Achieving Sustainability in the Assembly of Modified Nucleosides Using Green Solvents

Abstract

Chemical modifications of nucleosides have been a topic of special interest for researchers, given the plethora of applications these structural motifs have been able to demonstrate. For decades, such modifications have been performed in conventional volatile organic solvents that have severe environmental implications. A recent trend suggests a shift in the strategy, with many researchers using sustainable and green solvents such as ionic liquids (ILs), H₂O, deep eutectic solvents (DES), and 2-MeTHF for performing key transformations on the nucleoside’s structural motif. This review critically analyzes examples of nucleoside functionalization carried out in different sustainable solvents and also helps to assess the feasibility of such solvent choices for further applications.

Keywords

Nucleosides - Sustainable solvents - Green solvents - Chemical functionalization - Deep eutectic solvents - Ionic liquids - Suzuki–Miyaura cross-coupling - Amination

Significance

Nucleosides/nucleotides have become synonymous with a wide variety of antiviral and anticancer agents as well as vaccines, bringing sustainability in the synthetic processes in terms of the replacement of harmful volatile organic solvents with the environmentally benign sustainable solvents. This review comprehensively describes all such synthetic strategies for chemists in the academia and industry to achieve long-term benefits.

1

Introduction

The past decade has seen an upsurge in the infections caused by viruses (COVID-19, influenza, dengue) and bacteria, while cancer-related ailments have also risen exponentially [1], [2], [3]. The scientific community has been constantly on the lookout for more potent drug candidates that can help tackle a pandemic-like situation that had arisen a few years back [4]. A class of molecules that has emerged as a savior during the COVID-19 pandemic and will certainly define the treatment regimen for future situations is the chemically modified nucleosides (nucleotides) [5], [6], [7]. The introduction of mRNA vaccines during the pandemic proved to be a revolutionary scientific breakthrough, saving millions of lives and leading to the eventual recognition of its future potential with a Nobel Prize awarded to Kariko and Weissman for the application of base-modified nucleosides in mRNA [8], [9]. Similar is the story with a growing number of broad-spectrum antiviral agents such as remdesivir, molnupiravir, favipiravir, and so on that were widely applied to contain the rapidly spreading COVID-19 pandemic [10], [11], [12], [13]. After the pandemic, nucleosides/nucleotide-based treatments have become commonplace as the first line of defense against viral infections, and this field continues to grow at a fast pace.

With the growing requirement of nucleoside/nucleotide structural motifs for building the next level of ammunitions for tackling viruses or cancer, the development of sustainable synthetic methodologies for the construction of these molecules is necessary. Several reviews have recently been published discussing the various C–C, C–O, C–N, or C–X bond-forming technologies for the modification of nucleosides with most protocols being performed in volatile organic solvents such as DMF, CH₃CN, THF, etc [14], [15], [16], [17], [18], [19]. This trend has existed for many years, but the environmental impact of these solvents is far-reaching, and they not only pose a serious threat to the atmosphere but also contaminate water bodies, resulting in severe ecological impact [20]. Before the situation turns into a catastrophe, a definite push to promote a sustainable approach to the synthesis of nucleosides/nucleotides needs to be undertaken.

The use of sustainable or green solvents is one of the key principles of green chemistry as they can provide an alternative to the menace of volatile organic solvents. A large number of organic synthetic transformations over the years have been performed effectively in sustainable solvents such as H₂O, ionic liquids (ILs), deep eutectic solvents (DES), 2-MeTHF, glycerol, polyethylene glycol, and many more [21], [22], [23], [24]. Reviews focusing on each of these solvents have been published especially for general organic substrates rather than a very specific structural motif such as the nucleosides/nucleotides [25], [26], [27], [28], [29], [30], [31], [32]. The higher polarity, low vapor pressure, possible recyclable ability, and lower toxicity are the key contributors to the usage of sustainable solvents as a possible replacement for conventional organic solvents, with most of the criteria fitting well for applying and achieving sustainability in the nucleoside/nucleotide modification.

There are reports in the literature involving the use of some of these sustainable solvents in combination with conventional organic solvents, with many of them already covered in the previously published reviews [33], [34], [35], [36]. In this review, the selection of solvents is based on their compatibility with the principles of green chemistry, which include atom economy, nontoxic degradability, minimized environmental impact, and, in certain instances, natural sourcing. These solvents promoted sustainable, efficient, and eco-friendly processes without strict adherence to specific “green” criteria. This review will highlight literature examples involving the modification of nucleosides/nucleotides in sustainable solvents such as ILs, H₂O, DES, and 2-MeTHF. Herein, a critical analysis of the literature offering the usefulness of the derived protocol and wherever necessary provides pointers to improve the conditions to achieve sustainability.

2

Ionic Liquids

ILs are essentially defined as organic salts that are liquids under ambient conditions, preferably in the temperature range of 25–100 °C [37]. ILs have come a long way since the first reported ionic liquid [EtNH₃][NO₃] by Walden [38] in 1914 that had a melting point of just 12 °C [39]. The characteristic properties that make ILs so attractive are their highly polar nature providing the possibility of dissolution of a large variety of substrates as salts, having negligible vapor pressure and high boiling point which can be beneficial for performing reactions at high temperatures. ILs are also known to exhibit unique chemical and physical properties, such as nonvolatility, nonflammability, nonmiscibility with nonpolar solvents, and reasonable thermal and chemical stability [40], [41]. Additionally, ILs are more sustainable for scale-up applications due to their recyclability, simple product isolation, catalyst immobilization, and improved reaction selectivity [42], [43]. To this date, these have been explored extensively as solvents in numerous reactions such as esterification reactions, [44], [45], [46] cleavages of ethers, [47] aldol condensation, [48] protection of carbonyls, [49], [50], [51], [52] Koch carbonylation, [53] polymerization, [54] hydrogenation, regioselective alkylation, and Friedel-Crafts reactions, [55], [56], [57], [58] dimerization, [59], [60] Diels-Alder reactions, [61], [62] Mannich reaction, [63], [64] oximation and oxidation, [65], [66], [67] Heck reaction, [68] Knoevenagel reaction, [69], [70], [71], [72] Henry reactions, [73] heterocyclic synthesis, [74], [75] cross-coupling reactions, and some enzymatic reactions. Most of these processes have been performed on general organic substrates, and only at the beginning of the 20^th century, researchers started employing ILs for the modification of nucleosides. Initially, ILs such as 1-butyl-3-methyl imidazolium tetrafluoroborate ([BMIM]BF₄), 1-Methyl-3-octyl-imidazolium-tetrafluoroborate ([OMI]BF₄), and 1-Butyl-3-methylimidazolium hexafluorophosphate ([BMIM]PF₆) were tested as additives in organic solvents for promoting synthetic nucleoside chemistry. During this period, several reports described the enhancement in the reaction rate and selectivity due to the addition of ILs [76], [77], [78]. Encouraged by these findings, researchers subsequently started employing ILs as the sole solvent for the nucleoside modification processes. In this section, we summarize the published literature over the last 20 years addressing the importance and utility of ILs in nucleoside chemistry. This section has been divided into two parts, first on the modification of the sugar moiety of nucleosides and the next on the modification or functionalization of the base moiety.

2.1

Modification of Sugar Moiety

The past decade has seen an upsurge in the number of nucleosides and their modified analogues that have been widely explored as antiviral and anticancer drugs [79], [80]. A typical nucleoside structural motif (bearing different base moieties linked to either ribose or 2′-deoxyribose sugar) bearing hydroxyl (sugar part) and amino groups (base part) that have similar chemical reactivities are needed to be selectively protected as a part of the functionalization strategies [81], [82]. The selective protection/ deprotection of the hydroxyl group over the amino group is an important requirement in nucleoside chemistry and the employment of ILs as solvents for promoting these reactions has helped this issue effectively. Some of these protocols have been described in this section depending on the type of protecting group to be installed.

2.1.1

Acetylation

The most commonly employed protecting group for the sugar hydroxyl groups is the “acetyl” functionality, and these acetylated nucleosides have found common applicability as building blocks for the various synthetic nucleosides [83], [84], [85]. The usefulness of acetylated nucleoside analogues stems from the fact that the nonacetylated bioactive nucleosides are known to exhibit susceptibility to the cleavage of the glycosyl bond (C–N) in the presence of nucleoside phosphorylase leading to the reduction of their biological activity [86]. In such cases, the acetyl derivatives (sugar hydroxyl protection) of these analogues have proven to be more efficient and are known to resist such transformations [87], [88]. For example, the improved anticancer activity exhibited by 3′-O-retinoyl-FUdR compared with the parent drug [89] further highlights the importance of acetyl functionality (sugar hydroxyl protection) and the development of sustainable synthetic protocols for their introduction into the nucleoside structural motif is of great interest to synthetic chemists.

Scheme 1 Acetylation of 2′-deoxyribonucleosides in MOEMIM.OMs.

