Heteroaromatic nitriles

C NMR studies of various heteroaromatic nitriles, including 1/7-1,2,3- and 2/7-1,2,3-triazolyl nitriles, reveal a correlation between a value derived from the chemical shifts, cn and c-cn and the reactivity of nitriles in forming the corresponding enaminoketones via reactions with the enolate anion of acetone. Based on the correlation, a new reactivity index y is proposed <82H(l9)22l>. 

Few preparations of nitriles have been performed on insoluble supports (Table 13.19). Aromatic and heteroaromatic nitriles have been prepared on solid phase from the corresponding iodoarenes by metallation followed by reaction with tosyl cyanide (Entry 1, Table 13.19). Moreover, the reaction of chloromethyl polystyrene with NaCN has been used to prepare support-bound benzyl cyanide (Entry 2, Table 13.19). Cleavage with simultaneous formation of nitriles can be achieved by treating polystyrene-bound sulfonylhydrazones with KCN (Entry 3, Table 13.19) or by cleaving amides from a Rink or Sieber linker with TFA anhydride (Entry 10, Table 3.38 [262]). Support-bound benzaldehydes have been converted into 3-aryl-2-propenenitriles by means of a Horner-Emmons reaction with (Et0)2P(0)CH2CN [263]. 

The application of nitrilases is broad. A purified nitrilase from Bacillus pallidus was employed to hydrolyse a wide variety of aliphatic, aromatic and heteroaromatic nitriles and dinitriles (Scheme 6.33) [102]. Nitrilases have also been patented for the hydrolysis of a-substituted 4-methylthio-butyronitriles, however, no stereoselectivity was reported [103]. 

Fungal nitrilases immobilized on these columns were applicable to continuous biotransformation of heteroaromatic nitriles like 3- and 4-cyanopyridine, the products of which, nicotinic and isonicotinic acid, respectively, are of commercial interest. The enzyme from F. solani exhibited a higher stability than that from A. niger at 35 °C. The conversion of 3-cyanopyridine by the former enzyme was nearly quantitative within 24h [50], while it decreased by 30% within 15h in the case of the latter [49]. Similar differences in operational stabiUties were observed during conversion of 4-cyanopyridine. The stabiUty of the enzymes depended on the substrate used, both nitrilases being more stable during the conversion of 4-cyanopyridine in comparison with 3-cyanopyridine. 

The nitrile-converttng enzymes in R. rhodochrous J1 strain exhibit high versatUily against a variety of aromatic and heteroaromatic nitriles [5, 15, 23] with the only formation of amide, this strain being deficient of amidase activity toward aromatic amides. 

Researchers in Japan have claimed to produce l,2-dihydro-l,3,5-triazines by high-pressure reactions between aromatic or heteroaromatic nitriles and formaldehyde,249 acetaldehyde,250 or ketones251 in the presence of ammonia. 

Whereas the ammoxidation of lower hydrocarbons leads to more large-scale products such as acrylonitrile [7] or methacrylonitrile [8], the ammoxidation of substituted aromatics or heteroaromatics opens the way for the synthesis of fine chemicals or intermediates for fine-chemical syntheses. A variety of pharmaceuticals, pesticides, dyestuffs, and other speciality products are produced from substituted aromatic or heteroaromatic nitriles [e.g. 9,10]. 

Copper(I) cyanide in dimethylformamide displaces bromine in positions 5 or 6 of disubstituted imidazo[2,l-i][l,3,4]thiadiazoles (56) forming the corresponding heteroaromatic nitriles (Table 18) <83JHC1003, 88ZOR199). 

Aromatic and heteroaromatic nitriles were selectively transformed into the corresponding amides by a Rhodococcus rhodochrous strain [663] the products accumulated in the culture medium in significant amounts (Scheme 2.103). In contrast to the hydrolysis performed by chemical means, the biochemical transformations were highly selective and occurred without the formation of the corresponding carboxylic acids. 

Scheme 2.103 Chemoselective microbial hydrolysis of aromatic and heteroaromatic nitriles yielding carboxamides (product concentrations)...

The results showed that the supports did not present significant catalytic activity (Table 1.7, entry 11-13). On the other hand, the catalytic activity of TPA supported on high-surface-area Si02, active carbon, and PMP has been increased with respect to the use of TPA alone (Table 1.7, entry 10). The optimized reaction conditions were used for the synthesis of several 2-oxazoline derivatives (19) starting from various aromatic (or heteroaromatic) nitriles and 2-aminoethanol (or 2-amino-2-methylpropanol). As reported in Table 1.8, in all entries, high to excellent yields were obtained. Notably, the authors reported that both mono- and bis-oxazolines can be obtained by this... 

