After the first report of deep eutectic mixtures by the team of Abbott in 2003, the advent of green synthesis has been progressively changing the way synthetic chemistry is thought and also taught. Since then, a plethora of efforts worldwide have been taken to stretch the ideas of sustainable as well as environmentally benign approaches to do the crucial synthetic organic transformations under operationally simple yet effective conditions. Although, till date, several green synthetic strategies for examples ultrasound, microwaves, flow as well as grindstone chemistry etc., and green reaction media (e.g. ionic liquid, water, scCO2, and so forth) have successfully been invented. But a low melting mixture of L-(+)-tartaric acid (TA) and N,N′-dimethylurea (DMU), usually plays a double and/or triple role (solvent, catalyst, and/or reagent), though still infancy but enjoys several eye-catching properties like biodegradability, recyclability, non-toxicity, good thermal stability, tunable physiochemical properties, low vapor pressure as well as reasonable prices in addition to the easy preparation with wide functional groups tolerance. To this context, keeping the importance of this novel low melting mixture in mind, we intended to reveal the advancements taken place in this wonderful area of research since its first report by the Köenig’s group in 2011 to till date. In this particular chapter, firstly we would disclose the importance of the green synthesis followed by a brief description of deep-eutectic solvents (DESs) particularly emphasizing on the role of L-(+)-TA and DMU from modern synthetic chemistry perspective.
- low melting mixture
- 3-dimethyl urea
- tartaric acid
- sustainable chemistry
As can be inspected from the literature, there were rising concerns in the mid-1980s, regarding the plentiful of the waste being produced by the chemical industry [1, 2]. A paradigm change was undoubtedly desirable, from the old-fashioned perceptions of reaction selectivity, and efficiency which emphasis fundamentally on the chemical yields, to one that allocates the value to the enlargement of the bulk raw materials exploitation, avoidance of the utilization of the hazardous chemicals/reagents/solvents and also preventation of the waste being formed within the boundaries of environmental awareness. To this context, in 1987, the term sustainable development was coined by Brundtland, in his report; he mainly focused on the emergence of the societal and industrial development to afford an escalating global population with a suitable value of life in such a way that it should be sustainable over a long period of time . Therefore, complete balance necessities to be found among the three Ps-planet, people, profit i.e. environmental impact, societal equity and economic development. More specifically, in sharp contrast to the green chemistry, sustainable development also comprises an economic factor and if a technology is not economically viable, it could not be sustainable for a long time. Remarkably, a tremendous curiosity in sustainable and green progress, united with a cultivating concern for the climate change, has engrossed attention on resource competence and also driving the shift from a conventional linear flow of bulk materials in a “take−make−use−dispose”economy, towards the greener and even more sustainable globular economy. Interestingly, since the 12 principles of green chemistry (
Bearing all the above mentioned applications and peculiar physiochemical properties of the DMU/TA melt in mind, which we still feel is immature, although employed for a variety of successful reactions for instance Diels-Alder reaction, Stille, Sonogashira, Suzuki, and Heck coupling reactions, Biginelli reaction, 1,3-dipolar reaction, in addition to its applicability for the synthesis of quinolines, arylhomophthalimides, prymidopyrimidinediones, tetrahydropyrimidinones, hydantoins, dihydropyrimidinones, quinazolines, and a variety of functionalized indole systems with excellent selectivity in decent yields. Interestingly, the beauty of this method is its double and triple role in the reaction vessel to facilitate the accomplishment of the reactions in a clean and smooth fashion without the involvement of any catalyst/additives or solvent. In short, after a brief introduction related to the sustainability and green synthetic approaches, herewith, we have tried to display a deep survey of what has already been done in this field, and open the opportunities to the young researches to find out the new advances by employing this DES and also medium engineering might be utilized to optimize the synthetic utility of various other combinations of the DESs. Green chemistry 12 principles as well as the achievements made by employing a low melting mixture of DMU/TA in the domain of synthetic organic chemistry are displayed in the Figure 1.
2. Construction of indole systems under a low melting mixture of DMU/TA
The name indole was originated from portmanteau, a combination of both the words, indigo and oleum which was first isolated from the indigo dye, while treating it with oleum [16, 17]. As can be inspected from the literature, indole scaffold, a notable privileged lead bicyclic aromatic system (10π-electrons), formally known as benzopyrrole, have immeasurable potential applications ranging from the broad-spectrum biological (e.g.
The typical Fischer indolization (FI) reaction involving arylhydrazine (
Accordingly, synthetic chemists have long sought approaches for the construction of indole architectures, and a plethora of methods continue to be reported in this trend . Hardly surprising, to date, a myriad of methods involving both intra- and intermolecular transformations for the construction of indole derivatives, particularly the usage of named reactions such as, Gassman, Bartoli, Thyagarajan, Julia, Schmid, Wender, Couture, Kihara, Nenitzescu, Engler, Saegusa, Liebeskind, Sundberg, Hemetsberger, Magnus, Feldman, Reissert, Makosza, Leimgruber–Batcho, Watanabe, Larock, Yamanaka–Sakamoto, Hegedus–Mori–Heck, Fürstner, Castro, Natsume, Nordlander, and so on, have successfully been employed . But, to our best knowledge, despite its numerous complications, rearrangements, and also mechanistic mysteries, Fischer indole protocol, an old yet effective procedure which involve a pericyclic tool namely, [3,3]-sigmatropic rearrangement, remains the epitome for the scientific community around the globe to assemble diverse indole and its congeners . Although, a variety of acid catalysts for example HCl, AcOH, PPA, TiCl4, ZnCl2, SOCl2, PCl3, TsOH, H2SO4, mont-morilloniteclay zeolite etc., have been employed to synthesize the indole framework using FI protocol, but simple, and eco-friendly methods which involve non-hazardous, inexpensive and easily accessible chemicals as well as reagents utilizing the environmentally benign practices are always of particular interest. In this regard, König’s group in 2012, first time reported a green approach by employing the FI strategy under a low melting mixture of dimethyl urea (DMU):L-(+)-tartaric acid (TA) in (7:3) ratio to yield a range of indole derivatives in good-to-excellent yields . The beauty of this particular green method relies on the fact that, a clean low melting mixture is generated just by heating the two components in appropriate amount at much lower temperature than its individual components, and can be used without further purification. Herewith, the low melting mixture, acts as mild acidic catalyst (pH 3.7) as well as solvent to furnish the required indoles with great functional group compatibility and selectivity. As can be seen from an inspection of the Figure 4, these authors prepared a range of functionalized indole systems (
3. Synthesis of
bis-(indolyl)methane, indenylindoles and 2,2-disubstituted indolin-3-ones
In recent past,
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 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 (
In a separate study, Krishnakumar
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 as the intermediates for the generation of enantiomerically pure natural and non-natural
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 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.
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.
Conflicts of interest
The author declare no conflicts of interest.
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