New developments in direct functionalization of C–H and N–H bonds of purine bases via metal catalyzed cross-coupling reactions

Abstract

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.

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Morteza Abdoli

Morteza Abdoli was born in Miyandoab, West Azerbaijan Province, Iran, in 1987. He received his B.Sc. from the Payame Noor University in 2010. He pursued his postgraduate study at the same university under the supervision of Dr. H. Saeidian and obtained his M.Sc. (1st class honor) degree in 2013. Currently he is doing his doctoral research on synthesis and reactions of sulfur-containing compounds under the supervision of Prof. Dr. A. Kakanejadfard and Dr. H. Saeidian, at Lorestan University.

Zohreh Mirjafary

Zohreh Mirjafary was born in 1982 in Isfahan, Iran. She graduated from Isfahan University of Technology before moving to Sharif University of Technology where she became a Ph.D. student in the Professor F. Matloubi Moghaddam research group in 2006. She spent nine months in research group of Professor D. Enders at RWTH Aachen University financed by a research grant from the German Academic Exchange Service (DAAD) in 2008. Now she is working at Islamic Azad University as Assistant Professor. Her research focused on the heterocyclic chemistry, organic methodology and catalysis.

Hamid Saeidian

Hamid Saeidian was born in Tarom, Zanjan, Iran, in 1981. He received his B.S. degree in applied Chemistry from K.N. Toosi University of Technology, Tehran, Iran, and his M.S. degree in organic chemistry from Sharif University of Technology, Tehran, Iran, in 2005. He completed his Ph.D. degree in 2009 under the supervision of Professor F. Matloubi Moghaddam. Now he is working at Payame Noor University as Assistant Professor. His research interests include heterocyclic chemistry, new methodologies in organic synthesis and mass spectral studies of organic compounds.

Ali Kakanejadifard

Ali Kakanejadifard was born in 1957 in Khorramabad District of Lorestan, Iran. He received his M.Sc. degree in 1990 and Ph.D. degree in 1997 from Tehran University. He became a Lecturer at Lorestan University and subsequently became a Reader in 2003 and Professor in 2007. His research interests include synthesis of heterocycles, macromolecules, Dioximes and Schiff Bases.

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1. Introduction

The fused imidazo [4,5-d]pyrimidine was named purine by Emil Fisher in 1884 who later achieved its synthesis in 1898. He showed that various substances, such as adenine, xanthine, caffeine, uric acid, and guanine all belonged to one homogeneous family and corresponded to different hydroxyl and amino derivatives of the same fundamental system.¹ Purines constitute a major class of naturally occurring compounds (Fig. 1) and privileged medicinal scaffolds (Fig. 2) that exhibit a broad range of biological and pharmaceutical properties, such as antimicrobial,² antibacterial,³ antiviral,⁴ antileishmanial,⁵ antifungal,⁶ antitumor,⁷ anticonvulsant,⁸ antidepressant,⁹ anti-inflammatory,¹⁰ antiparkinson¹¹ and antidiabetic¹² activities. In this regard, developing more efficient methods for the construction of compounds containing purine is a topic of immense importance.

Fig. 1 Some natural sources of purines.

Fig. 2 Some purine-containing bioactive compounds.

Three strategies have been utilized for the synthesis of functionalized purines in literature (Scheme 1): heterocyclization¹³ (method A) which the scope of it has been limited due to the harsh conditions, poor substituent tolerance, low chemical yields, and multistep synthesis. Metal-catalyzed cross-coupling reactions¹⁴ (method B) is a powerful and flexible protocol for the synthesis of functionalized purines which is well highlighted in literature in recent years.¹⁵ Direct metal-catalyzed C–H bond functionalization (method C) has emerged over the past 25 years as a powerful tool for the synthesis of organic molecules and pharmaceutical scaffolds that may complement or even replace traditional catalytic cross-coupling reactions. In these methods the inactive C–H bonds can be treated as a functional group, similar to the traditionally used C–(pseudo)halide bonds.¹⁶ This synthetic methodology offers several advantages:

Scheme 1 The methods for the synthesis of functionalized purines.

