Amines, reactions with azirines

The highly strained and reactive 2iT-azirines have been extensively studied for various synthetic purposes, such as ring expansion reactions, cycloaddition reactions, preparation of functionalized amines and substituted aziridines. The older literature on azirines in synthesis has extensively been reviewed [69]. Concerning azirines with defined chirality only scarce information is available. Practically all reactions of azirines take place at the activated imine bond. Reduction with sodium borohydride leads to cz5-substituted aziridines as is shown in Scheme 48 [26,28]. 

Reaction of l-azirine-3-methylaciylates (155) with imidazoles and pyrazoles under mild conditions results in the formation of 2-aza-1,3-dienes (156), which are useful as dienes in hetero Diels-Alder reactions with electron-deficient dienophiles <99JOC49>. When the related methyl 2-aryl-2ff-azirine-3-carboxylate (157) was used as fee substrate, reaction with an amine induced a ting opening by addition of the amino group onto fee C=N bond followed by cleavage to provide enediamine 158 <99JCS(P1)1305>. 

Aziiines with electron-withdrawing substituents at the imine function can be used in ring-transformation reactions with enamines to give pyrrole mono- or di-carbox-ylates". L abbe and coworkers proposed a mechanism involving cycloaddilion of the enamine 232 to the C=N bond of the azirine 233, to give the zwitterion 234, which cyclizes to 235. Ring expansion of 235 and elimination of the amine residue give a pyrrole 239, whereas Katritzky and coworkershave proposed that the bicycle 235 is converted into a mixture of 2,3-dihydropyrrole 237 and a 3,4-dihydropyrrole 238, before elimination of amine (equation 49). 

Fluoride-ion-mediated generation ofbenzyne from silylaryl triflates (41) [20] is mild and excellent in chemical yields andsoithasbeen employed for a variety of electrophilic (42) [21 ], nucleophilic (43) [22], and cycloaddition reactions [23] (Scheme 3.26). N-Phenylations of sulfonamides (44), amines (45) [24], azirines [25], oxazoles [26], pyrroles [27], and imidazoles [28] with benzyne from 41 are also known. 

There are a few reports on the use of oximes as electrophilic amination reagents. Since 1984, ketone O-sulfonyloxknes have found applicability as amino transfer reagents to car-banions. In the reaction of organometaUic compounds with oximes, carbanions attack the carbonyl carbon of the oxime, giving Af-substituted hydroxylamines as addition products (Scheme 53, path a). However, a number of scattered reports have been also published on the formation of aziridines by a-deprotonation, followed by addition (path b) or formation of azirines by a-deprotonation before addition (path c). Addition of carbanions to azirines also yields aziridines, which are hydrolyzed to a-aminoalcohols. 

Photogenerated nitrenes can undergo cycloaddition with alkenes intermolecular reaction leads to aziridine products (5.38), and intramolecular reaction in vinyl azides gives azirines (5.39). The bicyclic azirine from phenyl azide has not been isolated, but it is the intermediate that best accounts for the formation of a substituted azepine when this azide is irradiated in the presence of a secondary amine (5.401. 

The photochemistry of aryl azides is quite complex, suggesting that the nitrene 14 may not be the only reactive intermediate and that insertion reactions may not be the only route to form photoconjugates.Although aryl nitrenes are much less susceptible to rearrangements than acyl nitrenes, they may still occur and lead to the formation of reactive intermediates such as azepines, which may go on to react with nucleophiles.[911 141 Addition of nitrenes to double bonds will generate azirines, while dimerization will produce azobenzenesJ11 Aryl azides are stable to most of the procedures used in the course of peptide synthesis except for reduction reactions. Non-photochemical reduction of aryl azides to the primary amines by thiols has been reported by Staros et al.[15]... 

Fluorinations of other functionalities containing C = N bonds, such as 2//-azirines and imines, are included in this section. Certain 2Ff-azirines and imines yield a-fluoro ketones. With other 2Ff-azirines, /i,/(-difluoro amines are the main reaction products. In a strict sense, these reactions cannot be considered as examples of substitution of nitrogen-containing functional groups no substitution takes place when /S. -difluoro amines are the reaction products. However, these methods have been included. 

The reaction of 2//-azirines (e.g.. 1) with hydrogen fluoride in pyridine [pyridinium poly(hy-drogen fluoride). Olah s reagent] gives /f,/f-difluoro amines (e.g., 7) or a-fluoro ketones (e.g., 5) (Table 10). In some cases, pyrazines (e.g.. 9) are the main reaction products (Table IQj 31-35 2//-Azirines arc more reactive than aziridines towards pyridinium poly(hydrogcn... 

Difluoro Amines and a-Fluoro Ketones by the Reaction of 2//-Azirines with Pyridinium Poly(hydrogen fluoride) General Procedure ... 

Thermal isomerization of amino-substitued 2i/-azirines (e.g. 183 -> 184) results in the formation of 2-azadienes. They react with activated alkynes, e.g. with acetylenedicarboxylic ester (ADE), in a hetero-Diels-Alder reaction, giving dihydropyridines (e.g. 185), which aromatize with elimination of amine yielding pyridine-3,4-dicarboxylic esters (e.g. 186). 

The synthesis of oxazoles via thermolysis or photolysis of /8-azido or 8,/8-diazido ketones, esters, or nitriles, which can be considered as enaminone derivatives, is well known and has been reviewed in detail (75AGE775). A recent example is the reaction of methyl 3,3-diazido-2-cyanoacrylate 266 with amines to give enaminones 267, which undergo thermolysis or photolysis to give, probably via azirine intermediates, the oxazoles 268 in good yields. Scheme 72 (90CB115). 

The nickel-iminophosphine-catalysed 4- -2-cycloaddition of enones with allenes formed highly substituted dihydropyrans. The enantioselective amine-catalysed 4-I-2-cycloaddition of allenoates with oxo-dienes produced polysubstituted dihydropyrans in high yields and with high enantioselectivities. Novel enam-ine/metal Lewis acid bifunctional catalysis has been used in the asymmetric inverse-electron-demand hetero-Diels—Alder reactions of cyclic ketones with Q ,j9-unsaturated a-ketoesters. The 4- -2-cycloaddition of acylketenes (80) with 2-unsubstituted and 2-monosubstituted 3-aryl-2//-azirines (81) produced 1 1 (82) or 2 1 (83) adducts, being derivatives of 5-oxa-l-azabicyclo[4.1.0]hept-3-ene or 5,7-dioxa-l-azabicyclo[4.4.1]undeca-3,8-diene. The formation of the monoadducts proceeds via a stepwise non-pericyclic mechanism (Scheme 25). A-heterocyclic carbene-catalysed 4- -2-cycloaddition of ketenes with 1-azadienes yielded optically active 3,4-dihydropyrimidin-2-ones (93% ee) ... 

The products of reactions of two methyl 2-aryl-2 f-azirine-3-carboxylates (21 aryl = 2,6-Cl2C6H3 or 4-MeC6H4) with a range of nucleophiles are reported. Although a wide range of compounds have been added (thiols, propargyl alcohol, amines, enamines, enones and -diketones), all appear to involve initial addition to the C=N bond. 

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