Hydrazines condensation with carbonyls

The formation of 4-cyano p3rrazole derivatives 3 can be rationalized as the acid protonated nitrogen of dimethylamino group and was replaced by hydrazine and then NH2 of the hydrazine condenses with carbonyl carbon to form pyrazole ring. When the condensation of 3-dimethylarnino-2-bezoyl-propenenitrile la and N-methyl ester of hydrazine was carried out, the ester group has been hydrolyzed and decarboxylated to give IH-pyrazole derivative 3f. 

Hydrazinolysis products obtained from oxazolones 528 are versatile synthetic intermediates and can be further elaborated to a variety of different heterocycles depending on the substituents and on the experimental conditions. For example, N-aminoimidazolones 529, isolated from reaction of 528 and hydrazine, have been acylated ° or condensed with carbonyl compounds to produce 530 and 531, respectively. On the other hand, ring-opening 528 with hydrazine affords a dehydroamino acid hydrazide 532. Condensation of 532 with aldehydes yields a hydrazone 533 that can be cyclized to an A -iminoimidazolone 534 (Scheme 7.168). ... 

Organic hydrazines or diazanes are substitution products of NH2—NH2 and have many properties similar to those of amines in being basic and forming acyl derivatives as well as undergoing alkylation and condensations with carbonyl compounds (Section 16-4C). Unsymmetrical hydrazines can be prepared by careful reduction of /V-nitrosamines. l,l-Dimethyldiazane is prepared in this way for use as a rocket fuel ... 

Hydrazides condense with carbonyl compounds analogously to alkyl- and aryl-hydrazines. Among these compounds, the semicarbazones have achieved special analytical importance because they crystallize readily and have sharp melting points. They are particularly useful for characterizing lower aliphatic aldehydes. 

Condensing certain hydrazine derivatives with carbonyl derivatives may, further, lead to heterocycles containing the structural unit of N,iV-acetals (aminals) for instance, 1,2,3,4-tetrahydrophthalazine (13) and formaldehyde give 5,7,9,14,16,18-hexahydrodiphthalazino[2,3-a 2, 3 -d]-,s-tetrazine (14) 970... 

However, the most suitable method for the identification of hydrazines of the R1R2NNH2 type is their condensation with carbonyl compounds. They are usually condensed with benzaldehyde. 

Scheme 4 shows in a general manner cyclocondensations considered to involve reaction mechanisms in which nucleophilic heteroatoms condense with electrophilic carbonyl groups in a 1,3-relationship to each other. The standard method of preparation of pyrazoles involves such condensations (see Chapter 4.04). With hydrazine itself the question of regiospecificity in the condensation does not occur. However, with a monosubstituted hydrazine such as methylhydrazine and 4,4-dimethoxybutan-2-one (105) two products were obtained the 1,3-dimethylpyrazole (106) and the 1,5-dimethylpyrazole (107). Although Scheme 4 represents this type of reaction as a relatively straightforward process, it is considerably more complex and an appreciable effort has been expended on its study (77BSF1163). Details of these reactions and the possible variations of the procedure may be found in Chapter 4.04. 

The free selenazole hydrazines are solids, sometimes well crystallized compounds. They show the typical properties of hydrazines. Thus they reduce Fehling s solution on warming and liberate silver, even in the cold, from ammoniacal silver nitrate solution. Further, they react with carbonyl compounds for example, benzylidene hydrazones are formed with benzaldehyde. These are identical with the hydrazones formed by direct condensation from benzaldehyde selenosemicarbazone and the corresponding a-halogenocarbonyl compound. 2-Hydrazino-4-phenylselenazole has also been reacted with acetophenone. The 2-a-methylbenzylidenehydrazone of 4-phenyl-selenazole (2, K = CJl, R" = H, R" = NH—N CMe-aH ) forms golden yellow plates mp 171°C. ... 

The product of condensation of a hydrazine and an aldehyde or ketone is called a hydrazone. Hydrazine itself gives hydrazones only with aryl ketones. With other aldehydes and ketones, either no useful product can be isolated, or the remaining NH2 group condenses with a second mole of carbonyl compound to give an azine. This type of product is especially important for aromatic aldehydes ... 

As with pyridazines, phthalazines, the other benzopyridazines, were also prepared most frequently through the condensation of hydrazines with carbonyl-containing compounds, typically phthalate derivatives. Recently, Napoletano and co-workers demonstrated the condensation of hydroxylactone 189 and hydrazine to afford phthalazones 190. After POCI3 chlorination, advanced intermediates for a novel series of PDE4 inhibitor I, phthalazines 191 were prepared <00BMC2235>. 

The successful synthesis of 2-thienyl and substituted 2- and 3-thienyl-acetylenes in yields as high as 60-80% opened a wide variety of synthetic applications. Various addition reactions with carbonyl compounds or epoxides could be carried out with ease. Aliphatic as well as aromatic amine addition reactions, or condensation reactions with hydrazine or hydroxylamine could be easily performed. 

