Synthesis of Five-Membered Heterocycles Using Water as a Solvent

Abstract

Water owing to its modest cost, easy accessibility, and non-toxic and non-flammable attributes has been considered one of the most ideal and promising solvents in organic synthesis, especially from the green and sustainable point of view. Furthermore, considering the immense enzyme-mediated biosynthesis in nature, water serves as a favourable medium for the versatile synthesis of a wide variety of complicated molecules and compounds. Over the past decades, considerable efforts have been deployed in conducting organic reactions using water as a solvent. In recent years, more and more general organic reactions were successfully exploited to perform in water instead of organic solvents to achieve sustainable and environmental benefits.

1. Introduction

Among pharmaceutically relevant natural and synthetic compounds, heterocyclic compounds hold a unique place. They have an incredible ability to serve as biomimetics and potential pharmacophores and are standard key components of several drugs [1, 2]. There is a critical need for new small organic molecules both in lead identification and lead optimization processes. Conventional methods of organic synthesis are often too slow to satisfy the demand for generation of such compounds. The synthetic chemists worldwide have been under tremendous pressure to produce them in good numbers and that too in an environmentally benign fashion. A typical reaction involves a reaction medium apart from reactants and reagents to form products. There are several issues that influence the choice of solvent, especially in context of green chemistry. It should be relatively non-reactive, non-toxic and non-hazardous. The solvent should also be contained, that is, it should not be released into the environment [3].

Water is one of the most intriguing media among all the alternative solvents available, owing to its peculiar properties. It is the most abundant and available molecule on the planet and many biochemical processes occur in aqueous medium. Despite its accessibility, it has not been a favourite reaction medium for organic chemists because its presence causes the decomposition of organometallic reagents, which are used preferably in dry organic solvents. In fact, water has been generally used to work-up organic reactions and, therefore, it has been associated with a waste-production step and to the consequent obvious problems of cleaning-up water from reactants’ residues arises. The low solubility of most organic compounds in water (hampering their reactivity), and the instability of many intermediates and catalysts in water are perhaps the two main causes of this problem. Today, it is a different scenario altogether. This very aqueous medium has captured the interest of organic chemists and many others, so much so that many surprising discoveries have been attributed to its use. Many organic reactions such as pericyclic, condensation, oxidation and reduction reactions can be conducted efficiently in aqueous medium and, in some cases, water is necessary to enhance the reaction rate and increase selectivity. Further, water-tolerant catalysts have been prepared that allow organometallic reactions to be carried out in aqueous medium. Reactions that were earlier thought impossible in water have today become a certainty [3].

1.1 Evolution of water as a solvent

Although Diels and Alder themselves used water as reaction medium in the cycloaddition of furan with maleic anhydride in 1931, but it was Breslow’s observations (in 1980) confirming the acceleration of some Diels-Alder reaction when carried out in water with respect to other organic solvents that played a pivotal role in the development of organic synthesis in aqueous media [4, 5]. Prior to this, in 1948, Woodward and Baer also employed aqueous maleic acid as dienophile, and in 1973 the beneficial effect of aqueous medium on the reaction was also successfully investigated by Koning and Carlson. In fact, Breslow’s kinetic work was the first that quantitatively showed the valuable effects of water on the reactivity and selectivity of an organic reaction. Herein, the reaction of butanone with cyclopentadiene in water was enhanced by 740 times as compared to that carried out in isooctane [6, 7, 8]. Though, there are numerous advantages of using an aqueous reaction media. Among them, the possibility of recovery and reuse of the aqueous medium containing all the soluble species dissolved in it (catalysts and reactants), and the possibility of controlling the pH is most prominent.

1.2 Water as a solvent in the synthesis of heterocycles

Water plays a dominant role as a solvent for the development of numerous heterocycles by replacing the use of hazardous organic solvents. Despite its overwhelming advantages as reaction solvent for organic synthesis, poor solubility of many organic compounds in water limits its use under standard conditions. However, when used in high temperature and pressure conditions, it undergoes a change in its properties and can act as a potent solvent for good number of organic reactions [9]. Owing to tremendous potential of water as a medium for production of heterocyclic moieties, in this chapter, we have tried to compile the ‘in water’ synthesis of five-membered heterocycles.

2. Synthesis of nitrogen-containing heterocycles

Nitrogen heterocycles are most abundant in nature and are of immense significance. Their structural subunits exist in many natural products, such as vitamins, hormones, antibiotics and alkaloids, as well as pharmaceuticals, herbicides, dyes and many more compounds.

