ChemComm

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

FEATURE ARTICLE

Cite this: DOI: 10.1039/c5cc03416g

View Article Online View Journal

Catalytic C–H bond functionalisation of purine and pyrimidine nucleosides: a synthetic and mechanistic perspective Vijay Gayakhe,a Yogesh S. Sanghvi,b Ian J. S. Fairlamb*c and Anant R. Kapdi*a

Received 24th April 2015, Accepted 21st May 2015

C–H bond functionalisation of heteroarenes, especially nucleosides, has received a lot of attention in the

DOI: 10.1039/c5cc03416g

past few years. This review describes the state-of the art in this area with a global aspiration for possibly functionalising purine and pyrimidine moieties in more complex biomolecular systems, such as DNA/RNA in

www.rsc.org/chemcomm

the near future.’

1. Introduction Transition-metal catalysed C–H bond functionalisation1–5 of heteroarenes is an ever-growing area of research that has intrigued organic chemists due to the possibility of avoiding chemicals that are environmentally detrimental as well as reducing the number of steps needed to furnish the same product via a classical cross-coupling6 pathway. The ubiquitous and inert nature of the C–H bonds in different

a

Institute of Chemical Technology, Mumbai, Nathalal road, Matunga, Mumbai-400019, India. E-mail: [email protected] b Rasayan Inc. 2802, Crystal Ridge Road, Encinitas, California, 92024-6615, USA c Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK. E-mail: [email protected]

Vijay Gayakhe

Vijay Gayakhe was born in Parner, Maharashtra, India, in 1988, and studied chemistry at the University of Pune (BSc 2008 & MSc 2010). Before he joined for PhD in 2012 under the supervision of Dr Anant R. Kapdi at the Institute of Chemical Technology Matunga, Mumbai, he worked in Calyx Pharmaceuticals, Mumbai as a Research Associate. His research topic for the doctoral studies is Transition metal-mediated synthesis and modification of fluorescent nucleosides and their applications.

This journal is © The Royal Society of Chemistry 2015

molecules is of importance to organic synthetic chemists as site selective functionalisation of these bonds could lead to the development of efficient and broadly applicable synthetic transformations.7 Some of the factors of C–H bond functionalisation that have directly influenced its popularity are more related to the economics and the environmental implications of the reaction. Other contributors such as elimination of waste through reduction in derivatisation steps commonly required for obtaining starting materials for cross-coupling reactions, higher E-factors and better toxicity management have allowed these type of processes to achieve the goal of up to four out of the ‘Twelve Principles of Green Chemistry’.8,9 C–H bond functionalisation has therefore been instrumental in revolutionising organic synthesis, highlighted through its application

Yogesh Sanghvi received his PhD from National Chemical Laboratory and did his postdoctoral research at University of London with Professor C. B. Reese. He worked at ICN Pharmaceuticals for four years and then for fourteen years at Isis Pharmaceuticals. He is founder and president of Rasayan Inc., a company focused on all aspects of nucleic acid chemistry. He has authored over 150 research papers and is an inventor on more than 30 Yogesh S. Sanghvi patents. His specific interests include design, synthesis, chemistry and biochemistry of novel carbohydrates, nucleosides, nucleotides, and oligonucleotides for their application in therapeutics, combinatorial chemistry and medical diagnostic research.

Chem. Commun.

View Article Online

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

Feature Article

in the modification of an eclectic array of heterocycles as well as the construction of complex organic molecules of synthetic and biological relevance. Nucleosides10 are a class of heteroaromatic compounds that constitute the basic subunit for deoxyribonucleic acids (DNA) and ribonucleic acids (RNA).11 Besides the natural nucleosides that form a part of the DNA super-structure, synthetic or chemically modified/functionalised nucleosides have found a wide variety of applications as antivirals (AZT or Zidovudine, Lamivudine (Epivir), Acyclovir, Abacavir), anticancer agents (Tiazofuran, Ara-FU, Neplanocin A), biological probes, biosensors and several others (Fig. 1).12 A closer look at these molecules reveals the presence of several unreactive C–H bonds that could potentially be functionalised via C–H bond activation, in addition to labile b-glycosyl bonds and considerable chemo-functionality. This presents scientists with a unique opportunity to develop synthetic tools which would allow activation of such C–H bonds directly without any kind of substrate pre-functionalisation.13–15 The motivation for developing efficient protocols for the modification of nucleosides also comes from the fact that numerous C5 or C6 substituted pyrimidines as well as C6 or C8 modified purines have been found to exhibit potent biological activity. To name a few, (a) Brivudine (BVDU) that has shown excellent antiviral activity against HSV-I (herpes) virus,16 (b) furanopyrimidin-2-one nucleoside: a highly potent antiviral drug used commonly against the Varicella-Zoster virus,17 (c) 2 0 deoxyuridine-linker that has found application as the most commonly applicable affinity probe,18 (d) 5-heteroarene substituted uridine nucleosides (amidite) exhibiting excellent fluorescence properties19 (Fig. 2). Synthesis of most of these molecules has been achieved by the transition-metal catalysed cross-coupling processes20 which involve the use of toxic organometallic reagents such as tin which could interfere in the studies related to their application in biological systems.

I. J. S. Fairlamb was appointed as lecturer in York in 2001, following a PhD with Dr J. M. Dickinson in Manchester (1996/9), and postdoctoral research with Prof. G. C. Lloyd-Jones in Bristol (2000/1). He was a Royal Society URF (2004/12) and promoted to full Professor in 2010. He leads a talented research group interested in catalysis, mechanism and synthesis. Recent work includes Pd catalyst and ligand design (e.g. imidate anions Ian J. S. Fairlamb and dba-Z ligands), involvement of higher order Pd species (e.g. nanoparticles) and exploiting mechanistic understanding in purine and amino acid C–H functionalisation.

Chem. Commun.

ChemComm

Fig. 1

Nucleoside-based antivirals and anticancer agents.

The C–H bond functionalisation strategy could therefore be used to provide an alternate and cleaner solution to the route presented by the transition-metal catalysed cross-coupling processes.

Anant Kapdi was born in Mumbai, Maharashtra, India, and studied Chemistry at the University of Mumbai (MSc 2002) and York (MSc 2005; Prof. Ian J. S. Fairlamb). After completing his PhD in 2008 under the supervision of Prof. Fairlamb at The University of York, he joined the research group of Prof. Lutz Ackermann at the Georg-August-University, Gottingen, as an Alexander von Humboldt fellow. He returned to Anant R. Kapdi India in 2010 and is currently working as UGC-FRP Assistant Professor. The unifying theme of his research program is the development of synthetically efficient processes including C–H bond functionalisation of (hetero)arenes using novel metallacycles.

This journal is © The Royal Society of Chemistry 2015

View Article Online

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

ChemComm

Feature Article

Scheme 1

Earliest example of C–H bond functionalisation of purines.

The possibility to functionalise purines directly via a C–H bond activation pathway therefore presents us with a more direct method for obtaining preferentially substituted structures. 2.1. Fig. 2 Biologically relevant nucleosides via transition-metal mediated processes.

The central purpose of this perspective is therefore to highlight the potential of C–H bond functionalisation reactions in the modification of nucleosides, with the possibility to design and directly synthesise potent bio-active molecules, possessing beneficial properties (e.g. bioactivity and biophysical characteristics, e.g. photophysical properties). The review also touches on the need to understand a particular reaction system, the type of catalyst/precatalyst used and any special additives needed. In this context it is necessary to seriously consider the reaction mechanism, which has, in several case studies, helped drive the development of nucleoside C–H bond functionalisation chemistry. Generally, these developments and synthetic approaches will, we hope, help to influence and enhance other related areas of research.

2. Historical perspectives on purine C–H bond functionalisation processes One of the earliest examples highlighting the potential of C–H bond activation by the functionalisation of heteroarenes (e.g. benzimidazoles) in an intermolecular fashion with unactivated and isomerisable alkenes, under Rh-catalysed conditions, was reported by Bergman and Ellman in 2002.21 A key feature of this reaction was the dramatic influence of weak acids on such functionalisation reactions. Addition of lutidinium chloride gave the best results over a wide range of heterocycles. In most cases the linear mono-alkylated product was obtained, however initial exploratory studies with purine 1a suggested its susceptibility to multiple alkylation reactions (Scheme 1). A closer look at the purine molecule suggests that there could possibly be three different sites for the functionalisation to take place, namely at C-4, C-6 or C-8 positions (Scheme 1). For the Rh-catalysed arylation22 reaction the selectivity was found to be C-8 4 C-6 (i.e. the reaction proceeded with a 5 : 1 selectivity towards C-8).

