**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. *anti*-HIV, antiviral, antimicrobial, antidiabetic, antimalarial, *anti*-cholinesterase, anticancer, *anti*-inflammatory, antioxidant, *anti*tubercular, *anti*-hypertensive, *anti*-convulsant, *anti*-analgesic, and *anti*-depressant activities etc.), agrochemical and clinical applications to the novel therapeutic agents in addition to their usage as dyes, and smart functional materials as well [18–20]. Interestingly, this venerable heterocyclic moiety is not only a part of several important drug molecules and remarkable receptors in host-guest chemistry but also reside in a variety of medicinally active natural products for instance strychnine, reserpine, alstonine etc.; widespread in diverse species of animals, plants, marine organisms, and the part of lysergic acid diethylamide (LSD) as well [21]. More interestingly, they have inimitable property of mimicking the structure of peptides and nicely bind to the enzymes, in addition to exhibit the momentous pharmacological, physiological, synthetic and industrial applications [22]. A list of some important biologically active molecules (**1–12**) containing the indole moiety is depicted in the **Figure 2** [23, 24].

The typical Fischer indolization (FI) reaction involving arylhydrazine (**13)** and aldehyde/ketone (**14**) in the presence of appropriate acid or acid catalyst along with its systematic mechanistic pathway is displayed in the **Figure 3**. Although, a number of pathways were anticipated for the FI, but the one proposed in 1924 by G.M. Robinson and R. Robinson was the most accepted by the scientific community as it was established by both kinetic as well as the spectroscopic means (**Figure 3**) [25]. The mechanism for this particular reaction commence with the activation of the carbonyl carbon of **14** through the protonation with acid/acid catalyst, employed in the operation, which on further reaction with **13** provide the *N*-arylhydrazone intermediate (**17**). Next, the intermediate (**17**) afforded the ene-hydrazine intermediate (**18**) by means of tautomerization, which upon subsequent [3,3]-sigmatropic rearrangement, distracting the aromaticity of aryl ring

**11**

**Figure 3.**

**Figure 2.**

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

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

*Structures of some important biologically active indole derivatives.*

*Representation of indole formation along with the plausible mechanism.*

*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 2.**

*Current Topics in Chirality - From Chemistry to Biology*

**of DMU/TA**

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** 

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. *anti*-HIV, antiviral, antimicrobial, antidiabetic, antimalarial, *anti*-cholinesterase, anticancer, *anti*-inflammatory, antioxidant, *anti*tubercular, *anti*-hypertensive, *anti*-convulsant, *anti*-analgesic, and *anti*-depressant activities etc.), agrochemical and clinical applications to the novel therapeutic agents in addition to their usage as dyes, and smart functional materials as well [18–20]. Interestingly, this venerable heterocyclic moiety is not only a part of several important drug molecules and remarkable receptors in host-guest chemistry but also reside in a variety of medicinally active natural products for instance strychnine, reserpine, alstonine etc.; widespread in diverse species of animals, plants, marine organisms, and the part of lysergic acid diethylamide (LSD) as well [21]. More interestingly, they have inimitable property of mimicking the structure of peptides and nicely bind to the enzymes, in addition to exhibit the momentous pharmacological, physiological, synthetic and industrial applications [22]. A list of some important biologically active molecules (**1–12**) containing the indole moiety is depicted in the **Figure 2** [23, 24]. The typical Fischer indolization (FI) reaction involving arylhydrazine (**13)** and aldehyde/ketone (**14**) in the presence of appropriate acid or acid catalyst along with its systematic mechanistic pathway is displayed in the **Figure 3**. Although, a number of pathways were anticipated for the FI, but the one proposed in 1924 by G.M. Robinson and R. Robinson was the most accepted by the scientific community as it was established by both kinetic as well as the spectroscopic means (**Figure 3**) [25]. The mechanism for this particular reaction commence with the activation of the carbonyl carbon of **14** through the protonation with acid/acid catalyst, employed in the operation, which on further reaction with **13** provide the *N*-arylhydrazone intermediate (**17**). Next, the intermediate (**17**) afforded the ene-hydrazine intermediate (**18**) by means of tautomerization, which upon subsequent [3,3]-sigmatropic rearrangement, distracting the aromaticity of aryl ring

