Exploring New Methods Toward Synthesis of The Benzimidazolone Derivatives

4125 words (17 pages) Essay

8th Feb 2020 Chemistry Reference this

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Proposal – Final Draft

Abstract: Many chemists’ major goal is to try to synthesize new compounds that are potentially useful to fight various diseases. They also try to improve the already existed and proved methods of the synthesis of those molecules in order to make those methods more efficient. Benzimidazolone derivatives are one of those molecules which are target of our proposed project. We hope to synthesize various benzimidazolone derivatives at the end of this project. Moreover, we hope to stablish a new method/conditions for the intramolecular C-H amination which is compatible with the rules of green chemistry either by using a less dangerous oxidant or eliminating DMSO as the solvent. We also hope to have a better understanding of the effects of having electron withdrawing versus electron donating groups at different positions of our substrates in both steps of making the urea substrates and the C-H amination step.

Aims

Background

Bacterial diseases are spreading among humans each day. Even though many scientists have developed various antibacterial drugs, but bacteria developing resistance to antibiotics and some of the antibiotics causing side effects are still a big concern among scientists. Therefore, in general, synthesis of biologically active molecules is a common interested among many organic chemistry laboratories. Benzimidazolone derivatives have shown several promising biological properties. The interesting and diverse chemical properties of these heterocyclic aromatic compounds make them attractive targets for chemical synthesis.  For example, some benzimidazolone derivatives are used for treatment of cystic fibrosis. While other derivatives have shown potential for treatment of cancer and type two diabetes. Moreover, they have shown anti-inflammatory and antivirus characteristics. Traditional approach of synthesizing benzimidazolone derivatives, while effective, do not incorporate principles of green chemistry such as atom economy. Oxidative C-H amination is a common method for synthesizing heterocyclic compounds. In this intramolecular reaction, we can synthesize different and new benzimidazolone derivatives by having different electron withdrawing and electron donating groups at different para, meta, and ortho positions of the urea substrates. Moreover, the thermodynamic effects on the C-H amination will be studied in order to achieve a greener method for our synthesis. The effects of kinetic factors can be observed for this project by running the cyclization reaction under different temperatures such as 70℃, 60℃, 50℃, etc.  In order to make the study of the kinematic effects more effective only one substrate with a specific substitute group should be chosen.

Specific Aims and Outcomes

The long-term goal is to synthesize new potentially biologically active benzimidazolone derivatives in the shortest pathway possible which also agrees with the rules of green chemistry. Direct C-H amination would help to eliminate the need for leaving groups and uses a catalyst to form the new C-N bond. Therefore, by having fewer steps than the traditional method of synthesizing Benzimidazolone derivatives, the reaction would follow the principles of green chemistry and have a better atom economy. Additionally, by making modifications to the traditional C-H amination condition, such as changing the base or the temperature we could make the reaction greener and more effective. Also, we hope to synthesize more varieties of benzimidazolone derivatives by looking at the effects of electron withdrawing versus electron donating groups at different (para, meta, and ortho) positions of the substrates.

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Aim 1 is to synthesize a larger variety of benzimidazolone derivatives in a two steps reaction using direct modified intramolecular C-H amination. Then these newly synthesized compounds will be sent to a biological laboratory to test for the potential anti-bactria or disease treatment characteristics. Aim two will help us to look at the effect of electron withdrawing versus electron donating groups on different positions of the substrate (meta, para, and ortho). This can be done both in the first step of the synthesis which leads to making the urea substrates and in the C-H amination step which would lead to making the benzimidazolone derivatives. In the latter step, we put different electron withdrawing and electron donating groups in the urea substrate to see how they affect the intramolecular C-H amination step. This will help us to attach electron withdrawing or electron donating groups at the desired position for the synthesis of the other benzimidazolone derivatives which have similar structures. Aim three is to establish a new method for intramolecular C-H amination and develop a more green method for the intramolecular C-H amination, either by having sodium carbonate as a base or looking into thermodynamic effects. This means that we will observe if the reaction would take place at temperatures lower than the proposed 80℃, so we can use solvents that are more compatible with the rules of green chemistry.

