Glycerol Carbonate as a Versatile Alkylating Agent for the Synthesis of β-Aryloxy Alcohols

Abstract

The possibility to use glycerol carbonate (GlyC) as an innovative alkylating agent for phenolic compounds in solventless conditions and in the presence of a catalytic amount of both homogeneous and heterogeneous bases is herein described. In particular, the peculiar, polyfunctional structure of GlyC allows one to obtain the formation not only of the mono-phenoxy-1,2propanediol (MPP) analogue but also of 1,3-diphenoxy-2-propanol (DPP), the latter being elusive using the more traditional, toxic, and carcinogenic reagents such as glycidol and/or 3-chloro-1,2propandiol. The production of DPP is indeed possible due to the in situ formation of a reactive intermediate, 4-(phenoxy)methyl-1,3-dioxolane-2-one (PhOGlyC), which may undergo a consecutive nucleophilic attack of a phenolate, leading to the selective formation of the disubstituted product. This reaction is nonetheless in competition with PhOGlyC decarboxylation that finally limits DPP yield up to 20%, with an MPP yield up to roughly 60% in the optimized conditions (atmospheric pressure, 140 °C, 5 h using Cs 2 CO 3 as the basic catalyst) starting directly from a GlyC/phenolic mixture. For this reason, a multistep synthetic strategy has also been developed, first by obtaining the quantitative formation and isolation of the PhOGlyC intermediate and then by promoting the consecutive reaction with phenol, in this way obtaining a DPP yield of 66% after only 1 h of reaction at 170 °C. The obtained phenyl glyceryl ethers are interesting drugs scaffolds (i.e., guaifenesin, mephenesin), intermediates in the preparation of active pharmaceutical ingredients (e.g., chlorphenesin carbamate, methocarbamol), and hydrotropic solvents; preliminary evaluations of MPP and DPP biodegradability and use as alternative surfactants have also been described in this paper.

A Career in Catalysis: Fabrizio Cavani

“…In this regard, Cavani and Tabanelli have investigated in depth the possibility to use organic carbonates as alternative alkylating agents for phenolics, avoiding the needs of toxic epoxides or alkyl halides. In particular, both ethylene carbonate (EC) and glycerol carbonate (GlyC) were successfully used for the alkylation of phenol in the presence of a basic catalyst, in the liquid phase without the needs for any external solvents; while diethyl carbonate (DEC) was used as effective ethylating agent for the same substrate under continuous-flow and gas phase conditions . Notably, GlyC was also used, for the first time in literature, in the alkylation of catechol, this way discovering a completely innovative way for the synthesis of substituted benzodioxanes .…”

Synthesis of Zeolitic Imidazolate Framework-8 Using Glycerol Carbonate

“…To overcome this limitation and with the ambitious idea to substitute DMF with greener alternatives, in this work we report for the first time the preparation of crystalline ZIF-8 in glycerol carbonate (GlyC). GlyC (4-hydroxymethyl-2-oxo-1,3-dioxolane) has attracted increasing interest as one of the most investigated bio-based compounds with many interesting applications in different fields, such as in the synthesis of new chemicals, , the manufacturing of polymers, building blocks for drug preparation, surfactants, cosmetics, and detergent industries. Moreover, the use of GlyC fully respects the 7th principle of Green Chemistry − due to its preparation from glycerol through transcarbonation with dimethyl carbonate.…”

Chemoenzymatic Synthesis of Chiral Building Blocks Based on the Kinetic Resolution of Glycerol‐Derived Cyclic Carbonates

“…[37,38] The resulting chiral carbonates can be employed as chiral building blocks, e. g. for the synthesis of terminal aromatic glycerol ethers (TAGEs) with pharmacological activity, such as (S)-Guaifenesin, (S)-Mephenesin and (S)-Chlorphenesin (Scheme 1). [39]…”