ILs certainly have played a useful role in achieving this goal and some of these methodologies have been described below. One of the first examples of the use of ILs as a greener alternative to conventional organic solvents in nucleoside chemistry for the execution of the protection strategy (of sugar hydroxyls) was reported in 2003 by Salunkhe and co-workers [84] for the acetylation of nucleosides. An extensive array of ILs such as 1-butyl-3-methyl imidazolium chloride (BMIM.Cl), BMIM.BF₄, BMIM.PF₆, N-butyl pyridinium methanesulfonate (BPy.OMs), 1-ethyl-3-methyl imidazolium methanesulfonate (EMIM.OMs), 1-methoxyethyl-3-methyl imidazolium methanesulfonate (MOEMIM.OMs) were employed to first study the solubilities of different nucleosides. After comparing the solubilities of protected and unprotected 2′-deoxynucleosides with the above-mentioned ILs with different organic solvents like pyridine and N,N-dimethylformamide (DMF), they chose MOEMIM.OMs as the solvent of choice for conducting further studies of acetyl protection of sugar hydroxyls. The authors further demonstrated the combination of (CH₃CO)₂O and (CH₃)₂COCl as acetylating agents, 1-methylimidazole (NMI) as the base, or in some cases, 4-N,N-dimethylaminopyridine (DMAP) was used in a catalytic amount to promote the acetylation reaction effectively in MOEMIM.OMs ionic liquid ([Scheme 1]). Good yields of the bisacetylated 2′-deoxynucleosides were obtained using the above synthetic strategy. However, when authors tried to execute a selective acetylation strategy for the amine functionality (base part of the nucleoside) over the 3′- and 5′-hydroxy functional groups (sugar part) using a stoichiometric amount of Ac₂O, they ended up with a mixture of products with no appreciable selectivity observed.

Scheme 2 Acetylation of silyl ether-protected nucleosides in [BMIM]ClFeCl₃.

Building upon the success obtained with the employment of ILs for the execution of protection strategy on the nucleoside structural motifs, Salunkhe, and co-workers [90] in 2005 undertook another interesting acetylation strategy of nucleosides involving the transprotection of the previously silyl protected (3′-OH and 5′-OH groups of the sugar part) nucleoside. This was achieved by using an IL different from the one employed in the previous report; that is, 1-butyl-3-methylimidazolium chloride.FeCl₃ ([BMIM]Cl.FeCl₃) had the ability to promote the deprotection of the silyl functionality in the presence of Ac₂O as the acetylating reagent, yielding the diacetate-protected nucleoside as the product ([Scheme 2]). The Lewis acidic character of the IL was fine-tuned along with the reaction temperature to accelerate the desilylation most effectively in [BMIM]Cl·xFeCl₃. It is, therefore, ascertained by the authors that the IL [BMIM] Cl·FeCl₃ played the dual role of firstly acting as an efficient sustainable solvent and then further as a possible Lewis acid catalyst for promoting the deprotection of silyl and subsequent acetylation of the hydroxyl groups.

2.1.2

Benzoylation

As previously discussed, functionalized nucleosides have in the past decade brought about a revolution in the area of drug discovery, with themselves showing promising bioactivity and at the same time acting as useful building blocks for the synthesis of therapeutic oligonucleotides [91], [92], [93]. Multistep synthesis protocols for the rapid generation of bioactive nucleosides/nucleotides are marred with many problems of which the selective manipulation of hydroxyl and amino groups as discussed above is a major challenge [94], [95]. Acyl protection is certainly useful, but the susceptibility of the acetate functionality toward hydrolysis makes it a less preferable protection strategy in a multistep synthetic model that can involve transformations that can prove detrimental to the acetate functionality [96], [97]. Benzoylation of the 3′-OH and 5′-OH groups (in the case of 2′-deoxyribose) of the sugar part of the nucleosides certainly could prove to be an effective strategy for the selective protection of hydroxyl functionality in the presence of a competitive amino group in nucleosides/nucleotides [98]. Due to the improved stability of the benzoyl group, it is most commonly preferred over the acetyl group, and in this part, we will be discussing the various benzoylation protocols involving ILs as the sole solvent to promote a sustainable protection methodology. Benzoylation has been performed most commonly using benzoyl chloride, which is a known lachrymator, and alternative benzoylating reagents have therefore been explored in literature for the protection of – OH functionality either in aromatics or heteroaromatics.

Scheme 3 Benzoylation of nucleosides using BzCN in MOEMIM.Ms.

Benzoyl cyanide as a benzoylating reagent is an interesting proposition and was first explored by Prasad, Parmar, and co-workers [99] who have reported a selective O-benzoylation (of the hydroxyl groups of the sugar part) over N-benzoylation (base part) of different nucleosides in MOEMIM.Ms ionic liquid ([Scheme 3]). Benzoylation using benzoyl cyanide was demonstrated to proceed effectively with a catalytic amount of DMAP for ribose as well as 2′-deoxyribose nucleosides. The authors predicted that the reason for benzoyl cyanide to be more selective than benzoyl chloride or benzoic anhydride toward favoring O-benzoylation over N-benzoylation was its comparatively lower reactivity. The role of the employed ionic liquid was also predicted to be promoting the selectivity due to its high polarizability allowing the hydroxyl group to be more nucleophilic than the amino group. The high solubility of nucleosides in MOEMIM.Ms is also a major contributor to achieving the highly efficient benzoylation protocol at ambient temperature and the reusability of the IL liquid further enhances its appeal as a solvent for such transformations.

Although the previous method for O-benzoylation of nucleosides in MOEMIM.Ms showed high selectivity, taking into consideration a serious limitation of the possible evolution of HCN as a toxic byproduct led the authors to explore benzoyl anhydride as a useful alternative.

Scheme 4 Benzoylation of nucleosides using benzoic anhydride in MOEMIM.TFA.

Benzoyl cyanide reactivity was also observed to be, in some cases, not very encouraging and to circumvent this problem, in 2007, Kumar and co-workers [100] extended the study of O-benzoylation of nucleosides in ILs by the employment of benzoic anhydride as the benzoylating reagent. The reaction was performed in 1-methoxyethyl-3-methylimidazolium trifluoroacetate (MOEMIM.TFA) ILs, however, the reaction temperature rather than being ambient temperature was increased to 50 °C with DMAP added as a catalyst ([Scheme 4]). The authors observed that the MOEMIM.TFA performed better than other ILs as well as conventional organic solvents and provided improved solubility as well as selectivity in the benzoylation of hydroxyl groups of both 2′-deoxyribose and ribonucleosides. The risk of HCN was also mitigated well using benzoic anhydride; however, it is important to note that the compound is a lachrymator, and one needs to be careful in working with benzoic anhydride too. An important advantage of using the MOEMIM.TFA ionic liquid was the recyclability (3 cycles) achieved using this medium, which is not possible under conventional reaction conditions.

The limited number of examples involving the modification of the sugar moiety of nucleosides in ILs suggests that beyond the selective protection of hydroxyl groups, little has been explored, and there is certainly scope to develop efficient protocols for sugar modification.

2.2

Modification of Nucleobases and Nucleoside

In the preceding section, we focused on the examples involving base modification (nucleobase) in the nucleosides. As most of these reactions have been performed in conventional organic solvents, the attractiveness of using a sustainable solvent such as an IL would be related to better solubility of the polar nucleosides, improved reactivity, better product separation, and possible recycling of the reaction solution. Herein, we describe such transformations that have been performed primarily in ILs specifically targeting the nucleobase modification.

2.2.1

Halogenation

Halogenation of aromatics and heteroaromatic moieties is one of the most applied and useful synthetic transformations in synthetic organic chemistry helping to create a useful handle (C–X) for further manipulation [101], [102], [103].

Scheme 5 Synthesis of 5-halouridines and 5-halo-2′-deoxyuridines in MOEMIM.Ms.

Selective halogenation of (hetero)aromatic compounds, especially nucleobases has been an extensively studied topic utilizing conventional organic solvents in combination with a wide variety of halogenating reagents. Previously reported methods for halogenation have many disadvantages like the use of toxic oxidizing agents or catalysts (HNO₃, H₂SO₄, sodium azide, etc.) and high boiling point solvents (DMSO, DMF, pyridine, acetic acid, etc.), leading to the contamination of the desired product. These methodologies are also known to suffer from poor selectivity, reduced reactivity, difficulty in isolation as well as the common problems of environmental pollution caused due to the usage of volatile solvents [18], [103], [104]. ILs can provide a sustainable solution to these issues in halogenation reactions.

The importance of halogenation of nucleosides stems from the usefulness of some of these analogues as potent anticancer or antiviral drugs. 5-Fluoro-2′-deoxyuridine (fluoxuridine) and 5-iodo-2′-deoxyuridine (idoxuridine) are known potent anticancer and antiviral drugs, respectively known for their highly effective bioactivities, while the other 5-halouridine nucleosides have also been explored as antineoplastic agents and in recent years as fluorescent probes for studying DNA metabolism [18], [105], [106], [107]. Halogenation of the C5 position of uridine (ribose or deoxyribose nucleoside) therefore, becomes a synthetically useful methodology, and in 2009, Kumar, Malhotra, and co-workers [108] reported the first synthesis of 5-halouridine in ionic liquid as a sustainable solvent ([Scheme 5]). For carrying out the halogenation of uridine nucleobase, authors performed the reaction using LiX as the halogenating agent with ceric ammonium nitrate (CAN) as the oxidizing agent at 80 °C in MOEMIM.Ms is the suitable solvent.

Scheme 6 Synthesis of acetylated derivatives of 5-halouridines and 5-halo-2′-deoxyuridines in MOEMIM.Ms.