(1) High atom economy.

(2) High functional group tolerance.

(3) Ease of handling.

(4) Shorter synthetic routes.

(5) Environmentally friendly processes (Green Chemistry).

To the best of our knowledge, a comprehensive review has not appeared on direct functionalization of C–H and N–H bonds of purines via transition-metal-catalyzed cross-coupling reactions in literature in recent years. In this review, we have classified these reactions based on the type (e.g. arylation, alkylation, alkenylation) and the position of functionalization. The most detailed discussion will be focused on the C⁸-arylation of titled compounds. There are few protocols for functionalization of C²–H and C⁶–H bonds via direct metal catalyzed processes, and inevitably we have only discussed C⁸-functionalization of the titled compounds. In the final section of this review, the new and regioselective methodologies for functionalization of N–H bonds of purines will be discussed. The main methods for direct functionalization of purines via metal catalyzed cross-coupling reactions are summarized in Fig. 3.

Fig. 3 The main methods for direct functionalization of purines via metal catalyzed cross-coupling reactions.

2. Direct C⁸–H arylation

2.1. Intermolecular Pd-catalyzed direct C⁸–H arylation

Almost all known direct C⁸–H arylations of purines proceeded by using palladium as a catalyst. The first example has been accomplished for synthesis of phenyl purine via direct C⁸–H activation employing Pd(OAc)₂/PPh₃ combination as catalytic system (Scheme 2).¹⁷ Hocek and co-workers described C⁸–H arylation of purines 3 using aryl iodides as an arylation agent in the presence of CuI and Cs₂CO₃ to form 4 (Scheme 3).^18,19 It is noted that aryl chlorides under similar conditions did not follow through C–H activation reactions.

Scheme 2 The first example of intermolecular Pd-catalyzed direct C⁸–H arylation of purines.

Scheme 3 C⁸–H arylation of purines 3 using aryl iodides.

However, in 2007 Chiong and Daugulis, attempted a similar conversion involving aryl chlorides instead of aryl iodides.²⁰ The authors extended their methodology to the first successful direct C⁸–H arylation of caffeine with aryl chlorides in N-methyl-2-pyrrolidone involved treating Pd(OAc)₂/BuAd₂P as catalytic system with K₃PO₄ as base.

Free-(NH₂) adenines 5 were found to undergo efficient C⁸–H arylation with various aryl halides in the presence of Pearlman's catalyst (Pd(OH)₂/C) (Scheme 4). The reaction was more efficient using microwave irradiation. This system shows relatively good reactivity for a range of aryl halides. Under these conditions the yields of C⁸–H arylation using aryl chlorides were equally effective with as iodo and bromo reagents.²¹ Para electron-rich aryl halides and 1-halonaphthalene worked well under these reaction conditions. Meta- and para electron-deficient aryl halides gave the coupling products in moderate to good yields. However, ortho-substituted and sterically hindered aryl halides were relatively incompatible in this system.

Scheme 4 C⁸–H arylation of free-(NH₂) adenines 5.

With the objective of designing a comprehensive protocol to direct C⁸-arylation of purines, the scope of electrophilic partners were extended to aromatic sulfinic acid sodium salt.²² So several palladium sources, oxidants, additives and solvents were tested, and the system Pd(PhCN)₂Cl₂/Cu(OAc)₂/dioxane/DMSO (9 : 1) was found to be superior. It is worth noting that the electronic character of the substituents in sulfinic acid had remarkably little effect on the facility of reaction. Various substrates were examined involving electron donating and withdrawing groups in the para, ortho, and meta positions according to Scheme 5.

Scheme 5 Using aromatic sulfinic acid sodium salts as an electrophilic partners in direct C⁸–H arylation of caffeine 7.

An interesting palladium-catalyzed selective dehydrogenative cross-coupling of purines with various heterocycles such as thiophenes and furans was reported by You et al.²³ The Pd(OAc)₂/Cu(OAc)₂·H₂O/pyridine/1,4-dioxane system was found to be optimal for this reaction, while addition of 10 mol% CuCl as an activator gave excellent results. In 2011, this methodology was extended to regioselective C³-heteroarylation of indoles (Scheme 6) and pyrroles (Scheme 7) with an array of purines.²⁴

Scheme 6 Regioselective C³-heteroarylation of indoles with purines.

