C▬H Activation Strategies for Heterofunctionalization and Heterocyclization on Quinones: Application in the Synthesis of Bioactive Compounds

*Andivelu Ilangovan and Thumadath Palayullaparambil Adarsh Krishna*

## **Abstract**

Quinone moieties in general and heterofunctionalized or heterofused quinones in particular find application in several fields such as medicinal chemistry, natural products, and functional materials. Due to its striking applications, scientists developed useful methods for the synthesis of quinone derivatives. C▬H activation strategy is a fast-developing and straightforward concept, used in the construction of a diverse variety of bonds such as carbon▬carbon (C▬C) and carbon▬hetero (C▬O/N/ S/P) bonds and also used is the heterofunctionalization/heterocyclization of quinones. Such approaches are useful in making use of unfunctionalized quinones for the synthesis of heterofunctionalized or heterocycle-fused quinones. The redox active nature and ligand-like properties make it difficult to carryout C▬H activation on quinones. In this chapter we summarized recent developments on strategies used for C▬hetero atom bond formation on quinones via C▬H activation, leading to heterofunctionalization and synthesis of heterofused quinones.

**Keywords:** quinone moiety, C▬H activation strategy, heterofunctionalization approaches, biomolecules

## **1. Introduction**

Inspired by quinone's reactive electrophilic character, easily accessible oxidation states [1], ubiquitous natural presence [2], and important roles played in living systems (phosphorylation to electron transfer process) [3], chemists tried to mimic its acts through synthetic equivalents consisting of biologically active compounds [4], natural product analogs [5], and functional materials [6]. Consequently, several methods were developed for the synthesis of quinone derivatives. Depending upon the basic subunits (**Figure 1**), quinones are classified as benzoquinone (BQ), naphthoquinone (NQ), anthraquinone (AQ), and polyquinones (PQ).

Current, statistics on number of publications (**Figure 2**) appeared during the past two decades, ever growing research highlights, interests, importance, and applications of quinone chemistry [18].

process as it involves breaking of C▬H bond having high energy (CH4, 100 kcal/ mol; benzene, 110 kcal/mol) and high pKa value (>40). In case of quinones, it is further more difficult, [32–34] as it interacts with transition metal reagents, such as Pd (Heck-type reaction), through redox reaction and ligand [35, 36] formation. The report made by Baran et al.*,* in 2011, on coupling of quinones with boronic acids [25] for the formation of C▬C bond, and by Poulsen et al., in 2018, for heterofunctionalization on quinone [26], is a notable example on C▬H activation reactions on quinones. Approaches for functionalization of quinone can be broadly classified as Lewis acid (MX3)-promoted nucleophilic addition of electron-rich arenes [27–30],

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on…*

transition metal-catalyzed addition of aryl radicals generated from prefunctionalized starting material [31, 32], and transition metal-catalyzed cross-

starting materials and finally to heterofunctionalization (**Figure 3**). Prefunctionalization combined with separation and purification leads to additional

steps, generates waste, and lowers the efficiency drastically.

C▬H heterofunctionalization reaction of quinones.

*Conventional heterofunctionalization vs. C*▬*H activation approach.*

*Example on direct C*▬*H heterofunctionalization of quinone.*

Conventional methods for the heterofunctionalization (HF) of quinones involves pre-functionalization of C▬H bond to form organo-halide [33–37] (Cl, Br, and I) or organo-boronic acid (▬B(OH)2) [38] or organo-metallic (SnBu3) [39, 40]

The arylation (C▬C bond formation) of quinone is one of the thoroughly studied reactions using several aryl coupling partners with and without a directing group [32]. Poulsen and coworker's [26] demonstration of the synthesis of natural product stronglylophorine-26, an inhibitor of cancer cell invasion, via C▬H heterofunctionalization of quinone (**Figure 4**) sets a good example on the importance of direct

The undirected C▬H functionalizations are much common in quinone chemistry. The presence of a directing group (DG) is helpful in achieving site-specific C▬H functionalization of quinone. However, the development of efficient synthetic approaches for site-specific C▬H functionalization of quinones is challenging [41– 47]. This could be achieved either by manipulation of the reagent used or the presence of a directing group. For example, Junior and coworkers [41] demonstrated Rh-catalyzed C5 and C2 site-selective C▬H halogenation of naphthoquinone (**Figure 5**). Similarly, by changing the type of reagent TBAI-TBHP [43] or RuCl2(*p*cymene)-PIFA [47], hydroxyl group was introduced on quinone at C-2 or C-5

coupling of halo-quinones [33–37].

*DOI: http://dx.doi.org/10.5772/intechopen.90930*

position (**Figure 5**) site specifically.

**Figure 3.**

**Figure 4.**

**127**

**Figure 1.**

*Selected biologically important quinone molecules [7–17].*

**Figure 2.** *Trends in the number of publications on quinones in the last 20 years based on the web of science data.*

## **2. C**▬**H activation and heterofunctionalization of quinones**

The construction of carbon▬carbon (C▬C) bond or carbon▬hetero atom (C▬X) bond on quinone has been reported either using pre-functionalized starting materials or direct functionalization of C▬H bonds [19–24]. The first step in C▬H functionalization is activation, followed by the formation of an intermediate carbon-metal (C▬M) bond, and final replacement with a functional group (FG). C▬H activation reaction is advantageous as it is straightforward and atom economic and does not require pre-functionalization [31]. Some typical steps involved in C▬H activation reaction mechanisms are oxidative addition, σ-bond metathesis, electrophilic activation, 1,2-addition, and metalloradical. C▬H activation is a difficult

### *C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on… DOI: http://dx.doi.org/10.5772/intechopen.90930*

process as it involves breaking of C▬H bond having high energy (CH4, 100 kcal/ mol; benzene, 110 kcal/mol) and high pKa value (>40). In case of quinones, it is further more difficult, [32–34] as it interacts with transition metal reagents, such as Pd (Heck-type reaction), through redox reaction and ligand [35, 36] formation. The report made by Baran et al.*,* in 2011, on coupling of quinones with boronic acids [25] for the formation of C▬C bond, and by Poulsen et al., in 2018, for heterofunctionalization on quinone [26], is a notable example on C▬H activation reactions on quinones. Approaches for functionalization of quinone can be broadly classified as Lewis acid (MX3)-promoted nucleophilic addition of electron-rich arenes [27–30], transition metal-catalyzed addition of aryl radicals generated from prefunctionalized starting material [31, 32], and transition metal-catalyzed crosscoupling of halo-quinones [33–37].

Conventional methods for the heterofunctionalization (HF) of quinones involves pre-functionalization of C▬H bond to form organo-halide [33–37] (Cl, Br, and I) or organo-boronic acid (▬B(OH)2) [38] or organo-metallic (SnBu3) [39, 40] starting materials and finally to heterofunctionalization (**Figure 3**). Prefunctionalization combined with separation and purification leads to additional steps, generates waste, and lowers the efficiency drastically.

The arylation (C▬C bond formation) of quinone is one of the thoroughly studied reactions using several aryl coupling partners with and without a directing group [32]. Poulsen and coworker's [26] demonstration of the synthesis of natural product stronglylophorine-26, an inhibitor of cancer cell invasion, via C▬H heterofunctionalization of quinone (**Figure 4**) sets a good example on the importance of direct C▬H heterofunctionalization reaction of quinones.

The undirected C▬H functionalizations are much common in quinone chemistry. The presence of a directing group (DG) is helpful in achieving site-specific C▬H functionalization of quinone. However, the development of efficient synthetic approaches for site-specific C▬H functionalization of quinones is challenging [41– 47]. This could be achieved either by manipulation of the reagent used or the presence of a directing group. For example, Junior and coworkers [41] demonstrated Rh-catalyzed C5 and C2 site-selective C▬H halogenation of naphthoquinone (**Figure 5**). Similarly, by changing the type of reagent TBAI-TBHP [43] or RuCl2(*p*cymene)-PIFA [47], hydroxyl group was introduced on quinone at C-2 or C-5 position (**Figure 5**) site specifically.

#### **Figure 3.**

**2. C**▬**H activation and heterofunctionalization of quinones**

*Trends in the number of publications on quinones in the last 20 years based on the web of science data.*

**Figure 1.**

**Figure 2.**

**126**

*Selected biologically important quinone molecules [7–17].*

*Organic Synthesis - A Nascent Relook*

The construction of carbon▬carbon (C▬C) bond or carbon▬hetero atom (C▬X) bond on quinone has been reported either using pre-functionalized starting materials or direct functionalization of C▬H bonds [19–24]. The first step in C▬H functionalization is activation, followed by the formation of an intermediate carbon-metal (C▬M) bond, and final replacement with a functional group (FG). C▬H activation reaction is advantageous as it is straightforward and atom economic and does not require pre-functionalization [31]. Some typical steps involved in C▬H activation reaction mechanisms are oxidative addition, σ-bond metathesis, electrophilic activation, 1,2-addition, and metalloradical. C▬H activation is a difficult

*Conventional heterofunctionalization vs. C*▬*H activation approach.*

**Figure 4.** *Example on direct C*▬*H heterofunctionalization of quinone.*

Amines undergo smooth conjugate addition to *p*-quinones in polar solvents at ambient temperature in the absence of a catalyst and additives. Baruah et al., in 2007, synthesized a series of 2,5-bis(alkyl/arylamino)1,4-quinones from the reaction of 1,4-benzoquinone (BQ) with different amines under aerobic condition [69]. The reaction was found to be exceptionally selective and leads to only 2,5-bis(alkyl/ arylamino)1,4-benzoquinones of the corresponding amine (**Figure 7**). 2,5-Isomer is formed exclusively due to electrostatic reasons. This is further evident from the fact that 1,4-naphthoquinone (NQ) on reaction with amines gives monosubstituted derivatives. In another study, Yadav et al. [70] studied H2O-accelerated C▬H amination to form highly substituted benzoquinone. In this reaction, water played a

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on…*

*DOI: http://dx.doi.org/10.5772/intechopen.90930*

Molecular iodine-promoted direct C▬H amination of NQ under ultrasonic irradiation was developed by Liu and Ji [71]. The method employs cheap, nontoxic molecular iodine as the catalyst; the desired products were obtained in moderate to excellent yield (**Figure 8**). In mechanism, molecular iodine activates the carbonyl group of the NQ to give intermediate (**A**) and is followed by amine attack at unsaturated position to give the initial addition product (**B**) which tautomerizes to form hydroquinone (**C**), which subsequently undergoes rapid oxidation finally to

Garden et al., in 2011, developed Cu(II)-catalyzed amination of NQ by oxidative coupling with derivatives of aniline (**Figure 9**). The best isolated yield was obtained in the presence of catalytic amount of copper, and the hydrated Cu(II) acetate shortens reaction time and reduces side-product formation. The study on the mechanism shows that Michael addition of anilines to NQ is facilitated by Cu(II)

dual role of simultaneously activating the *p*-quinone and amine.

form quinone system [71].

