An “all-water” strategy for regiocontrolled synthesis of 2-aryl quinoxalines†

RSC Advances View Article Online Published on 09 January 2015. Downloaded by KU Leuven University Library on 22/01/2015 09:59:33. PAPER View Journal | View Issue An “all-water” strategy for regiocontrolled synthesis of 2-aryl quinoxalines† Cite this: RSC Adv., 2015, 5, 11873 Babita Tanwar, Priyank Purohit, Banothu Naga Raju, Dinesh Kumar, Damodara N. Kommi and Asit K. Chakraborti* A new synthetic strategy of tandem N-aroylmethylation-nitro reduction–cyclocondensation has been Received 17th December 2014 Accepted 9th January 2015 developed for the first and generalized regioselective synthesis of 2-aryl quinoxalines adopting “all water chemistry.” Water plays the critical role through hydrogen bond driven ‘synergistic electrophile– nucleophile dual activation’ for chemoselective N-aroylmethylation of o-nitroanilines, that underlines the DOI: 10.1039/c4ra16568c origin of the regioselectivity, as the use of organic solvents proved to be ineffective. Water also provides www.rsc.org/advances beneficial effects during the nitro reduction and the penultimate cyclocondensation steps. Introduction Quinoxalines exhibit a wide range of biological activities,1 represent the essential pharmacophoric feature of various drugs (Scheme 1)2 and nd versatile applications in materials science.3 These have triggered interest to develop synthetic methodologies for quinoxalines that involve the Lewis/Brönsted acid or Lewis base promoted reaction of o-phenylenediamines (commercially available or prepared in situ by reduction of the corresponding o-nitroanilines or 1,2-dinitrobenzenes) with various coupling partners such as 1,2-diketones (preformed or prepared in situ from acetylene derivatives), 1,2-ketomonoximes, a-hydroxyketones/a-haloketones, 1,2-diols, a-methyleno aldehydes/ketones, substituted epoxides, substituted nitroolens.4 However, regiocontrolled construction of the quinoxaline scaffold from unsymmetrical substrates (reacting/ coupling partners) remains elusive. Some of the reported procedures5 form regioisomeric mixtures while in all others4 the regioselectivity issue remained unaddressed/suppressed. It was Scheme 1 realized that the reported procedures4,5 involve simultaneous condensation of 1,2-bisnucleophiles with 1,2-bis-electrophilic coupling partners (Scheme 2) and hence are ought to be associated with the regioselectivity problem. This presses the necessity for a new synthetic design for regioselective construction of the quinoxaline moiety. Herein we present a new strategy of “all-water” tandem N-aroylmethylation–reduction–cyclocondensation process for one-pot synthesis of 2-aryl quinoxalines in regiodened manner (Scheme 3). Results and discussion As the N-aroylmethylation is the critical step, to test the feasibility of the metal and base-free C–N bond formation, in a model study o-nitroaniline (1a) was treated with a-bromoacetophenone (2a) (Scheme 3, R ¼ H) in various solvents to form 2-[(2-nitrophenyl)amino]-1-phenylethanone (3a) (Table 1). Excellent yields (91–92%) of 3a was obtained in water. The comparable results in tap, pure, and ultra pure water (entries 2– 4, Table 1) indicate that the N-benzoylmethylation is not inuenced by any dissolved metallic/organic impurities. The specic assistance of water in promoting the metal/base free N-benzoylmethylation is revealed by the fact that 3a was formed in poor yield under neat condition (entry 1, Table 1) and in hydrocarbon, halogenated hydrocarbon, ethereal, and aprotic A few quinoxaline-based drugs. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India. E-mail: akchakraborti@niper.ac.in; akchakraborti@rediffmail.com † Electronic supplementary 10.1039/c4ra16568c information (ESI) This journal is © The Royal Society of Chemistry 2015 available. See DOI: Scheme 2 Regioselectivity in the synthesis of quinoxalines. RSC Adv., 2015, 5, 11873–11883 | 11873 View Article Online RSC Advances Paper Table 2 N-Benzoylmethylation of o-nitroaniline (1a) under different conditiona 3 “All-water” N-aroylmethylation–reduction–cyclocondensation strategy for regiocontrolled synthesis of quinoxalines. Published on 09 January 2015. Downloaded by KU Leuven University Library on 22/01/2015 09:59:33. Scheme polar solvents (entries 10–20, Table 1). Alcohols (protic polar solvents) gave moderate yields (entries 5–9, Table 1). Further studies on the variation of different reaction parameters, such as the molar equivalents of 2a, amount of water, temperature, and time revealed the use of 1.0 molar equivalent of 2a in water (2 mL mmol 1 of 1a) at 110  C (oil bath) for 3 h to be the optimal condition (entry 19, Table 2). The synthetic potential of the water-assisted N-aroylmethylation of o-nitroanilines is demonstrated by the reaction of a few substituted o-nitroanilines 1 with substituted a-bromoacetophenones 2 to form 3 (Table 3). Table 1 Influence of the reaction medium for a metal/catalyst and base-free selective N-monobenzoylmethylation of 1a with 2aa Entry Solvent Temp ( C) ab bb Yieldc (%) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 None Tap water Pure waterd Ultra pure watere MeOH EtOH i PrOH t BuOH TFE Toluene Hexane DCE 1,4-Dioxane THF Acetone MeNO2 DMF DMA Formamide MeCN 110 Reux Reux Reux Reux Reux Reux Reux Reux Reux Reux Reux Reux Reux Reux Reux 110 110 110 Reux — 1.17 1.17 1.17 0.93 0.83 0.76 0.68 1.51 0.00 0.00 0.00 0.00 0.00 0.08 0.22 0.00 0.00 0.71 0.19 — 0.18 0.18 0.18 0.62 0.77 0.95 1.01 0.00 0.11 0.00 0.00 0.37 0.55 0.48 0.00 0.69 0.76 0.00 0.31 7 92 91 92 59 65 68 74 50 31 Trace 35 55 21 13 33 36 Nil 23 Trace Entry Water (mL) Temp ( C) Time (h) Equiv. of 2ab Yieldc (%) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 5 5 5 5 5 5 0.5 1 2 3 4 2 2 2 2 2 2 2 2 2 5 2 2 2 110 110 110 110 110 110 110 110 110 110 110 rt 60 80 110 120 110 110 110 110 110 rt 80 120 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 1 2 3 4 2 12 8 2 1.0 1.1 1.2 1.3 1.4 1.5 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 92 92 92 93 92 92 68 79 92 92 92 0 Traces 