Intermediates nitriles

As shown by the Italian school, the formation of isoxazole derivatives by the action of nitric acid or nitrogen oxides on acetylene derivatives and related reactions proceeds through intermediate nitrile oxides and must, therefore, be included with this type of synthesis. 

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>... 

Chiral tricyclic fused pyrrolidines 29a-c and piperidines 29d-g have been synthesized starting from L-serine, L-threonine, and L-cysteine taking advantage of the INOC strategy (Scheme 4) [19]. L-Serine (23 a) and L-threonine (23 b) were protected as stable oxazolidin-2-ones 24a and 24b, respectively. Analogously, L-cysteine 23 c was converted to thiazolidin-2-one 24 c. Subsequent N-allylation or homoallylation, DIBALH reduction, and oximation afforded the ene-oximes, 27a-g. Conversion of ene-oximes 27a-g to the desired key intermediates, nitrile oxides 28 a-g, provided the isoxazolines 29 a-g. While fused pyrrolidines 29a-c were formed in poor yield (due to dimerization of nitrile oxides) and with moderate stereoselectivity (as a mixture of cis (major) and trans (minor) isomers), corresponding piperidines 29d-g were formed in good yield and excellent stereoselectivity (as exclusively trans isomers, see Table 3). 

As we found that furan and thiophene substituted oximes can be used as substrates for the INOC reactions (Eq. 5) [29b] similarly, furan substituted nitro alkane 134 is also a good substrate for INOC reactions (Eq. 13) [40]. The furfuryl derivative 134, prepared via Michael addition of furfuryl alcohol to 4-methoxy- -nitrostyrene, was subsequently transformed without isolation of the intermediate nitrile oxide 135 to the triheterocyclic isoxazoline 136 as a 5 1 mixture of isomers in high yield. 

Oxidation of oxime 422 with aqueous sodium hypochlorite has been used to synthesize the central piperidine ring of the tricyclic system 423 in moderate yield, which presumably proceeds via an intramolecular 1,3-diploar cycloaddition of the intermediate nitrile oxide (Equation 114) <2000EJ0645>. 

SCHEME 37. Synthesis of an Analogue of the Miharamycin Sugar Moiety Involving Silica Gel-Mediated Hydrolysis of the Intermediate Nitrile 197 and Lactonization. 

Interesting examples of the addition of N-nucleophiles to nitrile oxides are syntheses of chelated Z-amidoxime, N-[2-(dimethylaminomethyl)phenyl]mesitylene-carboamidoxime (118), and pyranosyl amidoximes (119) from the respective nitrile oxides and amines. Aromatic aldoximes undergo unusual reactions with chloramine-T (4 equiv, in refluxing MeOH). N-(p-toly 1 )-N-(p-tosy 1 )benzamides are formed via addition of 2 equiv of chloramine-T to the intermediate nitrile oxide followed by elimination of sulfur dioxide (120). 

Nitrile oxides react in situ with formaldehyde dimethylhydrazone (129) to give oxime-hydrazones RC( NOH)CH NNMe2 (R = 4-O2NC6H4, MeCO, MeC ( NOH)). The reaction is performed on treatment of oximes with CH2 NNMe2 in the presence of Et3N without isolation of the intermediate nitrile oxides. 

Intramolecular [3+2] dipolar cycloadditions have also been employed as a post-Ugi transformation to generate heterobicyclic structures, namely fused isoxazolines [130], isoxazoles [130] and triazoles [131] (Fig. 31). Isoxazoles were obtained through intramolecular nitrile oxide cycloaddition. The precursor of the nitrile oxide (a nitro group) was introduced into the carboxylic component, while a triple bond was positioned in the starting amine. Treatment of 152 with POCl3/Et3N gave the intermediate nitrile oxide, which spontaneously cyclized to isoxazoles 153. 

Notably, starting and intermediate nitriles used in the synthesis of 2-amino-3-cyanopyrans show moderate to weak nitrile group absorption at 2260-2220 cm, the nitrile band is very characteristic. 

Azolines of type (13) undergo thermal decomposition in an analogous way to that already discussed for azolones (see Section 4.14.5.2) (Scheme 19). Path (i) is followed by those azolines having Z = S and path (ii) by those with Z = O. Path (i) is a typical retro-1,3-dipolar cycloaddition process, via an intermediate nitrile sulfide, while path (ii) might involve an acyl (Y = Z = O) or thioacyl (Y = S, Z = O) nitrene intermediate (136), which in turn rearranges to iso(thio)cyanate. However, no systematic attempts to trap this possible nitrene intermediate seem to have been made, and so a concerted pathway for the fragmantation cannot be ruled out. 

An improved modification of this protocol has been described, which provides the desired molecule in three steps and 68% overall yield (Scheme 14.2). The route was essentially the same as in Scheme 14.3, except that the intermediate nitrile 15 was converted to the bicyclic aminal 17, which was then fiuther alkylated to provide the final target. This method was reported as being amenable for large-scale synthesis. 

Similarly, lipase-catalyzed kinetic resolution has also been applied to intermediate nitrile alcohol 46 (Scheme 14.14). Best results were obtained by using immobilized Pseudomonas cepacia (PS-D) in diisopropyl ether, leading to excellent yield and enantiomeric excess of the desired (5)-alcohol 46a, along with (/J)-nitrile ester 47. Reduction of 46a with borane-dimethylsulhde complex, followed by conversion to the corresponding carbamate and subsequent lithium aluminum hydride reduction gave rise to the desired (S)-aminoalcohol intermediate 36, a known precursor of duloxetine (3). 