Rapid conversions were observed for some of the nucleobases (10–20 min) and the conditions were found to be equally suitable for 2′-deoxyribose and ribonucleosides. Selective halogenation of unprotected nucleosides is certainly of interest as further manipulation of the sugar moiety could be made possible for further applications however, halogenation of protected nucleosides is equally important, which was achieved effectively by the authors using the developed protocol ([Scheme 6]). The protocol was found to work equally well on the protected uridine or deoxyribose uridine. The developed method in comparison to the previously reported ones has emerged as an effective greener alternative due to the following factors: negligible vapor pressure of ILs, recyclability, high thermal stability, high solubility of nucleosides in ILs, and easy workup for the isolation of the desired product.

2.2.2

Multicomponent Reactions

A multicomponent synthetic transformation involves the combination of two different substrates under uncatalyzed or catalyzed conditions to furnish the desired product. Complexity can be increased by many folds by the incorporation of more than 2 substrates in a single pot procedure to form products. Multicomponent reactions (MCRs) as they are called nowadays have been known in literature for decades and have become a cornerstone of organic chemical processes [109], [110]. MCRs have been applied extensively to general organic substrates to build complex synthetic molecules that have exhibited promising biological activities [111], [112]. However, functionalization of nucleosides is a difficult proposition due to the lower solubilities of these substrates in organic solvents. This leads to poor yields and tedious workup procedures while the environmental impact of using volatile organic solvents certainly outweighs most other problems [113], [114], [115]. In this part, MCRs performed on nucleosides in ILs are discussed.

Scheme 7 Multicomponent synthesis of pyrimidine nucleoside-thiopyran hybrids in [BMIM]BF₄.

Thiopyrans have been extensively used for the synthesis of biologically important derivatives of natural products such as tetrahydrodicranenone, [116], [117] serricornin, [118] thromoboxanes, [119], [120] and cyclopentanoids [121]. Fan, Qu, and co-workers [122] have contributed extensively in the field of multicomponent reactions, and in 2008, they reported a one-pot multicomponent synthesis of pyrimidine nucleoside-thiopyran hybrids in an ionic liquid [BMIM]BF₄. The authors demonstrated a [BMIM]BF₄-mediated reaction of 5-carbaldehyde-2′-deoxyuridine, cyanothioacetamide, and malononitrile to yield thiopyran derivative at 80 °C without any added catalyst ([Scheme 7]). In comparison with the conventional organic solvents (previously reported literature), [BMIM]BF₄ as an ionic liquid proved to be better in providing a protocol that requires mild reaction conditions, provides good selectivity and better yield as well as allows reusability of the reaction solution up to 5 reaction cycles. Accelerated reaction rates were also observed with the use of [BMIM]BF₄ as it promotes the MCR to be performed under shortened reaction time (within 0.3 h) compared to the reactions carried out in several conventional volatile organic solvents, such as methanol, ethanol, benzene, and THF (4–12 h).

Scheme 8 Synthesis of 5-substituted pyrimidine nucleoside derivatives in [BMIM]BF₄.

Building upon the success of employing sustainable ILs for the nucleoside modifications, Fan, Zhang, and co-workers [123] further decided to functionalize the 5-carbaldehyde-2-deoxyuridine (protected) with 2-pyranone (2 molecules) using a multicomponent approach. This methodology was based on the literature reports on pyran and its derivatives, which are known to show promising cytotoxic and antitumor properties. The transformation involved the synthesis of 2′-deoxyuridine nucleoside-fused pyran derivatives by the reaction of 5-carbaldehyde-2-deoxyuridine and 4-hydroxy-6-methyl-2-H-pyran-2-one in [BMIM]BF₄. In the presence of Ac₂O at 100 °C. The products, 2′-deoxyuridine nucleoside-bis(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl) methane hybrids were predicted to show promising bioactivity while the novel process thus developed exhibits high efficiency in a sustainable ionic liquid.

Scheme 9 Synthesis of pyrimidine nucleoside–thiazolidinone hybrids in [BMIM]PF₆.

Another moiety that has found widespread utility due to its promising biological activities such as anti-inflammatory, [124] antiproliferative, [125], [126] anticyclooxygenases (COX-1 and COX-2), [127], [128] antihistaminic, [129] and antibacterial [130] activities is the thiazolidinone and its derivatives. Combining thiazolidinone structural features with nucleosides could certainly help enhance the bioactivity further. Going with this idea, Fan, Qu, and co-workers [131] further expanded their methodology of utilizing ILs as solvents and promoters for carrying out MCRs on nucleosides, developed in 2009 an ionic liquid-mediated one-pot multicomponent synthesis of 2′-deoxyuridine nucleoside–thiazolidinone hybrids [Scheme 8]). The one-pot MCR was executed on 5-carbaldehyde-2′-deoxyuridine as the aldehyde coupling partner, with mercaptoacetic acid and ccorresponding amine as the other reactants in [BMIM]PF₆ at 80 °C. The developed protocol provided good to moderate yields of the desired hybrids in a shorter reaction time compared with other conventional organic solvents like EtOH, THF, PhMe, CH₂Cl_2, etc. The authors also demonstrated the successful recovery and reuse of [BMIM]PF₆ without any significant loss in activity. The synthesized hybrids were subjected to bioactivity analysis against trypomastigote forms of T. brucei brucei showing moderate activity.

Scheme 10 (A) Synthesis of pyrimidine nucleoside–pyrazolo[3,4-b]pyridine hybrids in [BMIM]BF₄. (B) Synthesis of pyrazolo[3,4-b]quinolinone hybrids in [BMIM]BF₄.

Another moiety that has attracted the attention of researchers because of its promising bioactivity is the pyrazolo[3,4-b]pyridines derivatives which have found relevance in studies on the identification of potent psychotropic, [132] cytotoxic, [133] antiviral, [134] antifungal, [135] and antichagastic agents [136]. Introducing such a useful structural motif on the nucleoside backbone will certainly enhance the bioactivity further and keeping this in mind, in 2009, Zhang and co-workers [137] demonstrated a novel one-pot multicomponent synthesis of 2′-deoxyuridine–pyrazolo[3,4-b]pyridin-6-one and 2′-deoxyuridine–pyrazolo[3,4-b]quinolinone hybrids. To achieve the synthesis of these hybrids, authors carried out a one-pot multicomponent reaction involving 5-amino-3-methyl-1-phenylpyrazole, Meldrum’s acid, and 5-carbaldehyde-2′-deoxyuridine in [BMIM]BF₄ as the ionic liquid at 80 °C yielding 2′-deoxyuridine–pyrazolo[3,4-b]pyridin-6-one hybrids (Part A, [Scheme 10]). To achieve the synthesis of 2′-deoxyuridine–pyrazolo[3,4-b]quinolinone hybrids a slight modification in the protocol was undertaken by the authors by using 5,5-dimethyl-1,3-cyclohexadione instead of Meldrum’s acid (Part B, [Scheme 10]). A comparison with the protocols developed in conventional organic solvents like THF, EtOH, and PhMe suggests that the ionic liquid, [BMIM]BF₄ provided improved product yield. The process also provides several advantages such as the reusability of solvent, high efficiency, simple procedure, and the environmentally benign nature of the solvent.

Scheme 11 (A) Synthesis of pyridinone or pyranone nucleoside hybrids in [BMIM]BF₄. (B) Synthesis of pyrano[3,2-c]pyridone, pyrano[4,3-b]pyran hybrids in [BMIM]BF₄.

In continuation of the successful use of ILs for the functionalization of nucleosides, Fan and co-workers [138] in 2010 demonstrated the synthesis of pyrano[3,2-c]pyridine as well as pyrano[4,3-b]pyran hybrids. The transformation was carried out by performing a one-pot reaction of 5-formyl-2′-deoxyuridine and heterocyclic derivatives in an ionic liquid, [BMIM]BF₄ at 80 °C to afford 2′-deoxyuridine nucleosides functionalized at the C5 position with pyridin-2(1H)-one or 2-pyranone (Part A, [Scheme 11]). They went on to also report a similar synthesis of -2′-deoxyuridine nucleoside functionalized with pyrano[3,2-c]pyridine moiety in the presence of malononitrile (Part B, [Scheme 11]). The use of [BMIM]BF₄ played a crucial role in promoting the reactivity of these transformations providing better yields compared with the conventional organic solvents. Higher polarity and the ability of IL to solubilize both organic and inorganic components essentially help enhance the rate and selectivity of reactions.

Scheme 12 Synthesis of pyrimidine nucleoside-benzothiazole hybrids in [BMIM]PF₆.

2.2.3

Miscellaneous Reactions in ILs

2-Substituted benzothiazoles are important synthetic compounds that have been investigated extensively for their pharmacological and biological activities such as antitumor, antiviral, antimicrobial, and antioxidant agents [139], [140]. Synthetic methodologies for the preparation of 2-substituted benzothiazoles are numerous ranging from cross-coupling, C–H bond functionalization, etc [141], [142]. Introduction of benzothiazole moiety on the nucleoside backbone can give rise to biologically useful derivatives which can also exhibit promising fluorescent activity [143], [144]. Coupling reactions especially, Suzuki–Miyaura coupling has been used for the incorporation of the benzothiazolyl functionality on nucleosides especially, 2′-deoxyuridine at the C5 position of the base. Other strategies have also been known but most have been performed in volatile organic solvents. In 2010, Fan and co-workers [145] illustrated a Ru(III)-catalyzed oxidative reaction in ionic liquid. The authors carried out the reaction of 5-formyl-2′-deoxyuridine nucleoside and o-aminobenzenethiol in the presence of RuCl₃/[BMIM]PF₆ at 80 °C to yield 5-benzothiazolyl substituted 2′-deoxyuridine nucleoside hybrids ([Scheme 12]). The reaction proceeded with good to moderate yields of the desired product and the reaction was governed by the key role of [BMIM]PF₆ to not only act as a solvent or a co-catalyst but also in helping to immobilize the Ru-catalyst thus enabling the recycling of the catalytic solution.