Research Plan

Significance:

Benzimidazolone derivatives are heterocyclic aromatic organic compounds which are attractive targets for chemical synthesis since they possess interesting and diverse biological activities. Compound 1 is an ion channel mediator used for treatment of cystic fibrosis[i]. Compounds 2 and 3 have shown potential for treatment of cancer. Compound 2 acts as a heat shock protein 90 inhibitor and compound 3 as both a PI-3 kinase and a mTOR inhibitor (Figure 1)[ii]. Therefore, synthesis of new and modified benzimidazolone derivatives is always an interesting area of research. Traditional approaches, while effective, do not incorporate principles of green chemistry such as atom economy (Figure 2)[iii].  Although this traditional approach which uses transition metals to synthesize the benzimidazolone derivatives have been proven to be significant, but this methodology has poor atom economy since it is substrate specific.

Green chemistry is an important subject of interest to pharmaceutical companies and organic chemists.  This is due to the fact that many potential investors and customers emphasize on environmental sustainability and environmental ethics. The principles of green chemistry place emphasis on maximizing atom economy, renewability, safety, energy efficiency, and waste reduction. The most important principles are statements of atom economy.  Atom economy describes a measurement for reaction efficiency that examines the fraction atoms present at the start of the reaction and the number of atoms present in the final product.  A reaction with good atom efficiency would incorporate every atom in the starting materials into the final product[iv].

Figure 1. Representative Biologically Active Benzimidazolone Derivatives

(a)AcOH, Ac2O, 0 ℃; (b) AcOH, HNO3; (c) Pd/C/H2, MOeH;(d)NaOH, MeOH; (e) CDI,THF; (f) NaH/(Boc2)O; (g) R2-Cl/Cs2CO3/DMF; (h) TFA/ MeOH; (i) R3-Cl/Cs2CO3/DMF

Figure 2. Example of an Approach to the Synthesis of Benzimidazolone Derivatives

Oxidative Carbon-Hydrogen (C-H) amination is a promising and effective approach to the synthesis of heterocyclic organic compounds. In this method, a new C-N bond is formed and the selective intramolecular of a C-H bond is functionalized[v]. This method has many advantages such as having a direct route to the complex product (increase atom economy) and has a low starting material energy. We hypothesize to use the same approach to synthesize benzimidazolone derivatives and eventually improve the conditions toward the principles of the green chemistry by using sodium percarbonate as the oxidant and running the reactions at lower temperatures so the need for using DMSO would be terminated. Moreover, by having different electron withdrawing and electron donating groups at the different positions of the starting material (para, meta, ortho) in the both steps of the synthesis, we would have a better understanding of how these reactions will proceed better to give us a better yield.

Innovation:

 We hypothesize that we can use intramolecular C-H amination to synthesize the benzimidazolone derivatives. This approach eliminates the need for leaving groups and uses a catalyst to form a new C-N bond. As a result, it follows the principles of green chemistry by having shorter steps to synthesize the compound. Moreover, we hypothesize to use a more green and efficient way by incorporating oxidant in sodium percarbonate. Sodium percarbonate is an environmentally friendly base and oxidant. Upon neutralization and reduction, it is converted to carbon dioxide and water which are innocuous products. Moreover, the effects of having electron withdrawing versus electron donating groups will be studied in both steps of the synthesis of the urea substrate and synthesis of the benzimidazolone derivatives. The electron donating and electron withdrawing groups will be installed at all three para, meta, and ortho positions of the substrates.

Approach:

In order to investigate substituent effects in the cyclization of N,N’-diphenyl ureas to 1-phenylbenzimidazolones via palladium (II) catalyzed C-H amination, first we need to synthesize the urea substrate. These substrates possess sigma and pi electron donating and withdrawing groups at the meta, para, or ortho positions of the substituent. After synthesizing the substrates, the goal is to cyclize benzimidazolones in order to analyze the effect of each substitute group on the reaction yield to make benzimidazolones. The figure below shows the approached mechanism for this project to synthesize the urea substrates and the cyclization to benzimidazolone derivatives via C-H amination.

