Copper catalyzed arylation with boronic acids for the synthesis of N 1 -aryl purine nucleosides J. Jacob Strouse, a Marjan Jeselnik, a Frederick Tapaha, a Colleen B. Jonsson, b William B. Parker b and Jeffrey B. Arterburn a, * a Department of Chemistry and Biochemistry MSC 3C, New Mexico State University, PO Box 30001, Las Cruces, NM 88003, USA b Southern Research Institute, 2000 9th Ave. So., Birmingham, AL 35205, USA Received 8 June 2005; revised 14 June 2005; accepted 16 June 2005 Available online 5 July 2005 Abstract—The synthesis of a series of N 1 -aryl inosine and guanosine derivatives is described. The procedure for chemoselective N 1 - arylation involves the mild oxidative copper(II) mediated coupling with boronic acids. This approach provides access to substituted N 1 -aryl purines with interesting structural characteristics and novel scaffolds for drug discovery. Ó 2005 Elsevier Ltd. All rights reserved. Modified nucleosides exhibit biomedical significance due to their antiviral and anticancer chemotherapeutic prop- erties, and are also of interest for applications as probes for investigating biological processes. 1 Derivatization of the purine heterocyclic bases of inosine 1 and guanosine 2 with sterically hindered or polar functional groups af- fects hydrogen bonding, p-stacking, and other interac- tions associated with base-pairing and protein receptor binding. Nucleophilic aromatic substitution reactions (S N Ar) have been widely used for the syntheses of aryl-purine derivatives, particularly at the C-6 and C-2 position. 2 The application of palladium catalyzed C–C and C–N coupling procedures have extended the synthetic versatil- ity and efficiency to a broad range of aryl-purine deriva- tives. 3 Complementary chemoselectivity has been observed with palladium and copper(I) catalyzed C–N couplings using aryl halides, with preferential arylation of amines or amides, using Pd or Cu(I) catalysts, respec- tively. 4 The methodology for copper(II) mediated N/O- arylation with aryl-boronic acids developed by Chan– Evans–Lam accommodates a broad range of substrates. 5 Copper catalyzed coupling procedures with boronic acids have been used for N-arylation at the N-9 position of purines, and the C-2 amine of aminopurines. 6 Our interest was drawn to N 1 -aryl purines as a novel structural class and potential scaffold for drug discov- ery. Few examples of N 1 -aryl purines have been de- scribed. The S N Ar reaction of highly electron deficient aryl-halides was used to synthesize N 1 -nitrophenyl ino- sine derivatives. 7 N 1 -phenylinosine was prepared by aryl- ation of tetrahydropyran-2-yl-protected inosine with iodobenzene and cuprous oxide under forcing condi- tions at high temperature (190 °C) with low yield. 8 Con- sidering the successful C–N arylation of 2-pyridinones with Cu(II)/aryl-boronic acids, we were encouraged to investigate the possible N 1 -arylation of purines. 9 Herein, we report a general procedure for N 1 -arylation of ino- sine and guanosine that employs copper catalyzed cou- pling with boronic acids. This approach provides efficient access to N 1 -aryl derivatives and accommodates diverse functionality in the aryl substrate. The b-D-ribose groups of inosine 1 and guanosine 2 were tri-protected as tert-butyldimethylsilyl (TBS) ethers N N O OH HO H H H H HO 1 N NH O N N O OH HO H H H H HO 2 N NH O NH 2 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.06.083 Keywords: Copper; Coupling; Heteroatom; Nucleoside. * Corresponding author. Tel.: +1 505 646 2738; fax: +1 505 646 2649; e-mail: jarterbu@nmsu.edu Tetrahedron Letters 46 (2005) 5699–5702 Tetrahedron Letters