On the preparation of cyclopentadienes by a novel homolytic annulation of but-3-en-1-ones with alkynes mediated by samarium diiodide

Treatment of substituted pent-4-en-2-ones and phenylacetylene with samarium diiodide in a mixture of THF and HMPA yielded 3-methyl-1-phenylcyclopent-1-en-3-ols that rapidly dehydrated and underwent [1,5] hydrogen migrations to afford substituted cyclopentadienes. The mechanism involved ketyl radical anions, generated from the unsaturated ketones by SmI 2 , initially adding to the alkyne. The resulting vinyl type radicals cyclised in the preferred 5-exo - mode to produce cyclopentenylmethyl radicals that were reduced to the corresponding anions and abstracted a proton from t -BuOH. The overall process amounted to a novel free-radical [3+2]-annulation.


Introduction
The concept of a novel homolytic annulation process, involving unsaturated radicals and alkenes or alkynes, has been turned into a reality by several research groups in the last few years.Essentially, the process is a two-stage cascade consisting of the intermolecular addition of a radical, containing an appropriately placed unsaturated group, to a radical acceptor, followed by intramolecular ring closure of the resulting adduct radical.Most frequently, the initial radical is a but-3-en-1-yl (homoallyl) 1, but-3-yn-1-yl, or analogous species, that adds (A) to a double or triple bond (A=B) to produce a hex-5-en-1-yl type of radical 2. The latter is well adapted to rapidly cyclise in the allowed 5-exo-mode (C 5x ) to produce a cyclopentane derivative 3.
][13] Samarium(II) iodide appeared to be a promising reagent for mediating radical annulations.Reaction of SmI 2 with a but-3-en-1-one 6 was expected to generate a ketyl radical anion 7 that should be nucleophilic.Intermolecular addition to a triple bond should, therefore, take place efficiently to generate vinyl radical 8 and hence, after a C 5x ring closure, cycloalkenylmethyl type radical 9. Radicals 7, 8 and 9 are ketyl, vinyl and alkyl types respectively, so these different electronic characters should lead to a sharp difference in reactivity, hence ensuring that oligomerisation is unimportant.
To test the practicality of this annulation sequence a short series of functionalised but-3-en-1ones was prepared and reacted under various sets of conditions. 14,15

Results and Discussion
The simplest suitable ketone, pent-4-en-2-one 6a was prepared via an organozinc intermediate that underwent addition to a nitrile (Scheme 3). 16Work-up proved to be problematic due to the volatility of product, the similar boiling points of starting materials and product and, most seriously, to the instability of the product with respect to the α,β-unsaturated isomer, pent-3-en-2-one 10a.Repeated careful distillation gave 6a in 39% yield.Unfortunately, isomerisation to 10a occurred rapidly, so 6a had to be prepared immediately prior to use.Hept-1-en-4-one 6b was made by the same technique, in the hope that purification would be easier.Distillation was again difficult, but the higher boiling point of 6b compared to 6a meant that column chromatography could be utilised.Chromatography on silica had previously been avoided because it was suspected that isomerisation would take place on the column.This surmise proved to be unfounded and 6b was isolated in 40% yield.Disappointingly, isomerisation to 10b occurred on standing for 24 hours, again necessitating use of 6b immediately upon preparation.
It was thought that isomerisation might be prevented if an aromatic substituent R 2 was introduced.The simple route to 5-phenylpent-4-en-2-one 6c shown in Scheme 3 was chosen. 17A Knoevenagel condensation yielded 3-styryl-pentane-2,4-dione which was converted to 6c with of zinc acetate dihydrate in 65% yield.Gratifyingly, 6c proved to be stable, and could be kept on the bench indefinitely.Before attempting any annulations, the addition stage of the process was tested separately by carrying out an intermolecular coupling of phenylacetylene with benzylacetone 11 (Scheme 4). 18amarium(II) iodide was added to phenylacetylene in t-butanol and HMPA followed by addition of the benzylacetone.1,5-Diphenyl-3-methylpent-1-en-3-ol 12 was obtained in 36% yield, after chromatography.Subsequently the annulation sequence shown in Scheme 2 above was tested for each of 6a-c.Isolation and purification of the final products was problematic because of the almost identical R F values of the product and starting material in whichever solvent system was used.The annulation with 6a was successful, although pure product could not be isolated.NMR spectroscopy indicated that the annulated product 13a had been formed; there was a characteristic singlet at 5.95 ppm in the 1 H NMR spectrum, corresponding to an uncoupled alkenyl proton.GC/MS analysis indicated that 13a dehydrated very easily to afford cyclopentadiene 15a.Treatment of 6b with SmI 2 under similar conditions yielded what was believed to be 13b.Addition of this material to deuteriochloroform resulted in the formation of a cloudy emulsion due to the expulsion of water.NMR analysis of the dried material indicated that 13b dehydrated with concomitant thermal rearrangement to give the thermodynamically more stable cyclopentadiene 15b (Scheme 5).Mass spectrometry of the initial material (i.e.product that had not been added to deuteriochloroform) verified this, but indicated that some enol 13b was present, even under the operating conditions of the mass spectrometer.The overall yield was 27%.Use of the more stable precursor enone 6c again led to annulated product.Employment of DMPU as a co-solvent in place of the highly toxic HMPA 19,20 greatly slowed the reaction.After 3 days of stirring, the reaction mixture was still deep blue.NMR analysis revealed that there was a substantial amount of starting material left in the mixture.Use of HMPA as the co-solvent resulted in complete reaction in under a minute.Unfortunately, purification by repeated column chromatography was not successful, but GC/MS analysis indicated that the annulated product had been formed.It was suspected that loss of product was occurring during column chromatography because cyclopentadienes readily undergo Diels-Alder dimerisation reactions, and it is possible that this was causing the difficulties in separation and low perceived yields.Samarium(II) iodide was found to be a suitable mediator of radical annulations.The success of the sequence was due to the difference in reactivity of the propagating radicals.The ketyl radicals generated were highly reactive, and intermolecular addition did not require a large excess of radical acceptor.Oligomerisation did not occur because the final alkyl radical was much less reactive.When the product was a cyclopent-2-enol, as in the examples studied here, dehydration occurred, followed by a concomitant [1,5]-H shift forming a thermodynamically more stable cyclopentadiene derivative.The less than excellent yields were probably a consequence of difficulties encountered in purification, and the dimerisation of the product cyclopentadienes.HMPA was found to be a superior co-solvent to DMPU in the annulation sequences.

Experimental Section
General Procedures. 1 H NMR spectra were obtained using a Bruker AM 300 MHz spectrometer unless otherwise stated, in which case the spectrum was obtained using a Varian Gemini 200 MHz spectrometer. 13C NMR spectra were run at 75 MHz using the Bruker mentioned above.All samples were dissolved in deuteriochloroform, with tetramethylsilane as an internal standard.Coupling constants are given in Hz.GC/MS analysis was carried out using a Finnigan Incos 50 quadrupole mass spectrometer interfaced with a Hewlett-Packard HP5890 capillary gas chromatograph fitted with a column coated with methylsilicone as the stationary phase.Petroleum ether (PE) refers to the fraction boiling between 40 and 60˚C unless otherwise stated.Column chromatography was performed using BDH silica gel (40 -63 mm).