41 92 92 28 75 92 92 84 Nil 35 87 a a 1a (1 mmol) was treated with 2a (1.5 mmol, 1.5 equiv.) in the appropriate solvent (5 mL), except for entry 1, under heating at 110  C (oil bath) for 5 h. b The a and b values represent the hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) property of the solvent as provided under ref. 13. c Isolated yield. d Pure water was obtained by purication of normal/tap water through reverse osmosis and ionic/organic removal and has the resistivity of 15 MU at 25  C. e Ultrapure water was obtained by further subjecting pure water to UV treatment (185/254 nm), deionization and ultra membrane ltration (0.01 mm) under pressure up to 145 psi (10 bar) and has the resistivity of 18.2 MU at 25  C. 11874 | RSC Adv., 2015, 5, 11873–11883 1a (1 mmol) was treated with 2a under different reaction condition in the water as a reaction medium. b Molar equiv. with respect to 1a. Isolated yield of 3a. c The reported method for the preparation of N-phenacyl-onitroanilines involve the use of base in DMF for 48 h.6 Anilines are known to react with a-halogenated ketones to form indoles.7 The base/catalyst-free N-aroylmethylation of different onitroanilines (1) with different a-bromoacetophenones (2) in water to form 3a Table 3 Entry R1 R2 R3 Time (h) Yieldb (%) 1 2 3 4 5 6 H H Cl H CH3 CH3 H H H Cl H H H Cl H H H OMe 3 3 4 4 3 3 92 91 89 90 92 90 a 1 (1 mmol) was treated with 2 (1 mmol, 1 equiv.) in water (2 mL) at 110  C (oil bath) for stipulated time period. b Isolated yield of 3. This journal is © The Royal Society of Chemistry 2015 View Article Online Published on 09 January 2015. Downloaded by KU Leuven University Library on 22/01/2015 09:59:33. Paper Thus, the results of Table 3 exemplify an excellent metal and base-free C–N bond formation protocol for chemoselective synthesis N-phenacyl-o-nitroanilines. The role of water can be visualized by its ability to form hydrogen bond (HB) with the NH2 hydrogen of 1 (nucleophilic activation). The second molecule of the water dimer8 in turn forms HB with the Br atom of 2 (electrophilic activation) and brings the bromomethylene carbon in close proximity to the NH2 nitrogen of 1 in the H-bonded species (Scheme 4). Further, the carbonyl oxygen of 2 also participates in HB formation with another water dimer in which the second water molecule forms HB with the other NH2 hydrogen in 1. The array/network of HBs gives stability9 to the H-bonded cluster (Scheme 4) and facilitates ‘amphiphile nucleophilic–electrophilic dual activation.’10 The hydrogen-bond assisted/mediated formation of noncovalent adduct of the reactants and the promoter has been invoked in various organo-catalytic chemical reactions/ synthesis.11 The physico-chemical parameters (acceptor/donor number etc.) of the solvent oen play key role in organic reactions,12 and the HB involving the reactant and the solvent has signicant inuence.13 Therefore, the role of the reaction medium for N-aroylmethylation can be visualized through the formation of the HB adducts (Scheme 4) due to the hydrogen bond donor (HBD) (a scale) and hydrogen bond acceptor (HBA) (b scale) properties of the solvent.14 Although, the HBD property (a value) is expected to play the predominant role in activating the electrophile (2a) the HBA ability (b value) is also important as it determines the ability of the solvent to activate the nucleophile (amine nitrogen of 1a). Therefore, TFE gave inferior results due to its poor b value (entry 9, Table 1). The reduction of nitro group of 3a would form the intermediate 4a which on cyclocondensation would form the 2-phenyl quinoxaline 5a (Scheme 3, R ¼ H). However, treatment of 3a with In (2.5 equiv.) and 12 N HCl (5 equiv.)15 in water (2 mL) afforded 5a in 24% yield at 110  C (oil bath) aer 3 h (Table 4). Further studies on standardization of the reaction conditions revealed that the best result (90% yield) is obtained in using 5 equiv. of 2 N HCl (entry 3, Table 4). Organic solvents gave inferior results highlighting the benecial effect of water on the reduction due to enhanced solvation of the In3+ cation in water making the electron transfer more efficient.16 To nd out whether indium metal can be replaced by other less costly metals such as Fe, Zn, Mg, Sn, or SnCl2$2H2O, 3a was RSC Advances The effect of solvent and the amount of aq. HCl and In metal on the cascade reduction–cyclocondensation stepa Table 4 Entry Solvent In metal (mmol) aq. HCl (mL) Equiv.b Yieldc,d (%) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 2.5 2.5 2.5 2.5 2.5 2.5 2.0 1.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 5 5 5 4 3 2 5 5 5 5 5 5 5 5 5 5 5 5 Water Water Water Water Water Water Water Water EtOH Toluene Toluene Dioxane DCE MeCN DCE THF DMF None 12 N (0.4 mL) 6 N (0.8 mL) 2 N (2.5 mL) 2 N (2 mL) 2 N (1.5 mL) 2 N (1 mL) 2 N (2.5 mL) 2 N (2.5 mL) 12 N (0.4 mL) 12 N (0.4 mL) 2 N (2.5 mL) 12 N (0.4 mL) 12 N (0.4 mL) 12 N (0.4 mL) 12 N (0.4 mL) 12 N (0.4 mL) 12 N (0.4 mL) 2 N (2.5 mL) 24 59 90e,f 67 42 21 64 44 Trace 42 27 Nil Nil Nil Nil Nil Nil 14 a To the mixture of 3a (1 mmol) in water (2 mL, entries 1–6) or the specied organic solvent (4.1 mL, entries 7–15) was added In metal (1.5–2.5 equiv. as indicated against each entry) and the indicated amount (in ML) of aq. HCl at 110  C (oil bath) and the mixture was stirred magnetically for 3 h. b Molar equiv. of HCl. c Isolated yield of 5a. d The unreacted 3a remained unchanged and could be recovered wherever 5a was formed in poor yields. e Only trace amount of 5a was formed in performing the reaction at room temperature (35–40  C). f 5a was obtained in 63% yield in performing the reaction at 80  C. Table 5 The effect of different metals/reducing agent on the cascade reduction–cyclocondensation stepa Entry Metal Isolated Yield of 5a (%) 1 2 3 4 5 6 7 In Fe Zn Mg Al Sn SnCl2$2H2O 90 61 Traceb Traceb 25b 64 65 a The envisaged role of water in promoting N-aroylmethylation of 1 with 2 to form 3. Scheme 4 This journal is © The Royal Society of Chemistry 2015 To the mixture of 3a (1 mmol) in water (2 mL) was added metal