Regioselective Suzuki–Miyaura Cross-Coupling Reactions of 2,6-Dichloroquinoxaline

Abstract

A variety of mono- and diarylated quinoxaline derivatives were prepared by site-selective Suzuki–Miyaura cross-coupling­ reactions of 2,6-dichloroquinoxaline. The selectivity is controlled by electronic parameters.

Quinoxalines[ ¹ ] show a broad spectrum of biological activities, including antifungal,[ ² ] antihistaminic, antioxidant and anti-inflammatory,[ ³ ] antibacterial,[ ⁴ ] antiamoebic,[ ⁵ ] antiproliferative,[ ⁶ ] fungicidal and algicidal,[ ⁷ ] antimalarial and antileishmanial,[ ⁸ ] cytotoxic,[ ⁹ ] anticancer,[ ¹⁰ ] anti-HIV and anti-HCV,[ ¹¹ ] and antituberculosis activity.[ ¹² ] In addition, quinoxalines represent potent and selective class III tyrosine kinase inhibitors[ ¹³ ] and potential influenza NS1A protein inhibitors.[ ¹⁴ ] Certain quinoxalines containing an octadepsipeptide substructure, such as echinomycin and triostin A, have been reported as antibacterial and antitumor agents, and as potent inhibitors of RNA synthesis.[ ¹⁵ ] Quinoxaline-derived molecules have been also studied as thermoplastics[ ¹⁶ ] and, due to their bipolar character, as potential emissive and electron-transport moieties and, hence, as potential building blocks for the synthesis of organic­ semiconductors.[ ¹⁷ ] In recent years, site-selective palladium-catalyzed cross-coupling reactions of polyhalogenated heterocyclic substrates have been studied.[ ¹⁸ ] Herein, we report what are, to the best of our knowledge, the first Suzuki–Miyaura cross-coupling reactions of 2,6-dichloroquinoxaline.[ ¹⁹ ] These reactions proceed with excellent site selectivity, which is controlled by electronic parameters, and provide a convenient approach to various pharmacologically relevant quinoxaline derivatives.

The reaction of commercially available 2,6-dichloroquinoxaline (1) with arylboronic acids 2a–t (1.3 equiv) afforded the 2-aryl-6-chloroquinoxalines 3a–t in 23–97% yield (Scheme [1, ]Table [1]). The reaction conditions were systematically optimized for derivative 3c (Table [2]) in order to isolate the products in optimal yields. Both electron-poor and electron-rich arylboronic acids could be successfully employed. In the case of arylboronic acids 2d,l,r,t, the yields were relatively low because of their electron-poor character and low reactivity. In the case of products 3d,k,l,n,q,r,t, a small amount of starting material could be recovered and a small amount of the corresponding diarylated quinoxaline was formed (less than 5%). Due to the more difficult chromatographic separation, the yields were lower. The best yields were observed using tetrahydrofuran as the solvent, Pd(PPh₃)₄ (5 mol%) as the catalyst, and K₃PO₄ (2 equiv) as the base. The reactions were carried out at 90 °C for 8 hours (see Table [2], entry 6) to obtain the best yields. The reactions of (more reactive) electron-rich arylboronic acids could be successfully carried out at slightly lower temperature and for a shorter reaction time (85 °C, 4 h; Table [2], entry 3). When the reactions were carried out in toluene or 1,4-dioxane, a higher temperature was necessary and the products were isolated in lower yield than the reaction in tetrahydrofuran (Table [2], entries 2 and 5). Thus, the optimized conditions given in entry 6 allowed the preparation of the 2-aryl-6-chloroquinoxalines 3a–t in optimal yields.

The structures of all products were established by spectroscopic methods. The structure of 3g (Figure [1]) was independently confirmed by X-ray crystal structure analysis.[ ²⁰ ]

The Suzuki–Miyaura reactions of 2,6-dichloroquinoxaline (1) with the arylboronic acids 2a,c,e,g,o,p gave the 2,6-diarylquinoxalines 4a–f in good yields (Scheme [2, ]Table [3]). The best yields were obtained using 2.5 equivalents of the arylboronic acid, Pd(PPh₃)₄ (5 mol%), and a 2 M aqueous solution of K₂CO₃ (1,4-dioxane, 120 °C, 12 h).

The Suzuki–Miyaura reactions of the 2-aryl-6-chloroquinoxalines 3c,h,m–o with 1.3 equivalents of the arylboronic acids 2c,e,g,m,p afforded the disubstituted products 5a–g in good yields (Scheme [3, ]Table [4]). The reactions were carried out using Pd(PPh₃)₄ (5 mol%) and a 2 M aqueous solution of K₂CO₃ (1,4-dioxane, 120 °C, 8 h).

The structures of all products were established by spectroscopic methods. The structure of 5e (Figure [2]) was independently confirmed by X-ray crystal structure analysis.[ ²⁰ ]

The syntheses of derivatives 3a–t, 4a–f, and 5a–g have not, to the best of our knowledge, been previously reported, except for 3c and 3h.[ ²¹ ] Compound 3c has been recently prepared using a copper-catalyzed condensation of a diazo ketone;[ ²¹ ] however, this compound could only be obtained as a 1:1 mixture of regioisomers. Thus, the method reported herein is much better suited for the synthesis of arylquinoxalines 3. Although a variety of quinoxaline derivatives (including heterocyclic and functionalized compounds) have been successfully prepared, the use of 4-cyanophenylboronic acid, 4-formylphenylboronic acid, 4-nitrophenylboronic acid, 2-pyridylboronic acid, and 2-indolylboronic acid resulted in the formation of complex mixtures from which no pure compounds could be isolated.

