Greener Approach towards the Synthesis of Nitrogen Based Heterocycles

Abstract

The preferable application of green chemistry in research is to utilize environment benign, mild, non toxic, reproducible catalyst and efficient solvents in synthesis of molecules. Use of green chemistry techniques had enabled in dramatically reducing chemical waste and reaction times as has recently been reported in several organic syntheses reactions. Greener routes are required in the synthesis of N-heterocycles, due to the remarkable importance of these compounds in medicinal chemistry. This chapter is dedicated to the synthesis of N containing heterocyclic compounds using eco-friendly solvent like water and bio-derived solvents (glycerol, ethyl lactate, and gluconic acid aqueous solution). Water and bio-based solvents for the synthesis of aromatic nitrogen heterocycles was chosen due to the negligible toxicity associated with these solvents. Apart from being eco-friendly, water also has the potential to become a universally acceptable solvent due to its abundance and low cost. Work on microwave synthesis is also reported as it is an eco-friendly and faster process for the synthesis of these N-based heterocyclic compounds. Due to its rapid action to produce products with greater purity and yield, it is now being used worldwide.

1. Introduction

Green chemistry, also known as sustainable chemistry, is an area of chemistry and chemical engineering which focus on the design of products and processes that minimize or eliminate the use and generation of hazardous substances [1]. In 1998, Paul Anastas and John C. Warner reported a set of 12 green chemistry principles [2]. Use of green chemistry can help us to create alternatives to hazardous sub stances. Chemical processes can be designed which reduce waste and prevent diminishing of natural resources. Processes can be designed that use lesser amounts of energy. Heterocyclic compounds had a special place among pharmaceutically important natural products and synthetic molecules. Among the heterocycles, nitrogen based molecules are abundant in nature and is of utmost importance to life because their structural subunits exists in natural products like hormones, vitamins, antibiotics, alkaloids, herbicides, Nucleic acid (DNA and RNA) etc [3]. The construction of complicated cyclic target molecules having minimum environment impact is a challenging task for academicians, scientists and industry people. Greener methods are required for the synthesis of N-heterocycles as these compounds are medicinally important [4, 5]. Environment friendly protocols have been explored all over the globe for heterocyclic synthesis to improve energy consumption, atom economy and reaction yields [6, 7]. In the past few decades, numerous research papers have reported the use of water as green solvent [8, 9]. Researchers are also making use of polyethylene glycol for its low price and low acute toxicity [10, 11]. More recently, research teams have demonstrated that the use of bio-based solvents is also a solvent of choice [12]. All these results prove that the concepts of green chemistry have made remarkable progress. The conventional methods for the synthesis of N-heterocyclic skeleton require the use of expensive starting materials and high temperature. Chemists play an important role in the construction of a sustainable future through the application of greener chemical processes. As so, the development of new synthetic methods using more efficient energy sources and less hazardous solvents as well as renewable and eco-friendly catalysts to attain the N-heterocyclic core can provide significant environmental and economic advantages.

2. Use of green solvents

2.1 Reactions in water

A novel and direct method for the synthesis of pharmacologically promising spiro[indoline-3,7′-pyrrolo[1,2-c]imidazole]-6′-carbonitrile derivatives has been developed via a three-component one pot reaction reaction. The reaction was cleaner and proceeded in good yields using isatin, malononitrile, and hydantoin or thiohydantoin in the presence of Et3N/water (Figure 1) [13].

Figure 1.

Synthesis of spiro[indoline-3,7′-pyrrolo[1,2-c]imidazole]-6′-carbonitrile derivatives.

A regioselective synthesis of polysubstituted pyrroles in good yields from α-azido chalcones and 1,3-dicarbonyl compounds using indium trichloride in water as an efficient catalyst is discussed (Figure 2) [14]. Under conventional heating InCl₃ in water has been found to complete the reaction in 30 min. Microwave irradiation on the other side reduced the reaction time from 30 min to 10 min.

Figure 2.