or the indicated reducing agent (2.5 equiv.) and aq. HCl (2 N, 2.5 mL; 5 equiv.) at 110  C (oil bath) and the mixture was stirred magnetically for 3 h. b The unreacted 3a remained unchanged and could be recovered. RSC Adv., 2015, 5, 11873–11883 | 11875 View Article Online Published on 09 January 2015. Downloaded by KU Leuven University Library on 22/01/2015 09:59:33. RSC Advances Paper treated with different metals/reducing agent (2.5 equiv.) in aq. HCl (2 N 2.5 mL, 5 equiv.) (Table 5). Thus, the use of indium metal provided the best results. The product isolation was found to be tedious in case of aluminium due to gel formation in the reaction mixture. The use of Sn metal or its popularly used salt SnCl2$2H2O was also less effective.17 To determine whether Fe, Zn, Mg, Sn, or SnCl2$2H2O would offer similar benecial effect compared to Fe, Zn, Mg, Sn, or SnCl2$2H2O for the one pot tandem N-aroylmethylation– reduction–condensation, 1a was sequentially treated with 2a in water followed by different metals/reducing agent (2.5 equiv.) in aq. HCl (2 N 2.5 mL, 5 equiv.) to form 5a (Table 6). The best result was obtained in using indium metal. Herein also poor yields were obtained with Sn metal and SnCl2$2H2O.17 The poor yields of 5a obtained in organic solvents (Table 4) during the treatment of 3a with In/HCl raised the query as to whether the use of aqueous medium exerts benecial effect only for the nitro reduction or its benecial effect extends for the subsequent cyclocondensation step as well. To distinguish any role of water in the cyclocondensation of 4a to 5a, it was felt necessary to treat the preformed 4a in water as well as in organic solvents. However 4a could not be isolated by the In/HCl reduction of 3a, although the MS spectra of the crude reaction mixture exhibited ion peak corresponding to 4a. Attempts such as (i) Pd/C mediated hydrogenation of 3a (Scheme 5), and (ii) reaction of o-phenylenediamine (6) with 2a (Scheme 6) were unsuccessful and resulted in the formation of 5a in 35 and 60% yields, respectively. Thus, it was planned to prepare 8a [pro-4a] which would generate 4a in situ through N-Boc deprotection under acid/ metal-free condition (Scheme 7). Although a few methods18 The effect of different metals/reducing agent on the tandem N-aroylmethylation–reduction–cyclocondensation during the reaction of 1a with 2a to form 5aa Table 6 Entry Metal Isolated yield of 5a (%) 1 2 3 4 5 6 7 In Fe Zn Mg Al Sn SnCl2$2H2O 84 59 Traceb Traceb 15b 63 57 Pd-Catalysed hydrogenation of 2-[(2-nitrophenyl)amino]1-phenylethanone (3a). Scheme 5 Scheme 6 Reaction of o-phenylenediamine (6) with a-bromoacetophenone (2a). were reported for mono-N-Boc formation of 6, repetition of some of these led to the mixture of the mono- and di-N-Boc derivatives of 6 (Table 7). The mono-N-Boc 7a was obtained in 71% yield following modication of literature report18e and was treated with 2a in water to form 8a (Scheme 7). The acid/metal-free N-Boc deprotection is reported to take place in water19 and triuoroethanol (TFE)20 under heating. The treatment of 8a in water 110  C (oil bath) gave 5a in 82% yield aer 2 h (Scheme 8). This indicated that the cyclocondensation of the in situ formed 4a to 5a is promoted by water. However, 5a was formed in 15% yield by the treatment of 8a in TFE under reux for 24 h. No signicant amount of 5a was obtained by the treatment of 8a in TFE under reux for 5 h. The treatment of 8a in water (in place of TFE) under similar condition (80  C for 5 h) afforded 5a in 71% yield. Thus, water is the best solvent for the cyclocondensation step due its favourable a and b values that render a better ‘dual activation’ ability of water compared to organic solvents. The generality of the new strategy of ‘all water’ one-pot tandem N-aroylmethylation–reduction–condensation for synthesis of 2-aryl quinoxalines is demonstrated by sequential treatment of various o-nitroanilines with different a-bromoacetophenones in water under heating followed by treatment with In/HCl (2 N) (Table 8). Condensation of o-phenylenediamine with phenacyl bromide has been reported in water as well as organic solvents in the presence of organic/inorganic catalysts to form 2-phenylqunoxalines.4a,d–j,5c However, a catalyst-free protocol in water that would reect the distinct inuence of water in the N-aroylmethylation and subsequent cyclo-condensation step is lacking. Thus, to evaluate any distinct advantage of water over organic solvents 6 was treated with 2a in various solvents in the a 1a (1 mmol) was treated with 2a in water (2 mL) at 110  C (oil bath) for 3 h followed by addition of the metal/reducing agent (2.5 equiv.) and aq. HCl (2 N, 2.5 mL; 5 equiv.) at 110  C (oil bath) and the mixture was stirred magnetically for further 3 h. b The unreacted 1a and 2a remained unchanged. Scheme 7 11876 | RSC Adv., 2015, 5, 11873–11883 Synthesis of 8a. This journal is © The Royal Society of Chemistry 2015 View Article Online Paper RSC Advances Published on 09 January 2015. Downloaded by KU Leuven University Library on 22/01/2015 09:59:33. Table 7 Preparation of tert-butyl-(2-aminophenyl)carbamate (7a)a Yieldb (%) Entry (Boc)2O (equiv.) Catalyst (mol%) Solvent (amt) Temp ( C) Time (h) 7a 7b 1 2 3 4 5 1.2 1 1 1 1 Gu$HClc (15) LiClO4 (20) None Iodine (10) None EtOH (1 mL) DCM (2 mL) DCM (1 mL) Neat EtOH (4 mL) 35–40 30–40 0 35–40 30 3 5 2 4 0.5 52 42 64 35 71 28 23 21 35 22 a c Treatment of 6 (1 mmol) under different reaction condition in different solvents at specied temperature for specied time. Gu$HCl stands for guanidinium hydrochloride. absence of any added base/acid catalyst at 110  C (oil bath) (Table 9). The best yield obtained in water clearly reect the distinct advantage of water as the reaction medium for the tandem N-aroylmethylation-cyclocondensation. Comparable yield (74%) obtained in performing the reaction in water in the presence of K2CO3 (1 equiv.) (Table 9, entry 2, footnote d) rules out the possibility of any essential role of the liberated HBr (during the initial N-aroylmethylation step) for the nal