Exploiting the Chiral Ligands of Bis(imidazolinyl)- and Bis(oxazolinyl)thiophenes-Synthesis and Application in Cu-Catalyzed Friedel-Crafts Asymmetric Alkylation.

Mohammad Shahidul Islam,Assem Barakat,Saeed Alshahrani,Abdullah Saleh Alammari,Matti Haukka,Abdullah Mohammed Al-Majid

doi:10.3390/molecules26237408

Mohammad Shahidul Islam, Assem Barakat + Show 4 more

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https://doi.org/10.3390/molecules26237408

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Abstract

Five new C2-symmetric chiral ligands of 2,5-bis(imidazolinyl)thiophene (L1–L3) and 2,5-bis(oxazolinyl)thiophene (L4 and L5) were synthesized from thiophene-2,5-dicarboxylic acid (1) with enantiopure amino alcohols (4a–c) in excellent optical purity and chemical yield. The utility of these new chiral ligands for Friedel–Crafts asymmetric alkylation was explored. Subsequently, the optimized tridentate ligand L5 and Cu(OTf)2 catalyst (15 mol%) in toluene for 48 h promoted Friedel–Crafts asymmetric alkylation in moderate to good yields (up to 76%) and with good enantioselectivity (up to 81% ee). The bis(oxazolinyl)thiophene ligands were more potent than bis(imidazolinyl)thiophene analogues for the asymmetric induction of the Friedel–Crafts asymmetric alkylation.

Highlights

Metal-catalyzed asymmetric transformation has become one of the most desirable strategies in advanced synthetic chemistry to access a variety of enantiopure organic molecules [1,2,3,4,5,6,7,8]
During the past few years, several chiral bidendate ligands have been developed and used in the Lewis acid metal-catalyzed asymmetric Friedel– Crafts alkylation reaction of indole with various substrates, including α,β-unsaturated-Rketoesters (R = alkyl, aryl) [27,28], R-hydroxy enones (R = alkyl, aryl) [29,30], alkylidene malonates [31,32,33], acyl phosphonates [34,35], acyl heterocyclic compounds [36,37,38], Nsulfonyl aldimines catalyzed by Schiff base complexes of Cu(II)-chiral amino alcohol [39], α-trifluoromethylated β-nitrostyrenes catalyzed by chiral BINOL metal phosphate [40], nitroolefins catalyzed by oxazoline-imidazoline-Zn(II) [41], bis(oxazolinyl)-Cu(II) [42] and 2,5-bis(oxazolinyl)thiophenes-Cu(II) complexes [43]
We report the synthesis of novel chiral ligands thiophene2,5-2,5-bis(imidazolinyl)thiophene (L1–L3) and thiophene-2,5-bis(oxazolinyl)thiophene (L4 and L5) and their applications in Lewis acid metal-catalyzed asymmetric Friedel–Crafts alkylations of indole with electron-deficient prochiral β-nitroolefins

Summary

Introduction

Metal-catalyzed asymmetric transformation has become one of the most desirable strategies in advanced synthetic chemistry to access a variety of enantiopure organic molecules [1,2,3,4,5,6,7,8]. Chiral ligand–Lewis acid metal complex-catalyzed asymmetric Friedel–Crafts alkylation reactions play a pivotal role in synthetic organic chemistry for the construction of new C–C bonds [22,23,24,25,26]. Very few examples of chiral metal–box-bis(oxazoline)/bis(imidazoline) complex-catalyzed enantioselective Friedel–Crafts alkylation of indole with nitroolefins have been documented to date [41,45,46,47]

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