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Organic Synthesis Methodology

Name: Padmaja 

Department: Chemistry

Name of supervisor: Santosh J. Gharpure

 

Description of research work: 5-exo-trig Cascade Radical Cyclization of Alkynyl Vinylogous Carbonates for the Synthesis of Tetrasubstituted Furans and Dihydrofurans 

Organic synthesis has emerged as an important area of research in recent times of a pandemic stricken world. It enables us to develop efficient strategies for the synthesis of molecules that already have a biological significance or could have the potential in future. Creativity in methodology development has led to the synthesis of those molecules which have had a significant effect in not just pharma but also in agrochemicals, biomolecular chemistry and energetic materials. One such heterocycle, furan is present in furanoflavanoids, furanocoumarins and furanolactones. Furans have proved to be an efficient synthon for the total synthesis of various natural products by transformations such as Piancatelli rearrangement, Ashmatowicz reaction as well as cycloaddition reactions.1 Synthesis of highly substituted furans, initiated from simple, achievable starting materials under neutral conditions, with varied functionalities, is a challenge to date for organic chemists. Moreover, functionalization of the parent furan is not practical due to poor regioselectivity. 

We began by preparing the alkynyl vinylogous carbonates from the propargyl alcohols by its oxa-Michael addition onto ethyl propiolate. Further, we subjected the vinylogous carbonates to radical conditions of PhSH and AIBN in refluxing toluene. This radical condition was primarily chosen to understand if the vinylic radical intermediate (that is formed by addition of thiophenol onto the alkyne) could undergo a 5-exo-trig cyclization in a cascade fashion.

 

After several trials, we obtained the tetrasubstituted furan in excellent yield and established that 3.5 equivalents of thiophenol and 2.0 equivalents of AIBN in refluxing toluene gave the best results. Interestingly, when another radical, nBu3SnH was added to the reaction flask instead of PhSH, the same alkynyl vinylogous carbonate gave the corresponding tetrasubstituted dihydrofuran exclusively. Thus, by changing the radical that was being added, we accomplished the exclusive synthesis of tetrasubstituted furan or dihydrofurans.2

The generality of the reaction was studied in terms of electronics and sterics by changing the substitutents at the α position (R1) of vinylogous carbonates and at the alkyne position (R2). The reaction furnished tetrasubstituted furans in good yields even when different thiyl radicals were used. Interestingly, substituents such as SPh, TMS did not get cleaved in the radical cyclization and gave the corresponding furans. Unfortunately, aliphatic substrates at R2 did not furnish the dihydrofuran or furan.

On subjecting a bisalkynyl vinylogous carbonate to the radical conditions, a bis-furan was synthesized, which exhibits atropisomerism (chiral axis). This is one of the first examples of bis-furans consisting of axial chirality. Polyheterocycles, such as furans tethered to thiophene were also synthesized. Unlike other strategies here substituents on furan were functionalized for the synthesis of homologated bis-furan by iterative strategy. The ester on the homologated bis-furan can be functionalized further in an iterative manner. 

In conclusion, tetrasubstituted furans and dihydrofurans were obtained from the same, easily prepared precursor by a 5-exo-trig cascade radical cyclization. Further, synthesis of polyheterocyclic furans and homologated bis-furan were amenable in a single step from uncomplicated precursors. Some scaffolds of dihydrofurans have the potential to be transformed into known odourants, such as rosefuran. This strategy also led to the synthesis of a new class of bis-fura ns which exhibit atropisomerism.3