This journal is © The Royal Society of Chemistry 2015

C–H bond functionalisation of purine nucleosides

2.1.1. C-8 position functionalisation in purines. The preferential functionalisation of purine 1a by Bergman21 laid the foundation for further exploration of the application of such a powerful methodology in synthesis. In this respect Hocek and co-workers23 explored the idea of employing a Pd catalyst towards the functionalisation of purines via a direct arylation reaction. The employment of Pd(OAc)2 for the reaction of 1b and 2-methyl-iodobenzene 4a to give 5, in the presence of CuI and Cs2CO3, proved to be most effective in catalysing the arylation at the C-8 position. The addition of PPh3 as a ligand had the effect of reducing product yields, with only traces of 5 recorded (Scheme 2). Based on these results Hocek and co-workers23,24 later developed a protocol to access 2,6,8,9-tetrasubstituted purines exhibiting a wide range of biological activity. Additional purine analogs have been reported by other researchers exhibiting inhibition of Kinases,25 tubulin polymerization26 and antagonistic effects to receptors.27 To tackle the problem of poor selectivity observed in the coupling reactions of 2,6,8-trichloropurines, Hocek proposed to combine Suzuki–Miyaura cross-couplings on the C-2 and C-6 positions, with direct arylation on the C-8 position. The sequential addition of arylboronic acid first resulted in the formation of 2,6-diarylated purine 6a, which was filtered through Celites and further subjected to the arylation conditions to give the triarylated product 6b in an overall yield of 61%, over 3 steps (Scheme 3). An important advancement in the direct arylation of free-NH2 adenines was reported by Alami28 in 2008 which employed the combination of Perlmann’s catalyst29 and microwave irradiation in NMP as a solvent to achieve both selectivity for C–H arylation over N–H and reduction in the reaction time (Scheme 4). The C-8 arylation of the free-adenine proceeded in good to excellent

Scheme 2

First example of direct arylation of purines.

Chem. Commun.

View Article Online

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

Feature Article

ChemComm

Scheme 5

First example for direct arylation of purine ribonucleoside.

Scheme 6

Direct arylation of adenosine and 2 0 -deoxyadenosine.

Scheme 3 Synthesis of 2,6,8-triarylpurines via consecutive regioselective Suzuki–Miyaura cross-coupling and direct arylation reactions.

Scheme 4 irradiation.

Direct arylation of purine with a free-NH group using microwave

yields under the conditions involving the use of 20% Pd(OH)2/C (5 mol%) and additive CuI in microwave for 15 minutes. The protocol was also shown to be effective towards the employment of aryl bromides and chlorides resulting in an array of C-8 arylated products selectively in the presence of an unprotected free-NH2 group. Although, the direct arylation of N-alkylated purines had been achieved by several groups,23,24,28 the possibility of employing purine ribonucleosides (6-(4-methoxyphenyl)purine ribonucleoside) as coupling partners was first reported by Hocek and co-workers.30 8-Arylpurine nucleosides have proved to be important structural motifs with a wide variety of applications such as metabolites of DNA,31 self-assembly applications and optical probes32 (Scheme 5). To facilitate the formation of the 8-arylated purine nucleosides, Hocek and co-workers employed a slight modification to the protocol used for the direct arylation of N-alkylated purines. Instead of using piperidine as the base and solvent the reaction was performed in DMF as the solvent at 125 1C with piperidine (acting as the base) added in 5 equivalents, for

Chem. Commun.

20 hours. Sterically bulky 1-pyrenylbromide was also tolerated, furnishing the 8-arylated product in 30% yield. In the same paper Hocek and co-workers30 reported the direct arylation of natural adenine nucleosides (ribose and 2 0 deoxyribonucleoside) at a slightly elevated temperature of 150 1C than that described above (Scheme 6). Rather than achieving arylation only at the C-8 position, it was observed that the natural adenine nucleosides underwent a competing copper-catalysed arylation at the free-NH2 (giving a diarylated product rather than monoarylation in the C-8 position). The selectivity was however, found to be favouring C-8 arylation over the arylation of the free-NH2 group with the best yield obtained in the case of the ribonucleoside analog rather than the 2 0 -deoxyribonucleoside. Subsequently in 2008, Fairlamb and co-workers33 reported a more selective protocol for achieving the direct arylation of natural adenine ribose and 2 0 -deoxyribonucleoside. Initial reports by Hocek30 allowed the direct arylations of these structural motifs at an elevated temperature of 150 1C which could lead to deglycosylation of the coupled product. To overcome this problem Fairlamb and co-workers employed Cs2CO3 as the base instead of piperidine (employed by Hocek) which improved the efficiency of the direct arylation and subsequently allowing the reduction in the reaction temperature from 150 1C to 130 1C, in the case of adenine ribonucleoside (Scheme 7).

This journal is © The Royal Society of Chemistry 2015

View Article Online

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

ChemComm

Feature Article

Scheme 7 More selective protocol for direct arylation of adenosine and 2 0 -deoxyadenosine.

A key finding by Fairlamb was that subjecting 20 -deoxyadenosine 1f to the arylation conditions at 160 1C resulted in substantial deglycosylation. Reducing the reaction temperature to 130 1C gave the arylated product in 65% yield. 8-Arylated ribonucleosides were generated by the employment of this protocol. The authors also undertook a thorough analysis of the reaction intermediates as well as the possibility of the reaction following a nanoparticular pathway (Scheme 8).33 To verify the assumption for the presence of nanoparticles, Fairlamb and co-workers carried out an extensive study involving TEM analysis of the reaction mixture (direct) as well as by trapping the nanoparticles with N-polyvinylpyrrolidone (PVP). An average nanoparticle size of 3–4 nm was observed in these cases. Furthermore, mechanistic studies were conducted to predict the intermediates that could be involved in the catalytic cycle for direct arylation. The presence of Cu(I) species was

Scheme 8 Mechanism for direct arylation of adenosine and 2 0 deoxyadenosine.

This journal is © The Royal Society of Chemistry 2015

Scheme 9

Direct arylation of ribose and deoxy purine nucleosides.

suggested based on the results obtained from XPS analysis of the reaction mixture. This species plays a key role in the activation of the C-8 position of the adenosine nucleoside eventually leading to the formation of the 8-arylated product. Further to the success obtained with the direct arylation of 2 0 -deoxyadenosine, Fairlamb and co-workers34 conducted a detailed study to understand the role of Cu(I) species in the catalytic cycle. In addition to the reagents identified for direct arylations of 20 -deoxyadenosine (see Scheme 7), a substoichiometric amount of piperidine was found to be necessary for providing better reactivity and selectivity (Scheme 9). The reaction could therefore be performed at a lower temperature of 80 1C, minimising deglycosylation. The substrate scope for the direct arylation was found to be independent of the nature of the aryl iodide (no significant substituent effect observed), although 4-nitroiodobenzene gave an unusually lower coupled product probably due to the competing N-arylation reaction. To gain further insight into the mechanism of the above reaction, Fairlamb and co-workers34 realised that the degradation of the DMF solvent was critical to the success of the lower temperature purine arylation reactions. It was found that the trace amount of dimethylamine in DMF was necessary to aid precatalyst activation. Piperidine can be used as a substitute for dimethyl amine, which plays the role of a ligand for PdII (Fig. 3). A trans-Pd(OAc)2{(CH2)5NH}2 complex IVA was isolated and characterised by single crystal X-ray analysis, which upon being subjected to the direct arylation conditions gave identical

Fig. 3 Possible intermediates in the direct arylation of ribose and deoxy purine nucleosides.

Chem. Commun.

View Article Online

Feature Article

ChemComm

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

Scheme 11 Intramolecular oxidative coupling of purines.

Scheme 10

Intramolecular C–H bond functionalisation.

results to those obtained earlier, suggesting the involvement of such a species in the catalytic reaction. Similarly, for understanding the involvement of Cu(I) species, a stoichiometric reaction between CuI and 2 0 -deoxyadenosine resulted in the formation of intermediate IVB, which was characterised by Electrospray Ionisation Mass Spectrometry35 and NMR spectroscopic analysis. This intermediate was subjected to the direct arylation conditions, which furnished the coupled product 10b in good yield. A key requirement for the formation of intermediate IVB is the additional CuI, which explains why it is necessary to use excess CuI for the reaction to take place. In a unique strategy, Hocek and co-workers reported an intramolecular C–H arylation protocol for the synthesis of 13-substituted purino[8,9-f]phenanthridines from adenine (Scheme 10).36 The authors initially tested oxidative coupling and double C–H arylation protocols without much success. The combination of two of the most powerful synthetic strategies namely, C–H arylation and Suzuki–Miyaura cross-coupling reactions led to the formation of the desired product after careful selection of reagents. The reactivity of the catalytic system was found to be influenced greatly by the presence or absence of a free-NH2 group on the adenine moiety. Substituting the NH2 group by methyl (1i1) resulted in good yields of the cyclised product, while the natural adenine (1i2) when subjected to the above conditions furnished the cyclised product 12b in lower yield. Hocek and co-workers36 in the same report also presented an intramolecular C–H arylation protocol for the synthesis of 5,6-dihydropurino[8,9-a]isoquinolines. Such a strategy was found to be independent of the influence of the free-NH2 group, as quantitative product formation was observed. More recent development in this area involves the employment of a tandem C–H activation strategy by Li and co-workers37 based on an intramolecular oxidative coupling38 protocol leading to the synthesis of fused N-heterocycles. The cyclisation was performed under mild conditions using AgOAc as the oxidant in AcOH at 110 1C using Pd(OAc)2 as the catalyst (Scheme 11).

Chem. Commun.

