Chemoenzymatic synthesis of novel 1,4-disubstituted 1,2,3-triazole derivatives from 2-heteroaryl substituted homopropargyl alcohols

The one-pot synthesis of novel 1,4-disubstituted 1,2,3-triazoles from homopropargyl alcohol backbones is described. The key intermediates 2-benzothiophenyl 1a and 2-benzofuranyl 1b substituted homopropargyl alcohols were synthesized starting from their corresponding carboxyaldehyde derivatives. The racemic heteroaryl-substituted homopropargyl alcohol derivatives are successfully resolved to give the corresponding enantiopure acetates and the alcohols with 84–99% ee by applying chemoenzymatic methods using various lipases. Enantiomerically enriched homopropargyl alcohol derivatives were reacted with various aromatic and aliphatic halides and sodium azide via a one-pot synthesis method and novel chiral benzothiophenyltriazoles 3a–9a and benzofuranyltriazoles 3b–9b were constructed without the isolation of potentially unstable organic azide intermediates.

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(+)-1-(Benzo[b]thiophen-2-yl)but-3-yn-1-olC12H10OSEe = 77%[α]D26 = +21.5 (c 0.50, acetone)Source of chirality: enzymatic resolutionAbsolute configuration: not determined

(+)-1-(Benzo[b]thiophen-2-yl)but-3-ynyl acetateC14H12O2SEe = 99%[α]D26 = +71.0 (c 0.50, acetone)Source of chirality: enzymatic resolutionAbsolute configuration: not determined

(−)-1-(Benzo[b]thiophen-2-yl)-2-(1-phenyl-1H-1,2,3-triazol-4-yl)ethanolC18H15N3OS[α]D25 = −22.8 (c 0.5, acetone)Source of chirality: (+)-1-(benzo[b]thiophen-2-yl)but-3-yn-1-olAbsolute configuration: not determined

(+)-1-(Benzo[b]thiophen-2-yl)-2-(1-(naphthalen-1-yl)-1H-1,2,3-triazol-4-yl)ethanolC22H17N3OS[α]D25 = +14.1 (c 0.5, acetone)Source of chirality: (+)-1-(benzo[b]thiophen-2-yl)but-3-yn-1-olAbsolute configuration: not determined

(−)-1-(Benzo[b]thiophen-2-yl)-2-(1-benzyl-1H-1,2,3-triazol-4-yl)ethanolC19H17N3OS[α]D25 = −5.0 (c 0.5, acetone)Source of chirality: (+)-1-(benzo[b]thiophen-2-yl)but-3-yn-1-olAbsolute configuration: not determined

(−)-2-(1-Allyl-1H-1,2,3-triazol-4-yl)-1-(benzo[b]thiophen-2-yl)ethanolC15H15N3OS[α]D25 = −18.8 (c 0.5, acetone)Source of chirality: (+)-1-(benzo[b]thiophen-2-yl)but-3-yn-1-olAbsolute configuration: not determined

(−)-2-(1-(4-Aminophenyl)-1H-1,2,3-triazol-4-yl)-1-(benzo[b]thiophen-2-yl)ethanolC18H16N4OS[α]D25 = −2.5 (c 0.5, acetone)Source of chirality: (+)-1-(benzo[b]thiophen-2-yl)but-3-yn-1-olAbsolute configuration: not determined

(−)-2-(1-(Anthracen-9-ylmethyl)-1H-1,2,3-triazol-4-yl)-1-(benzo[b]thiophen-2-yl)ethanolC27H21N3OS[α]D25 = −23.2 (c 0.5, acetone)Source of chirality: (+)-1-(benzo[b]thiophen-2-yl)but-3-yn-1-olAbsolute configuration: not determined

(−)-1-(Benzo[b]thiophen-2-yl)-2-(1-(but-2-ynyl)-1H-1,2,3-triazol-4-yl)ethanolC16H15N3OS[α]D25 = −11.5 (c 0.5, acetone)Source of chirality: (+)-1-(benzo[b]thiophen-2-yl)but-3-yn-1-olAbsolute configuration: not determined

(+)-1-(Benzofuran-2-yl)but-3-yn-1-olC12H10O2Ee = 95%[α]D26 = +40.2 (c 0.50, acetone)Source of chirality: enzymatic resolutionAbsolute configuration: not determined

(+)-1-(Benzofuran-2-yl)but-3-ynyl acetateC14H12O3Ee = 99%[α]D26 = +159.1 (c 0.50, acetone)Source of chirality: enzymatic resolutionAbsolute configuration: not determined

(−)-1-(Benzofuran-2-yl)-2-(1-phenyl-1H-1,2,3-triazol-4-yl)ethanolC18H15N3O2[α]D25 = −70.8 (c 0.25, MeOH)Source of chirality: (+)-1-(benzofuran-2-yl)but-3-yn-1-olAbsolute configuration: not determined

(+)-1-(Benzofuran-2-yl)-2-(1-(naphthalen-1-yl)-1H-1,2,3-triazol-4-yl)ethanolC22H17N3O2[α]D25 = +16.9 (c 1.0, MeOH)Source of chirality: (+)-1-(benzofuran-2-yl)but-3-yn-1-olAbsolute configuration: not determined

(+)-1-(Benzofuran-2-yl)-2-(1-benzyl-1H-1,2,3-triazol-4-yl)ethanolC19H17N3O2[α]D25 = +10.8 (c 1.0, MeOH)Source of chirality: (+)-1-(benzofuran-2-yl)but-3-yn-1-olAbsolute configuration: not determined

(+)-2-(1-Allyl-1H-1,2,3-triazol-4-yl)-1-(benzofuran-2-yl)ethanolC15H15N3O2[α]D25 = +7.2 (c 1.0, MeOH)Source of chirality: (+)-1-(benzofuran-2-yl)but-3-yn-1-olAbsolute configuration: not determined

(−)-2-(1-(4-Aminophenyl)-1H-1,2,3-triazol-4-yl)-1-(benzofuran-2-yl)ethanolC18H16N4O2[α]D25 = −3.2 (c 0.25, MeOH)Source of chirality: (+)-1-(benzofuran-2-yl)but-3-yn-1-olAbsolute configuration: not determined

(−)-2-(1-(Anthracen-9-ylmethyl)-1H-1,2,3-triazol-4-yl)-1-(benzofuran-2-yl)ethanolC27H21N3O2[α]D25 = −96.8 (c 0.25, MeOH)Source of chirality: (+)-1-(benzofuran-2-yl)but-3-yn-1-olAbsolute configuration: not determined

(−)-1-(Benzofuran-2-yl)-2-(1-(but-2-ynyl)-1H-1,2,3-triazol-4-yl)ethanolC16H15N3O2[α]D25 = −2.4 (c 1.0, MeOH)Source of chirality: (+)-1-(benzofuran-2-yl)but-3-yn-1-olAbsolute configuration: not determined