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[91] Asano A, Yamada T, Taniguchi T, Sasaki M, Yoza K, Doi M. Ascidiacyclamides containing oxazoline and thiazole motifs assume square conformations and show high cytotoxicity. Journal of Peptide Science. 2018;**24**:e3120. DOI: 10.1002/psc.3120

[92] Chen Q-Y, Liu Y, Cai W, Luesch H. Improved total synthesis and biological evaluation of potent apratoxin S4 based anticancer agents with differential stability and further enhanced activity. Journal of Medicinal Chemistry. 2014;**57**:3011-3029. DOI: 10.1021/jm4019965

[93] Cai W, Chen Q-Y, Dang LH, Luesch H. Apratoxin S10, a dual inhibitor of angiogenesis and cancer cell growth to treat highly vascularized tumors. ACS Medicinal Chemistry Letters. 2017;**8**:1007-1012. DOI: 10.1021/ acsmedchemlett.7b00192

[94] Cai W, Ratnayake R, Gerber MH, Q-y C, Yu Y, Derendorf H, et al. Development of apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent and its preliminary evaluation in an orthotopic patient-derived

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*DOI: http://dx.doi.org/10.5772/intechopen.82741*

xenograft (PDX) model. Investigational New Drugs. 2018;**10**. DOI: 10.1007/

[95] Onda Y, Masuda Y, Yoshida M, Doi T. Conformation-based design and synthesis of apratoxin a mimetics modified at the α,β-unsaturated thiazoline moiety. Journal of Medicinal Chemistry. **2017**(60):6751-6765. DOI: 10.1021/acs.jmedchem.7b00833

s10637-018-0647-0

*Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds DOI: http://dx.doi.org/10.5772/intechopen.82741*

xenograft (PDX) model. Investigational New Drugs. 2018;**10**. DOI: 10.1007/ s10637-018-0647-0

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Sasaki M, Yoza K, Doi M. Ascidiacyclamides containing oxazoline and thiazole motifs assume square conformations and show high cytotoxicity. Journal of Peptide Science. 2018;**24**:e3120. DOI: 10.1002/psc.3120

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[91] Asano A, Yamada T, Taniguchi T,

[92] Chen Q-Y, Liu Y, Cai W, Luesch H. Improved total synthesis and biological evaluation of potent apratoxin S4 based anticancer agents with differential stability and further enhanced activity. Journal of Medicinal Chemistry. 2014;**57**:3011-3029. DOI:

[93] Cai W, Chen Q-Y, Dang LH, Luesch H. Apratoxin S10, a dual inhibitor of angiogenesis and cancer cell growth to treat highly vascularized tumors. ACS Medicinal Chemistry Letters. 2017;**8**:1007-1012. DOI: 10.1021/ acsmedchemlett.7b00192

[94] Cai W, Ratnayake R, Gerber MH, Q-y C, Yu Y, Derendorf H, et al. Development of apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent and its preliminary evaluation in an orthotopic patient-derived

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Structural basis of the antiproliferative

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**79**

(HO•

**Chapter 6**

**Abstract**

Heterocycles

phase transfer catalyst, KO2

), superoxide anion radical O2

**1. Introduction**

*Sundaram Singh and Savita Kumari*

One-Pot-Condensation Reaction

1,3-Diketone and Aldehydes Using

*In Situ* Generated Superoxide Ion:

A Rapid Synthesis of Structurally

A novel, convenient one-pot multicomponent synthesis of tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-one derivatives has been reported in the presence of tetraethylammonium superoxide under non-aqueous condition. The superoxide induced three-component reaction of various aromatic aldehydes, 2-aminobenzimadazole/2-aminobenzothiazole and dimedone/1,3- cyclohexanedione produced tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-one derivatives at room temperature under the mild reaction conditions. The tetraethylammonium superoxide has been generated by phase transfer reaction of potassium superoxide and tetraethylammonium bromide in dry DMF at room temperature. The present study extended the applicability of tetraethylammonium bromide as a phase transfer catalyst for the efficient use of superoxide ion in multi-component synthesis of structurally diverse drug-like complex heterocycles (quinazolines).

**Keywords:** superoxide ion, multicomponent reaction, Tetraethylammonium bromide,

The importance of oxygen in sustaining life is unquestionable but the aerobic life-style is fraught with danger. However, some recent reports about oxygen toxicity have caused much concern among the whole scientific community. The oxygen toxicity is due to various reactive oxygen species (ROS) such as hydroxyl radical

(HOCl), hydrogen peroxide (H2O2), singlet oxygen and ozone are also included in this category, although they are not free radicals but can lead to free radical reaction. Out of all the reactive oxygen species, superoxide anion radical is probably the most important ROS, which has come to the forefront of current chemical and

• −, and perhydroxyl radical. Hypochlorous acid

Diverse Drug-Like Complex

of Heterocyclic Amine,

#### **Chapter 6**

## One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using *In Situ* Generated Superoxide Ion: A Rapid Synthesis of Structurally Diverse Drug-Like Complex Heterocycles

*Sundaram Singh and Savita Kumari*

#### **Abstract**

A novel, convenient one-pot multicomponent synthesis of tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-one derivatives has been reported in the presence of tetraethylammonium superoxide under non-aqueous condition. The superoxide induced three-component reaction of various aromatic aldehydes, 2-aminobenzimadazole/2-aminobenzothiazole and dimedone/1,3- cyclohexanedione produced tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-one derivatives at room temperature under the mild reaction conditions. The tetraethylammonium superoxide has been generated by phase transfer reaction of potassium superoxide and tetraethylammonium bromide in dry DMF at room temperature. The present study extended the applicability of tetraethylammonium bromide as a phase transfer catalyst for the efficient use of superoxide ion in multi-component synthesis of structurally diverse drug-like complex heterocycles (quinazolines).

**Keywords:** superoxide ion, multicomponent reaction, Tetraethylammonium bromide, phase transfer catalyst, KO2

#### **1. Introduction**

The importance of oxygen in sustaining life is unquestionable but the aerobic life-style is fraught with danger. However, some recent reports about oxygen toxicity have caused much concern among the whole scientific community. The oxygen toxicity is due to various reactive oxygen species (ROS) such as hydroxyl radical (HO• ), superoxide anion radical O2 • −, and perhydroxyl radical. Hypochlorous acid (HOCl), hydrogen peroxide (H2O2), singlet oxygen and ozone are also included in this category, although they are not free radicals but can lead to free radical reaction. Out of all the reactive oxygen species, superoxide anion radical is probably the most important ROS, which has come to the forefront of current chemical and

biochemical research for the two reasons [1–4]. First superoxide ion as a biochemical species which causes many diseases such as cancer, ageing, inflammation, heart attack and lung injury, etc. More recently, it has been implicated to play a key role in both aging and cancer. Second superoxide ion as a novel reagent. Further from its elementary reactivity pattern, this anion radical has been recognized as a multipotent reagent, which acts as a base, nucleophile, oxidant and reductant. In view of these two points, superoxide research has become an area of interdisciplinary investigation [5–13].

Multi-component reactions (MCRs), in which multiple reactions are combined into one synthetic operation, have been used extensively to form carbon-carbon bonds in synthetic chemistry. Such reactions offer greater possibilities for molecular diversity per step with minimum reaction time, labor, cost, and waste production. The rapid assembly of molecular diversity utilizing MCRs has gained a great deal of attention, most notably for the construction of 'drug-like' libraries [14–20].

Quinazolines are very interesting heterocycles [21–25] as they serve as building blocks in numerous natural and synthetic products [26]. They exhibit a wide spectrum of biological and pharmacological activities such as propyl hydroxylase inhibitor [27], antidiabetics [28], anti-inflammatory [29], antiviral [30], antimicrobial [31], antineoplastic [32] and potent immunosuppressive agents [33]. Moreover, benzimidazolo quinazolines have also been an important class of heterocyclic compounds in drug research, as they are formed from both biodynamic heterosystems, benzimidazole and quinazoline, which have shown significant anticancer activities. Many useful methods, have been reported for synthesis of tetrahydrobenzoimidazo [2,1-b] quinazolin-1(2H)-ones ring system skeletons, such as the condensation of aminoazoles with benzylidene compounds, or three-component condensation of 2-aminobenzothiazole or 2-aminobenzimidazole and an aldehyde with cyclic 1,3-diketone. These reported methodologies produce good results in many cases [34, 35]. However, some of them suffer with certain limitations such as expensive catalysts, low yields of products, long reaction times, tedious procedures for preparations of catalysts, and tedious workup conditions [36–40]. Thus, there is enough room for further investigation in this direction. With a view to investigate the behavior of the superoxide ion in multicomponent organic synthesis, which is of importance in itself and further to assess its synthetic scope, the reaction of this novel reagent was studied.

#### **2. Results and discussion**

In continuation of our ongoing program on superoxide research and the synthesis of biologically active compounds, it is our current endeavor to extent the applicability of Et4NO2 for the synthesis of tetraheterocyclicBenzimidazolo/ benzothiazolo quinazolin-1-one ring systems **4** by a one-pot three-component condensation reaction of various aromatic aldehydes **2** and 1,3-diketones **3** with 2-aminobenzimidazole/2-aminobenzothiazole **1** using tetraethylammonium superoxide under non aqueous conditions (**Figure 1**).

In order to achieve the optimum yield of the product, the effect of various parameters such as effect of solvents (DMF, DMSO, and CH3CN) and molar proportion of the reactants were investigated in detail using benzaldehyde **2**, dimedone **3** with 2-aminobenzimidazole **1** as a model reaction.

To investigate the effect of solvents, the model reaction was carried out in different aprotic solvents. The results obtained clearly indicate that DMF was the best solvent among all investigated solvents in terms of product yield and the reaction time (**Table 1**).

**81**

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using…*

*One-pot synthesis of compounds 4 by the three-component condensation reaction of various aldehydes and 1,3-diketones with 2-aminobenzimidazole/2-aminobenzothiazole under superoxide ion at room temperature.*

**Entry Solvents Time %Yield** Dichloromethane 12 h Trace Acetonitrile 8 h 70 Tetrahydrofuran 14 h 42 Dimethylsulfoxide 20 h Trace Dimethylformamide 6 h 88

**Entry Reactants molar ratio Product yield\* (%)**

**Benzaldehydes:dimidone:2-aminobezimidazole:KO2:Et4NBr** 1.0 1.0 1.0 1.0 1.0 40 1.0 1.0 1.0 1.0 0.5 38 1.0 1.0 1.0 1.0 0.25 28 1.0 1.0 1.0 2.5 1.25 69 **1.0 1.0 1.0 4.0 2.00 88** 1.0 1.0 1.0 6.0 3.00 90

In order to establish the reactants molar ratio on the yield of product the model

A perusal of the table clearly indicates the profound effect of the concentration of KO2 and Et4NBr on the yield of the product **4a**. As regards the ratio of KO2 and Et4NBr, it is evident from the entries 1, 2 and 3 that with the diminution of the concentration of Et4NBr, the yield of product **4a** decreases. But as may be seen only a little difference in the yield of the product in the case of entries 1 and 2, the ratio of KO2 and Et4NBr was further kept to be 2:1. Therefore, in subsequent studies, the concentration of KO2 has been increased manifold but the ratio of KO2 and Et4NBr was all along maintained to be 2:1. Furthermore, in case of entries 5 and 6, there is just a 2% increase in the yield of the product and for that 2% increase, the concentration of KO2 and Et4NBr have been increased

reaction was carried out in different concentration of reactants (**Table 2**).

*DOI: http://dx.doi.org/10.5772/intechopen.81146*

**Figure 1.**

**Table 1.**

**Table 2.**

*Effect of solvents on the yield of the product 4a.*

*\*Isolated yield based on aldehyde.*

*Optimized condition has been shown by bold letter (entry 5).*

*Effect of reactants molar ratio on the yield of product 4a.*

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using… DOI: http://dx.doi.org/10.5772/intechopen.81146*

#### **Figure 1.**

*Heterocycles - Synthesis and Biological Activities*

investigation [5–13].

**2. Results and discussion**

oxide under non aqueous conditions (**Figure 1**).

2-aminobenzimidazole **1** as a model reaction.

biochemical research for the two reasons [1–4]. First superoxide ion as a biochemical species which causes many diseases such as cancer, ageing, inflammation, heart attack and lung injury, etc. More recently, it has been implicated to play a key role in both aging and cancer. Second superoxide ion as a novel reagent. Further from its elementary reactivity pattern, this anion radical has been recognized as a multipotent reagent, which acts as a base, nucleophile, oxidant and reductant. In view of these two points, superoxide research has become an area of interdisciplinary

Multi-component reactions (MCRs), in which multiple reactions are combined into one synthetic operation, have been used extensively to form carbon-carbon bonds in synthetic chemistry. Such reactions offer greater possibilities for molecular diversity per step with minimum reaction time, labor, cost, and waste production. The rapid assembly of molecular diversity utilizing MCRs has gained a great deal of

Quinazolines are very interesting heterocycles [21–25] as they serve as building blocks in numerous natural and synthetic products [26]. They exhibit a wide spectrum of biological and pharmacological activities such as propyl hydroxylase inhibitor [27], antidiabetics [28], anti-inflammatory [29], antiviral [30], antimicrobial [31], antineoplastic [32] and potent immunosuppressive agents [33]. Moreover, benzimidazolo quinazolines have also been an important class of heterocyclic compounds in drug research, as they are formed from both biodynamic heterosystems, benzimidazole and quinazoline, which have shown significant anticancer activities. Many useful methods, have been reported for synthesis of tetrahydrobenzoimidazo [2,1-b] quinazolin-1(2H)-ones ring system skeletons, such as the condensation of aminoazoles with benzylidene compounds, or three-component condensation of 2-aminobenzothiazole or 2-aminobenzimidazole and an aldehyde with cyclic 1,3-diketone. These reported methodologies produce good results in many cases [34, 35]. However, some of them suffer with certain limitations such as expensive catalysts, low yields of products, long reaction times, tedious procedures for preparations of catalysts, and tedious workup conditions [36–40]. Thus, there is enough room for further investigation in this direction. With a view to investigate the behavior of the superoxide ion in multicomponent organic synthesis, which is of importance in itself and further to

attention, most notably for the construction of 'drug-like' libraries [14–20].

assess its synthetic scope, the reaction of this novel reagent was studied.

