Sulfone-Mediated S_NAr Reaction as a Powerful Tool for the Synthesis of 4-Quinolinyl Ethers and More—Application to the Synthesis of HCV NS3/4a Protease Inhibitor BI 201420

Abstract

An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via a highly reactive S N Ar reaction of 4-quinolinyl sulfones with a range of structurally diversified 1°, 2°, and 3°alcohols with a wide substrate scope and high yields. By adapting this methodology, a convergent synthesis of a complex target of HCV NS3/4a protease inhibitor BI 201420 was accomplished.

Divergent reactivity of sulfinates with pyridinium salts based on one-versustwo-electron pathways

“…Given the pivotal importance of C4-sulfonylated pyridines and quinolines as key moieties in pharmaceuticals 26 and synthetically useful components in organic chemistry, 27 we next set out to expand the utility of our strategy by investigating the C4-sulfonylation of pyridinium salts. After a survey of the reaction parameters such as base, solvent, and concentration, the optimized reaction conditions were identified (see the ESI † ), and the generality with respect to this protocol was explored, as illustrated in Table 3 .…”

H/D Exchange of Aromatic Sulfones via Base Promotion and Silver Catalysis

“…We also tested the performance of substrates bearing halogens (10−13), where perdeuteration was observed. Meanwhile, unexpected deuteration at the C4position was detected for the 1-naphthyl derivative (20), with ortho-sites intact. Subsequently, diphenyl sulfones (21−24) were treated with the standard condition, leading to a deuteration at the desired ortho-positions.…”

“…The following test with the 2-formyl substrate showed silver reduction (16), while the substrates bearing carboxylic acid (17), ester (18), and nitrile ( 19) also failed. The performance of 1-naphthyl methylsulfone (20) was also evaluated under silver catalysis. In this case, a lower C4-deuteration of 13% was detected, suggesting that the labeling may be driven by base promotion.…”

“…Although the base-promoted HDX showed a preliminary success, the low recovery suggested that the substrates could hardly tolerate the harsh condition. 20 Additionally, the high base intensity and its requirement for an anhydrous condition limited the protocol's utility. Therefore, we shifted our attention toward metal catalysis for a milder and heavy water compatible condition.…”

Radical Anion Promoted Chemoselective Cleavage of Csp2–S Bond Enables Formal Cross-Coupling of Aryl Methyl Sulfones with Alcohols

“…Photoinduced radical additions to pyrimidyl and the related N -heteroaryl methyl sulfones by the Kamijo (Scheme b) and Molander groups (Scheme c) also fall into this category but were limited by substrates scope. Moreover, nucleophilic aromatic substitution (S N Ar) represents another strategy avoiding transition-metal catalyst but is only applicable to electron-deficient arenes . We envisioned that the radical anion intermediate could chemoselectively induce the cleavage of a Csp 2 –S bond in the presence of a Csp 3 –S bond via an S RN 1 pathway .…”