Greener Synthesis of Nitrogen-Containing Heterocycles in Water, PEG, and Bio-Based Solvents

The solvents used in chemistry are a fundamental element of the environmental performance of processes in corporate and academic laboratories. Their influence on costs, health safety, and nature cannot be neglected. Quantitatively, solvents are the most abundant constituents of chemical transformations; therefore, acting on solvents and replacing standard solvents with safer products can have a great ecological impact. However, not all green solvents are suitable for the wide scope of organic chemistry reactions. A second point to consider is that 50% of pharmaceutical drugs are nitrogen heterocycles compounds. It therefore appeared important to provide an overview of the more ecological methodologies for synthesizing this class of compounds. In this review, all publications since 2000 that describe green reactions leading to the formation of nitrogen heterocycles using safe solvents were considered. We chose water, PEG, and bio-based solvents for their negligible toxicity. The synthesis of five-, six-, and seven-membered aromatic nitrogen heterocycles using green reactions reported in the literature to date is described.


Introduction
Even if the chemistry community has made significant efforts towards identifying greener processes by minimizing the quantity of catalysts or using multicomponent reactions and one-pot processes, solvents remain a major portion of the environmental performance of a process, and may have a significant influence on safety and health issues. Green solvents such as water, Poly(ethylene glycol) (PEG) and bio-based solvents hold considerable additional promise to reduce the environmental impact of organic chemistry. The study and search for greener synthetic methods have gained importance over the past two decades ( Figure 1).

Background and Methodology
After some time dedicated to the search for Green Reactions Leading to the Formation of N-Heterocycles, the excellent review entitled "More Sustainable Approaches for the Synthesis of N-Based Heterocycles", published by Candeias et al. in 2009 [1] was identified. More recently, other teams also presented well-documented work on green chemistry [2][3][4][5] and about the synthesis of heterocyclic compounds [6][7][8][9][10][11][12][13][14][15][16]. The instant review discusses the use of green reactions leading to the formation of nitrogen heterocycles by means of safe solvents, namely water, PEG and various biobased systems, since 2000. Methyl-THF, which is one of the bio-sourced green solvents widely used today to replace THF, will not be discussed in this review because we did not find any work reporting its use for the synthesis of nitrogen containing heterocycles. Similarly, we will not discuss the use of ionic liquids here since many reviews were already devoted to them. Herein, each of the synthetic strategies and examples are briefly described. We trust this review will be helpful to a broad community of scientists working in medicinal chemistry.

Sustainable Chemistry
Greener routes are required in the synthesis of N-heterocycles, due to the remarkable importance of these compounds in medicinal chemistry [17,18]. Solvents play an important role in the chemical industry and their effectiveness in acting along with reagents and products within chemical processes is a crucial factor. The choice of a solvent will influence the chemical reactivity, selectivity, and yield of the synthesis process. One way to try to minimize safety, toxicity, and emission problems is to find or develop new solvents to replace those commonly used [19,20]. In recent years, valid proposals for green solvents have been reported such as water [21][22][23], and polyethylene glycol for its low price and its low acute toxicity [24][25][26]. More recently, research teams have demonstrated that the use of bio-based solvents is also a relevant choice [27][28][29][30]. All these results in the quest for safer solvents are the best evidence that the concepts of green chemistry have made remarkable progress.

Water as Solvent
The use of water as solvent in reactions is a positive choice from the environmental and economic point of view as it is an inexpensive, nonflammable and widely available resource [31][32][33][34]. A report of water used as solvent for the synthesis of heterocycles was published in 1931 for the cycloaddition reaction of furan and maleic anhydride by Diels and Alder [35]. Later, an important example was disclosed by Breslow [36,37], who demonstrated that hydrophobic effects could strongly enhance the rate of several organic reactions. Water has many advantages as reaction solvent for organic synthesis, but the poor solubility of many organic compounds in water limits its use under standard conditions. However, when applied at high temperatures and pressures, it undergoes changes in its properties and can become a good solvent for organic synthesis [16].

