Methyl hydrazinocarboxylate as a practical alternative to hydrazine in the Wolff–Kishner reaction Article Accepted Version Cranwell, P. B., Russell, A. T. and Smith, C. D. (2016) Methyl hydrazinocarboxylate as a practical alternative to hydrazine in the Wolff–Kishner reaction. Synlett, 27 (1). pp. 131-135. ISSN 0936-5214 doi: https://doi.org/10.1055/s-0035-1560805 Available at http://centaur.reading.ac.uk/46749/ It is advisable to refer to the publisher’s version if you intend to cite from the work. See Guidance on citing . To link to this article DOI: http://dx.doi.org/10.1055/s-0035-1560805 Publisher: Thieme All outputs in CentAUR are protected by Intellectual Property Rights law, including copyright law. Copyright and IPR is retained by the creators or other copyright holders. Terms and conditions for use of this material are defined in the End User Agreement . www.reading.ac.uk/centaur CentAUR Central Archive at the University of Reading Reading’s research outputs online SYNLETT0936-52141437-2096 Imprimatur: © Georg Thieme Verlag Stuttgart · New York 2015, 26, A–E A Date, Signature letter st-2015-d0771-l.fm 10/16/15 Syn lett P. B. Cranwell et al. Letter Methyl Hydrazinocarboxylate as a Practical Alternative to Hydra- zine in the Wolff–Kishner Reaction Philippa B. Cranwell*1 1. H 1 N OMe Andrew T. Russell* H2N Christopher D. Smith*1 O O EtOH, cat. AcOH H H Department of Chemistry, University of Reading, Whiteknights, Ar R Ar R Reading, RG6 6AD, UK 2. KOH (4 equiv) [email protected] 2. triethylene glycol 14 examples [email protected] 2. 140 °C, 4 h Ar = aromatic [email protected] and heteroaromatic Dedicated to Professor Steven V. Ley on the occasion of his 70th birthday. Received: 28.09.2015 NH2 H H Accepted: 04.10.2015 O N H2NNH2 KOH Published online: R1 R2 DOI: 10.1055/s-0035-1560805; Art ID: st-2015-d0771-l R1 R2 Kishner R1 R2 heat, Pt 12 3 Abstract Herein we describe a facile protocol for the reduction of aro- matic ketones and aldehydes to the corresponding methylene unit. The procedure involves isolation of a carbomethoxyhydrazone intermediate Wolff H2N O that is easily decomposed to the reduced product without the require- ment for large quantities of pernicious hydrazine. NH NH2 H2NNH(CO)NH2 N NaOEt N Key words reduction, aldehydes, ketones, heterocycles, hydrazones, EtOH, heat R1 R2 R1 R2 alkanes 45 Scheme 1 The Wolff and Kishner reductions of aldehydes and ketones to the corresponding hydrocarbon Since its independent discovery by Kishner (1911)2 and Wolff (1912)3 the eponymous reduction has become a stan- dard method for the deoxygenation of aldehydes, ketones, as base with a distillation protocol to reduce water and hy- and, for certain substrates, the carbonyl of amides under drazine levels, permitting higher temperatures in the reac- basic conditions.4 However, the early investigations of tion pot. Recently, Kuethe et al. have adapted this protocol Staudinger (1911) should not be forgotten.5 In detail, they to the kilogram scale.9 Nagata and Itazaki proposed a vari- are two reactions proceeding through a common interme- ant based upon use of an excess of the safer 85% hydrazine diate. The original procedure reported by Kishner involved hydrate in the presence of a lesser quantity of its HCl salt, prior generation of a hydrazone from the carbonyl and followed by heating in triethylene glycol and KOH.10 100% hydrazine hydrate with subsequent base-catalysed Attempts to lower the reaction temperature have been decomposition over hot, solid KOH and platinised porous reported, initially by the Cram group; they reported reac- plate to deliver the corresponding hydrocarbon. Conversely, tions at room temperature using KOt-Bu in DMSO on the the Wolff version proceeded via an intermediate semicar- isolated hydrazone.11 The effectiveness of this protocol has bazone to decomposition over NaOEt in EtOH in a sealed been interpreted by Szmant to result from the slow addi- tube around 180 °C (Scheme 1). tion of the hydrazone, with consequent excess of base, and Since these initial disclosures, several modifications to one equivalent of t-BuOH trapped within the solvent cage.12 the original procedures have been developed but, in gener- Henbest favoured refluxing toluene with a KOt-Bu base; al, those modifying the Kishner procedure have found the again with the ability to generate the hydrazone anion with widest use. Perhaps the practically most significant devel- a molecule of t-BuOH within the solvent cage.13 More re- opment was introduced by Huang-Minlon.6 Refining work cently, Myers has developed a highly effective reaction that by Soffer et al.7 and Whitmore et al.,8 this procedure took begins with 1,2-bis(tert-butyldimethylsilyl)hydrazine, al- advantage of a high-boiling solvent such as diethylene or lowing silylhydrazone formation under Lewis acid mediat- triethylene glycol and