untitled European Journal of Chemistry 7 (2) (2016) 152‐155 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2016 Atlanta Publishing House LLC ‐ All rights reserved ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.7.2.152‐155.1403 European Journal of Chemistry Journal webpage: www.eurjchem.com Synthesis of new derivatives of aryl‐clonazepam via Suzuki Cross‐coupling reaction Mohammed Abed Al‐Hussein Salman and Nabeel Abed Abdul‐Rida * Department of Chemistry, College of Education, Al‐Qadisiyah University, 58002, Diwaniya, Iraq * Corresponding author at: Department of Chemistry, College of Education, Al‐Qadisiyah University, 58002, Diwaniya, Iraq. Tel.: +694.790.3620810. Fax: +694.790.3620810. E‐mail address: nabeel1959@yahoo.com (N.A. Abdul‐Rida). ARTICLE INFORMATION ABSTRACT DOI: 10.5155/eurjchem.7.2.152‐155.1403 Received: 01 February 2016 Received in revised form: 25 February 2016 Accepted: 27 February 2016 Published online: 30 June 2016 Printed: 30 June 2016 A new series of aryl clonazepam derivatives (11‐16) have been synthesized by employing Suzuki Cross‐coupling reaction, which includes the reaction of clonazepam with suitable derivative boronic acid at the presence of Pd(PPh3)4 as catalyst, and Na2CO3 as a base. The structures of the newly synthesized compounds were assigned by 1H, 13C and 2D NMR spectroscopic techniques. KEYWORDS Clonazepam Diazepine ring GABA receptor 2D NMR spectroscopy Benzodiazepine derivatives Suzuki Cross‐coupling reaction Cite this: Eur. J. Chem. 2016, 7(2), 152‐155 1. Introduction Benzodiazepine (BDZs) derivatives are considered the most important sedatives and hypnotic drugs due to their high therapeutic index number. On the other hand, BDZs have minor side effects on cardiovascular and respiratory systems due to the fact that there is no interaction between the drug and liver microsomal enzyme. All compounds of this group increase onset of sleep and hence increase total sleeping time [1‐3]. Benzodiazepine, if taken in low dose, produce relaxation mode with no evident effect on patients’ physical activities. The drugs are divided into two groups based on their half‐life: long term benzodiazepines such as diazepam, flurazepam, and short term lorazepam, oxazepam [4,5]. Mechanism of action act on mide‐brain ascending reticular formation and limbic system. This chemical reaction stimulates gamma‐amino‐ butyric acid (GABA) ergic neurotransmission, which activates of GABA receptors which in turn leads to Cl ionophore complex and increases the opening of the Cl channel, Therefore the increase of Cl conduction will lead to decrease activation region of central nervous system [6,7]. Clonazepam is considered one of long acting benzodiazepine drugs [8]. The seven amino ring (Diazepin ring) is vital for its biding with BDZs site [9]. The lipophilic properties of BDZs play an important role in metabolism, so reach to brain through pass blood brain barrier and high interact with receptor. There are many side effects to the drug, most important of all, is addiction to the drug which occurs over a long term used, as well as deformation of the