The assessment, comprehensively reviewed the challenges of gas flaring in Nigeria, including the exploration, formation and extraction of crude oil. Gas flaring is simply the open-air combustion of fuel gas. Initial start-up flaring, Continuous production flaring and Operational/Non-continuous production flaring which are the 3 major classified categories of flaring were discussed, including composition of flared gases, types of flare gases such as ground flares, pit flares and elevated flares. The cumulative effects of gas flaring under the headings: Environments, Health, Economy and other effects were thoroughly discussed. Flaring has many disastrous consequences such as; decrease in the life expectancy of people living near flare sites due to poisonous emissions which lead to a variety of health challenges and diseases. Flaring also contributes to global warming, which is a major concern today as it causes extreme weather conditions, extinction of certain species and climate change. Nigeria stands to gain a great deal from utilizing natural gas properly in terms of revenue and increased job opportunities, consequently it is necessary that the flaring of natural gas should be stopped. Several alternatives have been proposed, including using flared gas to produce electricity and as a petrochemical feedstock, liquefying of flare gas and reinjecting it into the earth as a secondary oil recovery technique. Nigeria has made several policies to reduce and subsequently end gas flaring and has set multiple deadlines which ended up being postponed severally. The new deadline to end gas flaring in Nigeria is now anticipated to be by 2030. However, due to many setbacks, it is possible that the deadline may yet be shifted again. 

In this paper we have been explored rapid and efficient synthesis to generate structurally complex bisheterocyclic libraries on soluble Ionic liquid support by the use of focused microwave irradiation. The bis-heterocyclic compounds, characterized by the presence of two heterocyclic cores connected by a single bond space, provided structurally linear heterogeneous libraries with skeletal diversity. The ionic liquid immobilized benzimidazole-1,2- diamine 5 has been used as a scaffold to generate structurally diverse analogues. The IL immobilized benzimidazole-1,2-diamine with various aliphatic and aromatic γ and δ -ketoacids using catalytic amount of trifluroacetic acid under focused microwave irradiation led to formation of diverse heterocyclic molecules have been described. The pyrrolo[1,2-a]bisbenziimidazol-1-one, isoindolo[1,2-a]bisbenzimidazole-1-one and pirido[1,2-a]bisbenziimidazol-1-one which are accessible in good yield from IL conjugate diamine in a single-step procedure, undergo a tandem reaction involving intermolecular electrocyclizations. The assembly of both heterocyclic rings was constructed on ionic liquid in a convergent combinatorial fashion. The relative high yield and purities with three points of diversity has been reported.   

Highly functionalized various ring size bis-heterocycles, with different hetero atoms and substitution patterns are of major interest in the Pharmaceutical and agricultural industry due to the many intrinsic biological properties of these substances1. Thus the composition of bis-heterocyclic comprises pyrido[1,2-a] benzimidazole derivatives are ligands for the BZD site on GABA-A receptors and are thus useful for the treatment of disorders of the central nervous system including convulsion such as epileptic seizures, anxiety, depression, muscular spams, sleep disorders, attention deficit hyperactivity disorder2. Polycyclic bis-heterocycles containing imidazopyridine and imidazopyrimidine or Imidazo-[2,1-a]isoindole moiety constitute basic structural frameworks of various derivatives have been found potent against respiratory syncytical virus infection which is a leading cause of lower respiratory tract infection3. The concern Oxazolo-[2,3-a]isoindole and imidazo[2,1-a]isoindole derivatives shown antiviral medicaments4. Benzimidazoles in combination with the Pyrrolo[2, 1-a] isoidol-5-ones are shown to be an inhibitory activity on the Hsp90 chaperon protein to exhibit anticancer activity, and more particularly via the inhibition of the ATPase-type catalytic activity of the Hsp90 chaperone protein5. The geometric assembly of bisheterocycles characterized by the benzimidazole as a core connected by a spacer of variable length/structure, provided structural relevant compounds are apparently currents drugs6. However, interest remain strong for new approaches to produce complex hybrid molecules warrant further consideration as a means to identify complex structures with novel biological activities.