A double strategy involving direct arylation in the C-8 position followed by Suzuki–Miyaura cross-coupling was recently disclosed by Fairlamb, Baumann and co-workers (Scheme 12).39 The strategy was found to be applicable towards the synthesis of a new class of 8-biaryl-20 -deoxyadenosine fluorescent analogues. A highly fluorescent 8-terphenyl-2-deoxyadenosine was obtained via a highly efficient direct arylation-double Suzuki–Miyaura crosscoupling reaction. Borylation of unactivated aromatic substrates has been a challenge for synthetic chemists for several years until the development of a direct one-pot iridium-catalysed borylation40 using pinacolboronate ester as the borylating agent (Scheme 13). Taking advantage of such a methodology Hocek and coworkers41 reported a direct C–H borylation of 7-deazapurine in the C-8 position. Subsequently, the borylated 7-deazapurines were subjected to Suzuki–Miyaura cross-coupling conditions with Pd(dppf)2Cl2 to provide C-8 arylated products in synthetically useful yields. This methodology however, failed to furnish a borylated product in the case of normal purine, perhaps due to the unstable nature of the boryl product.42 Until now we have seen examples of direct arylation of purine nucleosides with substituted aryl halides. The functionalisation

Scheme 12 Fluorescent nucleoside analogues via C–H bond functionalisation and Suzuki–Miyaura cross-coupling reactions.

This journal is © The Royal Society of Chemistry 2015

View Article Online

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

ChemComm

Feature Article

Scheme 13 Direct borylation of deazapurines.

of purines with unreactive alkane/cycloalkanes43 via C(sp3)–H is a more challenging prospect, given the lower reactivity exhibited by these types of substrates. Another problem relates to the lack of coordination possibility towards the transition metals.44 b-Hydride elimination processes lead to the formation of alkenes/ cycloalkene side products, and regularly compete with the desired coupling process. This needs to be addressed if efficient protocols for the alkylation of purines are to be found. A key driver for such chemistry is related to the unique biological properties exhibited by C8-alkyl and N6-alkyl purines.45 Guo and co-workers,46 recently addressed these problems by the development of a highly regioselective transition metal-free47 direct C8 alkylation of purine nucleoside promoted by tBuOOtBu (Scheme 14). In the same report the authors also presented a selective N6-alkylation of purines using tBuOOtBu and CuI. The metal-free C8-alkylation process was suggested to proceed via a free-radical mechanism initiated by a cyclohexyl radical (formed by tBuO ). A radical addition–oxidation occurring at the C8 position of the purine nucleoside leads to the formation of the alkylated product. This was confirmed by using a radical scavenger such as TEMPO leading to the suppression of the reaction. A strong isotope effect (kH/kD = 3.8) was also observed in this process pointing towards the the C–H bond cleavage step to be rate-limiting. Continuing on the idea of functionalising purinyl substrates, Hocek and co-workers introduced a sulfenyl group48 at the C-7 position of 6-phenyldeazapurines under copper-catalysed conditions in air (Scheme 15). Sulfenylation of (hetero)arenes via direct arylation49 has received considerable attention due to the potential applications of the sulfenylated substrates in downstream synthetic transformations.50 The direct arylation was shown to work selectively towards sulfenylation at the C-7 position. Only in some cases sulfenylation took place at the C-8 position, although the reaction was still found to strongly favour the functionalisation at C-7 (i.e. monosulfenylation). This was also found to be the case for the selective halogenation of the deazapurines brought about by the simple reaction of CuX in DMF as the solvent and air as the oxidant. The methodology was

This journal is © The Royal Society of Chemistry 2015

Scheme 14 Selective direct alkylation of purine-metal-free alkylation of the C–H bond vs. copper-catalysed alkylation of the N–H bond.

Scheme 15 Direct sulfenylation and halogenation of purines and deazapurines.

also extended towards the C-8 functionalisation of purines where a strong electronic effect was found to control the reactivity of the direct arylation reaction with the electron-donating and electronneutral sulphides providing the sulfenylated product in synthetically useful yields, while the sulfide brought about a complete retardation of the catalytic reaction. A unique strategy for selective amination and chloroamination51 of 7-deazapurines was recently disclosed by Hocek and co-workers52 that allows easy access to a series of 6,8,9-tri- and 6,7,8,9-tetrasubstituted 7-deazapurines (Scheme 16). A subtle change in the reaction conditions such as the type of base (amount) and ligand allowed the selectivity to shift from a normal amination taking place at the C-8 position with N-chloro-N-alkyl-arylsulfonamides to the chloroamination taking place at C-7 and C-8 positions (the chloro group migrates to the C-7 position). Chloroamination was

Chem. Commun.

View Article Online

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

Feature Article

ChemComm

Scheme 18

Scheme 16 C–H bond functionalised amination and chloroamination of 7-deazapurines.

generally promoted by the addition of LiCl as the additive (source of chloro for the chlorination to take place at the C-7 position). Given the utility of highly substituted purines as bioactive molecules such a methodology emerges as a useful tool, although the lower reactivity could be addressed further. Hong and co-workers53 applied the direct arylation strategy for the modification of 7-phenyltheophyllins at the C-8 position for their possible application towards the development of fluorescent xanthine-based kinase inhibitors (Scheme 17). With the intention of using a variety of functionalised 7-phenyltheophyllins as starting precursors for the synthesis of the xanthine-based inhibitors, Hong and co-workers screened different Pd and Cu-catalysts to come up with the optimum conditions of Pd (10 mol%) and Cu additive (3.0 equiv.), providing the C-8 arylated products in decent yields. It is of particular note that the conditions are similar to those used by Fairlamb and co-workers,33 albeit here a higher temperature was found to be necessary. 2.1.2. C-6 aryl functionalisation of purines. We have seen examples for the functionalisation of the C-8 position of purines under a variety of reaction conditions. In this section we will be considering the examples that involve the functionalisation of the C-6 position of the purine nucleoside. Accordingly, a slight change in strategy was introduced by Guo and Qu involving a chelation-assisted Pd-catalysed monoarylation of 6-arylpurines and protected 6-arylpurine ribonucleosides as outlined in Scheme 18.54 Lakshman and co-workers,55 went on to demonstrate the utility of a Ru-catalysed C–H bond activation/arylation towards

Scheme 17

Direct arylation of 7-phenyltheophyllines.

Chem. Commun.

Ortho-arylation of 6-arylpurines.

the modification of 9-benzyl-6-phenylpurine and 6-arylpurine nucleosides with aryl iodides (Scheme 19). Ru-catalysed arylation of heteroarenes56 has received a lot of attention in the past decade due to the unique reactivity pattern that it exhibits. The success could be attributed largely to the chelation-assisted C–H bond functionalisation2g strategy, allowing the synthesis of a wide variety of synthetically challenging molecules. This strategy also proved to be useful in developing an efficient arylation protocol for 9-benzyl-6-phenylpurine giving rise to a predominantly mono-arylation product. Similar reactivity was observed in the case of silyl-protected 6-arylpurine 20 -deoxyribonucleosides. The chelation-assisted arylation could be possible via coordination of Ru with either the N1 atom or the N7 atom. Lakshman55

Scheme 19 Ru-catalysed direct arylation of 6-phenylpurine and 6-phenylpurine-2-deoxynucleoside.

This journal is © The Royal Society of Chemistry 2015

View Article Online

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

ChemComm

Feature Article

Scheme 20 Proposed mechanism for Ru-catalysed direct arylation of 6-phenylpurine.

proposed that the mechanism for the Ru-catalysed direct arylation of purines takes place predominantly with the chelation of the N1 atom to the ruthenium-centre directing the aryl/RuIV complex for an attack onto the C6-aryl ring giving rise to a selective monoarylated product (Scheme 20). The potential of chelation-assisted direct arylation of purines was further explored by Guo, Qu and co-workers57 by functionalising C6-arylpurines (nucleosides) to obtain suitably functionalised substrates useful for further derivatisation (Scheme 21). Here we see that the higher oxidation state of Pd is taken advantage of giving acetoxylated products through the action of a hypervalent iodine reagent in AcOH–Ac2O. The regioselective pathway is facilitated by N1-chelation-assistance from the purinyl moiety, which led to the formation of delicately prefunctionalised structural motifs of potential relevance to medicinal chemistry. The authors proposed the involvement of a dinuclear acetatebridged PdII-complex, formed by the reaction of Pd(OAc)2 and purine nucleoside, with assistance from the N1 atom. The proposal would explain the site-selectivity observed. However, the authors did not provide experimental evidence in support of intermediate VI. A useful and mild protocol for the functionalisation of C6-arylpurines was described by Lakshman and co-workers58 in 2013, which allows the acetylation of the TBDMS-protected C6-aryl purines (nucleosides) selectively (Scheme 22). The mild nature of the protocol was attributed to the lower temperature and the use of acetonitrile solvent, as compared to the AcOH–Ac2O solvent system employed by Guo.57 Related to Guo’s proposals vide supra the related Pd-acetate bridged dimer VII was proven by its isolation and structural characterisation by single crystal X-ray crystallographical analysis by Lakshman (Scheme 23). The isolated intermediate was subjected to the C–H bond functionalisation conditions with PhI(OAc)2 as the oxidant, giving the mono-acetoxylated

This journal is © The Royal Society of Chemistry 2015

Scheme 21

Acetoxylation of 6-phenylpurine via C–H bond functionalisation.

