Hydrazides reaction with diketones

The 1,2,4-triazine core is a synthetically important scaffold because it could be readily transformed into a range of different heterocyclic systems such as pyridines (Sect. 3.1) via intramolecular Diels-Alder reactions with acetylenes. 1,2,4-Triazines have been synthesized by the condensation of 1,2-diketones with acid hydrazides in the presence of NH4OH in acetic acid for up to 24 h at reflux temperature. Microwave dielectric heating in closed vessels allowed the reaction to be performed at 180 °C (60 °C above the boiling point of acetic acid). As a result, the reaction time was reduced to merely 5 minutes. Subsequently, a 48-membered library of 1,2,4-triazines was generated from diverse acyl hydrazides and a-diketones [139]. Two thirds of the desired heterocycles precipitated from the reaction mixture upon cooling with > 75% purity, while the remaining part of the library was purified by preparative LCMS (Scheme 56). 

Monothiomalonic acid hydrazides (398), prepared by the reaction of cyanoacetohydrazides with H2S, react with diketones (e.g. (397)) to give pyridine-2-thiono-3-carboxhydrazides (399) which cyclize with the loss of H2S to give 1-substituted pyrazolo[3,4-Z>]pyridin-3-ones (e.g. (400)) (Scheme 44) <85S861>. 

M-Acetylsaccharinyl acid derivatives 408, which are structurally related to COX-2 inhibitor celecoxib, were designed and synthesised [133] from M-saccharinyl acetate 407a, prepared via the reaction of ethyl bromoacetate with sodium saccharin by heating the reactants in DMF (see [133]). Its transformation into the corresponding hydrazide 407b and subsequent reaction with ethyl acetoacetate, /3-diketones and maleic anhydride, afforded the heterocyclic compounds 408 [134] (Scheme 97). 

The rapid synthesis of 1,2,4-triazines has also been developed under microwave-assisted conditions [80]. Irradiation of a 1,2-diketone with acyl hydrazides and ammonium acetate for 5-10 min at 180 °C in a single-mode microwave reactor gave 3,5,6-trisubstituted 1,2,4-triazines in excellent yield and purity and reaction times that were reduced 60-300 fold over conventional conductive heating methodology (Scheme 22). 

A different kind of triazine, 3,5,6-trisubstituted 1,2,4-triazines 166, were prepared by reaction of 1,2-diketones 164 with acyl hydrazide in the presence of ammonium acetate and acetic acid at 180 °C for 5 min under microwave irradiation in a sealed tube [107]. Different substituents can be introduced in the final triazines providing a general approach for this kind of heterocycles (Scheme 59). 

Isoniazide, the hydrazide of pyridine-4-carboxylic acid, is still, well over half a century after its discovery, one of the mainstays for the treatment of tuberculosis. Widespread use led to the serendipitous discovery of its antidepressant activity. This latter activity is retained when pyridine is replaced by isoxazole. The requisite ester (45-4) is obtained in a single step by condensation of the diketo ester (45-1), obtained by aldol condensation of acetone with diethyl oxalate, with hydroxylamine. One explanation of the outcome of the reaction assumes the hrst step to consist of conjugate addition-elimination of hydroxylamine to the enolized diketone to afford (45-2) an intermediate probably in equilibrium with the enol form (45-3). An ester-amide interchange of the product with hydrazine then affords the corresponding hydrazide (45-5) reductive alkylation with benzaldehyde completes the synthesis of isocarboxazid (45-6) [47]. 

Zelenin and co-workers have shown (85KGS854, 85KGS1000 86KGS128 87KGS1210 88ZOR426) that the reaction products of 1,3-diketones with hydrazides in a molar ratio of 1 2 most frequently possess the cyclic structure of the corresponding 5-hydrazino-2-pyrazolines (such as 76B). They can also be produced in the reactions between the corresponding hydrazine derivatives and l-acyl-5-hydroxy-2-pyrazolines or 1-acyl-5-methylene-2-pyrazolines. 

Poltshettiwar and Varma [20] utilized the nano-organocatalyst for the micro-wave-assisted pyrazole (xviii) synthesis. The key step involved the reaction of 1,3-diketones (xvi) with hydrazides (xvii). 

The canthines are a tetracyclic subclass of j8-carboline alkaloids bearing an additional D-ring. Members of the canthine family have been shown to have pharmacological activity, including antifungal, antiviral, and antitumor properties. In 2003 Lindsley and coworkers described a microwave-mediated procedure for one-pot synthesis of the basic canthine skeleton [122]. The key step is an inverse-electron demand Diels-Alder reaction and subsequent chelotropic expulsion of N2, a reaction that can be achieved after a three-component condensation of an acyl hydrazide-tethered indole with a 1,2-diketone and excess ammonium acetate to form a triazine (Scheme 10.61). 

The traditional thermal conditions were applied to the reaction of heterocyclic acyl hydrazide with heterocycles containing a 1,2-diketone in a 1 1 ratio by using an excess of ammonium acetate in refluxing acetic acid for 10-24h to give 3-het-erocyclo-l,2,4-triazines 784 in less than 30% yield. On the other hand, when the... 

In a reaction tube, a mixture of 1,3-diketone (1 1 mmol) and hydrazines/hydrazides (2 1.1 mmol) was added with 0.1 mL of 20% PSSA solution in water. The whole mixture was stirred for 1 -2 min to complete the reaction. The crude product of pyrazole 3 was then extracted with ethyl acetate followed by washing with dilute sodium bicarbonate solution. After drying the organic layer over sodium sulfate and removal of the solvent, pure product of 3 was isolated by passing the crude reaction mixture over short silica gel column (Silica gel 20%EtOAc/hex-ane). Following the same procedure, diazepine 6 was synthesized from 1.0 equiv of 1,3-diketone and 1.1 equiv. of diamines. All the compounds were characterized from detailed spectral studies. 

A utility for this reaction was demonstrated by the reaction of the penicillin sulfoxide hydrazide derivative (143) with 2-propoxypropene to afford the enol ether (144). This was then hydrolyzed with mercuric nitrate to afford the ketone (145) (Ager et al., 1973). Ozonolysis of 145 gave the diketone (146) which on treatment with base cyclized to cepham... 

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