Aliphatic hydrazones

Reagent A is particularly useful for the treatment of the lower aliphatic aldehydes and ketones which are soluble in water cf. acetaldehyde, p. 342 acetone, p. 346). The Recent is a very dilute solution of the dinitrophenylhydrazine, and therefore is used more to detect the presence of a carbonyl group in a compound than to isolate sufficient of the hydrazone for effective recrystallisation and melting-point determination. 

Hydrazinopyridazines are easily formylated with formic acid or ethyl formate and acety-lated with acetic anhydride. A-Pyridazinylthiosemicarbazides are obtained from thiocyanates or alkyl- and aryl-isothiocyanates. Hydrazinopyridazines condense with aliphatic and aromatic aldehydes and ketones to give hydrazones. 

Alloxan forms an oxime (1007) which is the same compound, violuric acid, as that formed by nitrosation of barbituric acid likewise, a hydrazone and semicarbazone. Reduction of alloxan gives first alloxantin, usually formulated as (1008), and then dialuric acid (1004 R = OH) the steps are reversible on oxidation. Vigorous oxidation with nitric acid and alkaline hydrolysis both give imidazole derivatives (parabanic acid and alloxanic acid, respectively) and thence aliphatic products. Alloxan and o-phenylenediamine give the benzopteridine, alloxazine (1009) (61MI21300). 

Dihydroazoles can exist in at least three forms (cf. Section 4.01.1.3), which in the absence of substituents are tautomeric with each other. The forms in which there is no hydrogen on at least one ring nitrogen normally predominate because imines are generally more stable than vinylamines in aliphatic chemistry. Thus for dihydropyrazoles the stability order is A" (hydrazone) (288) > A (azo) (289) >A (enehydrazine) (290). 

Although the addition of hydrazine and its derivatives to acetylenic ketones has been studied in considerable detail, their interaction with hydrazones and mono-alkylhydrazones is less well known. Yandovskii and Klindukhova (74ZOR730) have studied the reaction between hydrazones and alkylhydrazones of aliphatic ketones with dipropynylketones and showed that hydrazones of acetone, methyl-ethylketone, and cyclohexane easily add to one of the triple bonds of dipropynylketone to form 4-methyl-1,1,3-trialkyl-2,3-diaza-l,4-nonadien-7-yn-6-ones (yields... 

Thus it is not surprising that three-membered rings with two hetero atoms were mentioned in the literature at an early stage. For example, at the turn of the century, nitrones, hydrazones, and aliphatic diazo compounds were all formulated with three-membered rings (I, 2, 3). Later the three-membered ring structures for these compounds became questionable. The structure of the aliphatic diazo compounds was studied very intensively. For diazomethane no clas-... 

Aliphatic azo compounds in which the carbon containing the azo group is attached to a hydrogen are unstable and tautomerize to the isomeric hydrazones (15), which are therefore the products of the reaction. 

The addition of KCN to triisopropylbenzenesulfonyl hydrazones (53) provides an indirect method for achieving the conversion RR CO RR CHCN. " The reaction is successful for hydrazones of aliphatic aldehydes and ketones. 

Nitrilimines react with hydrazones of aliphatic aldehydes and ketones to yield addition products 9 which cyclise when treated with palladium charcoal at room temperature to give 1,6-dihydro-j-tetrazines 10 <96JCR(S)174>. 

Isoxazolidinoindolizines and pyrazolidinoindolizines, 268, can be prepared from the oximes or hydrazones 267. 1,3-Dipolar cycloadditions of oxime or hydrazone on to the adjacent alkene occur cleanly by heating the substrate in acetonitrile, or in the case of the basic aliphatic hydrazones, under acidic conditions <1987JOC226> (Equation 40). 

Treated with thionyl chloride, hydrazones 490 (R1 = H, R2 = aryl) undergo cyclocondensation to thiadiazoles 506 whereas from aliphatic derivatives 490 (R1 = H, R2 = alkyl), mixtures of thiadiazoles 507 and 508 are formed... 

Whereas the reactions of allenephosphonates 171 (R2 = OEt) with primary aliphatic and aromatic amines 172 and the reactions of the phosphane oxides 171 (R2 = Ph) with aliphatic amines 172 afford the conjugated addition products 173 always in good yields, the addition of anilines to 171 (R2 = Ph) leads to an equilibrium of the products 173 and 174 [231]. However, treatment of both phosphane oxides and phos-phonates of type 171 with hydroxylamines 172 (R3 = OR4) yields only the oximes 174 [232, 233]. The analogous reaction of the allenes 171 with diphenylphosphinoylhy-drazine furnishes hydrazones of type 174 [R3 = NHP(0)Ph2] [234],... 

The addition of a-lithiomethoxyallene 144 [55] to benzaldehyde dimethylhydra-zone 145 (Eq. 13.48) leads to a mixture of pyrroline 146 and dihydroazete 147 [56]. The cydization in this case, which takes place in the same operation as the addition to the hydrazone, follows two distinct pathways, with attack of the nitrogen atom taking place at the inner, in addition to the terminal, carbon atom of the allene. A similar reaction of 144 with SAMP-hydrazone 148 (Eq. 13.49) leads to 3-pyrroline 149 in 88% yield and excellent diastereoselectivity [57]. Cleavage of the chiral auxiliary group from 149 takes place in two steps (1, methyl chloroformate 2, Raney nickel, 50 bar, 50 °C) in 74% overall yield. When the addition of 144 to 148 is conducted in diethyl ether, cydization of the adduct does not take place. Surprisingly, the hydrazones of aliphatic aldehydes react with 144 in poor yield in THF, but react quantitatively and diastereoselectively in diethyl ether to give the (uncyclized) allenyl hydrazone products. 

