**3. Synthesis of** *bis***-(indolyl)methane, indenylindoles and 2,2-disubstituted indolin-3-ones**

In recent past, *bis*-(indolyl)methanes (BIMs) have attracted a tremendous attention of the research community due to their potential applications both in pharmaceuticals and agrochemicals besides their activity in breast tumor cells, bladder cancer and also inhibits proliferation practice as well. Moreover, they display antitumorgenic, antibiotic, antimicrobial activity and *anti*-inflammatory activities etc., and are mostly found in marine natural sources. Fascinatingly, getting inspired from the above applications and also other, if any, the group of Nagarajan constructed the diverse BIMs (**67**) including the natural products arsindoline A and B *via* a green protocol in the presence of DMU:TA (70:30) (**Figure 6**) [46]. Surprisingly, the BIMs were not formed when instead of aldehydes (**66**); cyclicketones (**68**) were treated with indole derivatives in the Kotha's laboratory, rather they received indenylindoles (dienes) **69** under parallel reaction conditions (**Figure 6**) [30]. On the other hand, it has been found that, numerous medicinally active natural and non-natural products possess 2,2-disubstituted indolin-3-one scaffold in addition to their usage as the key building blocks in the total synthesis of diverse indole alkaloids. In this regard, Xie's group involved a deep eutectic mixture of DMU/TA to furnish a range of 2,2-disubstituted indolin-3-one derivatives (**72**) as displayed in the **Figure 6** [47].

Synthesis of heterocyclic compounds has always been of prime importance to the research community because of their vital role in a numerous areas ranging from material sciences and technology to the pharmaceutical and agrochemical

**15**

provided the best results.

electron donating groups containing contestants.

*Low Melting Mixture of L-(+)-Tartaric Acid and* N,N′*-Dimethyl Urea: A New Arrival...*

industries. To the best of our knowledge, to date, a choice of drugs containing heterocyclic scaffolds are available in the world market, and many hundred are under clinical trials around the globe. Therefore, there are always high demands to develop novel strategies for the generation of heterocyclic systems particularly involving milder reaction conditions in an environmentally friendlier manner from easily assessable bulk materials. To this context, although a number of methods having several advantages and disadvantages are available in the literature but in recent years, the deep eutectic solvents have changed the scenario of modern synthetic chemistry by providing a plethora of green approaches towards the construction of these valuable molecules. Among the heterocyclic systems, quinoline scaffold has received a considerable amount of interest because of its availability in a plethora of bioactive molecules. A very simple yet effective green procedure for the synthesis of a variety of quinoline derivatives (**75**) have been developed by Zhang and his co-workers with the involvement of a low melting mixture of DMU:TA (70:30) in moderate-to-excellent yields in a Friedländer fashion (**Figure 7**) [48]. On the other hand, the Biginelli procedure, a multi-component reaction, has been employed for assembling the dihydropyrimidinones (DHPMs) under a green reaction conditions by Köenig's team because of their utility in calcium channel blockers and also as HIV inhibitors and anticancer agent (**Figure 7**) [49]. Captivatingly, this procedure works equally well with masked aldehydes to furnish the required DHPMs in reasonable yields. In another study, the same group has utilized this powerful green methodology for assembling diverse functionalized pyrimidopyrimidinedione derivatives (**85**) with the help of Biginelli reaction in which the low melting mixture play a triple role such as solvent/catalyst/reagent (**Figure 7**) [50]. In this study, although, they have tried several low melting mixtures but DMU/TA in a ratio of 7:3

*Synthesis of* bis*-(indolyl)methane, indenylindoles and 2,2-disubstituted indolin-3-ones utilizing DMU/TA* 

In a separate study, Krishnakumar *et al.,* has reported a green chemical procedure for the construction of *N*-arylhomophthalimides (**83**) by employing the Michael addition reaction of the Michael-donor (homophthalimides) **82** with Michael-acceptor (chalcones) **81** in DMU:TA low melting mixture (**Figure 7**) [51]. In this report, the authors have screened various reaction conditions but the mention conditions provided the good results for both electron withdrawing as well as

The hydantoin and its congeners are the key scaffolds from biological point of view as they are the part of various molecules which exhibit a range of activities for instance antidepressants, antiulcer, antidiabetic agents, anticonvulsant, antiarrhythmic, and antiviral etc. Moreover, this moiety also play a significant role in agrochemistry, cosmetic industry, dye-sensitized solar cells, chiral auxiliaries and also used