2.1 Pyrroles

Tetra substituted pyrroles were synthesised by the three-component condensation reaction of acid chlorides, amino acids and dialkyl acetylenedicarboxylates, in the presence of ionic liquids, as catalysts in water at room temperature (Figure 1) [3].

Figure 1.

Synthesis of tetra substituted pyrroles.

Polysubstituted pyrroles are obtained in good yields from α-azido chalcones and 1,3-dicarbonyl compounds in water. InCl₃ was used as a catalyst for this regioselective transformation (Figure 2) [10].

Figure 2.

Synthesis of polysubstituted pyrroles using InCl₃ in presence of water as a solvent.

Another reaction involving water as a solvent employed a catalysed amination-annulation strategy for the synthesis of 2-aminopyrrole-4-carboxylates. This work developed a Zn(ClO₄)₂ catalysed approach to generate pyrrole ring-formation in high yields (Figure 3) [11].

Figure 3.

Zn(ClO₄)₂ catalysed synthesis of pyrrole in water.

An efficient approach for the synthesis of polysubstituted pyrrolidin-1,2-diones was achieved by a one-pot three-component reaction of nitroarenes, formaldehyde and dialkyl acetylenedicarboxylates using indium in dilute aqueous HCl at room temperature (Figure 4) [12].

Figure 4.

Synthesis of poly-substituted pyrrolidin-1,2-diones in water.

Pyrrolo[2,1-a]isoquinolines and pyrrolo[1,2-a]quinolines have been obtained in good to excellent yields using quinoline or isoquinoline, phenacyl bromide derivatives and activated alkynes in aqueous medium (Figure 5) [13].

Figure 5.

Synthesis of pyrrolo[2,1-a]isoquinolines and pyrrolo[1,2-a]quinolines.

2.2 Azines

A convenient and fast procedure for the synthesis of cycl[3.2.2]azines through a three-component reaction of 2-picoline, α-bromoacetophenone and alkyne in aqueous medium under microwave irradiation (Figure 6) [14].

Figure 6.

Synthesis of cycl[3.2.2]azines in aqueous medium.

2.3 Indoles

2-aryl indoles were obtained by alkynylation coupling of aryl iodides with terminal alkynes catalysed by a water-soluble copper complex (sulfonato–Cu(salen)). This reaction was stirred using 2-iodoaniline and aryl acetylene to obtain 2-arylindoles in excellent yields (Figure 7) [15].

Figure 7.

Synthesis of 2-aryl indoles catalysed by a water-soluble copper complex (sulfonato–Cu(salen).

A greener N-heterocyclization with water as solvent and no transition metal catalysts showed good yields in a fraction of the time to produce isoindolines (Figure 8) [16].

Figure 8.

Synthesis of isoindolines in aqueous medium.

2.4 Pyrazoles

A variety of substituted pyrazoles have been synthesised by the condensation of hydrazine with diketones and β-keto esters, respectively. One such method involves polystyrene sulfonic acid (PSSA) catalysed assembly of the above in water as a solvent (Figure 9) [17].

Figure 9.

Polystyrenesulphonicacid (PSSA) catalysed assembly of nitrogen-containing heterocycles in water.

2.5 Pyrrolo pyrazines

Pyrrolo[2–b]pyrazines were synthesised by treating phenylacetylene with 5-(alkyl-arylamino)-6-chloropyrazine-2,3-dicarbonitriles 39. This coupling reaction is a variant of the Larock indole synthesis and was performed in water using Pd(Ph₃P)₂Cl₂, CuI as a catalyst, sodium lauryl sulfate and K₂CO₃ at 70°C for 24 h (Figure 10) [18].

Figure 10.

Synthesis of pyrrolo[2–b]pyrazines in water using Pd(Ph₃P)₂Cl₂ and CuI.

3. Synthesis of oxygen-containing heterocycles

3.1 Furans

Furan moieties are important substructures that have been found in numerous natural products, such as kailolides and combranolides. These heterocycles are also found in a variety of commercial products such as pharmaceuticals, fragrances and dyes.

A simple three-component reaction between arylglyoxal monohydrates, acetylacetone and barbituric or thiobarbituric acid resulted in the synthesis of polyfunctionalized 5-(furan-3- yl)barbiturates and 5-(furan-3-yl)thiobarbiturate derivatives in good yields (Figure 11). The method employs readily available starting materials, neutral reaction conditions and water as an environmentally green solvent [19].