Owing, to the numerous problems associated with the solid phase synthesis7 such as low specific load and heterogeneous reaction phase, soluble polymer supported synthesis proved to be a useful alternative8. However, problems of high viscosity of the medium and the purification of the products and recycling of soluble polymers offered disadvantages over the Ionic liquid supported synthesis9. Ionic liquid substituted combinatorial synthesis has become a very effective method used for the production of combinatorial libraries with the high degree generation of chemical diversity10. The use suitable functionalized ionic liquids have made it possible to develop a multitude of methodologies for synthesis on ionic liquid supported synthesis11. The numerous advantageous associated with the ionic liquid supported syntheses as easy purification by simple washing, the possibility of using various techniques such as parallel synthesis making it possible to simultaneously produce a large quantity of products12. The nature of high thermal stability, their low volatilities and their very low vapor pressure, their low inflammability, their strong solubilization power of the salts as well as of the neutral organic molecules and polymers and finally the possibility of easy recycling has been strongly appealing the green media supported synthesis of small molecule libraries13. Despite advantages of ionic liquid supported synthesis to produce chemical library synthesis, applications of convergent, diversity-oriented synthesis to prepare libraries of natural-product-like molecules are underdeveloped. Synthetic organic chemistry has much impacted by the introduction of precision controlled microwave reactors14. The numerous reactions such has heterocycle formation, metal catalyzed cross-coupling, cycloaddition, condensation reactions have been explored under microwave irradiation15. The advantage of Microwave heating reduces the reaction times in comparison with traditional heating. In addition, the yields of the reactions are often increased and the time for optimizing the reaction conditions is minimized in comparison to conventional heating methods16. Due to the ionic conduction Ionic liquids absorbs microwave irradiation extremely well and transfers energy rapidly17. According to the present incarnation found that ionic liquid supported synthesis allows an easy automation together with microwave assisted heating, gives rise to unexpected advantages such as high yields of the compounds with high purity and possibility to eliminate time-consuming conventional heating methods, which are necessary when producing library of compounds. Furthermore, the reaction times in the homogeneous system substantially shortened as compared to other methods of heating.

Scheme 1: Library Scaffolds and Related Biologically Active Molecules

Despite the broad range of biological activities that was associated with the combination of benzimidazole with the pyrido[1,2-a]benzimidazole, pyrido[1,2-a]benzimidazole and imidazo[2,1-a]isoindole very few reports have been reported for the successful construction of aforementioned three classes of bis heterocycles in a linear fashion. Herein, we describe an efficient approach by the combination of ionic liquid supported synthesis 

under microwave irradiation in order to gain rapid access of the aforementioned three classes of heterocycles with the three points of structural diversity in a linear single bond space bisheterocycles. The strategic accommodation of bisheterocycles and the versatility of the synthetic route have introduced the greater molecular diversity building blocks in good purity and high yields were reported. 

Scheme 2: Microwave-Assisted multistep synthesis of Pyrrolo[1, 2-a]bis-benzimidazol-1-one, Pyrido[1, 2-a]bis-benzimidazol-1-one.

The synthesis has begun by choosing the 3-hydroxyethyl-(1-methylimidazolium)-tetrafluoroborate 1 as ionic liquid matrix for the preparation of the desired chemical library. Synthesis of the 3-hydroxyethyl-(1-methylimidazolium)-tetrafluoroborate was performed by the reported literature by taking the 1-methylimidazole and 2-bromoethanol18. In order to generate the benzimidazole based building block with one diversity point 4-fluoro-3-nitrobenzoicacid 2 has chosen the starting material to carry out the steps ahead on ionic liquid support. The 3-hydroxyethyl-(1-methylimidazolium)-tetrafluoroborate having the terminal hydroxyl group coupled molecules has been used to serve the Ionic liquid support for the growing chain. The esterification of Ionic liquid teriminal hydroxyl group with the 4-fluoro-3-nitrobenzoicacid was carried out in the presence of DCC and the catalytic amount of DMAP in acetonitrile and dichloromethane as a co-solvent for about 20 minutes in the microwave irradiaton to offered IL conjugate 3. Whereas the same reaction under room temperature reaction formation of esterbond took place two days reaction time. By taking the distinct solubility features of the ionic liquids, purification has been carried out by precipitation of Ionic liquid conjugate in the low polar organic solvents such as ether. Ionic liquid conjugate substrate further treated with the various primary amines in order to displace the fluorine atom in the nucleophilic substitution manner. This reaction has done in the presence of microwave irradiation for about 10 min of reaction time to offered ionic liquid supported conjugate 4. While the same preceding reaction has taken 5 hr. of reflux condition reaction time. Further IL conjugate 4 has treated with Zinc and ammonium formate for about 20 minutes at the room temperature to furnish IL conjugate diamine 5. In the course of planning and executing the synthesis of 14 and 17 analogues a built-in structural diverse Ortho-diamino ester 5 as an initiator for our present strategy. By taking an Ortho-diamino ester 5 coupled with 4-fluoro-3-nitrobenzoic acid  to get the anilide conjugates 6 where there is an ample opportunity to generate second diversity through nucleophilic substitution by various primary amines. This reaction was performed under microwave irradiation at 100oC, 8 bar for about 10 min in the presence of DCC and catalytic amount of DMAP in dichloromethane under sealed vessel. Whereas to carry out this reaction under conventional heating methods 20 h of reflux or 50 min of domestic microwave heating. In order to generate mono ring imidazole with one point of diversity we have been used anilide conjugate 6 to intromolecular ring cyclization through the nucleophilic addition of secondary amines to the amide carbonyl carbon. This reaction was performed under microwave irradiation in the presence of catalytic amount of Trifluoro acetic acid and anhydrous Megnesiumsulfate at 100oC for about 5 min in ethlenedichloride to convert into benzimidazole 7. 