A= H, CH3

, OCH3

, CF3

, NO2

Figure 3. The general hypothesized two-step synthesis to synthesize benzimidazolone derivatives

First, we hypothesize to synthesize a series of N, N-diphenyl ureas as substrates for the intramolecular C-H amination reaction. H, CH3

, OCH3

, CF3

, NO2

are the five different substitute groups that will be used to synthesize the substrates. These substrates possess sigma and pi electron donating and withdrawing groups at the meta, para, and ortho position of the substituent. These substituents include methoxy and methyl (OCH3, CH3) which are electron donors and trifluoromethyl and nitro which are electron acceptors. Accepting and donating groups decrease and increase electron density near the phenyl ring, respectively. This method to synthesize the urea substrate was important in terms of both atom economy and simplicity. This is due to the fact that there are no byproducts formed since each atom present in the starting material is also present in the final product. Therefore, the reactions are expected to yield pure products after performing flash chromatography. Each product will be characterized by

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H1

NMR, CNMR, IR, and melting point. In this step, it is hypothesized that having electron donating group at the para and ortho position of the substrate would not be a good idea since they can lead to reduction of net electrophilicity in isocyanatobenzene’s carbon which means it would be less electrophilic. However, having electron donating group at the meta position, would help to deactivating the ring slightly better. Therefore, it’s hypothesized that having electron donating group at the meta position would lead to faster reactions with better yields. In contrast, it is hypothesized for the similar reasons that was mentioned above, having electron withdrawing groups at the para and ortho would give us faster reactions with better yields than having electron withdrawing groups at the meta position.

A= H, CH3

, OCH3

, CF3

, NO2

Figure 4. The reaction to synthesize the urea substrates

In order to synthesize each substrate, all reactions are expected to take place in an oven-dried round bottom flask with an oven-dried magnetic stir bar. Substituted N-methylaniline (10 mmol) will be charged to the reaction vessel followed by dichloromethane (10 mL) and the appropriate isocyanate (10 mmol). The reaction will be stirred under the room temperature for about 24 hours. Then, TLC analysis will be run to make sure that the starting material had been completely consumed. We will start with (1:1 hexanes/ethyl acetate eluent), and then we would change the polarity of the TLC solvent as necessary to achieve a reasonable rf value. After the consumption of all the starting material, each urea substrate will be purified via flash chromatography on silica gel and will be confirmed by taking the carbon and proton NMR of the purified compound.

After synthesizing the desired urea substrates and purification of those compounds by flash chromatography, in order to continue this project, the next step would be the cyclization to benzimidazolones via C-H amination using the synthesized substituted substrates. In this method, we hypothesize to use transition metal catalyzed C-H functionalization which adheres to several principles of green chemistry.  The reaction uses palladium (II) as catalyst and possesses a high degree of atom economy[vi].  In this reaction, we will omit the need for a heavy leaving group as a result of a hydrogen atom functioning as a leaving group.  Additionally, palladium (II) has the potential to be recycled throughout the reaction with the presence of an oxidant. In this proposed intermolecular C-H amination method, we hope to establish a direct C-H amination as a proved route to synthesize benzimidazolone derivatives. Moreover, we hypothesize to use a more green and efficient way by incorporating oxidant in sodium percarbonate. Sodium percarbonate is an environmentally friendly base and oxidant. Upon neutralization and reduction, it is converted to an innocuous product. (carbon dioxide and water). The scheme of the hypothesized reaction to make the benzimidazolones is shown in the figure below. After the reaction, we can calculate the reaction yield using each substrate. In this step, we plan to use different substituents groups H, CH3

, OCH3

, CF3

, NO2

on the urea substrate to observe how they affect the cyclization and in which position (para, meta, or ortho) they will lead to higher yield of the final cyclized product. These substrates possess sigma and pi electron donating and withdrawing groups at the meta, para, and ortho position of the substituent. These substitutes include methoxy and methyl ( CH3

