2-Methyl-3-sulfolene

A range of 2-alkyl-3-methyl sulfolenes (189a,b) [104] were prepared by... 

W-Methylpiperidine, 52, 127 3-Methyl-3-sulfolene, in Diels-Alder reaction, 50, 48 MODIFIED CLEMMENSEN REDUCTION CHOLESTANE, 53, 86... 

Acylation of 1-methyl-3,4-dihydroisoquinolines with 3,5-hexadienoyl chloride, in which the dienoic moiety is expeditiously masked as a sulfolene derivative, gave the enamide 331 in 67% yield. Interestingly, thermolysis of 331 in refluxing xylene did not afford the expected spirocyclic compounds (332) but rather the bridged cycloadducts (333) in 97% yields (155,156). 

A report of Backer and Blaas6 is responsible for evolution of the present procedure these workers were first to conduct a Diels-Alder synthesis utilizing a 3-sulfolene in place of the free diene (by heating the cyclic adduct of sulfur dioxide and 2-methyl-3-thiomethyl-1,3-butadiene with maleic anhydride). The generality of the method as a variant of the conventional diene synthesis is limited largely by the availability of the appropriate 3-sulfolene its greatest utility, perhaps, will be presently realized in those diene reactions normally requiring 1,3-butadiene, since 3-sulfolene itself is now the least expensive and most widely available diene cyclic sulfone. 

Methoxycarbonyl-2,5-dihydrothiophen-l,l-dioxide (methyl 3-sulfolene-3-carhoxylate)... 

Extensive studies of the criss-cross addition (see Section 8.31.12.5.2) have shown that this reaction is general for the reaction of azines of aromatic aldehydes (e.g., benzaldazine (340)) with various electron deficient alkenes in which the double bond is terminal (e.g., methyl acrylate, acrylonitrile) <57HCA852, 87JOC2277), or in which allylic substituents do not sterically hinder the reaction, for example maleic anhydride <42RTC892, 57HCA852> or sulfolene <93PS(84)17> (Scheme 68). 

Methyl pelargonate Methyl phenyl sulfone 2-(Methylsulfonyl) ethanol p-Nitrophenol m-Nitrophenyl phenyl sulfide o-Nitrophenyi phenyl sulfide p-Nitrophenyl phenyi suifide Phenyl disulfide Phenylthioglycolic acid Phthalamide. Propargyl alcohol Propylene carbonate 3-Sulfolene 4,4 -Thiobis (6-t-butyl-o-cresol) 4,4 -Thiodibenzenethiol 4,4 -Thiodi (2,6-di-t-butylphenol) 4,4 -Thiodi (2,6-dimethylphenol) 2,2 -Thiodi (4-t-octylphenol) Thiophenol Tribromomethyl phenylsulfone... 

Under similar conditions, ethylation of 3-methyl-3-sulfolene (83) gave 2-substituted products (84) and (85) only, together with some starting material (13%) and isomerized starting material (20%) (Scheme 6.24). It was suggested that deprotonation occurred solely at the 2-position of 3-methyl-3-sulfolene (83) because of the stability of the more substituted C-2 anion. 

In later studies further regioselective alkylations on 3-methyl-3-sulfolene were carried out, extending further the range of side-chain substituents [54,55]. It was found that alkylations with reactive alkylating agents could be carried out without... 

It was discovered that sequential deprotonation of sulfolenes using butyllithium, followed by alkylation, could occiu- without ring fragmentation, provided the temperature was kept at -105°C [40,49,50]. Simple methylation of 3-sulfolene or 3-methyl-3-sulfolene occurred smoothly and in high yield. When acylation of (94) was attempted, the initial acyl product was further O-acylated via sulfolene anion (98). This intermediate anion could, however, be utilized for alkylation, providing access to 2-acyU2-alkyl-3-sulfolenes (100). Representative examples are shown in Scheme 6.29, Table 6.12. 

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]. 

From the examples above, it appears that 2,3-substituted sulfolenes with a methyl group as the 3-substituent open in a highly selective manner to provide the diene with the two substituents cis to one another, but this is not always the case with other 3-substituents. 

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... 

In a later study, a tetracyclic quassinoid skeleton was synthesized in optically active form, starting from (+)-methylcarvone. The sulfolene aldehyde (229) was prepared by regioselective allylation of 3-methyl-3-sulfolene, followed by oxidative cleavage of the alkene bond. Reaction of (229) with the enolate formed from methylcarvone (230) provided alcohol (231), which was acetylated to give (232). Heating (232) provided the tricycle (233) as a single diastereoisomer, and this was... 

Li-bis(trimethylsilyl)amide in THF added dropwise over 30 min to a soln. of 3-methyl-3-sulfolene, startg. 2-(bromomethyl)propene, and 4 eqs. HMPA in the same solvent at — 78°, and the mixture stirred for 2 h - 6-methyl-3-isopropylidene-8-thiabi-cyclo[3.2.1]oct-6-ene 8,8-dioxide (Y 74%), in THF added to a suspension of LiAlH4 in the same solvent, and the mixture heated at 50° for 30 min 2-methyl-6-isopropyl-idene-l,3-cycloheptadiene (Y 96%). F.e.s. T. Chou et al., J. Org. Chem. 52, 5082-3 (1987). 

As a proton source, phenol provides better results under safer conditions. An example is the reduction of 2-methyl-2-sulfolene followed by methylation (Eq. 27). Other proton donors (alcohols) improve the yield more efficiently, but the desired product is contaminated by a dienic sulfone, produced via a complex mechanism. 

Strategies employed by Chou and co workers for the synthesis of several indolizidine alkaloids (c Schemes 103, 139, 149, 182) have also been applied to the synthesis of ( )-indolizidine 167E (me-1682). In the first of their two approaches, aza-Diels—Alder reaction of sulfolene 1691 with p-toluenesulfonyl isocyanate gave the unsaturated piperidine-2-one 1692, which underwent cross-metathesis with methyl acrylate and the Grubbs second-generation catalyst (6) and p-cresol as stabilizer to produce 1693... 

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