*DOI: http://dx.doi.org/10.5772/intechopen.97392*

**Figure 6.**

*mediated green approach.*

*Low Melting Mixture of L-(+)-Tartaric Acid and* N,N′*-Dimethyl Urea: A New Arrival... DOI: http://dx.doi.org/10.5772/intechopen.97392*

**Figure 6.**

*Current Topics in Chirality - From Chemistry to Biology*

**3. Synthesis of** *bis***-(indolyl)methane, indenylindoles and** 

*Diverse indole derivatives assembled* via *FI utilizing the DMU/TA mixture.*

In recent past, *bis*-(indolyl)methanes (BIMs) have attracted a tremendous attention of the research community due to their potential applications both in pharmaceuticals and agrochemicals besides their activity in breast tumor cells, bladder cancer and also inhibits proliferation practice as well. Moreover, they display antitumorgenic, antibiotic, antimicrobial activity and *anti*-inflammatory activities etc., and are mostly found in marine natural sources. Fascinatingly, getting inspired from the above applications and also other, if any, the group of Nagarajan constructed the diverse BIMs (**67**) including the natural products arsindoline A and B *via* a green protocol in the presence of DMU:TA (70:30) (**Figure 6**) [46]. Surprisingly, the BIMs were not formed when instead of aldehydes (**66**); cyclicketones (**68**) were treated with indole derivatives in the Kotha's laboratory, rather they received indenylindoles (dienes) **69** under parallel reaction conditions (**Figure 6**) [30]. On the other hand, it has been found that, numerous medicinally active natural and non-natural products possess 2,2-disubstituted indolin-3-one scaffold in addition to their usage as the key building blocks in the total synthesis of diverse indole alkaloids. In this regard, Xie's group involved a deep eutectic mixture of DMU/TA to furnish a range of 2,2-disubstituted indolin-3-one derivatives (**72**) as

Synthesis of heterocyclic compounds has always been of prime importance to the research community because of their vital role in a numerous areas ranging from material sciences and technology to the pharmaceutical and agrochemical

**2,2-disubstituted indolin-3-ones**

displayed in the **Figure 6** [47].

**14**

**Figure 5.**

*Synthesis of* bis*-(indolyl)methane, indenylindoles and 2,2-disubstituted indolin-3-ones utilizing DMU/TA mediated green approach.*

industries. To the best of our knowledge, to date, a choice of drugs containing heterocyclic scaffolds are available in the world market, and many hundred are under clinical trials around the globe. Therefore, there are always high demands to develop novel strategies for the generation of heterocyclic systems particularly involving milder reaction conditions in an environmentally friendlier manner from easily assessable bulk materials. To this context, although a number of methods having several advantages and disadvantages are available in the literature but in recent years, the deep eutectic solvents have changed the scenario of modern synthetic chemistry by providing a plethora of green approaches towards the construction of these valuable molecules. Among the heterocyclic systems, quinoline scaffold has received a considerable amount of interest because of its availability in a plethora of bioactive molecules. A very simple yet effective green procedure for the synthesis of a variety of quinoline derivatives (**75**) have been developed by Zhang and his co-workers with the involvement of a low melting mixture of DMU:TA (70:30) in moderate-to-excellent yields in a Friedländer fashion (**Figure 7**) [48]. On the other hand, the Biginelli procedure, a multi-component reaction, has been employed for assembling the dihydropyrimidinones (DHPMs) under a green reaction conditions by Köenig's team because of their utility in calcium channel blockers and also as HIV inhibitors and anticancer agent (**Figure 7**) [49]. Captivatingly, this procedure works equally well with masked aldehydes to furnish the required DHPMs in reasonable yields. In another study, the same group has utilized this powerful green methodology for assembling diverse functionalized pyrimidopyrimidinedione derivatives (**85**) with the help of Biginelli reaction in which the low melting mixture play a triple role such as solvent/catalyst/reagent (**Figure 7**) [50]. In this study, although, they have tried several low melting mixtures but DMU/TA in a ratio of 7:3 provided the best results.

In a separate study, Krishnakumar *et al.,* has reported a green chemical procedure for the construction of *N*-arylhomophthalimides (**83**) by employing the Michael addition reaction of the Michael-donor (homophthalimides) **82** with Michael-acceptor (chalcones) **81** in DMU:TA low melting mixture (**Figure 7**) [51]. In this report, the authors have screened various reaction conditions but the mention conditions provided the good results for both electron withdrawing as well as electron donating groups containing contestants.