In continuation of our ongoing program on superoxide research and the synthesis of biologically active compounds, it is our current endeavor to extent the applicability of Et4NO2 for the synthesis of tetraheterocyclicBenzimidazolo/ benzothiazolo quinazolin-1-one ring systems **4** by a one-pot three-component condensation reaction of various aromatic aldehydes **2** and 1,3-diketones **3** with 2-aminobenzimidazole/2-aminobenzothiazole **1** using tetraethylammonium super-

In order to achieve the optimum yield of the product, the effect of various parameters such as effect of solvents (DMF, DMSO, and CH3CN) and molar proportion of the reactants were investigated in detail using benzaldehyde **2**, dimedone **3** with

To investigate the effect of solvents, the model reaction was carried out in different aprotic solvents. The results obtained clearly indicate that DMF was the best solvent among all investigated solvents in terms of product yield and the reaction

**80**

time (**Table 1**).

*One-pot synthesis of compounds 4 by the three-component condensation reaction of various aldehydes and 1,3-diketones with 2-aminobenzimidazole/2-aminobenzothiazole under superoxide ion at room temperature.*

#### **Table 1.**

*Effect of solvents on the yield of the product 4a.*

*Optimized condition has been shown by bold letter (entry 5).*

#### **Table 2.**

*Effect of reactants molar ratio on the yield of product 4a.*

In order to establish the reactants molar ratio on the yield of product the model reaction was carried out in different concentration of reactants (**Table 2**).

A perusal of the table clearly indicates the profound effect of the concentration of KO2 and Et4NBr on the yield of the product **4a**. As regards the ratio of KO2 and Et4NBr, it is evident from the entries 1, 2 and 3 that with the diminution of the concentration of Et4NBr, the yield of product **4a** decreases. But as may be seen only a little difference in the yield of the product in the case of entries 1 and 2, the ratio of KO2 and Et4NBr was further kept to be 2:1. Therefore, in subsequent studies, the concentration of KO2 has been increased manifold but the ratio of KO2 and Et4NBr was all along maintained to be 2:1. Furthermore, in case of entries 5 and 6, there is just a 2% increase in the yield of the product and for that 2% increase, the concentration of KO2 and Et4NBr have been increased

substantially (6 fold and 3 fold respectively). As a result, considering the high cost of KO2 and Et4NBr, the entry 5, with the reactants ratio **1:1:1:4:2**, has been selected as the optimum ratio.

The scope and limitations of this reaction were fully illustrated with various *ortho-, meta- and para-substituted* benzaldehydes in the presence of 2-aminobenzimidazole and 2-aminobenzothiazole.

As indicated in **Table 3**, the reaction proceeded efficiently with both electron-withdrawing and electron releasing *ortho-, meta- and para-*substituted benzaldehydes.

The products were identified by their physical and spectral data, which were in full agreement with the reported values.

**83**

**Figure 2.**

*derivatives (4a-o).*

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using…*

The proposed mechanism for the formation of tetraheterocyclicbenzimidazolo/ benzothiazolo quinazolin-1-ones ring system is given in **Figure 2**. The reaction was initiated by the abstraction of proton from 1,3-diketones **3** by tetraethylammonium superoxide which was *in situ* generated by the phase transfer reaction of potassium superoxide with tetraethylammonium bromide. Now, Knoevenagel condensation takes place between benzaldehyde **2** and subsequently, by dehydration, olefin 3-benzylidene-2,4-hexanedione **5** is produced. Then 2-aminobenzimidazole/2-aminobenzothiazole**1** is reacted with compound **5** through a Michael addition to produce a product of type **6** and after cyclisation to afford tetraheterocyclicbenzimidazolo/

Potassium superoxide (1.42 g, 0.02 mol) and tetraethylammonium bromide (2.10 g, 0.01 mol) were weighed under nitrogen atmosphere using an atmosbag and were transferred into a three-necked R. B. flask, dry DMF (20 mL) was added to it and the mixture was agitated magnetically for 15 min to facilitate the formation of tetraethylammoniumsuperoxide. To the stirred reaction mixture, dimedone (0.70 g, 0.005 mol) **3** were added. After 10 min, benzaldehyde (0.53 g, 0.005 mol) **2** and 2-aminobenzimidazole (0.665 g, 0.005 mmol) **1** were introduced, and the stirring was continued 6 h. After the reaction was over as indicated by TLC, mixture was treated with cold brine solution (2 mL) followed by saturated sodium hydrogen carbonate solution (2 mL) to decompose the unreacted KO2. The mixture was then extracted with dichloromethane (3 × 15 mL) and the combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated to give

the products **4a**, which were purified by column chromatography.

*Plausible mechanism for the formation of tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-one*

**2.1 Mechanism for the synthesis of tetraheterocyclicbenzimidazolo/**

*DOI: http://dx.doi.org/10.5772/intechopen.81146*

**benzothiazolo quinazolin-1-ones**

benzothiazolo quinazolin-1-one ring systems **4**.

**Table 3.** *Synthesis of tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-ones.*

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using… DOI: http://dx.doi.org/10.5772/intechopen.81146*

#### **2.1 Mechanism for the synthesis of tetraheterocyclicbenzimidazolo/ benzothiazolo quinazolin-1-ones**

The proposed mechanism for the formation of tetraheterocyclicbenzimidazolo/ benzothiazolo quinazolin-1-ones ring system is given in **Figure 2**. The reaction was initiated by the abstraction of proton from 1,3-diketones **3** by tetraethylammonium superoxide which was *in situ* generated by the phase transfer reaction of potassium superoxide with tetraethylammonium bromide. Now, Knoevenagel condensation takes place between benzaldehyde **2** and subsequently, by dehydration, olefin 3-benzylidene-2,4-hexanedione **5** is produced. Then 2-aminobenzimidazole/2-aminobenzothiazole**1** is reacted with compound **5** through a Michael addition to produce a product of type **6** and after cyclisation to afford tetraheterocyclicbenzimidazolo/ benzothiazolo quinazolin-1-one ring systems **4**.

Potassium superoxide (1.42 g, 0.02 mol) and tetraethylammonium bromide (2.10 g, 0.01 mol) were weighed under nitrogen atmosphere using an atmosbag and were transferred into a three-necked R. B. flask, dry DMF (20 mL) was added to it and the mixture was agitated magnetically for 15 min to facilitate the formation of tetraethylammoniumsuperoxide. To the stirred reaction mixture, dimedone (0.70 g, 0.005 mol) **3** were added. After 10 min, benzaldehyde (0.53 g, 0.005 mol) **2** and 2-aminobenzimidazole (0.665 g, 0.005 mmol) **1** were introduced, and the stirring was continued 6 h. After the reaction was over as indicated by TLC, mixture was treated with cold brine solution (2 mL) followed by saturated sodium hydrogen carbonate solution (2 mL) to decompose the unreacted KO2. The mixture was then extracted with dichloromethane (3 × 15 mL) and the combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated to give the products **4a**, which were purified by column chromatography.

#### **Figure 2.**

*Plausible mechanism for the formation of tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-one derivatives (4a-o).*

*Heterocycles - Synthesis and Biological Activities*

selected as the optimum ratio.

benzaldehydes.

imidazole and 2-aminobenzothiazole.

full agreement with the reported values.

substantially (6 fold and 3 fold respectively). As a result, considering the high cost of KO2 and Et4NBr, the entry 5, with the reactants ratio **1:1:1:4:2**, has been

The scope and limitations of this reaction were fully illustrated with various *ortho-, meta- and para-substituted* benzaldehydes in the presence of 2-aminobenz-

The products were identified by their physical and spectral data, which were in

As indicated in **Table 3**, the reaction proceeded efficiently with both electron-withdrawing and electron releasing *ortho-, meta- and para-*substituted

**82**

**Table 3.**

*Synthesis of tetraheterocyclicbenzimidazolo/benzothiazolo quinazolin-1-ones.*

All the products were characterized by IR and 1 H NMR (because of low solubility of compounds **4a-o**, 13C NMR was not obtained).

**3,3–Dimethyl–12–phenyl–3,4,6,12–tetrahydrobenzo[4,5]imidazo[2,1-b] quinazolin–1(2H)–one (4a):** M.p. > 300°C; IR (KBr, υ = cm−1 ) 3445, 2885, 1640, 1618, 1610, 1565 cm−1 ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.16 (br. s, 1H, NH), 7.39–7.30 (m, 6H), 7.23 (d, *J* = 8.0 Hz, 1H), 7.07–7.04 (m, 1H), 6.98–6.95 (m, 1H), 6.44 (s, 1H), 2.26 (d, *J* = 16.0 Hz, 2H), 2.06 (d, *J* = 16.0 Hz, 2H), 1.06 (s, 3H), 0.92 (s, 3H). Anal. Calcd for C22H21N3O: C, 76.94; H, 6.16; N, 12.24; O, 4.66. Found: C, 76.90; H, 6.20; N, 12.26; O, 4.64.

**12–(4–Methoxyphenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4b):** M.p. > 300°C; IR (KBr, υ = cm−1 ) 3391, 2850, 1670, 1644, 1610, 1590 cm−1 ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.06 (br. s, 1H, NH), 7.36 (d, *J* = 8.0 Hz, 1H), 7.26–7.24 (m, 3H), 7.04 (t, *J* = 7.5 Hz, 1H), 6.95 (t, *J* = 7.5 Hz, 1H), 6.78 (d, *J* = 8.5 Hz, 2H), 6.36 (s, 1H), 3.65 (s, 3H), 2.64–2.52 (m, 2H), 2.25 (d, *J* = 16.0 Hz, 1H), 2.05 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 3H), 0.94 (s, 3H). Anal Calcd for C23H23N3O2: C, 73.97; H, 6.21; N, 11.25; O, 8.57. Found: C, 73.92; H, 6.26; N, 11.23; O, 8.59.

**12–(4–Chlorophenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4c):** M.p. > 300°C; IR (KBr, υ = cm−1 ) 3440, 2934, 1655, 1650, 1613, 1580 cm−1 ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.10 (br. s, 1H, NH), 7.36 (d, *J* = 7.5 Hz, 1H), 7.33 (d, *J* = 6.5 Hz, 2H), 7.24 (s, 2H), 7.15 (s, 1H), 7.04 (s, 1H), 6.95 (s, 1H), 6.41 (s, 1H), 2.63 (d, *J* = 16.0 Hz, 2H), 2.26 (d, *J* = 16.0 Hz, 2H), 1.06 (s, 3H), 0.93 (s, 3H). Anal. Calcd for C22H20ClN3O: C, 69.93; H, 5.34; Cl, 9.38; N, 11.12; O, 4.23. Found: C, 69.90; H, 5.37; Cl, 9.34; N, 11.15; O, 4.24.

**12–(4–Bromophenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4d):** M.p. >300°C; IR (KBr, υ = cm−1 ) 3441, 2956, 1645, 1614, 1590, 1566 cm−1 ; 1 H-NMR (500 MHz, DMSO-*d6*): *δ* = 10.01 (br. s, 1H, NH), 6.99–7.89 (m, Ar–H), 6.43 (s, 1H), 2.59–2.67 (m, 2H), 2.20 (d, *J* = 16.00 Hz, 1H), 2.00 (d, *J* = 16.01 Hz, 1H) 1.05 (s, 3H), 0*.*94 (s, 3H). Anal. Calcd for C22H20BrN3O: C, 62.57; H, 4.77; Br, 18.92; N, 9.95; O, 3.79. Found: C, 62.67; H, 4.86; Br, 18.80; N, 9.83; O, 3.90.

**12–(4–Hydroxyphenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4e):** M.p. *>* 300°C; IR (KBr, υ = cm−1 ) 3449, 2891, 1642, 1613, 1587, 1566 cm−1 ; 1 H-NMR (500 MHz, DMSO-*d6*) *δ* = 11.02 (br. s, 1H, NH), 9.33 (s, 1H, OH), 6.61–7.36 (m, 8H, Ar–H), 6.18 (s, 1H), 2.51–2.74 (m, 2H), 2.25 (d, *J* = 9.24 Hz, 1H), 2.05(d, *J* = 8.94 Hz, 1H), 1.07 (s, 3H), 0*.*96 (s, 3H), Anal. Calcd for C22H21N3O2: C, 73.52; H, 5.89; N, 11.69; O, 8.90. Found: C, 73.63; H, 5.97; N, 11.80; O, 8.71.

**12–(3–Chlorophenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4f)** M.p. > 300°C; IR (KBr, υ = cm−1 ) 3400, 2891, 1660, 1652, 1613, 1575 cm−1 ; 1 H NMR (500 MHz, DMSO−*d6*): *δ* = 11.18 (br. s, 1H, NH), 7.46 (s, 1H), 7.39 (d, *J* = 8.0 Hz, 1H), 7.30–7.21 (m, 5H), 7.06 (s, 1H), 6.98 (s, 1H), 6.46 (s, 1H), 2.58 (d, *J* = 16.0 Hz, 1H), 2.26 (d, *J* = 16.0 Hz, 1H), 2.08 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 3H), 0.93 (s, 3H). Anal. Calcd for C22H20ClN3O: C, 69.93; H, 5.34; Cl, 9.38; N, 11.12; O, 4.23. Found: C, 69.90; H, 5.37; Cl, 9.35; N, 11.14; O, 4.24.

