Azines, from aldehydes

Hydrazine is hypergolic with cone, nitric acid [1]. Of a series of hydrazones and azines derived from aldehydes and ketones, only those which decomposed when heated alone were hypergolic with the acid when heated at 12.5°C/min [2], Solid hydrazones formed from various aldehydes with dimethylhydrazine or phenylhydrazine are hypergolic with the acid [3],... 

The reaction of azines 107, prepared in situ from aldehydes or ketones and hydrazine, afforded the Ugi adducts 108. The acid treatment of 108 resulted in the hydrolytic cleavage of the imino group with formation of the hydrazides, which immediately cyclized to phthalazinone amides 109 (Scheme 2.39) [70]. 

A novel reaction of hydrazones, including steroid derivatives, is their oxidation by iodine and triethylamine to give vinyl iodides (or diiodo compounds from aldehyde hydrazones) [x6]. Oxidation by iodine in a neutral non-polar solvent gives azines through the free-radical process ... 

Aromatic aidaiines and ketazines.1 Polyphosphoric acid is an excellent catalyst and solvent for production of azines from aromatic aldehydes and ketones in the presence of various carbonyl reagents, for example, hydrazine, its salts, semicarbazide hydrochloride, toluenep-sulfonohydrazide, and acid hydrazides. The reaction is usually complete at 100° within 15 min. The reaction is not useful in the case of aliphatic carbonyl compounds. 

Azines, Aldehydes react with hydrazine to yield azines the reaction cannot usually be arrested at the hydrazone stage. This reaction may be illustrated by the preparation of bevzalazine from benzaldehyde ... 

This silyl hydrazone formation-oxidation sequence was originally developed as a practical alternative to the synthesis and oxidation of unsubstituted hydrazones by Myers and Furrow [31]. The formation of hydrazones directly from hydrazine and ketones is invariably complicated by azine formation. In contrast, silyl hydrazones can be formed cleanly from /V,/V -bis(7< rt-butyldimethylsilyl)hydrazine and aldehydes and ketones with nearly complete exclusion of azine formation. The resulting silylhydrazones undergo many of the reactions of conventional hydrazones (Wolff-Kishner reduction, oxidation to diazo intermediate, formation of geminal and vinyl iodides) with equal or greater efficiency. It is also noteworthy that application of hydrazine in this setting may also have led to cleavage of the acetate substituents. 

The phosphazinium bromides (25), conveniently prepared from hydrazinotri-phenylphosphonium bromide and orthoesters, when treated with base (Scheme 6) give the thermally stable ylides as a mixture of syn- and a/ift-forms.28 These ylides are converted efficiently by various aromatic aldehydes into mixed azines. 

The azines represent another class of organic compounds which, in principle, should be reducible to azo compounds. The method is attractive since, with the availability of anhydrous hydrazine, azines are readily prepared from a wide variety of ketones and aldehydes. Evidently, introduction of 1 gram-molecule of hydrogen into an azine molecule has only recently been accomplished (see Section 6, Procedure 8) [73], Two preparations involving the 1,4-addition of chlorine to an azine system have been carried out and are illustrated here. 

Hydrazido(2-) and hydrazido(l-) complexes have also been shown to condense with aldehydes and ketones to give diazoalkane complexes containing the W=N—N=CRiR2 unit.387,388 Treatment of these complexes with LiAlFL, gives secondary amines and ammonia, whereas treatment with acid produces hydrazine, keto azines and N2-free tungsten compounds. Amines can also be produced from organohydrazido(2—) complexes.389,390... 

Wittig reactions with pyrrole-2-aldehyde led to the esters (79) which were cyclisized to 3a-azaazulen-4-ones (80).104,105 4-Methylene-3a-aza-azulenes (81) have been obtained from 80 with stabilized phos-phoranes.36 Reaction of dimethyl acetylenedicarboxylate with 81 could not be achieved. A similar cycloaddition was successful in the synthesis of cycl[3,3,3]azines (2) (Section V). 