*Bis(alkyl/arylamino) benzoquinone synthesis.*

*Iodine-promoted direct C*▬*H amination on NQ.*

**Figure 7.**

**Figure 8.**

**129**

**Figure 5.**

*Site-selective C*▬*H functionalization on quinone or aryl ring.*

**Figure 6.** *Heterofunctionalization strategies.*

The electrophilic character of quinone enables it to undergo facile nucleophilic attack using electron-rich nucleophilic species such as amino (R-NH2), hydroxyl (R-OH), and thiol (R-SH) groups, as in the case of classical Michael addition [48]. Using *p*-benzoquinone most of the nucleophilic reaction leads to the forms mono-, di-, tri-, and tetra-substituted benzoquinone and most of the times hydroquinones.

In continuation of our interest on the development of C▬H activation methodologies [49–55], we have developed methods for C▬H functionalization of quinones [51–55]. A review article covering C▬H activation of quinone with main emphasis on C▬C bond-forming reactions has been reported [32]. C▬H heterofunctionalization of quinone has been carried out using various catalytic systems, consisting of metal/nonmetal catalysts, organocatalyst, photocatalyst, etc. By choosing appropriate catalysts/reagents/additives, we can change the reaction pathway like radical/ electrophilic/nucleophilic, etc. (**Figure 6**). For example, recently we developed an I2-DMSO system [54] for C▬H/S▬H and FeCl3-K2S2O8 system [55] for C▬H/C▬H radical cross-coupling reactions, which normally occurs via Michael and Friedel-Crafts pathway.

Under this chapter we summarized C▬H activation strategies used in heterofunctionalization and heterocyclization of quinones and its application in the synthesis of bioactive heterocycles during the past decade.

#### **2.1 C**▬**H activation and C**▬**N bond formation on quinones**

Aminoquinone derivatives find prominent application in medicinal chemistry and are good building blocks for many heterocyclic compounds [56]. C▬N bondforming reactions are of great importance in quinone chemistry, and in general, oxidative coupling and nucleophilic substitution reactions are involved [57**–**61]. It has been intensively studied using pre-functionalized quinones [62**–**68]. Hence, we covered some of the important C▬N bond formation methodologies through C▬H activation strategies which are given below.

#### *C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on… DOI: http://dx.doi.org/10.5772/intechopen.90930*

Amines undergo smooth conjugate addition to *p*-quinones in polar solvents at ambient temperature in the absence of a catalyst and additives. Baruah et al., in 2007, synthesized a series of 2,5-bis(alkyl/arylamino)1,4-quinones from the reaction of 1,4-benzoquinone (BQ) with different amines under aerobic condition [69]. The reaction was found to be exceptionally selective and leads to only 2,5-bis(alkyl/ arylamino)1,4-benzoquinones of the corresponding amine (**Figure 7**). 2,5-Isomer is formed exclusively due to electrostatic reasons. This is further evident from the fact that 1,4-naphthoquinone (NQ) on reaction with amines gives monosubstituted derivatives. In another study, Yadav et al. [70] studied H2O-accelerated C▬H amination to form highly substituted benzoquinone. In this reaction, water played a dual role of simultaneously activating the *p*-quinone and amine.

Molecular iodine-promoted direct C▬H amination of NQ under ultrasonic irradiation was developed by Liu and Ji [71]. The method employs cheap, nontoxic molecular iodine as the catalyst; the desired products were obtained in moderate to excellent yield (**Figure 8**). In mechanism, molecular iodine activates the carbonyl group of the NQ to give intermediate (**A**) and is followed by amine attack at unsaturated position to give the initial addition product (**B**) which tautomerizes to form hydroquinone (**C**), which subsequently undergoes rapid oxidation finally to form quinone system [71].

Garden et al., in 2011, developed Cu(II)-catalyzed amination of NQ by oxidative coupling with derivatives of aniline (**Figure 9**). The best isolated yield was obtained in the presence of catalytic amount of copper, and the hydrated Cu(II) acetate shortens reaction time and reduces side-product formation. The study on the mechanism shows that Michael addition of anilines to NQ is facilitated by Cu(II)

**Figure 7.** *Bis(alkyl/arylamino) benzoquinone synthesis.*

**Figure 8.** *Iodine-promoted direct C*▬*H amination on NQ.*

The electrophilic character of quinone enables it to undergo facile nucleophilic attack using electron-rich nucleophilic species such as amino (R-NH2), hydroxyl (R-OH), and thiol (R-SH) groups, as in the case of classical Michael addition [48]. Using *p*-benzoquinone most of the nucleophilic reaction leads to the forms mono-, di-, tri-, and tetra-substituted benzoquinone and most of the times hydroquinones. In continuation of our interest on the development of C▬H activation methodologies [49–55], we have developed methods for C▬H functionalization of quinones [51–55]. A review article covering C▬H activation of quinone with main emphasis on C▬C bond-forming reactions has been reported [32]. C▬H heterofunctionalization of quinone has been carried out using various catalytic systems, consisting of metal/nonmetal catalysts, organocatalyst, photocatalyst, etc. By choosing appropriate catalysts/reagents/additives, we can change the reaction pathway like radical/ electrophilic/nucleophilic, etc. (**Figure 6**). For example, recently we developed an I2-DMSO system [54] for C▬H/S▬H and FeCl3-K2S2O8 system [55] for C▬H/C▬H radical cross-coupling reactions, which normally occurs via Michael and Friedel-

Under this chapter we summarized C▬H activation strategies used in

synthesis of bioactive heterocycles during the past decade.

**2.1 C**▬**H activation and C**▬**N bond formation on quinones**

activation strategies which are given below.

heterofunctionalization and heterocyclization of quinones and its application in the

Aminoquinone derivatives find prominent application in medicinal chemistry and are good building blocks for many heterocyclic compounds [56]. C▬N bondforming reactions are of great importance in quinone chemistry, and in general, oxidative coupling and nucleophilic substitution reactions are involved [57**–**61]. It has been intensively studied using pre-functionalized quinones [62**–**68]. Hence, we covered some of the important C▬N bond formation methodologies through C▬H

Crafts pathway.

**128**

**Figure 5.**

**Figure 6.**

*Heterofunctionalization strategies.*

*Site-selective C*▬*H functionalization on quinone or aryl ring.*

*Organic Synthesis - A Nascent Relook*

**Figure 9.** *Cu(II)-catalyzed oxidative coupling with anilines.*

**Figure 10.** *HClO4-SiO2-supported C*▬*N bond on naphthoquinone.*

salt. The copper▬hydroquinone (Cu▬HQ) complex interacts directly with oxygen to give the quinone product or could pass through sequential one electron oxidation steps where the resulting Cu(I) species would then be reoxidized to Cu(II) by oxygen. The mechanistic proposal was supported by ESI-MS experiment, to find that the only copper species reliably observed was the copper cation as the isotopologues Cu(I)(ACN)2 + (m/z 145) and Cu(I)(ACN)2 + (m/z 147) in an approximately 2:1 ratio [72].

quinone undergoes a thermal azide-alkene [3 + 2] cycloaddition followed by proton

sulfonamidation products. Moreover, they successfully used phosphoryl azide for

Recently, Chen et al. [75] developed an efficient protocol for the preparation of aminated naphthoquinone starting from NQ and nitro compounds. In the presence of Zn/AcOH system, the nitro compounds were reduced to the corresponding amines (**Figure 12**). Lewis acid Zn(OAc)22H2O, 1,4-naphthoquinone is activated to generate the complex, and the intermediate reacts with aniline through 1,4-nucleophilic addition to give the adduct (**A**). Then, compound (**A**) can be oxidized to afford product in the presence of molecular oxygen along with losing a proton and

Some of the amination reactions, including multicomponent reactions, which lead to the formation of quinone-fused nitrogen heterocycles are described under

Thioethers are common building blocks, found in numerous biologically active compounds and in medicinally useful natural products [76]. The C▬S bond construction via direct functionalization of C▬H bond with sulfenylating reagents is an

abstraction, ring opening, and elimination of a nitrogen molecule to form

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on…*

▬NH2 transfer on NQ and Menadione under optimal condition.

**2.2 C**▬**H activation and C**▬**S bond formation on quinones**

the Lewis acid.

**Figure 11.**

**Figure 12.**

*K2CO3 promoted 1,4-quinone sp<sup>2</sup> C*▬*H sulfonamidation.*

*DOI: http://dx.doi.org/10.5772/intechopen.90930*

*Zn(II) catalyzed amination using nitro compounds.*

the Section 3.1.

**131**

Heterogeneous SiO2-supported HClO4 catalyst promoting highly efficient and clean conjugate addition of primary and secondary amines with NQ was described by Upendra et al. [73]. Under the catalytic-ultrasonication condition, corresponding 2-amino-1,4-naphthoquinone derivatives were obtained in moderate to high yields without using any solvent (**Figure 10**). The proposed mechanism of this reaction includes two steps such as addition and oxidation. Nucleophilic addition of amines to HClO4-SiO2-activated naphthoquinone (**A**) leads to adduct (**B**). Further, the adduct (**B**) oxidized to afford NQ as final product. The authors also described a possibility of aerobic oxidation of hydroquinone (HNQ).

A base-promoted C(sp<sup>2</sup> )-H sulfonamidation of 1,4-naphthoquinones via [3 + 2] cycloaddition reaction using sulfonyl azides was reported by Ramanathan and Pitchumani [74]. The straightforward, atom, and step-economic protocol provided desired product in moderate to good yield (**Figure 11**). The active alkene moiety of *C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on… DOI: http://dx.doi.org/10.5772/intechopen.90930*

**Figure 11.**

*K2CO3 promoted 1,4-quinone sp<sup>2</sup> C*▬*H sulfonamidation.*

**Figure 12.** *Zn(II) catalyzed amination using nitro compounds.*

quinone undergoes a thermal azide-alkene [3 + 2] cycloaddition followed by proton abstraction, ring opening, and elimination of a nitrogen molecule to form sulfonamidation products. Moreover, they successfully used phosphoryl azide for ▬NH2 transfer on NQ and Menadione under optimal condition.

Recently, Chen et al. [75] developed an efficient protocol for the preparation of aminated naphthoquinone starting from NQ and nitro compounds. In the presence of Zn/AcOH system, the nitro compounds were reduced to the corresponding amines (**Figure 12**). Lewis acid Zn(OAc)22H2O, 1,4-naphthoquinone is activated to generate the complex, and the intermediate reacts with aniline through 1,4-nucleophilic addition to give the adduct (**A**). Then, compound (**A**) can be oxidized to afford product in the presence of molecular oxygen along with losing a proton and the Lewis acid.

Some of the amination reactions, including multicomponent reactions, which lead to the formation of quinone-fused nitrogen heterocycles are described under the Section 3.1.