used potassium or sodium hydroxide ed conditions, prior to base-mediated conversion into the © Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–E B Syn lett P. B. Cranwell et al. Letter H path A N N + OH H R3 R4 R1 R2 NH2 N H H N OH N N N 7 1 2 1 2 R R R1 R2 R1 R2 R R H H R1 R2 2 6 N 9 3 10 N azine + H2O + N2 + H2O path B R1 R2 H 8 Scheme 2 Proposed mechanism for the Wolff–Kishner reaction24 hydrocarbon with KOt-Bu between 23 °C and 100 °C.14 The faster rates of reduction than those lacking that stability.23 Myers method also facilitates good yields in the Barton Additionally, this fast rate of reduction gives less opportuni- variation that allows for the preparation of vinyl iodides.15 ty for azine formation. Because of the very significant toxic- Although less common, variations based upon the Wolff ity of hydrazine, it would be desirable to employ the Wolff procedure have been described. For volatile products, Lin- version of this reduction and in some cases this has indeed stead reported that distillation from KOH removes the need proved to very successful, occasionally being superior to the for pressure vessels16 and Quast et al. noted superior results classical Huang-Minlon procedure.16,17 In our hands, de- for the decomposition of a semicarbazone, as compared to a composing the semicarbazone of acetophenone with KOH Huang-Minlon protocol utilising hydrazine.17 Interestingly, in triethylene glycol gave a moderate yield of ethylbenzene. the substrate involved contains a 2-pyridyl subunit; a struc- We speculated that the initial cleavage of the semicarba- tural feature Szmant identified as promoting high reactivi- zone, to afford the corresponding hydrazone, occurred via a ty.18 Zengin also reports high yields of reductions from β-elimination reaction. Taking into account the recent work semicarbazones.19 of Beauchemin,26 in which facile elimination occurs from a Following early studies that explored Kishner’s plati- carboalkoxyhydrazone to afford an intermediate amino iso- num/base reagents,20 and the effect of different bases,21 the cyanate, we concluded that treatment of a carbomethoxy- mechanism of the solution-based Wolff–Kishner reduction hydrazone, under Huang-Minlon conditions, would afford was extensively studied by Szmant who determined the good yields of the reduced product. rate-limiting step to be C-protonation of the hydrazone an- To this end, condensation of acetophenone and methyl ion 6 to give 8 (Scheme 2).22,23 In a recent theoretical study, hydrazinocarboxylate provided the carbomethoxyhydra- Yamabe identifies imine 7 as the intermediate formed zone intermediate (13) as a crystalline solid in excellent during this protonation rather than the anion 8 favoured by yield. In all cases, formation of the hydrazone intermediate Szmant.24 Yamabe also identified a mechanistic distinction was achieved by condensation of the parent carbonyl with between substrates such as acetophenone, which give rise methyl hydrazinocarboxylate (1.3 equiv) in ethanol with an to a resonance-stabilised carbanion (with initial protona- acetic acid catalyst. The intermediates were bench-stable tion occurring in the aromatic ring), and those such as ace- solids, and in all cases could be isolated by either filtration tone for which the final protonation is concerted, with no or flash column chromatography. carbanion having an independent existence. The competi- After extensive investigation, the optimal conditions for tion experiment reported by Taber, in which a Wolff–Kish- decomposition of this intermediate were found to be KOH ner reaction was accompanied by a small fraction (ca. 5%) in triethylene glycol at 140 °C. When using four equivalents of stereoselective cyclisation onto a tethered alkene, sup- KOH, the reaction was usually complete within four hours. ported the intermediacy of at least a proportion of sp3 car- If a faster rate was required, the number of equivalents of banion.25 KOH could be increased with little effect on yield. It was no- Amongst the various substrates for the Wolf–Kishner ticed the predissolution of the KOH in the solvent was nec- reaction, those that might arise from a Friedel–Crafts reac- essary before addition of the carbomethoxyhydrazone for tion have a particular value as their reduction facilitates the optimal yield and reaction rate. classical approach for circumventing the overalkylation The reductions were performed on at least a 0.5 gram common in the corresponding alkylation reactions. It has scale and in one case, (Table 1, entry 1) up to 8 grams of been noted that substrates such as these, that give rise to starting hydrazone could be used, with no change to the relatively stable carbanion intermediates, generally give protocol, although upon initial addition of the substrate © Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–E C Syn lett P.