Scheme 13 N-Alkylation of nucleobases using alcohols in [BMIM]Br.

N-Alkylation of heteroarenes is an important synthetic strategy especially applied to nucleosides due to the significance of acyclic nucleosides is on the rise due to their enhanced stability compared to cyclic nucleosides and the promising activity as pharmaceutical agents for viral and cancer chemotherapy further contributes favorably for acyclic nucleosides [146], [147], [148]. Numerous N-alkylation protocols are known but none have been conducted in sustainable solvents such as ILs. In 2015, Rad and co-workers [149] reported a one-pot N-alkylation of nucleobases with alcohols as the alkylating agents using a reagent combination of TsCl/K₂CO₃/TEA in 1-butyl-3-methyimidazolium bromide ([BMIM]Br) ([Scheme 13]). The methodology was performed on purines, pyrimidines, and azole derivatives. Primary or secondary alcohols were used to provide good to excellent yields of the desired N-alkylated product, while tert-alcohols were found to be unsuitable for the given transformation. The developed process has been observed to be highly efficient, safe, and environmentally compatible as the use of toxic and hazardous materials such as DMF and alkyl halides has been prevented.

3

Water

Synthesis of structural analogues of naturally occurring nucleosides is challenging due to their physicochemical and structural properties. The poor solubility of nucleosides in organic solvents, the presence of multiple functionalities, and acid sensitivity toward hydrolytic cleavage of glycosidic bonds make the synthesis more complicated [150]. To carry out the synthesis of modified nucleosides in organic solvents, fully protected nucleoside analogues have commonly been employed. However, organic solvents often get contaminated with the desired product due to difficulties in their isolation. Although, ILs have been widely explored as sustainable solvents [41], [151] for their advantages, ILs could sometimes cause corrosion and may react with other chemicals in the reaction mixture. Furthermore, ILs could also get contaminated by moisture in the environment as well as other gases on exposure. Synthesis of ILs is often challenging, [152] and the products pose potential environmental impacts throughout their life cycle [153], [154], [155], [156]. Therefore, much attention has been drawn to water as a possible greener solution. A mixture of organic solvents with water has also been tried for developing the synthetic methodologies for various unprotected nucleosides as the combination can help facilitate the solubility of these substrates [35], [96], [157], [158]. However, performing nucleoside functionalization reactions in water as a sole solvent is a demanding proposition as the solubility of the nucleosides is not the only criterion but the compatibility of the various reagents also plays an important role. In recent years, several researchers have reported cross-coupling reactions of nucleosides in aqueous media especially, Suzuki–Miyaura coupling for the synthesis of fluorescent nucleosides. This section summarizes the methodologies that have been performed solely in water as the green solvent.

3.1

Modification of Nucleobases and Nucleosides

The modification of the sugar part of the nucleosides is more limited to protection strategies, while the base moiety provides more opportunities to install functional groups using a range of metal-mediated or metal-free synthetic methodologies. In our discussion, we excluded the protocols where a combination of solvents has been employed with water. What follows are the procedures using water as the primary solvent.

3.1.1

Heck Coupling

Heck reaction is a common strategy employed by researchers for C–C bond formation to construct useful derivatives of agrochemicals, fine chemicals, and pharmaceuticals [159], [160]. The first reaction was documented by Mizoroki [161] in 1971 and Heck [162] in 1972. Since then, this reaction has been extensively explored due to its high efficiency, simplicity, high chemoselectivity, mild reaction conditions, low toxicity, and low cost [163], [164], [165]. To expand the scope of the reaction and to make the catalytic process environmentally benign, tremendous efforts have been taken by researchers to study these reactions in various green solvents such as water.

Scheme 14 Heck coupling of 5-iodo-2′-deoxyuridine with acrylate derivatives in water.

Literature reports suggest that the structural modification of nucleosides with different functionalities especially alkenes has shown significant enhancement in their chemotherapeutic potential. In 2014, Herve and Len [166] made the first effort in the synthesis of modified nucleoside in aqueous media via the Heck alkenylation reaction that has been commonly used for the introduction of alkenyl functionalities on various substrates. The authors reported a ligand-free, microwave-assisted Heck cross-coupling reaction of nucleoside in neat water. The reaction was performed on 5-iodo-2′-deoxyuridine with various acrylate derivatives in the presence of Pd(OAc)₂ as a catalyst without the addition of any ligand, NEt₃ as the base in pure water at 80 °C under microwave conditions ([Scheme 14]). Several examples of derivatized nucleosides were obtained in good to excellent yields. Besides these examples, authors have also put forth a greener route for the synthesis of 2′-deoxyuridine-5-carboxylic acid (CVU) and anti-HSV-1 inhibitor, BVDU providing 80 and 56% yields of the respective products.

3.1.2

Suzuki–Miyaura Cross-Coupling

Suzuki–Miyaura coupling is the most applicable and useful C–C bond-forming technology allowing the cross-coupling reactions between the aryl or vinyl boron-based (boronic acids, boronate esters) reagents with aryl or vinyl halides catalyzed by a wide variety of Pd-complexes [167], [168], [169]. Although cross-coupling reactions like the Heck reaction, Stille reaction, and others also offer similar outcomes for C–C coupling, this reaction has been the most prevalent methodology due to the amazingly milder reaction conditions of the developed protocols, commercial availability of a diverse range of boron reagents, less toxic nature of the boron reagents compared to other organometallic reagents, excellent functional group tolerance, and operational simplicity. For the synthesis of structural constituents of numerous agrochemicals, natural products, pharmaceuticals, and polymers, the Suzuki–Miyaura reaction has been widely explored [170], [171], [172]. In the modification of nucleosides, Suzuki–Miyaura cross-coupling has also played an important role with several research groups reporting coupling reactions in volatile organic solvents (DMF or CH₃CN) or a combination of an organic solvent with H₂O (DMF:H₂O or CH₃CN:H₂O) [35], [173]. The use of water as a sole solvent for Suzuki–Miyaura cross-coupling of nucleosides would be a desirable option given the greener appeal of H₂O. This section provides an overview of what has been achieved to date in promoting Suzuki–Miyaura in water using a Pd-catalytic system.

Scheme 15 Suzuki–Miyaura cross-coupling reaction of 5-iodouridine with arylboronic acid.

One of the earliest examples of performing Suzuki–Miyaura cross-coupling of nucleosides in water was reported in 2003 by Williams and co-workers [174] who developed a Suzuki–Miyaura coupling protocol that involved the use of reverse-phase glass beads in combination with Pd(PPh₃)₄ wherein the Pd catalyst could be said to be immobilized on the glass beads surface. The catalytic system thus derived was further utilized for the functionalization of 5-iodouridine using 4-carboxyphenyl boronic acid via Suzuki cross-coupling ([Scheme 15]). As a part of the catalytic protocol, authors used 3.0 mol % of Pd(PPh₃)₄-derivatized glass beads in the presence of Na₂CO₃ under refluxing conditions using water as a solvent. It is important to note that the formation of a product during the reaction was determined by subjecting the crude reaction mixture to NMR analysis suggesting 28% product formation.

Scheme 16 Suzuki–Miyaura coupling of 8-bromoguanosine with arylboronic acid.

Collier and Wagner, [175] in 2006, working on the functionalization of 8-bromoguanosine using arylboronic acids via Suzuki–Miyaura coupling in water. The authors optimized the catalytic conditions and observed that Na₂PdCl₄/TPPTS (triphenylphosphine trisulfonic acid) catalytic system was more effective in catalyzing the transformation compared to Pd(NO₃)₂/TPPTS while also being a low-cost option as well as more stable ([Scheme 16]). The Suzuki–Miyaura coupling protocol was performed at 80 °C in water as the only solvent, with the desired products obtained in good to moderate yield. The effectiveness of the developed protocol allowed the authors to use the optimized conditions for the challenging coupling of 8-bromoguanosine monophosphate and 8-bromoguanosine triphosphate with different arylboronic acids, affording the coupled products in good to moderate yields in competitive reaction times.

Scheme 17 Suzuki–Miyaura cross-coupling reaction of 5-iodouridine with arylboronic acid.

Wagner and co-workers [176] continuing their previous work reported the synthesis of fluorescent analogues of uridine diphosphate-ribose derivatives ([Scheme 17]). To achieve these target molecules, they developed a synthetic route that involved the functionalization of 5-iodouridine via Suzuki–Miyaura cross-coupling in an aqueous medium. 5-Iodouridine was reacted with arylboronic acid in the presence of Na₂PdCl₄/TPPTS as the catalytic system, K₂CO₃ as the base, in water at 60 °C for 3.0 h. Although the reaction proceeds in water, product yields reported have been low to moderate, suggesting the less effectiveness of the developed catalytic system.

Scheme 18 Suzuki–Miyaura coupling of 5-iodouridine with arylboronic acid in water.