#### **2.2 C**▬**H activation and C**▬**S bond formation on quinones**

Thioethers are common building blocks, found in numerous biologically active compounds and in medicinally useful natural products [76]. The C▬S bond construction via direct functionalization of C▬H bond with sulfenylating reagents is an

salt. The copper▬hydroquinone (Cu▬HQ) complex interacts directly with oxygen to give the quinone product or could pass through sequential one electron oxidation steps where the resulting Cu(I) species would then be reoxidized to Cu(II) by oxygen. The mechanistic proposal was supported by ESI-MS experiment, to find that the only copper species reliably observed was the copper cation as the isotopologues Cu(I)(ACN)2 + (m/z 145) and Cu(I)(ACN)2 + (m/z 147) in an

Heterogeneous SiO2-supported HClO4 catalyst promoting highly efficient and clean conjugate addition of primary and secondary amines with NQ was described by Upendra et al. [73]. Under the catalytic-ultrasonication condition, corresponding 2-amino-1,4-naphthoquinone derivatives were obtained in moderate to high yields without using any solvent (**Figure 10**). The proposed mechanism of this reaction includes two steps such as addition and oxidation. Nucleophilic addition of amines to HClO4-SiO2-activated naphthoquinone (**A**) leads to adduct (**B**). Further, the adduct (**B**) oxidized to afford NQ as final product. The authors also described a

cycloaddition reaction using sulfonyl azides was reported by Ramanathan and Pitchumani [74]. The straightforward, atom, and step-economic protocol provided desired product in moderate to good yield (**Figure 11**). The active alkene moiety of

)-H sulfonamidation of 1,4-naphthoquinones via [3 + 2]

possibility of aerobic oxidation of hydroquinone (HNQ).

approximately 2:1 ratio [72].

**Figure 9.**

**Figure 10.**

**130**

*Cu(II)-catalyzed oxidative coupling with anilines.*

*Organic Synthesis - A Nascent Relook*

*HClO4-SiO2-supported C*▬*N bond on naphthoquinone.*

A base-promoted C(sp<sup>2</sup>

important reaction. Several metal and metal-free catalysts are developed for coupling of quinones with various sulfenylating reagents.

formed with the help of base through Baylis-Hillman process) produced

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on…*

arylsulfonyl hydrazides [83] systems gave sulfonyl hydroquinones.

loose H● to another iodine radical leading to the formation of the product.

Moreover, very recently, CuI-O2 [84] and Co(OAc)2-O2 [26] systems were utilized for direct thiol addition to quinone to form ether. In addition, there are limited reports available for the conversion of hydroquinone to quinone followed by in situ C▬S bond formation. Notably, under metal-free condition Runtao et al. [85] utilized S-alkylisothiouronium salts on hydroquinone for the synthesis of quinonyl

In 2015 Chou et al. [80] used silver catalyst system for the reaction of various aryl disulfides to synthesize a variety of quinonyl aryl thioether moderate to high yields. The authors carried out some control experiments to predict the plausible mechanism. Studies indicate that the reaction is initiated by active disulfide-silver intermediates formed through interactions of the silver with aryl disulfides in

Furthermore, under metal-free conditions, various sulfenylating reagents such as [bmim]BF4-arylsulfinic acids [81], NH4I-sodium arylsulfinates [82], and H2O-

Notably, I2-DMSO system [54] for the thiomethylation of quinone was recently developed by us (**Figure 17**). Based on the verification experiments, we proposed plausible radical pathway. At 120°C, DMSO decomposes to CH3SH and CH2O. Meanwhile, iodine releases two iodine radicals at high temperature that reacts with CH3SH to yield methylthiyl radical (**A**). The addition of methylthiyl radical (**A**) to naphthoquinone results in the formation of radical intermediate (**B**) which should

arylthioquinone derivatives.

*DOI: http://dx.doi.org/10.5772/intechopen.90930*

DMSO (**Figure 16**).

**Figure 16.**

**Figure 17.**

**133**

*Silver-catalyzed direct thiolation of quinones.*

*I2-DMSO-promoted thiomethylation on quinone.*

Coupling of arylsulfonyl salts with quinones in the presence of Pd(OAc)2-K2CO3 system was developed by Ge et al. [77]. Pd directed C▬sulfone to form quinone by C▬S coupling (**Figure 13**). Mechanistic study shows that initially oxidative addition of Pd with sulfonyl chloride affords intermediate species **A** which is followed by carbopalladation to form intermediate **B**. After β-H elimination, intermediate **B** released the coupling product to complete the catalytic cycle.

In another study, Huang et al., in 2016, developed reaction with [Cp\*IrCl2]2- AgSbF6 [78] system. Like palladium-catalyzed carbopalladation on sulfonyl chloride, here Ir(I) to form carboiridation (**Figure 14**). Further similar way, β-H elimination leads to the final product.

CuI-PPh3 catalytic system was used for the synthesis of quinonyl thioethers [79]. It was reported to produce sulfonyl-quinones when palladium catalyst was used [77]. In this reaction arylsulfonyl chloride (PhSCl) was formed on reaction with PPh3 (**Figure 15**) which on reaction with intermediate **B** (which might have been

**Figure 13.** *Pd-catalyzed direct C*▬*sulfone formation on quinone.*

**Figure 14.** *Ir-catalyzed C*▬*S coupling of quinones with sulfonyl chloride.*

**Figure 15.** *Cu-PPh3-promoted sulfenylation of quinones.*

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on… DOI: http://dx.doi.org/10.5772/intechopen.90930*

formed with the help of base through Baylis-Hillman process) produced arylthioquinone derivatives.

In 2015 Chou et al. [80] used silver catalyst system for the reaction of various aryl disulfides to synthesize a variety of quinonyl aryl thioether moderate to high yields. The authors carried out some control experiments to predict the plausible mechanism. Studies indicate that the reaction is initiated by active disulfide-silver intermediates formed through interactions of the silver with aryl disulfides in DMSO (**Figure 16**).

Furthermore, under metal-free conditions, various sulfenylating reagents such as [bmim]BF4-arylsulfinic acids [81], NH4I-sodium arylsulfinates [82], and H2Oarylsulfonyl hydrazides [83] systems gave sulfonyl hydroquinones.

Notably, I2-DMSO system [54] for the thiomethylation of quinone was recently developed by us (**Figure 17**). Based on the verification experiments, we proposed plausible radical pathway. At 120°C, DMSO decomposes to CH3SH and CH2O. Meanwhile, iodine releases two iodine radicals at high temperature that reacts with CH3SH to yield methylthiyl radical (**A**). The addition of methylthiyl radical (**A**) to naphthoquinone results in the formation of radical intermediate (**B**) which should loose H● to another iodine radical leading to the formation of the product.

Moreover, very recently, CuI-O2 [84] and Co(OAc)2-O2 [26] systems were utilized for direct thiol addition to quinone to form ether. In addition, there are limited reports available for the conversion of hydroquinone to quinone followed by in situ C▬S bond formation. Notably, under metal-free condition Runtao et al. [85] utilized S-alkylisothiouronium salts on hydroquinone for the synthesis of quinonyl

**Figure 16.** *Silver-catalyzed direct thiolation of quinones.*

**Figure 17.** *I2-DMSO-promoted thiomethylation on quinone.*

important reaction. Several metal and metal-free catalysts are developed for cou-

Coupling of arylsulfonyl salts with quinones in the presence of Pd(OAc)2-K2CO3 system was developed by Ge et al. [77]. Pd directed C▬sulfone to form quinone by C▬S coupling (**Figure 13**). Mechanistic study shows that initially oxidative addition of Pd with sulfonyl chloride affords intermediate species **A** which is followed by carbopalladation to form intermediate **B**. After β-H elimination, intermediate **B**

In another study, Huang et al., in 2016, developed reaction with [Cp\*IrCl2]2- AgSbF6 [78] system. Like palladium-catalyzed carbopalladation on sulfonyl chloride, here Ir(I) to form carboiridation (**Figure 14**). Further similar way, β-H elim-

CuI-PPh3 catalytic system was used for the synthesis of quinonyl thioethers [79]. It was reported to produce sulfonyl-quinones when palladium catalyst was used [77]. In this reaction arylsulfonyl chloride (PhSCl) was formed on reaction with PPh3 (**Figure 15**) which on reaction with intermediate **B** (which might have been

pling of quinones with various sulfenylating reagents.

ination leads to the final product.

*Organic Synthesis - A Nascent Relook*

*Pd-catalyzed direct C*▬*sulfone formation on quinone.*

*Ir-catalyzed C*▬*S coupling of quinones with sulfonyl chloride.*

*Cu-PPh3-promoted sulfenylation of quinones.*

**Figure 13.**

**Figure 14.**

**Figure 15.**

**132**

released the coupling product to complete the catalytic cycle.

thioether. In another study, laccase-catalyzed thiol Michael addition on naphthohydroquinone [86] and hydroquinone [87, 88] was observed. Less selectivity and poor yield are the main drawbacks of these enzymatic reactions.

most of the existing methods suffer from the requirement for strong alkaline or acidic conditions, metal catalysts, pre-halogenation, and fairly limited substrate

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on…*

*DOI: http://dx.doi.org/10.5772/intechopen.90930*

Recently, hydroxylation of naphthoquinone derivatives using tetrabutylammonium iodide (TBAI) as a catalyst and *tert*-butyl hydroperoxide (TBHP) as an oxidant was disclosed by Wang and coworkers [35]. This methodology allowed direct installation of hydroxyl groups on the quinone ring which was used for the synthesis of the corresponding substituted lawsone derivatives (**Figure 20**). Interestingly, parvaquone and lapachol were synthesized by this methodology. Poulsen et al. [26] disclosed powerful methods for oxidative *p*-quinone functionalization using Co(OAc)2 and Mn(OAc)32H2O with a collection of O, N, and S-nucleophiles, wherein oxygen was used as the terminal oxidant (**Figure 21**). Preliminary mechanistic observations and synthesis of the cytotoxic natural

product strongylophorine-26 for the first time were presented.

**2.4 C**▬**H activation for multiple heterofunctionalization of quinones**

multiple heterofunctionalization of quinones but not heterocyclization.

Multicomponent reactions (MCRs) constitute one of the most efficient tools in modern synthetic organic chemistry, since they have all features that contribute to an ideal synthesis. Features of this type of reaction are (i) high atom efficiency, (ii) quick and simple implementation, (iii) time and energy saving, (iv) environment friendly, and (v) offer a target and diversity-oriented synthesis. Under this section we have classified some of the multicomponent reaction which let the formation of

Hong et al., in 2017, reported Ag(I)-mediated one-pot multicomponent reaction in which BQ, diarylphosphine oxides, and imines underwent regioselective CDC reaction to undergo dual C▬H/P▬H (phosphination) and C▬H/N▬H (amination) on 1,4-benzoquinone (BQ), and the desired products were obtained in moderate yield (**Figure 22**). Under the optimized condition when 1,4-naphthoquinone (NQ) instead of BQ, and aniline instead of corresponding imine was used, lowering of yield of the desired product was observed. Moreover, interestingly a competitive side reaction, namely, hydrophosphinylation reaction was observed in the absence of Ag(I). In this strategy Ag(I) plays versatile role such as a mediator and oxidant. The authors characterized the X-ray crystal structures of several new functionalized

Based on the control experiments, Ag(I)-mediated mechanism was proposed. Firstly, Ag(I) ions coordinate with BQ oxygen atom, rendering BQ to act as a better

scope.

quinone derivatives [95].