**3,3–Dimethyl–12–(2–nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4 g):** M.p. > 300°C; IR (KBr, υ = cm−1 ) 3398, 2972, 1664, 1645, 1618, 1594 cm−1 ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.18 (br. s, 1H, NH), 7.46 (s, 1H), 7.31–7.19 (m, 5H), 7.06 (t, *J* = 7.5 Hz, 1H), 6.98 (t, *J* = 7.5 Hz, 1H), 6.46 (s, 1H), 2.62 (d, *J* = 16.0 Hz, 1H), 2.55 (s, 1H), 2.26 (d, *J* = 16.0 Hz, 1H), 2.08 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 2H), 0.93 (s, 2H). Anal. Calcd

**85**

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using…*

for C22H20N4O3: C, 68.03; H, 5.19; N, 14.42; O, 12.36. Found: C, 68.07; H, 5.15; N,

; 1

> ; 1

(d, *J* = 16.0 Hz, 1H), 2.06 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 3H), 0.91 (s, 3H). Anal. Calcd for C22H20N4O3: C, 68.03; H, 5.19; N, 14.42; O, 12.36. Found: C, 68.04; H,

**12–(4–Methoxyphenyl)–3,4,6,12–tetrahydrobenzo[4,5]imidazo[2,1-b]**

**12–(3–Nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5]imidazo[2,1-b]quin-**

**3,3–Dimethyl–12–phenyl–2,3,4,12–tetrahydro–1H–benzo[4,5]thiazolo[2,3–b]**

Hz, 1H), 7.43 (dd, *J* = 17.5, 7.7 Hz, 3H), 7.28 (dd, *J* = 16.0, 3H), 7.20 (dd, *J* = 16.0, 8.0 Hz, 2H), 6.51 (s, 1H), 2.47–2.36 (m, 2H), 2.24 (d, *J* = 16.0 Hz, 1H), 2.05

(d, *J* = 16.0 Hz, 1H), 1.02 (s, 3H), 0.86 (s, 3H). Anal. Calcd for C22H20N2OS: C, 73.30; H, 5.59; N, 7.77; O, 4.44; S, 8.89. Found: C, 73.33; H, 5.56; N, 7.79; O, 4.41; S, 8.88. 3,3–Dimethyl–12–(4-methylphenyl)–2,3,4,12–tetrahydro–1H–benzo[4,5]

(d, *J* = 8 Hz, 2H), 7.28–7.22 (m, 1H), 7.18–7.15 (m, 2H), 7.06 (d, *J* = 8 Hz, 2H), 6.47 (s, 1H), 2.49 (s, 2H), 2.28–2.17 (m, 5H), 1.09 (s, 3H), 0.97 (s, 3H). Anal. Calcd for C23H22N2OS: C, 73.77; H, 5.92; N, 7.48; O, 4.27; S, 8.56. Found: C, 73.68; H, 5.71; N,

**3,3–Dimethyl–12–(4-bromophenyl)–2,3,4,12–tetrahydro–1H–benzo[4,5]**

DMSO–*d6*): *δ* = 7.47 (d, *J* = 8 Hz, 1H), 7.37–7.28 (m, 5H), 7.19 (d, *J* = 8 Hz, 1H), 7.06

(br. s, 1H, NH), 8.12 (d, *J* = 8.5 Hz, 2H), 7.61 (d, *J* = 9.0 Hz, 2H), 7.40 (d, *J* = 7.5 Hz, 1H), 7.23 (d, *J* = 8.0 Hz, 1H), 7.07 (t, *J* = 7.5 Hz, 1H), 6.96 (t, *J* = 7.5 Hz, 1H), 6.60

)

)

) 3398, 2976,

) 3412, 2872, 2855, 1670,

) 3428, 2965, 1680,

H NMR (500 MHz,

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.26

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.27

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.07 (br. s, 1H,

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.28 (br. s, 1H, NH),

H NMR (500 MHz, DMSO–*d6*): *δ* = 7.79 (d, *J* = 10.0

H NMR (500 MHz, DMSO–*d6*): *δ* = 7.49–7.47 (m, 1H), 7.34

**3,3–Dimethyl–12–(3–nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4 h):** M.p. > 300°C; IR (KBr, υ = cm−1

(br. s, 1H, NH), 8.27 (s, 1H), 8.04 (d, *J* = 8.0 Hz, 1H), 7.73 (d, *J* = 7.5 Hz, 1H), 7.56 (t, *J* = 8.0 Hz, 1H), 7.40 (d, *J* = 8.0 Hz, 1H), 7.29 (d, *J* = 8.0 Hz, 1H), 7.07 (t, *J* = 7.5 Hz, 1H), 6.97 (t, *J* = 7.5 Hz, 1H), 6.65 (s, 1H), 2.27 (d, *J* = 16.0 Hz, 2H), 2.07 (d, *J* = 16.0 Hz, 2H), 1.06 (s, 3H), 0.91 (s, 3H). Anal. Calcd for C22H20N4O3: C, 68.03;

H, 5.19; N, 14.42; O, 12.36. Found: C, 68.08; H, 5.14; N, 14.44; O, 12.34. **3,3–Dimethyl–12–(4–nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4i):** M.p. > 300°C; IR (KBr, υ = cm−1

(s, 1H), 2.65 (d, *J* = 16.0 Hz, 1H), 2.54 (d, *J* = 16.0 Hz, 1H), 2.27

**quinazolin–1(2H)–one (4j):** M.p. = 238–240°C; IR (KBr, υ = cm−1

NH), 7.36 (d, *J* = 8.0 Hz, 1H), 7.26–7.22 (m, 3H), 7.06–7.01 (m, 1H), 6.95 (t, *J* = 7.2 Hz, 1H), 6.78 (d, *J* = 8.0 Hz, 2H), 6.37 (s, 1H), 3.65 (s, 3H), 2.68 (d, *J* = 5.0 Hz, 2H), 2.29 (dd, *J* = 10.5, 5.0 Hz, 1H), 2.22 (dd, *J* = 16.0, 5.0 Hz, 1H), 2.02–1.93 (m, 1H), 1.88–1.80 (m, 1H). Anal. Calcd for C21H19N3O2: C, 73.03; H, 5.54;

8.26 (s, 1H), 8.03 (d, *J* = 8.5 Hz, 1H), 7.70 (d, *J* = 7.5 Hz, 1H), 7.54 (t, *J* = 8.0 Hz, 1H), 7.40 (d, *J* = 8.0 Hz, 1H), 7.26 (d, *J* = 7.5 Hz, 1H), 7.06 (t, *J* = 7.4 Hz, 1H), 6.96 (t, *J* = 7.5 Hz, 1H), 6.66 (s, 1H), 2.40–2.18 (m, 2H), 1.93 (dd, *J* = 16.0, 2H);. Anal. Calcd for C20H16N4O3: C, 66.66; H, 4.48; N, 15.55; O, 13.32. Found: C,

; 1

N, 12.17; O, 9.26. Found: C, 73.01; H, 5.56; N, 12.14; O, 9.29.

**azolin–1(2H)–one(4 k):** M.p. > 300°C; IR (KBr, υ = cm−1

**quinazolin–1–one (4 l):** M.p. = 208–210°C; IR (KBr, υ = cm−1

**thiazolo[2,3–b]quinazolin–1–one (4n):** M.p. 182–184°C. 1

; 1

; 1

66.64; H, 4.50; N, 15.53; O, 13.34.

thiazolo[2,3–b]quinazolin–1–one(4 m):

1655, 1589, 1516, 1370 cm−1

M.p. = 203–205°C. 1

7.60; O, 4.35; S, 8.70.

*DOI: http://dx.doi.org/10.5772/intechopen.81146*

3394, 2970, 1660, 1648, 1615, 1598 cm−1

3396, 2980, 1662, 1641, 1612, 1594 cm−1

5.18; N, 14.40; O, 12.38.

1640, 1617, 1601 cm−1

1666, 1642, 1616, 1575 cm−1

14.46; O, 12.32.

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using… DOI: http://dx.doi.org/10.5772/intechopen.81146*

for C22H20N4O3: C, 68.03; H, 5.19; N, 14.42; O, 12.36. Found: C, 68.07; H, 5.15; N, 14.46; O, 12.32.

**3,3–Dimethyl–12–(3–nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4 h):** M.p. > 300°C; IR (KBr, υ = cm−1 ) 3394, 2970, 1660, 1648, 1615, 1598 cm−1 ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.26 (br. s, 1H, NH), 8.27 (s, 1H), 8.04 (d, *J* = 8.0 Hz, 1H), 7.73 (d, *J* = 7.5 Hz, 1H), 7.56 (t, *J* = 8.0 Hz, 1H), 7.40 (d, *J* = 8.0 Hz, 1H), 7.29 (d, *J* = 8.0 Hz, 1H), 7.07 (t, *J* = 7.5 Hz, 1H), 6.97 (t, *J* = 7.5 Hz, 1H), 6.65 (s, 1H), 2.27 (d, *J* = 16.0 Hz, 2H), 2.07 (d, *J* = 16.0 Hz, 2H), 1.06 (s, 3H), 0.91 (s, 3H). Anal. Calcd for C22H20N4O3: C, 68.03; H, 5.19; N, 14.42; O, 12.36. Found: C, 68.08; H, 5.14; N, 14.44; O, 12.34.

**3,3–Dimethyl–12–(4–nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4i):** M.p. > 300°C; IR (KBr, υ = cm−1 ) 3396, 2980, 1662, 1641, 1612, 1594 cm−1 ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.27 (br. s, 1H, NH), 8.12 (d, *J* = 8.5 Hz, 2H), 7.61 (d, *J* = 9.0 Hz, 2H), 7.40 (d, *J* = 7.5 Hz, 1H), 7.23 (d, *J* = 8.0 Hz, 1H), 7.07 (t, *J* = 7.5 Hz, 1H), 6.96 (t, *J* = 7.5 Hz, 1H), 6.60 (s, 1H), 2.65 (d, *J* = 16.0 Hz, 1H), 2.54 (d, *J* = 16.0 Hz, 1H), 2.27 (d, *J* = 16.0 Hz, 1H), 2.06 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 3H), 0.91 (s, 3H). Anal. Calcd for C22H20N4O3: C, 68.03; H, 5.19; N, 14.42; O, 12.36. Found: C, 68.04; H, 5.18; N, 14.40; O, 12.38.

**12–(4–Methoxyphenyl)–3,4,6,12–tetrahydrobenzo[4,5]imidazo[2,1-b] quinazolin–1(2H)–one (4j):** M.p. = 238–240°C; IR (KBr, υ = cm−1 ) 3398, 2976, 1666, 1642, 1616, 1575 cm−1 ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.07 (br. s, 1H, NH), 7.36 (d, *J* = 8.0 Hz, 1H), 7.26–7.22 (m, 3H), 7.06–7.01 (m, 1H), 6.95 (t, *J* = 7.2 Hz, 1H), 6.78 (d, *J* = 8.0 Hz, 2H), 6.37 (s, 1H), 3.65 (s, 3H), 2.68 (d, *J* = 5.0 Hz, 2H), 2.29 (dd, *J* = 10.5, 5.0 Hz, 1H), 2.22 (dd, *J* = 16.0, 5.0 Hz, 1H), 2.02–1.93 (m, 1H), 1.88–1.80 (m, 1H). Anal. Calcd for C21H19N3O2: C, 73.03; H, 5.54; N, 12.17; O, 9.26. Found: C, 73.01; H, 5.56; N, 12.14; O, 9.29.

**12–(3–Nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin–1(2H)–one(4 k):** M.p. > 300°C; IR (KBr, υ = cm−1 ) 3412, 2872, 2855, 1670, 1640, 1617, 1601 cm−1 ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 11.28 (br. s, 1H, NH), 8.26 (s, 1H), 8.03 (d, *J* = 8.5 Hz, 1H), 7.70 (d, *J* = 7.5 Hz, 1H), 7.54 (t, *J* = 8.0 Hz, 1H), 7.40 (d, *J* = 8.0 Hz, 1H), 7.26 (d, *J* = 7.5 Hz, 1H), 7.06 (t, *J* = 7.4 Hz, 1H), 6.96 (t, *J* = 7.5 Hz, 1H), 6.66 (s, 1H), 2.40–2.18 (m, 2H), 1.93 (dd, *J* = 16.0, 2H);. Anal. Calcd for C20H16N4O3: C, 66.66; H, 4.48; N, 15.55; O, 13.32. Found: C, 66.64; H, 4.50; N, 15.53; O, 13.34.

**3,3–Dimethyl–12–phenyl–2,3,4,12–tetrahydro–1H–benzo[4,5]thiazolo[2,3–b] quinazolin–1–one (4 l):** M.p. = 208–210°C; IR (KBr, υ = cm−1 ) 3428, 2965, 1680, 1655, 1589, 1516, 1370 cm−1 ; 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 7.79 (d, *J* = 10.0 Hz, 1H), 7.43 (dd, *J* = 17.5, 7.7 Hz, 3H), 7.28 (dd, *J* = 16.0, 3H), 7.20 (dd, *J* = 16.0, 8.0 Hz, 2H), 6.51 (s, 1H), 2.47–2.36 (m, 2H), 2.24 (d, *J* = 16.0 Hz, 1H), 2.05 (d, *J* = 16.0 Hz, 1H), 1.02 (s, 3H), 0.86 (s, 3H). Anal. Calcd for C22H20N2OS: C, 73.30; H, 5.59; N, 7.77; O, 4.44; S, 8.89. Found: C, 73.33; H, 5.56; N, 7.79; O, 4.41; S, 8.88.

