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6-Chloropurine and 2,6-dichloropurine were regioselectively glycosylated at position 7 to give the corresponding peracetylated N7-nucleosides, which can be suitable for other purine transformations. In this work, we study the distribution of N7/N9-isomers produced via the Vorbruggen method under different conditions, using an N-trimethylsilylated purine derivative and SnCl4 or TiCl4 as a catalyst. The main effort is devoted to reversing the disadvantageous predominant selectivity of most glycosylation reactions at the N9 position and thus to determining conditions that maximize the regioselectivity of glycosylation toward the desired N7-isomer.

A number of novel amides were synthesized by coupling of 6-[(9H-purin-6-yl)amino]hexanoic acid to heterocyclic amines. The antiviral activity of the obtained compounds, as well as of purine conjugates in which 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine is linked to position 6 of purine through a fragment of ω-amino acids with varying lengths of polymethylene chains against influenza A and B viruses was studied in vitro. Purine derivatives have been shown to have moderate activity against influenza A (H1N1) virus. The antiinfluenza activity and cytotoxicity of conjugates with 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine depend on the length of the linker fragment.

A convenient approach for the synthesis of diversely functionalized [1,2,4]triazolo[5,1-f]purine heterocyclic framework have been accomplished. The products were obtained through the combination of 5-amino-3-(methylthio)-1H-1,2,4-triazole with 5-bromo-2,4-dichloro-6-methylpyrimidine followed by a SNAr alkoxylation of the novel tricyclic heterocyclic core with various aliphatic alcohols. All newly synthesized heterocycles were fully elucidated by both computational and spectral evaluations.

A highly efficient PASE approach to a new class of polycyclic purine derivatives has been proposed. The strategy includes a consecutive reduction, auto-aromatization, and heterocyclization of the initial nitrobenzimidazopyrimidines obtained by a three-component condensation. It was shown that reduction of nitrobenzimidazopyrimidines by metals in acidic media was more efficient than heterogeneous hydro­genation. Novel derivatives of benz[4,5]imidazo[1,2-a]purines were obtained­ in good yields and the proposed structure was confirmed by X-ray crystal structure analysis. The obtained convergent benzimidazopurines combine two relevant medicinal chemistry scaffolds – benz­imidazole and purine.

A series of pyrimidine conjugates containing a fragment of racemic 7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and its (S)-enantiomer attached via a 6-aminohexanoyl fragment were synthesized by the reaction of nucleophilic substitution of chlorine in various chloropyrimidines. The structures of the synthesized compounds were confirmed by1H,19F, and 13 C NMR spectral data. Enantiomeric purity of optically active derivatives was confirmed by chiral HPLC. Antiviral evaluation of the synthesized compounds has shown that the replacement of purine with a pyrimidine fragment leads to a decrease in the anti-herpesvirus activity compared to the lead compound, purine conjugate. The studied compounds did not exhibit significant activity against influenza A (H1N1) virus. © 2022 by the authors. Licensee MDPI, Basel, Switzerland. Russian Science Foundation, RSF: 19-13-00231-P Funding: This research was funded by the Russian Science Foundation, grant number 19-13-00231-P.

The one-step copper-mediated regioselective formation of the C8–S bond for purine derivatives with arylthiols was achieved using air as the green oxidant in the presence of 1.0 equiv of Na2CO3 and ...

A rapid and expedient one-pot procedure for the synthesis of fused purine derivatives from a trisubstituted pyrimidine and various amines has been developed. The tandem substitution reaction and copper(I)-catalyzed annulation exhibited high efficiency. The fused heterocyclic products contain the purine scaffold and may be useful in medicinal chemistry and bioscience.

Thiazolo[2, 3-f]purine derivatives and their analogs – dihydrothiazolo[2, 3-f]purine, 7-(thietan-3-yl)purine, and 8-(2-hydroxypropylthio)purine derivatives – were synthesized. The compounds synthesized here had no effects on protein glycation reactions using glucose; they gave weak inhibition of glycogen phosphorylase; they had no hemorheological activity. Substances with hypotensive activity greater than that of Dibazol were found. A number of substances had hypoglycemic effects greater than those of chlorpropamide and Adebit. Two compounds inhibited dipeptidylpeptidase-4, but were less active than reference agent vildagliptin.