Scheme 22

C–H oxidation of 6-arylpurine nucleosides.

Scheme 23

Single crystal X-ray structure of intermediate VII.

product in similar yields to that obtained in the presence of precatalyst, Pd(OAc)2. Lakshman and co-workers58 postulated a mechanism involving the formation of a molecule of acetic acid through the protonation of one acetate-bridge in the dinuclear Pd complex, which involved deprotonation of the C6-arylpurine nucleoside (Scheme 24). This dinuclear Pd species then undergoes oxidative addition with PhI(OAc)2, leading to the formation of a pentacoordinate (PdIII) species. Subsequently, reductive elimination of the product

Chem. Commun.

View Article Online

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

Feature Article

ChemComm

Scheme 25 Scheme 24 Plausible mechanism for C–H bond functionalisation of C6-arylpurine.

could take place, however this step is generally promoted by the AcOH produced in the earlier mechanistic step (formation of the dinuclear palladacyclic complex). Direct C–H amination of (hetero)arenes59 has over the years proved to be a useful synthetic strategy for accessing functionalised amino(hetero)arenes. More recently, Chang and coworkers60 developed a Rh-catalysed site-selective monoamination reaction of purine nucleosides using aryl azides as the aminating agent (Scheme 25). A slight modification of the protocol using excess aryl azides resulted in relatively good yields of the diaminated product. The monoamination reaction was proposed to proceed via N1-chelation-assistance within the purinyl system. This assumption was supported by the isolation of intermediate VIII and characterisation by single crystal X-ray crystallographic analysis, revealing the structure of the RhIII complex, where Rh is coordinated to N1. For the reaction to proceed further towards diamination, the authors proposed the involvement of intramolecular hydrogen bonding between the first amino group and one of the nitrogen atoms N1 or N7 within the purinyl ring system. Electrospray ionisation mass spectrometric studies, coupled with density functional calculations, suggest that the N7 atom is involved in the intramolecular hydrogen bonding with the amine while the N1 atom provides chelating assistance for the functionalisation to take place.

Hydrogen-bond assisted C–H bond functionalisation of purines.

the closely-associated acidic character of the C-5 and C-6 protons making the process relatively difficult in terms of controlling the regioselectivity (site-selectivity). A smart choice of metal precursors and reaction conditions could allow access to functionalised pyrimidines. In order to address this issue of selective functionalisation of the pyrimidine structural motifs, Hocek and co-workers61 first reported the direct arylation of 1,3-dimethyluracil in 2009 (Scheme 26). The regioselectivity between the C-5 and C-6 position was differentiated based on a systematic screening of a variety of Pd, Cu and a combination of Pd/Cu catalytic systems. To selectively access the C-5 arylated 1,3-dimethyluracils, it was found that the employment of tri(pentafluorophenyl)phosphine with Pd(OAc)2 resulted in 45 : 1 selectivity towards the C-5 arylation over C-6. A concerted-metallation–deprotonation mechanism was proposed to be instrumental in providing the selectivity observed in the above transformation. Interestingly, the use of Pd/Cu or Cu catalyst systems led to the complete reversal in selectivity with the C-6 position

2.2. C–H bond functionalisation (C5 and C6 selectivity) of pyrimidine nucleosides To date we have seen the applicability of C–H bond activation methodology towards the functionalisation of purine-based nucleosides. By comparison the literature reports on the direct arylation of pyrimidine nucleosides are quite few. One of the challenges for the C–H bond functionalisation of pyrimidine is

Chem. Commun.

Scheme 26

Regioselective arylation of 1,3-dimethyluracil.

This journal is © The Royal Society of Chemistry 2015

View Article Online

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

ChemComm

arylated preferentially over the C-5 position. In a succeeding paper Hocek and co-workers62 further improved the selectivity of the catalytic process for direct arylation and also introduced a direct method via Cu-catalysed arylation of the C-6 position. A more efficient and highly regioselective protocol for direct arylation of 1,3-dimethyluracil was developed by Kim and co-workers63 which made use of PivOH as a proton shuttle.64 Such a system can allow formation of a more electrophilic Pd species capable of bringing about an improvement in the electrophilic palladation process, which in-turn can provide better site-selectivity towards C-5 arylation (Scheme 27). Excellent site-selectivity was observed for the C-5 arylation of 1,3-dimethyluracil. The site-selectivity was explained by the involvement of an electrophilic metalation–deprotonation pathway (EMD), rather than the usual Heck-type carbopalladation pathway65 which leads to epimerisation and subsequent loss in site-selectivity. A complete reversal in site-selectivity was observed when Pd(OAc)2 was replaced by Pd(TFA)2, in the presence of AgOAc with benzene as the solvent, under refluxing conditions. Site-selective direct arylation at the C-6 position of 1,3dimethyluracil was observed, which according to the authors, takes place via a double concerted-metalation–deprotonation mechanism.66–68 To date we have seen examples for the regioselective functionalisation of the C-5 position of uracil. Recently, Chen, Chien and co-workers disclosed a facile and efficient synthetic protocol for the synthesis of 6-aryluracil derivatives under copper-catalysed conditions (Scheme 28).69 The reaction was carried out with copper(I) bromide as the catalyst in DMF and LiOtBu as the base. The authors also carried out an extensive study to understand the mechanistic pathway for the catalytic process. The kinetic isotope effect calculated by performing deuterium isotope studies on the catalytic process was found to be greater than 3.35 suggesting the possible involvement of C-6 position proton cleavage as the rate-limiting step. A slightly modified procedure for the selective C-6 arylation of uracil was put forth by Roy and co-workers70 (Scheme 29) who employed arylboronic acids as the coupling partners rather than aryl iodides employed by Chien69 in the earlier scheme. The protocol however failed to provide the desired 6-arylated product in the case of acetate-protected uridine-ribonucleoside. The authors propose an oxidative Heck type mechanism to be acting in such processes. A unique intramolecular C-6 arylation leading to the formation of a variety of substituted benzopyrimido azepines was disclosed by Kim and co-workers71 via a Pd-catalysed C–H activation reaction. This was achieved by subjecting the Morita–Baylis–Hilman adduct to the intramolecular C-6 arylation conditions using Pd(OAc)2 in DMF at 120 1C (Scheme 30). The mechanism for the catalytic reaction was proposed to go through an 7-exocarbopalladation intermediate followed by epimerisation at the C-5 position and finally reductive elimination of Pd(0) results in the formation of the cyclised product. Wnuk and co-workers72 recently disclosed a ligand-less and milder protocol for the direct arylation of 1-benzyluracil with 4-iodoanisole using Pd(OAc)2 and TBAB and AgCl at 100 1C in a DMF solvent (Scheme 31).

This journal is © The Royal Society of Chemistry 2015

Feature Article

Scheme 27 Direct arylation of 1,3-dimethyluracil and mechanistic considerations.

Scheme 28

Copper-catalysed C-6 arylation of uracil.

Similar to the acetoxylation strategy employed for the functionalisation of purines, Kim and co-workers recently disclosed a highly selective protocol for the acetoxylation of the C-5 position of uracil using Pd(OAc)2 and PhI(OAc)2 (Scheme 32).73 Selective acetoxylation was also observed to take place for protected uridine ribonucleoside in decent yields. The selective nature of the catalytic system was attributed to the presence of an

Chem. Commun.

View Article Online

Feature Article

Selective C-arylation of uracil using arylboronic acids.

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

Scheme 29

Scheme 30

Intramolecular C-6 arylation of uracils.

electrophilic palladium insertion step into the C–H bond of the C-5 position although no evidence was provided for such a proposal. 2.3.

ChemComm

Miscellaneous reactions

Besides the examples discussed above for the direct arylation of purine and pyrimidine analogues,74 several other reactions on these important structural motifs are worth mentioning.

Chem. Commun.

Scheme 31

Direct arylation of 1-benzyluracil.

Scheme 32

Selective C-5 acetoxylation of uracil.

Oxidative homocoupling of (hetero)arenes catalysed75 by transition metals is an atom economical and useful methodology which is commonly applicable towards obtaining biaryls with simple arenes in a regioselective manner under relatively milder conditions than those for cross-coupling reactions. This methodology was recently employed by Kim and co-workers76 for the homocoupling of 1,3-dialkyluracil after discovering that such a product was formed in small amounts as a part of the direct arylation strategy (Scheme 33). The best site-selectivity for homocoupling of the uracil substrate was observed for sterically demanding arenes such as mesitylene; the employment of less sterically hindered arenes such as benzene and xylenes gave rise to more of C-6 arylated products rather than homocoupling. Kim and co-workers76 postulated a PivOH mediated electrophilic-metalation–deprotonation mechanism rather than the usual concerted-metalation–deprotonation mechanism, due to the possible involvement of a uracil–Pd intermediate which is required to obtain better site-selectivity towards the homocoupling product. A highly regioselective dehydrogenative C–H alkenylation of uracil was reported by Georg and co-workers in 2013 leading to an easy access of 5-alkenyluracils (Scheme 34).77 The importance of this protocol is related to the synthesis of molecules exhibiting potent antitumour and antiviral activities and therefore it was also extended towards the alkenylation of 2 0 -deoxyuridine. More recently, Peng and co-workers78 reported a Pd-catalysed oxidative C–H alkenylation of triazole-based nucleosides to afford arylvinyltriazole nucleoside analogues (Scheme 35). Protected triazole

This journal is © The Royal Society of Chemistry 2015

View Article Online

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

ChemComm

Feature Article

Scheme 36

Scheme 33

Oxidative homocoupling of 1,3-dimethyluracil.

