the thermal reaction of azirines with tetrazines (82) (74CC45, 74TL2303, 74CC782, 75JHC183). A variety of heterocyclic products are produced depending on the structure of the azirine and tetrazine used and the reaction conditions. 

The 1-azirine ring also undergoes a number of reactions in which the heterocycle plays the role of the nucleophile. Although the basicity of the nitrogen atom in the azirine ring is much lower than in simple aliphatic amines, this system can still function as a nucleophilic reagent. One example of this involves the acid-catalyzed hydrolysis of 1-azirines to a-aminoketones (200) which represents a well-established reaction. In fact, in many reactions of 1-azirines where acid catalysis is used, formation of a-aminoketones is difficult to avoid (67JA44S6). 

The reaction of 2-phenyl-l-azirine (201) with benzoic acid gaveN-benzoylphenacylamine (204) (67BCJ2938). The overall mechanism of the reaction involves initial protonation on nitrogen followed by addition of the nucleophile to the azirinium ion and finally ring opening. 

The protonated azirine system has also been utilized for the synthesis of heterocyclic compounds (67JA44S6). Thus, treatment of (199) with anhydrous perchloric acid and acetone or acetonitrile gave the oxazolinium perchlorate (207) and the imidazolinium perchlorate (209), respectively. The mechanism of these reactions involves 1,3-bond cleavage of the protonated azirine and reaction with the carbonyl group (or nitrile) to produce a resonance-stabilized carbonium-oxonium ion (or carbonium-nitrilium ion), followed by attack of the nitrogen unshared pair jf electrons to complete the cyclization. 

Preparative routes to aziridines and 1-azirines are derived from cycloelimination processes in which one, and sometimes two, bonds are formed directly to the nitrogen atom (Scheme 1). For aziridines these include the two intramolecular cyclization pathways involving either nucleophilic displacement by the amine nitrogen (or nitrenium anion) on the /3-carbon (route a) or nucleophilic displacement by a /3-carbanionic centre on the amine nitrogen... 

One of the more important approaches to 1-azirines involves a similar base-induced cycloelimination reaction of a suitably functionalized ketone derivative (route c. Scheme 1). This reaction is analogous to route (b) (Scheme 1) used for the synthesis of aziridines wherein displacement of the leaving group at nitrogen is initiated by a -carbanionic center. An example of this cycloelimination involves the Neber rearrangement of oxime tosylate esters (357 X = OTs) to 1-azirines and subsequently to a-aminoketones (358) (71AHC-(13)45). The reaction has been demonstrated to be configurationally indiscriminate both syn and anti ketoxime tosylate esters afforded the same product mixture of a-aminoketones... 

The addition of phthalimidylnitrene (374) to simple alkynes affords 1-azirines in yields of 1-15% (Scheme 10). In this reaction, which is of no real preparative value, the symmetrical 2-azirines (375) were suggested as the most plausible intermediates and unequivocal proof of the existence of such species was demonstrated from a series of 1,2,3-triazole pyrolysis reactions <71CC1518). Extrusion of nitrogen from the regioisomeric 4,5-disubstituted 1,2,3-triazoles (376) during flash vacuum pyrolysis furnished identical product mixtures which included both regioisomeric 1-azirines (377). 

Although by no means a preparative route to either 1- or 2-azirines, the elimination of nitrogen (by flash vacuum pyrolysis at 400 °C) from the regioisomeric 4,5-disubstituted IH-1,2,3-triazoles (376) leads to similarly regioisomeric 1-azirines (377) <73JCS(P1)550). 

It is known that unsaturated three-membered nitrogen heterocycles display tautomerism involving nonaromatic and antiaromatic (i.e., Air systems) forms. In all cases, the nonantiaromatic tautomer is the most stable 1-azirine la and 1-diazirine 2a. Nonetheless, antiaromatic tautomers are known, for instance, triazirines 3. 

