Synthesis of novel C-2 substituted imidazoline derivatives having the norbornene/dibenzobarrelene skeletons

Novel imidazoline derivatives were synthesized from the norbornene and dibenzobarrelene skeletons which were obtained by the Diels-Alder reactions of anthracene and cyclopentadiene with the different dienophiles, such as fumaronitrile and fumaric acid. Synthesis of the C-2 substituted imidazolines was performed with high yields from various dinitriles and diacyl dichlorides.


Introduction
The chemistry of heterocyclic compounds is one of the most complex and important branches of organic chemistry.The imidazoline ring is an important member of the class of the diaza-heterocyclic compounds.Since natural or synthetic originated imidazolines are found in the molecular structure of many drugs as biologically active residues, imidazoline compounds are extensively used in medicinal and pharmaceutical chemistry.These compounds have widely attracted the focus of biologists because of their potent properties such as anti-inflammatory, antitumor, and antiviral activities. 1 Imidazoline derivatives, like topsentin B1, D, cylindrospermopsin, and spongotine A-C have been isolated from several sea sponges and numerous studies have been carried out on the artificial synthesis and biological activities of these marine compounds. 2he synthesis of C-2 substituted imidazolines such as nutlin compounds is of great importance in terms of both organic and medicinal chemistry because nutlin compounds are known to exhibit anti-tumor activity.Substitution at C-2 of the imidazoline ring system is a requirement for anti-tumor activity. 3Since the discovery of the imidazoline receptor, many biologically active 2-imidazoline derivatives have been synthesized. 4lonidine, moxonidine, and phentolamine, which are the most well-known imidazoline receptors, are widely used in the treatment of the diseases such as heart diseases and high blood pressure.
There are quite a number of synthetic procedures developed using different starting materials for the synthesis of C-2 substituted imidazoline derivatives and some of them have been used for more than half a century. 5In the past two decades, imidazoline synthetic methods have been modified and optimized for better yields.In addition to classical methods, 5,6 different procedures such as on a solid support, 7 solventfree, 8 sonochemical 9 and microwave-assisted methods are used in the synthesis of these compounds. 10,11esides, effective and new enantioselective methods have been improved for the synthesis of chiral imidazoline compounds over the last years. 12,13 idazoline compounds are widely studied by organic chemists with regard to their different application areas as synthetic intermediates, protecting groups, chiral auxiliaries and catalysts for asymmetric synthesis.In recent years, they have gained importance as organocatalysts [14][15][16] in very diverse stereoselective reactions due to their basicity and nucleophilicity 17 as well as Brønsted acidity 18,19 of their salts.
It has been determined that some compounds having the dibenzobarrelene skeleton show a high fluorescence property at room temperature. 20Compounds which contain heterocyclic ring fused to the norbornene skeleton, 21 anthracene-9-imidazoline hydrazone, and its copper (II) complex are known to have antitumor and cytotoxic effects. 22here are no imidazoline derivatives associated with norbornene and dibenzobarrelene skeletons in the literature.In this respect, novel C-2 and N-acyl substituted imidazolines showing dibenzobarrelene or norbornene moieties were synthesized in this study for the first time.