foetus in pregnant women [10]. Clonazepam is usually prescribed as control drug to acute cases of epilepsy and it is very effective in controlling non‐ convulsive cases of epilepticus [11]. The following drugs: erythromycin, clarithromycin, ritonavir, itraconazole, ketoco‐ nazole, nefazodone, and grapefruit juice are inhibitors of CYP3A4, an enzyme that is responsible of metabolism of the BDZs in the liver, which rise the half‐life and toxicity [12]. Researchers have given immense attention to studies of benzodiazepine derivatives for its property of medical and biological activities, some of which have been used as antitumor drugs [13], antagonists of schistosomicidal [14], anti‐HIV [15], antagonists for the Bradykinin [16], anti‐ arrhythmic agents [17], cholecystokinin receptor agonists [18], and antimalaria [19]. Recent studies have shown that some BDZs compounds have been synthesized and the results have presented the important role of the drugs as therapeutic drugs used specifically as anti‐hepatitis B virus [20]. Anderw et al. [21] have prepared compound 1 (Figure 1) using Suzuki coupling reaction under standard aqueous conditions and conceder it a new method to prepared 1,4‐benzodiazepines. In Salman and Abdul‐Rida / European Journal of Chemistry 7 (2) (2016) 152‐155 153 2003, Nadin et al. [22] synthesized BDZs compound 2 (Figure 1) via Suzuki coupling reaction as a vital stage for synthesis of the active compound 3 (Figure 1) as γ‐secretase inhibitor for the handling of case of Alzheimer. In continuation of our program on the synthesis of BDZs derivatives, we investigated the synthesis of new derivatives of arylclonazepm via Suzuki Cross‐coupling reaction [23,24]. Figure 1. Some benzodiazepine derivatives. 2. Experimental 2.1. Instrumentation Melting points are uncorrected and were measured on a Büchi melting point apparatus B‐545 (Büchi Labortechnik AG, Switzerland). NMR data were obtained on 400 and 600 MHz (1H) and 150.91 MHz (13C) spectrometers (Avance III, Bruker, Germany) with TMS as internal standard and on the δ scale in ppm. Heteronuclear assignments were verified by 1H, 13C HMBC and 1H, 13C HSQC NMR experiments. Micro‐analytical data were obtained with a Vario, Elemental analyzer (Shimadzu, Japan). Analytical silica gel TLC plates 60F254 were purchased from Merck. All reagents were obtained from commercial suppliers and were used without further purification [25]. 2.2. General procedure for the synthesis of the biaryl derivatives of clonazepam via Suzuki Cross‐coupling reaction (11‐16) To a solution of clonazepam (4) (60 mg, 0.20 mmol) in mixture of chloroform (10 mL) with MeOH (5 mL), aryl boronic acid (0.2 mmol) was added, then the mixture was stirred for 15 min at suitable temperature then adding Pd(0)(PPh3)4 (100 mg, 5 %mmol) and aqueous solution of 2 M sodium carbonate (5 mL). The mixture was heated under reflux for 12‐14 h. After cooling phase, water (5 mL) was added and the mixture was partitioned with ethyl acetate (3 × 10 mL) and the combined organic extracts which were washed with aqueous solution of 5% Na2CO3 (3 × 10 mL), and dried with sodium sulfate and then evaporated in vacuum. The residue was then filtered on a short SiO2 column using hexane: ethyl acetate (3:2, v:v) as eluent to get the desired product [26] (Scheme 1). 