Imidazole formation was impressive yield by using 10% trifluoroacetic acid in ethelenedichloride, which generates the electrophilicity on amide carbonyl carbon than usual and in the presence of anhydrous megnesiumsulfate in order to avoid moisture contamination which decreases the product efficiency along with the high boiling point solvent led good yield. After completion of the reaction the ionic liquid supported conjugate was precipitated and washed with cold ether. The ortho nitro fluoro groups in imidazole 7 have been used to ipso-fluro displacement via SN Ar by various aliphatic and aromatic primary amines to generate second diversity. This reaction was performed under microwave irradiation at 100oC for about 5 min to give 8. 

The obtained ionic liquid bound O-nitro anilines 8 were used to perform reduction to convert nitro to amine group by using excess amount of Zn and Ammoniumformate in methanol. This reaction was completed within 30 min without starting any material left yield to get conjugate diamine 9. The completion of the reaction has been confirmed by the color change of the reaction mixture from dark brown to colorless. This has been used as a scaffold to generate third diversity oriented heterocyclic molecules by various γ and δ aliphatic and aromatic ketoacids. This reaction was performed in ethlenedichloride by taking conjugatediamine and ketoacids in the presence of catalytic amount of Trifluoroacetic acid and a dehydrating agent such as anhydrous Megnesiumsulfate or 4 Ao Molecular sieves in a sealed vessel under microwave irradiation at 130oC for about 10 min offered 12, 17. The formation of the products with the Il conjugate diamine by using various ketoacids such as β-ketoacids and γ-ketoacids with variation of substituents led to the five and six membered terminal pyrrolo, pyrido cycles on the bisbenzimidazole has proceeds well on the same reaction time intervals. This library of analogues has extended by taking the aromatic ketoacids under above mentioned reaction conditions proceeds well without leaving any undesirable products or unreacted starting material. Whereas the same reaction with 5% trifluoroacetic acid in ethlenedichloride under the same reaction conditions by applying the microwave irradiation under various ketoacids the formation of linear symmetrical keto tethered bis benzimidazoles 11, 18 have been observed. The products have been confirmed after the detachment of the support. The variation of TFA amount led to the various bisheterocycles under the short period of reaction times with impressive yields is an synergistic effect. These products have been observed in both the aromatic and aliphatic ketoacids in the same intervals upon microwave irradiation on the ionic liquid support. The ionic liquid conjugated products 12, 17 further treated with the lawesson’s reagent in the presence of ethlenedichloride for about 1500C of reaction temperature to 15 min to offered 13, 19 of thioamide analogues. Although, these types of reaction carried out in the literature using anhydrous toluene heated to reflux for 24 h with a Dean-Stark apparatus gained moderate yields. Furthermore, it involves tedious process and time consuming to generate large number of compounds19. Therefore, here we reported facile and an efficient process with high yield and purities with the association of two heterocycles in one molecule. The formation of the reaction products 12 have been observed by the naked eye. After the completion of the microwave irradiation we have been found that under the far Ultra-Violet light exposure these compounds are showed to be fluorescent in the presence of ionic liquid conjugate. Whereas the other group of isoindolo[1,2-a]bis benzimidazoles were cannot observed fluorescence up on far UV light exposure. Considering the mechanistic aspects of the formation of these products, It would be understood that the primary amine of conjugate diamine attack to the γ and δ keto carbonyl center which is most electrophilic centre induced by the trifluoroacetic acid there by formation of an imine to generate transient intermediate by the removal of 1 equiv. of water to offered the imine intermediate. The lone pair electrons on the secondary nitrogen attack to the preferred conformation B imine below the Ar-C=N- coplane, followed by elimination of another equivalent of water to form the products. Eventually cleavage of the soluble ionic liquid support was accomplished by using NaOMe in methanol under microwave conditions for about 120oC of reaction temperature to obtain Ionic liquid free 14, 20 desired analogues in good to excellent yields. We have been found that purity from 71-93% after detaching the each and every product from the support.  The characteristic peaks for all these compounds have been found that enantiomeric methyl group which was identified by the 1H NMR spectroscopy by the range of 1.45-1.80 ppm as a singlet and the quaternary carbon identified through the 13C by the range of 84-90 ppm. By the IR absorbance in the range of 1700-1720 cm-1 has confirmed the presence of tertiary amide carbonyl. 

