Nitrile ylides reactions

The ring opening of 2//-azirines to yield vinylnitrenes on thermolysis, or nitrile ylides on photolysis, also leads to pyrrole formation (B-82MI30301). Some examples proceeding via nitrile ylides are shown in Scheme 92. The consequences of attempts to carry out such reactions in an intramolecular fashion depend not only upon the spatial relationship of the double bond and the nitrile ylide, but also upon the substituents of the azirine moiety since these can determine whether the resulting ylide is linear or bent. The HOMO and second LUMO of a bent nitrile ylide bear a strong resemblance to the HOMO and LUMO of a singlet carbene so that 1,1-cycloadditions occur to carbon-carbon double bonds rather than the 1,3-cycloadditions needed for pyrrole formation. The examples in Scheme 93 provide an indication of the sensitivity of these reactions to structural variations. 

Nitrile ylides derived from the photolysis of 1-azirines have also been found to undergo a novel intramolecular 1,1-cycloaddition reaction (75JA3862). Irradiation of (65) gave a 1 1 mixture of azabicyclohexenes (67) and (68). On further irradiation (67) was quantitatively isomerized to (68). Photolysis of (65) in the presence of excess dimethyl acetylenedicar-boxylate resulted in the 1,3-dipolar trapping of the normal nitrile ylide. Under these conditions, the formation of azabicyclohexenes (67) and (68) was entirely suppressed. The photoreaction of the closely related methyl-substituted azirine (65b) gave azabicyclohexene (68b) as the primary photoproduct. The formation of the thermodynamically less favored endo isomer, i.e. (68b), corresponds to a complete inversion of stereochemistry about the TT-system in the cycloaddition process. 

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... 

The chalcogene heterocycles have been used as stable precursors for sulfur-said selenium-cantaining hetero-l,3-dienes in cycloaddition reactions 3//-l,2,4-Thiaselenazoles are a convenient source of 4,4-bis(trifluoromethyl)-l-thia-3-aza-buta-1,3-dienes, and 3//-diselenazoles are a convenient source of 4,4-bis(trifluoromethyl)-l-selena-3-azabuta-l,3-dienes as well as bis(tnfluoro-methyl)-substrtuted nitrile ylides [137]... 

Bis(tnfluoromethyl)-substituted nitrile ylides undergo dimerization reactions in the absence of trapping reagents [143, 168, 170] (equation 38)... 

Despite the above, there is also considerable evidence to suggest that oxazole formation proceeds via an intermediate nitrile ylide, particularly in the catalysed reactions (see below). Nitrile ylides have been detected in laser flash photolysis studies of diazo compounds in the presence of nitriles, and stable nitrile ylides can be isolated in some cases.<94CRV1091>... 

Reaction of iV-[(benzotriazol-l-yl)methyl]amide 707 with PCI5 gives chloroimine 708, which upon treatment with Bu OK is converted to nitrile ylide 709. Benzyl esters of ot,(3-unsaturated acids used as dipolarophiles trap species 709 to generate pyrroles 712 (Scheme 110) <2002JHC759>. When no trapping agent is added, the N-2 atom of benzotriazole act as a nucleophile, and tricyclic system 711 is formed <2001TL9109>. Addition of benzyl bromide... 

Cyclodditions to Carbon-Heteroatom Triple Bonds. Transient electrophilic carbenes are known to react with nitriles to give transient46 or even stable nitrile ylides 30.47 No reaction of transient nucleophilic carbenes with nitriles has been reported. 

Reaction between trichloroacetonitrile and Ph2CN2 at low temperatures yields 67 other electron-deficient nitriles give different products. It is possible that the reaction proceeds via an unstable 3//-1,2,4-triazole intermediate, which loses N2 to form a nitrile ylide before adding a second mole of nitrile as in Scheme 13. 

The highly effective desilylation routes to nonstabihzed azomethine ylides have provided the basis for much of this chemistry. Thus, the reaction of A-(silylmethyl)-thioimidates (30) with AgF in the presence of a range of dipolarophiles (electron-deficient alkenes and alkynes, and aldehydes) led to the isolation of nitrile ylide adducts in generally high yields (20,21). Differences in reactivity and regioselectivity... 

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. 

A similar reaction of 70 leads to an amino nitrile ylide synthon (36,37), which reacts with a range of aromatic and heteoaromatic aldehydes to give the 2-oxazolines (71), but which fails to react with ahphatic aldehydes, simple ketones, or activated alkenes. 

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. 

The direct assembly of nitrile ylides by the reaction of carbenes (e.g., 84) with nitriles has, in principle, great potential for structural variation as both components are easily accessible. The first reports of such reactions appeared in the early 1980s and were concerned with the reaction of nitriles with stabilized carbenes such as 84 and 86 (41 3). 

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. 

Much work has been done since the early 1980s on the detailed investigation of the azirine-nitrile ylide interconversion using pulsed-laser photolysis. Thus the azirines 103 (R =R =Ph, R =H R =Me, R = R =Ph R = p-napthyl, R = Me, R = H), on irradiation in isooctane, gave intense long-hved absorptions (250-400 nm) attributed to the nitrile ylides 104 (44). Quenching studies with electon-deficient alkenes led to the determination of absolute rate constants that were similar to those reported earlier for steady-state trapping experiments. The nitrile ylide-olefin reactions are discussed in more detail in Section 7.3.1. 

This method has been used extensively for the generation of diene- and triene-conjugated nitrile ylides (see Section 7.4.1.2) using strong bases. Potasium tert-butoxide (58) was used for the most part but in recent work (59,60) it was reported that lithium bisftrimethylsilyl)amide is both more effective and more convenient. It has also been shown that thermally unstable imidoyl chlorides for use in these reactions can be prepared by reaction of the corresponding amides with chlorodi-methylformiminium chloride at 0 °C, a reaction that is more effective than using either thionyl chloride or phosphoms pentachloride at higher temperatures (61). 

The cyano-substituted nitrile ylides 123 have been generated via 1,1-elimination reactions. For example, the benzyhdene derivative 122 (R=Ph) eliminated benzene on vapor phase pyrolysis to give 123 (R=Ph), which reacted via 1,5-electrocycli-zation [see also (66)] to give the isoindole 124 (41%) (67). In a similar way, 122 [R=(CH2)3CH=CH2] gave the corresponding nitrile yhde that reacted via intramolecular cycloaddition to give the pyrroline derivative 126. 

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... 

In the first addition of nitrile ylides to a,()-unsaturated lactones (92), it was found that the reaction of benzonitrilio 4-nitrobenzylide with the lactones 178-180 were strongly regioselective. Compounds 178 and 179 reacted to give [e.g., 181 from 178 (51%)] and its methyl analogue from 179 (54%). The exocyclic double bond in 180 was, however, the most reactive and gave 182 (69%). The six-membered analogue of 178 was less reactive (34%) and the seven-membered analogue failed to react. 

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. 

Intramolecular cycloaddition of nitrile ylides to olefinic dipolarophiles linked to the dipole by a three-atom chain leads to pyrazoles fused to five-membered rings. Work on stereoselectivity in such reactions has been carried out using the reactant 266 in which the alkene moiety is linked to the C-terminus via a tether that incorporates an enantiomerically pure (R) stereogenic group (165). Both diastereo-isomers 267 and 268 were isolated and it was found that the reaction showed moderate stereoselectivity favoring 267. 

Some interesting new chemistry has been produced on the well-known 1,5-electrocyclization reaction of alkene-conjugated nitrile ylides but the greatest... 

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