PEG as Solvent
In recent years, polyethylene glycols (PEGs) have attracted special attention as green solvents in various chemical transformations [38]. These low-cost compounds are available in a wide range of molecular weights [39]. PEG 400 is presented as a viscous liquid soluble in water and many organic solvents. It has the advantage of being biodegradable, non-toxic, odorless, neutral, non-volatile, and non-irritating, which has allowed its use in a variety of drugs and medications [40][41][42].

Reactions in PEG
The group of Yedukondalu performed the synthesis of substituted tetrahydrocarbazoles. By heating phenyl hydrazine hydrochlorides or 4-piperidone hydrochloride with substituted cyclohexanones or piperidone in PEG, the team was able to synthesize several derivatives, as shown in Scheme 10 [54]. Mishra et al. employed a one-pot synthesis protocol for the preparation of aminoindolizine. The results were achieved using pyridine-or quinoline-2-carboxaldehydes with secondary amines and terminal alkynes via tandem C-H activation, coupling, and cyclization reactions using copper chloride (Scheme 11) [55].

Reactions in Bio-Based Solvents
Dandia et al. reported the first ever 1,3-dipolar cycloaddition synthetic protocol for the synthesis of spirooxindole derivatives using ethyl lactate as bio-based solvent. The reaction proceeded in high yield with the 1,3-dipolar cycloaddition reaction of substituted isatin and proline with napthaquinone (Scheme 12) [56]. In 2015, Wang et al. reported an efficient novel and scalable process for the synthesis of pyrrole derivatives in lactic acid under ultrasonic irradiation. The synthesis, which gave excellent yields, consisting of several pyrrole derivatives, was achieved from the Knorr condensation reaction. The authors demonstrated that the condensation reaction in lactic acid under ultrasonication avoids the shortcomings of causticity, volatility, and recycling difficulties, when compared with traditional Knorr condensation using acetic acid as solvent (Scheme 13) [57]. Yang et al. investigated the use of lactic acid in three-component condensation of benzaldehydes, anilines and diethyl acetylene dicarboxylate to obtain polysubstituted pyrrolidinones. This team showed that the application of this bio-based solvent resulted in several improvements; the products were isolated in good yields using a single step and in a shorter time (Scheme 14) [58]. Li et al. employed a four-component coupling of amines, aldehydes, 1,3-dicarbonyl compounds, and nitromethane to obtain pyrrole derivatives. Compounds were prepared using a gluconic acid aqueous solution as an efficient and reusable promoting medium. This methodology demonstrated excellent functional group tolerance, short reaction time, and high yield of products (Scheme 15) [59].