Result and Discussion
In the first part of the work, Diels-Alder cycloaddition reaction was used to synthesize the starting reactants from the various dienophiles and dienes.In these reactions, while anthracene and cyclopentadiene were utilized as dienes, fumaronitrile and fumaric acid were employed as dienophiles.][25][26] There are many various methods in the literature [27][28][29][30] for the synthesis of 2-imidazoline derivatives from the compounds having a nitrile functional group.When these methods are analyzed, two different synthetic strategies come to the forefront.In the first one, the formation of the 2-imidazoline ring performs with twostep reaction from the imidic ester intermediate, which is also known as the Pinner method. 27,28In the second one, it proceeds with a one-step reaction using the catalyst. 10Scheme 1. Synthesis of imidazoline derivatives from the dinitriles having norbornene and dibenzobarrelene skeletons.
Unlike the literature, syntheses of compounds 3 and 4 were carried out through both conventional and microwave-assisted methods in the solvent-free conditions with high yields (Scheme 1).The reaction time, which is quite long in the conventional method, is rather short in the microwave-assisted procedure.Compound 3 was converted to the N-acyl derivative 5 by the reaction with 2-chlorobenzoyl chloride in basic medium.In the 1 H NMR spectrum of compounds 3 and 4, while the imidazoline ring protons signals appeared at 3.0-4.0ppm, the imidazoline methylene carbon signals were not observed in the APT 13 C NMR spectrum.However, when the APT 13 C NMR spectrum was taken over a very long time using CDCl 3 , these signals were observed very weakly.To clarify this situation, N-acyl derivative of compound 3 was prepared from the reaction of 2-chlorobenzoyl chloride with compound 3.In the APT 13 C NMR spectrum of compound 5, four different CH 2 carbon signals belonging to imidazoline ring were clearly observed at 48.3, 49.1 and-51.1 ppm.
To use in subsequent reactions, aromatic and heteroaromatic substituted imidazolines 6-10 were synthesized from the reaction of the requisite aldehydes with ethylenediamine and N-bromosuccinimide (NBS) in basic medium (Scheme 2). 31,322][33][34] In the APT 13 C NMR spectrum of compounds 9 and 10, the methylene carbon signals were observed very poorly.The similar problem was observed in the 1 H and 13 C NMR spectra of compound 3.The X-ray image of compound 10 was taken and the doubts about the structural analysis in NMR spectra were eliminated.(Details of the NMR analysis and experimental procedure of compounds 6-10 can be found in the Supporting Information section.) Compounds 15 and 16 were synthesized through the reaction of acyl chloride 14 with required 2imidazolines 10 and 7 (Scheme 3).The molecular structures of these compounds were characterized with HETCOR NMR spectra, as well as FT-IR, 1 H NMR, and APT 13 C NMR spectra.In the APT 13 C NMR spectra, two different methylene carbon signals belonging to imidazoline ring appeared without observing the situation mentioned above.Scheme 3. Synthesis of compounds 15 and 16 from acyl chloride 14 having the norbornene skeleton.
Compound 18 was synthesized by reacting SOCl 2 with the diacid 17, which was obtained from the cycloaddition reaction of anthracene and fumaric acid (Scheme 4).Similarly, the synthesis of compound 27 was performed by hydrolysis of the diester 25 obtained from the reaction of anthracene with dimethyl acetylenedicarboxylate (DMAD) followed by the reaction of the obtained diacid 26 with SOCl 2 (Scheme 5).Compounds 14, 18 and 27 were synthesized in our previous work. 23The various N-acyl C-2 substituted imidazoline derivatives 19-24 and 28-31 were prepared through an easy and simple nucleophilic substitution of the aromatic/heteroaromatic imidazolines with the two different acyl chlorides 18 and 27 having the dibenzobarrelene skeleton (Schemes 4 and 5).Scheme 4. Synthesis of compounds 19-24 from acyl chloride 18 having the dibenzobarrelene skeleton.
In the FT-IR spectra, carbonyl stretching vibrations belonging to acyl chlorides 18 and 27 were observed at about 1789 and 1783 cm -1 , while in the spectra of compounds 19-24 and 28-31, the signal belonging to amide carbonyl appeared at 1680 cm -1 .In the 1 H NMR spectra of the compounds 6-10, the methylene protons of the imidazoline ring were observed as a singlet at 3.60 to 3.80 ppm, while the methylene protons belonging to the imidazoline ring of the compounds 19-24, which has two protons equivalent to each other, appeared as four different triplets at 3.30-4.30ppm.Unlike compounds 19-24, in the 1 H NMR spectrum of compounds 28-31, two of the four different methylene groups which has four protons equivalent to each other were observed at 3.30-3.60ppm, while the other two methylene group protons appeared at lower fields (3.8 ppm, equivalent to four protons) as a singlet.In the APT 13 C NMR spectra of the compounds 19-24, the methylene carbons belonging to the 2-imidazoline ring were seen at 48 and 54 ppm as two different methylene carbons, as expected.However, these methylene carbons of the compounds 28-31 appeared at about 45-47 ppm at higher fields than the other two methylene carbons.These findings were also supported by HETCOR NMR spectra.

Conclusions
In this work, C-2 substituted imidazoline derivatives 3 and 4 (Scheme 1) were synthesized from dinitrile compounds, having norbornene and dibenzobarrelene skeletons, in both conventional heating and microwave-assisted methods.These syntheses were carried out under neat reaction conditions unlike the methods in the literature.In addition, novel C-2 and N-substituted imidazolines 15, 16, 19-24, 28-31 which contain aromatic, alicyclic, and heterocyclic structures (Schemes 3-5) were obtained in high yields starting from different diacyl dichlorides.