From the viewpoint of environmental protection and sustainable development, applying green inhibitors to inhibit the metal corrosion in industry is of great concern. In this work, two purine derivatives, 6-Furfurylaminopurine (FAP) and N-Benzoylaminopurine (N-BAP), were evaluated as eco-friendly corrosion inhibitors for mild steel (MS) in 1 M HCl solution by experimental and theoretical approaches. Electrochemical measurements indicate that both FAP and N-BAP present high inhibition performance, especially for N-BAP with a high inhibition efficiency of 97.0% and high stability of inhibition performance with the inhibition efficiency of 98.6% after 24 h immersion. Theoretical calculations were performed to elucidate the adsorption mechanism of FAP and N-BAP on MS surface. The adsorption of FAP is through the bonding of two N atoms of purine ring on the Fe surface, while for N-BAP molecule, besides the two N atoms in purine ring, its adsorption is also through the bonding of the O of carbonyl on the Fe surface. The diffusion behavior of corrosive species by molecular dynamics simulations indicates that the adsorbed FAP and N-BAP films can effectively prevent the diffusion of corrosive species from corrosive solution to MS surface, thereby inhibiting the corrosion of MS.

This Review summarizes all of the currently described strategies applicable for the solid-phase synthesis of purine derivatives. The individual approaches are classified according to the immobilization procedure used resulting in a linkage of the final scaffold at various positions.

A series of novel purine derivatives containing 1,4-pentadien-3-one moiety were designed and synthesized. The optimal conditions for the synthesis of the target compounds E 1 –E 25 were as follows: solvent, DMF; catalyst, KOH; temperature, 40 °C; time, 2 h; and molar equivalent of A:D:Catalyst, 1:0.8:1.2. Antiviral bioassays indicated that compounds E 1 , E 3 , E 5 , E 7 , E 18 , and E 19 showed excellent protection activities, with EC50 values of 188.9, 194.6, 125.2, 134.1, 137.8, and 195.4 µg/mL, respectively, which were better than that of Ningnanmycin (271.2 μg/mL). To the best of our knowledge, this study is the first report on the design, synthesis, and antiviral activity of novel purine derivatives containing 1,4-pentadien-3-one moiety.

meta-Selective C-H alkylations of bioactive purine derivatives were accomplished by versatile ruthenium catalysis. Thus, the arene-ligand-free complex [Ru(OAc)2 (PPh3 )2 ] enabled remote C-H functionalizations with ample scope and excellent levels of chemo- and positional selectivities. Detailed experimental and computational mechanistic studies provided strong support for a facile C-H activation within a ruthenium(II/III) manifold.

Kazak, Canan/0000-0003-2475-8775; Guven, Ebru Bilget/0000-0001-9734-9679; Cetin-Atalay, Rengul/0000-0003-2408-6606 WOS: 000348003500058 PubMed: 25462277 Novel 9-(substituted amino/piperazinoethyl)adenines (4-12), 6-(substituted piperazino/amino)purines (15-27), 9-(p-toluenesulfonyl/cyclopentyl/ethoxycarbonylmethyl)-6-(substituted amino/piperazino)purines (28-34,36,37,38-41) were synthesized and evaluated initially for their cytotoxic activities on liver Huh7, breast T47D and colon HCT116 carcinoma cells. N-6-(4-Trifluoromethylphenyl)piperazine derivative (17) and its 9-(p-toluene-sulfonyI)/9-cyclopentyl analogues (28, 36) had promising cytotoxic activities. Compounds 17, 28 and 36 were further analysed for their cytotoxicity in a panel of a liver cancer cell lines. The compound 36 had better cytotoxic activities (IC50

In order to study the anti-inflammatory activity of novel 6-substituted and 6,9-disubstituted purine derivatives, 20 compounds, L1–10 and W1–10, derived from purine and lacking a gold complex were designed, synthesized and their anti-inflammatory activity was screened. LPS-induced TNF-α, IL-1β, IL-6, PGE2, NO, COX-2 and iNOS mRNA were evaluated, and western blot and NF-κB p65 translocation assay were performed in RAW 264.7 macrophages. Furthermore, carrageenan-induced hind paw edema experiments were performed in mice. Compound L1, L4, W2, and W4 markedly exerted a dose-dependent inhibition of TNF-α, IL-1β, IL-6 and PGE2 release induced by LPS in RAW 264.7 macrophages. Moreover, these compounds strongly inhibited LPS-induced NO, COX-2 and iNOS mRNA in the same cells. Anti-inflammatory activity tests in vivo showed that L1 and L4 were more effective than Au(L3)(PPh3), a known anti-inflammatory agent, at 2–5 h, and W4 was the most effective at 3–5 h after dosing. Thus, W2, W4, and L1, L4, could effectively inhibit LPS-induced inflammatory response in vitro and in vivo suggesting a promising role as anti-inflammatory agents.