*Hydroxylation of naphthoquinone derivatives.*

*Oxidative C*▬*H functionalization of* p*-quinone with alcohols.*

**Figure 20.**

**Figure 21.**

**135**

## **2.3 C**▬**H activation and C**▬**O bond formation on quinones**

Naturally occurring quinone molecules, containing C▬O link, such as byrsonimaquinone, balsaminone A, maturone and lambertelinare, are biologically important. Several methods for the construction of C▬O bond through the activation of C▬H bonds on quinone have developed rapidly. However, this research area is less explored than C▬N and C▬S bond formation as oxygen has lower nucleophilicity than nitrogen and sulfur. In this section, we discuss the formation of the C▬O bond through C▬H functionalization.

In 2007, Tamura et al. [89] developed a simple method for the synthesis of dibenzofuranquinones, which is the core structure of the natural products balsaminone A, utilizing a novel oxidative cyclization of the quinone-arenols under the special condition (**Figure 18**). As an application of this method to natural product synthesis, a facile synthesis of violet-quinone was demonstrated.

Coupling of propargyl carbonate with quinone through Claisen rearrangement to furanonaphthoquinones (FNQ) was recently established by Zhiyu et al. [90] (**Figure 19**). Though two groups have reported the synthesis of FNQ, both of these methods had several disadvantages. The first method reported by Perez et al. [91] needs use of Cs2CO3, CsI, and CuI as mediator. The second method reported by da Silva Emery et al. [92] employs CuI as catalyst, which still required rigorous condition of refluxing for 24 h.

Weitz reported a useful method for the introduction of hydroxy group through a sequence of in situ Weitz-Scheffer-type epoxidation/epoxide cleavage reaction with H2O2/Na2CO3/H2SO4 [93]. In 2013, Schwalbe showed that brominated naphthoquinones could be hydroxylated with nucleophilic substitution under KOH/MeOH [94]. In 2016, Martins has accomplished the Suzuki coupling reactions between 2-hydroxy-3-iodo-1,4-naphthoquinone and boronic acids to prepare several 2-hydroxy-3-aryl-1,4-naphthoquinones by palladium catalyst [37]. In general

**Figure 18.** *Oxidative cyclization of quinone-arenols.*

**Figure 19.** *Synthesis of Furano-naphthoquinone.*

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on… DOI: http://dx.doi.org/10.5772/intechopen.90930*

most of the existing methods suffer from the requirement for strong alkaline or acidic conditions, metal catalysts, pre-halogenation, and fairly limited substrate scope.

Recently, hydroxylation of naphthoquinone derivatives using tetrabutylammonium iodide (TBAI) as a catalyst and *tert*-butyl hydroperoxide (TBHP) as an oxidant was disclosed by Wang and coworkers [35]. This methodology allowed direct installation of hydroxyl groups on the quinone ring which was used for the synthesis of the corresponding substituted lawsone derivatives (**Figure 20**). Interestingly, parvaquone and lapachol were synthesized by this methodology.

Poulsen et al. [26] disclosed powerful methods for oxidative *p*-quinone functionalization using Co(OAc)2 and Mn(OAc)32H2O with a collection of O, N, and S-nucleophiles, wherein oxygen was used as the terminal oxidant (**Figure 21**). Preliminary mechanistic observations and synthesis of the cytotoxic natural product strongylophorine-26 for the first time were presented.

#### **2.4 C**▬**H activation for multiple heterofunctionalization of quinones**

Multicomponent reactions (MCRs) constitute one of the most efficient tools in modern synthetic organic chemistry, since they have all features that contribute to an ideal synthesis. Features of this type of reaction are (i) high atom efficiency, (ii) quick and simple implementation, (iii) time and energy saving, (iv) environment friendly, and (v) offer a target and diversity-oriented synthesis. Under this section we have classified some of the multicomponent reaction which let the formation of multiple heterofunctionalization of quinones but not heterocyclization.

Hong et al., in 2017, reported Ag(I)-mediated one-pot multicomponent reaction in which BQ, diarylphosphine oxides, and imines underwent regioselective CDC reaction to undergo dual C▬H/P▬H (phosphination) and C▬H/N▬H (amination) on 1,4-benzoquinone (BQ), and the desired products were obtained in moderate yield (**Figure 22**). Under the optimized condition when 1,4-naphthoquinone (NQ) instead of BQ, and aniline instead of corresponding imine was used, lowering of yield of the desired product was observed. Moreover, interestingly a competitive side reaction, namely, hydrophosphinylation reaction was observed in the absence of Ag(I). In this strategy Ag(I) plays versatile role such as a mediator and oxidant. The authors characterized the X-ray crystal structures of several new functionalized quinone derivatives [95].

Based on the control experiments, Ag(I)-mediated mechanism was proposed. Firstly, Ag(I) ions coordinate with BQ oxygen atom, rendering BQ to act as a better

**Figure 20.** *Hydroxylation of naphthoquinone derivatives.*

**Figure 21.** *Oxidative C*▬*H functionalization of* p*-quinone with alcohols.*

thioether. In another study, laccase-catalyzed thiol Michael addition on naphthohydroquinone [86] and hydroquinone [87, 88] was observed. Less selectivity and poor

Naturally occurring quinone molecules, containing C▬O link, such as byrsonimaquinone, balsaminone A, maturone and lambertelinare, are biologically important. Several methods for the construction of C▬O bond through the activation of C▬H bonds on quinone have developed rapidly. However, this research area is less explored than C▬N and C▬S bond formation as oxygen has lower nucleophilicity than nitrogen and sulfur. In this section, we discuss the formation of the C▬O

In 2007, Tamura et al. [89] developed a simple method for the synthesis of dibenzofuranquinones, which is the core structure of the natural products

balsaminone A, utilizing a novel oxidative cyclization of the quinone-arenols under the special condition (**Figure 18**). As an application of this method to natural product synthesis, a facile synthesis of violet-quinone was demonstrated.

Coupling of propargyl carbonate with quinone through Claisen rearrangement to furanonaphthoquinones (FNQ) was recently established by Zhiyu et al. [90] (**Figure 19**). Though two groups have reported the synthesis of FNQ, both of these methods had several disadvantages. The first method reported by Perez et al. [91] needs use of Cs2CO3, CsI, and CuI as mediator. The second method reported by da Silva Emery et al. [92] employs CuI as catalyst, which still required rigorous

Weitz reported a useful method for the introduction of hydroxy group through a sequence of in situ Weitz-Scheffer-type epoxidation/epoxide cleavage reaction with

H2O2/Na2CO3/H2SO4 [93]. In 2013, Schwalbe showed that brominated naphthoquinones could be hydroxylated with nucleophilic substitution under KOH/MeOH [94]. In 2016, Martins has accomplished the Suzuki coupling reactions between 2-hydroxy-3-iodo-1,4-naphthoquinone and boronic acids to prepare several 2-hydroxy-3-aryl-1,4-naphthoquinones by palladium catalyst [37]. In general

yield are the main drawbacks of these enzymatic reactions.

**2.3 C**▬**H activation and C**▬**O bond formation on quinones**

bond through C▬H functionalization.

*Organic Synthesis - A Nascent Relook*

condition of refluxing for 24 h.

*Oxidative cyclization of quinone-arenols.*

*Synthesis of Furano-naphthoquinone.*

**Figure 18.**

**Figure 19.**

**134**

to intermediate (**B**) by Cu(I)/O2. Further, the oxidative addition of amine and CuI afforded the Cu(II) species (**C**), which then reacted with intermediate (**B**) giving Cu(III) species (**D**). Finally, intermediate (**D**) underwent reductive elimination

Heterocyclic compounds having oxygen (O), nitrogen (N), or sulfur (S) atoms are of tremendous importance [97, 98]. C▬X bond formation on quinone gives heterofunctionalized quinones which are very important in organic chemistry and medicinal chemistry, especially due to their striking biological activities [1]. Mitomycin C is an approved quinone-based anticancer drug having pyrrolidine ring [99]. Several other heterofused/linked quinone molecules show good pharmacological properties [100–102]. Structure activity relationship studies from quinonoid compounds showed that the position and increasing the number of heteroatoms are important factors to achieve biological activities [103]. In general, heterocyclization strategies on quinone is mainly classified into three, namely, C▬X bond formation, C▬C bond formation, and cascade C▬C and C▬X bonds formations (**Figure 24**). Selections of suitable intermediates for the synthesis of heterocyclic compounds are very important. Quinones are important intermediate for the assembly of heterocycles. There are several C▬H activation methods which are disclosed for the synthesis of valuable heterocyclic compounds such as phenazine, carbazole, indole,

**3. C**▬**H activation for the synthesis of quinone-heterocycle-fused**

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on…*

phenothiazine, benzothiophene, benzofuran, cumarin, chromene, etc.

Hybrid molecules are based on the principle of combining partial or whole structures in order to create new and possibly more active molecular entities [104–106]. Hybrid molecules can incorporate two or more pharmacophore which lead to the generation of new bioactive compound which show both the activities or altogether a new kind of bioactivity. This is useful to achieve activity on "multiple targets" of a biological system, and this is called multicomponent therapeutic

To achieve synthesis of hybrid organic molecules, different strategies have been adopted time to time [105]. Quinones display wide variety of biological activity, hence combining quinone skeleton with another bioactive heterocycle should basically provide a hybrid organic molecules which may show some valuable biological activity profiles. Some of the interesting quinone-heterocycle-fused hybrid molecules found in the literature are shown in **Figure 25**. There were several strategies

Recently, Mancini et al. [112] selected different compounds acting as inhibitors of the cancer protein targets tubulin, human topoisomerase II, and ROCK1 (**Figure 26**).

developed for the synthesis of quinone-based hybrid molecules [108–111].

producing the desired product.

*DOI: http://dx.doi.org/10.5772/intechopen.90930*

**hybrids**

strategy [107].

**Figure 24.**

**137**

*Heterocyclization approaches on quinone.*

**Figure 22.** *Ag-mediated regioselective phosphination and amination.*

**Figure 23.** *Cu-catalyzed thioamination on quinone.*

electrophile for diarylphosphine oxides, which is presumably released from the adduct (**A**). After the formation of intermediate (**B**), deprotonation takes place with the assistance of CO3 <sup>2</sup>, and then two electrons transfer from the intermediate to two AgI ions to give monosubstituted product (**C**) along with two equivalents of AgO species. Further, nucleophilic attack of aniline at the three positions of (**C**) forms intermediate (**D**) which subsequently forms 2,3-disubstituted intermediate (**E**) by deprotonation with the assistance of CO3 <sup>2</sup>. Yuan et al. [96] also reported C▬P and C▬N bond formation on quinone under the same conditions.