, OCH3

) which are electron donors and trifluoromethyl and nitro which are electron acceptors. Accepting and donating groups decrease and increase electron density near the phenyl ring, respectively. Therefore, we hypothesized that it would be better to have electron donation groups at ortho, meta, and para respectively. In contrast, we hypothesize that it would be better to have electron withdrawing groups at the para, meta and ortho positions respectively. Moreover, the effects of thermodynamic factors can be observed for this project by running the cyclization reaction under different temperatures such as 70℃, 60℃, 50℃, etc.  In order to make the study of the thermodynamic effects more significant only one substrate with a specific substitute group should be chosen. In case that we can successfully make the desired cyclized product at lower temperature, we can the eliminate the usage of DMSO in order to make this reaction more compatible with the rules of green chemistry.

A= H, CH3

, OCH3

, CF3

, NO2

Figure 5. The reaction to synthesize the desired benzimidazolone derivatives using C-H amination

The general procedure for the cyclization is to take place in an oven-dried 25 mL Schlenk tubes which includes an over dry magnetic stir bar. The vessel will be sealed with a rubber septum. After allowing the reaction vessel to cool down to room temperature, the substrate, molecular sieves (to avoid having excess amount of moisture in the (vessel), oxidant, and catalyst will be added to the reaction flask. The vessel will be sealed immediately, and an argon balloon will be place at the top of the septum in order to purge argon into the flask. Then, the anhydrous solvent will be added gradually to the reaction flask so the reaction will take under anhydrous conditions. Then the vessel will be placed in the oil bath and the reaction will be allowed to begin. The reaction mixture will be heated in an oil bath at 80º C. The reaction will be monitored by TLC continuously. After complete consumption of the starting material, the reaction will be taken out of the oil bath and column chromatography will be run in order to purify the compound. The purified compound will be characterized by taking carbon and proton NMR. However, there could be a major drawback to this method, which could bring the yield of the reaction lower than the desired amount. We hypothesize that we would observe degeneration of the urea substrates while trying to achieve intramolecular C-H amination cyclization.  In that case, the right-hand nitrogen of the urea substrate could get deprotonated by the Lewis base. This would lead to the formation of a C-N double bond. Also, This anionic intermediate then deprotonates the weak conjugate acid. In turn, the left-hand C-N bond is broken which separates the urea into the starting materials of the urea synthesis.

 

Figure 6. Possible degradation mechanism

Conclusion: We hope to synthesize various benzimidazolone derivatives at the end of this project. Benzimidazolone derivatives have shown biological activities in the past and the new synthesized molecules will be sent to a biology laboratory to test for the potential anti-bacterial or anti-disease characteristics. Moreover we hope to stablish a new method/conditions for the intramolecular C-H amination which is compatible with the rules of green chemistry either by using a less dangerous oxidant or eliminating DMSO as the solvent. We also hope to have a better understanding of the effects of having electron withdrawing versus electron donating groups at different positions of our substrates in both steps of making the urea substrates and the C-H amination step.

References

Proposal – Final Draft

Abstract: Many chemists’ major goal is to try to synthesize new compounds that are potentially useful to fight various diseases. They also try to improve the already existed and proved methods of the synthesis of those molecules in order to make those methods more efficient. Benzimidazolone derivatives are one of those molecules which are target of our proposed project. We hope to synthesize various benzimidazolone derivatives at the end of this project. Moreover, we hope to stablish a new method/conditions for the intramolecular C-H amination which is compatible with the rules of green chemistry either by using a less dangerous oxidant or eliminating DMSO as the solvent. We also hope to have a better understanding of the effects of having electron withdrawing versus electron donating groups at different positions of our substrates in both steps of making the urea substrates and the C-H amination step.

