27/-Azirine-3-carboxylates

Azirines can be prepared in optically enriched form by the asymmetric Neber reaction mediated by Cinchona alkaloids. Thus, ketoxime tosylates 173, derived from 3-oxocarhoxylic esters, are converted to the azirine carboxylic esters 174 in the presence of a large excess of potassium carbonate and a catalytic amount of quinidine. The asymmetric bias is believed to be conferred on the substrate by strong hydrogen bonding via the catalyst hydroxyl group <96JA8491>. 

Keywords Aziridine-2-carboxylic esters. Ring expansion reactions, Azirine carboxylic esters, Aziridine carbinols. Anomalous amino acids... 

Verstappen, M. M. H., Ariaans, G. J. A., Zwanenburg, B. Asymmetric Synthesis of 2H-Azirine Carboxylic Esters by an Alkaloid-Mediated Neber Reaction. J. Am. Chem. Soc. 1996,118, 8491-8492. 

Antibiotic Azirine carboxylate esters Neber reaction 60 28... 

The e.e. for the stoichiometric reaction was 60% in SCCO2 (200 bar with 7 vol% toluene cosolvent) and 70% in liquid toluene (126 Brown and Jessop, unpublished data, 2002). Without toluene cosolvent, the reaction had poor enantioselectivity. Several azirine carboxylic acids and esters related to the product are antibiotics (126). 

Verstappen MMH, Ariaans GJA, Zwanenburg B. Asymmetric synthesis of 2H-azirine carboxylic esters by an alkaloid-mediated Neber reaction. J Am Chem Soc 1996 118 8491-8492. 

B. Zwanenburg and L. Thijs, Aziridine and azirine carboxylic esters. Pure Appl. Chem., 68 (1996) 735-738. 

Skepper, C.K., Dalisay, D.S., and Molinsld, T.F. (2010) Synthesis and chain-dependent antifungal activity of long-chain 2ff-azirine-carboxylate esters related to dysidazirine. Bioorg. Med. Chem. Lett., 20, 2029-2032. 

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]. 

Wittig reaction of 3-phenyl-2//-azirine-2-carbaldehyde (1) with [3-(methoxycarbonyl)prop-2-enylidene]triphenylphosphorane (2) in hot benzene yields a mixture of methyl 7-phenyl-l//-azepine-2-carboxylate (3) and the 2//-azirine4.13 Diene 4 is extremely heat sensitive and isomer-izes on standing at room temperature to the lf/-azepine 3 (see also Section 3.1.1.5.7.). 

The 3//-azepines obtained by cycloaddition of azirines to cyclopentadienones (see Section 3.1.1.1.2.) are thought to arise from the initially formed 2/7-azepines by [1,5]-H suprafacial sigmatropic shifts.31-108 In contrast, 1/Z-azepine 9 results from the thermal rearrangement of the nonisolable 2//-azepine-2-carboxylate 8.13 Presumably, the 1 //-azepine is stabilized, relative to the 3//-isomer, by intramolecular hydrogen bonding between the NH and the adjacent ester group. 

H-Azirine-2-carboxylates such as 57 (Scheme 3.19) are a special class of imines that undergo additions to their C=N double bonds to give aziridine-2-carboxylates... 

Lewis acid-mediated asymmetric Diels-Alder reactions between 2H-azirines 59, bearing chiral auxiliaries, with enophiles such as 60 afforded mixtures of bicyclic aziridine-2-carboxylates 61 (Scheme 3.20) [68]. 8-Phenylmenthol appeared to be the auxiliary of choice in this reaction in terms of yield and diastereoselectivity. 

Treatment of N-sulfmyl-as-aziridine-2-carboxylate 206 (Scheme 3.75) with LDA at -78 °C afforded 2H-azirine-2-carboxylate 207 in 47 % yield. The trans-aziridine 206 gave only a 9% yield of the desired product 207 [95]. Treatment of N-tosyl 2-substi-tuted aziridines 208 (Scheme 3.76) with LDA resulted in the formation of azirines 209 in 61-87% yield [95],... 

Swern oxidation of N-unsubstituted aziridine-2-carboxylate 210 (Scheme 3.77) resulted in the formation of 2H-azirine 211 in >90% yield [95] Similar oxidation of 212 (Scheme 3.78) afforded azirine 213 in 60% yield [66]. 

Carbon-centered radicals have been shown to undergo addition reactions with azirine-3-carboxylates. Methyl 2-(2,6-dichlorophenyl)azirine-2-carboxylate thus reacts with alkyl and aryl iodides in the presence of triethylborane to give aziridines in good yields. The radical approaches from the opposite face to the aryl substituent, giving the cis products as single diastereoisomers (Scheme 4.43) [63],... 