Scheme 7 Regioselective C³-heteroarylation of pyrroles with purines.

The direct C–H arylation of purine nucleosides was reported by Hocek's research team in 2007.²⁵ Adenosines 16 and 6-(4-methoxyphenyl)purine ribonucleoside 17 (Fig. 4) were observed to undergo C⁸–H arylation in the presence of alkyl halides with catalytic amounts of Cu(OAc)₂ and CuI.

Fig. 4 Structure of adenosines 16 and 6-(4-methoxyphenyl)purine ribonucleoside 17.

In an effort towards the development of an effective methodology for regioselective C⁸-arylation of adenine, Fairlamb's group employed Pd(OAc)₂/CuI/Cs₂CO₃/DMF combination as a relatively efficient system for regioselective C⁸-arylation of unprotected adenine nucleoside using aryl iodides (Scheme 8).²⁶ High yield was obtained with iodonapthalene under these conditions, and para electron-deficient aryl iodides gave the coupling products in moderate yields. A plausible catalytic cycle for the direct arylation of adenosine mediated by Pd/Cu in the presence of Cs₂CO₃ is outlined in Fig. 5. CuI metalation of acidic C⁸–H bond of adenosine followed by deprotonation at C⁸, leads to in situ generation of an organocuprate, which participates in metal exchange with Pd(II) intermediate in the catalytic cycle.

Scheme 8 Regioselective C⁸-arylation of unprotected adenine 16b with aryl iodides.

Fig. 5 Proposed preliminary mechanism for C⁸-arylation of adenine 16b with aryl iodides.

To develop a practical method for the synthesis of C⁸-arylated purine nucleosides, Fairlamb showed Pd(OAc)₂/CuI is an effective catalytic system for direct C⁸-arylation of unprotected 2′-deoxyguanosine with aryl iodides at 80 °C (Scheme 9).²⁷ DMF and Cs₂CO₃ were the best solvent and base, respectively, and addition of secondary amines was found to be necessary for efficiency of the reaction.

Scheme 9 Direct C⁸-arylation of unprotected 2′-deoxyguanosine 16a with aryl iodides.

2.2. Intramolecular Pd-catalyzed direct C⁸–H arylation

In 2009, Barbero and co-workers reported an example of intramolecular C–H arylations of purines. They showed that 9H-purine 20 underwent intramolecular direct C⁸–H arylation in the presence of CuI as catalyst, LiOtBu as base in o-xylene at 150 °C. The corresponding fused purine 21 was obtained in yield of 58% (Scheme 10).²⁸

Scheme 10 An example of intramolecular C–H arylations of purines.

Comprehensive synthesis of fused purines 22 and 23 (Fig. 6) via intramolecular direct arylation were reported by Hocek's group.²⁹ They examined three approaches relying on palladium catalyzed C–H arylation for synthesis of purino[8,9-f]phenanthridines 22 (Scheme 11).

Fig. 6 Chemical structure of purino[8,9-f]phenanthridines 22 and 5,6-dihydropurino[8,9-a]isoquinolines 23.

Scheme 11 Retrosynthetic analysis of construction of the purino[8,9-f]phenanthridine core. (i) Several procedures.^30–34 (ii) Pd(OAc)₂ (10 mol%), P(Cy)₃·HBF₄ (20 mol%), TBAB (1 equiv.), KOAc (4 equiv.), 140 °C, 25 h. (iii) Pd(PPh₃)₄ (4 mol%), Na₂CO₃ (4 equiv.), aliquat 100 (8 mol%), toluene/H₂O (2:1), 110 °C, 36 h. (iv) Pd(OAc)₂ (5 mol%), P(Cy)₃·HBF₄ (10 mol%), K₂CO₃ (2.5 equiv.), DMF, 150 °C, 20 h (30 h for 1b).