A series of novel 2,6-disubstituted purine derivatives were designed and synthesized from 2,6-dichloropurine. The structures of target compounds were determined by 1H-NMR, 13C-NMR, and HRMS. The synthesized compounds were evaluated for their inhibitory activities against lung cancer cell lines of A549 and liver cancer cell lines of Bel-7402. 2-(4-Benzyloxy-phenylamino)-6-(cyclohexylamino)purine(3), 2-(4-chloro-phenylamino)-6-(n-butylamino)purine (5), 2-(4-morpholinoamino)-6-(4-hydroxy-phenylamino)purine (9), and 2-(4-O-galactosyl-phenylamino)-6-(cyclohexylamino)purine (12) exhibited moderate inhibitory activity.

Reaction between 5,7-dialkylated xanthine derivatives (2 equiv.) and an alkyl propiolate in the presence of catalytic amounts of triphenyl phosphine yields alkyl 2,3-bis(1,3-dialkyl-2,6-dioxo/oxothio-2,3-dihydro-1H-purin-7(6H)-yl)propanoates in excellent yield.

The first asymmetric hydrogenation of α-purine nucleobase-substituted α,β-unsaturated esters, catalyzed by a chiral rhodium (R)-Synphos catalyst, has been developed. A wide range of mono- and disubstituted acrylates were successfully hydrogenated under very mild conditions in high yields with good to excellent enantioselectivities (up to 99% ee). This method provides a convenient approach to the synthesis of a new kind of optically pure acyclic nucleoside and Tenofovir analogues.

The protection of the amino group in 2-amino-6-chloropurines using a THP group allows introduction of a variety of halogen and carbon substituents at the purine 8-position.

A series of novel N-(purin-6-yl)- and N-(2-aminopurin-6-yl) derivatives of heterocyclic amines was synthesized. It was found that preferred preparative method for N-(purin-6-yl) derivatives of heterocyclic amines is interaction of 6-chloropurine with heterocyclic amines without any catalyst; whereas N-(2-aminopurin-6-yl) derivatives were obtained in the moderate-to-high yields while heating 2-amino-6-chloropurine and heterocyclic amines in water in the presence of sulfuric acid.

Intramolecular glycosylation of purine derivatives that are temporarily connected to the 5 position of ribofuranosyl donors at their 8 position through an ethereal linkage leads to 8-oxo-purine β-nucleosides in a stereoselective manner.

A mild, efficient and highly regioselective addition of purine derivatives to N -Boc imines generated in situ in water was developed for the first time. A wide range of novel acyclic purine azanucleosides were synthesized in moderate to high yields through this transformation. This methodology was also appropriate for some other N-heterocycles.

Four- and five-bond heteronuclear J-couplings between the hydrogen H-8 and carbons C-6 and C-2 in a series of 7- and 9-benzyl substituted purine derivaties with variuous substituents in positions 2 and 6 were studied by coupled 13 C NMR and H,C-HMBC experiments and by DFT calculations. We have found that for some of the derivatives, the five-bond coupling H8-C2 is higher than the four-bond H8-C6 coupling, which is also evidenced by a stronger crosspeak in the HMBC. This finding contradicts the generally accepted opinion that only strong three-bond crosspeaks and one weak four-bond H8-C6 crosspeak can be observed in the HMBC spectra of purine derivatives. The misinterpretation of HMBC spectra may lead to an incorrect determination of the purine derivatives' structure. Copyright © 2012 John Wiley & Sons, Ltd.