One-pot three-component strategy for the direct thioamination of 1,4 naphthoquinone with thiols and amines was recently disclosed by Bing et al. [84]. This approach employed a catalytic amount of CuI as a catalyst and molecular oxygen as a green oxidant. Various 2-amino-3-thio-1,4-naphthoquinones products could be synthesized in moderate to good yields. This catalytic method represents a step-economic and convenient method for the difunctionalization of 1,4 naphthoquinone. Based on the systematic control experiment, the authors proposed the plausible mechanism shown in **Figure 23**. First, the Michael addition of 1,4 naphthoquinone and thiol gave intermediate (**A**), which was immediately oxidized

to intermediate (**B**) by Cu(I)/O2. Further, the oxidative addition of amine and CuI afforded the Cu(II) species (**C**), which then reacted with intermediate (**B**) giving Cu(III) species (**D**). Finally, intermediate (**D**) underwent reductive elimination producing the desired product.

## **3. C**▬**H activation for the synthesis of quinone-heterocycle-fused hybrids**

Heterocyclic compounds having oxygen (O), nitrogen (N), or sulfur (S) atoms are of tremendous importance [97, 98]. C▬X bond formation on quinone gives heterofunctionalized quinones which are very important in organic chemistry and medicinal chemistry, especially due to their striking biological activities [1]. Mitomycin C is an approved quinone-based anticancer drug having pyrrolidine ring [99]. Several other heterofused/linked quinone molecules show good pharmacological properties [100–102]. Structure activity relationship studies from quinonoid compounds showed that the position and increasing the number of heteroatoms are important factors to achieve biological activities [103]. In general, heterocyclization strategies on quinone is mainly classified into three, namely, C▬X bond formation, C▬C bond formation, and cascade C▬C and C▬X bonds formations (**Figure 24**).

Selections of suitable intermediates for the synthesis of heterocyclic compounds are very important. Quinones are important intermediate for the assembly of heterocycles. There are several C▬H activation methods which are disclosed for the synthesis of valuable heterocyclic compounds such as phenazine, carbazole, indole, phenothiazine, benzothiophene, benzofuran, cumarin, chromene, etc.

Hybrid molecules are based on the principle of combining partial or whole structures in order to create new and possibly more active molecular entities [104–106]. Hybrid molecules can incorporate two or more pharmacophore which lead to the generation of new bioactive compound which show both the activities or altogether a new kind of bioactivity. This is useful to achieve activity on "multiple targets" of a biological system, and this is called multicomponent therapeutic strategy [107].

To achieve synthesis of hybrid organic molecules, different strategies have been adopted time to time [105]. Quinones display wide variety of biological activity, hence combining quinone skeleton with another bioactive heterocycle should basically provide a hybrid organic molecules which may show some valuable biological activity profiles. Some of the interesting quinone-heterocycle-fused hybrid molecules found in the literature are shown in **Figure 25**. There were several strategies developed for the synthesis of quinone-based hybrid molecules [108–111].

Recently, Mancini et al. [112] selected different compounds acting as inhibitors of the cancer protein targets tubulin, human topoisomerase II, and ROCK1 (**Figure 26**).

**Figure 24.** *Heterocyclization approaches on quinone.*

electrophile for diarylphosphine oxides, which is presumably released from the adduct (**A**). After the formation of intermediate (**B**), deprotonation takes place

C▬P and C▬N bond formation on quinone under the same conditions. One-pot three-component strategy for the direct thioamination of 1,4 naphthoquinone with thiols and amines was recently disclosed by Bing et al. [84]. This approach employed a catalytic amount of CuI as a catalyst and molecular oxygen as a green oxidant. Various 2-amino-3-thio-1,4-naphthoquinones products could be synthesized in moderate to good yields. This catalytic method represents a

step-economic and convenient method for the difunctionalization of 1,4-

naphthoquinone. Based on the systematic control experiment, the authors proposed the plausible mechanism shown in **Figure 23**. First, the Michael addition of 1,4 naphthoquinone and thiol gave intermediate (**A**), which was immediately oxidized

to two AgI ions to give monosubstituted product (**C**) along with two equivalents of AgO species. Further, nucleophilic attack of aniline at the three positions of (**C**) forms intermediate (**D**) which subsequently forms 2,3-disubstituted intermediate

<sup>2</sup>, and then two electrons transfer from the intermediate

<sup>2</sup>. Yuan et al. [96] also reported

with the assistance of CO3

*Cu-catalyzed thioamination on quinone.*

**Figure 22.**

**Figure 23.**

**136**

(**E**) by deprotonation with the assistance of CO3

*Ag-mediated regioselective phosphination and amination.*

*Organic Synthesis - A Nascent Relook*

**Figure 25.** *Selected quinone-heterocycle hybrid molecules.*

**Figure 26.** *Quinone-heterocycle hybrids showing anticancer activity.*

The synthesized quinone-hybrid molecules displayed good and sometimes better growth inhibition GI50 than the ROCK inhibitor Y-27632, the Topo II inhibitor podophyllotoxin, and the tubulin inhibitor combretastatin A-4.

In this direction in the forthcoming sections, we have listed out methods known for the synthesis of quinone-heterocycle hybrid molecules and some of its importance.

## **3.1 C**▬**H activation for the synthesis of quinone-fused heterocycle hybrids through two component reaction**

The oxidative coupling reactions of NH isoquinolones with 1,4-benzoquinone proceeded efficiently to form spiro compounds through C▬C and C▬N bond in the presence of an Ir(III) catalyst (**Figure 27**) [113]. Cu(OAc)2H2O was used as external oxidant for substrates such as NQ and other substituted 1,4-benzoquinone. The authors performed preliminary mechanistic experiments and a catalytically competent five-membered iridacycle was isolated and structurally characterized, thus revealing a key intermediate in the catalytic cycle. The first step of mechanism is likely to be a C(sp<sup>2</sup> )-H activation process affording a five-membered iridacycle intermediate **A**. The coordination of BQ to **A** delivers intermediate **B**. The migratory insertion of the coordinated BQ into the Ir▬C bond leads to intermediate **C** which on protonation by HOAc forms intermediate **D**. Subsequent iridation occurs at the α-position to afford iridacycle I, which undergoes a C▬N reductive elimination to afford the final product and Cp\*Ir(I). Cp\*Ir(I) is oxidized by BQ in the presence of HOAc to Cp\*Ir(Oac)2 for the next catalytic cycle.

Shenghai et al. [114]. Mechanistic study revealed that Rh(III)-catalyzed dual N▬H/C▬H bond cleavage of indole occurs to afford a rhodacycle (**A**). Further, the coordination of BQ to A yields (**B**), which undergoes a migratory insertion of the coordinated BQ into the Rh▬C bond to furnish (**C**). Further (**C**) undergoes a selective Rh▬C protonolysis with one equivalent of HOAc to afford the key inter-

active Rh(III) catalyst by BQ in the presence of HOAc (**Figure 28**).

was suggested by the authors as shown in **Figure 29**.

Cu(II)-catalyzed sequential C,N-difunctionalization reaction between naphthoquinone and β-enaminones [115] which leads to the formation of

Subsequently, the promotion of nucleophilic attack by Et3N, the tertiary α-C atom on the Rh center, generates I, which undergoes a C▬N reductive elimination to give the desired product and a Rh(I) species. The Rh(I) species is oxidized to the

indaloquinone. New C▬C and C▬N bonds are easily formed in the reaction course. Cu(II) salt plays a dual role as Lewis acid and oxidative catalyst, and O2 acts as the terminal oxidant. Based on the experimental results, a plausible reaction pathway

mediate (**D**).

**139**

**Figure 28.**

**Figure 27.**

*Ir(III)-catalyzed oxidative coupling of NH isoquinolones.*

*DOI: http://dx.doi.org/10.5772/intechopen.90930*

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on…*

*Rh(III)-catalyzed oxidative coupling of NH indoles.*

In another study, an Rh-catalyzed substrate-tunable oxidative annulation and spiroannulation reaction of 2-arylindoles with benzoquinone was reported by

### *C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on… DOI: http://dx.doi.org/10.5772/intechopen.90930*

**Figure 27.** *Ir(III)-catalyzed oxidative coupling of NH isoquinolones.*

**Figure 28.** *Rh(III)-catalyzed oxidative coupling of NH indoles.*

Shenghai et al. [114]. Mechanistic study revealed that Rh(III)-catalyzed dual N▬H/C▬H bond cleavage of indole occurs to afford a rhodacycle (**A**). Further, the coordination of BQ to A yields (**B**), which undergoes a migratory insertion of the coordinated BQ into the Rh▬C bond to furnish (**C**). Further (**C**) undergoes a selective Rh▬C protonolysis with one equivalent of HOAc to afford the key intermediate (**D**).

Subsequently, the promotion of nucleophilic attack by Et3N, the tertiary α-C atom on the Rh center, generates I, which undergoes a C▬N reductive elimination to give the desired product and a Rh(I) species. The Rh(I) species is oxidized to the active Rh(III) catalyst by BQ in the presence of HOAc (**Figure 28**).

Cu(II)-catalyzed sequential C,N-difunctionalization reaction between naphthoquinone and β-enaminones [115] which leads to the formation of indaloquinone. New C▬C and C▬N bonds are easily formed in the reaction course. Cu(II) salt plays a dual role as Lewis acid and oxidative catalyst, and O2 acts as the terminal oxidant. Based on the experimental results, a plausible reaction pathway was suggested by the authors as shown in **Figure 29**.

The synthesized quinone-hybrid molecules displayed good and sometimes better growth inhibition GI50 than the ROCK inhibitor Y-27632, the Topo II inhibitor

In this direction in the forthcoming sections, we have listed out methods known for the synthesis of quinone-heterocycle hybrid molecules and some of its

**3.1 C**▬**H activation for the synthesis of quinone-fused heterocycle hybrids**

The oxidative coupling reactions of NH isoquinolones with 1,4-benzoquinone proceeded efficiently to form spiro compounds through C▬C and C▬N bond in the presence of an Ir(III) catalyst (**Figure 27**) [113]. Cu(OAc)2H2O was used as external oxidant for substrates such as NQ and other substituted 1,4-benzoquinone. The authors performed preliminary mechanistic experiments and a catalytically competent five-membered iridacycle was isolated and structurally characterized, thus revealing a key intermediate in the catalytic cycle. The first step of mechanism is

intermediate **A**. The coordination of BQ to **A** delivers intermediate **B**. The migratory insertion of the coordinated BQ into the Ir▬C bond leads to intermediate **C** which on protonation by HOAc forms intermediate **D**. Subsequent iridation occurs at the α-position to afford iridacycle I, which undergoes a C▬N reductive elimination to afford the final product and Cp\*Ir(I). Cp\*Ir(I) is oxidized by BQ in the

In another study, an Rh-catalyzed substrate-tunable oxidative annulation and spiroannulation reaction of 2-arylindoles with benzoquinone was reported by

presence of HOAc to Cp\*Ir(Oac)2 for the next catalytic cycle.