8,9-Diphenylpurines 24 underwent no reaction under oxidative coupling conditions.^30–34 Moreover, double C–H arylation of 9-phenylpurines 25 with 1,2-diiodobenzene 26 gave moderate yields of the desired products (∼35%). The best result was obtained with consecutive Suzuki cross-coupling of 9-(2-bromophenyl)purines 27 with 2-bromophenylboronic acid 28 followed by intramolecular direct C–H arylation using Pd(OAc)₂/PCy₃-HBF₄ as catalytic system at 130 °C for 8–16 h. Analogously, 5,6-dihydropurino[8,9-a]isoquinolines 23 were prepared via direct intramolecular C⁸–H arylation of 30. Intermediates 30 were generated by alkylation of purines 29 with 2-chlorophenethyl bromide in the presence of K₂CO₃ with reasonable yields (Scheme 12).

Scheme 12 Synthesis of 5,6-dihydropurino[8,9-a]isoquinolines 23.

2.3. Intermolecular Ni and Cu-catalyzed direct C⁸–H arylation

In 2011, Qu and co-workers developed a novel protocol for nickel-catalyzed direct C⁸-arylation of purines with Grignard reagent at room temperature (Scheme 13).³⁵ They tested several catalysts and oxidants, and the system Ni(dppp)Cl₂/1,2-dichloroethane was found to be superior. Under optimized conditions, the reaction tolerates electron-donating substituents at meta and para positions of aryl moiety and gave corresponding coupling products in good to high yields, but extension of the reaction to electron-withdrawing and ortho-substituents aryl rings was failed. However, this methodology for synthesis of C⁸-arylated purines was problematic due to the requirement of a very high catalyst loading (30 mol%).

Scheme 13 Direct C–H arylation of 9-benzyl-6-methoxy-9H-purine 31 with various aryl Grignard reagents.

A plausible mechanism for Ni-catalyzed C⁸–H arylation of purine 31 with Grignard reagents 32 in 1,2-dichloroethane is presented in Fig. 7. Reaction of Ni(dppp)Cl₂ with 1,2-dichloroethane afforded NiCl₂ which used for metalation of purine to give intermediate B. Transmetallation between 32 and B followed by reductive elimination provided the desired products.

Fig. 7 Proposed preliminary mechanism for intermolecular Ni-catalyzed direct C⁸–H arylation of 31.

Hong et al. described the use of CuI as a catalyst for selective dehydrogenative cross-coupling reactions of a range of azoles with quinolones³⁶ in the presence of LiOtBu in 1,4-dioxane at 110 °C, and only one C⁸-heteroarylated purine was obtained in a yield of 79%.

2.4. Direct C⁸-alkenylation

Alami and co-workers recently reported one of the first palladium catalyzed direct C⁸-alkenylation of caffeine 7 with alkenyl halides. The reaction was undertaken at 130 °C using Pd(acac)₂/CuI/P(o-tolyl)₃ as catalytic system and t-BuOLi as base in THF.³⁷ This method afforded the C⁸-alkenylated caffeine 36 in moderate to good yields with various mono-, di- and tri-substituted alkenyl halides 35 (Scheme 14).

Scheme 14 Direct C⁸-alkenylations of caffeine 7 with alkenyl halides.

One year later, Piguel and co-workers investigated the effect of reaction parameters, such as different palladium catalyst, additives, solvents, and electronic effects of the coupling partners on the efficiency of the coupling reactions.³⁸ Considering the catalyst, ligand, base and temperature, the optimized conditions of the reaction involved using Pd(OAc)₂/CuI paired with phenantroline as a catalytic system, t-BuOLi as the base at 120 °C in dioxane under microwave irradiation for 30 min (Scheme 15). Although their optimized conditions allowed the reaction to be carried out at a relatively low temperature and short time comparing with those reported by Alami, an increased catalyst loading of up to 5 mol% was essentially required for effective coupling. It should be mentioned that in the only same example, Alami's method (A) gave higher yield than Piguel's method (B) (Scheme 16). Oxidation of sulfur atom of 39 with m-CPBA in dichloromethane afforded the corresponding sulfone, which underwent facile SNAr displacement with amines.