3,3–Dimethyl–12–(4-methylphenyl)–2,3,4,12–tetrahydro–1H–benzo[4,5] thiazolo[2,3–b]quinazolin–1–one(4 m):

M.p. = 203–205°C. 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 7.49–7.47 (m, 1H), 7.34 (d, *J* = 8 Hz, 2H), 7.28–7.22 (m, 1H), 7.18–7.15 (m, 2H), 7.06 (d, *J* = 8 Hz, 2H), 6.47 (s, 1H), 2.49 (s, 2H), 2.28–2.17 (m, 5H), 1.09 (s, 3H), 0.97 (s, 3H). Anal. Calcd for C23H22N2OS: C, 73.77; H, 5.92; N, 7.48; O, 4.27; S, 8.56. Found: C, 73.68; H, 5.71; N, 7.60; O, 4.35; S, 8.70.

**3,3–Dimethyl–12–(4-bromophenyl)–2,3,4,12–tetrahydro–1H–benzo[4,5] thiazolo[2,3–b]quinazolin–1–one (4n):** M.p. 182–184°C. 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 7.47 (d, *J* = 8 Hz, 1H), 7.37–7.28 (m, 5H), 7.19 (d, *J* = 8 Hz, 1H), 7.06

*Heterocycles - Synthesis and Biological Activities*

3391, 2850, 1670, 1644, 1610, 1590 cm−1

; 1

73.92; H, 6.26; N, 11.23; O, 8.59.

3440, 2934, 1655, 1650, 1613, 1580 cm−1

3441, 2956, 1645, 1614, 1590, 1566 cm−1

3449, 2891, 1642, 1613, 1587, 1566 cm−1

3400, 2891, 1660, 1652, 1613, 1575 cm−1

3398, 2972, 1664, 1645, 1618, 1594 cm−1

4.86; Br, 18.80; N, 9.83; O, 3.90.

73.63; H, 5.97; N, 11.80; O, 8.71.

1610, 1565 cm−1

6.20; N, 12.26; O, 4.64.

All the products were characterized by IR and 1

ity of compounds **4a-o**, 13C NMR was not obtained).

**quinazolin–1(2H)–one (4a):** M.p. > 300°C; IR (KBr, υ = cm−1

**3,3–Dimethyl–12–phenyl–3,4,6,12–tetrahydrobenzo[4,5]imidazo[2,1-b]**

(s, 1H), 2.26 (d, *J* = 16.0 Hz, 2H), 2.06 (d, *J* = 16.0 Hz, 2H), 1.06 (s, 3H), 0.92 (s, 3H). Anal. Calcd for C22H21N3O: C, 76.94; H, 6.16; N, 12.24; O, 4.66. Found: C, 76.90; H,

**12–(4–Methoxyphenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4b):** M.p. > 300°C; IR (KBr, υ = cm−1

; 1

**12–(4–Chlorophenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4c):** M.p. > 300°C; IR (KBr, υ = cm−1

**12–(4–Bromophenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4d):** M.p. >300°C; IR (KBr, υ = cm−1

; 1

**12–(4–Hydroxyphenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4e):** M.p. *>* 300°C; IR (KBr, υ = cm−1

; 1

**12–(3–Chlorophenyl)–3,3–dimethyl–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b] quinazolin–1(2H)–one (4f)** M.p. > 300°C; IR (KBr, υ = cm−1

**3,3–Dimethyl–12–(2–nitrophenyl)–3,4,6,12–tetrahydrobenzo[4,5] imidazo[2,1-b]quinazolin–1(2H)–one (4 g):** M.p. > 300°C; IR (KBr, υ = cm−1

(br. s, 1H, NH), 7.46 (s, 1H), 7.31–7.19 (m, 5H), 7.06 (t, *J* = 7.5 Hz, 1H), 6.98 (t, *J* = 7.5 Hz, 1H), 6.46 (s, 1H), 2.62 (d, *J* = 16.0 Hz, 1H), 2.55 (s, 1H), 2.26 (d, *J* = 16.0 Hz, 1H), 2.08 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 2H), 0.93 (s, 2H). Anal. Calcd

; 1

; 1

(br. s, 1H, NH), 7.46 (s, 1H), 7.39 (d, *J* = 8.0 Hz, 1H), 7.30–7.21 (m, 5H), 7.06 (s, 1H), 6.98 (s, 1H), 6.46 (s, 1H), 2.58 (d, *J* = 16.0 Hz, 1H), 2.26 (d, *J* = 16.0 Hz, 1H), 2.08 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 3H), 0.93 (s, 3H). Anal. Calcd for C22H20ClN3O: C, 69.93; H, 5.34; Cl, 9.38; N, 11.12; O, 4.23. Found: C, 69.90; H, 5.37; Cl, 9.35; N,

(br. s, 1H, NH), 9.33 (s, 1H, OH), 6.61–7.36 (m, 8H, Ar–H), 6.18 (s, 1H), 2.51–2.74 (m, 2H), 2.25 (d, *J* = 9.24 Hz, 1H), 2.05(d, *J* = 8.94 Hz, 1H), 1.07 (s, 3H), 0*.*96 (s, 3H), Anal. Calcd for C22H21N3O2: C, 73.52; H, 5.89; N, 11.69; O, 8.90. Found: C,

(br. s, 1H, NH), 6.99–7.89 (m, Ar–H), 6.43 (s, 1H), 2.59–2.67 (m, 2H), 2.20 (d, *J* = 16.00 Hz, 1H), 2.00 (d, *J* = 16.01 Hz, 1H) 1.05 (s, 3H), 0*.*94 (s, 3H). Anal. Calcd for C22H20BrN3O: C, 62.57; H, 4.77; Br, 18.92; N, 9.95; O, 3.79. Found: C, 62.67; H,

(s, 1H), 7.04 (s, 1H), 6.95 (s, 1H), 6.41 (s, 1H), 2.63 (d, *J* = 16.0 Hz, 2H), 2.26 (d, *J* = 16.0 Hz, 2H), 1.06 (s, 3H), 0.93 (s, 3H). Anal. Calcd for C22H20ClN3O: C, 69.93; H, 5.34; Cl, 9.38;

; 1

(br. s, 1H, NH), 7.36 (d, *J* = 7.5 Hz, 1H), 7.33 (d, *J* = 6.5 Hz, 2H), 7.24 (s, 2H), 7.15

N, 11.12; O, 4.23. Found: C, 69.90; H, 5.37; Cl, 9.34; N, 11.15; O, 4.24.

(br. s, 1H, NH), 7.36 (d, *J* = 8.0 Hz, 1H), 7.26–7.24 (m, 3H), 7.04 (t, *J* = 7.5 Hz, 1H), 6.95 (t, *J* = 7.5 Hz, 1H), 6.78 (d, *J* = 8.5 Hz, 2H), 6.36 (s, 1H), 3.65 (s, 3H), 2.64–2.52 (m, 2H), 2.25 (d, *J* = 16.0 Hz, 1H), 2.05 (d, *J* = 16.0 Hz, 1H), 1.06 (s, 3H), 0.94 (s, 3H). Anal Calcd for C23H23N3O2: C, 73.97; H, 6.21; N, 11.25; O, 8.57. Found: C,

(m, 6H), 7.23 (d, *J* = 8.0 Hz, 1H), 7.07–7.04 (m, 1H), 6.98–6.95 (m, 1H), 6.44

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.16 (br. s, 1H, NH), 7.39–7.30

H NMR (because of low solubil-

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.06

H-NMR (500 MHz, DMSO-*d6*): *δ* = 10.01

H-NMR (500 MHz, DMSO-*d6*) *δ* = 11.02

H NMR (500 MHz, DMSO−*d6*): *δ* = 11.18

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.18

H NMR (500 MHz, DMSO–*d6*): *δ* = 11.10

) 3445, 2885, 1640, 1618,

)

)

)

)

)

)

**84**

11.14; O, 4.24.

(d, *J* = 8 Hz, 1H), 6.45 (s, 1H), 2.47 (s, 2H), 2.29–2.20 (m, 2H), 1.07 (s, 3H), 0.91 (s, 3H), Anal. Calcd for C22H19BrN2OS: C, 60.14; H, 4.36; Br, 18.19; N, 6.38; O, 3.64; S, 7.30. Found: C, 60.35; H, 4.49; Br, 18.37; N, 6.50; O, 3.80; S, 7.45.

**3,3–Dimethyl–12–(4-methoxyphenyl)–2,3,4,12–tetrahydro–1H–benzo[4,5] thiazolo[2,3–b]quinazolin–1–one (4o**): M.p. 87–88°C. 1 H NMR (500 MHz, DMSO–*d6*): *δ* = 7.49–7.46 (m, 2H), 7.38 (d, *J* = 8 Hz, 2H), 7.23–7.07 (m, 2H), 6.74 (d, *J* = 8 Hz, 2H), 6.44 (s, 1H), 3.62 (s, 3H), 2.48 (s, 2H), 2.31–2.17 (m, 2H), 1.06 (s, 3H), 0.93 (s, 3H). Anal. Calcd for C23H22N2O2S: C, 70.74; H, 5.68; N, 7.17; O, 8.19; S, 8.21. Found: C, 70.89; H, 5.80; N, 7.35; O, 8.39; S, 8.40.

#### **3. Conclusion**

In conclusion, the reaction of *in situ* generated O2 •− with imidazoles is able to mimic the *in vivo* biochemical reactions involved and corroborate the role of O2 •− in living cells. Since the investigation has been performed at an ambient temperature in the presence of *in situ* generated O2 •−, the results may be easily correlated with those occurring at physiological temperatures in more complex biological counterparts.

A novel synthetic route has been developed for the synthesis of tetraheterocyclic benzimidazolo/benzothiazolo quinazolin-1-one ring systems using tetraethylammonium superoxide under non aqueous condition at room temperature (mild reaction condition) within 6 h. The yield of the products was obtained up to 88% without using any tedious purification process. The applicability of tetraethylammonium bromide as an inexpensive alternative to 18-crown-6 for superoxide ion generation has been extended in present report.

#### **Acknowledgements**

The authors are thankful to IIT(BHU),Varanasi for financial support.

#### **Conflict of interest**

No conflict of interest.

#### **Author details**

Sundaram Singh\* and Savita Kumari Indian Institute of Technology (BHU), Varanasi, UP, India

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 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.

**87**

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using…*

disease. Critical Reviews in Food Science and Nutrition. 2004;**44**:275-295

[11] Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiological

Reviews. 2007;**87**:315-424

2007;**19**:1807-1819

2003;**7**:659-677

[12] Genestra M. Oxyl radicals, redox-sensitive signalling cascades and antioxidants. Cellular Signalling.

[13] Halliwell B. Biochemistry of oxidative stress. Biochemical Society Transactions. 2007;**35**:1147-1150

[14] Witt A, Bergman J. Recent

[15] Connolly DJ, Cusack D, O'Sullivan TP, Guiry PJ. Synthesis of quinazolinones and quinazolines. Tetrahedron. 2005;**61**:10153-10202

[16] Grasso S, Micale N, Monforte A-M, Monforte P, Polimeni S, Zappala M. Synthesis and in vitro antitumour activity evaluation of 1-aryl-1H, 3H-thiazolo [4, 3-b] quinazolines. European Journal of Medicinal Chemistry. 2000;**35**:1115-1119

[17] Testard A, Picot L, Lozach O, Blairvacq M, Meijer L, Murillo L, et al. Synthesis and evaluation of the antiproliferative activity of novel thiazoloquinazolinone kinases inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry.

[18] Weber L. The application of multicomponent reactions in drug discovery.

[19] Hulme C, Gore V. Multi-component Reactions: Emerging Chemistry in

Current Medicinal Chemistry.

2005;**20**:557-568

2002;**9**:2085-2093

developments in the field of quinazoline chemistry. Current Organic Chemistry.

*DOI: http://dx.doi.org/10.5772/intechopen.81146*

[1] Capozzi G, Modena G. In: Patai S, editor. The Chemistry of Thiol Group: Part 2. New York: John Wiley & Sons,

[2] Reid EE. Organic Chemistry of Bivalent Sulfur. Vol. I. New York: Chemical Publishing Co. Inc.; 1958.

[3] Tarbell DS. In: Kharash N, editor. Organic Sulfur Compounds: Chapter 10. Vol. 1. New York: Pergamon Press; 1961.

[4] Wallace JG. Hydrogen Peroxide in Organic Chemistry, E. I. Wilmington, U.S.A: du Pont de Nemours and Co.;

[5] Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine. 4th ed. Oxford, UK: Clarendon Press; 2007

[6] Bahorun T, Soobrattee MA, Luximon-Ramma V, Aruoma OI. Free radicals and antioxidants in cardiovascular health and disease. Internet Journal of Medical Update.

[7] Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J. Role of oxygen radicals in DNA damage and cancer incidence. Molecular and Cellular Biochemistry. 2004;**266**:37-56

[8] Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry and Cell Biology.

[9] Droge W. Free radicals in the physiological control of cell function. Physiological Reviews. 2002;**82**:47-95

[10] Willcox JK, Ash SL, Catignani GL. Antioxidants and prevention of chronic

**References**

pp. 118-126

pp. 97-102

1960

2006;**1**:1-17

2007;**39**:44-84

Inc; 1874. pp. 78-839

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using… DOI: http://dx.doi.org/10.5772/intechopen.81146*

#### **References**

*Heterocycles - Synthesis and Biological Activities*

**3. Conclusion**

(d, *J* = 8 Hz, 1H), 6.45 (s, 1H), 2.47 (s, 2H), 2.29–2.20 (m, 2H), 1.07 (s, 3H), 0.91 (s, 3H), Anal. Calcd for C22H19BrN2OS: C, 60.14; H, 4.36; Br, 18.19; N, 6.38; O, 3.64;

DMSO–*d6*): *δ* = 7.49–7.46 (m, 2H), 7.38 (d, *J* = 8 Hz, 2H), 7.23–7.07 (m, 2H), 6.74 (d, *J* = 8 Hz, 2H), 6.44 (s, 1H), 3.62 (s, 3H), 2.48 (s, 2H), 2.31–2.17 (m, 2H), 1.06 (s, 3H), 0.93 (s, 3H). Anal. Calcd for C23H22N2O2S: C, 70.74; H, 5.68; N, 7.17; O, 8.19;

mimic the *in vivo* biochemical reactions involved and corroborate the role of O2

living cells. Since the investigation has been performed at an ambient temperature in

occurring at physiological temperatures in more complex biological counterparts. A novel synthetic route has been developed for the synthesis of tetraheterocyclic benzimidazolo/benzothiazolo quinazolin-1-one ring systems using tetraethylammonium superoxide under non aqueous condition at room temperature (mild reaction condition) within 6 h. The yield of the products was obtained up to 88% without using any tedious purification process. The applicability of tetraethylammonium bromide as an inexpensive alternative to 18-crown-6 for superoxide ion

The authors are thankful to IIT(BHU),Varanasi for financial support.