)-H activation process affording a five-membered iridacycle

podophyllotoxin, and the tubulin inhibitor combretastatin A-4.

**through two component reaction**

*Quinone-heterocycle hybrids showing anticancer activity.*

importance.

**Figure 25.**

**Figure 26.**

*Selected quinone-heterocycle hybrid molecules.*

*Organic Synthesis - A Nascent Relook*

likely to be a C(sp<sup>2</sup>

**138**

#### **Figure 29.**

*Cu(II)-catalyzed NQ sequential C,N-difunctionalization.*

#### **Figure 30.**

*Pd/Mn-catalyzed C*▬*H functionalization of amino NQ derivatives.*

First, nucleophilic attack of α-carbon atom of β-enaminone to Cu2+ complexed NQ followed by tautomerization and oxidation by Cu2+ results in the formation of intermediate (**A**). Further, intramolecular Michael addition takes place. Finally, oxidative aromatization affords cyclic product. To complete the catalytic cycle, molecular oxygen was involved for the oxidation of Cu(I) and regeneration of Cu(II).

of various quinones, is sensitive to both steric and electronic elements on the anilines, as well as the steric hindrance introduced to the quinones. Although the yields are generally moderate, this reaction nevertheless provides a single-step alternative to prepare various otherwise difficult to make densely substituted 3-hydroxycarbazoles under mild conditions. Similarly to Nenitzescu indole synthesis, the mechanism of this carbazole formation is believed to involve a C▬C bond formation by a Michael-type nucleophilic addition of aniline to quinone, followed

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on…*

*DOI: http://dx.doi.org/10.5772/intechopen.90930*

In another study, a sequential Michael addition and intramolecular cyclization reaction of ketones and 1,4-benzoquinones by using triethyl orthoformate as an additive (**Figure 33**). In the presence of Sc(OTf)3 as catalyst, triethyl orthoformate may be utilized to convert enolizable ketone into ethyl vinyl ether. As a result, nucleophilicity increases. This reaction is a simple way to obtain 5-hydroxybenzofurans. The authors used this methodology to synthesize some important

Wang et al. [121] developed Pd(OAc)2/BQ catalytic system for ring contraction reactions which allow 2-hydroxyl-1,4-naphthoquinones to convert into various

by intramolecular cyclization and dehydration.

*Synthesis of benzofurans from ketones and 1,4-benzoquinones.*

2-phenylbenzofuran derivatives [120].

**Figure 31.**

**Figure 32.**

**Figure 33.**

**141**

*Ultrasound-assisted one-pot synthesis.*

*Annulation of electron-rich anilines and quinones.*

Chen and Hong [116] reported Pd(II)-catalyzed *ortho*-CH functionalization of amido-substituted 1,4-naphthoquinone with primary and tertiary amines (**Figure 30**). The reaction occurred through an intramolecular rearrangement followed by oxidation process, which lead to the formation of imidazole and pyrrole ring-fused quinone derivatives. In another study, Franco and coworkers [117] performed oxidative free-radical reaction of quinone with either aldehydes or simple ketones in the presence of Mn(OAc)3 to afford a series of indolenaphthoquinone-fused heterocycles [117].

Mito et al., in 2016, developed a method for benzo[f]indole-4,9-diones from inactivated naphthoquinone with α-aminoacetals [118]. This reaction underwent via intramolecular nucleophilic attack of aminoquinones to aldehydes. Based on the detailed mechanistic studies, the authors proposed the plausible mechanism represented in **Figure 31**.

Haiming and coworkers [119] developed a simple protocol for the synthesis of highly functionalized 3-hydroxycarbazoles by acetic acid-promoted annulation of electron-rich anilines and quinones (**Figure 32**). This chemistry, although tolerant

### *C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on… DOI: http://dx.doi.org/10.5772/intechopen.90930*

#### **Figure 31.** *Ultrasound-assisted one-pot synthesis.*

#### **Figure 32.** *Annulation of electron-rich anilines and quinones.*

**Figure 33.**

First, nucleophilic attack of α-carbon atom of β-enaminone to Cu2+ complexed NQ followed by tautomerization and oxidation by Cu2+ results in the formation of intermediate (**A**). Further, intramolecular Michael addition takes place. Finally, oxidative aromatization affords cyclic product. To complete the catalytic cycle, molecular oxygen was involved for the oxidation of Cu(I) and regeneration of

Chen and Hong [116] reported Pd(II)-catalyzed *ortho*-CH functionalization of amido-substituted 1,4-naphthoquinone with primary and tertiary amines (**Figure 30**). The reaction occurred through an intramolecular rearrangement followed by oxidation process, which lead to the formation of imidazole and pyrrole ring-fused quinone derivatives. In another study, Franco and coworkers [117] performed oxidative free-radical reaction of quinone with either aldehydes or simple ketones in the presence of Mn(OAc)3 to afford a series of indole-

Mito et al., in 2016, developed a method for benzo[f]indole-4,9-diones from inactivated naphthoquinone with α-aminoacetals [118]. This reaction underwent via intramolecular nucleophilic attack of aminoquinones to aldehydes. Based on the detailed mechanistic studies, the authors proposed the plausible mechanism

Haiming and coworkers [119] developed a simple protocol for the synthesis of highly functionalized 3-hydroxycarbazoles by acetic acid-promoted annulation of electron-rich anilines and quinones (**Figure 32**). This chemistry, although tolerant

Cu(II).

**140**

**Figure 30.**

**Figure 29.**

naphthoquinone-fused heterocycles [117].

*Cu(II)-catalyzed NQ sequential C,N-difunctionalization.*

*Organic Synthesis - A Nascent Relook*

*Pd/Mn-catalyzed C*▬*H functionalization of amino NQ derivatives.*

represented in **Figure 31**.

*Synthesis of benzofurans from ketones and 1,4-benzoquinones.*

of various quinones, is sensitive to both steric and electronic elements on the anilines, as well as the steric hindrance introduced to the quinones. Although the yields are generally moderate, this reaction nevertheless provides a single-step alternative to prepare various otherwise difficult to make densely substituted 3-hydroxycarbazoles under mild conditions. Similarly to Nenitzescu indole synthesis, the mechanism of this carbazole formation is believed to involve a C▬C bond formation by a Michael-type nucleophilic addition of aniline to quinone, followed by intramolecular cyclization and dehydration.

In another study, a sequential Michael addition and intramolecular cyclization reaction of ketones and 1,4-benzoquinones by using triethyl orthoformate as an additive (**Figure 33**). In the presence of Sc(OTf)3 as catalyst, triethyl orthoformate may be utilized to convert enolizable ketone into ethyl vinyl ether. As a result, nucleophilicity increases. This reaction is a simple way to obtain 5-hydroxybenzofurans. The authors used this methodology to synthesize some important 2-phenylbenzofuran derivatives [120].

Wang et al. [121] developed Pd(OAc)2/BQ catalytic system for ring contraction reactions which allow 2-hydroxyl-1,4-naphthoquinones to convert into various

phthalides. The significance of phthalide and fulvene scaffolds as structural units should render this method attractive for both medicinal chemistry and synthetic ring contraction reactions chemistry, paving the way for efficient synthesis of other complex cyclic systems (**Figure 34**). Moreover, they utilized phthalides as versatile synthetic intermediates toward many other useful synthetic building blocks.

Peddinti et al., in 2014, reported [122] Michael addition of the 1,4 benzoxazinone derivatives, a novel class of vinylogous carbamates to the Michael acceptors. 1,4-Benzoxazinone derivative undergoes Michael addition with *p*-quinone in the presence of trifluoroacetic acid, and subsequent cyclization affords corresponding products (**Figure 35**).

A nucleophilic addition of terminal alkynes to 2-methoxy-1,4-benzoquinone afforded the corresponding quinols containing an alkyne unit [123], which were converted to phenols via mild Zn-mediated reduction. After proper protection of the free phenolic OH group, under metal-free system, 5-endo-dig iodocyclization allowed facile access to a number of 3-iodobenzofurans (**Figure 36**).

After successful establishment of kinetic controlled, Rh(III)-catalyzed annulation of C▬H bonds with quinones for chemo-selective synthesis of dibenzo[*b,d*] pyran-6-ones [124] and phenanthridinones [125], Yang and coworkers [126] demonstrated a three-component cascade reaction for 6H-benzo[c]chromenes. Similarly, this reaction involved Rh(III)-catalyzed annulation of aryl ketone O-acyloximes, quinones, and acetone (**Figure 37**).

In another report [127], the synthesis of diverse dihydronaphtho[1,2-*b*]furans starting from 1,4-naphthoquinones and olefins in the presence of ceric ammonium nitrate (CAN) was reported. The reaction was based on the CAN-catalyzed [3 + 2] cycloaddition of 1,4-naphthoquinones. This methodology was also used to synthesize the biologically important natural product furomollugin in only two steps (**Figure 38**).

**3.2 C**▬**H activation for the synthesis of quinone-fused heterocycle hybrids**

on quinones were used for the generation of quinone-fused heterocycles.

The applications of MCRs have been sequenced with multiple ring-forming reactions that leads thereby to the synthesis of diverse heterocyclic scaffolds. MCRs

Seven mild basic ionic liquids [128] made out of 1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate, pyrrolidinium acetate, pyrrolidinium formate, piperidinium acetate, piperidinium formate, *N*-methylimidazolium formate, and 3-hydroxypropanaminium acetate were used as catalyst for three-component coupling of aldehyde, malononitrile, and 2-hydroxynaphthoquinone for the formation of 2-amino-3-cyano-4-aryl-5,10-dioxo-5,10-dihydro-4H-benzo[g]chromene and hydroxyl naphthalene-1,4-dione derivatives under ambient and solvent-free conditions (**Figure 39**). The main advantages of this protocol are mild, solvent-free conditions, ecofriendly catalysts and easy to work-up procedure. Similar reaction was also reported by Javanshir et al. [129] and Manisankar et al. [130] using

Notably, Cao and coworkers [131] developed one-pot, pseudo-four-component reaction of 2-hydroxy-1,4-naphthoquinone, aromatic amine, and formaldehyde in aqueous media under ultrasound irradiation (**Figure 40**) naphthoquinone-fused oxazine derivatives under this operationally simple and efficient condition.

A proposed mechanism shows that amination reaction occurred first between the formaldehyde and amine, followed by H2O elimination to furnish intermediate **A** which was then attacked by 2-hydroxy-1,4-naphthoquinone to furnish an intermediate **B**, which further reacted with formaldehyde and eliminated H2O to produce intermediate **C**. At last the final product was formed through an intramo-

**through multicomponent reaction**

*Three-component synthesis of functionalized 4H-pyrans.*

*CAN-catalyzed [3 + 2] cycloaddition of 1,4-naphthoquinones.*

*Rh(III)-catalyzed annulation for benzochromenes.*

*DOI: http://dx.doi.org/10.5772/intechopen.90930*

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on…*

**Figure 37.**

**Figure 38.**

**Figure 39.**

organocatalyst and copper catalyst, respectively.

lecular cyclization process.