Scheme 15 Microwave-assisted direct alkenylation of purines with alkenyl bromides.

Scheme 16 Comparing the efficiency of Alami's and Piguel's methods for direct C⁸-alkenylations of caffeine.

Interestingly, a recent work by You and co-workers disclosed that inactivated alkenes were also efficient coupling partners for direct alkenylation of purines.³⁹ They established the dehydrogenative Heck coupling of N-heteroarenes involving purines 41 with alkenes 42 in the presence of Pd(OAc)₂/CuCl/Cu(OAc)₂·H₂O afforded the corresponding π-extended alkenylated products 43 in good to high yields (Scheme 17).

Scheme 17 Direct C⁸-alkenylation of purines with inactivated alkenes.

2.5. Direct alkylation and benzylation

A preliminary example of intermolecular direct alkylation of purine with inactive alkenes has been reported by Bergman et al., requiring elevated temperature (150 °C), 5 mol% of [RhCl(coe)₂]₂ as a catalyst in the presence of LiCl. The low yields of C⁶/C⁸ alkylated byproduct (17%) were also observed (Scheme 18).⁴⁰ Following this work, the same group in 2004, has investigated the alkylation of caffeine with 4-methylpent-1-ene under the aforementioned rhodium catalyst, but the low yield of desired product was observed (15%).⁴¹

Scheme 18 Intermolecular direct alkylation of purine with inactive hexene.

Seven years later, a more robust and versatile method for benzylation of xanthines was contributed by Alami's team. They have exemplified the benzylation of C-8 position of xanthine with a variety of benzyl chlorides in the presence of a combination of 2.5 mol% of [PdCl₂(CH₃CN)₂] and 5 mol% of P(o-tolyl)₃ as catalytic system (Scheme 19).⁴² Generally, both electron-donating and electron-withdrawing groups in the phenyl ring periphery of either coupling partner were well tolerated. In addition, ortho-substituted as well as bicyclic derivatives were also viable substrates. However, 3-fluorobenzyl chloride was failed to react under reaction condition and the starting material was recovered unchanged. Notably, the reaction conditions were compatible with functional groups such as halogens, esters, and sulfanes which are useful for further synthetic transformations.

Scheme 19 Palladium-catalyzed direct benzylation of caffeine 7 with benzyl chlorides 46.

A fascinating opportunity for synthesis of C⁸-alkylated purines with relatively good yields has been observed by using different primary and secondary Grignard reagents as an efficient coupling reagent using 20 mol% of Ni(dppp)Cl₂ at room temperature (Table 1).⁴³ Possible mechanism for formation of C⁸-alkylated purines with Grignard reagents is the same as shown in Fig. 7.

Table 1 Direct C–H alkylation of various purines 48 with Grignard reagents 49

Entry	R^1	R^2	Alkyl	Product	Yield (%)
1	OMe	Bn	Cyclopentyl	50a	81
2	OMe	Me	Cyclopentyl	50b	87
3	OMe	Et	Cyclopentyl	50c	91
4	OMe	Cyclo-pentyl	Cyclopentyl	50d	75
5	Cl	Bn	Cyclopentyl	50e	77
6	4-Ethyl-phenyl	Bn	Cyclopentyl	50f	89
7	OMe	Bn	Pentyl	50g	76
8	OMe	Bn	Cyclopropyl	50h	72
9	OMe	Bn	Cyclohexyl	50i	94
10	4-Ethyl-phenyl	Bn	Ethyl	50j	53

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2.6. Direct C⁸–H sulfenylation

Hocek and co-workers recently applied aryldisulfidesin as the coupling reagent in direct oxidative C–S bond formation at the C⁸-position of purines, providing a novel entry to arylsulfanyl derivatives of purine (Scheme 20).⁴⁴ Purine 51 underwent sulfenylation with 1,2-diphenyldisulfane 52a and 1,2-bis(4-methoxyphenyl)disulfane 52b in the presence of t-BuOLi which gave corresponding C⁸-arylsulfenylation purines 53a–b in 60% and 56% yield, respectively. While the reaction with electron-poor 1,2-bis(4-nitrophenyl)disulfane 52c did not work. It should be mentioned that, the resulting 8-arylsulfanylpurines 53 undergo Liebeskind–Srogl coupling⁴⁵ with arylstannanes or boronic acids in moderate to high yields (Scheme 21). To the best of our awareness, this is the only example of direct C⁸–H sulfenylation of purines reported so far.

