SHORT COMMUNICATION DOI: 10.1002/ejoc.201402038 Catalyst-Free One-Pot Tandem Reduction of Oxo and Ene/Yne Functionalities by Hydrazine: Synthesis of Substituted Oxindoles from Isatins Mukund Jha,* [a] Ganesh M. Shelke, [a,b] and Anil Kumar [b] Keywords: Synthetic methods / Reduction / Nitrogen heterocycles / Fused-ring systems An unprecedented one-pot tandem reduction of oxo and ene/ yne functionalities of substituted isatins is disclosed for the synthesis of oxindole derivatives in excellent yields. The re- action is simply performed by treating N-(2-alkenyl)/prop- argylisatins with an excess amount of hydrazine hydrate Introduction The indolin-2-one or oxindole structural motif is consid- ered to be an important ring system in heterocyclic chemis- try owing to its presence in a wide variety of natural prod- ucts and biologically active compounds. [1] Substituted and unsubstituted oxindoles also serve as crucial synthetic pre- cursors for the synthesis of highly desirable indole-based heterocycles and alkaloids. [2] In the recent past, there has been considerable effort devoted to the development of an efficient and general synthesis of substituted oxindoles. Some of the synthetic strategies include cyclization of o- aminophenylacetic acid derivatives, oxidative N-hetero- cyclization of amino alcohols, [3] intramolecular amin- ation, [4] oxidation of indoles, [5] radical cyclization, [6] inter- molecular Heck reaction, [7] intramolecular arylation of amides [8] and amide enolates, [9] the Friedel–Crafts cycliza- tion of α-halo [10] and α-hydroxy [11] acetanilides, and its modifications involving C–H functionalization. [12] How- ever, the classical approach to access substituted oxindoles is based on the one-step derivatization of isatins under Wolff–Kishner reduction conditions involving hydrazine hy- drate. [13–15] This strategy is still widely used and is quite appealing to synthetic chemists because several substituted isatins are commercially available and are relatively inex- pensive. Moreover, the reductive transformation of isatins to oxindoles is generally a high-yielding process. There have been previous reports describing the use of hydrazine hydrate in the selective reduction of unsaturated [a] Department of Biology and Chemistry, Nipissing University, North Bay, ON, P1B 8L7, Canada E-mail: mukundj@nipissingu.ca www.nipissingu.ca [b] Department of Chemistry, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201402038. © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2014, 3334–3336 3334 (25 %) under catalyst-free refluxing conditions. The re- duction process appears to be quite unique and proceeds quite efficiently without the aid of any catalyst at ambient pressure. carbon–carbon bonds. [16] It is believed that hydrazine un- dergoes oxidation to produce diimide (N 2 H 2 ) in situ, which acts as a transfer-hydrogenation agent in the reduction pro- cess. [17] Oxidants such as H 2 O 2 , NaIO 4 ,K 3 [(FeCN) 6 ], and even molecular oxygen have been shown to catalyze the se- lective reduction of unsaturated carbon–carbon bonds by using hydrazine. [17] The oxidation of hydrazine to diimide by using molecular oxygen typically requires a catalyst (e.g., copper, iron, and guanidine salts and various flavin deriva- tives) to promote the reaction. [17] Catalyst-free oxidation of hydrazine with molecular oxygen is rather inefficient, as it requires an excess amount of hydrazine and proceeds at a sluggish rate. [16] The reactive diimide intermediate is also prone to disproportionation (reformation to hydrazine) and over oxidation under these conditions. [16] In recent times, specialized reactors have been developed to perform the cat- alyst-free selective reduction of terminal olefins by using hydrazine hydrate and molecular oxygen at high tempera- ture and pressure in continuous-flow mode. [17] Since the first application of the Wolff–Kishner reaction in the synthesis of oxindoles from isatins, [13a] the chemistry community has used this methodology extensively. A Sci- Finder survey revealed a total of 120 references to date re- porting the conversion of various substituted isatins into oxindoles under these conditions. To the best of our knowl- edge, there is only one report of a Wolff–Kishner reduction on a N-ene-/yne-substituted isatin in the chemical litera- ture. [18] Recently, while describing the synthesis of the hodg- kinsine and hodgkinsine B alkaloids, Willis et al. reported the synthesis of N-allyloxindole from N-allylisatin (1a) in only 20% yield (reported in the Supporting Information) by using hydrazine hydrate. [18] The reasons behind such a poor yield were not discussed in the paper. On the basis of our results (see below), we suspect the loss in yield could be caused by the reduction of the allyl group under these conditions. It is quite possible that other researchers may have faced a similar challenge while attempting to prepare