**143**

#### **Figure 34.**

*Synthesis of phthalides via ring contraction reactions.*

**Figure 35.** *TFA-catalyzed Michael addition reaction for cumarin.*

**Figure 36.** *5-Endo-dig iodocyclization reaction for 3-iodobenzofurans.*

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on… DOI: http://dx.doi.org/10.5772/intechopen.90930*

**Figure 37.**

phthalides. The significance of phthalide and fulvene scaffolds as structural units should render this method attractive for both medicinal chemistry and synthetic ring contraction reactions chemistry, paving the way for efficient synthesis of other complex cyclic systems (**Figure 34**). Moreover, they utilized phthalides as versatile synthetic intermediates toward many other useful synthetic building blocks. Peddinti et al., in 2014, reported [122] Michael addition of the 1,4-

benzoxazinone derivatives, a novel class of vinylogous carbamates to the Michael acceptors. 1,4-Benzoxazinone derivative undergoes Michael addition with

*p*-quinone in the presence of trifluoroacetic acid, and subsequent cyclization affords

A nucleophilic addition of terminal alkynes to 2-methoxy-1,4-benzoquinone afforded the corresponding quinols containing an alkyne unit [123], which were converted to phenols via mild Zn-mediated reduction. After proper protection of the free phenolic OH group, under metal-free system, 5-endo-dig iodocyclization

After successful establishment of kinetic controlled, Rh(III)-catalyzed annulation of C▬H bonds with quinones for chemo-selective synthesis of dibenzo[*b,d*] pyran-6-ones [124] and phenanthridinones [125], Yang and coworkers [126] demonstrated a three-component cascade reaction for 6H-benzo[c]chromenes. Similarly, this reaction involved Rh(III)-catalyzed annulation of aryl ketone

In another report [127], the synthesis of diverse dihydronaphtho[1,2-*b*]furans starting from 1,4-naphthoquinones and olefins in the presence of ceric ammonium nitrate (CAN) was reported. The reaction was based on the CAN-catalyzed [3 + 2] cycloaddition of 1,4-naphthoquinones. This methodology was also used to synthesize the biologically important natural product furomollugin in only two steps

allowed facile access to a number of 3-iodobenzofurans (**Figure 36**).

O-acyloximes, quinones, and acetone (**Figure 37**).

*Synthesis of phthalides via ring contraction reactions.*

*TFA-catalyzed Michael addition reaction for cumarin.*

*5-Endo-dig iodocyclization reaction for 3-iodobenzofurans.*

corresponding products (**Figure 35**).

*Organic Synthesis - A Nascent Relook*

(**Figure 38**).

**Figure 34.**

**Figure 35.**

**Figure 36.**

**142**

*Rh(III)-catalyzed annulation for benzochromenes.*

**Figure 38.** *CAN-catalyzed [3 + 2] cycloaddition of 1,4-naphthoquinones.*

**Figure 39.** *Three-component synthesis of functionalized 4H-pyrans.*

## **3.2 C**▬**H activation for the synthesis of quinone-fused heterocycle hybrids through multicomponent reaction**

The applications of MCRs have been sequenced with multiple ring-forming reactions that leads thereby to the synthesis of diverse heterocyclic scaffolds. MCRs on quinones were used for the generation of quinone-fused heterocycles.

Seven mild basic ionic liquids [128] made out of 1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate, pyrrolidinium acetate, pyrrolidinium formate, piperidinium acetate, piperidinium formate, *N*-methylimidazolium formate, and 3-hydroxypropanaminium acetate were used as catalyst for three-component coupling of aldehyde, malononitrile, and 2-hydroxynaphthoquinone for the formation of 2-amino-3-cyano-4-aryl-5,10-dioxo-5,10-dihydro-4H-benzo[g]chromene and hydroxyl naphthalene-1,4-dione derivatives under ambient and solvent-free conditions (**Figure 39**). The main advantages of this protocol are mild, solvent-free conditions, ecofriendly catalysts and easy to work-up procedure. Similar reaction was also reported by Javanshir et al. [129] and Manisankar et al. [130] using organocatalyst and copper catalyst, respectively.

Notably, Cao and coworkers [131] developed one-pot, pseudo-four-component reaction of 2-hydroxy-1,4-naphthoquinone, aromatic amine, and formaldehyde in aqueous media under ultrasound irradiation (**Figure 40**) naphthoquinone-fused oxazine derivatives under this operationally simple and efficient condition.

A proposed mechanism shows that amination reaction occurred first between the formaldehyde and amine, followed by H2O elimination to furnish intermediate **A** which was then attacked by 2-hydroxy-1,4-naphthoquinone to furnish an intermediate **B**, which further reacted with formaldehyde and eliminated H2O to produce intermediate **C**. At last the final product was formed through an intramolecular cyclization process.

**Figure 40.** *Synthesis of naphthoquinone-fused oxazine derivatives.*

**Figure 41.** *Synthesis of phenazine-dihydropyridine molecules.*

formation of pentacyclic benzo[a]thieno[3,2-c]phenazine derivatives in good yields

β-dicarbonyl compounds, and functionalized or unfunctionalized naphthoquinones was reported by Menendez et al. [62]. The enamine formation Michael addition-

Recent advances in the direct heterofunctionalization and heterocyclization of quinones were summarized in this chapter. Most of the C▬hetero bond formation on quinone occurred via Michael addition in the presence/absence of a metal catalyst. Transition metal-catalyzed cross-coupling reactions were another important strategy for the direct functionalization of quinones. These reactions allowed for the

Interestingly, Lee and coworkers [134] reported one-pot synthesis of benzofuran-2(3H)-one derivatives from nitriles. This result underscore the high potential of the Blaise reaction intermediate as an amphiphilic organozinc complex for forming carbon▬carbon bonds and provides a divergent synthetic platform

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on…*

CAN-catalyzed three-component reaction between primary amines,

intramolecular imine formation domino sequence starting from amines, β-dicarbonyl compounds, and quinones, in a three-component variation of the Nenitzescu indole synthesis (**Figure 45**). Further, protocol was extended to the synthesis of linear benzo[f]indolequinones by using pre-functionalized quinones as the starting materials. Moreover, the benzo[g]indole derivatives were transformed into 9,12-dihydro-8H-azepino[1,2-a]benzo[g]-indoles, a new class of fused indole

derivatives, using a C-alkylation/ring-closing metathesis strategy.

under solvent-free conditions.

*CAN-catalyzed three-component domino sequences.*

*Synthesis of benzothiophene-phenazine molecules.*

*DOI: http://dx.doi.org/10.5772/intechopen.90930*

*Tandem Blaise-Nenitzescu reaction forbenzofuran-2(3H)-ones.*

**Figure 43.**

**Figure 44.**

**Figure 45.**

toward heterocycles (**Figure 44**).

**4. Conclusion**

**145**

#### **Figure 42.** *Synthesis of uracil-phenazine molecules.*

Afshin and coworkers [132] developed L-proline-catalyzed one-pot, two-step, five-component reaction for the synthesis of novel 1,4-dihydrobenzo[a]pyrido[2,3 c]phenazines by the condensation reaction of 2-hydroxynaphoquinone, aromatic 1,2-diamines, aldehydes, ammonium acetate, and ethyl acetoacetate under conventional heating in solvent-free conditions. In this domino transformation, six bonds and two new rings such as phenazine and 1,4-dihydropyridine are efficiently formed (**Figure 41**). High yields, short reaction time, operational simplicity, easy work-up procedure, avoidance of hazardous or toxic catalysts, and organic solvents are the main advantages of this green methodology.

In another study [133], catalyst-free synthesis of aminouracils bearing naphthoquinone in DMF system was developed by Jamaledini et al. [133]. Further it was used as intermediate for the synthesis of uracil-phenazine linked heterocycles via condensation reaction with various vicinal diamines, in chloroform under reflux condition (**Figure 42**).

Copper-catalyzed, TEMPO-mediated straightforward synthesis of 2,3-disubstituted naphtho[2,1-b]thiophene-4,5-diones via cross-dehydrogenative thienannulation was reported [134]. The reaction proceeded via in situ generated naphthalene-1,2-diones by dearomatization of β-naphthols, followed by oxidative heteroannulation with α-enolic dithioesters chemoselectively (**Figure 43**).

Further, the naphtho[2,1-b]thiophene-4,5-diones undergo L-proline-catalyzed cross-dehydrogenative coupling (CDC) with *ortho*-phenylenediamine enabling

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on… DOI: http://dx.doi.org/10.5772/intechopen.90930*

#### **Figure 43.**

*Synthesis of benzothiophene-phenazine molecules.*

#### **Figure 44.**

*Tandem Blaise-Nenitzescu reaction forbenzofuran-2(3H)-ones.*

#### **Figure 45.**

Afshin and coworkers [132] developed L-proline-catalyzed one-pot, two-step, five-component reaction for the synthesis of novel 1,4-dihydrobenzo[a]pyrido[2,3 c]phenazines by the condensation reaction of 2-hydroxynaphoquinone, aromatic 1,2-diamines, aldehydes, ammonium acetate, and ethyl acetoacetate under conventional heating in solvent-free conditions. In this domino transformation, six bonds and two new rings such as phenazine and 1,4-dihydropyridine are efficiently formed (**Figure 41**). High yields, short reaction time, operational simplicity, easy work-up procedure, avoidance of hazardous or toxic catalysts, and organic solvents

In another study [133], catalyst-free synthesis of aminouracils bearing naphthoquinone in DMF system was developed by Jamaledini et al. [133]. Further it was used as intermediate for the synthesis of uracil-phenazine linked heterocycles via condensation reaction with various vicinal diamines, in chloroform under reflux

tuted naphtho[2,1-b]thiophene-4,5-diones via cross-dehydrogenative

Copper-catalyzed, TEMPO-mediated straightforward synthesis of 2,3-disubsti-

Further, the naphtho[2,1-b]thiophene-4,5-diones undergo L-proline-catalyzed cross-dehydrogenative coupling (CDC) with *ortho*-phenylenediamine enabling

thienannulation was reported [134]. The reaction proceeded via in situ generated naphthalene-1,2-diones by dearomatization of β-naphthols, followed by oxidative heteroannulation with α-enolic dithioesters chemoselectively (**Figure 43**).

are the main advantages of this green methodology.

condition (**Figure 42**).

**144**

**Figure 40.**

**Figure 41.**

**Figure 42.**

*Synthesis of naphthoquinone-fused oxazine derivatives.*

*Organic Synthesis - A Nascent Relook*

*Synthesis of phenazine-dihydropyridine molecules.*

*Synthesis of uracil-phenazine molecules.*

*CAN-catalyzed three-component domino sequences.*

formation of pentacyclic benzo[a]thieno[3,2-c]phenazine derivatives in good yields under solvent-free conditions.

