Synthesis and some (4+3) -cycloaddition chemistry of a sulfur-substituted allylic acetal

The preparation of a sulfur-substituted allylic acetal is described and its application in 4+3 cycloaddition reactions with furan and cyclopentadiene is reported.


Introduction
The (4+3)-cycloaddition reaction between allylic cations and dienes is a powerful method for the synthesis of seven-membered rings. 1 We have been interested in this area for some time and, in particular, in the application of heteroatom-stabilized allylic cations to the cycloaddition process.
The use of heteroatom-stabilized cations in the 4+3 cycloaddition reaction is known. 2This area is still of great interest as many possibilities remain for the development of (4+3)dienophiles using this approach.Heteroatom stabilization offers the chance of controlling reactivity, regioselectivity and facial selectivity in the (4+3)-cycloaddition reaction.Oxygen-stabilized allylic cations (vinyl oxocarbenium ions) can be produced in a number of ways.Allylic acetals were first used by Murray and Albizati as progenitors of such allylic cations for the (4+3) cycloaddition reaction. 3Both we and Hoffmann applied the basic approach to the development of chiral allylic cations capable of highly diastereoselective (4+3) cycloaddition reactions. 4,5 lfur-stabilized allylic cations have also been applied in (4+3) cycloaddition reaction chemistry by our group and by others. 6In the interest of extending the scope of the reaction and in understanding reactivity issues in (4+3) cycloaddition chemistry, we decided to begin a study of cations which were stabilized by both oxygen-and sulfur-electron donating groups.Our preliminary results are included in this report.

Results and Discussion
The synthesis of the target allylic cation precursor for our studies was relatively straightforward.The N,N-dimethylhydrazone of commercially available dimethoxyacetone (1) was prepared in 90% yield by reaction of the ketone with dimethylhydrazine in ether at 0 o C. 7 Deprotonation of the hydrazone 2 with LDA and trapping with diphenyl disulfide afforded the ketosulfide 3 in 67% yield after hydrolysis of the hydrazone functionality. 8Reaction of this species with triethylamine and chlorotrimethylsilane afforded the enol ether 4 in 91% isolated yield (Scheme 1).The stereochemistry of 4 was established as shown (Z) by NOESY spectroscopic data, which showed a cross peak between the olefinic hydrogen (5.83 ppm), and the hydrogens of the methoxy group (3.36 ppm).With 4 in hand, cycloaddition experiments were begun.Treatment of a stirred solution of 4 and 10 equivalents of furan in CH 2 Cl 2 (0.2 M) at -78 o C with 1 equivalent of TiCl 4 resulted only in the formation of the hydrolysis product 3.Given this result, we set out to find conditions under which cycloaddition would occur.Table 1 shows the results of a small study involving TiCl 4 as Lewis acid, varying stoichiometry, temperature and solvent.The results were not spectacular, but two trends became apparent that would be useful later.First, the reaction improved when more than a stoichiometric amount of Lewis acid was present (Table 1, entries 2 and 3).The reaction also appeared to proceed better when the reaction mixture was allowed to warm (Table 1, entries 3 and 4).In view of our earlier findings and in recognition of the possibility that 4 might serve as a bidentate ligand for titanium, 6b we examined the effect of variable amounts of TiCl 4 on the cycloaddition reaction.Having seen that higher temperatures affected the reaction favorably, we conducted these studies at 0 o C. The results are shown in Table 2.Note that the yield of cycloadduct did indeed increase as the number of equivalents of Lewis acid increased.The best yield was obtained when 4 equivalents of TiCl 4 were used.Additional Lewis acid caused a decrease in yield.At high TiCl 4 concentrations in CH 2 Cl 2 , or lower concentrations in EtNO 2 , a compound assigned the structure of the hydrolysis product 6 was isolated in low yield, but this species was not rigorously characterized.We observed that decomposition appeared to accompany the cycloaddition reaction, perhaps caused by destruction of both 4 and furan by the Lewis acid.We thus studied the use of milder Lewis acids in an attempt to improve the reaction; some success was achieved.The results are summarized in Table 3.As can be seen, the use of trichlorotitanium isopropoxide gave yields of cycloadduct 5 as high as 70%, when a fourfold excess of the Lewis acid was used in CH 2 Cl 2 at 0 o C. We have also used these reaction conditions with cyclopentadiene and obtained a 50% yield of the cycloadduct 7. It should be noted that the stereochemical assignments of both 5 and 7 are based at present on analogy with other alkoxy-and phenylthio-substituted cycloadducts we have prepared. 4  In conclusion, we have developed a protocol for the generation of an allylic cation stabilized by both sulfur and oxygen atoms that is capable of undergoing a (4+3) cycloaddition reaction.Exploring the scope of this chemistry, particularly with respect to regiocontrol and stereocontrol, will be the subject of future investigations.

Experimental Section
General Procedures.All air-or moisture sensitive reaction were carried out in oven-dried (120 o C) or flame-dried glassware under a nitrogen atmosphere.Reactive liquids (e.g., n-BuLi) were transferred by syringe or cannula and were added into reaction vessels through rubber septa.Ether and THF were freshly distilled from sodium benzophenone ketyl, and dichloromethane was distilled from CaH 2 .Titanium tetrachloride was freshly distilled from copper dust immediately before use.Triethylamine was distilled from CaH 2 and stored over molecular sieves.Analytical thin layer chromatography was performed on silica gel plates with F254 indicator.Compounds were visualized under a UV lamp or by developing with iodine, vanillin or phosphomolybdic acid solution following by heating on a hotplate.Flash chromatography was performed on 230-400 mesh silica gel with technical grade solvents that were distilled prior to use.Medium pressure liquid chromatography (MPLC) was done using Merck Lobar columns.Gas chromatographic analyses were performed on a Shimadzu GC-9A instrument equipped with an SPB-5 fused silica capillary column (15m, i.d.0.25 mm) and a flame ionization detector.Chromatograms were recorded on a Hewlett-Packard HP 3390A integrator. 1 H NMR spectra were recorded on Bruker AMX-250 or AMX-500 instruments at 250 MHz (62.9 MHz for 13 C) or 500 MHz (125 MHz for 13 C) as CDCl 3 solutions, with tetramethylsilane as the internal standard.Chemical shifts are reported in parts per million (ppm) downfield from tetramethylsilane (0 ppm).Multiplicities are reported as s (singlet), d (doublet), t ( triplet), q (quartet), m (multiplet), dd (doublet of doublets), bs (broadened singlet), etc. Infrared spectra were recorded on Nicolet 550 Magna FTIR-or Nicolet 20 DXB FTIR spectrometers, as neat liquids.Intensities are reported as s (strong, 67-100%), m (medium, 34-66%), and w (weak, 0-33%).Elemental analyses were performed by MHW Laboratories, Phoenix, Arizona.

Table 1 .
Cycloaddition of 4 and furan using TiCl 4 SnCl 4 , and Yb(OTf) 3 .None of these offered any advantage over TiCl 4 .In general, low yields of cycloadduct and hydrolysis product were obtained in attempted cycloaddition reactions with furan in CH 2 Cl 2 at -78 o C.

Table 2 .
Effect of Lewis acid stoichiometry on the reaction between 4 and furan Compound 3 formed.b Compound 6 was formed in low yield.