Azines formation

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. 

Ifcobs is directly proportional to pyridine concentration. Therefore a plot of kobs vs. [pyridine] is linear, with a slope (k ) equal to the second order rate constant for ylide formation, and an intercept (k0) equal to the sum of all processes that destroy the carbene in the absence of pyridine (e.g.) intramolecular reactions, carbene dimerization, reactions with solvent, and, in the case of diazirine or diazo carbene precursors, azine formation. 

In order to safely identify k0 with intramolecular carbenic reactions (e.g., k and the formation of alkene 4 in Scheme 1), product analysis should demonstrate that the yield of intramolecular products exceeds 90%, while dimer, azine, and solvent-derived (intermolecular) carbene products should be absent or minimal. If these conditions are not met, mechanistic interpretation is often ambiguous, a result that is well illustrated by the saga of benzylchlorocarbene (see below, Section IV.C). Less desirably, k0 can be corrected for competitive intermolecular carbenic reactions. Bimolecular reactions like dimerization and azine formation can be minimized by working at low carbene precursor concentrations, and careful experimental practice should include quantitative product studies at several precursor concentrations to highlight potential product contamination by intermolecular processes. 

Three possibilities were considered to account for the curved Arrhenius plots and unusual KIEs (a) the 1,2-H shift might feature a variational transition state due to the low activation energy (4.9 kcal/mol60) and quite negative activation entropy (b) MeCCl could react by two or more competing pathways, each with a different activation energy (e.g., 1,2-H shift and azine formation by reaction with the diazirine precursor) (c) QMT could occur.60 The first possibility was discounted because calculations by Storer and Houk indicated that the 1,2-H shift was adequately described by conventional transition state theory.63 Option (b) was excluded because the Arrhenius curvature persisted after correction of the 1,2-H shift rate constants for the formation of minor side products (azine).60... 

Of course carbene C-H insertion reactions are well known absolute kinetics have been reported for the insertions of ArCCl into isooctane, cyclohexane, and n-hexane,67 and of PhCCl into Si-H, Sn-H, and C-H bonds.68 More recently, detailed studies have appeared of PhCCl insertions into a variety of substrates bearing tertiary C-H bonds, especially adamantane derivatives.69 Nevertheless, because QMT is considered important in the low temperature solution reactions of MeCCl,60,63 and is almost certainly involved in the cryogenic matrix reactions of benzylchlorocarbene,59 its possible intervention in the low temperature solution reactions of the latter is a real possibility. We are therefore faced with two alternative explanations for the Arrhenius curvature exhibited by benzylchlorocarbene in solution at temperatures < 0°C either other classical reactions (besides 1,2-H shift) become competitive (e.g., solvent insertion, azine formation), or QMT becomes significant.7,59,66... 

The possible intervention of classical, competitive reactions in the low temperature solution chemistry of benzylchlorocarbene (10a) requires careful investigation. There are reasons to suspect azine (48) formation Goodman reported minor yields of azine in analogous MeCCl experiments,60 and Liu et al. found 40% of 48 in the photolysis of neat diazirine 9a.65 Perhaps azine formation is also significant at low temperature in hydrocarbon solvents. If so, the intervention of bimolecular azine formation, in competition with the unimolecular carbene 1,2-H shift, could lead to a nonlinear temperature dependence for the disappearance of 10a. Arrhenius curvature could then be explained without invoking QMT. 

Azine formation, shown in reaction (3), took place at 175-250° in the heated inlet system of a mass spectrometer but was not observed with a direct inlet system (Blythin and Waight, 1967 Nakata and Tatematsu, 1967). However, earlier it had been observed that similar azine formation occurred in sulphonylhydrazones (4) even with a direct inlet system... 

A Hershberg stirrer made of Nichrome wire is the most efficient for aiding dissolution of the potassium hydroxide added after azine formation is complete. 

It is of utmost importance that the flask temperature during the removal of the volatile materials be kept below 20° in order to minimize possible azine formation by decomposition of the hydrazone. 