**3,3–Dimethyl–12–(4-methoxyphenyl)–2,3,4,12–tetrahydro–1H–benzo[4,5]**

H NMR (500 MHz,

•− with imidazoles is able to

•−, the results may be easily correlated with those

•− in

S, 7.30. Found: C, 60.35; H, 4.49; Br, 18.37; N, 6.50; O, 3.80; S, 7.45.

**thiazolo[2,3–b]quinazolin–1–one (4o**): M.p. 87–88°C. 1

S, 8.21. Found: C, 70.89; H, 5.80; N, 7.35; O, 8.39; S, 8.40.

In conclusion, the reaction of *in situ* generated O2

generation has been extended in present report.

the presence of *in situ* generated O2

**Acknowledgements**

**Conflict of interest**

**Author details**

No conflict of interest.

Sundaram Singh\* and Savita Kumari

provided the original work is properly cited.

Indian Institute of Technology (BHU), Varanasi, UP, India

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 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,

**86**

[1] Capozzi G, Modena G. In: Patai S, editor. The Chemistry of Thiol Group: Part 2. New York: John Wiley & Sons, Inc; 1874. pp. 78-839

[2] Reid EE. Organic Chemistry of Bivalent Sulfur. Vol. I. New York: Chemical Publishing Co. Inc.; 1958. pp. 118-126

[3] Tarbell DS. In: Kharash N, editor. Organic Sulfur Compounds: Chapter 10. Vol. 1. New York: Pergamon Press; 1961. pp. 97-102

[4] Wallace JG. Hydrogen Peroxide in Organic Chemistry, E. I. Wilmington, U.S.A: du Pont de Nemours and Co.; 1960

[5] Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine. 4th ed. Oxford, UK: Clarendon Press; 2007

[6] Bahorun T, Soobrattee MA, Luximon-Ramma V, Aruoma OI. Free radicals and antioxidants in cardiovascular health and disease. Internet Journal of Medical Update. 2006;**1**:1-17

[7] Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J. Role of oxygen radicals in DNA damage and cancer incidence. Molecular and Cellular Biochemistry. 2004;**266**:37-56

[8] Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry and Cell Biology. 2007;**39**:44-84

[9] Droge W. Free radicals in the physiological control of cell function. Physiological Reviews. 2002;**82**:47-95

[10] Willcox JK, Ash SL, Catignani GL. Antioxidants and prevention of chronic disease. Critical Reviews in Food Science and Nutrition. 2004;**44**:275-295

[11] Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiological Reviews. 2007;**87**:315-424

[12] Genestra M. Oxyl radicals, redox-sensitive signalling cascades and antioxidants. Cellular Signalling. 2007;**19**:1807-1819

[13] Halliwell B. Biochemistry of oxidative stress. Biochemical Society Transactions. 2007;**35**:1147-1150

[14] Witt A, Bergman J. Recent developments in the field of quinazoline chemistry. Current Organic Chemistry. 2003;**7**:659-677

[15] Connolly DJ, Cusack D, O'Sullivan TP, Guiry PJ. Synthesis of quinazolinones and quinazolines. Tetrahedron. 2005;**61**:10153-10202

[16] Grasso S, Micale N, Monforte A-M, Monforte P, Polimeni S, Zappala M. Synthesis and in vitro antitumour activity evaluation of 1-aryl-1H, 3H-thiazolo [4, 3-b] quinazolines. European Journal of Medicinal Chemistry. 2000;**35**:1115-1119

[17] Testard A, Picot L, Lozach O, Blairvacq M, Meijer L, Murillo L, et al. Synthesis and evaluation of the antiproliferative activity of novel thiazoloquinazolinone kinases inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry. 2005;**20**:557-568

[18] Weber L. The application of multicomponent reactions in drug discovery. Current Medicinal Chemistry. 2002;**9**:2085-2093

[19] Hulme C, Gore V. Multi-component Reactions: Emerging Chemistry in

Drug Discovery From Xylocain to Crixivan. Current Medicinal Chemistry. 2003;**10**:51-80

[20] Dömling A, Ugi I. Multicomponent reactions with isocyanides. Angewandte Chemie, International Edition. 2000;**39**:3168-3210

[21] Shaabani A, Rahmati A, Naderi S. A novel one-pot three-component reaction: Synthesis of triheterocyclic 4H-pyrimido [2, 1-b] benzazoles ring systems. Bioorganic & Medicinal Chemistry Letters. 2005;**15**:5553-5557

[22] Johne S, Herz W, Grisebach H, Kirby GW, Tamm Ch. The quinazoline alkaloids. InFortschritte der Chemie organischer Naturstoffe/Progress in the Chemistry of Organic Natural Products. Vol. 46. Wien: Springer; 1984. pp. 159-229

[23] Johne S. In: Brossi A, editor. The Alkaloids, Chemistry and Pharmacology. Vol. 29. New York: Academic; 1986. pp. 99-140

[24] Liu JF, Kaselj M, Isome Y, Ye P, Sargent K, Sprague K, et al. Design and synthesis of a quinazolinone natural product-templated library with cytotoxic activity. Journal of Combinatorial Chemistry. 2006;**8**:7-10

[25] Hattori K, Kido Y, Yamamoto H, Ishida J, Kamijo K, Murano K, et al. Rational approaches to discovery of orally active and brainpenetrable quinazolinone inhibitors of poly (ADP-ribose) polymerase. Journal of Medicinal Chemistry. 2004;**47**:4151-4154

[26] Young I, Woodside J. Antioxidants in health and disease. Journal of Clinical Pathology. 2001;**54**:176-186

[27] Chai D, Fitch DM. WO Patent 09039322 A1. March, 2009

[28] Kato F, Kimura H, Omatsu M, Yamamoto K, Miyamoto R. WO Patent 02040485. May 23, 2002

[29] McMaster B. WO Patent 03105857. December 24, 2003

[30] Shigeta S, Mori S, Baba M, Hosoya M, Mochizuki N, Chiba T, et al. Inhibitory effect of pyridobenzoazoles on orthomyxo-and paramyxovirus replication in vitro. Antiviral Chemistry and Chemotherapy. 1992;**3**:171-177

[31] Nofal ZM, Fahmy HH, Mohamed HS. Synthesis, antimicrobial and molluscicidal activities of new benzimidazole derivatives. Archives of Pharmacal Research. 2002;**25**:28-38

[32] Abdel-hafez AA. Benzimidazole condensed ring systems: New synthesis and antineoplastic activity of substituted 3, 4-dihydro-and 1, 2, 3, 4-tetrahydro-benzo [4, 5] imidazo [1, 2-a] pyrinnidine derivatives. Archives of Pharmacal Research. 2007;**30**:678-684

[33] Lunn W, Harper R, Stone R. Benzimidazo [2, 1-b] quinazolin-12-ones. New class of potent immunosuppressive compounds. Journal of Medicinal Chemistry. 1971;**14**:1069-1071

[34] Lipson VV, Desenko SM, Shirobokova MG, Borodina VV. Synthesis of 9-Aryl-6, 6-dimethyl-5, 6, 7, 9-tetrahydro-1, 2, 4-triazolo [5, 1-b] quinazolin-8 (4H) ones. Chemistry of Heterocyclic Compounds. 2003;**39**:1213-1217

[35] Lipson VV, Desenko SM, Shishkina SV, Shirobokova MG, Shishkin OV, Orlov VD. Cyclocondensation of 2-aminobenzimidazole with dimedone and its arylidene derivatives. Chemistry of Heterocyclic Compounds. 2003;**39**:1041-1047

[36] Shaabani A, Farhangi E, Rahmati A. A Rapid Combinatorial

**89**

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using…*

*DOI: http://dx.doi.org/10.5772/intechopen.81146*

Library Synthesis of Benzazolo [2, 1-b] quinazolinones and Triazolo [2, 1-b] quinazolinones. Iranian Journal of Chemistry and Chemical Engineering

(IJCCE). 2013;**32**:3-10

17; 2013. pp. 1-9

[37] Ali M, Nakisa G. A three-

component onepot procedure for the synthesis benzimidazoloquinazolinone derivatives in the presence of chitosansupported metal nanocomposite as a green and reusable catalyst. In: ECSOC-

[38] Ahmad S, Elham F, Abbas R. Synthesis of tetrahydrobenzimidazo [1, 2-b] quinazolin-1 (2H)-one and tetrahydro-1, 2, 4-triazolo [5, 1-b] quinazolin-8 (4H)-one ring systems under solvent-free conditions. Combinatorial Chemistry & High Throughput Screening. 2006;**9**:771-776

[39] Atar AB, Jeong YS, Jeong YT. Iron fluoride: The most efficient catalyst for one-pot synthesis of 4H-pyrimido

solvent-free conditions. Tetrahedron.

[2, 1-b] benzothiazoles under

[40] Heravi MM, Derikvand F, Ranjbar L. Sulfamic acid–catalyzed, three-component, one-pot synthesis of [1, 2, 4] triazolo/benzimidazolo quinazolinone derivatives. Synthetic Communications®. 2010;**40**:677-685

2014;**70**:5207-5213

*One-Pot-Condensation Reaction of Heterocyclic Amine, 1,3-Diketone and Aldehydes Using… DOI: http://dx.doi.org/10.5772/intechopen.81146*

Library Synthesis of Benzazolo [2, 1-b] quinazolinones and Triazolo [2, 1-b] quinazolinones. Iranian Journal of Chemistry and Chemical Engineering (IJCCE). 2013;**32**:3-10

*Heterocycles - Synthesis and Biological Activities*

[28] Kato F, Kimura H, Omatsu M, Yamamoto K, Miyamoto R. WO Patent

[29] McMaster B. WO Patent 03105857.

Hosoya M, Mochizuki N, Chiba T, et al. Inhibitory effect of pyridobenzoazoles on orthomyxo-and paramyxovirus replication in vitro. Antiviral Chemistry and Chemotherapy. 1992;**3**:171-177

[31] Nofal ZM, Fahmy HH, Mohamed HS. Synthesis, antimicrobial and molluscicidal activities of new

benzimidazole derivatives. Archives of Pharmacal Research. 2002;**25**:28-38

[32] Abdel-hafez AA. Benzimidazole condensed ring systems: New synthesis and antineoplastic activity of substituted 3, 4-dihydro-and 1, 2, 3, 4-tetrahydro-benzo [4, 5] imidazo [1, 2-a] pyrinnidine derivatives. Archives of Pharmacal Research. 2007;**30**:678-684

[33] Lunn W, Harper R, Stone R. Benzimidazo [2, 1-b] quinazolin-12-ones. New class of potent immunosuppressive compounds. Journal of Medicinal Chemistry.

[34] Lipson VV, Desenko SM, Shirobokova MG, Borodina VV. Synthesis of 9-Aryl-6, 6-dimethyl-5, 6, 7, 9-tetrahydro-1, 2, 4-triazolo [5, 1-b] quinazolin-8 (4H) ones.

Chemistry of Heterocyclic Compounds.

[35] Lipson VV, Desenko SM, Shishkina

dimedone and its arylidene derivatives. Chemistry of Heterocyclic Compounds.

SV, Shirobokova MG, Shishkin OV, Orlov VD. Cyclocondensation of 2-aminobenzimidazole with

[36] Shaabani A, Farhangi E, Rahmati A. A Rapid Combinatorial

1971;**14**:1069-1071

2003;**39**:1213-1217

2003;**39**:1041-1047

[30] Shigeta S, Mori S, Baba M,

02040485. May 23, 2002

December 24, 2003

[20] Dömling A, Ugi I. Multicomponent reactions with isocyanides. Angewandte

Drug Discovery From Xylocain to Crixivan. Current Medicinal Chemistry.

Chemie, International Edition.

[21] Shaabani A, Rahmati A, Naderi S. A novel one-pot three-component reaction: Synthesis of triheterocyclic 4H-pyrimido [2, 1-b] benzazoles ring systems. Bioorganic & Medicinal Chemistry Letters. 2005;**15**:5553-5557

[22] Johne S, Herz W, Grisebach H, Kirby GW, Tamm Ch. The quinazoline alkaloids. InFortschritte der Chemie organischer Naturstoffe/Progress in the Chemistry of Organic Natural Products. Vol. 46. Wien: Springer; 1984.

[23] Johne S. In: Brossi A, editor. The Alkaloids, Chemistry and Pharmacology. Vol. 29. New York: Academic; 1986. pp. 99-140

[24] Liu JF, Kaselj M, Isome Y, Ye P, Sargent K, Sprague K, et al. Design and synthesis of a quinazolinone natural product-templated library with cytotoxic activity. Journal of Combinatorial Chemistry. 2006;**8**:7-10

[25] Hattori K, Kido Y, Yamamoto H, Ishida J, Kamijo K, Murano K, et al. Rational approaches to discovery of orally active and brainpenetrable quinazolinone inhibitors of poly (ADP-ribose) polymerase. Journal of Medicinal Chemistry.