Cycloaddition of azirines 5 to 1.2,4,5-tetrazines 6 is followed by loss of nitrogen and ring enlargement to yield 5//-1,2,4-triazepines 7, which tautomerize spontaneously by a [1,51-hydrogen shift to the 2/7-1,2,4-triazepines 8. The triazepinesare accompanied by variable amounts of pyrimidines and pyrazoles.335 - 338... 

The formation of 2H-pyrroles (21) and a pyrrole derivative (22) from the reaction of 3-phenyl-2//-azirines and acetylenic esters in the presence of molybdenum hexacarbonyl is intriguing mechanistically (Schemes 24, 25).53 Carbon-nitrogen bond cleavage must occur perhaps via a molybdenum complex (cf. 23 in Scheme 26) but intermediate organometallic species have not yet been isolated.53 Despite the relatively poor yields of 2H-pyrrole products, the process is synthetically valuable since the equivalent uncatalyzed photochemical process produces isomeric 2H-pyrroles from a primary reaction of azirine C—C cleavage54 (Scheme 24). 

The addition of methanol or hydrazoic acid to ethenylidenecydopentadiene 3 demonstrates that 3 behaves like an acceptor-substituted allene (Scheme 7.27) [226, 227]. More examples of nudeophilic additions to alkyl-substituted derivatives of 3 were reported by Hafner [228]. Photoelectron spectroscopy of the spirocyclic compound 165b, easily accessible from azide 164b, shows that the lone-pair orbital n(N) of the 2H-azirine nitrogen atom interacts strongly with the Jt1-orbital of the cyclo-pentadiene ring [227]. 

Formation of 2//-azirines by thermal decomposition of vinyl azides has been shown to exhibit small entropy of activation and insensitivity to solvent polarity acyclic vinyl azides decompose more readily than analogous cyclic ones and it is advantageous to have a hydrogen atom cis to the azido group ( -are more reactive than Z-isomers). These results and the linear correlation found for ring-substiment effects on decomposition of a-styryl azides are consistent with a nonconcerted mechanism in which elimination of nitrogen and cyclization into a three-membered ring proceeds synchronously. 

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 question of the correctness of such an explanation of the nonplanarity of 2-azirine and the planarity of pyrrole was analyzed in Mo et al. [89JMS(201)17]. The evolution of the MOs as a function of the pyramidalization angle in nitrogen was traced. For both 2-azirine and pyrrole nitrogen pyramidalization leads to the stabilization of all 7t-MOs of the planar structure and, conversely, to the destabilization of several [Pg.368]

Aromatic cyclic 7r-electron delocalization does indeed stabilize the planar structure with bond equalization (84ZOR897)—the problem is that, in addition to that effect, there may exist some others that may eventually overshadow it. Thus, the foregoing warrants the conclusion that the preference of a planar or nonplanar geometry of heterocycle depends on a number of factors including aromaticity (antiaromaticity), which may not even be the most important. In any case, this factor should not be disregarded if one wishes to obtain a correct overall energy balance. For example, aromaticity is reflected in the values of inversion barriers. Thus, for antiaromatic 2-azirine the nitrogen inversion barrier is, as was mentioned earlier, 37.7 kcal/mol, whereas in the case of its saturated... 

Work on the molecular structure of benzonitrilio methylide 8/9 has been carried out via Fourier transform infrared (FTIR) smdies on it and five isotope-labeled variants. The nitrile ylides were generated in nitrogen matrices at 12 K either directly, by photolysis of the azirine 7, or indirectly from the azidostyrenes 6 (4). 

The photochemical conversion of 3-phenylazirine into benzonitrilio methylide in a nitrogen matrix at 12 K was found to be a completely reversible process (4). In contrast, however, it is reported that acetonitrilio fluorenylide 85 (R=Me) is photostable at 77 K and does not convert into the corresponding azirine (55). This stability was attributed to a steric limitation on bond rotation. 

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