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. 2021 Dec 6;26(23):7408.
doi: 10.3390/molecules26237408.

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

Mohammad Shahidul Islam  1 , Abdullah Saleh Alammari  1 , Assem Barakat  1 , Saeed Alshahrani  1 , Matti Haukka  2 , Abdullah Mohammed Al-Majid  1
Affiliations

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

Mohammad Shahidul Islam et al. Molecules. .

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.

Keywords: Friedel−Crafts alkylation; asymmetric catalysis; bis-imidazoline; bis-oxazoline; indoles; thiophene; β-nitroolefins.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Previously reported potent ligand structures for asymmetric FC reaction.
Scheme 1
Scheme 1
2,5-bis(imidazolinyl)thiophene (L1–L3) and 2,5-bis(oxazolinyl) thiophene (L4 and L5). Reaction conditions: (I) SOCl2 (8 mL/g), cat. DMF, 24 h, reflux; (II) i. CH2Cl2, TEA (5 eq.), −10 °C; ii. Amino alcohol (3a–c) (2.1 eq.); (III) 4a, SOCl2 (8.8 mL/g), refluxed, 24 h; (IV) i. 5a, Et2O, TEA (12.0 eq.), 0 °C; ii. 2.5 eq. R1NH2 (6a–c), 0 °C, then r.t., 12 h; (V) NaOH (15% aq. soln., 15 mL/g), r.t, 24 h; (VI) 4b–4c, Tosylchloride (1.25 eq.), DMAP (cat. 0.1 eq.), TEA (4.0 eq.), CH2Cl2, r.t, 48 h, N2.
Figure 2
Figure 2
C2-symmetric 2,5-bis(imidazolinyl)thiophene (L1–L3) and ligands 2,5-bis(oxazolinyl)thiophene (L4 and L5) tested for the Friedel–Crafts alkylation reaction of indoles with trans-β-nitrostyrene derivatives.
Scheme 2
Scheme 2
Friedel–Crafts arylation of indole (8b) with nitrostyrene-based indole scaffold (9i and 9j).
Figure 3
Figure 3
Proposed mechanism: L5:Cu(OTf)2-catalyzed Friedel–Craft alkylation of indole with β-nitroolefin catalytic cycle.
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