cyclocondensation. The signicant role of the solvent (Table 9) in the nal cyclocondensation step can be demonstrated by the best results are obtained in water that acts both as good hydrogen bond donor and hydrogen bond acceptor with the second best results obtained in EtOH. The lesser yield obtained in TFE compared to that in water and EtOH is the clear reection of the inferior hydrogen bond acceptor ability of TFE. The use of 1,4-dioxane afforded the next best result due to its appreciable hydrogen bond acceptor ability (to activate the amino group of the intermediately formed 4a). The better result in 1,4-dioxane compared to that of THF could be due to the chelation effect of the two oxygen atoms in the former to form the HB with the NH2 group more effectively. The inferior yields in DMF, MeCN and toluene are also reection of the unfavourable hydrogen bond donor/acceptor ability of these solvents. Although the quinoxaline formation by a direct condensation of 6 with 2a becomes feasible in water under catalyst-free condition, the reaction of unsymmetrical o-phenylenediamine with phenacyl bromide is expected to form regioisomeric Scheme 8 Acid/metal-free cyclocondensation of 7a to form 5a. This journal is © The Royal Society of Chemistry 2015 b Isolated yield. quinoxalines as has been observed in one of the literature reports.5c However, the regioselectivity issue remained unaddressed/suppressed in the other reported methodologies.4a,d–j To throw light on this regioselectivity issue and establish the distinctiveness of the “all water” strategy of the Naroylmethylation–nitro reduction–cyclocondensation cascade for regioselective synthesis of 2-aryl quinoxalines, the condensation of 4-chloro-1,2-phenylenediamine 9 with phenacyl Table 8 ‘All water’ cascade synthesis of 2-aryl quinoxalinesa Entry R1 R2 R3 R4 Timeb (h) Yieldc (%) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 H H H H H Cl Cl Cl Cl H H H H Me Me OMe H H H H H H H H H Cl Cl Cl Cl H H H H H OMe H H H H H H H H H H H H H H OMe H Cl Br H OMe Cl Br H OMe Cl Br OMe Br H 5 5 5 5 5 6 6 6 6 6 6 6 6 5 5 5 86 83 84 82 84 81 80 82 80 83 81 82 83 80 80 82 a 1 (1 mmol) was treated with 2 (1 mmol, 1 equiv.) in water (2 mL) at 110  C (oil bath) for 3 h followed by addition of In (2.5 mmol, 2.5 equiv.), 2 N HCl (2.5 mL, 5 mmol, 5 equiv.) and allowed to proceed for remaining time. b Total time for the one-pot reaction. c Isolated yield of 5. RSC Adv., 2015, 5, 11873–11883 | 11877 View Article Online RSC Advances Paper with literature reports.5i,l On the other hand, the reaction of 4-chloro-2-nitroaniline with phenacyl bromide following the tandem N-aroylmethylation–reduction–cyclocondensation strategy resulted in exclusive formation of one of the regioisomeric quinoxalines without any concomitant formation of the other regioisomer (entry 10, Table 8). This clearly demonstrates the distinct advantage of this new synthetic strategy. The unambiguous route of construction of the quinoxaline scaffold under the present method forms the basis of regioselectivity control. Reaction of 6 with 2a in various solvents under catalyst-free conditiona Published on 09 January 2015. Downloaded by KU Leuven University Library on 22/01/2015 09:59:33. Table 9 Entry Solvent Temp ( C) Yieldb (%) 1 2 3 4 5 6 7 8 9 Water Water EtOH Toluene 1,4-Dioxane THF DMF MeCN TFE 80 Reux Reux Reux Reux Reux 110 Reux Reux 62 79, 71c and 74d 65 40 61 47 52 45 40 Conclusions A new synthetic strategy of ‘all water’ tandem aroylmethylation– nitro reduction–cyclocondensation is reported for the rst and generalized regioselective synthesis of 2-aryl quinoxalines. Water plays the critical role through hydrogen bond driven ‘synergistic electrophile nucleophile dual activation’ during the N-aroylmethylation and provides the basis of quinoxaline formation in regiodened manner. Water also exerts benecial effect during the nitro reduction–cyclocondensation cascade and makes this synthetic strategy a true example of ‘all-water chemistry.’ a 6 (1 mmol) was treated with 2a in the specic solvent (2 mL) at 80/ 110  C (oil bath temperature) for 4 h (unless specied). b Isolated yield of 5a. c The yield of 5a in performing the reaction for 3 h. d The yield of 5a in performing the reaction for 3 h in the presence of K2CO3 (1 equiv.). Experimental section bromide was performed in water as well as in organic solvents under the reported reaction conditions4a,d–j,5c (Table 10). In all of these cases the isolated product on being subjected to 1H NMR analyses revealed to be a mixture of the regioisomeric products. In each case, the pure regioisomers were isolated through ash column chromatography and were identied as A and B based on the spectral data of authentic compounds (products of entries 6 and 10, respectively, of Table 8) and on comparison General remarks The glasswares used were thoroughly washed and dried in an oven and the experiments were carried out with required precautions. Chemicals and all solvents were commercially available and used without further purication. The TLC experiments were performed on silica gel GF-254 and visualized under UV at 254 nm. Evaporation of solvent was performed at Table 10 Reaction of I with 2a under the reported reaction conditionsa Yieldd (%) Entry Catalystb (mol%) Solvent Temp ( C) Time (h) (A : B)c A B 1 2 3 4 5 6 7 8 9 Pyridine (10) — b-CD (1 equiv.) TMSCl (1 equiv.) CTAB (20) HClO4–SiO2 (50 mg) TBAB (20) + K2CO3 (2 equiv.) DABCO (20) — THF PEG-400 Water Water Water MeCN Water THF Water rt 80 70 70 10 rt Rt-70 rt 110 2 8 3 8 8 1 4.5 1 7 20 : 80 83 : 17 79 : 21 86 : 14 34 : 65 22 : 77 72 : 28 32 : 67 58 : 42 25 65 63 51 25 15 51 12 33 45 15 21 12 62 63 18 62 41e a I (1 mmol) was treated with 2a under the various reported reaction conditions. b Lit ref. 4a, e–j, and 5c for entries 1–8, respectively. c Regioisomeric distribution based on Ha and Hb proton integration value in the 1H NMR of the crude reaction mixture. d Isolated yield aer ash column chromatography. e Data generated under the condition of the present study. 