Similarly, triazolines from anils and mixed azines of thiophenecarbox-aldehyde and/or isatin also possess antimicrobial activity.352... 

Pyrazolines may be obtained readily from a,j3-unsaturated aldehydes or ketones and aliphatic diazo compounds.44,349 Convenient syntheses have been worked out using Mannich bases,488-494 by the cyclization of aldehydo- and keto-azines.495-499 The conversion of a number of 4- and 5-substituted pyrazolines to the corresponding pyrazoles by frams-elimination was noted above. The 4-amino-pyrazolines with the appropriate configuration (41) readily eliminate... 

Another facile synthesis of pyrimido[4,5-c]pyridazin-5,7(6/7,8//)-diones (51), pyrimido[4,5-c]py-ridazin-5(8//)-ones (52), and dihydropyrimido[4,5-c]pyridazin-5(6//)-ones (53) starts from 3-chloro-4-pyridazinecarbonitrile (48) via aminocarbonitriles (49) and aminocarboxamides (50) (Scheme 9). Cyclization of the latter with urea at high temperatures affords the pyrimido[4,5-c]pyrid-azin-5,7(6/7,8//)-diones (51). By heating of the carboxamides with aromatic aldehydes the dihydropyrimido[4,5-c]pyridazin-5(6/7)-ones (52) are obtained <88JHC119). 

Azine approach. 8,8a-Dihydro-l-oxo-l//,3//-oxazolo[4,3-c][l,4]thiazines (265) are available from the corresponding l,4-thiazine-3-carboxylic acids and aldehydes or ketones 2,2-dimethoxypropane with acid catalysis yields the 3,3-dimethyl derivative (265 R=Me), and acetaldehyde with a water absorbent yields the monomethyl derivative as a diastereoisomeric mixture (76JCS(P1)584>. 

A convenient synthesis [Eq. (13)] of 2-ary lidenehydrazono-4-thia-zolidinone (43) from ethyl thiocyanoacetate (44), arylideneazines (45), and hydrazine hydrate (46) has been reported.79 Presumably, the reaction proceeds via the intermediary hydrazone, which condenses with 44 to give 43. Subsequently, condensation of 43 with the aromatic aldehyde, generated in situ from disproportionation of the azine with hydrazine, affords the 5-arylidene derivative. The reaction of 44 with ammonium acetate and an aromatic aldehyde gives 5-arylidene-2-imino-4-thiazolidinones.80... 

Both hydrazones formed from ketones (Table 3, entries 1-6) and aldehydes (entry 7) react with bromine monofluoride, although the latter yield is low (28 %). Adamantanone azine (entry 8) reacts with bromine monofluoride afl ording the corresponding em-difluoride in high yield (77%). 

Methods for the preparation of hydrazones and oximes differ little from those used for the synthesis of imines from ketones and aldehydes in that the appropriate nitrogen species and the ketone are mixed. However, the equilibrium for the majority of reactions of ketones and aldehydes with hydrazines and hy-droxylamine favor the product hydr nes and oximes and removal of the water formed by the condensation is not required. 8(> Acid catalysis is complicated by the basicity of the reagent and, for example, the maximum rate of oxime formation is at approximately pH 4. Complicating reactions can occur such as the 1 2 combination of hydrazine with two ketones or aldehydes to form azines but this is not a problem with the substituted hydrazines that are used for asymmetric induction. 

Weller and Wolf (44) investigated a great number of azines, derived from aromatic o-hydroxy aldehydes and o-hydroxy-ketones. 

Timtcheva et al. (95DP131) (Scheme 50) studied the IR, NMR and the absorption and fluorescence spectra of 16 unsymmetrical azines 188 derived from the condensation of ( /Z)-4-(l-hydrazonoethyl)pyrazol-3-one 187 with various aldehydes 171. Comparisons with the electronic spectra of these compounds and the results of NMR and IR spectroscopy and also PPP-SCF-CI quantum chemical calculations suggest that the predominant tautomeric form in solution is enol 188. The other tautomeric forms of 188 are keto forms 189 191. 

---