As mentioned previously, DMSO as the reaction medium provides significant enhancement of Wolff-Kishner reaction rates and this allows the use of much lower temperatures to effect reductions. In 1962 Cram et al. introduced the use of r-butoxide in dry DMSO for the successful reduction of preformed hydrazones at room temperature. Using this process, benzophenone hydrazone (15) afforded an 88% yield of diphenylmethane (16), along with 11% of benzophenone azine (17) as side product (equation 5). However, maximum success requires very slow addition (i.e. over 8 h) of the hydrazone to the reaction solution, otherwise yields of reduced products are decreased and azine formation augmented. Thus, addition of (15) over 0.5 h in the above reaction lowered the yield of (16) to 72%, while the yield of (17) was increased to 22%. - Other successful reductions reported - include hydrazones of benzaldehyde (67%), camphor (64%) and cyclohexanone (80%). 

Monoaryldiazomethanes, readily prepared by a number of methods, are the carbene precursors most frequently used for the synthesis of arylcyclopropanes. When such diazo compounds are decomposed photochemically, thermally, or by using various transition-metal salts in the presence of an alkene, arylcyclopropanes are formed. The yield is often quite high, but in a number of cases cyclopropane formation has been hampered by competing reactions, of which, disregarding intramolecular reactions, azine formation, stilbene formation, and hydrogen abstraction followed by dimerization are the most predominant. Many aspects related to the use of diazomethane derivatives as carbene precursors have been thoroughly discussed by Wentrup. ... 

Occasionally reactions with hydrazine must be performed with precautions. In order to avoid azine formation, excess of the reagent must be used, and if a cyclopropane bears two carbonyl groups, bi- and polycyclic products can result. ... 

Hydrazones derived from unsubstituted hydrazine are mostly rather unstable and have only specialized preparative interest, e.g., in Wolff-Kishner reduction897 and synthesis of heterocycles. In many cases it is difficult to prepare them because hydrazine tends to react with both amino groups, thereby yielding azines an excess of hydrazine is usually used so as to avoid this azine formation. The condensing agent may be triethylamine, barium oxide, or sodium hydroxide, sometimes in alcohol. Diethyl phosphonate898 has been recommended as an excellent solvent that is said also to catalyse formation of the hydrazone. 

To avoid azine formation it has also been proposed900 that the carbonyl compound should first be converted into a 1,1-dialkylhydrazone and that this be then treated with hydrazine. 

Miscellaneous Methods of Preparing Phosphines. - Transformation of functional groups present in alkyl- and aryl-phosphines has been widely employed in the synthesis of new systems. Further examples of azine formation... 

So we looked for a reaction blocking the carbonyl group to avoid the side reactions and it was the reason why we investigated a new process passing through the azine formation. 

We tried a one pot reaction but it failed. The main reason being the unstability of hydrazine in the presence of catalysts such as cobalt or nickel. We noticed a large decomposition which prevents azine formation and subsequently the IPDA yield was very low (10-30 %). So, only a two step process was available. 

Azine formation is common when fluorodiazirines are decomposed, whether thermally or photochemically. Gas-phase pyrolysis of bis(trifluoromethyl)diazirine (263) gave hexafluoropropene, from rearrangement of bis(trifluoromethyl)carbene (276), and azine 277, from attack of the carbene on starting material. ... 

Many of the characteristic reactions of hydrazine may also be carried out with substituted hydrazines to afford a wide variety of products. In the case of reactions of substituted hydrazine derivatives, azine formation is ordinarily not possible. 

Hydrazones. Reaction of hydrazine with aldehydes and ketones is not generally useful due to competing azine formation or competing Wolff-Kishner reduction. Exceptions have been documented. Recommended conditions for hydrazone preparation are to reflux equimolar amounts of the carbonyl component and hydrazine in n-butanol. - A more useful method for simple hydrazone synthesis involves reaction of the carbonyl compound with dimethylhydrazine followed by an exchange reaction with hydrazine. For substrates where an azine is formed, the hydrazone can be prepared by refluxing the azine with anhydrous hydrazine. gem-Dibromo compounds have been converted to hydrazones by reaction with hydrazine (eq 6). ... 

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