A series of 2,6,9-substituted adenines were obtained from the easily accessible 5-amino-4-cyanoformimidoyl imidazoles 1, acetic and benzoic anhydrides and primary alkyl amines in a three-steps sequence. Acylation of 1 followed by addition of the amine led to the intermediates 5-amino-4-(N-acyl)formamidino imidazoles 4/5, under mild conditions. Cyclization of 4/5 under reflux in ethanol led to the desired substituted adenine. A preliminary stepwise study led to the development of three general and efficient one-pot methods for the synthesis of adenine derivatives. The one-pot three-step reaction in the presence of DMAP was the most convenient syn-thetic approach., The authors gratefully acknowledge the financial support by the University of Minho and Fundacao para a Ciencia e Tecnologia.

Intramolecular C−H arylations were employed as a key step in the synthesis of hitherto unknown fused purine systems: 13-substituted purino[8,9-f]phenanthridines and 11-substituted 5,6-dihydropurino[8,9-a]isoquinolines. The purino[8,9-f]phenanthridines were prepared in moderate yields by double C−H arylations of 9-phenylpurines with 1,2-diiodobenzene or, more efficiently, by consecutive Suzuki coupling of 9-(2-bromophenyl)purines with 2-bromophenylboronic acid followed by intramolecular C−H arylation. 5,6-Dihydropurino[8,9-a]isoquinolines were prepared in quantitative yields by intramolecular C−H arylations of 9-(2-chlorophenethyl)purines.

Aim of this paper was to compare urinary purine derivatives (PD) excretion in Italian Mediterranean dairy buffaloes and Fresian dairy cows during dry period. Six buffalo and six dairy cows at about 60 days to delivery were housed in individual cages and fed the same diet. Feed intake was monitored daily. After a period of adaptation, total daily urine was collected, weighed, sampled in test-tubes and frozen up to HPLC analysis. During the urine recovery period the daily feed intake was higher for dairy cows (kg/DM 9.0 vs 7.6) even if differences were not significant due to the high individual variability. Urine excretion was significantly (P

A series of 9-substituted and 2,9-disubstituted 6-(3-aminophenylamino) purines were synthesized and evaluated for their ability to mimic protein A binding to human IgG antibody. The structure–activity relationship (SAR) demonstrates that the 6-(3-aminoanilinyl) purine component was essential for activity. Purine 14 demonstrated significant activity, compared to protein A. These compounds may prove useful for the treatment of autoimmune diseases.

A novel approach to the synthesis of purine derivatives (bases and nucleosides) bearing 4,5-dihydrofuran-2-yl and tetrahydrofuran-2-yl substituents at the 6-position as partly and fully saturated analogues of biologically active 6-hetarylpurine nucleosides is reported. Palladium-catalyzed cross-coupling reactions of 6-iodopurines with new (4,5-dihydrofuran-2-yl)zinc chloride (1) gave 6-(4,5-dihydrofuran-2-yl)purines in high yields. Their catalytic hydrogenation gave 6-(tetrahydrofuran-2-yl)purines. These modified purine bases and nucleosides did not exhibit any significant cytostatic or anti-HCV activity.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

To determine the endogenous contribution of purine derivatives (PD) to renal excretion and the urinary recovery of duodenal purine bases (PB), five dairy Granadina goats (initial weight ± s.e.: 38.6 ± 2.78 kg) were each fitted with a duodenal infusion catheter. Animals were offered ad libitum a mixed diet (75 : 25; alfalfa hay : concentrate), which was supplied in equal portions every 3 h. To label microbial PB, (15NH4)2SO4 was added to the concentrate. The lower enrichment of urinary PD (15N-allantoin) compared with duodenal PB enrichment confirmed the presence of an endogenous PD fraction (268.5 ± 21.98 μmol/kg weight0.75 or 0.386 of the total PD excretion). The recovery of PD in urine and milk increased linearly in response to increasing amounts of duodenally infused RNA (starting on day 21 after parturition). On average, 0.74 of infused PB from RNA was recovered in urine. Milk PD constituted a minor (

A novel approach to the synthesis of 6-(2-hydroxyethyl)purines was developed based on Pd-catalyzed cross-coupling reactions of 6-chloropurines with the Reformatsky reagent followed by reduction by NaBH4 and treatment with MnO2. This methodology was successfully applied to the syntheses of 6-(ethoxycarbonylmethyl)- and 6-(hydroxyethyl)purine bases and nucleosides.

