Chapter 1 Synthesis of bio-active heterocycles using ionic liquids

Acknowledgments: B.C. Ranu is pleased to acknowledge the support of Indian National Science Academy, New Delhi with the offer of INSA Honorary Scientist (Grant no. INSA/SP/HS/2019/291). S. Ahammed thanks Sandipan Ghosal, Bankura Sammilani College for his help and acknowledges WBDSTBT, West Bengal, India (Project No. 1933 (Sanc.)/ST/P/S&T/15G-9/2019) for financial support.

1.1 Introduction

The ionic liquids are compounds that are composed of ions generally, an organic heterocyclic cation and an inorganic anion and are liquids at room temperature. The room temperature ionic liquids (RTIL) have received much interest as benign alternatives to volatile and toxic organic solvents because of their nonvolatility, noninflammability, controlled miscibility, thermal stability and reusability [1, 2, 3]. An attractive feature of ionic liquids is flexibility of their tuning of effectiveness and specificity by changing the counter ion of ionic liquids. A particular counter ion often enhances the efficiency of an ionic liquid toward catalysis of certain organic reactions. Recently, various modified ionic liquids are employed for the synthesis of a broad spectrum of organic molecules due to their distinctive chemical and physical properties [4, 5, 6]. The task-specific RTIL (TSIL) has emerged as powerful alternatives to organic solvents for their mild and environmentally benign nature [7, 8, 9]. Imidazolium ionic liquids are widely used in various reactions and are of considerable interest because of their efficiency as catalyst and green reaction media [10, 11, 12, 13].

Heterocycles are of much importance in pharmaceutical industries because of their biological activities [14]. Many heterocyclic compounds have been used as drugs for the treatment of cancer [15], Perkinson’s disease [16], malaria [17], etc. They also have antimicrobial [18], anti-inflammatory [19] and antioxidant [20] properties. Therefore, the demand of various bioactive heterocyclic compounds is continuously increasing. The large-scale synthesis of potent heterocyclic drugs by industries is of prime importance. However, large-scale synthesis often produces a large amount of harmful waste. In this context, the benign ionic liquids play important role as green reaction media and catalyst for the synthesis of heterocyclic compounds as they produce less waste being recyclable.

This chapter provides an overview of the synthesis of selected heterocyclic molecules of biological interest using RTIL avoiding toxic organic solvents, catalysts and ligands by greener approaches.

1.2 Synthesis of bioactive heterocycles

1.2.1 Synthesis of dihydropyrimidinone and perhydropyrimidine derivative

The dihydropyrimidinones are of much interest due to their therapeutic and pharmacological properties and act as important building blocks in chemical synthesis [21]. It was observed that several biologically active marine alkaloids contain perhydropyrimidine and dihydropyrimidine units [22]. Thus, the dihydropyrimidinone and perhydropyrimidine derivatives are of much utility and are usually obtained by one-pot Biginelli condensation reaction.

Deng and coworkers [23] reported a mild solvent-free Biginelli condensation under room temperature and neutral condition involving the ionic liquid, n-butyl-3 methylimidazolium tetrafluoroborate (BMImBF4) or hexafluorophosphorate (BMImPF6) as a catalyst to produce dihydropyrimidines in high yields (Figure 1.1). When quarternary ammonium salts were employed as catalyst, the yield was low. So, it was evident that cation and anion part of an ionic liquid played an important role as catalyst in Biginelli reaction. The best yield of dihydropyrimidines was obtained by the reaction of benzaldehyde, acetylacetone and urea using ionic liquid BMImBF4.

Figure 1.1: Reaction of aryl aldehyde with urea and ester or dicarbonyl compound.

Zuliang and coworkers [24] also reported an environmentally benign method for Biginelli reaction using an SO3H-functionalized, Bronsted-acidic, TSIL (3-tri-n-butylammonio propanesulfonate IL) as a catalyst (Figure 1.2). The best result was achieved by using benzaldehyde, ethyl acetoacetate and urea (1:1:1 mole ratio) as substrates. The ionic liquid was recyclable and reused six times without significant loss of the catalytic activity. Several substituted benzaldehydes and β-keto esters were subjected to this reaction. It was found that both β-ketoester and β-diketone participated in the reaction providing uniform yield. Thiourea can also be used in the place of urea to provide the corresponding thiodihdropyrimidines.

Figure 1.2: Reaction of aryl aldehyde (benzaldehyde) with acetoacetate and urea (thiourea).

Aromatic aldehydes containing electron donating and electron withdrawing groups provided good-to-moderate yield of DHPM with high purity. A variety of functional groups such as ester, ether, nitro, hydroxyl and halide were tolerated under the reaction conditions. The ionic liquid donates hydrogen ion which assists the dehydration process and enolizes the 1,3-dicarbonyl compound to form the enolate intermediate.

Laali and coworkers reported Biginelli reaction of aldehydes for the synthesis of dihydropyrimidinones and thiones using Bronsted acidic ionic liquid [bmim(SO3H)[OTf] or Zn(NTf)2 which is recyclable (Figure 1.3) [25]. The [BMIm(SO3H)(OTf)] provided high yield under mild conditions and short reaction time. Various aromatic aldehydes and both urea and thio urea were used to produce the corresponding products. It was observed that electron-withdrawing group at para position provided relatively low yield of the product. It was found that the Lewis acid served as pre-catalyst leading to in situ formation of the actual catalytic species.

Figure 1.3: Reaction of aryl aldehyde with acetoacetate and urea (thio urea).

Yadav et al. [26] have investigated Biginelli reaction with oxathiolan-5-one/oxazole-5-one as active methylene building block with aromatic aldehyde and urea or thio urea (Figure 1.4). Here, chiral ionic liquid l-proliniumsulfate (Pro2SO4) plays an important role by catalyzing the reaction and reducing the reaction time to provide an efficient one-pot synthesis of enantio- and diastereoselective poly-functionalized perhydropyrimidine products. During the reaction, acetophenones are used to activate mercaptoacetic acid as active methylene building block which was mechanically removed during the reaction without hampering the progress of the process.

Figure 1.4: Reaction of urea, thiourea moiety with aromatic aldehyde and oxathiolan-5-one and oxazol-5-one nuclei.

It was suggested that intramolecular nucleophilic attack of nitrogen atom of urea/thiourea moiety at the carbonyl carbon (C-5) of oxathiolane-5-one or oxazol-5-one nuclei leads to the final product (Figure 1.5).

Figure 1.5: Plausible mechanism for the formation of 5-mercaptoperhydropyridines.

1.2.2 Synthesis of substituted furan derivative

Substituted furan derivatives are considered as important scaffolds in medicinal chemistry due to their antiulcer and antibacterial properties [27]. Our group [28] reported that an ionic liquid promoted Feist–Benary reaction to produce dihydrofuran derivatives involving several cyclic and acyclic β-diketones and β-keto carboxylic ester (Figure 1.6). During the condensation reaction, basic ionic liquid, 1-butyl-3-methylimidazolium hydroxide [bmim]OH acts as an effective catalyst to produce the substituted hydroxy dihydro furan derivative with high diastereoselectivity.

Figure 1.6: Synthesis of hydroxydihydrofurans and substituted furans catalyzed by the ionic liquid.

In another experiment, it was observed that a neutral ionic liquid [pmim]Br catalyzed the condensation reaction to produce the corresponding furan derivative as a final product. High yield of the product was obtained with higher stereoselectivity using substituted α-bromo carbonyl compound.