Grubbs and Wilkinson catalyzed reactions of 2-phenyl-3-vinyl substituted 2 H -azirines

Treatment of 2-phenyl-3-vinyl-substituted 2 H -azirines with Grubbs’ catalyst induces a clean rearrangement and affords products derived from carbon-nitrogen bond cleavage of the 2 H - azirine ring. However, when the reaction was carried out using Wilkinson’s catalyst in an alcoholic solvent, the only product obtained in high yield corresponded to an α , β -unsaturated oxime


Introduction
2H-Azirines (2) are highly reactive three-membered unsaturated nitrogen-containing heterocycles that have been used for the preparation of a wide range of polyfunctional acyclic and cyclic nitrogen containing compounds. 1 This small membered ring can take part in various chemical transformations since it can act as a dienophile or as a dipolarophile and can also function as an electrophile or nucleophile.The ring strain undoubtedly contributes to the high reactivity of the 2H-azirine moiety and makes it an attractive intermediate for the preparation of complex heterocyclic ring systems.
A number of synthetic methods are available for forming 2H-azirines and include intramolecular reactions of N-functionalized imines, isoxazoles and oxazaphospholes. 2 2H-Azirines have also been prepared by the intermolecular reaction of nitriles and carbenes or nitrenes and acetylenes. 3The most common method for preparing 2H-azirines however, involves the photolysis or thermolysis of vinyl azides (1). 4 This rearrangement can take place in a concerted manner or via a vinyl nitrene intermediate (3) (Scheme 1). 5 Pyrolysis of vinyl azides is complicated by the fact that the product.2H-azirines (2) are themselves thermally active and thus react further, decreasing the yields of formation and causing difficulty in their isolation.To avoid these problems, the Neber reaction 6 route has also been extensively utilized and can be facilitated by the incorporation of electron-withdrawing groups at the α-position of a N-functionalized imine (4) (Scheme 2).Asymmetric syntheses of 2H-azirines containing a carboxylic ester group 7 or a phosphorous substituent 8 by this method have been reported in recent years.Earlier work from our laboratory demonstrated that 2H-azirines are photochemically active substrates. 9Upon irradiation into their n-π*absorption bands, the strained three-membered 2Hazirine ring opens selectively at the C-C bond in a heterolytic fashion resulting in the formation of a nitrile ylide dipole (5). 9 The nitrile ylide can be trapped by alkenes or alcohols.Due to the pronounced reactivity of nitrile ylides with dipolarophiles, 2H-azirines have been extensively utilized in [3+2] cycloaddition reactions (Scheme 3). 10 A recent example is the facile synthesis of exohedrally functionalized fullerenes. 11In the presence of alcohols, the photochemically generated nitrile ylide 5 reacts to form alkoxyimines 8 and this reaction presumably proceeds by a pathway involving the intermediate production of an azaallenium cation (6). 12[15]  In recent years there has been considerable interest in the use of both organometallic reagents and catalysts for effecting ring cleavage of small ring systems. 16By comparison with the extensive photochemical and thermal studies of the 2H-azirine ring system, its behavior toward organometallic reagents has been relatively unexplored.In some earlier work, Alper and Wollowitz 17 demonstrated that group VI metal carbonyls.M(CO) 6 , M=Cr, Mo, W] are useful reagents for converting 2-aryl azirines to pyrazines 9. Interestingly, pyrroles such as 10 were obtained in modest yields when diiron nonacarbonyl was employed as the organometallic reagent. 18Mechanistic studies indicate that the formation of the pyrrole proceeds via carbon-nitrogen bond cleavage of the 2H-azirine ring.More surprisingly, treatment of the aryl substituted 2H-azirine with dicobalt octacarbonyl [Co 2 (CO) 8 ] afforded 2styrylindoles such as 11 in good-excellent yields (Scheme 4). 19No mechanistic studies were carried out and the unusual chemoselectivity encountered as a function of the organometallic reagent used was not explained by the authors.
In a continuation of our own studies dealing with the chemical reactivity of 2H-azirines 9 , we thought it would be of interest to further investigate the transition metal catalyzed reactions of several 2-phenyl-3-vinyl substituted 2H-azirines.In this paper we report that the commonly employed Grubbs' catalyst induces a clean rearrangement which proceeds via carbon-nitrogen bond cleavage of the 2H-azirine ring.However, when the reaction was carried out using the popular Wilkinson's catalyst [Rh(PPh 3 ) 3 Cl] in an alcoholic solvent, the only product obtained in high yield corresponded to an α,β-unsaturated oxime (vide infra).These results provide further insight into the chemical behavior of this reactive three-membered heterocyclic ring with various transition metal catalysts.