Reactions in Water
Recently, Muthusamy and Gangadurai published the synthesis of benzopyranopyrazoles through a 1,3-dipolar cycloaddition approach involving an in situ generated aryl diazomethane from propargylated salicyl aldehydes and their intramolecular [3+2]-cycloaddition reaction with a suitably placed terminal alkyne/alkene. Aryl diazomethanes were generated by base-mediated decomposition of the corresponding aryl sulfonyl hydrazones; in addition, hydrazones were readily accessed from the corresponding aldehydes (Scheme 16) [60]. The group of Eswararao achieved the rapid synthesis of 1H-pyrazolo [1-b]phthalazine-5,10diones using InCl3 catalyzed reaction of phthalic anhydride, hydrazine hydrate, benzaldehydes and malononitrile/ethyl cynoacetate at reflux in good yields (Scheme 17) [61]. Maleki et al. worked on the preparation of pyrano [2,3-c]pyrazoles. These reactions were conducted with a one-pot, four-component synthesis process catalyzed by nano-structured diphosphate in water. The library of pyrano [2,3-c]pyrazoles was successfully synthesized with this method, which proved to be effective for aromatic aldehydes bearing either electron-donating or electron-withdrawing substituents as well as for the heterocyclic aldehyde (Scheme 19) [63]. Bakherad et al. demonstrated a reaction protocol using magnetized water as solvent. The water was prepared using a static magnetic system of 6000 G field strength with a flow rate of 500 mL s-1 at different magnetization times. The generation of pyrano [2,3-c]pyrazoles and pyrano[4ʹ,3ʹ:5,6]pyrazolo [2,3-d]pyrimidines proceeded through a one-pot four-component catalystfree protocol (Scheme 20) [64]. Marković and Joksović reported a methodology for the construction of the ethyl 5-aryl-1Hpyrazole-3-carboxylate ring system from 4-aryl(hetaryl,alkyl)-2,4-diketoesters and 1,3-diketones with semicarbazide hydrochloride. This approach did not require toxic hydrazine and product purification, eliminating the use of toxic liquid chemicals (Scheme 21) [65]. Dam et al. achieved a super-paramagnetic nanoparticle supported L-proline catalyst (nano-FDP) for the construction of the pyrazole ring. The strategy adopted was under ultrasonic irradiation. The various derivatives were prepared in excellent yields at room temperature (Scheme 22) [66]. The team of Srivastava reported an iodine-catalyzed sequential process to access pyrazole series from phenyl hydrazine, malanonitrile, and a diverse range of aldehydes. The strategy was performed using water as solvent and no purification by column chromatography was required (Scheme 23) [67].  Wu et al. reported a synthetic approach for the synthesis of pyranopyrazole using cetyltrimethylammonium chloride (CTACl) as catalyst. The catalyst applied showed high activity, high stability and the desired products were obtained in good to excellent yields from ethyl acetoacetate, hydrazine hydrate/phenylhydrazine, aromatic aldehydes, and malononitrile, using water as solvent at 90 °C (Scheme 27) [71]. Zonouz et al. presented a catalyst-free methodology for the synthesis of methyl 6-amino-5cyano-4-aryl-2,4-dihydropyrano [2,3-c]pyrazole-3-carboxylates in water using a one-pot, fourcomponent reaction. The key steps in the synthesis were the formation of benzylidine malononitrile via Knoevenagel condensation between aldehyde and malononitrile; then the formation of pyrazolone by reaction of hydrazine hydrate with dimethyl acetylenedicarboxylate; and lastly, the Michael addition of the formed intermediates, followed by cyclization and tautomerization (Scheme 28) [72]. Savant et al. obtained trisubstituted pyrazoles via a sequential condensation of various Racylketene dithioacetals with hydrazine hydrate, followed by the oxidation of sulfide to sulfone using water as solvent. The derivatives were successfully achieved using water as solvent and with a short reaction time. (Scheme 30) [74]. The team of Mali performed a condensation of 2-chloro-3-formyl quinolines and hydrazine hydrate/phenyl hydrazine for the synthesis of pyrazolo [3,4-b]quinolines. This protocol was carried out in aqueous medium and using thermal/microwave energy resources (Scheme 31) [75].

Reactions in PEG
Karnakar et al. synthesized spiro pyranopyrazole derivatives in good to excellent yields using PEG as solvent. This one-pot four-component reaction promoted by a Knoevenagel condensation occurred between isatin and malononitrile, which reacted with the pyrazolone intermediate formed by the condensation of dialkyl acetylene dicarboxylate and hydrazine hydrate. The sequential strategy was finalized with the Michael addition, followed by enolization and ring closure to provide the desired product (Scheme 32) [76].

Reactions in Bio-Based Solvents
Bhat et al. achieved the synthesis of 2-pyrazoline derivatives by applying a reaction approach catalyzed by cerium chloride heptahydrate (CeCl3 • 7H2O) and ethyl lactate as solvent. The team was able to successfully prepare 1,3,5-triaryl-2-pyrazoline from the condensation reaction between chalcones and phenyl hydrazine (Scheme 35) [79].  Wagare et al. developed an efficient microwave-assisted one-pot process for the synthesis of azaindolizines in PEG 400 and water. The construction of these compounds was achieved from 2aminopyridines and in-situ generated phenacyl bromides. This protocol avoided the use of lachrymatory α-haloketones as well as volatile toxic organic solvents and reduced the reaction time to obtain excellent yield (Scheme 38) [82]. Nikoofar et al. reported a catalytic system to be used for the synthesis of 2,4,5-triaryl-1Himidazoles in water under reflux conditions. The use of ZnO nanorods (ZnO NRs) as catalyst was developed. The authors showed that they were mild, benign, and effective catalysts for the preparation of tri-substituted imidazoles in high yield from a one-pot, three-component protocol (Scheme 39) [83].  Rustagi et al. obtained various fused benzimidazo[2,1-a]isoquinolines performing a one-pot approach to the regioselective tandem from o-alkynylaldehydes and arylamines with tethered nucleophiles using AgI as catalyst in water. This protocol was shown to have a broad substrate scope, good functional group tolerance, and high efficiency (Scheme 44) [88]. Rustagi et al. adopted a tandem reaction for the synthesis of substituted benzimidazoles. This protocol was conducted in aqueous media from o-alkynyl aldehydes and amines having an Ntethered nucleophile using Ag(I) as the catalyst. The sequential strategy involved the formation of two new carbon-nitrogen bonds and one new carbon-carbon bond, thereby leading to the formation of two heterocyclic rings in a one-pot reaction giving fused polycyclic heterocycles (Scheme 46) [90]. Peng et al. reported a study to obtain benzimidazole in water. For this process, they developed a Cu2O/DMEDA system to achieve intramolecular C-N Bond formation and consequently the benzimidazole ring system in high yields (Scheme 47) [91].