Aims

Background

Bacterial diseases are spreading among humans each day. Even though many scientists have developed various antibacterial drugs, but bacteria developing resistance to antibiotics and some of the antibiotics causing side effects are still a big concern among scientists. Therefore, in general, synthesis of biologically active molecules is a common interested among many organic chemistry laboratories. Benzimidazolone derivatives have shown several promising biological properties. The interesting and diverse chemical properties of these heterocyclic aromatic compounds make them attractive targets for chemical synthesis.  For example, some benzimidazolone derivatives are used for treatment of cystic fibrosis. While other derivatives have shown potential for treatment of cancer and type two diabetes. Moreover, they have shown anti-inflammatory and antivirus characteristics. Traditional approach of synthesizing benzimidazolone derivatives, while effective, do not incorporate principles of green chemistry such as atom economy. Oxidative C-H amination is a common method for synthesizing heterocyclic compounds. In this intramolecular reaction, we can synthesize different and new benzimidazolone derivatives by having different electron withdrawing and electron donating groups at different para, meta, and ortho positions of the urea substrates. Moreover, the thermodynamic effects on the C-H amination will be studied in order to achieve a greener method for our synthesis. The effects of kinetic factors can be observed for this project by running the cyclization reaction under different temperatures such as 70℃, 60℃, 50℃, etc.  In order to make the study of the kinematic effects more effective only one substrate with a specific substitute group should be chosen.

Specific Aims and Outcomes

The long-term goal is to synthesize new potentially biologically active benzimidazolone derivatives in the shortest pathway possible which also agrees with the rules of green chemistry. Direct C-H amination would help to eliminate the need for leaving groups and uses a catalyst to form the new C-N bond. Therefore, by having fewer steps than the traditional method of synthesizing Benzimidazolone derivatives, the reaction would follow the principles of green chemistry and have a better atom economy. Additionally, by making modifications to the traditional C-H amination condition, such as changing the base or the temperature we could make the reaction greener and more effective. Also, we hope to synthesize more varieties of benzimidazolone derivatives by looking at the effects of electron withdrawing versus electron donating groups at different (para, meta, and ortho) positions of the substrates.

Aim 1 is to synthesize a larger variety of benzimidazolone derivatives in a two steps reaction using direct modified intramolecular C-H amination. Then these newly synthesized compounds will be sent to a biological laboratory to test for the potential anti-bactria or disease treatment characteristics. Aim two will help us to look at the effect of electron withdrawing versus electron donating groups on different positions of the substrate (meta, para, and ortho). This can be done both in the first step of the synthesis which leads to making the urea substrates and in the C-H amination step which would lead to making the benzimidazolone derivatives. In the latter step, we put different electron withdrawing and electron donating groups in the urea substrate to see how they affect the intramolecular C-H amination step. This will help us to attach electron withdrawing or electron donating groups at the desired position for the synthesis of the other benzimidazolone derivatives which have similar structures. Aim three is to establish a new method for intramolecular C-H amination and develop a more green method for the intramolecular C-H amination, either by having sodium carbonate as a base or looking into thermodynamic effects. This means that we will observe if the reaction would take place at temperatures lower than the proposed 80℃, so we can use solvents that are more compatible with the rules of green chemistry.

Research Plan

Significance:

Benzimidazolone derivatives are heterocyclic aromatic organic compounds which are attractive targets for chemical synthesis since they possess interesting and diverse biological activities. Compound 1 is an ion channel mediator used for treatment of cystic fibrosis[i]. Compounds 2 and 3 have shown potential for treatment of cancer. Compound 2 acts as a heat shock protein 90 inhibitor and compound 3 as both a PI-3 kinase and a mTOR inhibitor (Figure 1)[ii]. Therefore, synthesis of new and modified benzimidazolone derivatives is always an interesting area of research. Traditional approaches, while effective, do not incorporate principles of green chemistry such as atom economy (Figure 2)[iii].  Although this traditional approach which uses transition metals to synthesize the benzimidazolone derivatives have been proven to be significant, but this methodology has poor atom economy since it is substrate specific.