Interestingly, Lee and coworkers [134] reported one-pot synthesis of benzofuran-2(3H)-one derivatives from nitriles. This result underscore the high potential of the Blaise reaction intermediate as an amphiphilic organozinc complex for forming carbon▬carbon bonds and provides a divergent synthetic platform toward heterocycles (**Figure 44**).

CAN-catalyzed three-component reaction between primary amines, β-dicarbonyl compounds, and functionalized or unfunctionalized naphthoquinones was reported by Menendez et al. [62]. The enamine formation Michael additionintramolecular imine formation domino sequence starting from amines, β-dicarbonyl compounds, and quinones, in a three-component variation of the Nenitzescu indole synthesis (**Figure 45**). Further, protocol was extended to the synthesis of linear benzo[f]indolequinones by using pre-functionalized quinones as the starting materials. Moreover, the benzo[g]indole derivatives were transformed into 9,12-dihydro-8H-azepino[1,2-a]benzo[g]-indoles, a new class of fused indole derivatives, using a C-alkylation/ring-closing metathesis strategy.

### **4. Conclusion**

Recent advances in the direct heterofunctionalization and heterocyclization of quinones were summarized in this chapter. Most of the C▬hetero bond formation on quinone occurred via Michael addition in the presence/absence of a metal catalyst. Transition metal-catalyzed cross-coupling reactions were another important strategy for the direct functionalization of quinones. These reactions allowed for the construction of not only simple coupling products but also many important biologically active compounds. Moreover, the formation of C▬O bond on quinone was less explored than C▬N and C▬S bond formation; it may be due to the fact that oxygen has lower nucleophilicity than nitrogen and sulfur, and lack of suitable synthetic reagents that can tolerate the presence of oxygen functional groups. However, due to the unique electronic property of quinones, the types of direct functionalization remain limited, and great efforts are still needed in the future.

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## **Acknowledgements**

AKTP would like to thank UGC-RFSMS (F.No.25-1/2014-2015 (BSR)/7-22/2007- (BSR) Dated: 13.03.2015), New Delhi, for the award of the fellowship for Ph.D.

## **Conflict of interest**

The authors declare no conflict of interest.

## **Author details**

Andivelu Ilangovan\* and Thumadath Palayullaparambil Adarsh Krishna School of Chemistry, Bharathidasan University, Tiruchirappalli, Tamilnadu, India

\*Address all correspondence to: ilangovanbdu@yahoo.com

© 2020 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, provided the original work is properly cited.

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on… DOI: http://dx.doi.org/10.5772/intechopen.90930*

## **References**

construction of not only simple coupling products but also many important biologically active compounds. Moreover, the formation of C▬O bond on quinone was less explored than C▬N and C▬S bond formation; it may be due to the fact that oxygen has lower nucleophilicity than nitrogen and sulfur, and lack of suitable synthetic reagents that can tolerate the presence of oxygen functional groups. However, due to the unique electronic property of quinones, the types of direct functionalization

AKTP would like to thank UGC-RFSMS (F.No.25-1/2014-2015 (BSR)/7-22/2007- (BSR) Dated: 13.03.2015), New Delhi, for the award of the fellowship for Ph.D.

Andivelu Ilangovan\* and Thumadath Palayullaparambil Adarsh Krishna

\*Address all correspondence to: ilangovanbdu@yahoo.com

provided the original work is properly cited.

School of Chemistry, Bharathidasan University, Tiruchirappalli, Tamilnadu, India

© 2020 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,

remain limited, and great efforts are still needed in the future.

The authors declare no conflict of interest.

**Acknowledgements**

*Organic Synthesis - A Nascent Relook*

**Conflict of interest**

**Author details**

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[133] Jamaledini A,

Mohammadizadeh MR, Mousavi SH. Catalyst-free, efficient, and green procedure for the synthesis of 5-

*DOI: http://dx.doi.org/10.5772/intechopen.90930*

*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on…*

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10.1007/s00706-018-2164-4

10.1021/acs.joc.7b03092

**157**

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*C*▬*H Activation Strategies for Heterofunctionalization and Heterocyclization on… DOI: http://dx.doi.org/10.5772/intechopen.90930*

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reaction with alkynes. Organic Chemistry Frontiers. 2016;**3**(5): 603-608. DOI: 10.1039/C6QO00045B

*Organic Synthesis - A Nascent Relook*

furomollugin. Organic and Biomolecular Chemistry. 2013;**11**(36):6097-6107. DOI:

[128] Shaterian HR, Mohammadnia M. Effective preparation of 2-amino-3 cyano-4-aryl-5,10-dioxo-5,10-dihydro-4H-benzo[g]chromene and hydroxyl naphthalene-1,4-dione derivatives under ambient and solvent-free conditions. Journal of Molecular Liquids. 2013;**177**:353-360. DOI: 10.1016/j.molliq.2012.10.012

[129] Dekamin MG, Alikhani M, Javanshir S. Organocatalytic clean synthesis of densely functionalized 4H-

under mild conditions. Green

**9**(2):96-105. DOI: 10.1080/ 17518253.2016.1139191

[130] Perumal M, Sengodu P, Venkatesan S, Srinivasan R,

copper triflate-mediated

potent anticancer activity.

2854-7

2008-7

DOI: 10.1002/slct.201700170

tetraethylammonium 2-(carbamoyl) benzoate using ball milling technique

Chemistry Letters and Reviews. 2016;

Paramsivam M. Environmentally benign

multicomponent one-pot synthesis of novel benzo[g]chromenes possess

ChemistrySelect. 2017;**2**(18):5068-5072.

[131] Cao YQ, Li XR, Wu W, Zhang D, Zhang ZH, Mo LP. A green approach for synthesis of naphthoquinone-fused oxazine derivatives in water under ultrasonic irradiation. Research on Chemical Intermediates. 2017;**43**(7): 3745-3755. DOI: 10.1007/s11164-016-

[132] Yazdani-Elah-Abadi A, Pour SA, Kangani M, Mohebat R. L-Proline catalyzed domino cyclization for the

phenazines. Monatshefte für Chemie-Chemical Monthly. 2017;**148**(12): 2135-2142. DOI: 10.1007/s00706-017-

green synthesis of novel 1,4 dihydrobenzo[a]pyrido[2,3-c]

pyrans by bifunctional

10.1039/c3ob40977e

[122] Naganaboina RT, Nayak A, Peddinti RK. Trifluoroacetic acidpromoted Michael addition–cyclization reactions of vinylogous carbamates. Organic and Biomolecular Chemistry. 2014;**12**(21):3366-3370. DOI: 10.1039/

[123] Jung Y, Kim I. Chemoselective reduction of quinols as an alternative to Sonogashira coupling: Synthesis of polysubstituted benzofurans. Organic and Biomolecular Chemistry. 2016; **14**(44):10454-10472. DOI: 10.1039/

[124] Yang W, Wang S, Zhang Q, Liu Q, Xu X. Rh (iii)-catalyzed oxidative C▬H bond arylation with hydroquinones: Sustainable synthesis of dibenzo[b,d] pyran-6-ones and benzo[d]naphtho[1,2-

Communications. 2015;**51**(4):661-664.

[125] Yang W, Wang J, Wei Z, Zhang Q, Xu X. Kinetic control of Rh (III) catalyzed annulation of C▬H bonds with quinones: Chemoselective synthesis of

[126] Yang W, Wang J, Wang H, Li L, Guan Y, Xu X, et al. Rhodium (iii) catalyzed three-component cascade synthesis of 6H-benzo[c]chromenes through C–H activation. Organic and Biomolecular Chemistry. 2018;**16**(38): 6865-6869. DOI: 10.1039/C8OB01938J

[127] Xia L, Lee YR. A novel and efficient synthesis of diverse dihydronaphtho [1,2-b] furans using the ceric ammonium

cycloaddition of 1,4-naphthoquinones to

nitrate-catalyzed formal [3 + 2]

olefins and its application to

**156**

b]pyran-6-ones. Chemical

DOI: 10.1039/C4CC08260E

hydrophenanthridinones and phenanthridinones. The Journal of Organic Chemistry. 2016;**81**(4): 1675-1680. DOI: 10.1021/acs.

c4ob00437j

c6ob01941b

joc.5b02903

[134] Shukla G, Srivastava A, Yadav D, Singh MS. Copper-catalyzed one-pot cross-dehydrogenative thienannulation: Chemoselective access to naphtho[2,1 b]thiophene-4,5-diones and subsequent transformation to benzo[a]thieno[3,2-c] phenazines. The Journal of Organic Chemistry. 2018;**83**(4):2173-2181. DOI: 10.1021/acs.joc.7b03092

**Chapter 8**

**Abstract**

products.

**1. Introduction**

coupling reactions, total synthesis

macrolide ring forming reactions.

**159**

Total Synthesis of Macrolides

Structurally complex macrolide natural products, isolated from a variety of marine and other sources, continue to provide a valuable source of targets for the synthetic chemist to embark. In this account, we provide the recent progress and pathways in the total synthesis of macrolides and discussed the synthesis of (+)-neopeltolide, aspergillide D, miyakolide and acutiphycin natural

**Keywords:** macrolide, aldolization, macrolactonization, ring closing metathesis,

Macrolides are a class of antibiotics that consist of a large macrocyclic lactone ring attached to deoxy sugars. These antibiotics are bacteriostatic in nature and act by inhibiting protein synthesis of bacteria. These are obtained mainly from certain

actinomycetes genus, such as *Streptomyces* and related species. The original macrolide complex, erythromycin A, was isolated in 1952 as a natural product of *Saccharopolyspora erythraea* (formerly *Streptomyces erythreus*). Other examples

modithromycin, etc. Macrolides structurally contain three characteristic parts in every molecule, that is, a macrocyclic lactone ring, multiple ketone & hydroxyl group, and two deoxy sugars attached by glycosidic bond. According to the carbon number of lactone ring, macrolides are classified into several types. That is, 12-membered ring, 13-membered ring, 14-membered ring, 15-membered ring, 16-membered rings, etc. (**Figure 1**). Out of these, most of the antibiotic drugs

The construction of macrocyclic structures is a recurrent and challenging problem in synthetic organic chemistry. Theoretically, macrocyclic systems can be generated by cyclization of open, long chain precursors or by cleavage of internal bonds in polycyclic systems. In the course of synthesis, numerous problems are encountered to achieve target molecules. Despite the several problems, however, recent interest in the chemistry of macrolide antibiotics and other biologically active macrolactones and macrolactams resulted in the discovery and development of several new synthetic methods for macrolide formation. In this chapter, total synthesis of some of the macrolides is discussed with scrupulous emphasis on the key

include clarithromycin, azithromycin, telithromycin, cethromycin,

comprised of 14-membered and 16-membered lactone rings.

*Chebolu Naga Sesha Sai Pavan Kumar*

## **Chapter 8**