5‐(4'‐(Methylthio)‐[1,1'‐biphenyl]‐2‐yl)‐7‐nitro‐3H‐benzo[e] [1,4]diazepin‐2‐ol (11): From 4‐methylthiophenyl boronic acid (80 mg). Yield: 40 mg (67%) as a light brown powder. M.p.: 248‐250 °C. Rf : 0.58. 1H NMR (600 MHz, DMSO‐d6, δ, ppm): 2.38 (s, 3H, SMe), 7.00 (br s., 1H, Harom.‐6'), 7.43 (m, 4H, Harom.‐ 5' + H‐3(CH2)+ Harom.‐6), 7.56 (m, 3H, Harom.‐9 + Harom.‐3" + Harom.‐5''), 7.62 (m, 4 H, Harom.‐2" + Harom.‐6"+Harom.‐4' + Harom.‐ 3'), 7.98 (d, 1H, J8,9 = 8.6 Hz, Harom.‐8). 13C NMR (150.91 MHz, DMSO‐d6, δ, ppm): 15.2 (SMe), 49.7 (C‐3), 124.9 (Carom.‐3'), 126.9 (Carom.‐9), 127.2 (Carom.‐2" + Carom.‐6"), 127.7 (Carom.‐3'' + Carom.‐5"), 129.2‐129.7 (Carom.‐6+Carom.‐5'+Carom.‐8), 131.9‐132.0 (Carom.‐2'+ Carom.‐6'), 132.5 (Carom.‐4'), 135.3 (Carom.‐5a), 137. 8 (Carom.‐4"), 141.1 (Carom.‐1' + Carom.‐1"), 147.8 (Carom.‐7), 156.8 (Carom.‐9a), 162.8 (C‐2), 167.65 (C‐5). Anal. calcd. for C22H17N3O3S: C, 65.49; H, 4.25; N, 10.42. Found: C, 65.22; H, 4.11; N, 10.20%. 2'‐(2‐Hydroxy‐7‐nitro‐3H‐benzo[e][1, 4]diazepin‐5‐yl)‐bi phenyl‐3‐carbonitrile (12): From 4‐cyanophenylboronic acid (80 mg). Yield: 35 mg (58 %) as a dark brown powder. M.p.: 264‐266 °C. Rf: 50. 1H NMR (600 MHz, DMSO‐d6, δ, ppm): 7.00 (br s, 1H, Harom.‐6'), 7.33‐7.56 (m, 4H, Harom.‐3' + H‐3(CH2) + Harom.‐6), 7.62‐7.64 (m, 3H, Harom.‐9 + Harom.‐4'+Harom.‐5'), 7.70‐ 7.73 (m, 1H, J = 7.8 Hz, Harom.‐5''), 7.86‐7.91 (d, 1H, J = 7.8 Hz, Harom.‐6''), 8.07‐8.14 (m, 1H, Harom.‐8), 8.30 (br s, 1H, Harom.‐2"), 8.43 (br s, 1H, Harom.‐4"). 13 C NMR (150.91 MHz, DMSO‐d6, δ, ppm): 49.8 (C‐3), 112.7 (CN), 119.1 (Carom.‐3"), 121.2 (Carom.‐3'), 129.1 (Carom.‐9), 129.2 (Carom.‐6), 129.3 (Carom.‐5"), 129.6 (Carom.‐5' + Carom.‐8), 129.8 (Carom.‐2"), 130.8 (Carom.‐6'), 131.9 (Carom.‐4"), 132.2 (Carom.‐6"), 132.4 (Carom.‐4'), 132.5 (Carom.‐2'), 135.3 (Carom.‐5a), 141.1 (Carom.‐1' + Carom.‐1"), 148.5 (Carom.‐9a), 156.8 (Carom.‐7), 162.8 (C‐2), 168.1 (C‐5). Anal. calcd. for C22H14N4O3: C, 69.10; H, 3.69; N, 14.65. Found: C, 68.82; H, 3.54; N, 14.41%. 5‐(4'‐Fluoro‐biphenyl‐2‐yl)‐7‐nitro‐3H‐benzo[e][1, 4] diaze pin‐2‐ol (13): From 4‐fluorophenylboronic acid (80 mg). Yield: 33 mg (55%) as a dark brown powder. M.p.: 261‐263 °C. Rf: 0.67. 1H NMR (600 MHz, DMSO‐d6, δ, ppm): 6.52 (br s, 1H, OH), 7.00 (br s, 1H, Harom.‐6'), 7.12‐7.14 (dd, 1H, J = 7.9,1.8 Hz, Harom.‐3'), 7.32‐7.45 (m, 7H, Harom.‐2" + Harom.‐6" + Harom.‐3" + Harom.‐5" + H‐3(CH2)+Harom.‐6), 7.55‐7.65 (m, 3H, Harom.‐9 + Harom.‐4', Harom.‐5'), 8.09 (br s, 1H, Harom.‐8). 13 C NMR (150.91 MHz, DMSO‐d6, δ, ppm):49.5 (C‐3), 114.6‐114.8 (Carom.‐ 3"+Carom.‐5"), 122.2 (Carom.‐3'), 127.7 (Carom.‐9), 129.19‐129.76 (Carom.‐6 + Carom.‐5'+Carom.‐8), 130.8 (Carom.‐2" + Carom.‐6"), 131.9‐ 132.0 (Carom.‐6'+ Carom.‐2'), 132.6 (Carom.‐4'), 135.3 (Carom.‐5a), 141.04 (Carom.‐1'+Carom.‐1"), 147.0 (Carom.‐7), 156.8 (Carom.‐9a), 159.0‐161.2 (Carom.‐4"), 162.81 (C‐2), 168.3 (C‐5). Anal. calcd. for C22H14FN3O3: C, 67.20; H, 3.76; N, 11.19. Found: C, 66.95; H, 3.59; N, 10.98%. 