Scheme 34

Dehydrogenative C–H alkenylation of uracil.

Scheme 35

Oxidative C–H alkenylation of triazole-based nucleosides.

nucleosides were subjected to Pd-catalysed alkenylation in acetic acid, using AgOAc as the oxidant and PivOH as the additive in air at 130 1C, giving the arylated products in good yields. The mildness of the reaction conditions allowed for large functional group tolerance in the substrate scoping studies. Furthermore, Roy, Majumdar and co-workers79 employed the idea of dehydrogenative C–H activation and have recently reported a novel copper-catalysed intramolecular cyclisation reaction under atmospheric oxygen to provide an easy access to pyrrolopyrimidines (Scheme 36). The authors propose a single electron transfer type mechanism that could be acting in such processes.

This journal is © The Royal Society of Chemistry 2015

Intramolecular dehydrogenative C–H activation.

Pyridines have proved to be important scaffolds that commonly occur in a variety of natural products, pharmaceutical intermediates and useful building blocks for further transformations.80 An easy way to access such synthetically important molecules is the functionalisation of the pyridine-N-oxides via C–H bond functionalisation processes that have been developed by several research groups in the past few years.81 Taking advantage of such a strategy Kianmehr and co-workers82 recently disclosed a highly selective dehydrogenative coupling of pyridine-N-oxides with uracils under Pd-catalysed coupling conditions (Scheme 37). The selectivity was found to be towards the C–H activation of the C-5 position of the uracil moiety. Radical trifluoromethylation of 1,3-dimethyluracil was attempted recently by Hocek and co-workers allowing the synthesis of 5-trifluoromethyluracil under mild conditions using NaSO2CF3 which was further functionalised in the C-6 position via the Pd-catalysed C–H activation protocol (Scheme 38).83 This allowed easy access to a variety of 6-aryl-5-trifluoromethyluracils in albeit poor yields. Although, lower reactivity was observed in such a case it holds a lot of potential if the arylation step that could be addressed further.

Scheme 37

Dehydrogenative coupling of pyridine-N-oxides and uracil.

Scheme 38

C-5 Trifluoromethylation followed by C-6 arylation.

Chem. Commun.

View Article Online

Feature Article

ChemComm

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

3. Conclusion, perspective and future studies It is quite evident from the research that has been going on in the area of purine and pyrimidine C–H bond functionalisation that general synthetic methodologies, developed by a number of leading groups from around the world, are now being tested and applied in challenging organic ring systems. Both purines and pyrimidines present issues as they contain chemofunctionalities that can both aid and hinder effective catalysis. However, through adaption of reaction conditions and embracing mechanistic information, several groups have been able to develop synthetically useful reaction conditions for the siteselective C–H bond functionalisation of purines and pyrimidines. We have seen examples employing Ru, Rh, Ir, Pd and Cu catalysts. Arguably, the most success has been obtained with Pd, but we note that high catalyst loadings are required in all the examples presented above in this perspective. Can more be done here utilising low Pd catalyst loadings? Work by Doucet and co-workers provide confidence that certain direct arylation reactions of heteroaromatics can be conducted at low Pd loadings84 (e.g. 0.1 and 0.01 mol%). There is also clear evidence that Pd nanoparticles are formed in certain purine C–H bond functionalisation reactions, as shown by Fairlamb and co-workers.28 Recent work has shown how polymer-stabilised Pd nanoparticles can be used as viable catalysts for the arylation of 2 0 -deoxyadenosine 1 h, providing the lowest temperature protocol for this system (at 60 1C85). Testing such Pd nanoparticles did not come about by chance, it was through observing that Pd(OAc)2 formed Pd nanoparticles under the working catalytic reaction conditions, which led to their subsequent characterisation, which were found to be similar in size to readily available pre-synthesised polymer-stabilised particles. Moreover, such Pd nanoparticles are catalytically active in other C–H bond functionalisation reactions.86 Within this area it is very tempting to propose reaction mechanisms that mirror simpler heteroaromatic ring systems. However, it is our opinion that the community might consider alternatives. More efforts directed to this mechanistic work would in our opinion help in driving reaction development in this area. Through the studies conducted on adenosine and 2 0 deoxyadenosine28,29,84 we were convinced that it was necessary to employ a carbonate base (Cs2CO3) for effective C–H bond functionalisation under milder reaction conditions. However, we later discovered87 that KOtBu can be used as a base and that Pd(OAc)2 could be substituted for the activated Pd0 precursor complex, Pd2(dm-dba)3dm-dba (dm-dba = 3,5-dimethoxydibenzylidene acetone) (Scheme 39). Interestingly, this carbonate and acetate free catalytic system was found to enable the C–H functionalisation of 2 0 -deoxyadenosine at 80 1C giving the arylated product in 68% yield. More recent developments in this area also relates to the use of unprotected uracils (nucleosides) as coupling partners for the C–H bond activation of simple (hetero)arenes. This was

Chem. Commun.

Scheme 39

Carbonate and acetate-free arylation of 2 0 -deoxyadenosine.

Scheme 40 nucleoside.

C–H bond functionalisation of (hetero)arenes using 5-iodouracil

achieved by Wnuk and co-workers under Pd-catalysed conditions with the coupled products in good to excellent yield, thus addressing the issue of lower reactivity and selectivity of the pyrimidine analogues at the C-5 position (Scheme 40).88 Tolerance of a sugar moiety on the nucleoside is a major advancement compared to the previous protocols. It is through these types of observations that we ought, as a community, be able to expand the scope of purine and pyrimidine C–H bond functionalisation processes. Moreover, lowering catalyst loading, improving catalyst recycling, perhaps through catalyst immobilisation or using continuous flow devices, we can improve the way in which C–H functionalisation reactions are carried out with both purines and pyrimidines. A global aspiration is to be able to functionalise purine and pyrimidine moieties in more complex biomolecular systems, such as DNA/RNA – catalysis may one day allow this aspiration to be realised.

Acknowledgements The authors would like to thank Department of Science and Technology, India, for DST Inspire faculty award (IFA12-CH-22) for A.R.K. We also would like to thank UGC-FRP. We are also indebted to Alexander von Humboldt foundation for providing equipment grant to A.R.K. A.R.K. also would like to thank UGC-SAP for research fellowship for V.G. I.J.S.F. is grateful for funding from the Royal Society, BBSRC, EPRSC and University of York, in addition to previous in-kind support from AstraZeneca and Replizyme Ltd I.J.S.F. also acknowledges the contributions of Dr T. E. Storr, Dr S. de Ornellas and Dr C. G. Baumann (cited in the references).

