Sulfolenes 3.5- disubstituted

A series of 4,6-disubstituted-l,3-dihydrothieno[3,4- ]thiophene-2,2-dioxides (sulfolenes) 477-480 was obtained <2002JOC9267> from 5,7-disubstituted l,4-dihydrothieno[3,4-7l[2,3]oxathiin-3-oxides (thienosultines) 476a-d by heating in benzene in sealed tube (Equation 15). 

Cycloaddition of the 2,5-disubstituted sulfolenes (559) with diazomethane takes place on the less hindered face, resulting in cis -fused compounds (560) in which the substituents occupy the exo position. Irradiation of these gives the cyclopropanes (561) (70JA6918). Photochemical [2 + 2] cycloaddition of sulfolene with maleic anhydride and maleimides is known (Scheme 216) (77AHC(2l)253). 

Interestingly, from these rram-2.5-disubstituted-3-sulfolenes (5), desulfonylation conditions [547] yielding stereoselectivity either (E,Z) or (E,E) conjugated dienes were found and applied to stereoselective syntheses of insect pheromones (including (2)). 

The alkylation of 2-alkyl-substituted sulfolenes takes place with complete regio- and high stereo-selectivity to yield approximately 60% of rra/ -2,5-disubstituted 3-sulfolenes. When 1,4-diiodobutane and 1,3-diiodopropane are used instead, one-pot dialkylation occurs at the 2-position in the first case and leads to a spiro sulfolene, whereas 2,3-dialkylation proceeds in the second case leading to a fused bicy-clic product. Interestingly 2,S-dialkylation has been achieved, from 3-bromo(bromomethylpropene), thus allowing the synthesis of bicyclo[3.2.1]sulfones. ... 

Sulfolenes are valuable precursors of 1,3-dienes. Thermolytic desulfonylations of 2,S-disubstituted derivatives lead exclusively to ( ,Z)-dienes in agreement with the symmetry rules. The stereoselectivity of the reaction is dramatically changed however by carrying out the reaction in a protic solvent and in the presence of a base (which probably isomerizes the trans sulfolene to the cis isomer), since ( , )-dienes are now obtained exclusively and contrary to the symmetry rules. a-Metallo sulfolenes may be viewed therefore as masked 1,3-dienyl anion equivalents ( C =>C—C =C—R). The above mentioned set of reactions has been used for the regioselective syntheses of 6- and 16-alkyl-substituted vitamin D3 analogs, as well as rrani-3-ocimene and oi-famesene. ... 

Sulfur dioxide extrusion from 2,5-disubstituted sulfolenes 263... 

Sulfur dioxide extrusion from 3,4-disubstituted sulfolenes 266... 

On further alkylation, 2-substituted-3-sulfolenes delivered tran5-2,5-disubstituted 3-sulfolenes (72) in moderate to high yield with -90% stereoselectivity and 100% regioselectivity. A selection of the results is shown in Scheme 6.20, Table 6.5. 

The presence of a phenyl group at the 3-position of the sulfolene nucleus stabilizes an anion at C-5, and thus alkylation occurs selectively in that position. The selectivity is slightly reduced when the phenyl ring carries an electron donating methoxy substituent. The disubstituted compounds (91), obtained after alkylation, could then be selectively alkylated in the 2-position. 

A large-scale one-pot preparation of 3-thiophenyl-3-sulfolene (128) was achieved by addition of phenylsulfenyl chloride, followed by triethylamine [61] (Scheme 6.39), In a later study 3-methyl-3-sulfolene was reacted in a similar manner to give a 52% yield of the 3,4-disubstituted sulfolene (133) [93]. The route was also adapted for the synthesis of 3-phenylselenyl-3-sulfolene (134) [77]. 

Sulfur Dioxide Extrusion from 2,5-Disubstituted Sulfolenes... 

Trans-2,5-disubstituted sulfolenes (e.g., (170aA )) can be prepared by alkylation procedures as described in Section 6.3. Under thermal (neutral) or reductive conditions these extrude SO2 to give the predicted ( ,Z)-dienes (171). However, a dramatic reversal of stereoselectivity was observed when the reactions were carried out under basic conditions [116,117] (Scheme 6.54, Table 6.23). This appears to be because the rate of SO2 extrusion to the (Z)-alkene is relatively low. Thus, under basic conditions, epimerization to the c/s-sulfolene (172) can occur and this will extrude SO2 at a much higher rate than (170). This principle has been used in the synthesis of (173b), a sex pheromone of the coding moth, and (E,E)-11,12-hexadecadienal, a cabbage webworm sex pheromone. 

An alternative approach to 2,5-cis disubstituted sulfolenes (172) and their (E,E)-diene derivatives (173) involves the sequential exo-alkylation of (174), followed by tandem retro-Diels-Alder-S02 extrusion [12,13] (Scheme 6.55). 

In general, SO2 extrusion from 3,4-disubstituted sulfolenes is straightforward and there are no stereochemical implications. Alternative methods for SO2 extrusion have been reported. Examples of some sulfolenes which underwent reductive desulfonylation in LiAlH4 are shown in Scheme 6.58 [57]. It was postulated that the cheletropic elimination of SO2 proceeds via thermal cleavage, with LiAlH4... 

The geometrical preferences during SO2 extrusion from 3,5-disubstituted sulfolenes are similar to those for mono-2-substituted compounds, and dienes with ( )-geometry are generated. For example, sulfolene (180) opened to give diene (181) exclusively and the geometry was easily established by NMR coupling-constant data [50]. 

In our laboratories, problems have been encountered in predicting the stereoselectivity of intramolecular Diels-Alder reactions from 2,3-disubstituted sulfolenes bearing a methyl ester or dimethylamide in the 3-position, intermediate dienes of differing geometries perhaps being responsible [70,72,75]. Model sulfolenes we therefore constructed to find out the effect of changing substituents... 

Sulfolenes are masked 1,3-dienes [96]. At about 150 °C they undergo (4+ 1)-cycloreversion into 1,3-dienes and sulfur dioxide. As this is a thermal concerted reaction, this cycloreversion proceeds in a disrotatory manner according to the Woodward-Hoffmann rules. Thus, a ds-2,5-disubstituted 3-sulfolene stereospecifically yields an (F,E)-l,3-diene, while the trans-diastereomer gives an (F,Z)-1,3-diene ... 

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