Early examples were focused on the functionalization of ribose nucleosides in water, but given the significance of deoxyribose nucleosides in the development of DNA-based functional probes and the related study, the contribution by Len and co-workers [177] in 2012 for demonstrating the synthesis of 5-substituted 2′-deoxyuridine analogues using Suzuki–Miyaura cross-coupling in water needs special mention. Water as a reaction solvent was chosen over other organic solvents because of its nontoxic nature, ready availability, and being environmentally benign. The catalytic system selected by Len and co-workers was the same previously used by Wagner and co-workers, that is, Na₂PdCl₄/TPPTS. Using the preformed catalyst in water, Len and co-workers synthesized the derivatized 5-substituted 2′-deoxyuridine analogues in the presence of KOH as the base in water at 100 °C ([Scheme 18]). Improved reactivity for the developed catalytic system was attributed to the solubility of 5-iodonucleoside, arylboronic acid, and the inorganic base in the water while the catalyst also is solubilized as TPPTS is a water-soluble ligand coordinating strongly with the Pd-center.

Scheme 19 Suzuki–Miyaura coupling of 5-iodo-2′-deoxyuridine with arylboronic acid in water.

Compared to the previously reported literature, this method is superior due to the low catalyst loading achieved and greener for the use of water as sole solvents instead of a mixture of water with organic solvents (H₂O/THF/MeOH, H₂O/MeCN or H₂O/MeOH). They have reported good to moderate yields of the desired product. Several parameters are essential to be considered for the modification of nucleosides as these are in general acid and temperature labile due to the readily dissociable glycosidic C–N bond. Reaction time can also play a crucial role in avoiding the formation of any undesired byproduct during the coupling process. Berteina-Raboin and co-workers [178] in 2012 accordingly described the synthesis of 5-substituted-2′-deoxyuridine derivatives via Suzuki–Miyaura reaction in aqueous media under microwave conditions at 120 °C with the reaction proceeding smoothly in just 10 min ([Scheme 19]). During the optimization of the synthetic protocol, the authors started with a mixture of water and acetonitrile as the solvent and achieved a 62% yield of the desired product. Further switching to only an aqueous medium improved the product yield albeit only slightly, but they demonstrated that organic solvents such as CH₃CN could be completely avoided. The catalytic reactions were thus carried out in the water as a sole solvent by the addition of Pd(OAc)₂ (3.0 mol %) as the catalyst, PPh₃ (5.5 mol %) as ligand, and Na₂CO₃ (1.5 equiv) as the base at 80 °C under microwave conditions to rapidly convert 5-iodo-2′-deoxyuridine into the respective derivatized products in good yields with different arylboronic acids.

Scheme 20 Microwave-assisted Suzuki–Miyaura cross-coupling of 5-iodouridine with arylboronic acid in pure water.

Another methodology involving the Suzuki–Miyaura cross-coupling under microwave conditions in water as the reaction solvent was further reported by Len and co-workers [179] ([Scheme 20]). This methodology was an enhanced protocol than the previously reported work and demonstrated the improved ligand-free, microwave-assisted Suzuki–Miyaura cross-coupling of 5-iodo-2′-deoxyuridine using low catalyst loading of Pd catalyst (0.05–0.1 mol %) resulting into a marked improvement in the catalytic efficiency. Reaction time was also shortened, and higher yields of desired products were obtained. The protocol was effective in providing several functionalized 5-iodo-2′-deoxyuridine.

Scheme 21 Synthesis of 6-arlyuridnes via Suzuki–Miyaura coupling at room temperature in water.

Previous protocols focused on the functionalization of 5-iodo-2′-deoxyuridine, which certainly is of importance to synthetic chemists but the functionalization at other positions of the base substructure also garners a lot of interest among researchers. Keeping this in mind, Len and co-workers [180] in 2013, reported a room-temperature protocol for the synthesis of 6-aryluridines via Suzuki–Miyaura cross-coupling reaction in aqueous media under ligand-free conditions ([Scheme 21]). The authors carried out the reaction of 6-iodouridine with different arylboronic acids in the presence of Na₂PdCl₄ as the catalyst and KOH as the base at ambient temperature (25 °C).

Scheme 22 Synthesis of C5-arylated pyrimidine nucleosides via Suzuki–Miyaura Coupling reaction.

6-Aryluridine analogues were obtained in good yields and a wide variety of functionalities were tolerated containing electron-donating as well as electron-withdrawing groups, especially in the para position of arylboronic acids that were used as the coupling reagents. The procedure was made simple, economical as no protection/deprotection steps were included, and greener with the use of neat water as a solvent.

Despite the advancements taking place in the arena of nucleoside modifications using Suzuki–Miyaura cross-coupling, reaction conditions such as higher reaction temperature, lower catalytic yields, and limited substrate scope (other than uridines, not much had been reported on other nucleosides) have plagued these protocols. To address these issues, Kapdi, Serrano, and co-workers [181] reported a series of water-soluble Pd-imidate complexes as highly efficient catalysts for the synthesis of C5-arylated pyrimidine 2′-deoxyribose nucleosides as well as C-8 arylated purine 2′-deoxyribose nucleosides ([Scheme 22]). The synthetic methodology initiated from the arylation of 5-iodo-2′-deoxyuridine with arylboronic acids, [Pd(imidate)₂(PTA)₂] (1.0 mol %) as the catalyst, triethylamine (NEt₃) as a base (2.0 equiv) and water as solvent. The developed protocol gives access to functionalized 5-arylated-2′-deoxyuridines in good to excellent yields incorporating functionalities such as electron-rich and electron-withdrawing arylboronic acid. They further reported a good yield of a 5-arylated-2′-deoxyribose nucleoside with naphthalene boronic acids, which are synthetically challenging due to their nucleophilic nature. This was a preliminary report by the authors to show the versatility of the developed catalytic system [Pd(imidate)₂(PTA)₂] wherein imidate saccharinate was found to be the most effective.

Scheme 23 Synthesis of C5-substituted pyrimidine and C8-substituted purine nucleosides using a water-soluble Pd-imidate complex.

In continuation of the improved reactivity of the [Pd(saccharinate)₂(PTA)₂] complex toward the Suzuki–Miyaura cross-coupling of 5-iodo-2′-deoxyuridine Kapdi and co-workers [182] further undertook an extensive study for the development of the first catalytic protocol allowing the functionalization of both pyrimidine as well as purine 2′-deoxy nucleosides. An extensive optimization was performed by the research group and the developed [Pd(saccharinate)₂(PTA)₂] was able to provide direct access to a large variety of functionalized C5-substituted pyrimidine and C8-substituted purine 2′-deoxy nucleosides. Under mild reaction conditions, [Pd(saccharinate)₂(PTA)₂] was able to activate iodo derivatives of purine and pyrimidine 2′-deoxy nucleosides with aryl as well as heteroarylboronic acids in the presence of NEt₃ (2.0 equiv) as the base, and water as a solvent at 80 °C ([Scheme 23]). They obtained good to excellent yields for unprotected nucleosides in 6-12 h. This development marked a significant advancement in the arena of nucleoside modification as a single catalyst can perform both pyrimidine and purine modifications effectively rather than using different catalytic systems as reported in the literature.

Scheme 24 Suzuki–Miyaura coupling of iodonucleoside with arylboronic acid in water.

The development in the functionalization of purine and pyrimidine nucleosides came at a point when the biological importance of modified nucleosides in the field of antivirals, anticancer drugs, and fluorescent biological probes was on an exponential trajectory [183], [184], [185], [186]. The requirement for more efficient catalytic systems that can provide easy access to these compounds was certainly of interest to chemists, and accordingly, Kapdi and co-workers [187] again came up with an efficient Pd-based catalytic system involving the use of a highly water-soluble phosphine ligand, PTABS (Kapdiphos) demonstrating an efficient route for the Suzuki–Miyaura reaction of nucleoside in aqueous media ([Scheme 24]). Catalytic reactions were performed at lower catalyst loading than the previously reported protocol involving [Pd(saccharinate)₂(PTA)₂], and the isolation of the product was achieved using a column-free method (via simple filtration) as the Pd/PTABS system exhibited high water solubility and stability therefore avoiding leaching of the metal (as confirmed by the ICP-AES of the isolated product). The effectiveness of the catalyst allowed the cross-coupling of all four 2′-deoxy nucleosides in good to excellent yields in water. The catalyst combination also was tested for catalyzing a copper-free Sonogashira coupling of halonucleoside with phenyl acetylene although in the mixed H₂O/CH₃CN solvent system due to the lower solubility of the acetylene substrate, yielding 75% of the desired product in 45 min. It is to be noted that the developed protocol proved to be simple and efficient and can be considered a step toward green and sustainable synthesis in nucleoside chemistry.

Scheme 25 Synthesis of modified nucleoside via Suzuki–Miyaura coupling in aqueous media at low temperatures.

The desire while developing any catalytic systems for cross-coupling of substrates would be to achieve these transformations under ambient temperature conditions, and many such examples have been reported for general substrates. Especially around nucleoside modifications, this could prove to be crucial due to the temperature lability of the nucleoside analogues, but it can also open the possibility of applying the catalytic system for the late-stage modifications of oligonucleotides, DNA, or RNA for which catalytic systems are known but less explored and less efficient. Improving upon their previous contributions to the Suzuki–Miyaura transformation of 2′-deoxyribose nucleosides, Serrano, Kapdi, and co-workers [188] developed a phosphine-free palladacyclic complex (SerrKap) for carrying out low-temperature Suzuki–Miyaura modification of nucleosides in aqueous media ([Scheme 25]). This was the first example of functionalization of 5-iodo-2′-deoxyuridine without any added phosphine/N-heterocyclic carbene ligand. The authors carried out the reaction with lower catalyst loading (0.5 mol %) in water as the sole solvent at 60 °C for 24 h and obtained the desired products in good to excellent yields. They further elaborated their study toward the synthesis of modified 2′-deoxycytidine derivatives and like 2′-deoxyuridine obtained good to moderate yields of the desired product.