This journal is © The Royal Society of Chemistry 2015

View Article Online

ChemComm

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

Notes and references 1 (a) L. Ackermann, A. R. Kapdi, S. I. Kozhuskov and H. Potukuchi, in Synthesis via C–H Bond Functionalisation:in Handbook of Green Chemistry Series, ed. C.-J. Li, Wiley-Interscience, New York, 2012, p. 259; (b) V. T. Trepohl and M. Oestreich, in Modern Arylation Methods, ed. L. Ackermann, Wiley-VCH, Weinheim, 2009; (c) G. Lessene and K. S. Feldman, in Modern Arene Chemistry, ed. D. Astruc, Wiley-VCH, Weinheim, 2002. 2 For reviews on C–H bond functionalisations, see: (a) J. F. Hartwig, Chem. Soc. Rev., 2011, 40, 1992; (b) I. A. I. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy and J. F. Hartwig, Chem. Rev., 2010, 110, 890; (c) M. C. Willis, Chem. Rev., 2010, 110, 725; (d) L. Ackermann and H. K. Potukuchi, Org. Biomol. Chem., 2010, 8, 4503; (e) K. Fagnou, Top. Curr. Chem., 2010, 292, 35; ( f ) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147; ( g) A. S. Dudnik and V. Gevorgyan, Angew. Chem., Int. Ed., 2010, 49, 2096; (h) L. Ackermann, R. Vicente and A. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792; (i) M. Miura and T. Satoh, in Modern Arylation Methods, ed. L. Ackermann, Wiley-VCH, Weinheim, 2009; ( j) F. Kakiuchi and T. Kochi, Synthesis, 2008, 3013; (k) J. C. Lewis, R. G. Bergman and J. A. Ellman, Acc. Chem. Res., 2008, 41, 1013; (l ) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174; (m) D. R. Stuart and K. Fagnou, Aldrichimica Acta, 2007, 40, 35; (n) I. V. Seregin and V. Gevorgyan, Chem. Soc. Rev., 2007, 36, 1173; (o) T. Satoh and M. Miura, Chem. Lett., 2007, 36, 200; (p) I. J. S. Fairlamb, Chem. Soc. Rev., 2007, 36, 1036; (q) R. G. Bergman, Nature, 2007, 446, 391; (r) K. Godula and D. Sames, Science, 2006, 312, 67; (s) G. Dyker, Angew. Chem., Int. Ed., 1999, 38, 1698; (t) B. M. Trost, Science, 1991, 254, 1471. 3 For more recent advances in C–H bond functionalisations see: (a) R. H. Crabtree, Chem. Rev., 2010, 110, 575; (b) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem. Rev., 2011, 111, 1293; (c) L. Ackermann, Chem. Rev., 2011, 111, 1315; (d) G. Song, F. Wang and X. Li, Chem. Soc. Rev., ´mez-Gallego and M. A. Sierra, Chem. Rev., 2012, 41, 3651; (e) M. Go 2011, 111, 4857; ( f ) H. Li, B.-J. Li and Z.-J. Shi, Catal. Sci. Technol., 2011, 1, 191. 4 Some recent reviews of C–H bond activation by organometallic complexes: (a) A. Sen, Acc. Chem. Res., 1998, 31, 550; (b) Y. Guari, S. Sabo-Etiennne and B. Chaudret, Eur. J. Inorg. Chem., 1999, 1047; (c) W. D. Jones, Science, 2000, 287, 1942; (d) R. H. Crabtree, J. Chem. Soc., Dalton Trans., 2001, 2437; (e) F. Kakiuchi and S. Murai, Acc. Chem. Res., 2002, 35, 826; ( f ) V. Ritleng, C. Sirlin and M. Pfeffer, Chem. Rev., 2002, 102, 1731. 5 (a) A. S. Goldman and K. I. Goldberg, Activation and Functionalisation of C–H bonds, ACS Symposium Series, 2004, vol. 885; (b) A. R. Kapdi, in Organometallic Aspects of C–H bond activation/functionalisation: Specialist Periodical Reports-Organometallic Chemistry, ed. I. J. S. Fairlamb, Organomet. Chem., RSC, 2012, vol. 38, p. 47; (c) A. R. Kapdi, Dalton Trans., 2014, 43, 3021. 6 (a) Metal-Catalyzed Cross-Coupling Reactions, ed. A. de Meijere and F. Diederich, 2nd edn, Wiley-VCH Verlag GmbH & Co, KGaA, 2004, vol. 2; (b) Metal-Catalyzed Cross-Coupling Reactions, ed. A. de Meijere and F. Diederich, Wiley-VC CH Verlag GmbH & Co; KGaA, 2nd edn, 2004, vol. 1; (c) Metal-catalyzed Cross-Coupling Reactions, ed. F. Diederich and P. J. Stang, Wiley-VCH, Weinhein, Germany, 1998; (d) Cross-Coupling and Heck-Type Reactions, ed. G. Molander, C. Wolfe and M. Larhed, Science of Synthesis, Thieme Chemistry, Workbench edn, 2013, vol. 1–3. 7 For application of C–H bond functionalisation to complex organic synthesis see: (a) J. Wencel-Delord and F. Glorius, Nat. Chem., 2013, 5, 369; (b) M. C. White, Synlett, 2012, 2746; (c) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew. Chem., Int. Ed., 2012, 51, 8690; (d) H. M. L. Davies, J. Du Bois and J.-Q. Yu, Chem. Soc. Rev., 2011, 40, 1855; (e) W. R. Gutekunst and P. S. Baran, Chem. Soc. Rev., 2011, 40, 1976; ( f ) L. McMurray, F. O’Hara and M. J. Gaunt, Chem. Soc. Rev., 2011, 40, 1885; ( g) D. Sames, C–H Bond Functionalisation in Complex Organic Synthesis, in Activation and Functionalisation of C–H Bonds, ed. K. I. Goldberg and A. S. Goldman, ACS Symposium Series 885, American Chemical Society, Washington, DC, 2004. 8 (a) R. A. Sheldon, I. Arends and U. Hanefeld, Green Chemistry and Catalysis, Wiley-VCH, Weinheim, 2007; (b) P. Tundo and P. T. Anastas, Green Chemistry, Oxford University Press, Oxford, 2000.

This journal is © The Royal Society of Chemistry 2015

Feature Article 9 (a) S. Y. Tang, R. A. Bourne, R. L. Smith and M. Poliakoff, Green Chem., 2008, 10, 268; (b) S. L. Y. Tang, R. L. Smith and M. Poliakoff, Green Chem., 2005, 7, 761; (c) R. A. Sheldon, Green Chem., 2007, 9, 1273. 10 (a) C. Simons, Nucleoside Mimetics: The Chemistry and Biological Properties, CRC Press, London, 2000; (b) M. G. Blackburn, M. Gait, D. Loakes and D. M. Williams, Nucleic Acids in Chemistry and Biology, RSC Publishing, London, 3 edn, 2006. 11 D. L. Nelson and M. M. Cox, Nucleotides and Nucleic Acid: Lehninger Principles of Biochemistry, W. H. Freeman and Company, New York, 2012, ch. 8. 12 (a) D. M. Huryn and M. Okabe, Chem. Rev., 1992, 92, 1745; (b) S. Knapp, Chem. Rev., 1995, 95, 1859; (c) L. R. Jordheim, D. Durantel, F. Zoulim and C. Dumontet, Nat. Rev. Drug Discovery, 2013, 12, 447; (d) D. R. Bobeck, R. F. Schinazi and S. J. Coats, Antiviral Ther., 2010, 15, 935; (e) E. Ichikawa and K. Kato, Curr. Med. Chem., 2001, 8, 385. 13 (a) H. Wojtowicz-Rajchel and H. Koroniak, J. Fluorine Chem., 2012, 135, 225; (b) V. Suryanarayana.Ch, V. Anuradha, G. Jayalakshmi and G. Sandhya Rani, J. Nat. Sci. Res., 2013, 3, 123; (c) V. Vongsutilers, J. R. Daft, K. H. Shaughnessy and P. M. Gannett, Molecules, 2009, 14, 3339; (d) G. Herve, G. Sartori, G. Enderlin, G. Mackennzie and C. Len, RSC Adv., 2014, 4, 18558; (e) For a comprehensive review on this topic see: I. J. S. Fairlamb, S. De Ornellas, T. J. Williams and C. G. Baumann, in Catalytic C–H/C–X Bond Functionalisation of Nucleosides, Nucleotides, Nucleic Acids, Amino Acids, Peptides and Proteins. C–H C–C bond functionalisation: Transition Metal Mediation, ed. S. Ribas, RSC Catalysis Series, Royal Society of Chemistry, United Kingdom, 2013, vol. 11, pp. 409–447. 14 (a) P. Wigerinck, L. Kerremans, P. Claes, R. Snoeck, P. Maudgal, E. De Clercq and P. Herdewijn, J. Med. Chem., 1993, 36, 538; (b) E. Mayer, L. Valis, R. Huber, N. Amann and H. A. Wagenknecht, Synthesis, 2003, 2335. 15 (a) S. Gallagher-Duval, G. Herve, G. Sartori, G. Enderlin and C. Len, New J. Chem., 2013, 37, 1989; (b) N. Fresneau, M. A. Hiebel, L. A. Agrofoglio and S. Berteina-Raboin, Molecules, 2012, 17, 14409; (c) M. Ahmadian, D. A. Klewer and D. E. Bergstrom, Current Protocols in Nucleic Acid Chem., 2000, ch. 1.1.1–1.1.18; (d) G. Sartori, G. Enderlin, G. Herve and C. Len, Synthesis, 2012, 767; (e) G. Sartori, G. Herve, G. Enderlin and C. Len, Synthesis, 2013, 330. 16 E. De Clercq, J. Descamps, P. de Somer, P. J. Barr, A. S. Jones and R. T. Walker, Proc. Natl. Acad. Sci. U. S. A., 1979, 76, 2947. 17 C. McGuigan, H. Barucki, S. Blewett, A. Carangio, J. T. Erichsen, G. Andrei, R. Snoeck, E. de Clercq and J. Balzarini, J. Med. Chem., 2000, 43, 4993. 18 M. H. Lyttle, T. A. Walton, D. J. Dick, T. G. Carter, J. H. Beckman and R. M. Cook, Bioconjugate Chem., 2002, 13, 1146. 19 N. J. Greco and Y. Tor, J. Am. Chem. Soc., 2005, 127, 1078. 20 L. A. Agrofoglio, I. Gillaizeau and Y. Saito, Chem. Rev., 2003, 103, 1875. 21 K. L. Tan, R. G. Bergman and J. A. Ellman, J. Am. Chem. Soc., 2002, 124, 13964. 22 For reviews on Rhodium-catalysed C–H activation see: D. A. Colby, R. G. Bergman and J. A. Ellman, Chem. Rev., 2010, 110, 624. 23 I. Cerna, R. Pohl, B. Klepetarova and M. Hocek, Org. Lett., 2006, 8, 5389. 24 I. Cerna, R. Pohl, B. Klepetarova and M. Hocek, J. Org. Chem., 2008, 73, 9048. 25 M. Legraverend and D. S. Grierson, Bioorg. Med. Chem., 2006, 14, 3987. 26 N. Kato, T. Sakata, G. Breton, K. G. Le Roch, A. Nagle, C. Ersen, B. Bursulaya, K. Henson, J. Johnson, K. A. Kumar, F. Marr, D. Mason, C. McNamara, D. Plouffe, V. Ramachandran, M. Spooner, T. Tuntland, Y. Zhou, E. C. Peters, A. Chatterjee, P. G. Schultz, G. E. Ward, N. Gray, E. Harper and E. A. Winzeler, Nat. Chem. Biol., 2008, 4, 347. 27 G. R. Rosania, Y.-T. Chang, O. Perez, D. Sutherlin, H. L. Dong, D. J. Lockhart and P. G. Schultz, Nat. Biotechnol., 2000, 18, 304. 28 S. Sahnoun, S. Messaoudi, J. F. Peyrat, J.-D. Brion and M. Alami, Tetrahedron Lett., 2008, 49, 7279. 29 Y. Mori and M. Seki, J. Org. Chem., 2003, 68, 1571. 30 I. Cerna, R. Pohl and M. Hocek, Chem. Commun., 2007, 4729.

