Aqueous‐Phase Sonogashira Alkynylation to Synthesize 5‐Substituted Pyrimidine and 8‐Substituted Purine Nucleosides

Joon Hyung Cho1, Kevin H. Shaughnessy1

1 Department of Chemistry, The University of Alabama, Tuscaloosa, Alabama
Publication Name:  Current Protocols in Nucleic Acid Chemistry
Unit Number:  Unit 1.27
DOI:  10.1002/0471142700.nc0127s49
Online Posting Date:  June, 2012
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In this unit, an efficient method for the synthesis of alkyne‐modified nucleosides in an aqueous solvent system is described. The method allows direct palladium‐catalyzed alkynylation of readily available unprotected 8‐bromo‐2′‐deoxyguanosine (8‐BrdG), 8‐bromo‐2′‐deoxyadenosene (8‐BrdA), 8‐bromoadenosine (8‐BrA), and 5‐iodo‐2′‐deoxyuridine (5‐IdU) precursors. The optimal catalyst is derived from palladium acetate, tri‐(2,4‐dimethyl‐5‐sulfonatophenyl)phosphane (TXPTS), and CuI. Curr. Protoc. Nucleic Acid Chem. 49:1.27.1‐1.27.10. © 2012 by John Wiley & Sons, Inc.

Keywords: modified nucleoside; alkynylation; palladium; cross‐coupling

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Table of Contents

  • Introduction
  • Basic Protocol 1: Preparation of Alkynylated Nucleosides from Halonucleosides
  • Commentary
  • Literature Cited
  • Figures
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Basic Protocol 1: Preparation of Alkynylated Nucleosides from Halonucleosides

  • Palladium acetate [Pd(OAc) 2], reagent grade, 98% (Sigma‐Aldrich)
  • Trisodium tri(2,4‐dimethyl‐5‐sulfonatophenyl)phosphane (TXPTS), prepared according to literature method (Gulyás et al., )
  • Copper iodide (CuI), 98% pure (Sigma‐Aldrich)
  • 5‐Iodo‐2′‐deoxyuridine ( S.1, 5‐IdU), ≥ 99% pure (Sigma‐Aldrich)
  • 8‐Bromo‐2′‐deoxyadenosine ( S.4, 8‐BrdA), prepared according to literature method (Ikehara and Kaneko, )
  • 8‐Bromoadeonsine ( S.5, 8BrA), reagent grade (Sigma‐Aldrich)
  • 8‐Bromo‐2′‐deoxyguanosine ( S.8, 8‐BrdG), prepared according to literature method (Gannett and Sura, )
  • Deionized water
  • Acetonitrile, ≥ 99.9% pure, for HPLC (Sigma‐Aldrich)
  • Nitrogen gas, ultra high purity
  • Triethylamine, ≥ 99% pure (Sigma‐Aldrich)
  • Alkynes:
    • Phenylacetylene ( S.2a), 98% pure (Sigma‐Aldrich)
    • 1‐Hexyne ( S.2b), 97% pure (Sigma‐Aldrich)
    • 3‐Butyn‐1‐ol ( S.2c), 97% pure (Sigma‐Aldrich)
    • 2‐Methyl‐3‐butyn‐2‐ol ( S.2d), 98% pure (Sigma‐Aldrich)
  • Methanol (MeOH), ≥ 99.8%, anhydrous (Sigma‐Aldrich)
  • Concentrated (37%) hydrochloric acid, ACS reagent (Sigma‐Aldrich)
  • Acetone, ACS reagent, ≥ 99.5% pure
  • Ethyl acetate, ACS reagent, ≥ 99.5% pure
  • Dichloromethane (CH 2Cl 2)
  • MBraun LabMaster 130 dual length drybox with nitrogen atmosphere at <10 ppm H 2O and O 2 concentration
  • 10‐mL round‐bottom flasks
  • 3/8‐in. egg‐shaped Teflon‐coated magnetic stirring bar
  • Rubber septum
  • Nitrogen manifold
  • 20‐G stainless steel needles
  • 5‐mL syringes
  • 65°C or 80°C oil bath
  • Magnetic stirrer/hot plate
  • 100‐µL glass syringes
  • TLC plate, silica‐coated glass plate with fluorescent indicator (Merk silica gel 60 F 254)
  • Reverse‐phase (RP) silica gel‐coated glass plate with fluorescent indicator (Merk silica gel 60 RP‐18 F 254s)
  • 254‐nm UV lamp
  • Rotary evaporator equipped with a water aspirator
  • Normal phase silica gel, SiliaFlash Irregular Silica Gels ‐ P60 Silica (40 to 63 µm; Silicycle)
  • RP silica gel, C18, carbon 17%, particle size 40 to 63 µm (Silicycle)
  • Additional reagents and equipment for performing thin‐layer chromatography (TLC; appendix 3D) and silica gel column chromatography ( appendix 3E)
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Literature Cited

Literature Cited
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