Hydroxylamine addition, nitrile

The two major methods of preparation are the cycloaddition of nitrile oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamines. Additional methods include reaction of /3-haloketones and hydroxylamine, the reaction of ylides with nitrile oxides by activation of alkyl nitro compounds from isoxazoline AT-oxides (methoxides, etc.) and miscellaneous syntheses (62HC(i7)i). 

The pharmacological versatility of this general substitution strategy is further illustrated by diazonium coupling of 14 with 2-nitrobenzenediazonium chloride to produce biarylal-dehyde 18. Formation of the oxime with hydroxylamine is followed by dehydration to the nitrile. Reaction with anhydrous methanolic hydrogen chloride leads to imino ether and addition-elimination of ammonia leads to the antidepressant amid-ine, nitrafudam (20). ... 

Nitro compounds are versatile precursors for diverse functionalities. Their conversion into carbonyl compounds by the Nef reaction and into amines by reduction are the most widely used processes in organic synthesis using nitro compounds. In addition, dehydration of primary nitro compounds leads to nitrile oxides, a class of reactive 1,3-dipolar reagents. Nitro compounds are also good precursors for various nitrogen derivatives such as nitriles, oximes, hydroxylamines, and imines. These transformations of nitro compounds are well established and are used routinely in organic synthesis. 

A previous review has highlighted the following methods of ring synthesis intramolecular cyclization of oximes, nitro alkenes, and nitrones, and [4+2] cycloaddition reactions <1996CHEC-II(6)279>. In addition to that, this review includes the intramolecular cyclization of hydroxylamines, hydroxamates, hetero-Diels-Alder [4+2], 1,3-dipolar cycloaddition of nitrile oxides to alkenes, and [3+3] cycloaddition reactions. This review does not cover cycloaddition reactions of the [4+2] [3+2] and [4+2] [3+2] [3+2] types which primarily led to heterocycle-fused oxazine ring systems. 

Ammonia or an amine can also be introduced between a terminal aldehyde or a ketone and a suitably placed double or triple bond, although the method is of limited use. A poor yield of 4-picoline is obtained when the aldehyde (262) is treated with ammonia or an ammonium salt (49JCS1430) and dihydroquinolines from the phenylethyl ketones (263) and hydroxylamine (76MI20800). More commonly, cyclization occurs by insertion of ammonia, amines or hydroxylamine between two triple or double bonds in the former case, pyrid-4-ones (264) are obtained (54BSF734) in the latter, a piperid-4-one (265) results (1897CB231). Amines have also been used to give N -substituted piperid-4-ones (70OMR(2)197>. In these cases a double 1,4-addition must be involved in the cyclization of the unsaturated nitrile... 

Nach diesen Vorstellungen erfolgt in der ersten Stufe eine Reduktion von Nitro-ethan mit Ammoniak zu Hydroxylamin, das mit dem Arylaldehyd iiber ein Aldoxim ein Arylnitril bildet. Die weiteren Reaktions-schritte bestehen dann in einer Addition von Hydroxylamin an dieses Nitril zum Carbonsaure-amid-hydroximid, aus dem mit Essigsaure iiber die O-Acetyl-Derivate 1,2,4-Oxadiazole gebildet werden31. 

Cyclization of the initial acyclic adducts is also possible and several heterocyclic ring systems can be formed.157 Addition of hydrazine or hydroxylamine to the nitrile (618 equation 143) produces the ami-... 

Acid derivatives including esters, amides, halides and nitriles are readily accessible. Dicyanofuroxan (72) shows in its reactions some similarities to phthalonitrile (75LA1029) it also provides a source of fused pyridazino- and oxazino-furoxans (73) and (74) via addition with hydrazine and hydroxylamine, respectively (82H(19)1063). The tetronic acid compound (75) yields a hydroxyamide (76) on aminolysis (79S977). 