Scheme 20 Direct C–S bond formation at the C⁸-position of purine 51.

Scheme 21 Liebeskind–Srogl coupling of 8-arylsulfanylpurines. (i) ArSnBu₃ (1.2 equiv.), Pd(PPh₃)₄ (5% mol), CuMeSal (2.2 equiv.), 50 °C, THF, 17 h. (ii) ArB(OH)₂, Pd(dba)₃ (4 mol%), (2-furyl)₃P (16 mol%), CuTc (1.3 equiv.), 50 °C, THF, 18 h.

3. Functionalization of N–H bonds

3.1. N⁹–H arylation

There are two general routes for generation of N⁹-arylpurines 57 (Scheme 22). Traditionally, N⁹-arylpurines are prepared from the reaction of arylamine with chloropyrimidine 56 followed by ring closing (method A).⁴⁶ An efficient and new method for the one-step synthesis of N⁹-arylpurines involves N⁹-arylation of purine via a C–N cross-coupling reaction (method B). The method A was not an efficient access because many tedious steps are required.^47–49

Scheme 22 The general methods for generation of N⁹-arylpurines.

N⁹-arylation of purines has been reported by Lam and Chan, by using arylboronic acids as electrophilic partners.⁵⁰ The use of Cu(OAc)₂/N(C₂H₅)₃ or Cu(OAc)₂/pyridine system was found to be optimal for the Lam–Chan reaction conditions.^51–54 This method is compatible with a very large range of meta- and para-substituted arylboronic acids, but it could not be extended to ortho-substituted arylboronic acids.⁵² It should be mentioned that during N⁹-arylation of purines with the Lam and Chan's method, low yields (10%<) of N⁷-regioisomer 59′ were also observed (Scheme 23).⁵⁵

Scheme 23 N⁹-arylation of purine 58 via the Lam and Chan's method.

A completely regioselective N⁹-arylation of purines 60 has been developed in the presence of Cu(OAc)₂, molecular sieves and phenanthroline (Table 2).⁴⁸ It is noteworthy that this method doesn't work well for adenine, due to its low solubility.

Table 2 Cu-mediated reaction between purines 60 and arylboronic acids 61

Entry	X	Y	R^1	R^2	Yield (%)
1	H	Cl	H	H	71
2	H	Cl	H	CH3	68
3	H	Cl	H	OCH3	52
4	H	Cl	H	Cl	41
5	H	Cl	Cl	H	73
6	Cl	Cl	H	H	52
7	Cl	Cl	H	CH3	48
8	NH2	Cl	H	H	42
9	H	NH2	H	H	N.R
10	H	SCH3	H	H	76
11	H	SH/SPh	H	H	81
12	H	2-Thienyl	H	H	68

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Adenine can be efficiently arylated at the N⁹ position with arylboronic acids at room temperature in a CH₃OH–H₂O (4 : 1) mixture as solvent.⁴⁹ This method is compatible with a very large range of substrates, and gave corresponding coupling products in moderate to high yields.

A versatile process for N⁹-arylation of amino-protected adenine 63 with arylboronic acids was described by Gothelf et al.⁵⁶ They showed that the bis-Boc-adenine can be efficiently reacted with electron-rich, electron-poor and sterically hindered arylboronic acids at room temperature (Scheme 24).

Scheme 24 N-arylation of bis-Boc-adenine 63.

The reported methods for N⁹-arylation of purines with arylboronic acids are associated with some drawbacks such as: (1) tedious separation of products from the arylboronic acid anhydrides, (2) low reaction yields with electron-deficient arylboronic acids and (3) in the most cases, long reaction time is required.

