A mini-review on organic synthesis in water

Organic synthesis in water has attracted the attention of chemists for many years. Water is the nature’s solvent and possesses distinguished physical and chemical properties. It exhibits powerful hydrogen bonding and wide temperature range to remain in liquid state. In recent years, many organic transformations have been carried out in water.1,2 Many organic solvents like benzene, methanol, toluene are carcinogenic and can be toxic to human health and cause an environmental menace by polluting the atmosphere. The replacement of volatile organic solvents in organic reaction is an important aim of green chemistry.3,4 Earliest known examples of organic synthesis in water include Wohler’s urea synthesis and Baeyer and Drewsen’s indigo synthesis.5–7


Introduction
Organic synthesis in water has attracted the attention of chemists for many years. Water is the nature's solvent and possesses distinguished physical and chemical properties. It exhibits powerful hydrogen bonding and wide temperature range to remain in liquid state. In recent years, many organic transformations have been carried out in water. 1,2 Many organic solvents like benzene, methanol, toluene are carcinogenic and can be toxic to human health and cause an environmental menace by polluting the atmosphere. The replacement of volatile organic solvents in organic reaction is an important aim of green chemistry. 3,4 Earliest known examples of organic synthesis in water include Wohler's urea synthesis and Baeyer and Drewsen's indigo synthesis. [5][6][7] In recent years, several N, O, and S containing heterocyclic compounds are synthesized employing green synthetic protocols. It is of considerable interest to learn more about varied green technology platforms, which have been utilized for the synthesis of important heterocyclic scaffold. Being an important and growing area of research, these green protocols have been regularly reviewed. The present attempt is to review briefly water mediated organic reactions, resulting in the synthesis of various heterocyclic frame works and to highlight the significance as well as utility of water as a green solvent. 8 Zarei M et al. 8 reported the synthesis of pure azo Schiff bases (2) in high yields by mixing of the reagents either as aqueous slurry or by grinding at room temperature. Azoaldehyde (1) was prepared from p-anisidine and 2-hydroxy-3-methoxybenzaldehyde (o-vanillin) in aqueous medium at 0-5°C and then 1 was allowed to react with amines in a small amount of water at room temperature to produce azo Schiff bases (2) in excellent yields ( Figure 1).

Synthesis of pyrano[2,3-c]pyrazoles 9
Silica-water reaction medium was applied by Pravin et al. 9 for the synthesis of various pyrano [2,3-c]pyrazole derivatives based on the adsorptive nature of silica. The reaction was carried out under mild and neutral conditions accepting several functional groups present in the molecules thus reducing the possibility of many unwanted side reactions. Present method offers marked improvements with regard to product yield, reaction time, and greenness of procedure, avoiding hazardous organic solvents/toxic catalysts and provides a better, clean and practical alternative to the existing protocols ( Figure 2).

Synthesis of aryldipyrromethanes 10
Taoufik et al. 10 have reported the oxidation of aryldipyrromethanes with p-chloranil (in dichloromethane), or DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) at room temperature to obtain the corresponding dipyrrins in good yields (50-78%) ( Figure 3). has been developed by Kidwai et al. 11 without using any catalyst and hazardous organic solvents and corrosive acids or bases. Waterinsoluble solid products obtained in short time are found to be essentially pure and in very high yield ( Figure 4).

Synthesis of 2-aminothiazoles 12
A highly efficient and facile method has been described by Taterao et al. 12 for the synthesis of substituted 2-aminothiazoles in water without any added catalyst or co-organic solvent. The reaction was carried out at ambient temperature and the products were obtained in excellent isolated yields. The developed protocol is successfully applied for the preparation of an anti-inflammatory drug, fanetizole ( Figure 5).

Synthesis of alkyl or aryl-14H-dibenzo [a, j]xanthenes 13
Alkyl-or aryl-14H-dibenzo [a,j]xanthene derivatives were synthesized efficiently by the reaction of beta-naphthol and aliphatic and aromatic aldehydes in the presence of KAl(SO 4 ) 2 x12H 2 O (alum) under aqueous condition at 100°C by Dabiri et al. 13 Different types of aromatic and aliphatic aldehydes were used in the reaction and in all cases the products synthesized successfully. Several solvents were examined for this reaction; however, in terms of reaction yield and time, water was found to be the optimum solvent ( Figure 6). Syntheses of N-azacycloalkanes, pyrazole, pyrazolidine, and phthalazine derivatives 14 Ju et al. 14 have reported the synthesis of nitrogen-containing heterocycles from alkyl dihalides (ditosylates) and primary amines and hydrazines via a simple and efficient cyclocondensation in an alkaline aqueous medium that occurs under microwave irradiation. This improved greener synthetic methodology provides a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles, such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted 2,3-dihydro-1H-isoindoles, 4,5-dihydropyrazoles, pyrazolidines, and 1,2-dihydrophthalazines ( Figure 7).  15 Polshettiwar et al. 15 have reported an expeditious room temperature synthesis of pyrazoles and diazepines by condensation of hydrazines/ hydrazides and diamines with various 1, 3-diketones. This greener protocol was catalyzed by polystyrene supported sulfonic acid (PSSA) and preceded efficiently in water in the absence of any organic solvent within 1-2 min (Figure 8).

