Azirine intermediate

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]. 

Salicylonitrile is believed to arise by direct cleavage with subsequent hydrogen transfer, while the benzoxazoles were produced by an isocyanide intermediate (73JA919, 74HCA376). Photolysis in D2O tends to confirm this possibility and rule out an azirine intermediate (39), due to deuterium corporation into the molecule (Scheme 10) (74HCA376). 

Some data were obtained from the photochemical isomerization of amino-isoxazoles. 5-Aminoisoxazoles gave the corresponding azirine (Scheme 21) [70JCS(C)1825] when a4-carboethoxy-substituted derivative was used, no azirine was isolated and the oxazole was the only product obtained (Scheme 21) (72CB748). The azirine intermediate was not observed upon irradiating 3-amino derivatives [91H(32)1765]. 

The best evidence for this mechanism is that the azirine intermediate has been... 

Bromo-j3-nitrostyrene and triphenylphosphine in dry benzene gave the phosphonium bromide (47). Using methanol as the solvent, the rearranged product (48) was formed, possibly via an azirine intermediate. Substituted -bromo-/3-nitrostyrenes yield the phosphoranes (49) and a phosphonium salt. When the aryl group is electron-donating, the reaction follows a different course to form the styrene (50) by initial attack of the phosphine on halogen. 

Our calculations on the ring expansion of the lowest singlet state of phenylnitrene ( A2-lb) to azacycloheptatetraene (3b) predict a two-step mechanism that is analogous to that for the rearrangement of la to 3a and which involves the bicyclic azirine intermediate 2b.61 The CASPT2 energetics are depicted in Fig. 5, and the CASSCF optimized geometries of the stationary points are shown in Fig. 6. 

Generally, the Neber rearrangement is a base-catalysed conversion of 0-acylated ketoximes 523 (but not aldoximes) to a-amino ketones 525 via an isolable 2//-azirine intermediate 524 (equation 232). The azirine itself may be used as a valuable synthetic tooP and the Neber rearrangement is commonly used to produce it. 

As the product amino ketone has a great tendency to dimerize, it is usual to produce the amino ketal from the azirine intermediate by treatment with acidic alcohols. 

The 2//-azirine may be optically active and therefore be regarded as a chiral building block for enatioselective synthesis. This opens a wide field of investigation and recently efforts have been made to produce optically pure azirines. Considering the anionic displacement as the main pathway (and not the nitrene pathway), the Neber reaction may be modified to serve as a synthetic tool for the production of optically active 2//-azirine intermediates. 

The Dimroth rearrangement has been utilized for the conversion of (108) to the 2,N-polymethylene-bridged 6-aminopyrimidine (109) (75AJC119). Photochemical rearrangements of isoxazolophanes (110) into oxazolophanes (111) have been demonstrated to go through an azirine intermediate (112) (79TL1875). Chemical modification of these... 

The best evidence for this mechanism is that the azirine intermediate has been isolated.203 In contrast to the Beckmann rearrangement, this one is sterically indiscriminate 204 Both a syn and an anti ketoxime give the same product. The mechanism as shown above consists of three steps. However, it is possible that the first two steps are concerted, and it is also possible that what is shown as the second step is actually two steps loss of OTs to give a nitrene, and formation of the azirine. In the case of the dichloroamines, HC1 is first lost to... 

MNDO results suggest that the activation energies are similar for the gas phase thermal isomerization of isoxazole to oxazole via either a nitrile ylide or a keteneimine, through an azirine intermediate. The first step is rate limiting, which is in good agreement with experimental results (90JPO611). 

The pyrolysis of indazoles 113-115 with bulky substituents R has also given some interesting results. For R = Ph3C, FVP of 113 at 400 °C leads to partial conversion into 114, while at 300 °C 114 gives 113. The less stable isomer 115 is converted at 300 °C into a mixture of 113 and 11465. For R = 1-adamantyl, 113 and 114 are again interconverted at 600 °C, while at 700 °C the new product 117 is formed from either by way of the azirine intermediate 11666. 

Azirines have also been shown to be likely intermediates in the Campbell aziridine synthesis.62 This reaction is analogous to the Neber reaction in which the intermediate azirine is hydrolyzed to the aminoketone. Here the proposed azirine intermediate prepared from oxime (144) reacts with a Grignard reagent to give the aziridine (145). 

Intermediate three-membered rings have never been detected in the cycloaddition reaction and a direct route to the five-membered rings is probable in most cases. For example, benzoyl nitrene adds to triple bonds and in contrast to the addition to nonpolar double bonds, a five-membered oxazole is obtained (Sch. 22) [21,38]. An azirine intermediate is not detected, however it cannot be excluded that the three-membered ring containing a 7i-bond rearranges rapidly giving rise to the oxazole. 

At that time it was suggested that the isomerization occurred by way of an initial photo-ring contraction to an undetected 2-(A-methylimino)-2//-azirine intermediate (2) and subsequent ring expansion to the observed product, 1-methylimidazole (3). Although the intermediacy of acylazirines has been adequately demonstrated in the analogous isoxazole-to-oxazole phototransposition, such iminoazirines have not been detected in a pyrazole to imidazole isomerization, and thus, this mechanistic suggestion has never been experimentally substantiated. 

Perhaps their most significant result is that the opposite trends in changes in the barrier heights for the two steps with increasing steric bulk infers that the intermediate azirine might be observable if a sufficiently bulky substituted phenylnitrene could be produced. Just such a molecule is 2,4,6-tri-t-butylphenylnitrene. Computations indicate a barrier of 4.1 kcal mol for the first step and 6.3 kcal moC for the second step. Laser flash photolysis detected the azirine intermediate 27 having a lifetime of 62 ns and a barrier to ring open to the azepine 28 of 7.4 0.2 kcal moL. ... 

In addition to the reactions of diaminomaleonitrile shown in Scheme 11 there are also some examples of photochemical transformations which lead to imidazole products. The initial reaction isomerizes the cw-dinitrile to the trans form which then forms a 5-aminoimidazole-4-carbonitrile via the iminoazetine (34). There are a number of related reactions, although the photochemical isomerization of enaminonitriles (35) probably involves an azirine intermediate (Scheme 17) (8UOC2872). 

There are a number of examples of photochemical transformations of DAMN which may have some synthetic applications. At first, irradiation isomerizes the cir-dinitrile to the rrani -dinitrile, which then forms 5-amino-4-cyanoimidazole (18). Both azctidine or azirine intermediates have been postulated for these cyclizations [54, 55]. Although yields are good the photolytic conditions require dilute solutions ( lO moll solutions of the enaminonitriles) and may not prove practicable for the synthesis of larger quantities of imidazoles. On a small scale, however, the method merits consideration particularly since the process works for a wide variety of enaminonitriles (Scheme 2.1.9) [56-58]. 

RCH2CH(NCl2)R , where the product is also RCH(NH2)COR The mechanism of the Neber rearrangement is via an azirine intermediate 19 ... 

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