11878 | RSC Adv., 2015, 5, 11873–11883 This journal is © The Royal Society of Chemistry 2015 View Article Online Published on 09 January 2015. Downloaded by KU Leuven University Library on 22/01/2015 09:59:33. Paper RSC Advances reduced pressure using a rotary evaporator. Melting points were measured using a melting point apparatus and were uncorrected. The 1H and 13C NMR spectra were recorded on a 400 MHz NMR spectrometer in CDCl3 with residual undeuterated solvent (CHCl3: 7.26/77.0) using Me4Si as an internal standard. The chemical shi (d) values are given in ppm and J values are given in Hz. The 13C NMR spectra were fully decoupled and were referenced to the middle peak of the solvent CDCl3 at 77.00 ppm. Splitting pattern were designated as s, singlet; bs, broad singlet; d, doublet; dd, doublet of doublet; t, triplet; dt, doublet of triplet and m, multiplet. The mass spectra (MS) were recorded under atmospheric pressure chemical ionization (APCI) and electrospray ionization (ESI). The high resolution mass spectra (HRMS) were recorded under electrospray ionization (ESI). The infra-red (IR) spectra were recorded in the range of 4000–600 cm 1 as KBr pellets for all solid samples. (M + H)+. HRMS (ESI) m/z calcd for C14H12N2O3Na+ [M + Na+], 279.0740; found 279.0740. Preparation of pure water (15 MU cm resistivity at 25  C) Typical procedure for ‘all water’ one-pot tandem Naroylmethylation–reduction–condensation for synthesis of 2-aryl quinoxalines The pure water was prepared by subjecting the tap water for reverse osmosis and ionic/organic removal by passing through pre-packed cartridge. Preparation of ultrapure water (18.2 MU cm resistivity at 25  C) The ultrapure water was prepared by subjecting the pure water for UV treatment (185/254 nm UV Lamp), deionization by passing through deionization cartridge followed by ultra membrane ltration (0.01 mm) under pressures up to 145 psi (10 bar). Ultrapure water (UPW) is generally considered to be $18.2 MU cm resistivity at 25  C, low ppt in metals, less than 50 ppt in inorganic anions and ammonia, less than 0.2 ppb in organic anions, and below 1 ppb total organic carbon (TOC) and silica (dissolved and colloidal). Typical procedure for selective mono-N-benzoylmethylation of o-nitroaniline (1a) The mixture of o-nitroaniline 1a (138 mg, 1 mmol) and a-bromoacetophenone 2a (199 mg, 1 mmol, 1 equiv.) in water (2 mL) was stirred magnetically at 110  C (oil-bath). Aer completion of the reaction (3 h, TLC), the reaction mixture was extracted with EtOAc (3  5 mL). The combined EtOAc extracts were dried (anh Na2SO4), ltered, and the ltrate was concentrated under rotary vacuum evaporation. The crude product was adsorbed on silica gel (230–400 mesh size, 500 mg), charged on to a ash chromatography column of silica-gel (230–400 mesh size, 2.5 g), and eluted with hexane–EtOAc (95 : 5) to obtain analytically pure 2-((2-nitrophenyl)amino)-1-phenylethanone (Table 2, entry 1) (3a) as yellow solid (236 mg, 92%); mp ¼ 147–149  C; IR (KBr) nmax ¼ 3433, 2926, 2872, 1735, 1619, 1570, 1514, 1453, 1352, 1259, 1106, 951, 749 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 8.92 (bs, 1H), 8.25 (dd, J ¼ 1.5, 8.5 Hz, 1H), 8.07–8.05 (m, 2H), 7.69–7.65 (m, 1H), 7.58–7.48 (m, 3H), 6.84–6.82 (m, 1H), 6.76–6.72 (m, 1H), 4.80 (d, J ¼ 4.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz, TMS) d: 192.71, 143.97, 136.22, 134.44, 134.22, 132.70, 129.04, 127.89, 127.08, 115.98, 114.14, 49.42; MS (APCI) m/z: 257 This journal is © The Royal Society of Chemistry 2015 Typical procedure for the cascade reduction–condensation of 3a to 5a To the mixture of 2-[(2-nitrophenyl)amino]-1-phenylethanone 3a (256 mg, 1 mmol) in water (2 mL) was added In metal (287 mg, 2.5 mmol, 2.5 equiv.) and 2 N HCl (2.5 mL, 5 mmol, 5 equiv.), and the mixture was stirred magnetically at 110  C (oil-bath) for 3 h (TLC). The reaction mixture was extracted with EtOAc (3  5 mL). The combined EtOAc extracts were dried (anh Na2SO4), ltered, and the ltrate was concentrated under rotary vacuum evaporation. The crude product was adsorbed on silica gel (230–400 mesh size, 500 mg), charged on to a ash chromatography column of silica-gel (230–400 mesh size, 2.5 g), and eluted with hexane–EtOAc (99 : 1) to obtain analytically pure 5a as a pale orange solid (185 mg, 90%)4a (Table 4). Synthesis of 5a. The mixture of o-nitroaniline 1a (138 mg, 1 mmol) and a-bromoacetophenone 2a (199 mg, 1 mmol, 1 equiv.) in water (2 mL) was stirred magnetically at 110  C (oil-bath) for 3 h followed by addition of In (287 mg, 2.5 mmol, 2.5 equiv.), 2 N HCl (2.5 mL, 5 mmol, 5 equiv.) and the reaction mixture was allowed to stir till the completion of reaction (2 h, TLC). The reaction mixture was extracted with EtOAc (3  5 mL). The combined EtOAc extracts were dried (anh Na2SO4), ltered, and the ltrate was concentrated under rotary vacuum evaporation. The crude product was recrystallized from EtOH to afford analytically pure 2-phenylquinoxaline (Table 8, entry 1) (5a) as a pale orange solid (177 mg, 86%). mp ¼ 75–76  C; nmax ¼ 3005, 2325, 1275, 1260, 764, 750 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.26 (s, 1H), 8.15–8.05 (m, 4H), 7.72–7.65 (m, 2H), 7.52–7.45 (m, 3H); 13C NMR (CDCl3, 100 MHz, TMS) d: 151.68, 143.26, 142.21, 141.53, 136.69, 130.19, 130.13, 129.57, 129.45, 129.07, 127.48; MS (ESI) m/z: 207 (M + H)+.4a In an alternative purication procedure the crude product was adsorbed on silica gel (230–400 mesh size, 500 mg), charged on to a ash chromatography column of silica-gel (230–400 mesh size, 2.5 g), and eluted with hexane–EtOAc (99 : 1) to obtain analytically pure 2-phenylquinoxaline (Table 8, entry 1) (5a) as a pale orange solid (173 mg, 84%). In general, the purication was made by crystallization except for low melting (<65  C) compounds wherein the purication was made through column chromatography. Experimental procedure for the various attempts for the synthesis of 2-((2-aminophenyl)amino)-1-phenylethanone (4a) Pd-catalysed hydrogenation of 2-[(2-nitrophenyl)amino]-1phenylethanone (3a) (Scheme 5). Pd/C (5%) (10 mg) was added to the