Ambient temperature Suzuki–Miyaura cross-coupling of aryl and heteroaryl halides has been achieved by several research groups using a combination of metal precursors (more commonly Pd) with electron-rich ligands (phosphines or N-heterocyclic carbenes) in volatile organic solvents [189], [190], [191]. These catalytic systems, however, fail to furnish any cross-coupled products when water has been employed as the solvent due to the possible degradation of the catalyst in aqueous media (less compatible).

Scheme 26 Synthesis of modified nucleoside via Suzuki–Miyaura coupling in aqueous media at room temperature.

A similar situation has been observed for the modification of nucleosides as electron-rich phosphines have proven to be ineffective and many times either the employment of π-acceptor phosphines such as PTABS (KapdiPhos) in combination with Pd-precursor or ligand-free Pd-catalysts have furnished more promising results albeit at slightly higher temperature. Accordingly, in 2022 Serrano, Kapdi, and co-workers [192] were able to solve this conundrum by the development of another highly active phosphine-free Pd-based precatalyst [Pd(Sacc)₂(THPEN)] allowing the room-temperature Suzuki–Miyaura cross-coupling of 2′-deoxyribose nucleoside analogues in aqueous media ([Scheme 26]). Good to excellent yields of the functionalized 2′-deoxyribose nucleosides were obtained which sets the stage for the catalytic system to be further applied to the late-stage modification of oligonucleotides, DNA, or RNA in the near future at room temperature.

All the previous examples pertaining to the modification of the 2′-deoxypurine/pyrimidine nucleosides as the requirement of derivatized analogues in DNA-related research have escalated dramatically in the past decade. However, on the other hand, Suzuki–Miyaura cross-coupling protocols for accessing functionalized ribose nucleoside analogues are limited and mostly performed on protected ribose nucleosides in volatile organic solvents. Development of an effective synthetic protocol to address this gap was undertaken by Serrano, Kapdi, and co-workers [193] and a phosphine-free, water-soluble catalyst Na₂[Pd(sacc)₄] provided the desired result when previously developed catalytic system fell short of the modification of nucleosides to be performed at room temperature. Serrano, Kapdi, and co-workers accordingly have demonstrated a protocol for synthesizing modified ribose nucleosides involving the phosphine-free, water-soluble catalyst Na₂[Pd(sacc)₄] that catalyzes Suzuki–Miyaura coupling reaction of ribose nucleosides (uridine) with different arylboronic acids ([Scheme 27]). The developed protocol involves Na₂[Pd(sacc)₄] (1.0 mol %) as a catalyst for the coupling of 5-iodouridine with arylboronic acids in aqueous media at room temperature, giving good to moderate yields of the desired products ([Scheme 26]). Significant improvement in the reaction time (4 h) was also achieved using the developed catalyst, as in most reported protocols, reactions took 24 h.

Scheme 27 Synthesis of modified ribose nucleoside via Suzuki–Miyaura coupling in aqueous media at room temperature.

3.1.3

Amination

C–N bond formation has gained a lot of importance due to the extensive occurrence of aryl/heteroaryl amines in pharmaceuticals, natural products, organic materials, and catalysts [194]. The exploration of C–N bond formation in nucleosides is of significant interest due to the occurrence of amine-functionalized purine or purine ribosides in various pharmaceutically active molecules, including puromycin, underscores their importance [195], [196]. The controlled introduction of the amino group was first documented by Ullmann [197] and Goldberg [198] using copper metal over a century ago. Significant advancements have been made in the palladium-catalyzed amination of heteroaryl chlorides, with extensive research conducted by Buchwald et al., [199] Organ et al., [200] and Reetz et al. [201] at elevated temperatures and using organic solvents [202], [203]. Several research groups, such as Koomen et al., [204] Lanver and Schmalz, [205] and Lakshman et al., [15], [206] Kapdi et. al, [207], [208], [209] have in recent years reported the amination process for nucleosides using palladium catalysis. However, these methodologies present several limitations, such as the requirement for increased catalyst concentrations, a narrow substrate scope, high reaction temperatures, and the use of organic solvents. Hence, forming a C–N bond under mild and inexpensive reaction conditions remains challenging. Especially the possibility of conducting amination reactions in water remains a distant possibility due to the water sensitivity of the various catalytic systems used previously.

Scheme 28 Amination of chloropurines and chloronucleosides in water as a solvent.

In 2021, Kapdi and co-workers [210] successfully addressed these challenges by conducting the amination reaction of chloroheteroarenes, purines, and purine ribose in water for the first time. They employed a water-soluble Cu(OAc)₂/PTABS (KapdiPhos) catalytic system along with K₃PO₄ as a base at room temperature, which yielded good to excellent yields of the amination products ([Scheme 28]). The coupling of 6-chloropurine riboside with various secondary amines produced satisfactory to excellent yields. Notably, the reaction of benzylamine with 6-chloropurine riboside yielded a product with 92% yield, which has been recognized as a highly useful analogue of adenosine in commercial applications. Furthermore, the authors demonstrated the functionalization of 6-chloropurine riboside with valine amino acid in water for the first time.

Scheme 29 N,N-dialkylamination of chloropurines and chloronucleosides.

The increased solubility of purines in water led to a more intricate column-free isolation process than the typical heteroarenes which were also aminated using the same protocol. Remarkably, the catalyst also provided an opportunity to recycle the catalytic solution for up to 12 cycles in water. Scale-up reactions were also performed furnishing excellent yield of the coupled product, while the recovery of the utilized water (as a solvent) was also carried out to make it a truly sustainable synthetic methodology.

Amination of aromatic and heteroaromatic substrates with gaseous amines is a major synthetic challenge in academia as well as industry due to the complications related to the storage, transportation, and hazards associated with the gases [211], [212]. Dialkylamine is one such gaseous amine that is a key component in various synthesis processes and is commonly found in agrochemicals and pharmaceuticals. Limited studies have focused on the dimethylamination of chloroheteroarenes through in situ DMF decomposition. Despite the few examples in the literature, expensive palladium catalysts have been predominantly used. Hence, in 2022, Kapdi and co-workers [208] reported the N.N-dimethylamination of chloroheteroarenes, chloropurines, and chloropurine ribose using Cu/PTABS system via in situ generation of N,N-dimethylamine using DMF as a surrogate molecule and water as an additive at room temperature. 6-Chloropurine, 6-chloro-7-deazapurine, 2,6-dichloropurine, and 2-amino-6-chloropurine were subjected to the developed protocol, which provided good to excellent N,N-dialkylamination products. The established method has proven successful in synthesizing deuterated dialkylaminated purines and purine ribose using deuterated dimethylformamide and important drugs like puromycin precursor. Even though DMF was used as the source of dimethylamine gas, the authors have explicitly indicated that the reaction can also be exclusively performed in water as the sole solvent as the catalytic system is very much compatible.

Scheme 30 Synthesis of C-5-substituted O⁶,5′-cyclopyrimidine nucleoside analogues in ammonia–water.

3.1.4

Miscellaneous Reactions in Water

Cyclonucleosides are useful synthetic intermediates, with potential biological impact on enzymatic repair processes. They are also crucial in nucleoside configurational studies [213], [214], [215]. In 2013, Guo and co-workers [216] demonstrated an efficient, one-step process for synthesizing C-5-substituted O⁶,5′-cyclopyrimidine nucleoside analogues using molecular iodine in ammonia–water at 60 °C, resulting in good yields ([Scheme 30]). Ammonia–water acts as both a base and a solvent, eliminating the need for organic solvents. This approach yielded satisfactory results for purine cyclonucleosides but was not suitable for unprotected pyrimidine nucleosides, resulting in low yields of the corresponding pyrimidine cyclonucleosides.

Scheme 31 Trifluoromethylation of nucleosides using CF₃SO₂Na/tert-butyl-hydroperoxide (tBuOOH) system in aqueous media.

The introduction of a trifluoromethyl group into low-molecular-weight compounds often enhances their bioactivity by increasing the lipophilicity of the associated molecular scaffolds, thereby facilitating improved cellular uptake [217], [218], [219], [220]. In 2013, Montesarchio and co-workers [221] developed a mild protocol for the synthesis of 5-CF₃-2′-deoxycytidine, 8-CF₃-2′-deoxyadenosine, 8-CF₃-2′-deoxyguanosine and 8-CF₃-inosine derivatives utilizing a CF₃SO₂Na/tert-butyl-hydroperoxide (tBuOOH) system in aqueous conditions at ambient temperature, achieving good yields ([Scheme 31]).

Scheme 32 Alkylation at N1 and N9 position of purines and pyrimidines under microwave conditions using water as solvent.

However, the yields for 2′-deoxyguanosine and 2′-deoxyadenosine were lower than that of 2′-deoxycytidine, which is attributed to their limited solubility in water and the glycosidic bond cleavage under the conditions. Consequently, a biphasic solvent system was employed for the trifluorination of 2′-deoxyguanosine and 2′-deoxyadenosine, necessitating a three-step process. Preliminary in-vitro bio screenings revealed an intriguing dose-dependent antiproliferative activity of the synthesized derivatives. Notably, 5-trifluoromethyl-2′-deoxycytidine exhibited significant antitumor activity, while the 8-trifluoromethylated derivatives of 2′-deoxyadenosine and 2′-deoxyguanosine also demonstrated potential as antitumor agents.

