Reaction of Nitrilimines and Nitrile Oxides with Hydrazines, Hydrazones and Oximes

This review article discusses the reaction of nitrilimines and nitrile oxides with hydrazines, hydrazones, and oximes. Three reaction modes were observed. The article mainly covers our work published over the last fifteen years, in which interesting heterocyles such as oxadiazoles, triazoles, and tetrazines were synthesized and fully characterized.


Introduction
The concept of 1,3-dipoles was first introduced by Huisgen in 1963 [1]. Since that time, a lot of work has been done on their reactions and the mechanism of 1,3-dipolar cycloaddition. A comprehensive review discussing the chemistry of 1,3-dipoles appeared in 1984 [2]. Numerous significant papers have been published over the last two decades on the reaction of nitrilimines and nitrile oxides with substituted hydrazines, hydrazones and oximes. Different aspects of these reactions will be outlined in this short review.

Nitrilimines and nitrile oxides
Nitrilimines 2, also called nitrile imides, are transient intermediates in solution. The most common method for their generation is dehydrohalogenation of hydrazonoyl halides 1 in the presence of triethylamine [2,3]. Likewise, nitrile oxides 4 are usually generated and trapped in situ; the most common method for their generation is dehydrohalogenation of α-chloro-oximes 3 upon reaction with a base (usually triethylamine). Nitrile oxides dimerize easily and it is usually beneficial to generate them slowly at low temperature, in presence of the trapping agent, so their concentration remains low [2]. iii) Cyclocondensation reactions with nucleophiles incorporating suitably located electrophilic centers leading to five-or six-membered heterocyclic rings. An example is the reaction of nitrilimines generated in situ from the respective hydrazonoyl halides 1 with α-amino acid esters 5 leading to 4,5-dihydro-1,2,4-triazin-6-ones 6 [4]. All the above modes of reaction were observed for the reaction of nitrilimines 2 and nitrile oxides 4 with differently substituted hydrazines, hydrazones and oximes.

Reaction with methylhydrazine
The reaction with methylhydrazine occurs at the N-Me group, rather than the NH 2 group, leading to the acyclic adducts 10 [7].

Reaction of nitrilimines with 1-ethoxycarbonyl-2-phenylhydrazine
This reaction gave the acyclic adducts 28. Refluxing 28 with charcoal in either toluene or xylene for several hours gave no reaction and the starting material was recovered unchanged [9].

Reaction with substituted simple hydrazones
Simple hydrazones derived from aliphatic aldehydes and ketones 33 reacted with C-acetyl-and Cmethoxycarbonyl nitrilimines at ambient temperature to furnish the acyclic products 34. Attempts to cyclize the latter by heating in tetrahydrofuran or ethanol were unsuccessful. However, treatment of solutions of these acyclic adducts with Pd-C at room temperature brought about oxidative cyclization to the orange-red coloured 1,6-dihydro-s-tetrazines 36 [15]. Attempts to isolate the tetrahydrotetrazine intermediate 35 were generally unsuccessful. C-benzoyl and C-2-naphthoyl nitrilimines were also found to give acyclic adducts 34. However, these adducts gave a mixture of complicated products upon heating with Pd-C from which amidrazones 27 were separated as the major products.

Reaction of nitrilimines with hydrazones carrying electron withdrawing groups
Hydrazonoyl halides reacted with alkanone and cycloalkanone alkoxycarbonylhydrazones 54 to give the cycloaddition products 4,5-dihydro-1,2,4-triazoles 55, rather than the tetrazine cyclocondensation products 56 [23]. The 1 H-NMR spectra showed a signal at 6.5 -7.0 ppm characteristic for the N-H of the five membered ring compounds 55. The N-H of the six membered ring structure 56 is expected to appear at 4-5 ppm [1]. Signal doubling is observed both in the 1 H-and 13 C-NMR spectra of compound 55f containing the 4-methylcyclohexane moiety due to tautomeric isomerism. The 13 C-NMR spectra display the characteristic signals of the suggested structures. The signal for C5 (quaternary or spiro carbon) appears in the range of 80 -90 ppm. This was similar to reported values of quaternary and spiro carbons flanked by two nitrogens in five-membered heterocycles. This provided strong evidence in support of structures 55, rather than the six-membered heterocyclic structure 56, which was expected to have a C6 signal at about 70 ppm. Similarly, alkanone and cycloalkanone hydrazones 57 carrying electron withdrawing groups (OCOCH 3 , COCH 3 , COPh) react with C-benzoyl-and C-2-naphthoyl nitrilimines to give the cycloaddition triazole products 58. IR, 1 H-NMR, 13 C-NMR and mass spectral data are consistent with the assigned triazole ring system. Compounds 58 having an acetyl group, showed signal doubling in their 13 C-NMR spectra, apparently, owing to their presence as two different mesomeric structures [24]. Ferwanah et al. also reported the synthesis of another series of these triazoles 60 from the reaction Cacetyl-N-arylnitrilimines (2) with acetaldehyde, alkanone and cycloalkanone benzoylhydrazones 59. Intersting spiro compounds containing heteroatoms were prepared from this reaction [25]. C-methoxycarbonyl hydrazonoyl halides 2 were also found to react with substituted hydrazones of alkanone, cycloalkanone and heterocyclic ketones 57 to give the cycloaddition products 3methoxycarbonyl-4,5-dihydro-1,2,4-triazoles 61 [26].

Conclusions
Nitrilimines and nitrile oxides react with hydrazines giving acyclic adducts. The acyclic adducts resulting from the reaction of 1-substituted-1-methylhydrazines with nitrilimines cyclize to give s-tetrazines, and those resulting from the reaction of nitrile oxides with 1-ethoxycarbonyl-1methylhydrazine cyclize to oxatriazinones upon stirring with sodium hydride. The reaction of nitrilimines with hydrazones give the acyclic adducts which also cyclize to s-tetrazines. The reaction with nitrile oxides gives, however, the 1,3-dipolar cycloaddition oxadiazole derivatives. s-Tetrazines and oxatriazines were obtained from the reaction of methylhydrazones with nitrilimines and nitrile oxides, respectively. Hydrazones carrying electron withdrawing groups react with nitrilimunes affording the respective cycloaddition triazole products. Ketooximes react with nitrilimines yielding the respective triazoles.