As with ciimolines, phthalazines were also prepared most frequently through condensations of hydrazine derivatives and carbonyl-containing compounds. For example, Monneret and co-workers reported the condensation of dialdehyde 148 with hydrazine to produce phthalazine derivative 149, an advanced intermediate in the preparation of anticancer analogs of etoposide <99T12805>. 

Most ring synthesis methods focus on formation of the five-membered pyrazole through cyclizations involving condensation of hydrazine with carbonyl moieties attached to the [l,2,4]triazine <1996CHEC-II(7)489>. A typical synthesis of the pyrazole ring to give various pyrazolo[4,3-< ][l,2,4]triazines 84 was reported by Rykowski eta/, using a... 

The quinazolinone moiety (36-3) for the cardiotonic agent prindoxan (36-5) is formed by reaction of diamine (36-1) with carbonyl diimidazole (36-2). Friedel-Crafts acylation of the product with the half-acid chloride from methyl succinate gives the corresponding keto-ester (36-4). The pyridazinone (36-5) is then obtained by condensation of that product with hydrazine [38]. 

Dicarbonyl compounds with a double bond in the 2,3-position condense with hydrazine to give pyridazines (e.g. 91 — 92). If one of the carbonyl groups in the starting material is part of a carboxyl group or a potential carboxyl group, then reactions with hydrazines or hydroxylamine lead to pyridazinones or 1,2-oxazinones (e.g. 93 — 94 Z = NH, NPh, O). Similarly a cyano group leads to an amino or imino product. 

Amino-1 //-1,2,4-triazole and its derivatives are frequently used as precursors for this ring via their reaction with suitable carbonyl compounds. The 5-amino-l,2,4-triazoles (27), prepared from calcium cyanide by hydrolysis to cyanamide followed by condensation with hydrazine (92MI4), reacted with the appropriate acetophenone in presence of ZnCl2 to give the... 

A variety of macrocyclic complexes which have adjacent nitrogen atoms (cyclic hydrazines, hydrazones or diazines) are formed by condensations of hydrazine, substituted hydrazines or hydrazones with carbonyl compounds. The reactions parallel in diversity those of amines, but are often more facile since the reacting NH2 groups is generally not coordinated and the electrophile is thus not in competition with the metal ion. The resulting macrocycles may be capable of coordination isomerism, since either of the adjacent nitrogen atoms can act as donor atom. 

Two closely related reports of pyrazole generation by condensation of substituted hydrazines with enamino carbonyl compounds have appeared. In situ formation of an enaminoketone, by treatment of a diketone with dimethylformamide dimethyl acetal, was followed by tandem Michael addition-elimination/cyclodehydration under aqueous conditions in sealed microwave vessels (Scheme 3.12)17. Isoxazoles and pyrimidines were also prepared by replacing the substituted hydrazine with hydroxylamine or amidines, respectively (see Chapter 5, Section 5.3.2). The overall process may be regarded as another example of a multi-component coupling. In a similar fashion, enamino propenoates were condensed with substituted hydrazines to afford substituted pyrazoles (see Chapter 5, Section 5.3.2) (Scheme 3.12)18. 

Macrocycles with 2 nitrogen and 3 sulfur donors have been prepared (14) by a template synthesis in which the dialdehyde (XCI) is condensed with primary diamines, e.g., ethylenediamine gives XCII in boiling acetonitrile containing Fe(II) perchlorate. The reaction is typical of template condensation between carbonyl compounds and primary amines. An unusual monanionic macrocyclic ligand was produced (2) when formaldehyde was condensed with the hydrazine (XCIII) instead of a primary amine in the presence of Ni(II) salts, and complexes XCIV have been characterized. 

These derivatives (59) are generally obtained by condensation of the appropriate sulfonyl chloride (51) with an excess of hydrazine (Scheme 53). Sulfonyl hydrazides (59) react with nitrous acid (sodium nitrite-dilute acid) to form the corresponding sulfonyl azides (84), and with carbonyl compounds they yield the sulfonyl hydrazones (85) (Scheme 54). 

Tetrazines can be produced by condensation of hydrazine with carbonyl compounds at acid oxidation level, followed by oxidation of the dihydro products this generally produces 3,6-identically substimted derivatives, crossed condensation reactions being inefficient. 

The course of the condensation reaction can be influenced by the presence of agents such as sodium hydrogen sulfite or hydrazine which react with carbonyl groups. For example, 2-phenylpyrimidine-4,5,6-triamine reacts with 2-oxopropanal at pH 7 to give 7-methyl-2-phenyl-pteridin-4-amine (3, 60%).51 However, when hydrazine is added to 2-oxopropanal prior to admixture with the pyrimidine, the only product which is obtained is 6-methyl-2-phenylpterid-in-4-amine (4).5 2... 

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