[26] Young I, Woodside J. Antioxidants in health and disease. Journal of Clinical

[27] Chai D, Fitch DM. WO Patent

2004;**47**:4151-4154

Pathology. 2001;**54**:176-186

09039322 A1. March, 2009

2003;**10**:51-80

2000;**39**:3168-3210

pp. 159-229

**88**

[37] Ali M, Nakisa G. A threecomponent onepot procedure for the synthesis benzimidazoloquinazolinone derivatives in the presence of chitosansupported metal nanocomposite as a green and reusable catalyst. In: ECSOC-17; 2013. pp. 1-9

[38] Ahmad S, Elham F, Abbas R. Synthesis of tetrahydrobenzimidazo [1, 2-b] quinazolin-1 (2H)-one and tetrahydro-1, 2, 4-triazolo [5, 1-b] quinazolin-8 (4H)-one ring systems under solvent-free conditions. Combinatorial Chemistry & High Throughput Screening. 2006;**9**:771-776

[39] Atar AB, Jeong YS, Jeong YT. Iron fluoride: The most efficient catalyst for one-pot synthesis of 4H-pyrimido [2, 1-b] benzothiazoles under solvent-free conditions. Tetrahedron. 2014;**70**:5207-5213

[40] Heravi MM, Derikvand F, Ranjbar L. Sulfamic acid–catalyzed, three-component, one-pot synthesis of [1, 2, 4] triazolo/benzimidazolo quinazolinone derivatives. Synthetic Communications®. 2010;**40**:677-685

**91**

**Chapter 7**

**Abstract**

(benzoxazepines).

**1. Introduction**

are taken into consideration.

**2. Classification of oxygen heterocycles**

The Oxygen-Containing Fused

The oxygen-containing heterocycles are an important class of compounds in organic chemistry. These compounds are used as drugs (coumarin and oxazole), solvent (tetrahydrofuran), flavors, and fragrances (lactones). The fusion of aromatic ring to the oxygen-heterocycle will change the electron density; thereby, the physical/chemical/biological properties will alter. Also, the preparation of these fused molecules will require a different strategy/method/reaction condition. The topics covered in this chapter are the general synthetic methods and uses of fused heterocyclic compounds containing oxygen as a heteroatom. The derivatization of the primary scaffold is excluded from this chapter. Some of the fused compounds are coumarin (benzopyrans) and piclozotan

**Keywords:** heterocycles, oxygen heteroatom, fused molecules, coumarin, a flavonoid

The oxygen-containing heterocycles are an important class of compounds in organic chemistry mainly because of their natural abundance and diverse biological functions. Natural and semi-synthetic oxygen heterocyclic compounds such as Taxol [1] (anticancer), Digoxin (CHF treatment), Cyclosporine-A (immunosuppressant) and Lovastatin (hypolipidemic) are well known used as promising therapeutic compounds [2]. Kaur et al. reviewed the oxygen heterocycles wherein saturated and unsaturated compounds are considered. They discussed the classification and chemistry of each of those compounds [1]. Reports are available wherein the synthesis of natural products containing oxygen as heteroatom is reviewed by Cossy and Guérinot [2]. Also, Rowlands and Farley chaptered the book on the anion radicals from oxygen-containing heterocycles [3]. None of these reports target the oxygen-containing heterocyclic compounds where fused rings

The oxygen-containing heterocycles can be classified in several ways like the classification based on (a) the number of oxygen atoms, (b) saturation level, (c) aromaticity or (d) abundance. For the clarity of the concept, the classification

Heterocyclic Compounds

*and Nanjangud Venkatesh Anil Kumar*

*Hillemane Venkatachalam*

#### **Chapter 7**

## The Oxygen-Containing Fused Heterocyclic Compounds

*Hillemane Venkatachalam and Nanjangud Venkatesh Anil Kumar*

#### **Abstract**

The oxygen-containing heterocycles are an important class of compounds in organic chemistry. These compounds are used as drugs (coumarin and oxazole), solvent (tetrahydrofuran), flavors, and fragrances (lactones). The fusion of aromatic ring to the oxygen-heterocycle will change the electron density; thereby, the physical/chemical/biological properties will alter. Also, the preparation of these fused molecules will require a different strategy/method/reaction condition. The topics covered in this chapter are the general synthetic methods and uses of fused heterocyclic compounds containing oxygen as a heteroatom. The derivatization of the primary scaffold is excluded from this chapter. Some of the fused compounds are coumarin (benzopyrans) and piclozotan (benzoxazepines).

**Keywords:** heterocycles, oxygen heteroatom, fused molecules, coumarin, a flavonoid

#### **1. Introduction**

The oxygen-containing heterocycles are an important class of compounds in organic chemistry mainly because of their natural abundance and diverse biological functions. Natural and semi-synthetic oxygen heterocyclic compounds such as Taxol [1] (anticancer), Digoxin (CHF treatment), Cyclosporine-A (immunosuppressant) and Lovastatin (hypolipidemic) are well known used as promising therapeutic compounds [2]. Kaur et al. reviewed the oxygen heterocycles wherein saturated and unsaturated compounds are considered. They discussed the classification and chemistry of each of those compounds [1]. Reports are available wherein the synthesis of natural products containing oxygen as heteroatom is reviewed by Cossy and Guérinot [2]. Also, Rowlands and Farley chaptered the book on the anion radicals from oxygen-containing heterocycles [3]. None of these reports target the oxygen-containing heterocyclic compounds where fused rings are taken into consideration.

#### **2. Classification of oxygen heterocycles**

The oxygen-containing heterocycles can be classified in several ways like the classification based on (a) the number of oxygen atoms, (b) saturation level, (c) aromaticity or (d) abundance. For the clarity of the concept, the classification

**Figure 1.**

*Mono-oxygen containing fused heterocyclic compounds.*

**Figure 2.**

*Di-oxygen containing fused heterocyclic compounds.*

based on a number of oxygen atoms is used. The benzene fused furan and pyrans are listed in **Figure 1**, whereas **Figure 2** represents the compounds with two oxygen atoms in the ring system.

#### **3. Synthesis of benzofurans**

#### **3.1 Mono-substituted benzofurans**

#### *3.1.1 Substitution on furan ring*

The ortho-hydroxystilbenes are cyclized in 70–90% yield in a metal-free environment using hypervalent iodine and 1 eq. of (diacetoxyiodo) benzene to get 2-substituted benzofurans [4]. The acids are converted to 2,4,6- trichloro-1,3,5-triazine esters, which are subsequently added to toluene, 2-hydroxybenzyl triphenylphosphonium bromide (1 eq.), and NEt3 and irradiated at 110°C for two cycles of 30 min to get the 2-substituted benzofurans having a chiral stereocenter adjacent to the heterocycle in 60–80% yield [5]. Pd-catalyzed cyclisation of 2-chloroaryl alkynes using KOH at 100°C for 8 h resulted in the formation of benzofurans [6]. All three reactions are as shown in **Figure 3**.

#### *3.1.2 Substitution on the benzene ring*

Also, the substituted 1-allyl-2-allyloxybenzenes cyclizes to give substituted benzofurans by isomerization followed by ring-closure metathesis reaction using 5 mol.% catalyst [7]. The homologous members of benzofurans can be prepared by 0.1 eq. of Ru-catalyzed cycloisomerization of homo- and bis-homopropargylic alcohols in presence of pyridine at 90°C for 1–6 h [8] as shown in **Figure 4**.

**93**

**3.2 Di-substituted benzofurans**

*Benzene ring substituted benzofuran.*

*Preparation of mono-substituted benzofuran.*

**Figure 3.**

**Figure 4.**

*3.2.1 Substitution on furan and benzene ring of benzofuran*

These reaction schemes are as shown in **Figure 5**.

The reaction between 1 eq. of 2-(2-hydroxyphenyl)acetonitriles with 2 eq of aryl boronic acids along with Pd(OAc)2 (5 mol.%), bpy (10 mol.%), TFA (10 eq.), with TFA as solvent heated to 80°C for 36 h resulted in benzofuran derivatives with more than 80% yield [9]. Sonogashira cross-coupling reaction of halide with terminal alkynes followed by cyclization of the resulting 2-alkynylphenols in one-pot method results in benzofuran. The method employs the t-BuOH, PdCl2- (CH3CN)2 (2 mol.%), t-BuOLi (3.6 eq.) and 2-chlorophenol (1 eq.), alkyne

(1.5 eq.) were taken in a sealed tube and heated to 110°C for 22 h to get benzofuran [10]. Reaction of N-tosylhydrazones and terminal alkyne in a ligand free environment, using 10 mol.% of CuBr and 3 eq. of Cs2CO3 at 100°C for 4 h resulted in the formation of benzofurans with 38–91% yield [11]. Reductive cyclization of 1-(2-hydroxyphenyl)-propargyl alcohols in presence of Pd(OAc)2 (5 mol.%), t-BuNC (1.2 eq.), Cs2CO3 (1.2 eq.) and MeCN as solvent gives benzofurans [12].

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

**Figure 3.**

*Heterocycles - Synthesis and Biological Activities*

*Di-oxygen containing fused heterocyclic compounds.*

*Mono-oxygen containing fused heterocyclic compounds.*

atoms in the ring system.

**3. Synthesis of benzofurans**

*3.1.1 Substitution on furan ring*

**3.1 Mono-substituted benzofurans**

*3.1.2 Substitution on the benzene ring*

based on a number of oxygen atoms is used. The benzene fused furan and pyrans are listed in **Figure 1**, whereas **Figure 2** represents the compounds with two oxygen

The ortho-hydroxystilbenes are cyclized in 70–90% yield in a metal-free environment using hypervalent iodine and 1 eq. of (diacetoxyiodo) benzene to get 2-substituted benzofurans [4]. The acids are converted to 2,4,6- trichloro-1,3,5-triazine esters, which are subsequently added to toluene, 2-hydroxybenzyl triphenylphosphonium bromide (1 eq.), and NEt3 and irradiated at 110°C for two cycles of 30 min to get the 2-substituted benzofurans having a chiral stereocenter adjacent to the heterocycle in 60–80% yield [5]. Pd-catalyzed cyclisation of 2-chloroaryl alkynes using KOH at 100°C for 8 h resulted in

the formation of benzofurans [6]. All three reactions are as shown in **Figure 3**.

Also, the substituted 1-allyl-2-allyloxybenzenes cyclizes to give substituted benzofurans by isomerization followed by ring-closure metathesis reaction using 5 mol.% catalyst [7]. The homologous members of benzofurans can be prepared by 0.1 eq. of Ru-catalyzed cycloisomerization of homo- and bis-homopropargylic alcohols in presence of pyridine at 90°C for 1–6 h [8] as shown in **Figure 4**.

**92**

**Figure 2.**

**Figure 1.**

*Preparation of mono-substituted benzofuran.*

**Figure 4.** *Benzene ring substituted benzofuran.*

#### **3.2 Di-substituted benzofurans**

#### *3.2.1 Substitution on furan and benzene ring of benzofuran*

The reaction between 1 eq. of 2-(2-hydroxyphenyl)acetonitriles with 2 eq of aryl boronic acids along with Pd(OAc)2 (5 mol.%), bpy (10 mol.%), TFA (10 eq.), with TFA as solvent heated to 80°C for 36 h resulted in benzofuran derivatives with more than 80% yield [9]. Sonogashira cross-coupling reaction of halide with terminal alkynes followed by cyclization of the resulting 2-alkynylphenols in one-pot method results in benzofuran. The method employs the t-BuOH, PdCl2- (CH3CN)2 (2 mol.%), t-BuOLi (3.6 eq.) and 2-chlorophenol (1 eq.), alkyne (1.5 eq.) were taken in a sealed tube and heated to 110°C for 22 h to get benzofuran [10]. Reaction of N-tosylhydrazones and terminal alkyne in a ligand free environment, using 10 mol.% of CuBr and 3 eq. of Cs2CO3 at 100°C for 4 h resulted in the formation of benzofurans with 38–91% yield [11]. Reductive cyclization of 1-(2-hydroxyphenyl)-propargyl alcohols in presence of Pd(OAc)2 (5 mol.%), t-BuNC (1.2 eq.), Cs2CO3 (1.2 eq.) and MeCN as solvent gives benzofurans [12]. These reaction schemes are as shown in **Figure 5**.

**Figure 6.** *Preparation of di-substituted benzofuran.*

#### *3.2.2 2,3-Substituted benzofuran*

Ring closure of 2-haloaromatic ketones (1 eq.) in presence of K3PO4 (1.5 eq.), CuI (10 mol.%) and DMF at 105°C for 12–16 h results in di-substituted benzofurans [13]. The good yield coupled with atom economy was achieved, when o-alkynyl

**95**

**Figure 8.**

*Substituted benzofuran carbaldehydes.*

**Figure 7.**

*Substituted benzofurans.*

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

schemes are as shown in **Figure 6**.

phenyl acetals are cyclized using PtCl2 (2 mol.%), olefin (8 mol.%) in tolene at 30°C [14]. Cyclization of o-iodoanisoles and terminal alkynes under mild conditions using an electrophile (EX like PhSeCl or p-O2NC6H4SCl) (1.5 eq.), DCM at room temperature for 2–6 h yields 2,3-disubstituted benzofurans [15]. These reaction

Selective dehydrative C—H alkylation reaction of alkenes with alcohols using [(C6H6)(PCy3)(CO)RuH]BF4, cyclopentene, toluene at 100°C for 6–12 h results in 2,3-substituted benzofurans [16]. O-Arylhydroxylamine hydrochloride (1 eq.) with cyclic or acyclic ketones (1 eq.) in the presence of methanesulfonic acid (2 eq.), THF at 60°C for 2–24 h yields benzofurans in 40–90% yield [17]. Ketones (1 eq.) on treatment with Grignard reagents (3 eq.), benzofurans are formed, in a regioselective manner via [1,2]-aryl migration [18]. These reactions are depicted in **Figure 7**.