of 3a (256 mg, 1 mmol) in toluene (10 mL) and kept under H2 atmosphere at room temperature at 40 psi pressure. Aer 6 h, the Pd/C was removed by ltration and the ltrate was concentrated under rotary vacuum evaporation. The crude RSC Adv., 2015, 5, 11873–11883 | 11879 View Article Online Published on 09 January 2015. Downloaded by KU Leuven University Library on 22/01/2015 09:59:33. RSC Advances product was adsorbed on silica gel (230–400 mesh size, 500 mg), charged on to a ash chromatography column of silica-gel (230–400 mesh size, 2.5 g), and eluted with hexane–EtOAc (99 : 1) to obtain analytically pure 5a as a pale orange solid (72 mg, 35%).4a Reaction of o-phenylenediamine (6) with a-bromoacetophenone (2a) (Scheme 6). To the mixture of o-phenylenediamine (6) (108 mg, 1 mmol) and a-bromoacetophenone (2a) (199 mg, 1 mmol, 1 equiv.) in MeCN (2 mL) was added K2CO3 (276 mg, 2 mmol, 2 equiv.) and stirred magnetically under reux condition. Aer completion of the reaction (4 h, TLC), the reaction mixture was extracted with EtOAc (3  5 mL). The combined EtOAc extracts were dried (anh Na2SO4), ltered, and the ltrate was concentrated under rotary vacuum evaporation. The crude product was adsorbed on silica gel (230–400 mesh size, 500 mg), charged on to a ash chromatography column of silica-gel (230–400 mesh size, 2.5 g), and eluted with hexane– EtOAc (99 : 1) to obtain analytically pure 5a as a pale orange solid (123 mg, 60%).4a Experimental procedure for the synthesis of tert-butyl-(2-[(2oxo-2-phenylethyl)aminophenyl]carbamate (8a) (Scheme 7/ Table 7) Step 1: preparation of tert-butyl-(2-aminophenyl)carbamate (7a). o-Phenyldiamine (6) (108 mg, 1 mmol) was stirred at 30  C in absolute EtOH (2 mL), and di-tert-butyl dicarbonate (218 mg, 1.1 mmol, 1.1 equiv.), dissolved in absolute EtOH (2 mL), was added dropwise to the reaction mixture. Aer 30 min, the solvent was evaporated to dryness, and the crude material. The crude product was adsorbed on silica gel (230–400 mesh size, 500 mg), charged on to a ash chromatography column of silica-gel (230–400 mesh size, 2.5 g), and eluted with hexane– EtOAc (96 : 4) to obtain analytically pure tert-butyl-(2-aminophenyl)carbamate (7a) as a white solid (147 mg, 71%); mp ¼ 110–113  C; IR (KBr) nmax ¼ 3414, 3356, 2973, 1896, 1682, 1595, 1490, 1456, 1387, 1366, 1162, 1054, 1027, 850, 749 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 7.28–7.27 (m, 1H), 7.00 (dt, J ¼ 1.36, 7.6 Hz, 1H), 6.81–6.75 (m, 2H), 6.35 (bs, 1H), 3.75 (bs, 2H), 1.52 (s, 9H); 13C NMR (CDCl3, 100 MHz, TMS) d: 153.91, 139.99, 126.13, 124.77, 119.56, 117.57, 80.50, 28.35; MS (ESI) m/z: 209 (M + H)+. HRMS (ESI) m/z calcd for C11H16N2O2Na+ [M + Na+], 231.1109; found 231.1114.18e Di-tert-butyl-1,2-phenylenedicarbamate (7b). White solid (65 mg, 22%); mp ¼ 105–106  C; IR (KBr) nmax ¼ 3307, 2978, 2931, 1699, 1601, 1527, 1457, 1248, 1158, 1049, 1025, 749 cm 1; 1 H NMR (CDCl3, 400 MHz, TMS) d: 7.47 (bs, 2H), 7.11 (s, 2H), 6.89 (s, 2H), 1.52 (s, 18H); 13C NMR (CDCl3, 100 MHz, TMS) d: 153.90, 130.29, 125.31, 124.22, 80.76, 28.46; MS (ESI) m/z: 309 (M + H)+.18a Step 2 (Scheme 7): synthesis of tert-butyl-(2-[(2-oxo-2phenylethyl)aminophenyl]carbamate (8a) from 7a. The mixture of tert-butyl-2-aminophenylcarbamate (7a) (208 mg, 1 mmol) and a-bromoacetophenone (2a) (199 mg, 1 mmol, 1 equiv.) in water (2 mL) was stirred magnetically at rt. Aer completion of the reaction (12 h, TLC), the reaction mixture was extracted with EtOAc (3  5 mL). The combined EtOAc extracts 11880 | RSC Adv., 2015, 5, 11873–11883 Paper were dried (anh Na2SO4), ltered, and the ltrate was concentrated under rotary vacuum evaporation. The crude product was adsorbed on silica gel (230–400 mesh size, 500 mg), charged on to a ash chromatography column of silica-gel (230–400 mesh size, 2.5 g), and eluted with hexane–EtOAc (94 : 6) to obtain analytically pure 8a as a light yellow solid (189 mg, 58%); mp ¼ 130–132  C; IR (KBr) nmax ¼ 3368, 2925, 1698, 1607, 1498, 1449, 1356, 1248, 1166, 1048, 739 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 8.03 (d, J ¼ 7.4 Hz, 2H), 7.64 (t, J ¼ 7.36 Hz, 1H), 7.53 (t, J ¼ 7.72 Hz, 2H), 7.39 (t, J ¼ 7.04 Hz, 1H), 7.15–7.11 (m, 1H), 6.81 (t, J ¼ 7.44 Hz, 1H), 6.74 (d, J ¼ 7.96 Hz, 1H), 6.27 (s, 1H), 4.99 (bs, 1H), 4.61 (bs, 2H), 1.56 (s, 9H); 13C NMR (CDCl3, 100 MHz, TMS) d: 195.22, 154.16, 141.16, 134.93, 133.89, 128.92, 127.78, 126.58, 125.60, 124.68, 118.59, 112.93, 80.57, 50.75, 28.36; MS (ESI) m/z: 237 (M + H)+. HRMS (ESI) m/z calcd for C19H22N2O3Na+ [M + Na+], 349.1528; found 349.1545. Experimental procedure for the synthesis of 5a from 8a (Scheme 8) The mixture of tert-butyl-(2-[(2-oxo-2-phenylethyl)aminophenyl]carbamate (8a) (326 mg, 1 mmol) in water (3 mL) was stirred magnetically at 110  C (oil-bath). Aer completion of the reaction (2 h, TLC), the reaction mixture was extracted with EtOAc (3  5 mL). The combined EtOAc extracts were dried (anh Na2SO4), ltered, and the ltrate was concentrated under rotary vacuum evaporation. The crude product was adsorbed on silica gel (230–400 mesh size, 500 mg), charged on to a ash chromatography column of silica-gel (230–400 mesh size, 2.5 g), and eluted with hexane–EtOAc (99 : 1) to obtain analytically pure 5a as a pale orange solid (168 mg, 82%).4a Experimental procedure for the synthesis of 5a from 8a (Scheme 8) The mixture of tert-butyl-(2-[(2-oxo-2-phenylethyl)aminophenyl]carbamate (8a) (326 mg, 1 mmol) in TFE (3 mL) was stirred magnetically at 90  C (oil-bath). Aer completion of the reaction (24 h, TLC), the reaction mixture was extracted with EtOAc (3  5 mL). The combined EtOAc extracts were dried (anh Na2SO4), ltered, and the ltrate was concentrated under rotary vacuum evaporation. The crude product was adsorbed on silica gel (230–400 mesh size, 500 mg), charged on to a ash chromatography column of silica-gel (230–400 mesh size, 2.5 g), and eluted with hexane–EtOAc (99 : 1) to obtain analytically pure 5a as a pale orange solid (31 mg, 15%).4a 1-(4-Chlorophenyl)-2-[(2-nitrophenyl)amino]ethanone (Table 3, entry 2). Yellow solid (266 mg, 91%); mp ¼ 153–156  C; IR (KBr) nmax ¼ 2981, 1275, 1260, 1054, 1033, 764, 750 cm 1; 1 H NMR (CDCl3, 400 MHz, TMS) d: 8.87 (bs, 1H), 8.24 (dd, J ¼ 1.52, 8.52 Hz, 1H), 7.99 (dd, J ¼ 1.84, 6.8 Hz, 2H), 7.53–7.46 (m, 3H), 6.81–6.72 (m, 2H), 4.76 (d, J ¼ 4.