Nitriles heteroaromatic compounds

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 1,4-dinucleophilic building blocks used most are 1,2-disubstituted ethanes of the type HXCHiCHjYH, semicarbazides, thiosemicarbazides, hydroxamic acid amides, amidrazones, and 1,2-disubstituted aromatic and heteroaromatic compounds. 1,1-Dielectrophilic building blocks preferentially used are perfluorinated carboxylic acids and their derivatives, such as acid halides, anhydrides, imidoesters, nitriles, perfluoroalkyl chlorosul-... 

Both batch reactors (autoclaves) and continuous fixed-bed reactors are suitable for alcohol amination. High pressure in the range 50-150 bar is necessary only for reactions with ammonia. The usual temperature is ca 200 °C, but achieving good selectivity for unsaturated amines, nitriles, or heteroaromatic compounds requires 300-400 °C. Solvents other than ammonia are rarely applied. 

Ammoxidation refers to the formation of nitriles by oxidation of hydrocarbons with oxygen in the presence of ammonia (Figure 1) [1]. Ammoxidation is best conducted with olefins, or with aromatic or heteroaromatic compounds, containing a readily abstractable H atom (allylic or benzylic intermediates are formed), although the ammoxidation of alkanes (e. g. propane to acrylonitrile [e. g. 2-4] or ethane to acetonitrile [e. g. 5]) is also possible. An exceptional example is the ammoxidation of methane to hydrogen cyanide by the Andrussov reaction [6]. 

Figure 1. Formation of nitriles by ammoxidation of alkanes, alkenes, methyl aromatic and heteroaromatic compounds.

The ammoxidation of methyl aromatic and heteroaromatic compounds is a convenient route to many nitriles required for further synthesis of fine chemicals. For example, for the production of amines by hydrogenation or of carboxylic acids and amides by hydrolysis. 

Fragmentation of an adduct with release of a nitrile, CO2 or N2 are most common and the latter provide an irreversible method for the formation of a new diene or aromatic compound. Cycloaddition of a pyran-2-one or a 1,2-diazine (pyridazine) with an alkyne gives an intermediate bridged compoimd that loses CO2 or N2 to generate a benzene derivative (see Scheme 3.46). Many other aromatic and heteroaromatic compounds can be prepared likewise. For example, a synthesis of lavendamycin made use of the inverse electron demand Diels-Alder reaction between the 1,2,4-triazine 116 and the enamine 117, followed by in situ elimination of pyrrolidine and retro Diels-Alder reaction, releasing N2 and the substituted pyridine 118 (3.88). 2... 

Although acetonitrile is a common solvent in aryne chemistry, it is rarely involved as a reactant in the coupling reactions with arynes. Recently, a three-component coupling of arynes, N-heteroaromatic compounds, and nitriles was reported by Jeganmohan and Cheng (Scheme 12.18) [42] where the reachon was initiated by a nucleophilic attack of the N-heteroaromatic on the aryne, leading to a zwitterionic species 50. The zwitterion 50 then abstracted a proton from acetonitrile (or other nitrile) to afford intermediate 51, alongside anion 52. Anion 52... 

Miscellaneous Transformations. The hypervalent iodine(III) reagent phenyliodine bis(trifluoroacetate) (PIFA) mediates the selective cyanation reaction of a wide range of electron-rich heteroaromatic compounds such as pyrroles, thiophenes, and indoles under mild conditions (eq 42). Nonactivated arylalkenes are effectively converted to tertiary benzylic nitriles in the presence of triflic acid and cyanotrimethylsilane (eq 43). ... 

Imines, azo derivatives, and heteroaromatic compounds (nitrogen sp -hybridized) form nitrones (2), azoxy derivatives (3), and heteroaromatic N-oxides (4), respectively. Nitriles (nitrogen sp-hybridized) form nitrile N-oxides (5, Equation 99.2). 

Nitriles and nitrilium salts, heterocyclic synthesis involving, 6, 95 Nitro-compounds, heteroaromatic, ring synthesis of, 25, 113 Nitrogen-bridged six-membered ring systems, 16, 87... 

Methods of deoxygenation of nitrones (28), nitrile oxides (29), heteroaromatic N-oxides (30) and tertiary amine oxides (31) are described in this section. There are some reagents, such as trialkyl phosphites, which can deoxygenate compounds of all these types as well as those in the preceding section, whereas others are more limited in scope. Oae and coworkers have outlined three distinct mechanistic types of deoxygenation process, which are illustrated in Scheme 17. Clearly, a mechanism of type C will not apply to tertiary amine oxides (31) on the other hand, these compounds are more easily deoxygenated than heteroaromatic N-oxides, such as (30), by some reagents because the aromatic N-oxides are inherently more stable. 

Although aryl iodides represent the most reactive substrates, a very large number of reactions have been run with the bromides, as these are more easily available and still offer satisfactory reactivity. From chloroaryl iodides the corresponding chloronitriles may be obtained with remarkable selectivity. Many heteroaromatic halogen compounds have been transformed into the corresponding nitriles in an analogous manner. ... 

If the heterocyclic nucleus is fully aromatic, the compounds are called heteroaromatic enamino esters and nitriles (see Scheme 2). Because of the aromatic ring there might be a modified electronic situation with respect to the enaminocarbonyl chromophore (cf. Section III). 

Nitrile oxides are conveniently generated in situ by dehydration of primary nitro compounds (with phenylisocyanate or ethyl chloroformate or di-tert-butyl dicarbonate) or from a-chloro-oximes (by treatment with a base). The nitrile oxide reacts with an alkene to form an isoxazoUne or with an alkyne to give a heteroaromatic isoxazole (3.131). Nitrile oxides are prone to undergo dimerization, although this can be minimized by maintaining alow concentration of the dipole in the presence of the dipolarophile. 

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