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

*Heterocycles - Synthesis and Biological Activities*

**94**

**Figure 6.**

**Figure 5.**

*Di-substituted benzofurans.*

*3.2.2 2,3-Substituted benzofuran*

*Preparation of di-substituted benzofuran.*

Ring closure of 2-haloaromatic ketones (1 eq.) in presence of K3PO4 (1.5 eq.), CuI (10 mol.%) and DMF at 105°C for 12–16 h results in di-substituted benzofurans [13]. The good yield coupled with atom economy was achieved, when o-alkynyl

phenyl acetals are cyclized using PtCl2 (2 mol.%), olefin (8 mol.%) in tolene at 30°C [14]. Cyclization of o-iodoanisoles and terminal alkynes under mild conditions using an electrophile (EX like PhSeCl or p-O2NC6H4SCl) (1.5 eq.), DCM at room temperature for 2–6 h yields 2,3-disubstituted benzofurans [15]. These reaction schemes are as shown in **Figure 6**.

Selective dehydrative C—H alkylation reaction of alkenes with alcohols using [(C6H6)(PCy3)(CO)RuH]BF4, cyclopentene, toluene at 100°C for 6–12 h results in 2,3-substituted benzofurans [16]. O-Arylhydroxylamine hydrochloride (1 eq.) with cyclic or acyclic ketones (1 eq.) in the presence of methanesulfonic acid (2 eq.), THF at 60°C for 2–24 h yields benzofurans in 40–90% yield [17]. Ketones (1 eq.) on treatment with Grignard reagents (3 eq.), benzofurans are formed, in a regioselective manner via [1,2]-aryl migration [18]. These reactions are depicted in **Figure 7**.

**Figure 7.** *Substituted benzofurans.*

**Figure 8.** *Substituted benzofuran carbaldehydes.*

Base-catalyzed, the condensation of o-hydroxyphenones with 1,1-dichloroethylene, gives substituted benzofuran carbaldehydes [19].

Similarly, o-cinnamyl phenols, on oxidative cyclisation, results in 2-benzyl benzofurans [20], while o-alkylphenols, on annulative reaction, gives 3-aminobenzofurans [21] (**Figure 8**).

#### **4. Synthesis of benzofuranones**

Alkenylphenols and phenyl formate reacts to give benzofuranones [22], while phenylacetic acids undergo cyclisation to give benzofuranones [23] (**Figure 9**).

**Figure 9.** *Synthesis of benzofuranones.*

#### **5. Synthesis of dibenzofurans**

Iododiaryl ether cyclizes under mild conditions to yield dibenzofurans [24]. Ortho-diazonium slats of diaryl ethers undergo intramolecular cyclisation,

**97**

**Figure 12.**

**Figure 11.**

*Coumarin synthesis using phenol derivatives.*

*Coumarin synthesis using benzaldehyde derivatives.*

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

3-aryl-4-methyl-coumarins) [32] (**Figure 12**).

**6. Synthesis of coumarins**

resulting in dibenzofurans [25]. Cross-coupling of 6-diazo-2-cyclohexenones and

Phenols react with beta-keto esters to give coumarins [27]. If phenolic acetates are used, then, acrylates are used [28]. Aromatic alkynoate undergoes cyclisation

Substituted 2-hydroxybenzaldehydes react with phenylacetic acids resulting in substituted 3-aryl coumarins [30]. With dialkyl acetylenedicarboxylate, 2-hydroxybenzaldehydes gives 4-carboxyalkyl-8-formyl coumarins [31]. 2-Hydroxybenzaldehydes (or 2-hydroxybenzaldehydes) cyclizes with aryl acetic acids to give 3-aryl coumarins (or

ortho-haloiodobenzenes gives substituted dibenzofuran [26] (**Figure 10**).

with aldehydes to form 3-acyl-4-arylcoumarins [29] (**Figure 11**).

**Figure 10.** *Mono substituted dibenzofurans.*

resulting in dibenzofurans [25]. Cross-coupling of 6-diazo-2-cyclohexenones and ortho-haloiodobenzenes gives substituted dibenzofuran [26] (**Figure 10**).

### **6. Synthesis of coumarins**

*Heterocycles - Synthesis and Biological Activities*

**4. Synthesis of benzofuranones**

**5. Synthesis of dibenzofurans**

[21] (**Figure 8**).

gives substituted benzofuran carbaldehydes [19].

Base-catalyzed, the condensation of o-hydroxyphenones with 1,1-dichloroethylene,

Similarly, o-cinnamyl phenols, on oxidative cyclisation, results in 2-benzyl benzofurans [20], while o-alkylphenols, on annulative reaction, gives 3-aminobenzofurans

Alkenylphenols and phenyl formate reacts to give benzofuranones [22], while phenylacetic acids undergo cyclisation to give benzofuranones [23] (**Figure 9**).

Iododiaryl ether cyclizes under mild conditions to yield dibenzofurans [24].

Ortho-diazonium slats of diaryl ethers undergo intramolecular cyclisation,

**96**

**Figure 10.**

**Figure 9.**

*Synthesis of benzofuranones.*

*Mono substituted dibenzofurans.*

Phenols react with beta-keto esters to give coumarins [27]. If phenolic acetates are used, then, acrylates are used [28]. Aromatic alkynoate undergoes cyclisation with aldehydes to form 3-acyl-4-arylcoumarins [29] (**Figure 11**).

Substituted 2-hydroxybenzaldehydes react with phenylacetic acids resulting in substituted 3-aryl coumarins [30]. With dialkyl acetylenedicarboxylate, 2-hydroxybenzaldehydes gives 4-carboxyalkyl-8-formyl coumarins [31]. 2-Hydroxybenzaldehydes (or 2-hydroxybenzaldehydes) cyclizes with aryl acetic acids to give 3-aryl coumarins (or 3-aryl-4-methyl-coumarins) [32] (**Figure 12**).

**Figure 11.** *Coumarin synthesis using phenol derivatives.*

**Figure 12.** *Coumarin synthesis using benzaldehyde derivatives.*

#### **7. Synthesis of isocoumarins**

Bromoalkynes reacts with benzoic acid and produces 3-substituted isocoumarins [33]. o-Halobenzoic acids and 1,3-diketones reacts to give 3-substituted isocoumarins [34]. 2-Halobenzoates and ketones react to give the same product [35]. o-Halobenzoic acids add to alkynes resulting in isocoumarin derivatives [36] (**Figure 13**).

**Figure 13.** *Synthesis of isocoumarins.*

#### **8. Synthesis of flavones and flavonols**

#### **8.1 Baker-Venkataraman rearrangement**

The chemical reaction between 2-hydroxyacetophenone and acid chloride in the presence of base yields 1,3-diketone which undergo rearrangement and

**99**

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

concomitant cyclisation to produce flavone [37]. This reaction is often used to

In this method, chalcone (1,3-diaryl-2-propen-1-one) is produced by condensing 2-hydroxyacetophenone with an aryl aldehyde in alkaline medium (Claisen-Schmidt condensation) followed by oxidative cyclisation of chalcone to get

A mixture of acetophenone and aromatic aldehyde when exposed to Microwave irradiation, 2-phenyl γ-benzopyrones are obtained [39]. The same compound can

In this chapter, the synthesis of fused heterocyclic compounds having oxygen as heteroatom is considered. The care is taken not to consider the reactions, where the reactions of the compounds leading to derivatizations are not included.

synthesize chromones and flavones (**Figure 14**).

be prepared by cyclizing 1,3-diaryl propanediones (**Figure 16**).

**8.2 Algar-Flynn-Oyamada synthesis**

*Preparation of 2-phenyl γ-benzopyrones.*

flavone [38] (**Figure 15**).

**9. Conclusions**

**Figure 15.**

**Figure 16.**

*Synthesis of flavone (from chalcone).*

**Figure 14.** *Synthesis of flavone (from 1,3-diketone).*

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

**Figure 15.** *Synthesis of flavone (from chalcone).*

*Heterocycles - Synthesis and Biological Activities*

**8. Synthesis of flavones and flavonols**

**8.1 Baker-Venkataraman rearrangement**

Bromoalkynes reacts with benzoic acid and produces 3-substituted isocoumarins [33]. o-Halobenzoic acids and 1,3-diketones reacts to give 3-substituted isocoumarins [34]. 2-Halobenzoates and ketones react to give the same product [35]. o-Halobenzoic

The chemical reaction between 2-hydroxyacetophenone and acid chloride in the presence of base yields 1,3-diketone which undergo rearrangement and

acids add to alkynes resulting in isocoumarin derivatives [36] (**Figure 13**).

**7. Synthesis of isocoumarins**

**98**

**Figure 14.**

*Synthesis of flavone (from 1,3-diketone).*

**Figure 13.**

*Synthesis of isocoumarins.*

**Figure 16.** *Preparation of 2-phenyl γ-benzopyrones.*

concomitant cyclisation to produce flavone [37]. This reaction is often used to synthesize chromones and flavones (**Figure 14**).

#### **8.2 Algar-Flynn-Oyamada synthesis**

In this method, chalcone (1,3-diaryl-2-propen-1-one) is produced by condensing 2-hydroxyacetophenone with an aryl aldehyde in alkaline medium (Claisen-Schmidt condensation) followed by oxidative cyclisation of chalcone to get flavone [38] (**Figure 15**).

A mixture of acetophenone and aromatic aldehyde when exposed to Microwave irradiation, 2-phenyl γ-benzopyrones are obtained [39]. The same compound can be prepared by cyclizing 1,3-diaryl propanediones (**Figure 16**).

#### **9. Conclusions**

In this chapter, the synthesis of fused heterocyclic compounds having oxygen as heteroatom is considered. The care is taken not to consider the reactions, where the reactions of the compounds leading to derivatizations are not included. Benzofurans, benzofuranones, dibenzofurans, coumarins, isocoumarins, chromones, and flavones are the fused heterocyclic compounds considered in this chapter. Also, the reactions are indicative and not the detailed reaction conditions, and appropriate reagents are not included in this chapter.

### **Conflict of interest**

No conflict of interest from both the authors.

### **Author details**

Hillemane Venkatachalam and Nanjangud Venkatesh Anil Kumar\* Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, India

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 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.

**101**

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

> aryl ketones and 2-arylbenzofurans. Synthesis. 2013;**45**(16):2241-2244

Hydroxyterphenylphoshine−palladium catalyst for benzo[b]furan synthesis from 2-chlorophenols. Bifunctional ligand strategy for cross-coupling of chloroarenes. The Journal of Organic Chemistry. 2010;**75**(15):5340-5342

[11] Zhou L et al. CuBr-catalyzed coupling of N-tosylhydrazones and terminal alkynes: Synthesis of benzofurans and indoles. Organic Letters. 2011;**13**(5):968-971

[12] Rajesh M et al. Pd-catalyzed isocyanide assisted reductive cyclization of 1-(2-hydroxyphenyl) propargyl alcohols for 2-alkyl/benzyl benzofurans and their useful oxidative derivatization. The Journal of Organic Chemistry. 2015;**80**(24):12311-12320

[13] Chen C-Y, Dormer PG. Synthesis of benzo[b]furans via CuI-catalyzed ring closure. The Journal of Organic Chemistry. 2005;**70**(17):6964-6967

[14] Nakamura I, Mizushima Y, Yamamoto Y. Synthesis of 2,3-disubstituted benzofurans by platinum−olefin-catalyzed

o-alkynylphenyl acetals. Journal of the American Chemical Society.

[15] Yue D, Yao T, Larock RC. Synthesis of 2,3-disubstituted benzo[b]furans by the palladium-catalyzed coupling of o-iodoanisoles and terminal alkynes, followed by electrophilic cyclization. The Journal of Organic Chemistry.

carboalkoxylation of

2005;**127**(43):15022-15023

2005;**70**(25):10292-10296

[16] Lee D-H, Kwon K-H, Yi CS. Dehydrative C–H alkylation and alkenylation of phenols with alcohols: Expedient synthesis for substituted

[10] Wang J-R, Manabe K.

[1] Kaur P, Arora R, Gill NS. Review on oxygen heterocycles. Indo American Journal of Pharmaceutical Research.

[2] Cossy J, Guérinot A. Natural products containing oxygen heterocycles—Synthetic advances between 1990 and 2015. Advances

[3] Rowlands CC, Farley RD. 15.3.1 Oxygen Containing Heterocycles, vol.

[4] Singh FV, Wirth T. Hypervalent iodine mediated oxidative cyclization of o-hydroxystilbenes into benzoand naphthofurans. Synthesis.

[5] De Luca L, Giacomelli G, Nieddu G. A facile approach to the synthesis of chiral 2-substituted benzofurans. The Journal of Organic Chemistry.

[6] Anderson KW et al. The selective reaction of aryl halides with KOH: Synthesis of phenols, aromatic ethers, and benzofurans. Journal of the American Chemical Society.

in Heterocyclic Chemistry.

26E1. 2008. pp. 308-315

2012;**44**(08):1171-1177

2007;**72**(10):3955-3957

2006;**128**(33):10694-10695

[7] van Otterlo WAL et al. An

strategy for the synthesis of

[8] Varela-Fernández A et al.

Letters. 2009;**11**(22):5350-5353

2005;**61**(32):7746-7755

isomerization-ring-closing metathesis

substituted benzofurans. Tetrahedron.

Cycloisomerization of aromatic homoand bis-homopropargylic alcohols via catalytic Ru vinylidenes: Formation of benzofurans and isochromenes. Organic

[9] Wang X et al. Palladium-catalyzed reaction of arylboronic acids with aliphatic nitriles: Synthesis of alkyl

2016;**119**:107-142

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*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

#### **References**

*Heterocycles - Synthesis and Biological Activities*

**Conflict of interest**

and appropriate reagents are not included in this chapter.

No conflict of interest from both the authors.