In search of novel purine antimetabolites, a series of 8-substituted methylxanthine derivatives was prepared in order to explore their in vitro anticancer, anti-HIV-1 and antimicrobial activities. The target compounds include: 8-[(3-substituted-4-oxo-thiazolidin-2-ylidene)hydrazino]-1,3-dimethyl (or 1,3,7-trimethyl)-3,7-dihydropurine-2,6-diones 5a-e, 8-[(3,4-disubstituted 2,3-dihydrothiazol-2-ylidene)hydrazino]-1,3,7-trimethyl-3,7-dihydropurine-2,6-diones 6a-d and 8-(5-amino-3-arylpyrazol-1-yl)-1,3-dimethyl- (or 1,3,7-trimethyl)-3,7-dihydropurine-2,6-diones 7a-g. The in vitro anticancer results revealed that compound 5d exhibited a super sensitivity profile towards leukemia K-562 with a GI(50) value of

Asmarines are tetrahydro[1,4]diazepino[1,2,3- g , h ]purine derivatives isolated from marine sponges ( Raspailia sp). They possess profound cytotoxic activity towards cancer cell lines, and are thus attractive synthetic targets. The tetrahydrodiazepinopurine ring skeleton has been prepared employing the RCM reaction on Boc-protected 6-allylamino-7-(propen-1-yl)purine as the key step for the construction of the seven-membered ring. 7-(Propen-1-yl)purines were formed by a novel rearrangement of 7-allylpurines under basic conditions. Boc-protected N 6 ,7-diallylpurine also participated in RCM to give the eight-membered ring analog of the diazepinopurine.

Purine bases have attracted much attention due to their potential biological activities. Developing more efficient methods for the modification of purine bases with a substitution such as aryl or alkyl is particularly interesting. This review gives an overview of new developments in direct functionalization of C–H and N–H bonds of purine bases via metal catalyzed cross-coupling reactions in recent years.

A facile and selective one-pot N-acylation of nucleobases via carboxylic acids using cyanuric chloride (2,4,6-trichloro-1,3,5-triazine) is described. In this protocol, the reaction of diverse carboxylic acids with pyrimidine and/or purine nucleobases is efficiently achieved in the presence of cyanuric chloride and NaH/Et3N in DMF/MeCN (1:1, v/v) to afford the corresponding N-acyl nucleobases in good yields.

The synthesis of novel 2-amino-9-alkoxyalkylpurine derivatives with both identical and different sulfur containing substituents at positions 6 and 8 of the purine cycle has been accomplished. The thionation and alkylation of the key intermediate - 2-[2-(acetylamino)-6,8-dichloro-9H-purin-9-yl]methoxyethyl acetate or its reactions with thiolates were used. The structures of compounds obtained were confirmed by spectroscopic data and X-ray diffraction analysis.

An expeditious synthesis of modified purine bases and nucleosides bearing a difluoromethyl group in position 6 is described starting from the corresponding 6-(hydroxymethyl)purine derivatives. Their oxidation using Dess-Martin reagent gave 6-formylpurines that were converted to the title compounds by reaction with Deoxofluor. 6-(Difluoromethyl)purine ribonucleoside exerted significant cytostatic effect against leukemia cell lines.

(1R*,3R*,6R*,7S*,9S*)- and (1R*,3R*,6R*,7S*,9R*)-9-Amino-5-oxatricyclo[4.2.1.03,7]nonane-3-methanols (16aand17a) were prepared from 2-(hydroxymethyl)bicyclo[2.2.1]hept-5-ene-2-methanol (10) in five easy steps. The amines16aand17awere used to construct 6-chloro-9H-purine20and21, 2-amino-6-chloro-9H-purine30and31, and 6-chloro-8-methyl-9H-purine analogues34and35. Ammonolysis of these compounds led to 6-amino-9H-purine22aand23a, 2,6-diamino-9H-purine32and33, and 6-amino-8-methyl-9H-purine derivatives of 5-oxatricyclo[4.2.1.03,7]nonane-3-methanol36and37. (1R*,3R*,6R*,7S*,9S*)- and (1R*,3R*,6R*,7S*,9R*)-9-[6-(Dimethylamino)-9H-purin-9-yl]-5-oxatricyclo[4.2.1.03,7]nonane-3-methanols (22band23b), and (1R*,3R*,6R*,7S*,9S*)- and (1R*,3R*,6R*,7S*,9R*)-9-[6-(cyclopropylamino)-9H-purin-9-yl]-5-oxatricyclo[4.2.1.03,7]nonane-3-methanols (22cand23c) were prepared by aminolysis of20and21.