Experimental Section
General.Reagents were of commercial quality, and all solvents were used after purification.Infrared (IR) spectra were determined on a Perkin-Elmer Spectrum One Fourier transform-infrared (FT-IR) spectrometer.NMR spectra were recorded on Bruker 400 MHz spectrometer.Chemical shift δ is reported in parts per million relatives to CHCl 3 ( 1 H δ 7.27), CDCl 3 ( 13 C δ 77.0).X-ray analyses were carried out at Gebze Technical University.

General synthesis of bis(4,5-dihydro-1H-imidazol-2-yl) derivatives 3 and 4
Conventional synthesis (Method A). 6.94 mmol of compound 1 (or compound 2) were dissolved in ethylenediamine (50 mL).The clear solution was heated with stirring in an argon atmosphere at 115 °C for 24 hours.The resulting yellow color solution was cooled to 25 o C and allowed to stand at this temperature for 24 hours.The occurred solid was filtered.The crude product was crystallized from benzene.Compound 3 was obtained as colorless powder (1.21 g, 5.25 mmol) in 76% yield.Compound 3 was washed with chloroform and recrystallized from ethanol.Compound 4 was obtained (1.69 g, 4.93 mmol) in 71% yield.Microwave-assisted synthesis (Method B). 6.94 mmol of compound 1 (or compound 2) were dissolved in ethylenediamine (40 mL).The solution was irradiated at atmospheric pressure using a mono-mode microwave device at 125 °C for 65 minutes with 250 W power.The resulting yellow color solution was cooled to room temperature and allowed to stand for 24 hours at this temperature.The occurred solid was filtered.The crude was crystallized from benzene.Compound 3 was obtained as colorless powder (1.41 g, 6.12 mmol) in 88% yield, and compound 4 was isolated as colorless powder (1.97 g, 5.76 mmol) in 83% yield.

trans-Bicyclo[2.2.1]hept-5-ene-2,3-dicarbonyl dichloride (14).
Compound 13 (5.49mmol) was dissolved in dry benzene (25 mL) and DMF (0.1 mL) and then oxalyl chloride (1.02 mmol) rapidly added to the mixture.The mixture was refluxed for 4 hours until the HCl gas evolution had ceased.The gas evolved during the reaction was monitored by measuring the pH of the medium.After cooling the mixture to room temperature, the solvent was removed at reduced pressure.Anhydrous benzene (10 mL) was added to the crude product and stirred at room temperature for 10 minutes.The solvent was removed under reduced pressure.This process has been repeated three times.The light yellow liquid was isolated with 98% yield (1.18 g, 5.39 mmol).The product was used in the next step without purification. 23,26

General synthesis of trans-5,6-bis[[4,5-dihydro-1H-imidazol-1-yl]carbonyl]bicyclo[2.2.1]hept-2-enes 15 and 16.
To a solution of compound 7 (3.28 mmol, or compound 10), in dry THF (50 mL), triethylamine (3.66 mmol, 0.37 g, 0.51 mL) was added and stirred at room temperature for 30 minutes.Compound 14 (0.36 g, 1.64 mmol) was added dropwise to the mixture at 0 o C and stirred at room temperature for 24 hours.The white solid which occurred at the end of the process was filtered.The solvent was removed in vacuum from the filtrate.The oily product was dissolved in methanol (10 mL) and precipitated in ice water (200 mL).The crude product was filtered and dried in vacuo.The colorless solid was crystallized with ethyl acetate.General synthesis of N-acyl substituted imidazolines with dibenzobarrelene skeleton 19-24.To a solution of the requisite imidazolines (3.72 mmol, compounds 6, 7, 9-12) in dry THF (50 mL), triethylamine (0.37 g, 3.66 mmol, 0.51 mL) was added, and then stirred at room temperature for 30 minutes.Compound 18 (0.57g, 1.72 mmol) was added to this mixture at 0 °C and stirred at room temperature for 24 hours.The formed colorless solid was filtered.The solvent was removed in vacuo.The oily product was dissolved in methanol (10 mL) and precipitated in ice-water (200 mL).The resulting colorless solid was filtered and dried at vacuum.The crude products were crystallized from THF, except for compound 23, crystallized from methanol.