Chem. Commun.

View Article Online

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

Feature Article 31 J. L. Sessler, C. M. Lawrence and J. Jayawickramarajah, Chem. Soc. Rev., 2007, 36, 314. 32 (a) E. Mayer, L. Valis, R. Huber, N. Amann and H.-A. Wagenknecht, Synthesis, 2003, 2335; (b) L. Valis and H.-A. Wagenknecht, Synlett, 2005, 2281; (c) L. Valis, E. Mayer-Enthart and H.-A. Wagenknecht, Bioorg. Med. Chem. Lett., 2006, 16, 3184. 33 T. E. Storr, A. G. Firth, K. Wilson, K. Darley, C. G. Baumann and I. J. S. Fairlamb, Tetrahedron, 2008, 64, 6125. 34 T. E. Storr, C. G. Baumann, R. J. Thatcher, S. De Ornellas, A. C. Whitwood and I. J. S. Fairlamb, J. Org. Chem., 2009, 74, 5810. 35 For the application of Electro-spray Ionisation Mass Spectrometry as tool for characterising intermediates see: V. Katta, S. K. Chowdhury and B. T. Chait, J. Am. Chem. Soc., 1990, 112, 5348. 36 I. Cerna, R. Pohl, B. Klepetarova and M. Hocek, J. Org. Chem., 2010, 75, 2302. 37 G. Meng, H. Y. Niu, G. R. Qu, J. S. Fossey, J. P. Li and H. M. Ming, Chem. Commun., 2012, 48, 9601. 38 For more examples of intramolecular oxidative couplings see: (a) D. G. Pintori and M. F. Greaney, J. Am. Chem. Soc., 2011, 133, 1209; (b) J. K. Laha, K. P. Jethava and N. Dayal, J. Org. Chem., 2014, 79, 8010. 39 T. E. Storr, J. A. Strohmeier, C. G. Baumann and I. J. S. Fairlamb, Chem. Commun., 2010, 46, 6470. 40 For a review on C–H borylation, see: (a) T. Ishiyama and N. Miyaura, J. Organomet. Chem., 2003, 680, 3. Recent examples: (b) T. Ishiyama, J. Takagi, K. Ishida, N. Miyaura, N. R. Anastasi and J. F. Hartwig, J. Am. Chem. Soc., 2002, 124, 390; (c) J. Y. Cho, M. K. Tse, D. Holmes, R. E. Maleczka and M. R. Smith III, Science, 2002, 295, 305; (d) T. Ishiyama, J. Takagi, J. F. Hartwig and N. Miyaura, Angew. Chem., Int. Ed., 2002, 41, 3056; (e) T. Ishiyama, Y. Nobuta, J. F. Hartwig and N. Miyaura, Chem. Commun., 2003, 2924; ( f ) T. M. Boller, J. M. Murphy, M. Hapke, T. Ishiyama, N. Miyaura and J. F. Hartwig, J. Am. Chem. Soc., 2005, 127, 14263; ( g) G. A. Chotana, M. A. Rak and M. R. Smith III, J. Am. Chem. Soc., 2005, 127, 10539; (h) S. Paul, G. A. Chotana, D. Holmes, R. C. Reichle, R. E. Maleczka and M. R. Smith III, J. Am. Chem. Soc., 2006, 128, 15552. 41 M. Klecka, R. Pohl, B. Klepetarova and M. Hocek, Org. Biomol. Chem., 2009, 7, 866. 42 (a) K. L. Billingsley and S. L. Buchwald, Angew. Chem., Int. Ed., 2008, 47, 4695; (b) A. E. Smith, K. M. Clapham, A. S. Batsanov, M. R. Bryce and B. Tarbit, Eur. J. Org. Chem., 2008, 1458. 43 C–H activation of alkanes and cycloalkanes see: (a) F. Yonehara, Y. Kido, S. Morita and M. Yamaguchi, J. Am. Chem. Soc., 2001, 123, 11310; (b) D. Astuc, Organometal. Chem. & Catal., 2007, p. 409; (c) Y. Zhang and C. J. Li, Eur. J. Org. Chem., 2007, 4654. 44 R. H. Crabtree, in Organometallic Chemistry of Alkane Activation: Alkanes and Cycloalkanes, ed. S. Patai and Z. Rapoport, Wiley Interscience, New York, 2006, ch. 14. 45 (a) I. Kavai, L. H. Mead, J. Drobniak and S. F. Zakrzewski, J. Med. Chem., 1975, 18, 3272; (b) L. C. W. Chang, R. F. Spanjersberg, J. K. Frijtag Drabbe Kunzel, T. Mulder’Krieger and A. P. Jzerman, J. Med. Chem., 2006, 49, 2861. 46 R. Xia, H.-Y. Niu, G.-R. Qu and H.-M. Guo, Org. Lett., 2012, 14, 5546. 47 For reviews on transition metal-free reactions see: (a) C.-J. Sun and Z.-J. Shi, Chem. Rev., 2014, 114, 9219; (b) A. Bhunia, S. R. Yetra and A. T. Bittu, Chem. Soc. Rev., 2012, 41, 3140. 48 M. Klecka, R. Pohl, J. Cejka and M. Hocek, Org. Biomol. Chem., 2013, 11, 5189. 49 For more examples of Sulfenylation via C–H bond activation see: (a) Ch. Dai, Z. Xu, F. Huang, Z. Yu and Y.-F. Gao, J. Org. Chem., 2012, 77, 4414; (b) G. L. Regina, V. Gatti, V. Famiglini, F. Piscitelli and R. Silvestri, ACS Comb. Sci., 2012, 14, 258; (c) L. H. Zou, J. Reball, J. Mottweiler and C. Bolm, Chem. Commun., 2012, 48, 11307; (d) S. Ranjit, R. Lee, D. Heryadi, C. Shen, J. Wu, P. Zhang, K.-W. Huang and X. Liu, J. Org. Chem., 2011, 76, 8999; (e) X.-L. Fang, R.-Y. Tang, P. Zhong and J.-H. Li, Synthesis, 2009, 4183. 50 Sulfides are known to undergo Liebeskind–Srogl coupling reaction: ´ and C. O. Kappe, Angew. Chem., Int. Ed., 2009, see: (a) H. Prokopcova 48, 2276; (b) L. S. Liebeskind and J. Srogl, J. Am. Chem. Soc., 2000, 122, 11260; (c) L. S. Liebeskind and J. Srogl, Org. Lett., 2002, 4, 979. 51 For examples of direct amination of arenes via C–H bond functionalisation see: (a) X.-Y. Liu, P. Gao, Y.-W. Shen and Y.-M. Liang, Org. Lett.,

Chem. Commun.