In Summary, we have been successfully developed rapid and efficient synthesis of pyrrolo[1,2-a]bisbenzimidazole, pirido[1,2-a]bisbenzimidazole and isoindole[1,2-a]bisbenzimidazoles and their thioamide derivatives on  soluble ionic liquid support by using the focused microwave energy under acid catalyzed conditions affording three class of bisheterocyclic products. The reaction progression was monitored by the conventional spectroscopic methods like 1H, 13C NMR and Mass spectroscopy. The intramolecular condensation of β, γ-Ketoacids with ionic liquid bound conjugate diamine has been optimized for library production. It is noteworthy to mention that at all the stages we have been found that substrate containing ionic liquid was stable although in the harsh microwave conditions. By the use of optimized microwave reaction conditions from hours to min and with the ease of simple purification resulting drug like substances with high purities have been achieved.

General Procedure for the Synthesis of Ionic Liquid conjugated Diamine 5.

Ionic Liquid 1 (0.5 g, 0.2 mmol) in acetonitrile (5 mL) was added to the solution of 4-fluro-3-nitrobenzoic acid 2 (0.51 g, 2.7 mmol, 1.2 equiv) in dichloromethane/acetonitrile (5 mL) in the presence of N,N’–dicyclohexylcarbodiimide (0.57 g, 2.7 mmol, 1.2 equiv) as coupling reagent and a catalytic amount of N,N’-dimethylamino pyridine (DMAP, 0.002 g) under microwave irradiation at 80 oC for about 20 minutes to afford the ester 3. The precipitated dicyclohexyl urea (DCU) was filtered through a fritted Celite plug. The Celite plug was rinsed with acetinitrile and the combined organic phase was concentrated under vacuum.  The crude reaction mixtures were precipitated by slow addition of excess of cold ether (100 mL). The precipitated ester conjugate was then filtered through a fritted funnel and washed several times to remove the byproducts and dried. To a solution of 3 in acetonitrile (5 mL), various primary amines (6.7 mmol, 3.0 equiv) in (5 mL) dichloromethane was added and the reaction mixtures were irradiated in microwave cavity at 80 oC for 10 min to afford the Ionic-liquid immobilized nitroamines 4. Upon concentration under reduced pressure, the crude residue was precipitated by addition of excess of cold ether (100 mL). The precipitated IL conjugate was then filtered through a fritted funnel and washed several times to remove the byproducts and dried. The subsequent reduction of nitro group proceeded by using Zn (7.0 equiv) and NH4COOH (15.0 equiv) in methanol at room temperature for about 15 minutes under vigorous stirring. The insoluble Zn was removed by filtration and the mixture was dried under vacuum. The obtained residue was dissolve in dichloromethane and washed with 2M HCI (10 mLx3). The organic phase was dried over MgSO4 and concentrated to afford ionic liquid supported dimaine 5.

General Synthetic Procedure for the Preparation of the ionic liquid Bound3-(4-Fluoro-3-nitrobenzamido)-4 (substituted amino) Carboxylates 6.

Ionic liquid bound o-phenylene diamine 5 (0.5 g, 0.25 mmol, 1.0 equiv) has been taken into the microwave vessel in 5ml of dichloromethane  to this a solution of 4-fluoro-3-nitrobenzoic  acid  (0.11 g,  0.60  mmol, 1.2  equiv)  in dichloromethane/acetonitrile (5 ml) was added in the presence of N,N′-dicyclo- hexylcarbodiimide (DCC) (0.144 g, 0.70 mmol, 1.2 equiv) and N,N′- dimethylamino pyridine (DMAP) (3 mg). The reaction mixture was allowed to stir at room temperature for few minutes and subsequently irradiated microwave for 10 min to obtain the ionic liquid bound amide conjugates 6. After completion of the reaction, the insoluble dicyclohexylurea (DCU) was filtered. The obtained filtrate was concentrated and precipitated by slow addition of cold ether, the  amide conjugate 6 was filtered through fritted funnel. The crude product was washed successively with ether to remove the impurities and dried for further steps.