Unsaturated bonds are significant in the carbohydrate cycles associated with various drugs and bioactive compounds. The introduction of unsaturation or an alkene functionality onto the sugar moiety of nucleosides can certainly help improve the bioactivity as these acyclic nucleosides have been studied extensively in literature [222], [223], [224], [225]. In 2016, Xia and Sun [226] performed a regioselective alkylation at N1 and N9 positions of purines and pyrimidines under microwave conditions using water as a solvent, resulting in a series of acyclic nucleoside analogues containing unsaturated functionality on the sugar moiety in good to excellent yields ([Scheme 32]). A wide variety of functionalities such as allyl, benzyl, and substituted benzyl were well tolerated. However, reduced yields were observed when electron-withdrawing groups were present at the C5 position of pyrimidine, as compared to the presence of electron-donating groups. Furthermore, this technique eliminated the requirement for protecting hydroxyl and amino groups which was necessary in the previous reported protocols. The reaction was successfully scaled up to a 50 mmol scale, and product purification was achieved through recrystallization instead of the more laborious chromatography method, making it suitable for industrial applications.

This section discussed at length several known examples of functionalization of ribose and 2′-deoxyribose nucleoside modifications conducted in water as the sole reaction solvent. Although water provides a sustainable alternative to the usage of environmentally polluting volatile organic solvents, there certainly are questions about its usage too given the problems associated with the limited availability of drinkable water sources, and further contamination could pose a major environmental problem. Therefore, it is very important to recover the water used during the reaction as well as possibly conduct several recycles of the catalytic solutions to achieve sustainability.

4

Deep Eutectic Solvents

Previous sections discussed in detail the usefulness and importance of ILs and water as sustainable solvents with each having several issues that limit their applications beyond academia. DES have been in recent years identified as a suitable alternative to ILs due to the special properties offered by them. DES are environmentally benign solvents formed from the combination of two or more substances and have melting points lower than that of the individual components due to hydrogen bonding interactions [227], [228]. The term “eutectic” was first introduced by British physicist F. Guthrie in 1884, [229] while the concept of DES was introduced by Abbott et al. in 2003. Abbott first synthesized DES by mixing choline chloride and urea, resulting in a liquid with a eutectic melting point of 12 °C [230]. DES are useful in sustainable chemistry for their biodegradability and low toxicity, making them suitable for various applications, including electrochemistry, organic synthesis, biotransformation, and catalysis [231], [232], [233].

DES is often compared with ILs due to their similarities, such as high thermal stability, low volatility, and low vapor pressure. However, DES offers advantages over traditional ILs, including more straightforward synthesis, lower cost, and less environmental impact as, many times, they are a combination of biocompatible substrates. They effectively address issues like moisture sensitivity and high costs associated with some ILs [152], [234]. However, nucleoside chemistry in ILs is more common than in DES. In biocatalysis, DES has proven beneficial compared to aqueous solvents and polar organic solvents such as acetone, DMSO, or methanol which can denature enzymes. DES allows for the dissolution of substrates while maintaining enzyme activity. Research has shown that DES can support various biocatalytic processes, such as lipase-catalyzed transesterification, aminolysis, epoxide hydrolysis, N-alkylation of aromatic amines, and Knoevenagel condensation, often achieving comparable or superior rates and selectivity relative to conventional organic solvents [235], [236], [237], [238].

Despite having many advantages, DES has been relatively underexplored in nucleoside chemistry. This is primarily due to the high polarity of nucleosides and the fact that DES does not offer the same level of solubility for nucleosides as ILs or water. The following section will address the modification of nucleosides using DES.

4.1

Modification of Nucleobase Moiety

4.1.1

Sonogashira Coupling

Significant modifications in pyrimidine and purine moieties, through the introduction of aryl, polyaryl, heteroaryl, heteropolyaryl, alkenyl, and alkynyl groups via C–C cross-coupling, have been explored to study biological environments like DNA and RNA structural probes, protein–DNA complexes, DNA damage, mutation, and cancers. The palladium-catalyzed Sonogashira coupling reaction is effective for alkyne group installation and has emerged as a crucial synthetic tool in recent years. This method facilitated the synthesis of fluorescent nucleosides for biological probe applications [239], [240], [241]. In 1975, Sonogashira, Hagihara, and Tohda reported the Pd(PPh₃)₂Cl₂ catalyzed reaction involving CuI as the co-catalyst and amine as the base [242]. Subsequent modifications have employed various catalysts, additives, and ligands under diverse conditions. However, using copper salts can negatively impact catalysis and require stoichiometric amounts of copper co-catalyst, which may contaminate the modified nucleosides [187].

Consequently, significant research focuses on developing copper-free and preferably amine-free Sonogashira catalytic systems. In recent decades, nearly 40% of the Sonoghashira coupling reactions have been conducted in N,N-dimethylformamide (DMF), a toxic solvent [243]. Hence, recent advances in Sonoghashira reaction protocols have emphasized developing eco-friendly methodologies, including reactions conducted in water or aqueous organic solvent mixtures, glycerol, and under aqueous micellar conditions with surfactants as additives. In nucleoside chemistry, only a few methodologies have been employed for the alkynylation of purines and pyrimidines, and these typically involve water-organic solvent mixtures [158], [244].

Scheme 33 Sonoghashira coupling of 6-iodouracil derivative under using ChCl/Gly deep eutectic solvent.

Uracil derivatives are valuable frameworks in drug discovery, showing various biological and pharmacological properties [245], [246]. Few studies have explored using DESs or low melting mixtures (LMMs) for Sonoghashira coupling. Notable contributions include Fuxiang et al., [247] König and Ilgen, [248] and Ramón, Alonso, and Guillena et al., [249], [250] who conducted Sonogashira couplings using various eutectic mixtures. A commonality among these procedures is the necessity of a suitable ligand complexed with palladium. Ligand-free Sonoghashira coupling reactions in eco-friendly unconventional solvents are relatively rare.

In 2020, Capriati, Salomone, and colleagues [251] illustrated the ligand-free Pd/C catalyzed Sonogashira cross-coupling of (hetero)aryl iodides and protected 6-Iodouracil derivative utilizing a choline chloride/glycerol eutectic mixture as an environmentally friendly solvent ([Scheme 33]). The authors primarily demonstrated the coupling of various (hetero)aryl iodides with aromatic and aliphatic alkynes without the need for copper as a co-catalyst. They also explored the effectiveness of the developed methodology for a 6-iodouracil derivative. The 6-iodouracil derivative was cross-coupled with phenylacetylene in the presence of CuI (20 mol %) at 60 °C, resulting in a 50% yield of the desired product. One advantage of this approach is its ability to successfully apply to electron-rich iodides, which are typically challenging substrates for Sonogashira coupling. Furthermore, the eutectic mixture and the catalyst can be reused for up to four cycles. While significant progress in nucleoside chemistry using DES has not been achieved, this solvent could be a promising choice for future advancements.

5

2-Methyltetrahydrofuran

2-Methyltetrahydrofuran (2-MeTHF) is a readily available, cost-effective, and environmentally friendly solvent derived from renewable biomass, specifically from furfural obtained from corn, sugar cane bagasse, and oat hulls [26], [252]. Substituting 2-MeTHF for traditional solvents such as tetrahydrofuran (THF), dichloromethane, or dichloroethane promotes greener chemical processes by adhering to reduction, recycling, and reuse principles. 2-MeTHF, a cyclic ether with a higher boiling point (80 °C) than THF (66 °C), minimizes solvent evaporation during reactions. It also demonstrates superior resistance to hydrochloric acid compared to THF, while the lower possibilities of forming the dangerous peroxides also make 2-MeTHF more suitable for usage [253]. Preliminary toxicological studies have not linked 2-MeTHF to genotoxicity or mutagenicity, enhancing its safety profile [254]. As a result, 2-MeTHF is increasingly employed as a replacement for THF in various applications, including the preparation of Grignard reagents, [255] low-temperature lithiation, [256] lithium aluminum hydride reductions, the Reformatsky reaction, [257] and metal-catalyzed coupling reactions [258], [259] but less explored in the nucleoside chemistry field. Additionally, 2-MeTHF has shown promise in lipase-catalyzed transesterification [260], [261] and other chemical processes, demonstrating its utility and effectiveness as a bio-based solvent.

Nucleosides, characterized by their polar nature due to multiple hydroxyl and amino groups, are poorly soluble in nonpolar solvents. Consequently, polar solvents such as tetrahydrofuran (THF), pyridine, and binary solvent mixtures have been traditionally employed for the enzymatic acylation of nucleosides, as they offer satisfactory solubility [262], [263]. However, the polar solvents can deactivate enzymes, limiting enzymatic processes’ effectiveness [264], [265]. 2-MeTHF is more compatible with enzymes than THF. Hence, nowadays, researchers have started using 2-methyltetrahydrofuran (2-MeTHF) as an alternative to other polar solvents for the enzymatic acylation of the 5′-hydroxyl group of nucleosides. This topic will be discussed in detail in the next section.