**10**

*Structures of some important biologically active indole derivatives.*

system, followed by rearomatization deliver another intermediate (**20**) through the *bis*-iminobenzyl ketone (**19**). Latter furnishes the required indole derivatives (**15**) by virtue of cyclization followed by the loss of ammonia molecule *via* **21** (**Figure 3**). Interestingly, it has been observed that the reaction conditions as well as the nature of the substrate decide the rate determining step (rds). Generally, ene-hydrazine intermediate (**18**) formation or the [3,3]-sigmatropic rearrangement step has been noticed as the rate-limiting step depending on the situation, as discussed further below. The [3,3]-sigmatropic rearrangement has been observed as rate determining step, in a specific case of *α*-*N*-acyl hydrazones in addition to weak acidic solutions as well as when ammonia elimination is prevented due to steric effects [25]. Whileas, in most of the cases including the strong acidic condition favors the ene-hydrazine (**18**) formation as the rds-step of the reaction. More specifically, unsymmetrical 1,l-diarylhydrazines under strong acidic condition provide the indolization at most activated ring (i.e. most susceptible to the protonation), whileas under neutral reaction conditions almost equal amount of isomers are generally being formed.

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 [26]. 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 [27]. 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 [28]. 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 [24]. 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 (**22**–**47**) in decent yields using acyclic and cyclicketones in addition to cyclic enol ethers for instance dihydrofuran and dihydropyran. Fascinatingly, optically active ketone deliver the indole with retention of the configuration. Moreover, indolenines (**31**), was also prepared through this powerful technique in respectable yields under mild reaction conditions (**Figure 4**). Besides, hormone melatonin (**25**) and dimebon (**26**) were also obtained by utilizing this wonderful green approach as a crucial step (**Figure 4**). Inspiring form this simple yet powerful procedure and also from the applications of the indole moiety containing molecules, two years later to this report, in 2014, Kotha and his teammates have successfully employed this strategy for the synthesis of *C*2*-*and *C*s-symmetric *bis*-indole

**13**

**Figure 4.**

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

systems (**52**, **53**, **58**, **60–62**) from bicyclo-3,7-diones and 1-methyl-1-phenylhydrazine under DMU/TA (7:3) reaction conditions (**Figure 5**) [29]. Later on, Kotha's team nicely expanded this delightful method for the generation of a variety of carbazole derivatives (**32–35**) including pyrano-carbazole (**36**) and *aza*-cyclophane based carbazoles (**37** and **38**) as depicted **Figure 4** [30–32] in **Figure 4**. Interestingly, utilizing this tactic, they have also prepared carbazole-based natural products such as tijapinazole D (**32**) and tijapinazole I (**33**) in addition to the crown-based indolocarbazole (**47**). Moreover, in the laboratory of Kotha's group, diverse heteropolycyclic compounds (**39–43**) in addition to the propellane derivatives (**44**) have been assembled by using ring-closing metathesis (RCM) and Fischer indolization in a low melting mixture of DMU/TA as crucial steps, (**Figure 4**) [33–35]. Keeping the importance of *C*3-symmetric molecules in medicinal and bioorganic chemistry besides their vital role in material science and technology, the same group has also prepared star-shaped *C*3-symmetric compounds **45** and **46** involving cyclotrimerization and DMU/TA mediated indolization approach (**Figure 4**) [36]. Furthermore, as can be inspected from the **Figure 5**, they design and constructed varied cyclophane derivatives (**48**, **49**, **54**, **55** and **59**) through the involvement of the Grignard reaction, RCM and a low melting mixture mediated indolization sequences in respectable yields because of their applicability in supramolecular chemistry [37–41]. In addition to these, Kotha's group has also prepared diverse polycyclic mono- (**50**, **56**, **63**) and *bis*-indole derivatives (**51**, **57**, **58**, **64**) by means of a deep eutectic mixture of DMU/

*Indole derivatives constructed using DMU/TA mediated green protocol.*

TA (70:30) under operationally simple reaction conditions [42–45].