General Synthetic Procedure for the Preparation of ionic liquid Bound Benzimidazole 7:

To a solution of 6 in 1,2-dichloroethane has been taken into microwave vessel for this trifluoroacetic acid (0.4 mL) and MgSO4 (0.5 g) were added and irradiated under microwave conditions for about 5 min. After completion of the reaction, the reaction mixture allowed to room temperature, MgSO4 was removed through celite. The reaction mixture were precipitated by slow addition of excess of cold ether (150 mL) and  filtered through  a  fritted funnel  to give the compound 7, and dried for further steps. 

General synthetic procedure for the preparation of the ionic liquid immobilized diamine 9.

The resulting conjugate 7 was taken into the microwave vessel to treated with various amines (2.31 mmol, 7.0 equiv) in dichloromethane (5 mL) under microwave irradiation for about 5 min. After the completion of the reaction, reaction mixture was subjected to the rotavapor. The resultant crude was precipitated by the slow addition of cold ether to get the ionic liquid conjugate 8. The conjugate 8 was dissolved in appropriate amount of methanol added zinc (3.3 mmol, 30.0 equiv) and ammonium formate (3.75 mmol, 15.0 equiv) allowed stirring at room temperature for about 30 minutes. The reduced nitrogroup was confirmed by the colure change of the reaction mixture from yellow to colorless. Zinc was removed by centrifugation and filtration, and dichloromethane was added to precipitate ammoniumformate. After filtration through Celite, ionic liquid-immobilized diamine 9 was obtained.

General Synthetic procedure for the preparation of Pyrrolo[1,2-a]bisbenziimidazole and isoindolo [1,2-a]bisbenzimidazl-1-one 12, 17.

To a solution of conjugate diamine 9 in 5 mL of ethylenedichloride has been placed in microwave vessel. To this catalytic amount Trifluotoaceticacid and a dehydrating agent such as anhydrous Megnesiumsulphate (0.5 g) or 4 Ao MS (0.5 g) along with various aliphatic and aromatic γ, δ- ketoacids or ketoesters (1.2 equiv) were added. The reaction mixture was allowed to stir for a while at room temperature subsequently subjected to microwave irradiation for about 10 min at 130oC, 10 bar pressure. After the completion of the reaction, the reaction mixture was filtered through the celite in order to remove dehydrating agents. The residue was precipitated by the slow addition of cold ether, and dried to obtain 12, 17.

General Synthetic procedure for the preparation of Pyrrolo[1,2-a]bisbenziimidazole and isoindolo [1,2-a]bisbenzimidazl-1-one thioamides 13, 19.

To the solution of ionic liquid conjugates 12, 17 ethlenedicholoride (10 ml), was added by the Lowesson’s reagent (0.7 equiv) and subjected to MW irradiation for about 10 min at 150 oC, to offered 13&17 derivatives. The solvent evacuated crude residue has been precipitated by the addition of excess cold ether (100 mL). The precipitation of IL conjugate filtered through the fritted funnel, fritted funnel was rinsed acetonitrile and thereby evaporated the solvent to offered 13, 19 derivatives. 

General Procedure for the Cleavage of ionic liquid bound Polycylic Derivatives 14, 15.

To a solution of conjugates 12, 17 in methanol (10 mL), NaOMe (0.1 g) was added and allowed to microwave irradiation for about 120oC, 15 min. The reaction mixture was monitored by TLC, after completion of the reaction, the reaction mixture was extracted by the slow addition of cold ether (120 mL) and the ionic liquid was filtered off and subjected to the rotavapor. The residue was dried under vacuum and the crude was analyzed by the HPLC with UV detection at λ= 254 nm (column Sphereclone 5µ Si (250×4.6 mm); gradient 50% ethyl acetate in hexane; flow rate 1 mL/min.). The obtained solid was then purified by neutral silica gel column chromatography and eluted with a mixture of ethylacetate and hexane (1:1) to get the title compounds 14 or 15 in good yield.

 This work was financially supported by the National Science Council (NSC) of Taiwan and also the authorities of the National Chiao Tung University, for providing laboratory facilities.

Supporting Information Available. 

The detailed experimental procedure for the synthesis of compounds; spectral characteristics of the synthesized compounds; 1H NMR, 13C NMR spectra of final compounds were available.