Synthesis of Substituted 3,4-dihydropyrimidin-2(1H)--ones 16
An environmentally benign aqueous Biginelli protocol for the synthesis of substituted 3,4-dihydropyrimidin-2(1H)-ones using polystyrenesulfonic acid (PSSA) as a catalyst has been achieved by Polshettiwar et al. 16 These microwave-assisted reactions proceed efficiently in water in the absence of organic solvent, with simple filtration as the product isolation step (Figure 9).

Synthesis of 1,3 dioxanes 17
A novel tandem bis-aldol reaction of ketone with paraformaldehyde catalyzed by polystyrenesulfonic acid is reported by Polshettiwar et al. 17 in aqueous medium to yield 1,3-dioxanes. This one-pot, operationally simple microwave-assisted synthetic protocol proceeds efficiently in water in the absence of any organic solvent, with excellent yield (Figure 10).

Synthesis of coumarins 19
A simple and convenient method for the efficient synthesis of coumarins in water catalyzed by K 2 CO 3 is developed by Rehanaanjum. 19 Optimal result was obtained using 20mol% of K 2 CO 3 . The experiment was conducted with phenolic substrate and β-keto ester in the presence of catalytic amount of K 2 CO 3 (20mol%) in water. The reaction proceeded spontaneously at ambient temperature and was completed within 1 hr. The precipitated solid was filtered, dried and washed with 20% ethyl acetate in petroleum ether to afford coumarins ( Figure 12). 20 Kumaravel et al. 20 have developed a catalyst-free combinatorial library of novel 2-amino-4-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-4H-chromene-3-carbonitrile derivatives by the reaction of hydrazine hydrate, ethyl acetoacetate, 2-hydroxybenzaldehydes and malononitrile in water at ambient temperature ( Figure 13).

Synthesis of 3, 4-dihydroquinoxalin-2-amine derivatives 24
A simple and efficient one-pot synthetic approach for the preparation of biologically interesting 3,4-dihydroquinoxalin-2amine derivatives using EDTA-catalyzed three component reactions of o-phenylenediamines, carbonyl compounds, and isocyanides in an aqueous medium is described by Kolla et al. 24 This method is of great value because of its environmentally benign character, high yields, and ease of handling ( Figure 17).

Synthesis of substituted fused thiazole derivatives 25
Alison et al. 25  This stands as a significant advance over the previous methods using Pt, Cu or Ag salts paired with ligands in organic solvents such as benzene, acetonitrile or methylene chloride ( Figure 18).

Figure 18
Synthesis of substituted fused thiazole derivatives. 25 Gawande 26 provided a brief overview of some selective catalystfree reactions in aqueous media. 26 Further, many organic molecules are partially soluble in water and reactions that appear as heterogeneous mixtures and suspensions may involve on-water and in-water reaction modes occurring simultaneously. Organic synthesis reactions on water at the organic-liquid water interface were studied by Butler et al. 27 García-García et al. 28 have reported the preparation of a mesoscopic metal-organic structure based on single-layer assembly of aluminium chains and organic alkylaryl spacers. The material markedly accelerates condensation reactions in water in the absence of acid or base catalyst, as well as organocatalytic Michael-type reactions that also show superior enantioselectivity when comparing with the host-free transformation. 28 Alaoui et al. 29 have reported the ultrasound assisted facile one pot synthesis of sulfonamide-isoxazoles using cerium (IV) ammonium nitrate (CAN) as an efficient oxidant in aqueous medium. 29 Dilauro et al. 30 have reported the nucleophilic additions of highly polar organometallic compounds to imines and nitriles using water as a reaction medium. 30 They reported that the addition of highly polar organometallic compounds to non-activated imines and nitriles proceeds quickly, efficiently, and chemoselectively with a broad range of substrates at room temperature and under air with water as the only reaction medium.

Conclusion
In this review article, we have focused on some aqua mediated organic transformations which will surely help scientists and researchers across the globe to develop new inexpensive, clean and environmentally benign strategies to carry out organic synthesis.