7‐Nitro‐5‐(4'‐trimethylsilanyl‐biphenyl‐2‐yl)‐3H‐benzo [e] [1,4]diazepin‐2‐ol (14): Form 4‐(trimethylsilyl)phenylboronic acid (90 mg). Yield: 39 mg (65%) as a dark brown powder. M.p.: 246‐248 °C. Rf: 0.54. 1H NMR (600 MHz, DMSO‐d6, δ, ppm): 0.18‐0.27 (m, 9H, SiMe3), 7.00 (br s, 1H, Harom.‐6'), 7.31‐ 7.35 (dd, 1H, J = 7.8, 1.9 Hz, Harom.‐6"), 7.41‐7.44 (m, 4H, Harom.‐5' + H‐3(CH2) +Harom.‐6), 7.47‐7.48 (d, 1H, J = 7.8 Hz, Harom.‐3"), 7.54‐7.57 (dd, 1H, J= 8.1, 1.8 Hz, Harom.‐9), 7.60‐7.65 (m, 3H, Harom.‐4' + Harom.‐3' + Harom.‐5"), 7.75‐7.77 (d, 1H, J = 7.8 Hz, Harom.‐2"), 8.03 (br s, 1H, Harom.‐8). 13 C NMR (150.91 MHz, DMSO‐d6, δ, ppm): 0.45 (SiMe3), 49.4 (C‐3), 119.0 (Carom.‐3') 126.8 (Carom.‐3" + Carom.‐5"), 127.9 (Carom.‐2"+Carom.‐6"), 129.4‐ 129.9 (Carom.‐9 + Carom.‐6 + Carom.‐5'+Carom.‐8), 130.9 (Carom.‐6'), 132.2 (Carom.‐4'), 132.7 (Carom.‐2'), 135.7 (Carom.‐5a), 141.3 (Carom.‐4"), 142.4 (Carom.‐1' + Carom.‐1"), 148.5 (Carom.‐7), 156.9 (Carom.‐9a), 162.7 (C‐2), 168.3 (C‐5). Anal. calcd. for C24H23N3O3Si: C, 67.11; H, 5.40; N, 9.78. Found: C, 66.90; H, 5.38; N, 9.52%. 5‐(3',4'‐Dimethoxy‐[1,1'‐biphenyl]‐2‐yl)‐7‐nitro‐3H‐benzo[e] [1,4]diazepin‐2‐ol (15): Form 3,4‐dimethoxyphenylboronic acid (80 mg). Yield: 38 mg (63%) as a brown red powder. M.p.: 241‐243 °C. Rf : 0.54. 1H NMR (600 MHz, DMSO‐d6, δ, ppm): 3.78 (d, 3H, OMe), 3.84 (d, 3H, OMe), 6.99‐7.01 (m, 2H, Harom.‐ 2"+Harom.‐6'), 7.14‐7.16 (dd, 1H, J= 7.8, 1.8 Hz, Harom.‐3'), 7.17 (d, 1H, J = 1.8 Hz, Harom.‐5"), 7.35‐7.36 (m, 1H, Harom.‐6"), 7.41‐ 7.44 (m, 4H, Harom.‐5'+H‐3(CH2)+Harom.‐6), 7.54‐7.56 (dd, 1H, Harom.‐9), 7.61‐7.63 (m, 1H, Harom.‐4'), 7.87 (br s, 1H, Harom.‐8). 13C NMR (150.91 MHz, DMSO‐d6, δ, ppm): 50.7 (C‐3), 56.1 (2×OMe), 110.9 (Carom.‐5"), 112.7 (Carom.‐2"), 119.0 (Carom.‐3'), 127.7 (Carom.‐6"), 127.2 (Carom.‐9), 129.2 (Carom.‐6), 129.6 (Carom.‐ 5'), 129.8 (Carom.‐8'), 130.8 (Carom.‐6'), 131.9 (Carom.‐4'), 131.9 (Carom.‐2'), 135.3 (Carom.‐5a), 141.1 (Carom.‐1'+Carom.‐1"), 148.5 (Carom.‐7), 149.4 (Carom.‐4"), 151.0 (Carom.‐3"), 156.8 (Carom.‐9a), 162.8 (C‐2), 168.3 (C‐5). Anal. calcd. for C23H19N3O5: C, 66.18; H, 4.59; N, 10.07. Found: C, 66.98; H, 3.67; N, 10.89%. 154 Salman and Abdul‐Rida / European Journal of Chemistry 7 (2) (2016) 152‐155 Scheme 1 2'‐(2‐Hydroxy‐7‐nitro‐3H‐benzo[e][1, 4]diazepin‐5‐yl)‐5‐ nitro‐[1,1'‐biphenyl]‐3‐carboxylic acid (16): From 3‐nitro‐5‐ nitrophenylboronic acid (90 mg). Yield: 39 mg (65%) as a brown powder. M.p.: 258‐260 °C. Rf : 0.55. 1H NMR (600 MHz, DMSO‐d6, δ, ppm): 6.30 (s, 1H, NH), 6.62‐6.64 (m, 3H, Harom.‐ 3'+Harom.‐4' + Harom.‐5'), 6.99‐7.00 (d, 1H, J = 7.8, Hz, Harom.‐6'), 7.41‐7.43 (m, 3H, H‐3(CH2) + Harom.‐9), 7.60‐7.63 (m, 2H, Harom.‐ 6+Harom.‐8), 8.51 (s, 1H, Harom.‐4b), 8.61 (s, 1H, ‐Harom.‐6b), 8.66‐ 8.67 (s, 1H, Harom.‐2b), 12.26 (s, 1H, CO2H). 13C NMR (150.91 MHz, DMSO‐d6, δ, ppm): 49.8 (C‐3), 120.1 (Carom.‐3'), 120.8 (Carom.‐4"), 127.6 (Carom.‐9), 128.3 (Carom.‐6), 129.0 (Carom.‐5'), 129.3 (Carom.‐8), 130.03 (Carom.‐6"), 131.1 (Carom.‐6'), 133.44 (Carom.‐2'+Carom.‐3"), 134.2 (Carom.‐4'), 134.5 (Carom.