Pd(0)/Cu(I)-mediated direct arylation of 2′-deoxyadenosines: Mechanistic role of Cu(I) and reactivity comparisons with related purine nucleosides

Storr, Thomas E., Baumann, Christoph G., Thatcher, Robert J., De Ornellas, Sara, Whitwood, Adrian C. and Fairlamb, Ian J. S. (2009) Pd(0)/Cu(I)-mediated direct arylation of 2′-deoxyadenosines: Mechanistic role of Cu(I) and reactivity comparisons with related purine nucleosides. The Journal of Organic Chemistry, 74 (16). pp. 5810-5821. ISSN 0022-3263

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Pd/Cu-mediated direct arylation of 2′-deoxyadenosine with various aryl iodides provides 8-arylated 2′-deoxyadenosine derivatives in good yields. Following significant reaction optimization, it has been determined that a substoichiometric quantity of piperidine (secondary amine) in combination with cesium carbonate is necessary for effective direct arylation. The general synthetic protocol allows lower temperature direct arylations, which minimizes deglycosylation. The origin of the piperidine effect primarily derives from the in situ generation of Pd(OAc)2[(CH2)5NH]2. Various copper(I) salts have been evaluated; only CuI provides good yields of the 8-arylated-2′-deoxyadenosines. Copper(I) appears to have a high binding affinity for 2′-deoxyadenosine, which explains the mandatory requirement for stoichiometric amounts of this key component. The conditions are compared with more general direct arylation protocols, e.g., catalytic Pd, ligand, acid additives, which do not employ copper(I). In each case, no detectable arylation of 2′-deoxyadenosine was noted. The conformational preferences of the 8-aryl-2′-deoxyadenosine products have been determined by detailed spectroscopic (NMR) and single crystal X-ray diffraction studies. Almost exclusively, the preferred solution-state conformation was determined to be syn-C2′-endo (ca. 80%). The presence of a 2-pyridyl group at the 8-position further biases the solution-state equilibrium toward this conformer (ca. 88%), due to an additional H-bond between H1′ and the pyridyl nitrogen atom. The Pd/Cu catalyst system has been found to be unique for adenosine type substrates, the reactivity of which has been placed into context with the reported direct arylations of related 1H-imidazoles. The reactivity of other purine nucleosides has been assessed, which has revealed that both 2′-deoxyguanosine and guanosine are incompatible with the Pd/Cu-direct arylation conditions. Both substrates appear to hinder catalysis, akin to the established inhibitory effects in Suzuki cross-couplings with arylboronic acids.

Item Type: Article
Faculty \ School: Faculty of Science > School of Chemistry
UEA Research Groups: Faculty of Science > Research Groups > Chemistry of Materials and Catalysis
Depositing User: Pure Connector
Date Deposited: 13 Jan 2017 00:06
Last Modified: 05 May 2024 01:14
URI: https://ueaeprints.uea.ac.uk/id/eprint/62042
DOI: 10.1021/jo9012282

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