Synthetic route for polysubstituted pyrroles.

Highly efficient, green and simple method for the construction of pyrazole-3-carboxylates and 3,5-disubstituted pyrazoles by cyclization of 4-aryl(hetaryl, alkyl)-2,4-diketoesters and 1,3-diketones with semicarbazide hydrochloride using water has been developed (Figure 3) [15]. This synthesis did not require toxic hydrazine and product purification, eliminating the use of toxic liquid chemicals.

Figure 3.

Synthesis of 3,5-disubstituted pyrazoles.

Compound	R^2	R^3	R^1	Yield (%)	Time (h)
13a	C6H5	H	C6H5	87	5.0
13b	C6H5	H	4-ClC6H4	90	6.0
13c	C6H5	H	NH2	92	1.0
13d	C6H5	H	CH3	82	5.0
13e	C6H5	H	4-OCH3C6H4	80	4.0
13f	C6H5	H	3-Indolyl	70	4.0
13g	C6H5	H	4-Pyridyl	65	5.0
13h	C6H5	H	1-Methyl-3-indolyl	85	4.0
13i	CH3	COCH3	C6H5	85	5.0
13j	CH3	COCH3	4-ClC6H4	90	3.0
13k	CH3	COCH3	4-OCH3C6H4	90	3.0
13l	4-OCH3C6H4	H	C6H5	88	3.0
13m	4-OCH3C6H4	H	4-ClC6H4	93	3.0
13n	4-OCH3C6H4	H	NH2	80	4.0
13o	4-ClC6H4	H	C6H5	85	3.0
13p	4-ClC6H4	H	4-ClC6H4	90	4.0
13q	4-ClC6H4	H	3-Indolyl	87	4.0
13r	1-PhSO2-3-indolyl	H	C6H5	75	6.0
13s	1-PhSO2-3-indolyl	H	1-Methyl-3-indolyl	86	5.0
13’a	C6H5	H	C6H5	70	3.0
13’b	C6H5	H	4-ClC6H4	65	3.5
13’c	C6H5	H	4-Pyridyl	65	2.5
13’d	4-ClC6H4	H	C6H5	70	3.0
13’e	4-ClC6H4	H	4-ClC6H4	63	3.0
13’f	4-ClC6H4	H	4-Pyridyl	55	2.0
13’g	4-OCH3C6H4	H	4-ClC6H4	55	3.0
13’h	4-OCH3C6H4	H	4-Pyridyl	60	2.5
13’i	4-OCH3C6H4	H	C6H5	50	3.5

Table 1.

Synthesis of diarylthiazoles [13] and diarylimidazoles 13′ [16].

Synthesis of diarylthiazoles and diarylimidazoles utilizing a reaction between α-tosyloxyketones with a variety of thioamide/amidine in water without any additives is reported. This methodology demonstrated several advantages such as being simple, efficient and high yielding, also it a greener protocol (Figure 4 and Table 1) [16].

Figure 4.

Synthesis of diarylthiazoles and diarylimidazoles.

An environmentally friendly, green, practical, attractive and effective method to construct 4H-pyrido[1,2-a]pyrimidin-4-one has been developed (Figure 5) [17]. The reaction using water as the solvent in absence of catalyst under the mild conditions makes these transformations very efficient (Table 2).

