Heteroaryl-sulfones

Perfluoro heteroaryl sulfonates derivatives, (I), prepared by Heil (2) were effective CB2 receptor antagonists and used in treating chronic pain and inflammatory disorders. 

Using structure-based computational methods, the group of Silvestri [89] proposed three pyrrolyl heteroaryl sulfones, (Et l-[(lH-benzimidazol-2(3H) one-5-yl)sulfonyl] -1 H-pyrrole-2-carboxylate, Et l-[(lH-benzimidazol-5(6)-yl)sulfonyl]-lH-pyrrole-2-carboxylate and Et l-[(lH-benzotriazol-5(6)-yl) sulfonyl]-lH-pyrrole-2-carboxylate), as novel NNRTIs. Although these compounds were inactive in the cell-based assay, they inhibited the target enzyme with micromolar potency. 

In most cases, the Michael reactions are applicable only for the bond formation between two -hybridized carbon atoms. The asymmetric bond formation between spsp or sp -sp centers remains a challenging task. Recent developments have demonstrated that the use of (3-carbonyl heteroaryl sulfones as necliphiles could easily tackle this synthetic challenge [105]. Jprgensen and co-workers [106]... 

SCHEME 5.49. Michael addition of p-carbonyl heteroaryl sulfones to a,(3-unsaturated... 

SCHEME 5.50. Michael addition of (i-carbonyl heteroaryl sulfones to cyclic a,(3-unsaturated ketones. 

More recently, the modified Julia olefination, which eirployed certain heteroaryl sulfones instead of the traditional phenyl sul-fones, has emerged as a powerful tool for alkene synthesis. Although the reaction was first reported with LDA, bases such as LHMDS, NaHMDS, and KHMDS are now commonly used. In addition, solvent as well as base counter-cation have been shown to markedly affect the stereochemical outcome of the olefination reaction. LHMDS has been selected as the base of choice in some systems, particularly the one that led to the formation of dienes and trienes. Indeed, triene 25 was obtained in 68% yield from sulfone 23 and aldehyde 24 in the presence of LHMDS (eq 59). ... 

The cleavage of heteroaryl sulfones from polymeric supports can be achieved by reaction with azide ions. Suckling el al. applied this strategy to the synthesis of pteridines. In fact, the starting pyrimidine was linked to polystyrene via a thioether 214. After con-stmction of the pteridine ring system, the activation of the sulfur linker by oxidation to the sulfone with dimethyldioxirane followed by nucleophilic substitution with sodium azide affords the target molecule 218 in 41% overall yield (Scheme 3.30). 

The one-port olefination of Sylvestre Julia is operationally simpler and more amenable to scale up than the classical y4-step variant originally reported by Marc Julia. This reaction consists of the replacement of the phenyl sulfone moiety traditionally in the classical reaction, with different heteroaryl sulfones, such as benzothiazol-2-yl (BT, 5) sulfone. This allows the direct olefination process and eliminates the sulfone reduction step. The stereochemistry of the reaction in the synthesis of 1,2-disubstituted alkenes is dependent on the base and solvent. 

The heteroaryl sulfone 18 is deprotonated to give the carbanion 21. Addition of canbanion to the carbonyl compound gives adduet 22, which then undergoes a series of transformations resulting in the expulsion of sulphur dioxide and the potassium derivative of PT alcohol 25 with concomitant formation of the alkene 20. The use of larger counterion (such as K ) and polar solvents (such as DME) favors an open transitin state 26 (PT = phenyltetrazolyl) ... 

With a similar strategy of combined diarylprolinol silyl ether and N-heterocyclic carbene catalysts, j0rgensen and coworkers [21] examined the cascade reaction of easily accessible i-keto heteroaryl-sulfones as nucleophiles with a,P-unsaturated aldehydes (Scheme 43.11). In this cascade reaction, following the initial iminium ion-catalyzed Michael reaction of nucleophiles to a,(i-unsaturated aldehydes, the subsequent step was then promoted by carbene catalyst 57 to afford 2,4-disubstituted cyclopentenones 55 via an intramolecular benzoin condensation initiated Smiles rearrangement. The superiority of combinational use of two catalysts in the similar Michael/benzoin cascade reaction was also independently demonstrated by Enders et al. (Scheme 43.12) [22]. 

Recently, fluoro-Julia olefination reaction using a-fluorinated heteroaryl sulfone has been actively studied for the synthesis of fluoroaUcene [38]. Fluorinated... 

Aryl and heteroaryl sulfonates are extensively used as electrophilic coupling partners. The reaction of vinyl sulfonates is generally limited to triflates, even if some couplings of mesylates and tosylates are reported. It was observed that the addi-... 

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