The aliphatic diazo-compounds can also be prepared by careful dehydrogenation of the hydrazones (with HgO) (Curtius, Staudinger) and, conversely, they are converted into the latter by hydrogenation ... 

The mechanism of the coupling reaction has been very exhaustively studied. Summarising first what has already been mentioned, it must be noted that the reaction is not confined to the aromatic series, for diazo-compounds condense also with enols and with the very closely related aliphatic aci-nitro-compounds. The final products of these reactions are not azo-compounds, but the isomeric hydrazones formed from them by rearrangement. 

Although the present procedure illustrates the formation of the diazoacetic ester without isolation of the intermediate ester of glyoxylic acid />-toluenesulfonylhydrazone, the two geometric isomers of this hydrazone can be isolated if only one molar equivalent of triethylamine is used in the reaction of the acid chloride with the alcohol. The extremely mild conditions required for the further conversion of these hydrazones to the diazo esters should be noted. Other methods for decomposing arylsulfonyl-hydrazones to form diazocarbonyl compounds have included aqueous sodium hydroxide, sodium hydride in dimethoxyethane at 60°, and aluminum oxide in methylene chloride or ethyl acetate." Although the latter method competes in mildness and convenience with the procedure described here, it was found not to be applicable to the preparation of aliphatic diazoesters such as ethyl 2-diazopropionate. Hence the conditions used in the present procedure may offer a useful complement to the last-mentioned method when the appropriate arylsulfonylhydrazone is available. 

Non-functionalized aliphatic diazo compounds are fairly rare, and so are their reductions. Good examples of the reduction of diazo compounds to either amines or hydrazones are found with a-diazo ketones and a-diazo esters (pp. 124, 125, 160). 

In Ketazine processes, hydrazine derivatives are obtained first. Ammonia is oxidized by chlorine or chloramines in the presence of aliphatic ketones. The products are hydrazones and isohydrazones. These are converted to ketazines with excess ketone. The ketazines or the intermediate hydrazine derivatives may be hydrolyzed to hydrazine after all the oxidizing reactants, such as CI2, NaOCl, or NH2CI are consumed. Unlike hydrazine, ketazines do not readily oxidize, and, therefore, the product yield is higher in these processes. 

Numerous methods to prepare individual classes of aliphatic diazo compounds have been extensively developed. The major strategies for their synthesis involve the alkaline cleavage of N-alkyl-N-nitroso-ureas, -carboxamides and -sulfonamides, dehydrogenation of hydrazones, as well as diazo group transfer from sulfonyl and related azides to active methylene compounds, and electrophilic diazoalkane substitution reactions. These synthetic methods have been comprehensively reviewed (15,16). Useful information on the preparation of selected diazo compounds can be found elsewhere (6,17). 

SAMP-Hydrazones derived from ketones may also be cleaved by treatment with three equivalents of sodium perborate tetrahydrate at pH 7 in water/rert-butyl alcohol at 60 °C. Hydrolysis of aliphatic derivatives is effected in 4-24 hours and reactions yielding aromatic ketones proceed within 2- 3 days. This cleavage reaction furnishes the desired ketones chemoselectively in the presence of olefinic double bonds in 85-95% yield (cyclopentanone 70% yield)30. 

The oxidation of both aliphatic and aromatic azo compounds to the corresponding azoxy derivative may be carried out with a variety of reagents. While older techniques favored chromic or nitric acid as the oxidizing agent, newer methods make use of various organic peracids or hydrogen peroxide. In the oxidation of aliphatic azo compounds, relatively weak peracids are favored to reduce the possibility of acid-catalyzed isomerization of azo compounds to hydrazones. Under controlled conditions cis azo compounds may be converted into cis azoxy compounds. 

The oxidation of aromatic phenylhydrazones leads to cis azoxy compounds. At one time, these products were designated hydrazone oxides, but more recent work has established them as azoxy compounds. Aliphatic hydrazones give more complex oxidation products. At low temperatures, azoxy compounds form at reflux temperatures, hydrazides are isolated. 

It must be reiterated that, whereas aromatic azo compounds are relatively stable thermally and can be subjected to typical reactions of aromatic compounds [67, 68a, 88], the aliphatic azo compounds may be substantially less stable thermally. Aliphatic azo compounds, such as oc,a -azobis(isobutyro-nitrile), do decompose on heating and are used as free radical sources. Hence adequate safety precautions must be taken in handling them. This, by the way, does not mean that aliphatic azo compounds have not been subjected to distillation and to vapor phase chromatography. Many have been distilled and, as will be pointed out in a subsequent section, their preparation by isomerization of hydrazone depends on a distillation technique. 

It may well be, as Buckingham points out [104], that, at room temperature, under neutral conditions, and for a limited number of structural types, such as phenylhydrazones, no tautomeric shift to azo compounds takes place. The experimental facts are, however, that, under forcing conditions, aliphatic hydrazones have indeed been converted into azo compounds although often only in modest yield. 

Evidence has been presented that a genuine equilibrium exists between azo compounds and hydrazones, at least in the case of aliphatic cyclic compounds [106] (Eq. 46). The proposed mechanism was assumed to involve anion... 

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