Green chemistry is an important subject of interest to pharmaceutical companies and organic chemists.  This is due to the fact that many potential investors and customers emphasize on environmental sustainability and environmental ethics. The principles of green chemistry place emphasis on maximizing atom economy, renewability, safety, energy efficiency, and waste reduction. The most important principles are statements of atom economy.  Atom economy describes a measurement for reaction efficiency that examines the fraction atoms present at the start of the reaction and the number of atoms present in the final product.  A reaction with good atom efficiency would incorporate every atom in the starting materials into the final product[iv].

Figure 1. Representative Biologically Active Benzimidazolone Derivatives

(a)AcOH, Ac2O, 0 ℃; (b) AcOH, HNO3; (c) Pd/C/H2, MOeH;(d)NaOH, MeOH; (e) CDI,THF; (f) NaH/(Boc2)O; (g) R2-Cl/Cs2CO3/DMF; (h) TFA/ MeOH; (i) R3-Cl/Cs2CO3/DMF

Figure 2. Example of an Approach to the Synthesis of Benzimidazolone Derivatives

Oxidative Carbon-Hydrogen (C-H) amination is a promising and effective approach to the synthesis of heterocyclic organic compounds. In this method, a new C-N bond is formed and the selective intramolecular of a C-H bond is functionalized[v]. This method has many advantages such as having a direct route to the complex product (increase atom economy) and has a low starting material energy. We hypothesize to use the same approach to synthesize benzimidazolone derivatives and eventually improve the conditions toward the principles of the green chemistry by using sodium percarbonate as the oxidant and running the reactions at lower temperatures so the need for using DMSO would be terminated. Moreover, by having different electron withdrawing and electron donating groups at the different positions of the starting material (para, meta, ortho) in the both steps of the synthesis, we would have a better understanding of how these reactions will proceed better to give us a better yield.

Innovation:

 We hypothesize that we can use intramolecular C-H amination to synthesize the benzimidazolone derivatives. This approach eliminates the need for leaving groups and uses a catalyst to form a new C-N bond. As a result, it follows the principles of green chemistry by having shorter steps to synthesize the compound. Moreover, we hypothesize to use a more green and efficient way by incorporating oxidant in sodium percarbonate. Sodium percarbonate is an environmentally friendly base and oxidant. Upon neutralization and reduction, it is converted to carbon dioxide and water which are innocuous products. Moreover, the effects of having electron withdrawing versus electron donating groups will be studied in both steps of the synthesis of the urea substrate and synthesis of the benzimidazolone derivatives. The electron donating and electron withdrawing groups will be installed at all three para, meta, and ortho positions of the substrates.

Approach:

In order to investigate substituent effects in the cyclization of N,N’-diphenyl ureas to 1-phenylbenzimidazolones via palladium (II) catalyzed C-H amination, first we need to synthesize the urea substrate. These substrates possess sigma and pi electron donating and withdrawing groups at the meta, para, or ortho positions of the substituent. After synthesizing the substrates, the goal is to cyclize benzimidazolones in order to analyze the effect of each substitute group on the reaction yield to make benzimidazolones. The figure below shows the approached mechanism for this project to synthesize the urea substrates and the cyclization to benzimidazolone derivatives via C-H amination.

A= H,

CH3

,

OCH3

,

CF3

,

NO2

Figure 3. The general hypothesized two-step synthesis to synthesize benzimidazolone derivatives

First, we hypothesize to synthesize a series of N, N-diphenyl ureas as substrates for the intramolecular C-H amination reaction. H,

CH3

,

OCH3

,

CF3

,

NO2

are the five different substitute groups that will be used to synthesize the substrates. These substrates possess sigma and pi electron donating and withdrawing groups at the meta, para, and ortho position of the substituent. These substituents include methoxy and methyl (OCH3, CH3) which are electron donors and trifluoromethyl and nitro which are electron acceptors. Accepting and donating groups decrease and increase electron density near the phenyl ring, respectively. This method to synthesize the urea substrate was important in terms of both atom economy and simplicity. This is due to the fact that there are no byproducts formed since each atom present in the starting material is also present in the final product. Therefore, the reactions are expected to yield pure products after performing flash chromatography. Each product will be characterized by