Hillemane Venkatachalam and Nanjangud Venkatesh Anil Kumar\*

\*Address all correspondence to<EMAIL_ADDRESS>
Department of Chemistry, Manipal Institute of Technology, Manipal Academy of

© 2019 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,

Benzofurans, benzofuranones, dibenzofurans, coumarins, isocoumarins, chromones, and flavones are the fused heterocyclic compounds considered in this chapter. Also, the reactions are indicative and not the detailed reaction conditions,

**100**

**Author details**

Higher Education, Manipal, India

provided the original work is properly cited.

[1] Kaur P, Arora R, Gill NS. Review on oxygen heterocycles. Indo American Journal of Pharmaceutical Research. 2013;**3**(11):18

[2] Cossy J, Guérinot A. Natural products containing oxygen heterocycles—Synthetic advances between 1990 and 2015. Advances in Heterocyclic Chemistry. 2016;**119**:107-142

[3] Rowlands CC, Farley RD. 15.3.1 Oxygen Containing Heterocycles, vol. 26E1. 2008. pp. 308-315

[4] Singh FV, Wirth T. Hypervalent iodine mediated oxidative cyclization of o-hydroxystilbenes into benzoand naphthofurans. Synthesis. 2012;**44**(08):1171-1177

[5] De Luca L, Giacomelli G, Nieddu G. A facile approach to the synthesis of chiral 2-substituted benzofurans. The Journal of Organic Chemistry. 2007;**72**(10):3955-3957

[6] Anderson KW et al. The selective reaction of aryl halides with KOH: Synthesis of phenols, aromatic ethers, and benzofurans. Journal of the American Chemical Society. 2006;**128**(33):10694-10695

[7] van Otterlo WAL et al. An isomerization-ring-closing metathesis strategy for the synthesis of substituted benzofurans. Tetrahedron. 2005;**61**(32):7746-7755

[8] Varela-Fernández A et al. Cycloisomerization of aromatic homoand bis-homopropargylic alcohols via catalytic Ru vinylidenes: Formation of benzofurans and isochromenes. Organic Letters. 2009;**11**(22):5350-5353

[9] Wang X et al. Palladium-catalyzed reaction of arylboronic acids with aliphatic nitriles: Synthesis of alkyl

aryl ketones and 2-arylbenzofurans. Synthesis. 2013;**45**(16):2241-2244

[10] Wang J-R, Manabe K. Hydroxyterphenylphoshine−palladium catalyst for benzo[b]furan synthesis from 2-chlorophenols. Bifunctional ligand strategy for cross-coupling of chloroarenes. The Journal of Organic Chemistry. 2010;**75**(15):5340-5342

[11] Zhou L et al. CuBr-catalyzed coupling of N-tosylhydrazones and terminal alkynes: Synthesis of benzofurans and indoles. Organic Letters. 2011;**13**(5):968-971

[12] Rajesh M et al. Pd-catalyzed isocyanide assisted reductive cyclization of 1-(2-hydroxyphenyl) propargyl alcohols for 2-alkyl/benzyl benzofurans and their useful oxidative derivatization. The Journal of Organic Chemistry. 2015;**80**(24):12311-12320

[13] Chen C-Y, Dormer PG. Synthesis of benzo[b]furans via CuI-catalyzed ring closure. The Journal of Organic Chemistry. 2005;**70**(17):6964-6967

[14] Nakamura I, Mizushima Y, Yamamoto Y. Synthesis of 2,3-disubstituted benzofurans by platinum−olefin-catalyzed carboalkoxylation of o-alkynylphenyl acetals. Journal of the American Chemical Society. 2005;**127**(43):15022-15023

[15] Yue D, Yao T, Larock RC. Synthesis of 2,3-disubstituted benzo[b]furans by the palladium-catalyzed coupling of o-iodoanisoles and terminal alkynes, followed by electrophilic cyclization. The Journal of Organic Chemistry. 2005;**70**(25):10292-10296

[16] Lee D-H, Kwon K-H, Yi CS. Dehydrative C–H alkylation and alkenylation of phenols with alcohols: Expedient synthesis for substituted

phenols and benzofurans. Journal of the American Chemical Society. 2012;**134**(17):7325-7328

[17] Contiero F et al. Direct preparation of benzofurans from O-arylhydroxylamines. Synlett. 2009;**2009**(18):3003-3006

[18] Pei T et al. Controlled synthesis of 2- and 3-substituted benzo[b]furans. Organic Letters. 2010;**12**(21):4972-4975

[19] Schevenels F, Markó IE. Efficient and connective assembly of highly functionalized benzofurans using o-hydroxyphenones and dichloroethylene. Organic Letters. 2012;**14**(5):1298-1301

[20] Rehan M et al. Synthesis of functionalized benzo[b]furans via oxidative cyclization of o-cinnamyl phenols. The Journal of Organic Chemistry. 2017;**82**(7):3411-3424

[21] Hirano K, Satoh T, Miura M. Copper-catalyzed annulative amination of ortho-alkynylphenols with hydroxylamines: Synthesis of 3-aminobenzofurans by umpolung amination strategy. Organic Letters. 2011;**13**(9):2395-2397

[22] Wang H et al. A palladiumcatalyzed regioselective hydroesterification of alkenylphenols to lactones with phenyl formate as CO source. Organic Letters. 2014;**16**(1):186-189

[23] Cheng X-F et al. Pd(II)-catalyzed enantioselective C—H activation/C—O bond formation: Synthesis of chiral benzofuranones. Journal of the American Chemical Society. 2013;**135**(4):1236-1239

[24] Panda N, Mattan I, Nayak DK. Synthesis of dibenzofurans via C—H activation of o-iodo diaryl ethers. The Journal of Organic Chemistry. 2015;**80**(13):6590-6597

[25] Du Z et al. Synthesis of dibenzofurans by palladium-catalysed tandem denitrification/C—H activation. Synlett. 2011;**2011**(20):3023-3025

[26] Zhao H et al. A one-pot synthesis of dibenzofurans from 6-diazo-2 cyclohexenones. Organic Letters. 2015;**17**(23):5744-5747

[27] Potdar MK, Mohile SS, Salunkhe MM. Coumarin syntheses via Pechmann condensation in Lewis acidic chloroaluminate ionic liquid. Tetrahedron Letters. 2001;**42**(52):9285-9287

[28] Gadakh SK, Dey S, Sudalai A. Rh-catalyzed synthesis of coumarin derivatives from phenolic acetates and acrylates via C—H bond activation. The Journal of Organic Chemistry. 2015;**80**(22):11544-11550

[29] Mi X et al. Preparation of 3-acyl-4-arylcoumarins via metal-free tandem oxidative acylation/cyclization between alkynoates with aldehydes. The Journal of Organic Chemistry. 2014;**80**(1):148-155

[30] Sashidhara K et al. Efficient and general synthesis of 3-aryl coumarins using cyanuric chloride. Synlett. 2012;**23**(04):611-621

[31] Majumdar K et al. Aromatic electrophilic substitution vs. intramolecular Wittig reaction: Vinyltriphenylphosphonium salt mediated synthesis of 4-carboxyalkyl-8-formyl coumarins. Synlett. 2011;**2011**(05):694-698

[32] Phakhodee W et al. Ph3P/I2 mediated synthesis of 3-aryl-substituted and 3,4-disubstituted coumarins. Synlett. 2017;**28**(07):825-830

[33] Jiang G et al. Palladium-catalyzed sequential nucleophilic addition/ oxidative annulation of bromoalkynes with benzoic acids to construct

**103**

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

functionalized isocoumarins. Organic Letters. 2017;**19**(17):4440-4443

[34] Cai S, Wang F, Xi C. Assembly of 3-substituted Isocoumarins via a CuI-catalyzed domino coupling/ addition/deacylation process. The Journal of Organic Chemistry.

[35] Casnati A et al. Pd-catalyzed/ iodide-promoted α-arylation of ketones for the regioselective synthesis of isocoumarins. The Journal of Organic Chemistry. 2017;**82**(15):8296-8303

[36] Guo X-X. Synthesis of isocoumarin derivatives by copper-catalyzed

addition of o-halobenzoic acids to active internal alkynes. The Journal of Organic Chemistry. 2013;**78**(4):1660-1664

[37] Baker W. 322. Molecular rearrangement of some

1933:1381-1389

Science. 1934;**42**:1-8

2009;**74**(7):2755-2759

o-acyloxyacetophenones and the mechanism of the production of 3-acylchromones. Journal of the Chemical Society (Resumed).

[38] Algar J, Flynn JP. A new method for the synthesis of flavonols. Proceedings of the Royal Irish Academy. Section B: Biological, Geological, and Chemical

[39] Fridén-Saxin M et al. Synthesis of 2-alkyl-substituted chromone

derivatives using microwave irradiation. The Journal of Organic Chemistry.

2012;**77**(5):2331-2336

*The Oxygen-Containing Fused Heterocyclic Compounds DOI: http://dx.doi.org/10.5772/intechopen.88026*

functionalized isocoumarins. Organic Letters. 2017;**19**(17):4440-4443

*Heterocycles - Synthesis and Biological Activities*

[25] Du Z et al. Synthesis of

2015;**17**(23):5744-5747

2001;**42**(52):9285-9287

2015;**80**(22):11544-11550

2014;**80**(1):148-155

2012;**23**(04):611-621

[27] Potdar MK, Mohile SS,

dibenzofurans by palladium-catalysed tandem denitrification/C—H activation. Synlett. 2011;**2011**(20):3023-3025

[26] Zhao H et al. A one-pot synthesis of dibenzofurans from 6-diazo-2 cyclohexenones. Organic Letters.

Salunkhe MM. Coumarin syntheses via Pechmann condensation in Lewis acidic chloroaluminate ionic liquid. Tetrahedron Letters.

[28] Gadakh SK, Dey S, Sudalai A. Rh-catalyzed synthesis of coumarin derivatives from phenolic acetates and acrylates via C—H bond activation. The Journal of Organic Chemistry.

[29] Mi X et al. Preparation of 3-acyl-4-arylcoumarins via metal-free

[30] Sashidhara K et al. Efficient and general synthesis of 3-aryl coumarins using cyanuric chloride. Synlett.

[31] Majumdar K et al. Aromatic electrophilic substitution vs. intramolecular Wittig reaction: Vinyltriphenylphosphonium salt mediated synthesis of 4-carboxyalkyl-

8-formyl coumarins. Synlett. 2011;**2011**(05):694-698

[32] Phakhodee W et al. Ph3P/I2-

mediated synthesis of 3-aryl-substituted and 3,4-disubstituted coumarins. Synlett. 2017;**28**(07):825-830

[33] Jiang G et al. Palladium-catalyzed sequential nucleophilic addition/ oxidative annulation of bromoalkynes with benzoic acids to construct

tandem oxidative acylation/cyclization between alkynoates with aldehydes. The Journal of Organic Chemistry.

phenols and benzofurans. Journal of the American Chemical Society.

[18] Pei T et al. Controlled synthesis of 2- and 3-substituted benzo[b]furans. Organic Letters. 2010;**12**(21):4972-4975

[19] Schevenels F, Markó IE. Efficient and connective assembly of highly functionalized benzofurans using o-hydroxyphenones and dichloroethylene. Organic Letters.

2012;**134**(17):7325-7328

2012;**14**(5):1298-1301

2011;**13**(9):2395-2397

2014;**16**(1):186-189

[20] Rehan M et al. Synthesis of functionalized benzo[b]furans via oxidative cyclization of o-cinnamyl phenols. The Journal of Organic Chemistry. 2017;**82**(7):3411-3424

[21] Hirano K, Satoh T, Miura M. Copper-catalyzed annulative amination of ortho-alkynylphenols with hydroxylamines: Synthesis of 3-aminobenzofurans by umpolung amination strategy. Organic Letters.

[22] Wang H et al. A palladiumcatalyzed regioselective

hydroesterification of alkenylphenols to lactones with phenyl formate as CO source. Organic Letters.

[23] Cheng X-F et al. Pd(II)-catalyzed enantioselective C—H activation/C—O

[24] Panda N, Mattan I, Nayak DK. Synthesis of dibenzofurans via C—H activation of o-iodo diaryl ethers. The Journal of Organic Chemistry.

bond formation: Synthesis of chiral benzofuranones. Journal of the American Chemical Society.

2013;**135**(4):1236-1239

2015;**80**(13):6590-6597

[17] Contiero F et al. Direct preparation of benzofurans from O-arylhydroxylamines. Synlett. 2009;**2009**(18):3003-3006

**102**

[34] Cai S, Wang F, Xi C. Assembly of 3-substituted Isocoumarins via a CuI-catalyzed domino coupling/ addition/deacylation process. The Journal of Organic Chemistry. 2012;**77**(5):2331-2336

[35] Casnati A et al. Pd-catalyzed/ iodide-promoted α-arylation of ketones for the regioselective synthesis of isocoumarins. The Journal of Organic Chemistry. 2017;**82**(15):8296-8303

[36] Guo X-X. Synthesis of isocoumarin derivatives by copper-catalyzed addition of o-halobenzoic acids to active internal alkynes. The Journal of Organic Chemistry. 2013;**78**(4):1660-1664

[37] Baker W. 322. Molecular rearrangement of some o-acyloxyacetophenones and the mechanism of the production of 3-acylchromones. Journal of the Chemical Society (Resumed). 1933:1381-1389

[38] Algar J, Flynn JP. A new method for the synthesis of flavonols. Proceedings of the Royal Irish Academy. Section B: Biological, Geological, and Chemical Science. 1934;**42**:1-8

[39] Fridén-Saxin M et al. Synthesis of 2-alkyl-substituted chromone derivatives using microwave irradiation. The Journal of Organic Chemistry. 2009;**74**(7):2755-2759

**105**

Section 2

Synthetic and Biological

Activity Section

### Section 2