In 2011, Guo and co-workers reported an efficient and elegant protocol for regioselective N⁹-arylation of purines by using diaryliodonium salts 65 in the presence of CuBr/K₂CO₃/CH₂Cl₂ system.⁴⁷ This method has several advantages such as good to excellent yields and broad substrate scope. It is worth to note that due to the poor solubility, (3-NO₂C₆H₄)₂I⁺Br⁻ underwent no reaction (Table 2, entry 5), and (3-NO₂-6-MeC₆H₃)₂I⁺Br⁻ gave a low yield (20%) (Table 3, entry 6).

Table 3 N⁹-arylation of purine 58 with Ar₂I⁺Cl⁻

Entry	Ar	Yield (%)
1	Ph	>99
2	4-Cl-Ph	99
3	3,4-Di-Me-Ph	96
4	4-tBu-2-Me-Ph	>99
5	3-NO2	0
6	2-Me-3-NO2	20

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Recently, a new and beautiful method was reported for selective aromatic N-arylation of amino-containing purines with aryl halides in water.⁵⁷ The CuBr/DPPhen 67/KOH combination was found to be optimal for this reaction. Theophylline and adenine underwent coupling reaction with iodo- and bromobenzene in moderate to good yields (Scheme 25).

Scheme 25 Cu-mediated synthesis of N⁹-phenylated theophylline 68 and adenine 69 with phenyl iodide.

3.2. N⁷–H arylation

Dvořák and co-workers utilized the copper(II) catalyzed a cross-coupling reaction for the synthesis of N⁷-arylated guanine 72 and adenine derivatives.⁵⁸ The amino-protected guanine 70 was found to undergo N⁷/N⁹ arylation with moderate to high selectivity (2 : 1 to 6 : 1) by using Cu(OAc)₂/CH₃OH/TMEDA system. The regioselectivity for this coupling reaction was highly affected by substitution on arylboronic acids (Table 4).

Table 4 N-Arylation of N²-(dimethylamino)methyleneguanine

Boronic acid	R	Yield of 72 + 73 (%)	Ratio 72/73
71a	H	62	6 : 1
71b	2-Me	58	9 : 1
71c	3-Me	63	4 : 1
71d	4-Me	69	3 : 1
71e	4-CH2=CH	52	2 : 1

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A reported route for the synthesis of N⁷-arylated guanines 77 involves the copper-mediated arylation of 7-methylpyrimido[1,2-a]purin-10(3H)-one 74 with arylboronic acids 71 by using Cu(OAc)₂/TMEDA system followed by hydrolysis of generated 1-aryl-7-methylpyrimido[1,2-a]purin-10(3H)-ones 75 (Scheme 26).⁵⁸

Scheme 26 Cu-mediated synthesis of N⁷-arylated guanines 77a–e from 7-methylpyrimido[1,2-a]purin-10(3H)-one 74.

3.3. N¹–H arylation

Arterburn and co-workers investigated N¹-arylation of inosine 78a and guanosin 78b with arylboronic acids in 2005 (Scheme 27).⁵⁹ Both electron-donating and electron-withdrawing substituents at the meta- and para-position of arylboronic acids underwent the coupling in moderate to excellent yields, but it could not be extended to ortho-substituted aryl moiety. The presence of pyridine-N-oxide (pyr-N-O) as a co-oxidant or oxygen is vital for this reaction. In the absence of co-oxidant or oxygen, low reaction yields and long reaction time were observed.

Scheme 27 N¹-arylation of inosine 78a and guanosin 78b with arylboronic acids.

A method for the synthesis of N¹-arylated 2′-deoxyribonucleosides 81 have been reported by Harvey et al. (Scheme 28).⁶⁰ Copper(II)-catalyzed cross-coupling reaction of unprotected 2′-deoxyribonucleoside 80 with arylboronic acids in DMSO, affording N¹-arylated 2′-deoxyribonucleosides in a vast range of yields (in the presence and the absence of ligand 0–92% and <10–95%, respectively).

Scheme 28 Synthesis of N¹-aryl-2′-deoxyribonucleosides 81 from 80 via cross-coupling reaction.