ChemComm

52 53 54 55 56

57 58 59

60 61 62 63 64 65

66 67

68 69 70

2011, 13, 4196; (b) A. John and K. Nicolas, Organometallics, 2012, 31, 7914. N. Sabat, M. Klecka, L. Slaventinska, B. Klepetarova and M. Hocek, RSC Adv., 2014, 4, 62140. D. Kim, H. Jun, H. Lee, S. S. Hong and S. Hong, Org. Lett., 2010, 12, 1212. H.-M. Guo, L.-L. Jiang, H.-Y. Niu, W.-H. Rao, L. Liang, R.-Z. Mao, D.-Y. Li and G.-R. Qu, Org. Lett., 2011, 13, 2008. M. K. Lakshman, A. C. Deb, R. R. Chamala, P. Pradhan and R. Pratap, Angew. Chem., Int. Ed., 2011, 50, 11400. For reviews on direct arylation by Ruthenium-catalysed C–H activation see: (a) C. Fischmeister and H. Doucet, Green Chem., 2011, 13, 741; (b) P. B. Arockiam, C. Bruneau and P. H. Dixneuf, Chem. Rev., 2012, 112, 5879; (c) L. Ackermann, Acc. Chem. Res., 2014, 47, 281. H.-M. Guo, W.-H. Rao, H.-Y. Niu, L.-L. Jiang, G. Meng, J.-J. Jin, X.-N. Yang and G. R. Qu, Chem. Commun., 2011, 47, 5608. R. R. Chamala, D. Parish, P. Pradhan and M. K. Lakshman, J. Org. Chem., 2013, 78, 7423. For examples of direct amination of arenes via C–H bond functionalisation see: (a) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2011, 40, 5068; (b) Q. Wang and S. L. Schreiber, Org. Lett., 2009, 11, 5178; (c) T. Kawano, K. Hirano, T. Satoh and M. Miura, J. Am. Chem. Soc., 2010, 132, 6900; (d) B. Xiao, T. J. Gong, J. Xu, Z. J. Liu and L. Liu, J. Am. Chem. Soc., 2011, 133, 1466; (e) W. C. P. Tsang, N. Zheng and S. L. Buchwald, J. Am. Chem. Soc., 2005, 127, 14560; ( f ) Y. Lian, J. R. Hummel, R. G. Bergman and J. A. Ellman, J. Am. Chem. Soc., 2013, 135, 12584. H. J. Kim, M. J. Ajitha, Y. Lee, J. Ryu, J. Kim, Y. Lee, Y. Jung and S. Chang, J. Am. Chem. Soc., 2014, 136, 1132. M. Cernova, R. Pohl and M. Hocek, Eur. J. Org. Chem., 2009, 3698. M. Cernova, I. Cerna, R. Pohl and M. Hocek, J. Org. Chem., 2011, 76, 5309. K. H. Kim, H. S. Lee and J. N. Kim, Tetrahedron Lett., 2011, 52, 6228. For seminal work on the use of PivOH as proton shuttle in C–H bond activation processes see: M. Lafrance and K. Fagnou, J. Am. Chem. Soc., 2006, 128, 16496. For examples of Heck-Type carbopalladation mechanism in C–H activation see: (a) C. C. Hughes and D. Trauner, Angew. Chem., Int. Ed., 2002, 41, 1569; (b) E. J. Hennessy and S. L. Buchwald, J. Am. Chem. Soc., 2003, 125, 12084; (c) B. Glover, K. A. Harvey, B. Liu, M. J. Sharp and M. F. Tymoschenko, Org. Lett., 2003, 5, 301; (d) C. H. Park, V. Ryabova, I. V. Seregin, A. W. Sromek and V. Gevorgyan, Org. Lett., 2004, 6, 1159; (e) B. S. Lane, M. A. Brown and D. Sames, J. Am. Chem. Soc., 2005, 127, 8050; ( f ) M. Toyota, A. Ilangovan, R. Okamoto, T. Masaki, M. Arakawa and M. Ihara, Org. Lett., 2002, 4, 4293; (g) L. Ackermann and R. Born, in The MizorokiHeck Reaction, ed. M. Oestreich, Wiley, Chichester, 2009, p. 383; (h) V. T. Trepohl and M. Oestreich, in Modern Arylation Methods, ed. L. Ackermann, Wiley-VCH, Weinheim, 2009, p. 221; (i) J.-P. Ebran, A. L. Hansen, T. M. Gogsig and T. Skrydstrup, J. Am. Chem. Soc., 2007, 129, 6931; ( j) A. L. Hansen, J.-P. Ebran, M. Ahlquist, P.-O. Norrby and T. Skrydstrup, Angew. Chem., 2006, 118, 3427 (Angew. Chem., Int. Ed., 2006, 45, 3349); (k) D. E. Ames and D. Bull, Tetrahedron, 1982, 38, 383; (l ) D. E. Ames and A. Opalko, Synthesis, 1983, 234; (m) D. E. Ames and A. Opalko, Tetrahedron, 1984, 40, 1919. For an excellent report on study carried out in support of CMD mechanism in various (hetero)arenes see: S. I. Gorelsky, D. Lapointe and K. Fagnou, J. Am. Chem. Soc., 2008, 130, 10848. For previous proposals of a CMD mechanism, see (a) V. I. Sokolov, L. L. Troitskaya and O. A. Reutov, J. Organomet. Chem., 1979, 182, 537; (b) D. L. Davies, S. M. A. Donald and S. A. Macgregor, J. Am. Chem. Soc., 2005, 127, 13754; (c) W. J. Tenn III, K. J. H. Young, G. Bhalla, J. Oxgaard, W. A. Goddard III and R. A. Periana, J. Am. Chem. Soc., 2005, 127, 14172; (d) Y. Feng, M. Lail, K. A. Barakat, T. R. Cundari, T. B. Gunnoe and J. L. Petersen, J. Am. Chem. Soc., 2005, 127, 14174 for a review, see ; (e) A. D. Ryabov, Chem. Rev., 1990, 90, 403. J. Oxgaard, W. J. Tenn, III, R. J. Nielsen, R. A. Periana and W. A. Goddard, III, Organometallics, 2007, 26, 1565. C. Cheng, Y. C. Shih, H. T. Chen and T. C. Chien, Tetrahedron, 2013, 69, 1387. B. Mondal, S. Hazra and B. Roy, Tetrahedron Lett., 2014, 55, 1077.

This journal is © The Royal Society of Chemistry 2015

View Article Online

Published on 08 June 2015. Downloaded by UNIVERSITY OF NEW ORLEANS on 08/06/2015 14:04:22.

ChemComm 71 H. S. Lee, K. H. Kim, S. H. Kim and J. N. Kim, Tetrahedron Lett., 2012, 53, 497. 72 Y. Liang, J. Gloudeman and S. F. Wnuk, J. Org. Chem., 2014, 79, 4094. 73 H. S. Lee, S. H. Kim and J. N. Kim, Bull. Korean Chem. Soc., 2010, 31, 283. 74 For more examples of C–H bond functionalisation of purines and pyrimidines see: (a) B. Vankova, V. Krchnak, M. Soural and J. Hlavac, ACS Comb. Sci., 2011, 13, 496; (b) D. Brackemeyer, A. Herve, C. Schulte, M. C. Jahnke and F. E. Hahn, J. Am. Chem. Soc., 2014, 136, 7841; (c) A. B. Pawar and S. Chang, Org. Lett., 2015, 17, 660; (d) I. Sokolovs, D. Lubriks and E. Suna, J. Am. Chem. Soc., 2014, 136, 6920. 75 For pioneering work on the oxidative homocoupling of arenes via C–H bond activation see: (a) I. Moritani and Y. Fujiwara, Tetrahedron Lett., 1967, 8, 1119; (b) Y. Fujiwara, I. Moritani, S. Danno, R. Asano and S. Teranishi, J. Am. Chem. Soc., 1969, 91, 7166; (c) C. Jia, T. Kitamura and Y. Fujiwara, Acc. Chem. Res., 2001, 34, 633. 76 K. H. Kim, H. S. Lee, S. H. Kim and J. N. Kim, Tetrahedron Lett., 2011, 52, 6228. 77 Y. Y. Yu and G. I. Georg, Chem. Commun., 2013, 49, 3694. 78 J. Tang, M. Cong, Y. Xia, G. Quelever, Y. Fan, F. Qu and L. Peng, Org. Biomol. Chem., 2015, 13, 110.

This journal is © The Royal Society of Chemistry 2015

Feature Article 79 B. Roy, S. Hazra, B. Mondal and K. C. Majumdar, Eur. J. Org. Chem., 2013, 4570. 80 M. C. Bagley, C. Glover and E. A. Merritt, Synlett, 2007, 2459. 81 For examples of direct arylation of pyridine-N-oxides see: (a) L. C. Campeau, M. Bertrand-Laperle, J. P. Leclerc, E. Vilemure, S. Gorelsky and K. Fagnou, J. Am. Chem. Soc., 2008, 130, 3266; (b) L. C. Campeau, D. D. J. Schipper and K. Fagnou, J. Am. Chem. Soc., 2008, 130, 3276. 82 E. Kianmehr, M. Razeefard, M. R. Khalkhali and K. M. Khan, RSC Adv., 2014, 4, 13764. 83 M. Cernova, R. Pohl, B. Klepatarova and M. Hocek, Heterocycles, 2014, 89, 1159. 84 H. Y. Fu, L. Chen and H. Doucet, J. Org. Chem., 2012, 77, 4473. 85 C. G. Baumann, S. De Ornellas, J. P. Reeds, T. E. Storr, T. J. Williams and I. J. S. Fairlamb, Tetrahedron, 2014, 70, 6174. 86 (a) T. J. Williams, A. J. Reay, A. C. Whitwood and I. J. S. Fairlamb, Chem. Commun., 2014, 50, 3052; (b) D.-T. D. Tang, K. Collins and F. Glorius, J. Am. Chem. Soc., 2013, 135, 7450. 87 T. E. Storr, A direct arylation approach to highly fluorescent C8-modified purine nucleosides, PhD thesis, University of York, 2010. 88 Y. Liang, J. Gloudeman and S. F. Wnuk, J. Org. Chem., 2014, 79, 4094.

Chem. Commun.