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

*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 4.** *Indole derivatives constructed using DMU/TA mediated green protocol.*

systems (**52**, **53**, **58**, **60–62**) from bicyclo-3,7-diones and 1-methyl-1-phenylhydrazine under DMU/TA (7:3) reaction conditions (**Figure 5**) [29]. Later on, Kotha's team nicely expanded this delightful method for the generation of a variety of carbazole derivatives (**32–35**) including pyrano-carbazole (**36**) and *aza*-cyclophane based carbazoles (**37** and **38**) as depicted **Figure 4** [30–32] in **Figure 4**. Interestingly, utilizing this tactic, they have also prepared carbazole-based natural products such as tijapinazole D (**32**) and tijapinazole I (**33**) in addition to the crown-based indolocarbazole (**47**). Moreover, in the laboratory of Kotha's group, diverse heteropolycyclic compounds (**39–43**) in addition to the propellane derivatives (**44**) have been assembled by using ring-closing metathesis (RCM) and Fischer indolization in a low melting mixture of DMU/TA as crucial steps, (**Figure 4**) [33–35]. Keeping the importance of *C*3-symmetric molecules in medicinal and bioorganic chemistry besides their vital role in material science and technology, the same group has also prepared star-shaped *C*3-symmetric compounds **45** and **46** involving cyclotrimerization and DMU/TA mediated indolization approach (**Figure 4**) [36]. Furthermore, as can be inspected from the **Figure 5**, they design and constructed varied cyclophane derivatives (**48**, **49**, **54**, **55** and **59**) through the involvement of the Grignard reaction, RCM and a low melting mixture mediated indolization sequences in respectable yields because of their applicability in supramolecular chemistry [37–41]. In addition to these, Kotha's group has also prepared diverse polycyclic mono- (**50**, **56**, **63**) and *bis*-indole derivatives (**51**, **57**, **58**, **64**) by means of a deep eutectic mixture of DMU/ TA (70:30) under operationally simple reaction conditions [42–45].

*Current Topics in Chirality - From Chemistry to Biology*

system, followed by rearomatization deliver another intermediate (**20**) through the *bis*-iminobenzyl ketone (**19**). Latter furnishes the required indole derivatives (**15**) by virtue of cyclization followed by the loss of ammonia molecule *via* **21** (**Figure 3**). Interestingly, it has been observed that the reaction conditions as well as the nature of the substrate decide the rate determining step (rds). Generally, ene-hydrazine intermediate (**18**) formation or the [3,3]-sigmatropic rearrangement step has been noticed as the rate-limiting step depending on the situation, as discussed further below. The [3,3]-sigmatropic rearrangement has been observed as rate determining step, in a specific case of *α*-*N*-acyl hydrazones in addition to weak acidic solutions as well as when ammonia elimination is prevented due to steric effects [25]. Whileas, in most of the cases including the strong acidic condition favors the ene-hydrazine (**18**) formation as the rds-step of the reaction. More specifically, unsymmetrical 1,l-diarylhydrazines under strong acidic condition provide the indolization at most activated ring (i.e. most susceptible to the protonation), whileas under neutral reac-

tion conditions almost equal amount of isomers are generally being formed.

of indole architectures, and a plethora of methods continue to be reported in this trend [26]. 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 [27]. 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 [28]. 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 [24]. 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 (**22**–**47**) in decent yields using acyclic and cyclicketones in addition to cyclic enol ethers for instance dihydrofuran and dihydropyran. Fascinatingly, optically active ketone deliver the indole with retention of the configuration. Moreover, indolenines (**31**), was also prepared through this powerful technique in respectable yields under mild reaction conditions (**Figure 4**). Besides, hormone melatonin (**25**) and dimebon (**26**) were also obtained by utilizing this wonderful green approach as a crucial step (**Figure 4**). Inspiring form this simple yet powerful procedure and also from the applications of the indole moiety containing molecules, two years later to this report, in 2014, Kotha and his teammates have successfully employed this strategy for the synthesis of *C*2*-*and *C*s-symmetric *bis*-indole

Accordingly, synthetic chemists have long sought approaches for the construction

**12**

**Figure 5.** *Diverse indole derivatives assembled* via *FI utilizing the DMU/TA mixture.*