There has been some investigation of auxiliary-controlled cycloadditions of azir-ines. Thus, camphor-derived azirine esters undergo cycloaddition with dienes, with poor diastereoselectivity [70]. The same azirines were also observed to react unselectively with phenylmagnesium bromide. Better selectivities were obtained when Lewis acids were used in the corresponding cycloaddition reactions of 8-phe-nylmenthyl esters of azirine 2-carboxylates (Scheme 4.48) [71]. The same report also describes the use of asymmetric Lewis acids in similar cycloadditions, but mediocre ees were observed. 

H-azirine-2-carboxylate 80, 102 2H-azirine-2-phosphonate 104 2H-azirine-3-phosphonate 104 azirinomycin 435 azomethine ylide 25, 474... 

Komendantov et al. found that thermal decomposition of methyl diazoacetate in the presence of benzonitrile yielded two products.<73JOU431> One is the expected 2-phenyl-5-methoxyoxazole 4 in about 35% yield and the other product was methyl 3-phenyl-2//-azirine-2-carboxylate 5 in around 1% yield (Scheme 4). 

The first compound is an antibiotic isolated from Streptomyces aureus [20], while the second compound is a cytotoxic antibiotic isolated from Dysidea fragilis, a marine sponge [21]. A logical approach to the synthesis of azirines would be an elimination reaction of a suitably M-substituted aziridine. Thus, AT-chlorination of aziridine-2-carboxylic esters was carried out using ferf-butyl hypochlorite (Scheme 8). 

The regiochemistry of this elimination reaction resembles that observed by Davis et al. (see Scheme 9) [23]. The special nature of the bonds in three-mem-bered rings is probably responsible for this exclusive regiochemistry. It is of interest to note that 3,3-dimethylaziridine-2-carboxylic ester indeed leads to the corresponding 3H-azirine ester upon Swern oxidation here there is, of course, no choice. 

The lipase-catalyzed resolution of (2/ , 35 )-3-methyl-3-phenyl-2-aziridine-methanol ( )-H by using the low-temperature method gave synthetically useful (2/ ,35 )-ll and its acetate (2S, iR)- a with (25 )-selectivity E = 55 at —40°C), while a similar reaction of (2/ , 3f )-3-methyl-3-phenyl-2-aziridinemethanol ( )-12 gave (25,35 )-12 and its acetate (2/ ,3/ )-12a with (2/ )-selectivity E = 73 at —20°C) (Scheme 2). Compound ( )-ll was prepared conveniently via diastereos-elective addition of MeMgBr to t-butyl 3-phenyl-2//-azirine-2-carboxylate, which was successfully prepared by the Neber reaction of oxime tosylate of t-butyl... 

Intramolecular addition of trialkylboranes to imines and related compounds have been reported and the main results are part of review articles [94, 95]. Addition of ethyl radicals generated from Et3B to aldimines affords the desired addition product in fair to good yield but low diaster control (Scheme 40, Eq. 40a) [96]. Similar reactions with aldoxime ethers [97], aldehyde hydrazones [97], and N-sulfonylaldimines [98] are reported. Radical addition to ketimines has been recently reported (Eq. 40b) [99]. Addition of triethylborane to 2H-azirine-3-carboxylate derivatives is reported [100]. Very recently, Somfai has extended this reaction to the addition of different alkyl radicals generated from trialkylboranes to a chiral ester of 2ff-azirine-3-carboxylate under Lewis acid activation with CuCl (Eq. 40c) [101]. 

Ab initio calculations on aza-Diels-Alder reactions of electron-deficient imines with buta-l,3-diene show that these reactions are HOMO (diene)-LUMO(dienophile)-controlled and that electron-deficient imines should be more reactive than alkyl-or aryl-imines. The Diels-Alder reaction of r-butyl 2//-azirine-3-carboxylate (80) proceeds with high diastereoselectivity with electron-rich dienes (81) (Scheme 28). The hetero-Diels-Alder additions of imines with sterically demanding dienes yield perhydroquinolines bearing an angular methyl group. The asymmetric hetero-Diels-Alder reaction between alkenyloxazolines and isocyanates produces diastereometri-cally pure oxazolo[3,2-c]pyrimidines. °... 

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>. 

Annular prototropy is not of great importance for small heterocycles. However, it should be mentioned that 1-azirine (2) is much more stable than its antiaromatic 2-isomer (3). By analogy, antiaromaticity is certainly a key factor determing instability of lH-azepines which have never been observed. Thus, demethoxycarbonylation of methyl-3,6-di-r-butylazepine-l-carboxylate (46) by DBU gives a mixture of the corresponding 2H-, 3H-, and 4//-azepines in the approximate ratio 13 56 1 (Scheme 9) (94JCS(P1)1753). The distribution of the azepine isomers is proportional to their relative thermal stabilities as they interconvert via allowed 1,5-hydrogen shifts. 

Zhang, Y. Fang, T. Titus, D. D. Asymmetric synthesis of 2H-azirine 2-carboxylate esters. 

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