‐5a), 141.0 (Carom.‐1'+Carom.‐1"), 147.5 (Carom.‐7), 148.2 (Carom.‐3"), 155.4 (Carom.‐9a), 161.6 (C‐2), 168.1 (C‐5), 169.5 (CO2H). Anal. calcd. for C22H14N4O7: C, 59.20; H, 3.16; N, 12.55. Found: C, 58.98; H, 3.01; N, 12.31%. 3. Results and discussion Suzuki Cross‐coupling reaction [24] has been used in the preparation of new clonazepam analogues. Thus, treatment of clonazepam (4) with the appropriate arylboronic acids (e.g.: 4‐ methylsulfanylphenyl‐, 3‐cyanophenyl‐, 4‐fluorophenyl‐, 4‐tri methylsilylphenyl‐, 3,4‐dimethoxyphenyl‐, 5‐nitro‐3‐carboxy phenyl boronic acid (5‐10) using palladium(0) tetrakis‐ triphenylphosphine (Pd(0)(Ph3P)4) and sodium bicarbonate as catalyst in mix chloroform with MeOH as solvent afforded compound 11‐16 in 55‐67% (Scheme 1). The structure of compounds 11‐16 were assigned on the basis of their 1H and 13C NMR which showed similar patterns of aliphatic proton and carbon atoms .The 1H NMR spectra of compound 11‐16 were characterized by the presence of additional aromatic protons and carbon atoms, indicative for arylation of clonazepam backbone. The aromatic proton appeared at the region δ 6.62‐8.67 ppm, the diazepine ring protons (CH2) appeared at δ 7.32‐7.56 ppm, the other aliphatic protons and substituents have been fully identified (c.f. Experimental part). The compounds 11‐16 contain tauto‐ merism in amide bond so that appeared signal OH in compounds 11‐15, while signal NH in compound 16. Regarding the 1H NMR to see the OH and NH, in general, the 1H NMR spectra of some compounds do not show the OH and NH, either they appeared under the other signals or due to the use of DMSO‐d6 as a solvent. In the 13C NMR spectra of compound 11‐16, the aromatic carbon atoms appeared at δ 110.9‐156.9 ppm, the diazepine ring carbon atoms at δ 49.42‐50.96 ppm to C‐3, at δ 161.6‐ 162.8 ppm to C‐2, at δ 168.1‐168.3 ppm to C‐5. The other aliphatic carbon atoms and subtituents have been fully analysed (c.f. Experimental part). However, compound 11 has been selected for further NMR experiments [27‐29]. The HSQC NMR spectrum [30] of compound 11 showed JC,H correlations between Harom.‐3’ together with Harom.‐4’ at the region δ 7.61‐ 7.63 ppm and C‐3’ at δ 124.9 ppm as well as C‐4’ at δ 132.4 ppm. Furthmore, a correlation between Harom.‐6’ at δ 7.00 ppm and C‐6’ at δ 132.0 ppm is observed. In addition, a correlation between H‐6 at δ 7.42‐7.44 ppm and C‐6 at the region δ 129.2‐ 129.7 ppm is witnessed (Figure 2). Figure 2. JC,H correlations in the HSQC NMR spectrum of compound 11. In the gradient‐selected HMBC spectrum [30] of compound 11, C‐9a of the diazepin ring at δ 156.8 ppm showed a 3JC,H coupling with H‐8 of the same ring at δ 7.98 ppm. A 3JC,H coupling between Carom.‐2’ at δ 131.9‐132.0 ppm and Harom.‐6’’ at δ 7.62 ppm was observed. Another 3JC,H coupling was shown between Carom.‐1’’ at δ 141.1 ppm and Harom.‐3’ at δ 7.62 ppm. The spectrum showed a 2JC,H coupling between Carom.‐1’ at δ 141.1 ppm and Harom.‐6’ at δ 131.9‐132.0 ppm well (Figure 3). Figure 3. JC,H correlations in the HMBC NMR spectrum of compound 11. 4. 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