The reaction of cyclobutanone oxime 277 with S2GI2 affords the conjugated 1,2-thiazine 70 in 45% yield (Equation 38) <1996JOC9178>. The proposed mechanism for this transformation involves the intermediate nitrile 278, which reacts to form imino-disulfide 279. Following ring contraction of 279 and further chlorination, product 70, whose structure was confirmed by X-ray analysis, is obtained. 

The hitherto unknown oxazolo[4,5-f]isoxazole system has been synthesized by Nesi et al. in their studies on isoxazoles and their reactions. Oxazole 118 reacts with 1-dimethylaminopropyne through, what the authors describe as a four-step hetero-domino sequence, which they postulate includes a 1,3-dipolar cycloaddition of intermediate nitrile oxide 122 (Scheme 13) <1999T13809>. 

Several years ago, Jim-Min Fang of National Taiwan University reported that an aldehyde 9 was smoothly converted into the corresponding nitrile 10 by iodine in aqueous ammonia. He has now observed (J. Org. Chem. 68 1158,2003) that the intermediate nitrile can be carried on in situ to the amide 11, the tetrazole 12, or the triazine 13. 

Ring fused products can be elaborated from isoxazolines (80S757). Several nitrocyclo-alkenes (516) were prepared and reacted with phenyl isocyanate to generate the intermediate nitrile oxides which underwent internal cycloaddition to afford the tricyclic isoxazolines (517). Cleavage of the N—O bond by hydrogenation in the presence of a catalytic amount of Raney nickel and subsequent hydrolysis afforded the /3-ketol (518 Scheme 113). 

A one-step synthesis of tricyclic diazadihydroacenaphthylenes with an isoxazoline ring has been developed from 1 -benzylamino-1 -methylthio-2-nitroethene derivatives induced by a large excess of triflic acid715 [Eq. (5.265)]. Dications 169, similar to those detected by Coustard,197 were observed by NMR spectroscopy. Quenching with water gives a reactive intermediate nitrile oxide, which undergoes an intramolecular cyclization to furnish the final products in fair yields. 

The potential of laser flash photolysis in the study of carbene reactions with heteroatoms has come to be recognized in recent years. A number of kinetic studies using this technique have been carried out with carbene precursors in nitrile solvents.122-127 An absorption band at 470 nm was observed in the laser flash photolysis of diazofluorene (246) in inert solvents. This band was assigned to triplet fluorenylidene (247). In acetonitrile, however, a second band was also detected at 400 nm and whose buildup is concurrent with the decay at 470 nm.122 Laser flash experiments in other nitrile solvents (i.e., benzonitrile and pivalonitrile) also produced a transient absorption band which is very similar to that observed in acetonitrile. The band at 400 nm was assigned to an intermediate nitrile ylide (248). This absorption could be quenched on addition of an electron-deficient olefin providing good support for its... 

The thermolysis of (358) also leads to aromatisation, in this case in a process believed to involve an intermediate nitrile ylid. Evidence for this is obtained by thermolysis of a series of cyclopropenyl-substituted oxazolinones such as (359) for which cycloreversion with elimination of C02 is known to lead to a nitrile ylid. In some cases the ylid could be trapped by addition to methyl propiolate. Substituent effects suggest that the nitrile ylids undergo stepwise addition to produce a bicyclobutyl zwitterion which can either collapse to an azabenzvalene or rearrange to a cyclobutenyl cation 286>. 

A more recent method which provides 3,5-disubstituted products (301) of unequivocal structure involves the thermolysis of a 5-substituted l,3,4-oxathiazol-2-one (338) in the presence of a nitrile (usually in excess) (Scheme 143) (77JOC1813). Best yields are obtained when the intermediate nitrile sulfides (70TL1381) are generated in the presence of nitriles which are electron deficient (see Scheme 122). Another excellent method for the synthesis of C-linked 1,2,4-thiadiazoles involves the amidation of thioacylamidines (353) as indicated in Scheme 144 (80JOC3750) (also see Scheme 117). 

Some imidoyllithiums 52 derived from triphenylmethyl isocyanide (51) dissociate to produce nitriles, which react with an organolithium reagent to give the corresponding imines and, after their hydrolysis, ketones. The intermediate nitrile can be isolated working at —78°C, whereas for the isolation of imines or ketones, after addition of the organolithium, the reaction was allowed to warm to room temperature (Scheme 14)74. The structure of the imidoyllithium intermediate has been assigned by IR spectroscopy... 

Reactions of carbenes with nitriles produce an intermediate nitrile ylide, which readily undergoes 1,3-dipolar cycloaddition, lire formation of pyrro-... 

Cherest, M., and Lusinchi, X., The Action of Acetyl Chloride and of Acetic Anhydride on the Lithium Nitronate Salt of 2-Phenylnitroethane. Reactivity of the Intermediate Nitrile Oxide as an Electrophile or as a Dipole, Depending on the Nature of the Medium, Tetrahedron, 42 (14) 3825-3840 (1986). (English Abstract). 

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