Nitrile ylides, cycloaddition with

The 1,3-dipolar cycloadditions of benzonitrile oxides with tertiary cinnamides yield the 5-phenyl and 4-phenyl regioisomers in a reversal of the expected regioselectiv-ities shown with methyl cinnamate. Calculations have shown that steric factors are responsible for this reversal of regioselectivity." The 1,3-dipolar cycloadditions of benzonitrile oxide with electron-rich and electron-poor dipolarophiles are accelerated by sodium dodecyl sulfate micelles. Phenyl nitrile ylides react with electron-deficient alkenes to produce five-membered -heterocycles where measured rate constants are between 4 x 10 and 7 x 10 lmoP ... 

Irradiation of 2,3-diphenyl-2//-azirine in the presence of fullerene leads to the formation of mono- and oligo adducts (98,99). A monoadduct, l,9-(3,4-dihydro-2,5-diphenyl-2//-pyrrolo)fullerene-60 was isolated and characterized. Mechanistic studies showed that under conditions of direct irradiation it was formed by a classic nitrile ylide cycloaddition but in the presence of 1,4-napthalenedicarbonitrile (DCA) it resulted from reaction of the radical cation intermediate 108. Cycloaddition reactions have also been carried out with diaza-phospholes and diazaarsoles (100) to give adducts of the type 189 (A = As,P) and with cyanogen to give 190 and with aryldiazocyanides where addition to both the azo moiety and the cyano group were observed (101). 

The other path by which nitrile ylides react with tr-bonds occurs only in certain intramolecular cases and has been designated as a 1,1-cycloaddition reaction.87 It occurs when the p-orbitals of the alkenic group have been deliberately constrained to attack perpendicular to the nitrile ylide plane. Houk and Ca-ramella have suggested that the 1,1-cycloaddition reaction is initiated by interaction of the terminal cafb-... 

The irradiation of 2i/-azirine 35 in the presence of ethyl acetoacetate is of interest since, in this case, protonation of the nitrile ylide competes with cycloaddition. The protonation reaction is followed by hydrolysis and elimination of ammonia to eventually give ethyl benzylideneacetoacetate 66. ... 

A series of 3-imino-2-aryl-l-azetines has been prepared by cycloaddition of nitrile ylides to isocyanides. Thus generation of the nitrile ylides (215) in the presence of cyclohexyl isocyanide gives the 3-cycIohexyIimino-2-aryI-l-azetines (205). Similar 1-azetines are formed by interception of nitrile ylides with a-methylbenzyl isocyanide (72AG(E)47) cf. Section 5.09.4.2.2). 

Recently, Burger devised an improved method of carrying out mild, regiospecific cyclizations that involve an intermediate that acts as a synthon for a nitrile ylide of HCN [47 (equation 48). With this methodology, cycloadditions with activated alkenes, alkynes, and azo compounds were earned out [47] (equation 49). All such reported reactions were regiospecific and had the same orientational preference... 

Reactions of thiocarbonyl ylides with nitriles are scarce. Simple nitriles do not undergo bimolecular cycloaddition (171). There is, however, a single example of an intramolecular case that was reported by Potts and Dery (24c,62). By analogy to the intramolecular cycloaddition with acetylenic dipolarophiles (Scheme 5.40), the primary product derived from the reaction of a thiocarbonyl ylide with a nitrile group undergoes a subsequent elimination of phenylisocyanate to give the fused 1,3-thiazole (131). 

A -Silylmethyl-amidines and -thioamides (42) (X=NR or S) undergo alkylation at X with, for example methyl triflate, and then fluorodesilylation to give the azomethine ylides 43 (identical with 38 for the thioamides) (25,26). Cycloaddition followed by elimination of an amine or thiol, respectively, again leads to formal nitrile ylide adducts. These species again showed the opposite regioselectivity in reaction with aldehydes to that of true nitrile ylides. The thioamides were generally thought to be better for use in synthesis than the amidines and this route leads to better yields and less substituent dependence than the water-induced desilylation discussed above. 

The 4-phospha-1,3-butadiene 77/80 serves as an effective synthon for the unknown H-substituted nitrile ylide 79 in [3+ 2]-cycloaddition reactions with a range of electron-poor dipolarophUes (e.g., reaction with DMAD gave 78 in 80% yield). Similar yields were also obtained using methyl propiolate, azodicaboxylic esters, ethyl acrylate, and acrylonitrile (39). The reactant was generated under very mild conditions from 75 as shown below. 

