Critical Ligand and Salt Effects in Organomagnesiate‐Promoted 3,3‐Disubstituted Phthalides Synthesis from 2‐Iodobenzoate Derivatives

Abstract

Phthalides, also called isobenzofuranones, are widespread in many biologically active compounds and natural products. To date, most of their synthetic routes are non‐convergent. Herein we report a convergent route using a metal halogen exchange (MHE) strategy. Indeed MHE of easily available 2‐iodobenzoate derivatives, using the bimetallic organomagnesiate complex (rac)‐(BIPHEN)BuMgLi, where (rac)‐BIPHEN is (rac)‐5,5′,6,6′‐tetramethyl‐3,3′‐di‐t‐butyl‐1,1′‐biphenyl‐2,2′‐diol, followed by addition of a ketone which lead to an intramolecular cyclisation, and the formation of a series of diverse 3,3‐disubstituted isobenzofuranones in good yield. Among the several MHE agents investigated, (rac)‐(BIPHEN)BuMgLi was the only one to make such a process possible with full tolerance of various reactive functional substituents useful for subsequent transformations. The synthetic pathway to access the magnesiate has been found to play a prominent role in its reactivity. Therefore, the bimetallic magnesiate complex has been characterized by solution‐state 1H, 7Li and 1H DOSY NMR experiments.

Organometallic Reagents: Efficient Tools for the Synthesis of Fused Pyridinyl‐Lactones

“…Our initial investigations focused on the use of n BuLi or t BuLi although alkyllithium derivatives are well known to exhibit high efficiency but lower chemoselectivity (Scheme 2). Indeed, in our previous work to access isobenzofuran‐1(3 H )‐ones, [2b] in aromatic series, no addition of n Bu unit was observed with ethyl 2‐iodobenzoate as substrate using n BuLi at −78 °C while exchange reaction was occurring. However, the choice of the halogeno‐nicotinates 1 a – b as precursors makes the reaction more difficult due to the presence of the π‐deficient pyridine ring which is more susceptible to nucleophilic attack (Chichibabin‐like reaction) and the electrophile character of the ester moiety is increased.…”

An Organocatalytic Highly Enantioselective Stereospecific Synthesis of 1,1‐Disubstituted‐1,3‐Dihydroisobenzofurans

“…The development of lactonization techniques continues to gain substantial interest, given that lactones are thought to be present in around one-third of all pharmaceuticals and natural products. [18] Inspired by the importance of the 3,3-disubstituted phthalides moiety in bioactive molecules such as Dermacozine D, [19] anti-HIV, [20] and protein kinase C modulators [21] in Figure 1, we intended to convert our synthesized chiral 1,1-disubstituted 1,3-dihydroisobenzofuran derivative to the corresponding phthalide 4 (Scheme 5). By the mCPBA oxidation, the 3,3-disubstituted phthalide moiety (R)-4 k, (R)-4 s, and (R)-4 t were observed without losing enantioselectivity (Scheme 5).…”