Entry^* [17]	R^1/X		R		Product	Yield (%)
	14a	H/C	15a	Me	16aa	82
	14b	3-Me/C	15a	Me	16ba	60
	14c	4-Me/C	15a	Me	16ca	74
	14d	5-Me/C	15a	Me	16da	83
	14e	6-Me/C	15a	Me	—	—
	14f	5-F/C	15a	Me	16fa	45
	14g	4-Cl/C	15a	Me	16ga	71
	14h	5-Cl/C	15a	Me	16ha	39
	14i	5-Br/C	15a	Me	16ia	47
	14j	6-Br/C	15a	Me	—	—
	14k	3-BnO/C	15a	Me	16ka	40
	14l	4-COOEt/C	15a	Me	16la	72
	14a	H/C	15′b	Et	16ab	82
	14b	3-Me/C	15′b	Et	16bb	35
	14c	4-Me/C	15b	Et	16cb	86
	14d	5-Me/C	15b	Et	16db	97
	14e	6-Me/C	15b	Et	—	—
	14f	5-F/C	15b	Et	16fb	52
	14g	4-Cl/C	15b	Et	16gb	53
	14i	5-Br/C	15b	Et	16ib	50
	14j	6-Br/C	15b	Et	—	—
	14k	3-BnO/C	15b	Et	16kb	15
	14l	4-COOEt/C	15b	Et	16lb	56
	14m	H/N	15a	Me	—	—

Table 2.

* Reaction conditions: 14a (0.32 mmol), 15a (0.38 mmol), catalyst-free, in 30 mL water for 6 h under air.

Figure 5.

Construction of 4H-pyrido[1,2-a]pyrimidin-4-one.

2.2 Reactions in bio-based solvents

Bio based green solvent Ethyl lactate was used, for the 1,3-dipolar cycloaddition reaction to generates a series of medicinally important spiro[benzo[f]pyrrolo[2,1-a]isoindole-5,3′-indoline]-2′,6,11-trione derivatives in excellent yields at room temperature (Figure 6) [18]. The product was obtaind in high yield (approximately 90%) with the 1,3-dipolar cycloaddition reaction of substituted isatin and proline with napthaquinone.

Figure 6.

Synthesis of spiro[benzo[f]pyrrolo[2,1-a]isoindole-5,3′-indoline]-2′,6,11-trione derivatives.

The first investigation of the use of eucalyptol as a new solvent for organic synthesis was reported by a group [19]. Heterocycles having oxygen, sulfur and nitrogen were chosen as targets or as starting materials for widely used palladium-catalysed cross-coupling reactions, like Suzuki-Miyaura and Sonogashira-Hagihara reactions. Eucalyptol turned out to be a viable sustainable solvent and was shown to be an interesting alternative to conventional solvents for the one-pot synthesis of 2,3-diarylimidazol[1,2-a]pyridines (Figure 7).

Figure 7.

One-pot synthesis of 2,3-diarylimidazol[1,2-a]pyridines.

A simple and chemoselective method of synthesizing T-shaped oxazolonaphtho[1′,2′:4,5]imidazo[1,2-a]pyridines (Figure 8) in a one-pot selective fashion was developed in good yields using lactic acid as an alternative solvent to acetic acid [20]. The reaction exhibited advantages like bio-based origin, ease of isolating the product and superior synthetic efficiency. The synthetic strategy adopted was highly compatible with various functionalities.

Figure 8.

Synthesis of T-shaped oxazolonaphtho[1′,2′:4,5]imidazo[1,2-a]pyridines.

A Group of researchers published a paper on an efficient and environmentally benign synthetic protocol for the synthesis of pyrrole derivatives (Figure 9) using gluconic acid aqueous medium as an eco-friendly bio-based catalytic solvent system. The synthesis was done by the four-component coupling of amines, aldehydes, 1,3-dicarbonyl compounds, and nitromethane [21]. Gluconic acid aqueous solution could be recycled and reused several times without significant loss of its efficiency. This reaction showed excellent functional group tolerance, short reaction time, and high yield of products.

Figure 9.

Environmentally benign synthetic protocol for the synthesis of structurally diverse pyrrole derivatives.

3. Microwave irradiation

One of the potential green chemistry method using microwaves (MW) have emerged during the recent years [22, 23]. A review outlines the use of MW technique for the synthesis of N-containing heterocycles [24]. Novel 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indole derivatives (Figure 10) has been synthesised regioselectively in good yields from the reaction of 5-aryldihydro-3(2H)-thiophenones and arylhydrazine hydrochloride under microwaves [25]. The group also did a comparison of the efficacies of the thermal and microwave reactions, by carrying out the reaction under microwave for the synthesis of 34a (Ar = C₆H₅, R = H) at the reflux temperature of 80°C. At 80°C, the reaction using microwaves was completed in 5 min, that is ten times faster than that under thermal condition (50 min) using the same solvent.