Reactions in PEG
Mekala et al. carried out an efficient procedure for the synthesis of 1,2-disubstituted benzimidazoles. The construction of these compounds was achieved by the nucleophilic attack of the phenylenediamine on the carbonyl carbon. The electrophilicity of the carbonyl carbon was enhanced in the PEG 400 medium compared to the other solvents, and hence accelerated the reaction by removing the liberated water, which was soluble in PEG 400. It enabled its conversion to the corresponding benzimidazole (Scheme 51) [95]. In 2014, Berteina-Raboin et al. generated 2-arylimidazo[1,2-a]pyridines in good yields within 10 minutes from readily available 2-amino pyridines and α-bromo ketones. A one-pot procedure was engineered to achieve 2,3-diarylimidazo[1,2-a]pyridines using a reduced amount of palladium catalyst without ligand for the C-H arylation step in the same environmentally sound medium (Scheme 52) [96]. Guchhait and Madaan studied the scope and limitations of an Ugi-Type Multicomponent Reaction mediated by Zirconium(IV) Chloride in PEG. The construction of these compounds was carried out using reaction of heterocyclic amidines with aldehydes and isocyanides. The team reported that the combination of catalyst and solvent was crucial for the regioselectivity and versatility of the method (Scheme 53) [97].

Reactions in Bio-Based Solvents
Berteina-Raboin et al. demonstrated, for the first time, that eucalyptol could be used as solvent for organic synthesis. They have shown that it could be an interesting alternative to conventional solvents for the one-pot synthesis of 2,3-diarylimidazol[1,2-a]pyridines involving a condensation between 2-aminopyridine and bromoacetophenones, followed by a C-H activation at C-3. This solvent, derived from biomass and recyclable, was also effective for various transformations of heteroatom-containing heterocycles such as oxygen, sulfur, or nitrogen (Scheme 54) [44].

Reactions in Water
In 2017, Dheer et al. reported the synthesis of iodo substituted 1,2,3-triazoles. The scope of the reaction was explored by using substituted benzyl bromides and acetylenes in water at 90 °C. The desired products, 5-iodo-1,4-disubstituted-1,2,3-triazoles were obtained in major quantity with 1,4disubstituted-1,2,3-triazoles as minor product. In general, substituted phenylacetylene reacted smoothly with in-situ synthesized benzyl azide to furnish the triazole derivatives. It was observed that aliphatic halides were moderately reactive as compared to benzyl halides and furnished the products in moderate to lower yields (Scheme 55) [80]. Hiroki et al. adopted a copper(I) chloride catalyzed reaction using 2-ethynylpyridine as catalyst, and were able to synthesize 1,4-disubstituted 1,2,3-triazoles in good yields from azides and alkynes at room temperature (Scheme 56) [98].

Kumar et al. employed an Intramolecular Huisgen
[3+2] cycloaddition in water for the preparation of pyrrolidine-triazole derivatives. Compounds were prepared with complete 1,5regioselectivity and no metal catalyst. Azido-alkynes derived from amino acid/tartaric acid were used, and an alkyne attached to an electron withdrawing group provided the final product with a better yield and stability (Scheme 58) [100]. Anil et al. prepared 1,4-disubstituted 1,2,3-triazoles through magnetically separable and reusable copper ferrite nanoparticles in a one-pot reaction, in tap water. This protocol was successfully achieved from the initial substitution of benzyl halides with sodium azide to generate in situ benzyl azides, followed by copper ferrite catalyzed cycloaddition reaction with alkynes in water at 70 °C (Scheme 59) [101].

