Stereocontrolled Synthesis of Fluorinated Isochromans via Iodine(I)/Iodine(III) Catalysis

Abstract

The success of saturated, fluorinated heterocycles in contemporary drug discovery provides a stimulus for creative endeavor in main group catalysis. Motivated by the ubiquity of isochromans across the bioactive small molecule spectrum, the prominence of the anomeric effect in regulating conformation, and the metabolic lability of the benzylic position, iodine(I)/iodine(III) catalysis has been leveraged for the stereocontrolled generation of selectively fluorinated analogs. To augment the current arsenal of fluorocyclization reactions involving carboxylic acid derivatives, the reaction of readily accessible 2‐vinyl benzaldehydes is disclosed (up to >95 : 05 d.r. and 97 : 03 e.r.). Key stereoelectronic interactions manifest themselves in the X‐ray crystal structures of the products, thereby validating the [CH2‐CHF] fragment as a stereoelectronic mimic of the [O‐CH(OR)] acetal motif.

5‐(Trifluorovinyl)dibenzothiophenium Triflate: Introducing the 1,1,2‐Trifluoroethylene Tether in Drug‐Like Structures

“…1 H NMR (400 MHz, CD 3 CN) δ = 8.42 (d, J = 8.2 Hz, 2H), 8.35 (d,J = 7.8 Hz,2H),2H),2H) ppm. 19 F NMR (377 MHz, CD 3 CN) δ = À 67.75 (dd, J = 43.6, 13.7 Hz), À 79.34, À 94.34 (ddd, J = 116. 5,13.9,3.3 Hz),À 181.96 (dd,J = 116.5,43.7 Hz) ppm.…”

“…Finally, the scope of the cyclisation process towards 3,3,4trifluoroisochromans was explored. [19] A range of these compounds 6 a-d and closely related 2,2,3-trifluoro-2,3-dihydrobenzofuranes 6 e-f were smoothly generated under the standard conditions developed, but often the desired isochroman structures were obtained as mixtures of two regioisomers 6 b/ 6b' and 6 c/6 c' (Scheme 3E). It has been reported for related cyclisations towards 6H-benzo[c]chromen-6-ones and dihydrophenanthridines that the kinetically favoured ipso attack of the radical to the aromatic ring results in the formation of a spirocyclic radical structure, which subsequently undergoes ring expansion and rearomatization.…”

Progress in organocatalysis with hypervalent iodine catalysts

“…Moreover, iodine(III) catalysis has been used to synthesise fluorinated isochromans. 170 An environmental friendly synthesis of 2-arylbenzofurans 267 was developed by indine(III)-catalysed intramolecular cyclisation of o-hydroxystilbenes 266 with the help of PIDA 1 as catalyst (Scheme 77). 171 The reaction is performed at room temperature and required a longer time to complete as unwanted side products were formed at higher temperatures.…”

Recent Advances in Catalytic Asymmetric Syntheses of Functionalized Heterocycles via Halogenation/Chalcogenation of Carbon‐Carbon Unsaturated Bonds

“…and 94% ee). Furthermore, the utility of this methodology was demonstrated by the synthesis of fluorinated analog of the highly selective D4 receptor antagonist Sonepiprazole [96] …”

“…Furthermore, the utility of this methodology was demonstrated by the synthesis of fluorinated analog of the highly selective D4 receptor antagonist Sonepiprazole. [96] In the field of fully intermolecular difunctionalization of alkenes, Hashimoto and co-workers performed a significant development regarding organoiodine (I/ III)-catalyzed, highly enantioselective intermolecular oxyamination of alkenes 172 (Scheme 76). [97] Owing to strong electron-withdrawing nature and small size of the fluorosulfonyl group, a novel N-(fluorosulfonyl)carbamate 171 was identified as a crucial bifunctional N,O-nucleophile in this transformation.…”