Syntheses of Aromatic Substituted
6′-Thiothalidomides

Weiming Luo; Qian-sheng Yu; David Tweedie; Jeffery Deschamps; Damon Parrish; Harold W. Holloway; Yazhou Li; Arnold Brossi; Nigel H. Greig

doi:10.1055/s-0028-1083179

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Synthesis 2008(21): 3415-3422
DOI: 10.1055/s-0028-1083179

PAPER

Syntheses of Aromatic Substituted 6′-Thiothalidomides

Weiming Luo^a, Qian-sheng Yu^a, David Tweedie^a, Jeffery Deschamps^b, Damon Parrish^b, Harold W. Holloway^a, Yazhou Li^a, Arnold Brossi^c, Nigel H. Greig*^a
^a Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, 251 Bayview Blvd., Baltimore, MD 21224, USA
Fax: +1(410)5588695; e-Mail: Greign@grc.nia.nih.gov;
^b Laboratory for the Structure of Matter, Department of the Navy, Naval Research Laboratory, Washington, DC 20375, USA
^c School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA

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Publication History

Received 29 April 2008
Publication Date:
16 October 2008 (online)

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Abstract

A resurgence of interest in thalidomide has occurred as a consequence of its diverse immunomodulatory and anticancer actions, which has fuelled interest in synthetic analogues with higher potencies or less undesirable side effect profiles. Several novel aromatic substituted 6′-thiothalidomides were synthesized whose synthetic route and strategy were developed on the basis of an analysis of reaction mechanisms. The regioselectivity of mono-thionation of aromatic substituted thalidomides with Lawesson’s reagent is described, and the chemoselectivity of hydrogenation between the nitro group and 6′-thiocarbonyl group is discussed. Full characterization of eight substituted 6′-thiothalidomides is reported.

Key words

6′-thiothalidomides - TNF-α - thionation - regioselectivity - HMBC

References

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18

X-ray crystal data for 23: Empirical formula: C₂₁H₂₁O₆P₃S₃; Colorless; Formula weight: 558.47; Crystal system = triclinic; Space group P 1; Unit cell dimensions: a = 9.644 (4) Å, b = 12.105 (5) Å, c = 20.512 (9) Å; α = 86.147 (9)˚, β = 85.609 (8)˚, γ = 82.504 (9)˚; V = 2363.2 (18) Å^³; Z = 4; T = 103 (1) K; F ₀₀₀ = 1152; R1 = 0.0554, wR2 = 0.1595. The supplementary crystallographic data for this structure (CCDC 682848) can be obtained free of charge from the Cambridge Crystallographic Data Centre via the following website: www.ccdc.cam.ac.uk/products/csd/request.

19

X-ray crystal data for 15: Empirical formula: C₁₃H₁₀N₂O₄S; Yellow; Formula weight: 290.29; Crystal system = monoclinic; Space group P2₁/c; Unit cell dimensions: a = 12.677 (7) Å, b = 13.698 (8) Å, c = 7.520 (4) Å; α = 90˚, β = 105.474 (11)˚, γ = 90˚; V = 1258.6 (12) Å^³; Z = 4; T = 293 (2) K; F ₀₀₀ = 600; R1 = 0.0764, wR2 = 0.2009. The supplementary crystallographic data for this structure (CCDC 682849) can be obtained free of charge from the Cambridge Crystallographic Data Centre via the following website: www.ccdc.cam.ac.uk/products/csd/request.

20

X-ray crystal data for 18: Empirical formula: C₁₅H₁₂N₂O₅S; Yellow; Formula weight: 332.33; Crystal system = triclinic; Space group P 1; Unit cell dimensions: a = 6.8299 (7) Å, b = 7.9952 (9) Å, c = 14.1890 (15) Å; α = 86.247 (5)˚, β = 83.849 (5)˚, γ = 82.475 (5)˚; V = 762.68 (14) Å^³; Z = 2; T = 293 (2) K; F ₀₀₀ = 344; R1 = 0.0982, wR2 = 0.2851. The supplementary crystallographic data for this structure (CCDC 682850) can be obtained free of charge from the Cambridge Crystallographic Data Centre via the following website: www.ccdc.cam.ac.uk/products/csd/request.