A few 6- and 8-cyanopurines have been prepared and undergo characteristic nitrile addition reactions rather readily. Thus, alkaline hydrolysis produces carboxamides, then carboxylic acids, alcoholysis leads to imidates, ammonolysis to amidines, hydrazinolysis to amidhydrazines, hydroxylamine to amidoximes, and hydrogen sulfide to thioamides. Acid hydrolysis tends to give the decarboxylated acid derivative. Reduction either by sodium-ethanol or, preferably, by catalytic hydrogenation affords aminoalkylpurines and addition of Grignard reagents produces, in the first place, acylpurines. As with aldehydes, most of the compounds examined have been relatively non-polar derivatives. Table 28 lists some reactions and relevant literature. 

Using this pulse sequence to estimate the nature of derivatization of Suwannee River fulvic acid with N-enriched hydroxylamine to leam more about the carbonyl functionality of fulvic acid, Thom et al.(76) obtained signals for the primary products as oximes. Additional signals of secondary products arising from Beckmann rearrangements of the initial oxime derivatives were identified as nitriles, secondary amides and lactams. The bands assigned to hydroxamic acid result from a reaction of esters with NH2OH and are evidence for the presence of esters in the fulvic acid. 

Related metallacycles have also been prepared from diamines at Pt11 centers137 and from hydrazines which give the amidrazone chelates (14) (M = Fe,138 Ru,139 Os,140 W141). In addition O-containing metallacycles, (15) (M = MoIV142 WVI143), have been reported from /V-addilions, to nitriles, of hydroxylamines. The O-additions of these ambidentate nucleophiles were discussed above. 

Aliphatic aldehydes, their trimers, or bisulfite addition compounds, when refluxed in 95% ethanol with hydroxylamine hydrochloride and a few drops of hydrochloric acid for 6 hrs., give the corresponding nitriles in practically quantitative yield.16... 

Dipolar cycloaddition of nitrile oxides to cyclohexenes and the action of hydroxylamine on 2-acylcyclohexanones constitute the main synthetic routes to 4,5,6,7-tetrahydroindoxazenes. A convenient one-step synthesis utilizes the addition of a nitrile oxide to cyclohexenones of type 69 (X = OH, OMe, OAc, Cl, NH2, or NR2) (Eq. 4).88... 

Another aspect to Rogers s work on the synthesis of unsymmetrical hydroxylamines (Section 4.2.5.1) is that the elimination step is base catalyzed (occurring at room temperature).16 Salts of amine oxides derived from P-aminopropionic esters 45 or nitriles 46 undergo the reaction, which involves a retro-Michael addition, facilitated by the formal positive charge on nitrogen. 

Regioselective functionalization of the N-3 of 125 with 1,2,4-oxadiazole as amide isostere using an IL-bound 125 with chloroacetonitrile afforded N-3 substituted 126 (Scheme 48). The nitrile group of 126 was transformed into amidoxime 127 with hydroxylamine hydrochloride. Addition of aliphatic carboxylic anhydrides or aromatic carboxylic acid to 127 furnished 129 via the 0-acylamidoxime intermediate 128, after cleavage from the IL (07TL1063) (Scheme 48). 

This reaction was initially reported by Granacher in 1922. It is the preparation of thionic acid by the treatment of Aldol Condensation product from an aldehyde and rhodanine with a base (e.g., NaOH). Therefore, this reaction is known as the Granacher synthesis or Granacher reaction." The prepared thionic acid in this reaction can be further converted into a variety of derivatives under different conditions. For example, it can be transformed into a-thiol acid under a basic sodium amalgam reduction, whereas aliphatic acid is formed under an acidic zinc amalgam reduction. In addition, when the thionic acid is treated with ammonia, a-keto acid is generated, and the thionic acid can be converted into af-carboxyl oxime in reaction with hydroxylamine, from which either cy-amino acid or aliphatic nitrile forms via the treatment of sodium amalgam reduction or acetic anhydride, respectively. 

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