A facile and efficient methodology of the synthesis of 6-(hydroxymethyl)purine derivatives (bases and nucleosides) was developed based on Pd-catalyzed cross-coupling reactions of 6-halopurines or N-protected 2-amino-6-halopurines with (benzoyloxymethyl)zinc iodide followed by deprotection. Regioselective hydroxymethylations of 2,6-dihalopurines were also studied and used for the synthesis of 2-chloro-6-(hydroxymethyl)- or 2,6-bis(hydroxymethyl)purines. The 6-(hydroxymethyl)purine ribonucleoside 5f exerted high cytostatic effect and moderate inhibition of adenosine deaminase, while all the other derivatives were much less effective or entirely inactive.

An investigation of the purine derivatives N,N-dimethyl-N'-(7(9)-H-purin-6-yl)-formamidine, 6-chloropurine and 6-methoxy purine at low temperatures by NMR spectroscopy has been carried out. Low temperature enabled us in two cases to detect the separate NMR signals of N7-H and N9-H tautomers.

From commercially available chiral building blocks, we have developed methods for the syntheses of imidazole derivatives that contain a chiral alkyl substituent at ring atom. These compounds are suitable for further transformation into Nalkyl purine derivatives. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Anomeric α- and β-N,O-psiconucleosides were prepared by 1,3-dipolar cycloaddition of C-ethoxycarbonyl N-methyl nitrone with ethyl 2-acetyloxyacrylate, followed by Vorbruggen nucleosidation. The synthetic scheme has been applied to all purine and pyrimidine nucleobases. Nucleosidation can proceed under kinetic and under thermodynamic control; under thermodynamic control conditions only β-nucleosides are obtained for pyrimidine derivatives and α-nucleosides for purine derivatives. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Two 2,6,9-trisubstituted purine derivatives, 9-isopropyl-2,6-bis[(4-methoxybenzyl)amino]-9H-purine (myoseverin, PMYO, 1) and 9-isopropyl-2,6-bis[(2-methoxybenzyl)amino]-9H-purine (OMYO, 2), and two 6,9-disubstituted derivatives, 9-isopropyl-6-[(4-methoxybenzyl)amino]-9H-purine (3) and 9-isopropyl-6-[(2-methoxybenzyl)amino]-9H-purine (4), were synthesized with the aim to examine their cell proliferation inhibiting activity, and possible additional effects in cultures of hybridoma cells producing monoclonal antibody. The substances were tested over a concentration range from 0.003 to 30 μmol l-1. The most active compound 1 caused a total loss of cell viability at 1 μmol l-1, while its isomer 2 showed the same effect at 10 μmol l-1 concentration. In the presence of compound 1, but not of compound 2, the character of the cell cycle phases profile changed dramatically, most cells being arrested in the G2/M phase. At intermediate concentrations of compound 2 a substantially higher viable cell concentration was observed, relative to control. These differences demonstrated the principal significance of the position of the methoxy groups on the benzene rings for the biological effect. The 6,9-disubstituted derivatives 3 and 4 were without significant effect in the whole range of concentrations tested. The enhancement of monoclonal antibody production, observed in certain concentration intervals of added substances, was of marginal character.

A highly regioselective Minisci reaction for the decarboxylative alkylation of Purine derivatives under mild conditions is presented.

In recent years, there has been a resurgence of interest in the synthesis of purine derivatives due to the discovery of purine-derived ligands for a variety of nucleotide dependent enzymes. The majority of chemistry has focused on substitution of the purine core structure by alkylation at N9 and nucleophilic–aromatic substitution reactions at C2 and C6. Here we report the syntheses of aryl, N -aryl, O -aryl substituted purine libraries by the palladium-mediated coupling of boronic acids, anilines or phenols at the C2 position, and copper(II)-mediated N -arylation with boronic acids at the N9 position. The chemistry described here greatly expands our ability to introduce different functionality and create new purine scaffolds.