3.4. Exocyclic amino group arylation

Protected derivative of 2′-deoxyguanosine (dG) 82 or 2′-deoxyadenosine (dA) 84 underwent Buchwald–Hartwing reaction in excellent yields with ortho-nitro aryl bromide or triflate, in the presence of catalytic amounts of palladium(II) acetate and racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (Scheme 29).⁶¹

Scheme 29 Buchwald–Hartwing reaction of 82 and 84 with ortho-nitro aryl bromides and triflates.

The selective N-arylation of aminopurines with arylboronic acids has been developed in 2004.⁶² Treatment of the N⁹-benzyl-protected 6-chloro guanine 86 with arylboronic acids in the presence of Cu(OAc)₂/NEt₃/DMAP system was shown to be an effective reaction for exocyclic amino group arylation of purines (Scheme 30).

Scheme 30 Synthesis of exocyclic amino group alkylated 87.

2′-Deoxyadenosine 16a was found to undergo efficient N⁶-arylation via copper-catalyzed direct coupling reaction with aryl halides as shown in Scheme 31. It is interesting to note that the electronic character of the substituents in the aryl halides had little effect on the facility of reaction. Moreover aryl chlorides failed to enter into the coupling reaction but aryl bromides reacted smoothly to give the desired products with reasonable yields. The reaction rate of the aryl bromides was increased by addition of sodium iodide.⁶³

Scheme 31 Selective coupling reaction at exocyclic amino group of 2′-deoxyadenosine 16a with aryl halides.

A different method for exocyclic N-arylation of aminopurines has been developed by using aryl iodide reagents in the presence of Pd₂(dba)₃ and xantphos 90. This study was mainly focused on arylation of 2′-deoxyguanosine 89 with ortho-iodonitrobenzenes (Scheme 32), some cases of other aryl donors such as 3-iodopyren and purines was also disclosed.⁶⁴

Scheme 32 Pd-catalyzed arylamination of DG with selected iodoarenes.

A very similar approach for arylation of the exocyclic amino group of nucleosides 92 and 94 was reported by Ngassa and co-workers (Scheme 33).⁶⁵ Pd₂(dba)₃/xantphos/Cs₂CO₃/PhCH₃ system was found to be optimal for arylation of 2′-deoxyadenosine analogue 92. The optimized conditions for 2′-deoxyguanosine analogue 94 is Pd(OAc)₂/xantphos/tert-BuONa/PhCH₃. The reactions work well with electron-rich, electron-poor, naphthalene systems, and sterically hindered aryl bromides. The authors demonstrated that Pd catalyst with xanthos 90 as the supporting ligand is superior to BINAP-based ones.

Scheme 33 Arylation of the exocyclic amino group of nucleosides 92 and 94 with aryl bromides.

3.5. Intramolecular N-arylation

The 6-anilinopurine derivatives 96 was found to undergo efficient direct C–H activation/intramolecular amination by using Cu(OTf)₂ (5 mol%) and PhI(OAc)₂ as oxidant (1.5 equiv.) in a mixture of AcOH/Ac₂O as shown in Scheme 34. Depending on the electronic and steric effects of substituents on the aniline ring, substrates with electron-withdrawing groups gave higher yields than those with electron-donating groups, and para-substituted aniline ring were more reactive than ortho-substituted. A plausible catalytic cycle is depicted in Fig. 8.⁶⁶ Combination of Cu(OTf)₂ with purines 96, followed by an electrophilic substitution reaction resulted metallated purines B. Reductive elimination afforded the desired products 97.

Scheme 34 Cu-mediated direct C–H activation/intramolecular amination of 96.

Fig. 8 Plausible catalytic cycle for direct C–H activation/intramolecular amination.

4. Summary and outlook

In conclusion, this review provides concise overview on the cross-coupling reactions on direct functionalization of purine bases. In these transformations the inactive C–H bonds can be treated as a functional group, similar to the traditionally used C–(pseudo)halide bonds. This research area has still further possibilities for growth and we believed that the highly versatile and extremely effective and novel procedures for the synthesis of functionalized purine bases will be attainable in the near future.

Acknowledgements

We would like to thank Professor M. Farnia for providing helpful feedback that improved the manuscript.

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