Allenyl Sulfones as Substrates in [4+2] Annulation to Access Thiochroman-4-ols

Significance

Despite limited methodologies to access sulfur-containing heterocycles, medicinal chemists always had an interest in these motifs, such as thiochromans. Most methods rely on [4 + 2] annulations between ortho-sulfanyl benzaldehydes and Michael acceptors, but require harsh reaction conditions. The authors report a mild approach to these scaffolds, starting from diaryl disulfites ortho-substituted with an α-keto ester. Mechanistically, the reaction began with the reductive cleavage of the S–S bond of 1 with rongalite to generate the reactive thiolate. The latter adds to the electrophilic β-carbon atom of the allenyl sulfone 2. Ultimately, the γ-carbon atom reacts in an intramolecular regioselective fashion with the ketone of the keto ester group, leading to the desired product. Interestingly, the mild reaction conditions do not trigger dehydration, and thiochroman-4-ols were isolated in moderate to good yields with constant E diastereoselectivity.

Comment

After optimization, the model substrate delivered desired thiochroman 3a in 90 % yield. Upon scaling to a gram-scale, both yield and E/Z selectivity were maintained. The reaction tolerated electron-donating and electron-withdrawing groups (3b vs. 3c) equally well. A sterically hindered α-keto ester led to a drop in yield (3e) without loss in stereoselectivity, whereas methyl ester analogue 3 d was isolated in 78 % yield. An allenyl sulfone bearing a long carbon chain allowed access to 3f in 76 % yield. Methyl sulfone gave to the corresponding product 3 g in 81 % yield. Finally, p-chlorophenylsulfonyl analogue 3 h was isolated in good yield. Based on the proposed mechanism, the diastereoselectivity is mostly driven by the allenyl sulfone substituents. The sulfone and sulfide substituents were likely anti to each other prior to the final cyclization, leading to a constant E-selectivity across the scope, regardless of the steric bulk of the R³ group. 

Publication History

Article published online:
23 June 2025

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