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz, TMS) d: 191.64, 143.86, 140.80, 138.96, 136.24, 129.45, 129.30, 127.17, 116.17, 114.05, 49.43; MS (APCI) m/z: 291 (M + H)+. HRMS (ESI) m/z calcd for C14H11ClN2O3Na+ [M + Na+], 313.0350; found 313.0349. 2-[(4-Chloro-2-nitrophenyl)amino]-1-phenylethanone (Table 3, entry 3). Yellow solid (258 mg, 89%); mp ¼ 158–160  C; IR This journal is © The Royal Society of Chemistry 2015 View Article Online Published on 09 January 2015. Downloaded by KU Leuven University Library on 22/01/2015 09:59:33. Paper (KBr) nmax ¼ 3342, 3005.58, 1691, 1628, 1561.90, 1517, 1402, 1351, 1275, 1261, 1156, 1070, 808, 764, 750 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 8.89 (bs, 1H), 8.24 (d, J ¼ 2.36 Hz, 1H), 8.04 (d, J ¼ 7.52 Hz, 2H), 7.67 (t, J ¼ 7.4 Hz, 1H), 7.55 (t, J ¼ 7.76 Hz, 2H), 7.44 (dd, J ¼ 2.36, 9.04 Hz, 1H), 6.79 (d, J ¼ 9.04 Hz, 1H), 4.77 (d, J ¼ 4.24 Hz, 2H); 13C NMR (CDCl3, 100 MHz, TMS) d: 192.30, 142.62, 136.28, 134.38, 134.30, 129.11, 127.92, 126.32, 120.83, 115.54, 49.44; MS (APCI) m/z: 291 (M + H)+. HRMS (ESI) m/z calcd for C14H11ClN2O3Na+ [M + Na+], 313.0350; found 313.0350. 2-[(5-Chloro-2-nitrophenyl)amino]-1-phenylethanone (Table 3, entry 4). Yellow solid (262 mg, 90%); mp ¼ 155–158  C; IR (KBr) nmax ¼ 3362, 2924, 1695, 1623, 1491, 1275, 1259, 1078, 750 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.00 (bs, 1H), 8.20 (d, J ¼ 9.08 Hz, 1H), 8.06 (d, J ¼ 1.2 Hz, 2H), 7.69 (t, J ¼ 7.44 Hz, 1H), 7.57 (t, J ¼ 8 Hz, 2H), 6.84 (d, J ¼ 1.96 Hz, 1H), 6.72 (dd, J ¼ 2, 9.14 Hz, 1H), 4.78 (d, J ¼ 4.28 Hz, 2H); 13C NMR (CDCl3, 100 MHz, TMS) d: 192.12, 144.41, 142.70, 134.41, 134.23, 130.17, 129.28, 129.11, 128.52, 128.32, 127.96, 116.48, 113.71 49.39; MS (ESI) m/z: 291 (M + H)+. HRMS (ESI) m/z calcd for C14H11ClN2O3Na+ [M + Na+], 313.0350; found 312.1499. 2-[(4-Methyl-2-nitrophenyl)amino]-1-phenylethanone (Table 3, entry 5). Light yellow solid (248 mg, 92%); mp ¼ 162–164  C; IR (KBr) nmax ¼ 3362, 2923, 1742, 1692, 1637, 1561, 1528, 1275, 1155, 750 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 8.78 (bs, 1H), 8.06 (d, J ¼ 7.56 Hz, 3H), 7.67 (t, J ¼ 7.36 Hz, 1H), 7.56 (t, J ¼ 7.56 Hz, 2H), 7.33 (d, J ¼ 8.52 Hz, 1H), 6.75 (d, J ¼ 8.6 Hz, 1H), 4.78 (d, J ¼ 4.28 Hz, 2H), 2.31 (s, 3H); 13C NMR (CDCl3, 100 MHz, TMS) d: 192.91, 142.19, 137.62, 134.52, 134.17, 132.33, 129.03, 127.89, 126.44, 125.59, 114.12, 49.55, 20.01; MS (APCI) m/z: 271 (M + H)+. HRMS (ESI) m/z calcd for C15H14N2O3Na+ [M + Na+], 293.0897; found 293.0785. 1-(4-Methoxyphenyl)-2-[(4-methyl-2-nitrophenyl)amino] ethanone(Table 3, entry 6). Yellowish orange solid (270 mg, 90%); mp ¼ 128–130  C; IR (KBr) nmax ¼ 3364, 2912, 1676, 1632, 1600, 1560, 1524, 1424, 1348, 1262, 1241, 1181, 764 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 8.75 (bs, 1H), 8.01 (s, 2H), 7.99 (d, J ¼ 1.96 Hz, 1H), 7.28 (dd, J ¼ 2, 14.5 Hz, 1H), 6.99 (d, J ¼ 1.9 Hz, 2H), 6.71 (d, J ¼ 8.6 Hz, 1H), 4.68 (d, J ¼ 4.4 Hz, 2H), 3.88 (s, 3H), 2.27 (s, 3H); 13C NMR (CDCl3, 100 MHz, TMS) d: 191.31, 164.26, 142.30, 137.59, 132.32, 132.20, 127.51, 126.42, 125.42, 114.18, 113.75, 55.61, 49.15, 20.00; MS (ESI) m/z: 301 (M + H)+. HRMS (ESI) m/z calcd for C16H16N2O4Na+ [M + Na+], 323.1008; found 323.1005. 2-(4-Methoxyphenyl)quinoxaline (Table 8, entry 2).5k Light yellow solid (377 mg, 83%); mp ¼ 97–98  C; IR (KBr) nmax ¼ 2926, 1606, 1584, 1274, 1252, 1175, 1028, 834, 763 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.28 (s, 1H), 8.18–8.07 (m, 4H), 7.76–7.67 (m, 2H), 7.08–7.04 (m, 2H), 3.87 (s, 3H); 13C NMR (CDCl3, 100 MHz, TMS) d: 161.45, 151.37, 143.04, 142.30, 141.20, 130.14, 129.39, 129.26, 129.07, 129.01, 128.95, 114.56, 55.41; MS (ESI) m/z: 237 (M + H)+. 2-(3-Methoxyphenyl)quinoxaline (Table 8, entry 3).5k Light yellowish orange solid (198 mg, 84%); mp ¼ 87–88  C; IR (KBr) nmax ¼ 3434, 2918, 2846, 2225, 1733, 1275, 1260, 1022, 750 cm 1; 1 H NMR (CDCl3, 400 MHz, TMS) d: 9.36 (s, 1H), 8.19–8.13 (m, 2H), 7.92 (dd, J ¼ 1.8, 7.64 Hz, 1H), 7.80–7.74 (m, 2H), 7.52– 7.48 (m, 1H), 7.22–7.17 (m, 1H), 7.09 (d, J ¼ 8.24 Hz, 1H), 3.93 (s, 3H); 13C NMR (CDCl3, 100 MHz, TMS) d: 157.40, 152.23, This journal is © The Royal Society of Chemistry 2015 RSC Advances 147.30, 142.71, 141.06, 131.61, 131.44, 129.76, 129.55, 129.37, 129.07, 126.56, 121.54, 111.43, 55.65; MS (ESI) m/z: 237 (M + H)+. 2-(4-Chlorophenyl)quinoxaline (Table 8, entry 4).4a Light orange solid (197 mg, 82%); mp ¼ 120–122  C; IR (KBr) nmax ¼ 3004, 2325, 1260, 1275, 764, 750 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.31 (s, 1H), 8.19–8.13 (m, 4H), 7.83–7.75 (m, 2H), 7.57–7.54 (m, 2H); 13C NMR (CDCl3, 100 MHz, TMS) d: 150.59, 142.87, 142.22, 141.66, 136.59, 135.19, 130.48, 129.79, 129.60, 129.41, 129.17, 128.78; MS (ESI) m/z: 241 (M + H)+. 2-(4-Bromophenyl)quinoxaline (Table 8, entry 5).5k Light brown solid (238 mg, 84%); mp ¼ 138  C; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.29 (s, 1H), 8.15–8.07 (m, 4H), 7.82–7.74 (m, 2H), 7.71–7.68 (m, 2H); 13C NMR (CDCl3, 100 MHz, TMS) d: 150.66, 142.83, 142.22, 141.68, 135.62, 132.80, 130.37, 131.88, 130.52, 129.84, 129.60, 129.18, 129.02, 125.00; MS (ESI) m/z: 284 (M + H)+. 7-Chloro-2-phenylquinoxaline (Table 8, entry 6).5i Light orange solid (194 mg, 81%); mp ¼ 104–106  C; IR (KBr) nmax ¼ 3047, 2922, 2852, 1606, 1539, 1483, 1449, 1404, 1314, 1131, 1073, 958, 913, 834, 758, 686, 666 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.30 (s, 1H), 8.20–8.14 (m, 3H), 8.04 (d, J ¼ 8.92 Hz, 1H), 7.68 (dd, J ¼ 2.16, 8.84 Hz, 1H), 7.58–7.55 (m, 3H); 13C NMR (CDCl3, 100 MHz, TMS) d: 152.48, 143.38, 142.62, 140.07, 136.27, 136.07, 130.56, 130.48, 130.34, 129.21, 128.95, 128.49, 127.84, 127.60; MS (ESI) m/z: 240 (M)+. 