Figure 11.

Synthesis of 5-(furan-3-yl)barbiturate/thiobarbiturate derivatives.

An efficient and a simple synthesis of 2-(cyclohexylamino)-3-aryl- indeno[1,2-b]furan-4-ones was attained via a one-pot three-component reaction of aldehydes, cyclohexylisocyanide and 1,3-indandione in water for 5 h in excellent yields (Figure 12). Water was used as a solvent to avoid the use of other highly toxic and environmentally unfavourable solvents for this synthesis [20].

Figure 12.

Synthesis of 2-(cyclohexylamino)-3-aryl-indeno [1,2-b] furan-4-ones in water.

4. Synthesis of Sulphur containing heterocycles

Sulphur heterocycles are also important classes of heterocycles in pharmaceuticals and organic synthesis, which are known to possess important biological properties and have attracted much attention from medicinal chemists over the years.

4.1 Thiophenes

A simple and convenient synthesis of 2-aminothiophenes was investigated by the reaction of ketones with malononitrile using water as a solvent in a reaction ignited by sodium polysulfides in catalyst-free conditions under ultrasound activation with 42–90% product yields (Figure 13). The use of water as a solvent as well as sonification activation is part of green chemistry principles for this protocol [21].

Figure 13.

Synthesis of 2-aminothiophenes from ketones and malonodinitrile in water.

A simple and effective reaction of ketones with nitriles and elemental sulphur (S8) in a mixture of triethylamine and water at room temperature led to the desired 2-aminothiophenes in 75–98% yields after recrystallization from a mixture of ethyl acetate and hexanes (Figure 14) [22]. The use of water as solvent at room temperature with a good atom economy makes the reaction green compatible.

Figure 14.

Synthesis of 2-aminothiophenes from ketones and nitriles.

5. Miscellaneous

Substituted 2-aminothiazoles were prepared in water through a highly efficient and facile synthesis, without the use of a catalyst or co-organic solvent. The reaction was carried out at ambient temperature and the products were obtained in excellent yields. The developed protocol is successfully utilised for the preparation of an anti-inflammatory drug, fanetizole (Figure 15) [23].

Figure 15.

Synthesis of substituted 2-aminothiazoles in water.

A new and facile protocol for the synthesis of 2-amino-1,3,4-thiadiazoles in water by the reaction of acid hydrazides with dithiocarbamates in moderate to excellent yields (Figure 16) [24].

Figure 16.

Synthesis of 2-amino-1, 3, 4-thiadiazoles.

The reaction between TosMIC 63 and benzaldehyde 64 was carried out in the presence of various amounts of Et₃N and β-CD (β-Cyclodextrin) at 50°C in water (Figure 17). The simple procedure, relatively short reaction times, easy workup and high yields are the reasons that promote the use of β-CD/water as an inexpensive and environmentally benign catalyst for the synthesis of differently substituted oxazoles [25, 26].

Figure 17.

Green method for the Van Leusen synthesis of oxazoles.

6. Recent literature

Ring-closing metathesis of oxygen-containing dienes with ruthenium catalyst, in H₂O as a solvent, provides a good platform for the synthesis of dihydro furan (Figure 18) [27].

Figure 18.

Synthesis of dihydrofuran.

The hydrosilylation and olefin ring-closing metathesis reaction in the presence of Grubbs-2 catalyst in an aqueous medium is another alternative route (Figure 19) [27].

Figure 19.

Synthesis of 2,5-dihydrofuran using Grubbs second Generation catalyst.

Candida rugosa lipase (CRL) mediated reaction of 1,3-diketone with fumaronitrile resulted in the formation of poly cyano substituted indoles in excellent yields (Figure 20) [28].

Figure 20.

Lipase-catalysed synthesis of cyano-containing multisubstituted indoles.

Polyhydroxyalkyl furans were also prepared from lipase-catalysed Knoevenagel reaction in water using malononitrile and reducing sugars as substrates. Out of the various lipases deployed in the reaction Novozyme-435 showed the highest catalytic activity (Figure 21) [28].

Figure 21.

Lipase-catalysed synthesis of polyhydroxyalkyl furans.

7. Conclusion

The chapter has attempted to recapitulate some of the most promising new organic reactions in aqueous medium. It has been observed that organic synthesis when carried out in water as a solvent can significantly reduce the number of steps. This shortening of synthetic routes, increasing product selectivity and reducing volatile organic consumption will certainly provide economic, health and environmental benefits to the mankind.