**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<sup>0</sup> -pyrrolo[1,2-*c*]imidazole]-6<sup>0</sup> -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].

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 1.** *Synthesis of spiro[indoline-3,7*<sup>0</sup> *-pyrrolo[1,2-*c*]imidazole]-6*<sup>0</sup> *-carbonitrile derivatives.*

**Figure 2.**

*Synthetic route for polysubstituted pyrroles.*

**Figure 3.** *Synthesis of 3,5-disubstituted pyrazoles.*

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.

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].

An environmentally friendly, green, practical, attractive and effective method to construct 4*H*-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**).

**Figure 4.** *Synthesis of diarylthiazoles and diarylimidazoles.*


#### **Table 1.**

*Synthesis of diarylthiazoles [13] and diarylimidazoles 13*<sup>0</sup> *[16].*

**Figure 5.** *Construction of 4*H*-pyrido[1,2-*a*]pyrimidin-4-one.*


*Greener Approach towards the Synthesis of Nitrogen Based Heterocycles DOI: http://dx.doi.org/10.5772/intechopen.108489*

**Table 2.**

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

#### **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<sup>0</sup> -indoline]-2<sup>0</sup> ,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.

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 6.**

*Synthesis of spiro[benzo[*f*]pyrrolo[2,1-*a*]isoindole-5,3*<sup>0</sup> *-indoline]-2*<sup>0</sup> *,6,11-trione derivatives.*

**Figure 7.**

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

A simple and chemoselective method of synthesizing T-shaped oxazolonaphtho [1<sup>0</sup> ,20 :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.

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 8.** *Synthesis of T-shaped oxazolonaphtho[1*<sup>0</sup> *,2*<sup>0</sup> *:4,5]imidazo[1,2-*a*]pyridines.*

*Greener Approach towards the Synthesis of Nitrogen Based Heterocycles DOI: http://dx.doi.org/10.5772/intechopen.108489*

#### **Figure 9.**

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