1,3-Dienes from ketones via the Shapiro reaction

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Introduction
1,3-Dienes are important synthetic intermediates, finding particular application in the Diels-Alder reaction. 1We have a long-standing interest in the preparation of conjugated polyenes 2,3 and recently reported a convenient entry to 1,4-disubstituted buta-1,3-dienes via the palladium(II)-mediated homocoupling of organostannanes. 4In seeking to convert ketones 1 into 2,3-disubstituted-and more highly substituted butadienes 4, we envisaged a new extension of the Shapiro reaction 5 (Scheme).
Thus, conversion of the ketones 1 into the corresponding sulfonylhydrazones 2 followed by the organolithium-induced Shapiro reaction is known to produce vinyllithium intermediates 3. 5 We planned to transmetallate 3 to produce a vinyl organometallic species which would undergo dimerisation to give dienes 4.

Results and Discussion
Initial studies were carried out with tosylhydrazones but it was soon established that better results were obtained using 2,4,6-triisopropylbenzenesulfonyl (trisyl) hydrazones.5b The trisylhydrazones 2a-h were readily prepared, most in almost quantitative yield (Table ), simply by stirring a THF solution of the appropriate ketone and trisylhydrazide and then removing the solvent in vacuo following the procedure reported by Bertz and Dabbagh. 6reatment of a THF solution of the trisylhydrazones 2 with 2.1 equivalents of nbutyllithium at -78 ˚C gave deep orange coloured solutions.Upon warming to 0 ˚C for a few minutes, the evolution of nitrogen gas was evident leaving a yellow solution of vinyllithium species 3.This solution was then recooled to -78 ˚C.Preliminary investigations into the transmetallation-dimerisation were carried out with MnCl 2 , Ti(O i Pr) 3 Cl and PhI(OAc) 2 giving no observable diene upon workup, although a combination of Pd(MeCN) 2 Cl 2 and CuCl 2 produced 4a in low yield (43%).It is known that vinyllithium reagents undergo transmetallation to organocopper species and that these can undergo oxidative coupling to produce 1,3-dienes. 7A range 8 of copper(I) salts were therefore employed to effect the dimerisation of the vinyllithium reagent derived from trisylhydrazone 2a (Table, entry i).The use of copper(I) iodide gave good yields for the formation of 4a (66-78%) but was not general.The optimum procedure, and the one which appeared the most general, involved the use of one equivalent of (CuI.PBu 3 ) 4 7a in THF at -78 ˚C followed by warming to room temperature and stirring at this temperature for 18 hours.The efficiency of (CuI.PBu 3 ) 4 compared to other Cu(I) salts may well be due to its high solubility in THF.The optimised procedure produced diene 4a in 68% yield; no other products were observed indicating regioselective deprotonation at the methyl group as was anticipated. 5Diene 4a has been used to prepare protein kinase C inhibitors: this synthesis from nonanone (68% over 2 steps) compares favourably with the published route from nonanoic acid (6 steps, ca.10%). 3ddition of 1% triethylamine to column chromatography eluents was found to be necessary to avoid double bond isomerisation, but when pure the dienes could be stored under a nitrogen atmosphere in the freezer for a number of months.Two other 2,3-disubstituted butadienes were also prepared using this methodology (Table, entries ii and iv).In the case of cyclohexyl methyl ketone trisylhydrazone 2b, selective deprotonation of the methyl group occurred giving diene 4b in good yield.Cyclohexyl ethyl ketone trisylhydrazone 2c did not produce any diene 4c, however, apparently failing to undergo the Shapiro reaction and demonstrating a limitation of this methodology (Table, entry iii).In the case of acetophenone trisylhydrazone 2d vinyllithium formation appeared to proceed normally but the coupling was sluggish (Table entry iv).In this example the reaction was heated to reflux for 18 hours after the addition of the copper complex: this produced 4d in 23% yield (no diene was obtained under the standard conditions).It seems likely that this low yield reflects the thermal stability of the intermediate organocopper species.
Next, we investigated the use of cyclic ketones ultimately producing 1,2,3,4tetrasubstituted butadienes (Table entries v and vi).Efficient deprotonation of the hydrazones 2e-i could only be achieved by using a THF-TMEDA (9:1) solvent mixture in the Shapiro reaction, 5b but the standard transmetallation-dimerisation conditions afforded dienes 4f and 4g in satisfactory yield.No dienes were isolated from the reaction of cyclopentanone trisylhydrazone 2e but the low stability of cyclopentenyllithium prepared in this way has been noted previously. 9In the case of cyclododecanone trisylhydrazone 2h, no diene was obtained but a 53% yield of cyclododecene was isolated, presumably indicating that the dimerisation may be precluded for steric reasons.Finally, the substituted cyclohexanone trisylhydrazone 2i, underwent efficient transformation to give diene 4i.
In summary, an efficient two-step procedure for the preparation of substituted buta-1,3dienes from ketones has been developed and information on the scope and limitations of the methodology has been established.a Unless otherwise stated, n-BuLi in THF at -78 ˚C was used for deprotonation.
(CuI.PBu 3 ) 4 was added at -78 ˚C followed by warming to room temperature and stirring at this temperature for 18 hours.b A 12% yield of a 1:1 mixture of 4a and 1-nonene was obtained with nonan-2-one tosylhydrazone, using CuI for the transmetallation.Using 2a and CuI, 4a was obtained in 66-78% yield.c None of the expected product was observed with only unidentified polar by-products being obtained.d THF-TMEDA (9:1) was used as solvent for the second step.e Coupling reaction heated to reflux for 18 h (no diene was obtained under standard conditions).f Cyclododecene (53%) was obtained.

Experimental Section
Compounds 2b-i and 4a,b,d,f,g,i are known andgave data consistent with those published.