Reactions in PEG
Reddyʹs group reported the synthesis of triazolo-1,2,4-benzothiadiazine-1,1-dioxides via a copper-catalyzed tandem cyclisation of ynamides. This approach was crucial because fused triazolo ring system could be prepared through an intermolecular C-N bond formation followed by subsequent cycloaddition between ynamide and azide. Thus, three new C-N bonds were formed in a single step (Scheme 60) [102].   In 2011, Kumarʹs team also presented the preparation of thiazoles. The library was achieved from readily available α-tosyloxy ketones with several thioamides using water as solvent in good yields (Scheme 69) [89]. Yavari et al. reported a one-pot procedure to achieve N-alkylthiazoline-2-thiones. The strategy adopted was a catalyst-free reaction system that started by the formation of an alkylammonium dithiocarbamate salt, followed by addition to 2-chloro-1,3-dicarbonyl compounds to generate the acyclic dithiocarbamate derivatives; then cyclization (and closure of the ring) and elimination of water in the presence of alkylammonium chloride led to the desired product. The various derivatives were prepared from primary amines, carbon disulfide, and 2-chloro-1,3-dicarbonyl compounds in water (Scheme 71) [112]. This work developed an approach catalyzed by ceric ammonium nitrate in PEG to afford benzothiazoles in good yields in 5 h at room temperature. Additionally, the team was able to recover and reuse the catalyst system without any noticeable loss in activity (Scheme 78) [117].

Reactions in Bio-Based Solvents
Vaidya et al. adopted a reaction catalyzed by cerium chloride heptahydrate in ethyl lactate as bio-based solvent to achieve isoxazolone derivatives. The methodology was carried out at room temperature; the catalyst and solvent were reused (Scheme 91) [128].
The reported protocol allows the formation of two pyridine rings in a one-pot reaction through the synthetic route without starting from any nitrogen-containing heterocycle moiety (Scheme 111) [145]. Akbari et al. adopted a one-pot Friedlander reaction for a domino approach to quinoline synthesis in aqueous medium. The series were accomplished from 2-aminoaryl ketones and βketoesters/ketones using the catalytic system of SO3H-functionalized ionic liquid. With this strategy, it was possible to recover and reuse the catalytic system (Scheme 116) [150].

Reactions in Water
Rimaz and Khalafy reported the synthesis of a series of alkyl 6-aryl-3-methylpyridazine-4carboxylates in water. The reaction protocol involved a condensation reaction of β-ketoesters with arylglyoxals in the presence of hydrazine hydrate at room temperature (Scheme 139) [170]. These results were achieved using short reaction times and without any catalyst (Scheme 153) [183]. The same group adopted a similar strategy to obtain 2,3-dihydroquinazolin-4(1H)-one derivatives. In a one-pot procedure and using three components (isatoic anhydride, anilines and aromatic aldehydes) the desired products were successfully achieved (Scheme 158) [ [190]. reaction. The catalytic complex system was prepared previously and was reusable (Scheme 164) [194]. In 2013 Bardajee reported another strategy to achieve quinoxaline and pyrazine derivatives using water as solvent. In this case the reaction was catalyzed by Zirconium(IV) oxide chloride.

Reactions in Water
The group of Alinezhad accomplished the synthesis of diazepines in aqueous medium using 2methylpyridinium trifluoromethanesulfonate as catalyst. The 1,5-benzodiazepine were produced in good yields by reacting o-phenylenediamine with ketone. The methodology presented relevant advantages, such as short reaction time and reusable catalyst system (Scheme 182) [194].

Conclusion
In this review, we listed the reactions reporting with green methodologies for the synthesis of 5, 6 or 7-membered nitrogen or poly-nitrogen heterocyclic compounds. These molecules often have interesting biological activities and are structures often generated in medicinal chemistry. We hope that gathering information will enable the scientific community to implement syntheses that respect our environment a little better in order to reduce our impact as organic chemists on the state of the planet.

Conflicts of Interest:
The authors declare no conflict of interest.