Hydrazines isatins

Keywords Hydrazines, isatins, p-keto esters, malononitrile, ethyl cyanoacetate, piperidine, ethanol, room temperature, ultrasound irradiation, one-pot multicomponent synthesis, spiro[indoline-3,4 -pyrano[2,3-c]pyrazole] derivatives... 

Z = 0, NH), then the carbonyl group not adjacent to the heteroatom is preferentially attacked. Thus, isatin and indoxyl and their O- and 5-analogues (279, 282) react with hydroxylamine, hydrazine, phenylhydrazine, semicarbazide, etc., to give oximes, hydrazones, phenylhydrazones, semicarbazones, etc. (282 — 283 279 — 284). 

The first microwave-assisted Wolff-Kishner reduction was described by Parquet and Lin in 199763. The transformation of isatin to oxindole was performed on a small scale in a domestic microwave oven in two steps with a total reaction time of 40 s, as compared to 3—4 h if classical heating was utilised (Scheme 4.36). The first step involved the transformation of the carbonyl group into the hydrazone with 55% hydrazine in ethylene glycol and medium power microwave irradiation for 30 s. In the subsequent reduction step, KOH in ethylene glycol was used to substitute the more hazardous sodium ethoxide. The reaction mixture was irradiated for 10 s and the product was obtained in a yield of 32%. 

Isatin and 1-alkylisatins furnish condensation products at the C-3 position when reacted with hydrazine, alkyl and arylhydrazines , heteroarylhydrazines derived from pyrimidine240, pyrazine241, thiazole242, 1,2,4-triazine243, quinazoline244 245,... 

Isatin-3-imines also react with hydrazine derivatives such as heteroarylhydrazines264, thiosemicarbazides265 and acylhydrazides266, resulting in a substitution reaction at the C-3 position. Substitution reactions are also described to occur when O-methylisatin is treated with thiosemicarbazines, furnishing isatin-2-thiosemicarbazones91. 

Amines and hydroxylamine and hydrazine derivatives react with 36 at the lactim ether group and not at the keto group76 88 [Eq. (2)]. By contrast, in the reaction between the imidochloride of isatin and tosylhydrazine (or aniline) the keto group at position 3 was found to be attacked and at the same time the imidochloride was transformed into the lactam89 [Eq. (3)]. Thus it may be argued that, at least in the case of the isatin derivatives, the lactim ether function is more reactive than the imidochloride. 

Examples of synthesis following path b arc given by the formation of benzopyrazine derivative starting from N-aminomethyl-isatine and by the preparation of pyiridazine derivative 318 (Fig. 122) from aminomethyl-y-ketoearboxyacid and hydrazine. In this... 

A variety of arylhydrazines have been reacted with isatins to give isatin-3-arylhydrazones (83). - - ° Similar reactions have also been carried out with isatins and alkylhydrazines, hydrazides/ and hydrazine - to give 84, 85, and 86, respectively. Aldehyde hydrazones also react with... 

Indoloquinoxaline 693 was obtained in 83-90% yield by irradiating a mixture of isatin with o-phenylenediamine in acetic acid in an MW oven in either an open flask or closed Teflon vessel for 1-2 min. Carbethoxymethylation of isatin with ethyl chloroacetate in the presence of K2CO3 and Nal was carried out under MWI to give compound 694 in 70% yield within 4min. It could be converted into 695 by reaction with o-phenylenediamine in acetic acid in either an open flask (2 min) or closed Teflon vessel (Imin) (Scheme 134). Alternatively, carbethoxymethylation of 693 under MWI for 6 min afforded a 53% yield of 695. Reaction of 695 with hydrazine hydrate in ethanol under MWI gave the hydrazide 696 in 84% yield. MWI has been also used to condense 696 with aromatic aldehydes and monosaccharides to yield the hydrazone derivatives 697 in 58-99% yields (Scheme 134) (05JCR(S)299). 

The preparation of azido diazo substrates 17a and 17b proved to be feasible (Scheme 3). A three-step, one-pot procedure modified from the literamre converted isatin to azido acid 14 in 84% yield. Treating 14 with p-toluenesulfonyl hydrazine in hot acetic acid afforded hydrazone 15 in 81 % yield. The latter was reacted with thionyl chloride at 80 °C for 1 h in benzene. Removal of excess thionyl chloride and finally recrystallization yielded the stable acyl chloride 16 in 71% yield. Condensations of 16 with 10a or 10b... 

Siddiqui et al. have synthesized an efficient three-component synthesis of highly functionalized 4-methyl-l/7-quinohn-2-ones in one-pot reaction from readily available coumarin, hydrazine and isatin catalysed by a recyclable and moisture-compatible InClj under MWI. The synthesis involves a InClj catalysed dehydrative nucleophilic substitution on the lactone moiety of coumarin by the isatin hydrazone resulting in the formation of iV-substituted lactams, 6-substituted-4-methyl-l-(2-0X0-1,2-dihydroindol-3-ylidenamino)-l/f-qninolin-2-ones (45). The conmarin-based transformation into substituted l/f-quinolin-2-ones proceeded smoothly with quantitative yields at ambient temperature (Scheme 6.18) [57]. 

Keywords Isatin, hydrazine hydrate, l,l-bis(methylthio)-2-nitroethylene, ethanol, room temperature, one-pot multicomponent reaction, spirooxindole-pyrazolines... 

A 100 mL flask was charged with hydrazine (1 1 mmol), p-keto ester (2 1 mmol), isatin (3 1 mmol) and malononitrile/ethyl cyanoacetate (4 1 mmol) and piperdine (20 mol%, 0.2 mmol) in ethanol (15 mL). The mixture was sonicated in the water bath of an ultrasonic cleaner (power 250 W irradiation frequency 40 kHz) at room temperature (25 30 °C). After the completion of the reaction (monitored by TLC), the resulting precipitate was filtered and washed with ethanol to afford the pure product of spiro[indoline-3,4 -pyrano[2,3-c]pyrazole] 5 as solid in good to excellent yields. Each of the products was characterized by IR, NMR, C-NMR and HRMS studies. 

An efficient one-pot, four-component reaction of hydrazine derivatives 37, p-keto ester 33, isatins 20, and malono-nitrile 3 leading to the S5nthesis of spiro[indoline-3,4 -pyrano[2,3-c]pyrazole derivatives 38 catalyzed by L-proline in water under heating conditions with good yields has recently been reported by Yu et al. [121] (Scheme 20). 

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