The hydantoin and its congeners are the key scaffolds from biological point of view as they are the part of various molecules which exhibit a range of activities for instance antidepressants, antiulcer, antidiabetic agents, anticonvulsant, antiarrhythmic, and antiviral etc. Moreover, this moiety also play a significant role in agrochemistry, cosmetic industry, dye-sensitized solar cells, chiral auxiliaries and also used

**Figure 7.** *A variety of heterocycles assembled by employing the DMU/TA melt.*

as the intermediates for the generation of enantiomerically pure natural and nonnatural *α*-amino acids by means of the dynamic kinetic resolution. Therefore, keeping the consequence of these molecules in mind, König's group in 2013 developed a simple and eco-friendly method for the synthesis of 1,3,5-trisubstituted hydantoin derivatives (**93**/**94**) in excellent yields by means of DMU/TA melt-mediated green approach (**Figure 7**) [52]. Interestingly, during their experimentation, they noted down good diastereoselectivity in which *anti*-isomers were isolated in major amount whileas *syn*-diastereomers were obtained as minor products, confirmed by nuclear overhauser effect (NOE) and X-ray analysis means. On another front, quite recently, Kotha's team has reported mono-hydantoins as well as thiohydantoins by means of three component reaction under low melting mixture of DMU/TA with electron neutral, electron donating, and electron withdrawing groups possessing aniline derivatives (**Figure 7**) [53]. Finally, the tetrahydropyrimidinones (**80**) and quinazoline derivatives (**88**) have been reported, by the groups of Baskaran and Zhang, respectively by employing the same low melting mixture of DMU/TA under similar reaction conditions as can be inspected from the **Figure 7** [54, 55].

## **4. Conclusions and outlook**

In summary, a novel method involving DMU/TA as a low melting mixture has comprehensively been revealed in this chapter, depicting its pivotal role in the heart of modern synthetic organic chemistry particularly for the generation of a variety

**17**

**Author details**

New Delhi, India

Rashid Ali

*Low Melting Mixture of L-(+)-Tartaric Acid and* N,N′*-Dimethyl Urea: A New Arrival...*

of valuable heterocyclic systems. Herein, we have disclosed, a decade advancements made in this field since its inspection (2011). As discussed above in detail, this simple, environmentally benign, cost effective, and productive method has already been shown its impact in the domain of modern preparative chemistry in general, and green chemistry in particular. We assure that this chapter based on greener transformations, will not only help the readers for complete understanding of a low melting mixture of DMU/TA, and its contribution towards the vital synthetic organic transformations, but also would inspire the motivated researchers to exploit the masked opportunities. More importantly, this method might provide a new way to the chiral catalyst mediated reaction since herewith, chiral tartaric acid is part of the melt, and may act as a valuable handle for the generation of chirality in a

Dr. Rashid Ali is grateful to DST-SERB New Delhi for financial support (Project

File no. ECR/2017/000821). In addition, he also thanks Jamia Millia Islamia,

New Delhi, India, for providing the necessary research facilities.

The author declare no conflicts of interest.

Organic and Supramolecular Functional Materials Research Laboratory, Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, Okhla,

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: rali1@jmi.ac.in

provided the original work is properly cited.

*DOI: http://dx.doi.org/10.5772/intechopen.97392*

molecule under the operation.

**Acknowledgements**

**Conflicts of interest**

*Low Melting Mixture of L-(+)-Tartaric Acid and* N,N′*-Dimethyl Urea: A New Arrival... DOI: http://dx.doi.org/10.5772/intechopen.97392*

of valuable heterocyclic systems. Herein, we have disclosed, a decade advancements made in this field since its inspection (2011). As discussed above in detail, this simple, environmentally benign, cost effective, and productive method has already been shown its impact in the domain of modern preparative chemistry in general, and green chemistry in particular. We assure that this chapter based on greener transformations, will not only help the readers for complete understanding of a low melting mixture of DMU/TA, and its contribution towards the vital synthetic organic transformations, but also would inspire the motivated researchers to exploit the masked opportunities. More importantly, this method might provide a new way to the chiral catalyst mediated reaction since herewith, chiral tartaric acid is part of the melt, and may act as a valuable handle for the generation of chirality in a molecule under the operation.
