In Tandem Enantioselective Intramolecular Heck‐Matsuda Reactions directly from Anilines

Abstract

A new enantioselective intramolecular strategy for the synthesis of enantioenriched bridged benzoxacines, unsaturated spirobenzofurans, 2,3‐dihydrobenzofuran and 2,3‐indoline acetate scaffolds in a tandem‐like diazotization/Heck‐Matsuda process directly from anilines has been developed. The process combines the in situ diazotization of the aniline, followed by the intramolecular Heck‐Matsuda reaction, thus skipping the isolation and purification of potentially unstable or hard‐to‐synthesize aryldiazonium salts. The practicality and robustness of the sequence were demonstrated by the synthesis of 30 complex motifs in yields up to 91% and enantiomeric ratios up to 97:3, including quaternary stereocenters. The in‐tandem processes from anilines were compared to conventional Heck‐Matsuda reactions using pre‐synthesized aryldiazonium salts. With few exceptions, the reactions starting directly from the anilines afforded better overall yields and enantioselectivity, demonstrating the efficiency of the method.

Enantioselective Synthesis of Dihydrobenzofurans, Dihydrobenzosulfones, and Dihydroindoles by Merging One‐pot Intramolecular Heck‐Matsuda Reactions from Anilines with Redox‐Relay Process

“…We started this work by using reaction conditions similar to those reported previously by us: Pd(OAc) 2 , N,N-ligand, MeOH, t BuONO, and 2,6-di-tert-butyl-4-methylpyridinium tetrafluoroborate salt (DTBMPHBF 4 ) at 40 °C. [39] Due to the redox-relay process, our initial expectation was of getting an aldehyde as the final product, but under the acidic methanolic conditions, it was anticipated that the corresponding dimethyl acetal could also be formed in situ. Preliminary studies were carried out with (E)-alkene aniline 1.…”

“…The same outcome was observed by us in a previous work with a similar substrate. [39] For the sake of completeness, we also investigated other nitrogen-protecting groups. The methyl-carbamate sub-strate 6 provided the corresponding dihydroindole 9 h in 46 % overall yield, in a lower e.r.…”

“…Since we disclosed the first enantioselective HM reaction in 2012, [33] we have been expanding the scope of the HM reactions associated with aryldiazonium salt [34–38] . More recently, we reported the tandem enantioselective HM reaction with in situ generation of aryldiazonium salt in their inter‐ and intramolecular versions (Scheme 1c) [39] . This recent one‐pot process obviates the need to isolate and purify aryldiazonium salts that might be thermally unstable and/or hard to synthesize, especially on a synthetically useful scale.…”

Catalyst-free photoarylation reactions promoted by visible light

“…Numerous modifications have been reported, such as Heck–Matsuda reactions, oxidative Heck-type reactions, C Ar –H functionalization cross-coupling of alkenes and enantioselective Heck reactions. 79–84…”

“…Numerous modifications have been reported, such as Heck-Matsuda reactions, oxidative Heck-type reactions, C Ar -H functionalization crosscoupling of alkenes and enantioselective Heck reactions. [79][80][81][82][83][84] In 2020, Xia and co-workers reported a regio-and stereoselective photochemical Heck-type strategy for arylation of vinylphenols 29 with aryl and heteroaryl halides 25 using blue LEDs (18 W), without the need for sacrificial reducers (Scheme 16). 85 Iodides (30a and 30d), bromides (30b and 30e) and aryl chlorides (30c, 30f and 30h) were suitable for this transformation, and a reactivity order I > Br > Cl was observed.…”