Figure 10.

Construction of novel 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indole derivatives.

A rapid solvent-less synthesis of 5-hydroxy-benzo[g]indole scaffolds (Figure 11) is accomplished from Lewis acid-catalyzed one-pot reaction of naphthoquinone, ω-morpholinoacetophenone, and urea under microwave irradiation [26]. To investigate the role of Lewis acid, the researchers also carried microwave-mediated reaction using Lewis acids like TiCl₄, AlCl₃, ZnCl₂, SmCl₂, and InCl₃ under similar reaction conditions. They found that in comparison to BF₃·OEt₂ catalyzed reaction, all the other Lewis acids gave poor yields. Also the reaction failed to proceed in the absence of the Lewis acid (Figure 12).

Figure 11.

Solvent-less synthesis of 5-hydroxy-benzo[g]indole scaffolds.

Figure 12.

Proposed mechanism for the synthesis of benzo[g]indole derivative (38a).

Researchers have developed a novel, convenient, environmentally friendly one-pot synthesis of imidazo[1,2-a]pyridines (Figure 13) using 2-aminopyridines and in-situ generated phenacyl bromides under microwave irradiation in polyethylene glycol (PEG-400) and water (1:2) [27]. This protocol is a better alternative to the existing method as it involves use of in-situ-generated α-bromoacetophenones, utilization of lachrymatric α-haloketones and volatile toxic organic solvents is avoided. There is reduction in the reaction time also to obtain excellent yield.

Figure 13.

One-pot synthesis of imidazo[1,2-a]pyridines.

A series of substituted quinolines (Figure 14) was developed via the Friedländer reaction employing microwave irradiation (MW), in the presence of a catalytic amount of hydrochloric acid [28]. The products were tested in vitro against the parasites causative of malaria, leishmaniasis, sleeping sickness and Chagas’ disease (TDR, WHO). Some of these compounds exhibited activity against Plasmodium falciparum and others resulted moderately active against Trypanosoma cruzi. The MW syntheses were carried out in a domestic oven adapted for the use of a reflux condenser, with constant power of (400 W). All the reactions were completed between 1.5 and 12 min.

Figure 14.

Synthesis of a series of substituted quinolines.

In search for green reactions leading to the Formation of N-Heterocycles, an excellent review was identified entitled “More Sustainable Approaches for the Synthesis of N-Based Heterocycles”, published in 2009 [29]. A recent review on multi-component green synthesis of N-containing heterocycles using mixed oxides as heterogeneous catalysts is also reported [30]. A group of workers had recently published review on “Eco-friendly and sustainable synthetic approaches to biologically significant fused N-heterocycles” [31]. Other groups had also presented well-documented work on the synthesis of heterocyclic compounds using greener methods [32, 33, 34].

4. Conclusion

In this chapter, I had listed the reactions using green methodologies for the synthesis of nitrogen heterocyclic compounds. These molecules often have interesting biological activities and are structures often generated in medicinal chemistry. Recently, numerous publications concerning the synthesis of heterocycles under solvent-free, use of bio-based solvent, reactions carried on solid support, microwave irradiation condition have appeared. Work on the use of green reactions leading to the formation of nitrogen heterocycles mainly indole, pyrrole, imidazole, pyrimidine, pyridine derivatives is reported in the present chapter using safe solvents, namely water, various bio-based systems is discussed. Green synthetic reactions using microwaves for the one pot synthesis of N-heterocyclic compounds is of immense utility in terms of yield, being faster, cheaper, eco-friendly than conventional reactions. I hope that gathering information will enable the scientific community to implement heterocyclic syntheses that respect our environment a little better.

Conflict of interest

The authors declare no conflict of interest.