Enantioselective Synthesis of 3-Fluorochromanes via Iodine(I)/Iodine(III) Catalysis.

The chromane nucleus is common to a plenum of bioactive small molecules where it is frequently oxidized at position 3. Motivated by the importance of this position in conferring efficacy, and the prominence of bioisosterism in drug discovery, an iodine(I)/iodine(III) catalysis strategy to access enantioenriched 3-fluorochromanes is disclosed (up to 7:93 e.r.). In situ generation of ArIF2 enables the direct fluorocyclization of allyl phenyl ethers to generate novel scaffolds that manifest the stereoelectronic gauche effect. Mechanistic interrogation using deuterated probes confirms a stereospecific process consistent with a type IIinv pathway.

Enantioselective, Catalytic Vicinal Difluorination of Alkenes.

The enantioselective, catalytic vicinal difluorination of alkenes is reported by II /IIII catalysis using a novel, C2 -symmetric resorcinol derivative. Catalyst turnover via in situ generation of an ArIIII F2 species is enabled by Selectfluor oxidation and addition of an inexpensive HF-amine complex. The HF:amine ratio employed in this process provides a handle for regioselective orthogonality as a function of Brønsted acidity. Selectivity reversal from the 1,1-difluorination pathway (geminal) to the desired 1,2-difluorination (vicinal) is disclosed (>20:1 in both directions). Validation with electron deficient styrenes facilitates generation of chiral bioisosteres of the venerable CF3 unit that is pervasive in drug discovery (20 examples, up to 94:06 e.r.). An achiral variant of the reaction is also presented using p-TolI (up to >95 % yield).

Deconstructing the Catalytic, Vicinal Difluorination of Alkenes: HF-Free Synthesis and Structural Study of p-TolIF2.

Recently, contemporaneous strategies to achieve the vicinal difluorination of alkenes via an I(I)/I(III) catalysis manifold were independently reported by this laboratory and by Jacobsen and co-workers. Both strategies proceed through a transient ArI(III)F2 species generated by oxidation of the ArI catalyst. Herein, an efficient synthesis of p-TolIF2 from p-TolI and Selectfluor is presented, together with a crystallographic and spectroscopic study. To mitigate safety concerns and simplify reaction execution, an HF-free protocol was devised employing CsF as a substitute fluoride source. The study provides insight into the initial I(I)→I(III) oxidation stage of the catalytic protocol using Selectfluor.