Spectroscopic and structural characterization of products arising from the base-promoted benzylation of 3-sulfolene

Reaction of the title sulfone ( 1 ) with benzyl iodide at –78°C in the presence of LiHMDS and using THF/DMPU as solvent affords a chromatographically separable mixture of the compounds 2 – 5 in a combined yield of 42%. These products have been subjected to comprehensive spectroscopic characterization and the structures of products 2 and 5 established through single-crystal X-ray analyses.


Introduction
In connection with a program directed towards the synthesis of cyclohexenyl-based antiangiogenic agents, 1 we required access to a range of 1,4-dibenzylated and 1,1,4-tribenzylated-1,3-butadienes posessing varying double-bond geometries.To that end we have investigated the reaction of commercially available 3-sulfolene (1) with benzyl iodide in the presence of lithium hexamethyldisilazide (LiHMDS) and in the expectation that, through control of reactant stoichiometry, the cis-and trans-2,5-dibenzyl-and/or 2,2,5-tribenzyl-3-sulfolenes, 2, 3 and 4 respectively, would be produced selectively.It was anticipated that thermolysis of these products would then deliver, through stereospecific cheleotropic extrusion of sulfur dioxide, the corresponding 1,3-butadienes that would serve as 4π-components in Diels-Alder cycloaddition reactions with appropriate dienophiles and so leading to the target cyclohexenes.This sort of approach to substituted 1,3-butadienes (and thence cyclohexenes) has been employed by various groups 2 and even applied to the preparation of the required precursors 2 and 3 by Takayama and co-workers. 3However, the structures of the 2,5-dibenzylated products this group obtained were not rigorously established in so far as it was not absolutely clear that the major isomer possessed a trans-relationship between the two benzyl groups.Accordingly, we now detail the outcomes

Results and Discussion
The benzylation of commercially available 3-sulfolene (1) was carried out at -78°C in THF using benzyl iodide 3 as electrophile and LiHMDS as base.Since the trans-and cis-2,5dibenzylated products, compounds 2 and 3 respectively, were deemed the most important of the possible products of reaction, two molar excesses of both the electrophile and base were employed.In addition, DMPU was used as co-solvent given the capacity of this polar aprotic species to facilitate alkylation reactions.Under such conditions four chromatographically separable products, 2-5, were obtained in a combined yield of 42%.Despite the low yield involved, no other products of reaction were isolated and nor was any of the starting material recovered.The major product of reaction (32%) was one of the expected (and crystalline) 2,5dibenzylation products and this was accompanied by much lower yields (3%) of its isomer.The spectral data obtained on these compounds matched those reported by Takayama. 3However, spectroscopic analysis of these materials did not permit unambiguous assignment of their structures since each possess symmetry elements (C 2 vs C s ) that lead to very similar NMR spectra.For example, seven signals are seen in the 13 C NMR spectra of each of these compounds while there is remarkably little difference in the chemical shifts of the resonances arising from the benzylic and allylic protons in each of the isomers.Accordingly, the major and crystalline product of reaction was subjected to single crystal X-ray analysis (see Figure 1 and Experimental Section) and by such means it was established that this compound is the trans-isomer 2. The predominance of this species over isomer 3 is not unexpected 3 and presumably arises through the operation of kinetic and not thermodynamic effects since molecular mechanics calculations ARKAT (OPLS-2003) indicate that the difference in ground-state energies of these cis-and trans-isomers is less than 1 kJ/mole.Thus, the mono-benzylated anion that serves as the common precursor to compounds 2 and 3 is expected, on steric grounds, to react with benzyl iodide such that the former product is formed more rapidly.
ORTEP derived from the single-crystal X-ray analysis of compound 2.
The spectral data derived from the tribenzylated product 4, which was obtained in only 2% yield, were in full accord with the assigned structure.The analogous data derived from the fourth and final product, namely compound 5 (which was obtained in 5% yield), clearly indicated the compound had incorporated three benzyl units while the presence of three olefinic protons suggested that the 3-sulfolene ring had been cleaved.Nevertheless, this product still incorporated a sulfone residue as evidenced by the appearance of diagnostic absorption bands at 1300, 1115 and 698 cm -1 in the infra-red spectrum.These and other spectroscopic properties led to the conclusion that product 5 possessed the illustrated structure but final confirmation of this followed from a single-crystal X-ray analysis, the outcomes of which are shown in Figure 2 as well as in the Experimental Section.This analysis reveals that both double-bonds possess the Econfiguration.The formation of product 5 under the conditions described here is not unexpected since it is known that anions derived from 3-sulfolenes can undergo fragmentation to give sulfinate anions and that these, in turn, react with added electrophiles to give ring-opened sulfones. 4Thus, the anion derived from deprotonation of compound 2 and/or 3 presumably engages in the aforementioned fragmenation process and the resulting anion 6 is then benzylated, by the added electrophile, to give the observed product 5.General Procedures.Spectral and physical data were recorded as detailed elsewhere. 5Medium pressure liquid chromatography was performed using a Versa Flash medium pressure system fitted with a SUPELCO Versa Pak SiO 2 cartridge and operating at 65 psi while flash chromatography was conducted using protocols developed by Still et al. 6

Figure 2 .
Figure 2. ORTEP derived from the single-crystal X-ray analysis of compound 5.