Tetrazole derivatives are of interest as important components of drugs, e.g., antibiotics, antiallergics, or hormonal preparations. The simplest synthesis of tetrazoles is based on the [3+2] cycloaddition reaction of nitriles with hydra-zoic acid or its derivatives. Makhova et al. [180] reported the synthesis of 5-mono- and 1,5-disubstituted tetrazoles 90 91, respectively by reaction of aliphatic, aromatic, and heteroaromatic nitriles with NaNa or activated nitriles with organic azides in the presence of ILs functioning both as a reaction medium and as a catalyst (Scheme 45). They... 

Supported Ln(0Tf)3-Si02 triflate catalyst affords a facile and atom economical synthesis of 5-substituted IH-tetrazoles from various aromatic/heteroaromatic nitriles in the reaction with sodium azide (Equation (8.66)) [140]. This protocol enables the cycloaddition process in a shorter time, eliminating the hazards of direct use of hydrazoic acid with an enhancement of yield, separation, and reusability of the catalyst. 

Nickel-bpy and nickel-pyridine catalytic systems have been applied to numerous electroreductive reactions,202 such as synthesis of ketones by heterocoupling of acyl and benzyl halides,210,213 addition of aryl bromides to activated alkenes,212,214 synthesis of conjugated dienes, unsaturated esters, ketones, and nitriles by homo- and cross-coupling involving alkenyl halides,215 reductive polymerization of aromatic and heteroaromatic dibromides,216-221 or cleavage of the C-0 bond in allyl ethers.222... 

Probably, the diversity of nitrile oxide chemistry is not conducive to writing reviews related to all aspects of their reactivity. Therefore, only several references can be mentioned, which are connected with several topics in this section. Among these are the reviews devoted to the photochemistry of N-oxides (including nitrile oxides) (100) and reactions of nitrilium betaines with heteroaromatic compounds (101). Other references on reviews will be given in corresponding subsections or paragraphs. 

Heterocycles Both non-aromatic unsaturated heterocycles and heteroaromatic compounds are able to play the role of ethene dipolarophiles in reactions with nitrile oxides. 1,3-Dipolar cycloadditions of various unsaturated oxygen heterocycles are well documented. Thus, 2-furonitrile oxide and its 5-substituted derivatives give isoxazoline adducts, for example, 90, with 2,3- and 2,5-dihydro-furan, 2,3-dihydropyran, l,3-dioxep-5-ene, its 2-methyl- and 2-phenyl-substituted derivatives, 5,6-bis(methoxycarbonyl)-7-oxabicyclo[2.2.1]hept-2-ene, and 1,4-epoxy-l,4-dihydronaphthalene. Regio- and endo-exo stereoselectivities have also been determined (259). 

Among heteroaromatic compounds able to react with nitrile oxides as dipo-larophiles, furan, probably, is the best known. Recently, a novel nitrile oxide was generated from a sulfoximine and converted in situ to a cycloadduct with furan (Scheme 1.25) (287). The starting racemic N-methyl-S-nitromethyl-S-phenylsul-foximine 124 was prepared in 87% yield via nitration of N,S-dimethyl-S-phenyl-sulfoximine. Reaction of 124 with p-chlorophenyl isocyanate and a catalytic quantity of triethylamine, in the presence of furan, afforded dihydrofuroisoxazole 125, the product of nitrile oxide cycloaddition, in 42% yield (65 35 diastereomer ratio). The reaction of 125 with phenyllithium and methyllithium afforded compounds 126, which are products formed by replacement of the sulfoximine group by Ph and Me, respectively. 

The scope of the aldehyde inputs includes a wide range of (hetero)aromatic aldehydes as well as a,(3-unsaturated aldehydes. With the use of aliphatic aldehydes, side products due to aldol condensations could be observed. Allowed ot-substituents at the isocyano acetate (1) includes R" = Ph, H, Me, Et, Bn, iBu, iPr. The scope according to the nitrile input includes aromatic, heteroaromatic, and aliphatic nitriles. However, the use of primary aliphatic nitriles should be avoided. 

A mechanism for 1,2,5-thiadiazole formation was proposed in the 1960s (1967JOC2823) and seems to be reliable this includes the formation of the M-chlorodithio intermediate followed by chlorination of the nitrile function, ring closure, addition of the second molecule of sulfur monochloride and formation of the heteroaromatic 1,2,5-thiadiazole cycle (Scheme 18). 

Heteroaromatic A-imines undergo 1,3-dipolar cycloaddition reactions across the A-imine nitrogen atom and the a-position of the ring. With nitriles, triazolopyridines are formed by dehydrogenation of... 

Water was not formerly regarded as a suitable solvent for the reaction of nitriles with azides. Demko and Sharpless <2001JOC7945> were the first to show that 1/7-tetrazoles with various aromatic and heteroaromatic substituents on the ring carbon could be obtained by refluxing in water the corresponding nitriles, NaN3, and ZnBr2 in equimolar... 

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