H1

NMR, CNMR, IR, and melting point. In this step, it is hypothesized that having electron donating group at the para and ortho position of the substrate would not be a good idea since they can lead to reduction of net electrophilicity in isocyanatobenzene’s carbon which means it would be less electrophilic. However, having electron donating group at the meta position, would help to deactivating the ring slightly better. Therefore, it’s hypothesized that having electron donating group at the meta position would lead to faster reactions with better yields. In contrast, it is hypothesized for the similar reasons that was mentioned above, having electron withdrawing groups at the para and ortho would give us faster reactions with better yields than having electron withdrawing groups at the meta position.

A= H,

CH3

,

OCH3

,

CF3

,

NO2

Figure 4. The reaction to synthesize the urea substrates

In order to synthesize each substrate, all reactions are expected to take place in an oven-dried round bottom flask with an oven-dried magnetic stir bar. Substituted N-methylaniline (10 mmol) will be charged to the reaction vessel followed by dichloromethane (10 mL) and the appropriate isocyanate (10 mmol). The reaction will be stirred under the room temperature for about 24 hours. Then, TLC analysis will be run to make sure that the starting material had been completely consumed. We will start with (1:1 hexanes/ethyl acetate eluent), and then we would change the polarity of the TLC solvent as necessary to achieve a reasonable rf value. After the consumption of all the starting material, each urea substrate will be purified via flash chromatography on silica gel and will be confirmed by taking the carbon and proton NMR of the purified compound.

After synthesizing the desired urea substrates and purification of those compounds by flash chromatography, in order to continue this project, the next step would be the cyclization to benzimidazolones via C-H amination using the synthesized substituted substrates. In this method, we hypothesize to use transition metal catalyzed C-H functionalization which adheres to several principles of green chemistry.  The reaction uses palladium (II) as catalyst and possesses a high degree of atom economy[vi].  In this reaction, we will omit the need for a heavy leaving group as a result of a hydrogen atom functioning as a leaving group.  Additionally, palladium (II) has the potential to be recycled throughout the reaction with the presence of an oxidant. In this proposed intermolecular C-H amination method, we hope to establish a direct C-H amination as a proved route to synthesize benzimidazolone derivatives. Moreover, we hypothesize to use a more green and efficient way by incorporating oxidant in sodium percarbonate. Sodium percarbonate is an environmentally friendly base and oxidant. Upon neutralization and reduction, it is converted to an innocuous product. (carbon dioxide and water). The scheme of the hypothesized reaction to make the benzimidazolones is shown in the figure below. After the reaction, we can calculate the reaction yield using each substrate. In this step, we plan to use different substituents groups H,

CH3

,

OCH3

,

CF3

,

NO2

on the urea substrate to observe how they affect the cyclization and in which position (para, meta, or ortho) they will lead to higher yield of the final cyclized product. These substrates possess sigma and pi electron donating and withdrawing groups at the meta, para, and ortho position of the substituent. These substitutes include methoxy and methyl (

CH3

,

OCH3

) which are electron donors and trifluoromethyl and nitro which are electron acceptors. Accepting and donating groups decrease and increase electron density near the phenyl ring, respectively. Therefore, we hypothesized that it would be better to have electron donation groups at ortho, meta, and para respectively. In contrast, we hypothesize that it would be better to have electron withdrawing groups at the para, meta and ortho positions respectively. Moreover, the effects of thermodynamic factors can be observed for this project by running the cyclization reaction under different temperatures such as 70℃, 60℃, 50℃, etc.  In order to make the study of the thermodynamic effects more significant only one substrate with a specific substitute group should be chosen. In case that we can successfully make the desired cyclized product at lower temperature, we can the eliminate the usage of DMSO in order to make this reaction more compatible with the rules of green chemistry.