Results and Discussion
2-Formyl-3-phenyl-2H-azirine (12) was prepared by the addition of iodine azide to the dimethyl acetal of cinnamaldehyde and this was followed by dehydrohalogenation, thermolysis and aqueous hydrolysis.Further reaction of the aldehyde with aniline as well as various Wittig reagents gave the substituted 2H-azirines 13-15 shown in Scheme 5 in good yield.Our first transition metal catalyzed experiments centered around the use of the ruthenium 4,5-dihydroimidazo-2-ylidene complex developed by Grubbs and widely known for its application in organic and polymer synthesis. 20To date, this catalyst is routinely used for ring closing metathesis (RCM), cross metathesis (CM), and other metathesis-type reactions.The commercial availability and effectiveness of the Grubbs' catalyst now allow olefin metathesis strategies to be viewed as practical methods for the synthesis of medium size ring, 21 spiro and polycyclic systems 22 and natural products. 23A growing number of newly discovered catalytic processes mediated by Grubbs' carbene complex also broaden its synthetic utility beyond olefin metathesis. 24An investigation of its chemistry with 2H-azirine 12 led to the discovery that it rapidly induced a rearrangement at 25 o C producing 3-phenylisoxazole ( 16) in 90% yield.Reaction of the corresponding N-phenylimine 13 proceeded similarly and gave 1,3diphenylpyrazole (17) as the exclusive product (Scheme 6).These results stand in marked contrast to the photochemical behavior of 12 and 13 which afforded 2-phenyloxazole ( 18) and 1,2-diphenylimidazole (19) as the exclusive products.The photoproducts are formed by C-C bond fragmentation and subsequent cyclization of the resulting nitrile ylide.Our attempts to carry out a related rearrangement using Wilkinson's catalyst [RhCl(PPh 3 ) 3 ] proved to be more problematic.Exposure of the 2H-azirinyl acrylate 14 to RhCl(PPh 3 ) 3 in CH 2 Cl 2 resulted only in recovered starting material.When heated at reflux, the reaction afforded a complex mixture of products which resisted separation and purification.However, when 14 was treated with 5 mol% of Wilkinson's catalyst in methanol, a clean reaction ensued and the major product isolated in 65% yield was identified as 5-methoxyimino-5-phenyl-pent-3-enoic acid methyl ester (26).Similar results were obtained using ethanol and trifluoroethanol which furnished the α,β-unsaturated oximes 27 (40%) and 28 (53%).A possible mechanism for the 2Hazirine-RhCl(PPh 3 ) 3 reaction involves initial π-complexation of the organometallic catlyst with the imino bond.Ring opening by C-N bond cleavage would give 24 which can then react with the alcohol to afford 25.Loss of the rhodium complex occurs upon protonation to furnish the observed product.An investigation of the reaction of variously substituted 2H-azirines with other commonly used transition metal catalysts is currently in progress and will be reported at a later date.

Experimental Section
General Procedures.Melting points are uncorrected.Mass spectra were determined at an ionizing voltage of 70eV.Unless otherwise noted, all reactions were performed in flame dried glassware under an atmosphere of dry argon.Solutions were evaporated under reduced pressure with a rotary evaporator and the residue was chromatographed on a silica gel column using an ethyl acetate/hexane mixture as the eluent unless specified otherwise.All solids were recrystallized from ethyl acetate/hexane for analytical data.
A 7.8 g sample of 3-phenyl-2-(dimethoxymethyl)azirine dissolved in 100 mL of dioxane and 150 mL of 20% aqueous acetic acid was heated at 85 o C for 45 min.The reaction mixture was rapidly cooled to 0 o C and extracted with ether.The combined organic extracts were washed successively with 100 mL of aqueous 5% sodium bicarbonate and 100 mL of saturated sodium chloride.Removal of the solvent after drying over magnesium sulfate gave a clear oil which solidified on standing.The crystalline solid that formed (3.8 g, 55%) was collected and was sublimed at 35 o C (0.01 mm) to give white crystals of 2-formyl-3-phenyl-2H-azirine (12); mp 45-47 0 C; IR (KBr) 1785 and 1710 cm -1 ; uv (95% ethanol) 245 nm (15,500); A solution containing 0.3 g of 12 in 50 mL of cyclohexane was irradiated through a Vycor filter sleeve for 75 min.Removal of the solvent under reduced pressure gave dark oil which was purified by chromatography on a silica gel thick layer plate using a 1:4 ethyl acetate-benzene mixture as the eluent.The clear oil obtained (0.21 g) was identical in all respects with an authentic sample of 3-phenyl)oxazole ( 18). 25