Confirmation was provided by the observation that the species produced by the photolysis of two different carbene sources (88 and 89) in acetonitrile and by photolysis of the azirine 92 all had the same strong absorption band at 390 nm and all reacted with acrylonitrile at the same rate (fc=4.6 x 10 Af s" ). Rate constants were also measured for its reaction with a range of substituted alkenes, methanol and ferf-butanol. Laser flash photolysis work on the photolysis of 9-diazothioxan-threne in acetonitrile also produced a new band attributed the nitrile ylide 87 (47). The first alkyl-substituted example, acetonitrilio methylide (95), was produced in a similar way by the photolysis of diazomethane or diazirine in acetonitrile (20,21). This species showed a strong absorption at 280 nm and was trapped with a variety of electron-deficient olefinic and acetylenic dipolarophiles to give the expected cycloadducts (e.g., 96 and 97) in high yields. When diazomethane was used as the precursor, the reaction was carried out at —40 °C to minimize the rate of its cycloaddition to the dipolarophile. In the reactions with unsymmetrical dipolarophiles such as acrylonitrile, methyl acrylate, or methyl propiolate, the ratio of regioisomers was found to be 1 1. 

Some interesting work has been carried out on the generation and reactions of nitrile ylides (e.g., 164 and 171) with different substituents at the nitrile carbon. The effect of such substituents on regioselectivity in cycloaddition reactions throws... 

Extensive work has been done to determine and understand the factors controlling diastereoselectivity in the cycloaddition of nitrile oxides to alkenes but very little is known about nitrile ylides in this regard. Work on their reactions with alkenes that are geminally disubstituted with electron-withdrawing groups (e.g., 187) has illustrated some of the difficulties in such studies. When the imidoyl chloride-base route was used to generate the nitrile ylides it was found that the products 188 epimerized under the reaction conditions. When the azirine route was used, the reaction was complicated by the photochemical isomerization of the dipolarophiles (96,97). Thus, in both cases, it proved impossible to determine the kinetic product ratio. 

Variously substituted nitrile imines are easily available and react readily with a wide range of double and triple bonds. Intermolecular cycloaddition is therefore an area of major interest, and a large proportion of the papers on the use of nitrile ylides in synthesis is concerned with the exploitation of this reaction. Space limitation means, regrettably, that work leading to results that were predictable on the basis of known chemistry (19) has generally not been included. 

In all of the above reactions, a chiral center of the alkene was located in the allylic position. However, as shall be demonstrated next, more distant chiral centers may also lead to highly selective cycloadditions with 1,3-dipoles. In two recent papers, the use of exocyclic alkenes has been applied in reactions with C,N-diphenylnitrone (165,166). The optically active alkenes 109 obtained from (S)-methyl cysteine have been applied in reactions with nitrones, nitrile oxides, and azomethine ylides. The 1,3-dipolar cycloaddition of 109 (R=Ph) with C,N-diphenyl nitrone proceeded to give endOa-1 Q and exOa-110 in a ratio of 70 30 (Scheme 12.36). Both product isomers arose from attack of the nitrone 68 at the... 

Karlsson and Hogberg (291,292) applied the thiocarbonyl ylide 175 in a diastereoselective 1,3-dipolar cycloaddition with 165. The thiocarbonyl yhde was generated in situ by an elimination reaction. The reaction with 165 gave 176 (R = Bu, BnO, Ph) with selectivities of up to 64—80% de. Furthermore, the cycloaddition of a chiral galactose-derived nitrile imine with 165 has been reported (104). 

These results are rationalized on the basis of the intermediate formation of thio-substituted nitrile ylides 58 that undergo regioselective 1,3-dipolar cycloadditions with the dipolarophiles. Some examples are shown in Scheme 7.15. If a dipolaro-phile is not present in the reaction mixture the nitrile ylides 58 (R2 = Me) isomerize to give the 2-aza-1,3-butadienes 59 that can be trapped in a Diels-Alder reac-... 

Phosphites and 2,2-bis(trifluoromethyl)-5(2//)-oxazolone 71 react with elimination of carbon dioxide to give 2-aza-4-phospha-l,l-bis(trifluoromethyl)-l,3-butadiene 72 that can be used as a synthon for the previously unknown hydrogen-substituted nitrile ylide 72a in [3 + 2]-cycloaddition reactions. Examples of cycloadditions of 72a with dipolarophiles to give heterocyclic compounds 12t-ll are shown in Scheme 7.18. 

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