A= H,

CH3

,

OCH3

,

CF3

,

NO2

Figure 5. The reaction to synthesize the desired benzimidazolone derivatives using C-H amination

The general procedure for the cyclization is to take place in an oven-dried 25 mL Schlenk tubes which includes an over dry magnetic stir bar. The vessel will be sealed with a rubber septum. After allowing the reaction vessel to cool down to room temperature, the substrate, molecular sieves (to avoid having excess amount of moisture in the (vessel), oxidant, and catalyst will be added to the reaction flask. The vessel will be sealed immediately, and an argon balloon will be place at the top of the septum in order to purge argon into the flask. Then, the anhydrous solvent will be added gradually to the reaction flask so the reaction will take under anhydrous conditions. Then the vessel will be placed in the oil bath and the reaction will be allowed to begin. The reaction mixture will be heated in an oil bath at 80º C. The reaction will be monitored by TLC continuously. After complete consumption of the starting material, the reaction will be taken out of the oil bath and column chromatography will be run in order to purify the compound. The purified compound will be characterized by taking carbon and proton NMR. However, there could be a major drawback to this method, which could bring the yield of the reaction lower than the desired amount. We hypothesize that we would observe degeneration of the urea substrates while trying to achieve intramolecular C-H amination cyclization.  In that case, the right-hand nitrogen of the urea substrate could get deprotonated by the Lewis base. This would lead to the formation of a C-N double bond. Also, This anionic intermediate then deprotonates the weak conjugate acid. In turn, the left-hand C-N bond is broken which separates the urea into the starting materials of the urea synthesis.

 

Figure 6. Possible degradation mechanism

Conclusion: We hope to synthesize various benzimidazolone derivatives at the end of this project. Benzimidazolone derivatives have shown biological activities in the past and the new synthesized molecules will be sent to a biology laboratory to test for the potential anti-bacterial or anti-disease characteristics. Moreover we hope to stablish a new method/conditions for the intramolecular C-H amination which is compatible with the rules of green chemistry either by using a less dangerous oxidant or eliminating DMSO as the solvent. We also hope to have a better understanding of the effects of having electron withdrawing versus electron donating groups at different positions of our substrates in both steps of making the urea substrates and the C-H amination step.

References


  • [i]  Liu, W.; Lau, F.; Liu, K.; Wood, H. B.; Zhou, G.; Chen, Y.; Li, Y.; Akiyama, T. E.;Castriota, G.; Einstein, M.; Wang, C.; McCann, M. E.; Doebber, T. W.; Wu, M.; Chang, C. H.; McNamara, L.; McKeever, B.; Mosley, R. T.; Berger, J. P.; Meinke, P. T.,Benzimidazolones: A New Class of Selective Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma) Modulators. J Med. Chem. 2011, 54, 8541-54.
  • [ii] Bruncko, M.; Tahir, S. K.; Song, X.; Chen, J.; Ding, H.; Huth, J. R.; Jin, S.; Judge, R. A.; Madar, D. J.; Park, C.-M.; Park, C. H.; Petros, A. M.; Tse, C.; Rosenberg, S. H.;Elmore, S. W., N-Aryl-benzimidazolones as Novel Small Molecule HSP90 Inhibitors. Bioorganic & Medicinal Chemistry Letters 2010, 20, 7503-7506.
  • [iii] Tsang, W. C., Munday, R. H., Brasche, G., Zheng, N., & Buchwald, S. L.. Palladium-Catalyzed Method for the Synthesis of Carbazoles via Tandem C-H Functionalization and C-N Bond Formation. ChemInform. 2009, 40, 7603 -7610
  • [iv] Choi Sang L, Ho Sin Y, Ismail K, Abdul Rasid S. International Journal of Academic Research. 2012; 4: 10-14.
  • [v] Subramanian, P.; Rudolf, G. C.; Kaliappan, K. P., Recent Trends in CopperCatalyzed C-H Amination Routes to Biologically Important Nitrogen Scaffolds. Chem. – Asian J. 2015.
  • [vi]namoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K., Palladium Catalyzed C-H Activation/Intramolecular Amination Reaction: A New Route to 3- Aryl/Alkylindazoles. Organic Letters 2007, 9, 2931-2934.

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