5.1

Modification of Sugar Moiety

5.1.1

Acylation of 5′-OH

Nucleosides are crucial polyhydroxylated compounds with significant applications as antiviral and antitumor agents [266], [267]. Despite their therapeutic benefits, these nucleoside drugs often exhibit low oral bioavailability and short plasma half-lives due to their high polarity and rapid cleavage of the glycosyl bond by nucleoside phosphorylase [266], [268]. To address these limitations, acylation of nucleosides has proven beneficial. For example, valganciclovir, [269] an ester derivative of ganciclovir, [270] shows improved therapeutic efficacy compared to its parent drug. However, regioselective chemical acylation of nucleosides remains a complex and labor-intensive process involving multiple protection and deprotection steps. Enzymatic methods offer a promising alternative, providing regiospecific 5′-OH acylation with mild reaction conditions and reduced environmental impact, thus presenting a more efficient and eco-friendly approach for nucleoside modification [271], [272].

Scheme 34 Enzyme-catalyzed acylation of cordycepin in anhydrous 2-MeTHF solvent.

In 2012, Li, Zong, and co-workers [273] demonstrated a regioselective enzyme acylation of 8-chloroadenosine and its analogues in MeTHF using immobilized Penicillium expansum lipase (PEL). The 5′-O-regioselectivity depended on the nucleoside structures, particularly the 2′-substituents. The lipase-catalyzed regioselective undecylenoylation of purine nucleosides was carried out with 25 U/mL of immobilized enzyme, 7.5 to 15.0 equiv of undecylenic acid vinyl ester, and incubated at 35 °C, resulting in yields of acylated products ranging from 63 to 95% and excellent regioselectivities (94 → 99%). The study revealed that the lipase exhibited enhanced catalytic activity and improved thermostability in MeTHF compared to other organic solvents and co-solvent systems. The use of solvents derived from biomass holds the potential to open up new avenues for environmentally friendly and sustainable biocatalytic processes.

Scheme 35 Enzyme-catalyzed regioselective undecylenoylation of 8-chloroadenosine and its derivative.

Cordycepin possesses a wide range of interesting biological and pharmacological activities, but it undergoes rapid hydrolytic deamination by adenosine deaminase (ADA). Cordycepin exhibits hydrophilic properties, making it challenging to pass through cell membranes via passive diffusion. Several studies have suggested that fatty acid ester derivatives have the potential to serve as effective prodrugs for numerous nucleoside drugs. Thus, the acylation of cordycepin will help prevent rapid deamination and increase its pharmacological activity. In 2013, Chen and co-workers [261] conducted the first enzyme-catalyzed regioselective acylation of cordycepin using Novozyme 435 and vinyl acetate at 45 °C in an environmentally friendly solvent 2-MeTHF.

Scheme 36 Enzyme-catalyzed acylation of pyrimidine nucleosides in anhydrous 2-MeTHF solvent.

They tested nine lipases and three proteases to assess their effectiveness in enzymatically acylating cordycepin with vinyl acetate in organic media. Novozyme 435 exhibited exceptional operational stability in MeTHF, leading to the most favorable results, characterized by the highest conversion rate and superior initial reaction speed ([Scheme 36]). The biocatalytic process was found to be applicable for scales of up to 25 g, yielding 95.2%. Novozym 435 can be recycled for up to 7 cycles to synthesize cordycepin derivative on a 25-g scale.

Later in 2013, the same research group [274] employed the PEL enzyme for the regioselective acylation of pyrimidine nucleosides using 2-MeTHF as a solvent and analyzed the interaction between the enzyme and substrate based on the nucleoside structures. They examined the solubility of 5-fluorouridine in four solvents: 2-MeTHF, acetone, acetonitrile, and THF. Although the nucleoside’s solubility was highest in THF, the hydrophobic nature of 2-MeTHF resulted in a lower activation energy (E _a) than the other solvents. As a result, MeTHF demonstrated the highest catalytic activity for the lipase, exceeding that in THF by more than six times.

Additionally, they investigated the impact of 5-substituents found in the base moiety of nucleoside structures on the regioselective enzymatic acylation reaction. Furthermore, the influence of 2′- and 3′-substituents in the sugar moiety was also studied. Halogenated uridine derivatives displayed increased solubility and achieved a conversion rate of 99%. Later, Substituting the 2′-hydroxy group with a hydrophobic methoxy group or fluorine notably enhanced solubility and initial reaction rates. However, minimal impact was seen on the 5′-O-regioselectivity. The absence of a 3′-hydroxyl in the sugar component significantly enhanced nucleoside solubility, although enzymatic acylation rates decreased. The effect of the solvent and structural characteristics of the nucleoside is evident in the results obtained.

Scheme 37 Regioselective and diastereoselective [3+2] annulation of α-purine-substituted acrylates with nitrones using 2-MeTHF as a green solvent.

5.1.2

Miscellaneous Reactions in 2-MeTHF

Recently, in 2023 Wang and co-workers [275] demonstrated a catalyst-free, regioselective, and diastereoselective [3+2] annulation of α-purine-substituted acrylates with nitrones using 2-MeTHF as an eco-friendly solvent at room temperature for 24 h, resulting in good to excellent yields of the single diastereomeric isoxazolidinyl product ([Scheme 37]). Various solvents were evaluated, with 2-MeTHF demonstrating the excellent yield and diastereoselectivity of >20:1. Steric hindrance, electronic properties, and substituents on the aryl and styryl groups do not affect regio-, diastereoselectivity of the product. The introduction of different substituents at the C2 and C6 positions of the purine skeleton showed minimal impact on the reaction outcome.

6

Solvent-free Reactions

Mechanochemistry is an emerging discipline within organic chemistry that employs mechanical force to form or break bonds. This approach not only diminishes the reliance on solvents but also accelerates reaction rates and facilitates the synthesis of various products. Mechanochemistry is attracting interest in the nucleotides, nucleotide and phosphoramidites chemistry, as it lessens exposure to aqueous conditions, thereby reducing or potentially eliminating side reactions associated with solvents and heating [276], [277], [278]. Prior research has thoroughly investigated solid-state reactions with grinding mode [279], [280]. Reactions such as Reformatsky and Luche, [281] cyclopropanation, [282] Aldol condensations, [283] Dieckmann condensations, [284] Knoevenagel condensations, [285] reductions, [286] Michael addition, [287] and phenol coupling reactions [288] have been reported. Simplicity, selectivity, and yield are some of the advantages of these reactions. High-speed ball milling has been implemented under solvent-free conditions for reactions such as the synthesis of flavones from β-dicarbonyl compounds, [289] dimerization of C₆₀, [290] Horner–Wadsworth–Emmons reaction, [291] synthesis of polysubstituted pyrroles, [292] halogenation of aromatic compounds, [293] etc. This procedure offers rapid conversion of a desired product under solvent-free conditions and requires low catalyst loading. Although this methodology is widely used in the organic chemistry field, [294] its application to nucleoside or nucleotide substrates on preparative scales has been limited. But this approach could be viewed as a viable sustainable alternative to conventional solvent practices.

7

Conclusions and Outlooks

Nucleosides and oligonucleotide-based pharmaceutical drug requirements in the world market have risen exponentially in the past decade. This rise has coincided with the rapid development of synthetic protocols allowing the efficient functionalization of the basic nucleoside unit and has certainly helped industry to cater to these increased demands in a timely manner. However, the ramifications of utilizing large amounts of reagents and solvents for the reactions as well as for the purification has put researchers in academia/industry under increased pressure to develop sustainable synthetic solutions. Volatile organic solvents used extensively in these processes have commonly been associated with problems of environmental pollution, toxicity, and risk of explosion. Industry is under increased pressure to identify greener alternatives to the existing technologies mainly in terms of curtailing the usage of VOCs and replacing them effectively with green or sustainable solvents while reducing overall process mass intensity (PMI) [295].

Academic researchers have led the way in addressing this crucial issue and have identified several green/sustainable solvents that could provide the desired solution to VOCs. This review details the state-of-the-art in the quest to provide improved sustainability to the modification/functionalization of nucleosides which are the important building blocks for oligonucleotides/oligonucleotide-based drug synthesis. Solvents such as ILs, water, DES, and 2-MeTHF have been identified and applied effectively to obtain improved yields of the modified nucleosides in various processes. However, this is just the tip of the iceberg and much more needs to be done to address the burning issue in front of the industry of making the oligonucleotide manufacturing process more sustainable by achieving a lower PMI. There should also be an attempt from the industry to incorporate some of these methodologies if they offer better yield, and improved reaction conditions and therefore help achieve sustainability in manufacturing. Alternatively, the usage of solvents for these processes could also be curtailed by the employment of solvent-less, solvent-free, or chromatography-free synthetic protocols utilizing efficient mechanochemical methods such as ball milling that has in recent years demonstrated its effectiveness [296].

Contributorsʼ Statement

Data Collection: Manisha Patel, Mahadev Kudalkar, Anant R. Kapdi Drafting of Manuscript: Manisha Patel, Mahadev Kudalkar, Anant R. Kapdi Critical revision of manuscript: Anant R. Kapdi and Yogesh S. Sanghvi.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgments

The authors would like to acknowledge CSIR India for providing a junior research fellowship to M.P. and UGC India for providing a junior research fellowship to M.K.

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Publication History

Received: 21 September 2024

Accepted after revision: 14 November 2024

Accepted Manuscript online:
19 November 2024

Article published online:
21 January 2025