7-Chloro-2-(4-methoxyphenyl)quinoxaline (Table 8, entry 7).5i Off-white solid (216 mg, 80%); mp ¼ 103–105  C; IR (KBr) nmax ¼ 2922, 1607, 1539, 1487, 1258, 1225, 1181, 1125, 1071, 1025, 957, 914, 841, 827, 750, 571, 515 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.30 (d, J ¼ 5.92 Hz, 1H), 8.19 (dd, J ¼ 3.04, 8.76 Hz, 2H), 8.12 (dd, J ¼ 2.12, 10.88 Hz, 1H), 8.08–8.03 (m, 1H), 7.73–7.66 (m, 1H), 7.10 (d, J ¼ 8.72 Hz, 2H), 3.93 (s, 3H); 13 C NMR (CDCl3, 100 MHz, TMS) d: 161.77, 143.88, 143.15, 135.97, 131.21, 130.61, 130.29, 130.00, 129.10, 128.99, 128.79, 128.28, 128.03, 114.68, 55.49; MS (APCI) m/z: 271 (M + H)+. HRMS (ESI) m/z calcd for C15H11ClN2ONa+ [M + Na+], 293.0452; found 293.0452. 7-Chloro-2-(4-chlorophenyl)quinoxaline (Table 8, entry 8). Light orange solid (225 mg, 82%); mp ¼ 180–182  C; IR (KBr) nmax ¼ 2922, 1521, 1275, 1260, 1022, 764, 750 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.30 (s, 1H), 8.18–8.15 (m, 3H), 8.07 (d, J ¼ 8.92 Hz, 1H), 7.72 (dd, J ¼ 2.32, 8.92 Hz, 1H), 7.58–7.55 (m, 2H); 13C NMR (CDCl3, 100 MHz, TMS) d: 151.30, 142.92, 142.56, 140.17, 137.01, 136.33, 134.70, 131.53, 130.77, 130.39, 129.48, 128.82, 128.73, 128.45; MS (APCI) m/z: 275 (M + H)+. HRMS (ESI) m/z calcd for C14H8Cl2N2Na+ [M + Na+], 296.9957; found 297.1305. 2-(4-Bromophenyl)-7-chloroquinoxaline (Table 8, entry 9).5c Light brown solid (256 mg, 80%); mp ¼ 144–146  C; IR (KBr) nmax ¼ 2922, 2075, 1633, 1421, 1176, 1075, 957, 880, 835, 775, 711 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.28 (s, 1H), 8.13 (d, J ¼ 2.24 Hz, 1H), 8.09–8.04 (m, 3H), 7.72–7.68 (m, 3H); 13C NMR (CDCl3, 100 MHz, TMS) d: 151.40, 142.89, 142.58, 140.21, 136.37, 135.16, 132.46, 130.82, 130.41, 129.06, 128.97, 128.47, 128.13, 125.44; MS (APCI) m/z: 321 (M + 2H)+. 6-Chloro-2-phenylquinoxaline (Table 8, entry 10).5i Colorless crystal (199 mg, 83%); mp ¼ 125–127  C; IR (KBr) nmax ¼ 3367, RSC Adv., 2015, 5, 11873–11883 | 11881 View Article Online Published on 09 January 2015. Downloaded by KU Leuven University Library on 22/01/2015 09:59:33. RSC Advances 2162, 1276, 1256, 752 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.34 (s, 1H), 8.21–8.19 (m, 2H), 8.13–8.09 (m, 2H), 7.74 (dd, J ¼ 2.36, 8.96 Hz, 1H), 7.62–7.55 (m, 3H); 13C NMR (CDCl3, 100 MHz, TMS) d: 151.95, 144.16, 141.82, 140.85, 136.38, 135.26, 131.34, 130.85, 130.45, 129.24, 128.09, 127.53; MS (APCI) m/z: 241 (M + H)+. 6-Chloro-2-(4-methoxyphenyl)quinoxaline (Table 8, entry 11).5i Off-white solid (219 mg, 81%); mp ¼ 140–142  C; IR (KBr) nmax ¼ 2930, 2837, 1674, 1606, 1577, 1538, 1519, 1454, 1309, 1287, 1273, 1257, 1171, 1066, 1026, 957, 827, 764, 750, 570, 515 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.29 (s, 1H), 8.18 (dd, J ¼ 1.84, 7 Hz, 2H), 8.09 (d, J ¼ 2.2 Hz, 1H), 8.05 (d, J ¼ 8.96 Hz, 1H), 7.71 (dd, J ¼ 2.28, 8.92 Hz, 1H), 7.09 (dd, J ¼ 1.76, 6.92 Hz, 2H), 3.92 (s, 3H); 13C NMR (CDCl3, 100 MHz, TMS) d: 161.68, 151.53, 143.84, 141.42, 140.87, 134.66, 131.18, 130.60, 128.97, 128.86, 128.02, 114.67, 55.46; MS (APCI) m/z: 271 (M + H)+. HRMS (ESI) m/z calcd for C15H11ClN2ONa+ [M + Na+], 293.0452; found 293.0451. 6-Chloro-2-(4-chlorophenyl)quinoxaline (Table 8, entry 12). Yellowish orange solid (225 mg, 82%); mp ¼ 130–132  C; IR (KBr) nmax ¼ 2917, 2849, 1275, 1260, 750 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.32 (s, 1H), 8.17 (dd, J ¼ 1.92, 6.72 Hz, 2H), 8.14 (d, J ¼ 2.28 Hz, 1H), 8.09 (d, J ¼ 8.96 Hz, 1H), 7.76 (dd, J ¼ 2.28, 8.96 Hz, 1H), 7.57 (dd, J ¼ 1.96, 6.68 Hz, 2H); 13C NMR (CDCl3, 100 MHz, TMS) d: 150.70, 143.67, 141.88, 140.76, 139.29, 136.88, 135.55, 134.77, 131.55, 130.80, 129.49, 128.73, 128.12, 114.07; MS (APCI) m/z: 275 (M + H)+. HRMS (ESI) m/z calcd forC14H8Cl2N2Na+ [M + Na+], 296.9957; found 297.1298. 2-(4-Bromophenyl)-6-chloroquinoxaline (Table 8, entry 13). Off-white solid (257 mg, 83%); mp ¼ 175–177  C; IR (KBr) nmax ¼ 3049, 2923, 2849, 1604, 1539, 1476, 1328, 1275, 1176, 1004, 919, 825, 750, 569 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.27 (s, 1H), 8.09 (d, J ¼ 2.24 Hz, 1H), 8.06 (d, J ¼ 8.48 Hz, 3H), 7.73– 7.67 (m, 3H); 13C NMR (CDCl3, 100 MHz, TMS) d: 150.74, 143.61, 141.90, 140.76, 135.58, 135.20, 132.45, 131.56, 130.81, 130.40, 129.04, 128.95, 128.12, 125.29; MS (APCI) m/z: 321 (M + H)+. HRMS (ESI) m/z calcd for C14H8BrClN2Na+ [M + Na+], 340.9452; found 341.1820. 2-(4-Methoxyphenyl)-7-methylquinoxaline (Table 8, entry 14).4e Light yellow solid (200 mg, 80%); mp ¼ 52–57  C; IR (KBr) nmax ¼ 2917, 2857, 2307, 1956, 1739, 1618, 1451, 1384, 1179, 1050, 746 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.26 (s, 1H), 8.19–8.16 (m, 2H), 8.01 (dd, J ¼ 8.52, 12.32 Hz, 1H), 7.97 (d, J ¼ 14.28 Hz, 1H), 7.62–7.55 (m, 1H), 7.10 (d, J ¼ 8.44 Hz, 2H), 3.92 (s, 3H), 2.62 (s, 3H); 13C NMR (CDCl3, 100 MHz, TMS) d: 161.30, 142.99, 142.19, 139.57, 132.48, 131.37, 129.51, 128.92, 128.82, 128.58, 128.29, 127.97, 114.56, 55.45, 21.80; MS (ESI) m/z: 251 (M + H)+. 2-(4-Bromophenyl)-7-methylquinoxaline (Table 8, entry 15).5c Yellowish orange (238 mg, 80%); mp ¼ 96–98  C; IR (KBr) nmax ¼ 2920, 2851, 1624, 1587, 1488, 1436, 1131, 1072, 1009, 960, 834, 777 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.22 (s, 1H), 8.06 (dd, J ¼ 1.92, 6.64 Hz, 2H), 7.99 (d, J ¼ 8.56 Hz, 1H), 7.91 (s, 1H), 7.68 (dd, J ¼ 1.84, 6.72 Hz, 2H), 7.58 (dd, J ¼ 1.84, 8.56 Hz, 1H), 2.61 (s, 3H); 13C NMR (CDCl3, 100 MHz, TMS) d: 150.58, 142.31, 141.92, 141.11, 140.21, 135.82, 132.32, 132.18, 128.97, 128.89, 128.66, 128.43, 124.83, 21.91; MS (APCI) m/z: 299 (M + H)+. 11882 | RSC Adv., 2015, 5, 11873–11883 Paper HRMS (ESI) m/z calcd for C15H11BrN2Na+ [M + H+], 299.0106; found 299.0178. 7-Methoxy-2-phenylquinoxaline (Table 8, entry 16).5i Colorless crystal (193 mg, 82%); mp ¼ 86–88  C; IR (KBr) nmax ¼ 2917, 2840, 1733, 1459, 1260, 1078, 1025, 750 cm 1; 1H NMR (CDCl3, 400 MHz, TMS) d: 9.19 (s, 1H), 8.20–8.18 (m, 2H), 8.02 (d, J ¼ 9.12 Hz, 1H), 7.61–7.54 (m, 3H), 7.45 (d, J ¼ 2.72 Hz, 1H), 7.42 (dd, J ¼ 2.76, 9.12 Hz, 1H), 4.02 (s, 3H); 13C NMR (CDCl3, 100 MHz, TMS) d: 161.09, 151.98, 143.99, 140.79, 137.81, 137.03, 130.06, 129.14, 127.53, 122.92, 106.90, 55.86; MS (ESI) m/z: 237 (M + H)+. 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