A new method for the synthesis of pyrazolidines

Fully protected pyrazolidines can be readily obtained by acid-catalysed cyclisations of the corresponding allylic hydrazines by carbenium ion generation using concentrated sulfuric acid in dichloromethane. Pyrazoles and their partly and fully reduced derivatives, pyrazo-lines and pyrazolidines, form an important group of heterocycles, with potentially important contributions to make to drug design by reason of their ability to form strong hydrogen bonds at either or both nitrogen atoms. It is perhaps also signiÞcant that Nature does not seem able to form NAN bonds directly and hence such compounds will occupy an entirely non-natural portion of chemi-cal space and hence are likely to continue to play a central role in the discovery of novel pharmaceuticals.1 Despite the enormous contribution made by heteroaromatic residues, both with and without incorporated nitrogen atoms in a majority of commercial drug structures, it has recently become plain that to achieve a con-tinuation of this success, it would be wise to embrace semi-satu-rated and fully saturated analogues of such structural features, in order to introduce both greater ßexibility and increased three dimensional shape.1 Many synthetic routes have been deÞned for the syntheses of such heterocyclic systems, but quite often these suffer from a lack of regioselectivity, particularly when both CAN bonds are formed effectively simultaneously from a hydrazine and an all-carbon bis-electrophile such as a 1,3-dicarbonyl or a conjugated enone.2 Hence, often it is preferable to assemble such structures using a stepwise approach.3,4 The inspiration for the present methodology was derived from a possible extension of our Þnding that unsatu-rated sulfonamides 1 are readily converted into the corresponding ⇑ Corresponding author. E-mail address: [email protected] (D.W. Knight). y On leave from the Institute of Chemistry, University of the Punjab, Lahore, Pakistan. pyrrolidines 2 following exposure to acid,5 in an intramolecular hydroamination reaction. A particularly rapid and efÞcient exam-ple (Scheme 1) features favourable tertiary carbenium ion genera-tion by protonation of the alkene group in the precursor sulfonamide 1, which is then trapped by the sulfonamide group to give an essentially quantitative yield of the corresponding pyrrolidines 2. Such cyclisations are quite general and are also successful when secondary carbenium generation is required. The fact that concen-trated sulfuric acid can be used in less than stoichiometric quanti-ties gives the method some positive environmental credentials as the only by-product of these usually very clean cyclisations is the sodium or potassium sulfate generated upon mild, basic work-up. Of course, the highly acidic nature of the method will impose some restrictions on future applications; thus far, remote alkenes, alkynes, sulfones, esters and alcohols protected as the correspond-ing acetates have been found to be stable and not to interfere with such cyclisations. It was against this background that we wondered if such methodology could be extended to include cyclisations of suitably protected allylic hydrazines 3 which, if successful, would result in the deÞnition of a new and perhaps efÞcient approach to pyrazolidines 4 (Scheme 2). Herein, we report our preliminary results, which show that this idea is indeed viable. A recent report strongly suggested that the methodology shown in Scheme 2 would be successful. In this study, the discovery of novel, twostep cyclisations was described in which the acylhydrazones 5 having a distal prenyl alkene under-went conversion into the annulated pyrazolidines 7 (Scheme 3).4 A likely mechanism involves imine protonation followed by cyclisa-tion to form a cyclohexane which generates exactly the type of R 0.4 eq. TfOH or c.H2SO4 OH HNTs ref. 10 NTs + NHCO2Me NHCO2Me HN CH2Cl2, Ts 0 oC, ~15 min. 1 ~100% N R Ts 16 17 12 2 Scheme 5. Regioselective Mitsunobu coupling. Scheme 1. Intramolecular, acid-catalysed hydroamination. R3 N R1 H + ? N R3 HN N R1 R2 R2 3 4 Scheme 2. Idea: would protected hydrazines cyclise?