The monoarylated products 3a–t were synthesized by Suzuki­–Miyaura reactions of 2,6-dichloroquinoxaline (1) in good yields. The site selectivity can be explained by the fact that position 2 of 2,6-dichloroquinoxaline is more electron deficient than position 6 (Figure [3]).

In conclusion, a variety of mono- and diarylated quinoxaline derivatives were prepared by site-selective Suzuki–Miyaura cross-coupling reactions of 2,6-dichloroquinoxaline.

All solvents were dried by standard methods and all reactions were carried out under an inert atmosphere. For ¹H and ¹³C NMR spectra the deuterated solvents indicated were used. Mass spectrometric data (MS) were obtained by electron ionization (EI, 70 eV), chemical ionization (CI, isobutane) or electrospray ionization (ESI). For preparative-scale chromatography silica gel 60 (0.063–0.200 mm, 70–230 mesh) was used.��

Synthesis of 3a–t; General Procedure

A THF soln (8 mL) of 2,6-dichloroquinoxaline (1, 1.0 mmol), an arylboronic acid 2 (1.3 equiv), K₃PO₄ (2 equiv), and Pd(PPh₃)₄ (5 mol%) was heated at 90 °C for 8 h. The reaction mixture was cooled to r.t., then H₂O (100 mL) was added and the mixture was extracted with CH₂Cl₂ (100 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (gradient elution, n-heptane–EtOAc).

6-Chloro-2-(o-tolyl)quinoxaline (3a)

Starting with 1 (0.1 g, 0.5 mmol), 2a (0.088 g, 1.3 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), K₃PO₄ (0.212 g, 2 equiv), and THF (4 mL), 3a was isolated as a white solid; yield: 0.098 g (77%); mp 121–123 °C.

IR (ATR): 3074 (w), 3043 (w), 2986 (w), 2930 (w), 2746 (w), 1606 (m), 1568 (w), 1539 (m), 1445 (w), 1417 (w), 1385 (w), 1335 (w), 1268 (w), 1175 (m), 1065 (m), 1037 (s), 960 (s), 901 (s), 870 (m), 827 (s), 785 (m), 754 (s), 726 (s), 701 (m), 579 (s), 553 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 2.38 (s, 3 H, CH₃), 7.25–7.36 (m, 3 H, ArH), 7.44–7.48 (m, 1 H, ArH), 7.65 (dd, J = 9.1, 2.3 Hz, 1 H, ArH), 7.98–8.06 (m, 2 H, ArH), 8.92 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 20.4 (CH₃), 126.4 (CH), 128.1 (CH), 129.6 (CH), 129.9 (CH), 130.8 (CH), 131.2 (CH), 131.3 (CH), 135.5 (C), 136.6 (C), 136.7 (C), 140.5 (C), 141.3 (C), 146.7 (CH), 155.1 (C).

GC-MS (EI, 70 eV): m/z (%) = 254 (35) [M⁺], 253 (100).

HRMS (EI): m/z [M + H]⁺ calcd for C₁₅H₁₂ClN₂: 255.06835; found: 255.06869.

6-Chloro-2-(m-tolyl)quinoxaline (3b)

Starting with 1 (0.1 g, 0.5 mmol), 2b (0.088 g, 1.3 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), K₃PO₄ (0.212 g, 2 equiv), and THF (4 mL), 3b was isolated as a white solid; yield: 0.085 g (67%); mp 125–127 °C.

IR (ATR): 3024 (w), 2960 (w), 2856 (w), 1952 (w), 1841 (w), 1711 (w), 1606 (w), 1588 (m), 1537 (m), 1453 (m), 1330 (w), 1314 (m), 1169 (m), 1135 (m), 962 (s), 912 (s), 869 (m), 831 (s), 789 (s), 692 (s), 673 (m), 585 (s) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 2.41 (s, 3 H, CH₃), 7.26 (d, ³ J = 7.5 Hz, 1 H, ArH), 7.37 (t, J = 7.7 Hz, 1 H, ArH), 7.63 (dd, J = 8.9, 2.3 Hz, 1 H, ArH), 7.87 (d, ³ J = 7.5 Hz, 1 H, ArH), 7.92 (s, 1 H, ArH), 7.98–8.02 (m, 2 H, ArH), 9.22 (s, 1 H, ArH).

¹³C NMR (75.46 MHz, CDCl₃): δ = 20.5 (CH₃), 123.6 (CH), 127.0 (CH), 127.1 (CH), 128.1 (CH), 129.8 (CH), 130.22 (CH), 130.23 (CH), 134.1 (C), 135.3 (C), 138.0 (C), 139.8 (C), 140.8 (C), 143.3 (CH), 151.1 (C).

GC-MS (EI, 70 eV): m/z (%) = 254 (100) [M⁺], 239 (4), 227 (18), 219 (5), 192 (10), 165 (11), 75 (12).

HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₁ClN₂: 254.06053; found: 254.06032.

6-Chloro-2-(p-tolyl)quinoxaline (3c)

Starting with 1 (0.1 g, 0.5 mmol), 2c (0.088 g, 1.3 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), K₃PO₄ (0.212 g, 2 equiv), and THF (4 mL), 3c was isolated as a white solid; yield: 0.096 g (75%); mp 136 °C.

IR (ATR): 3063 (w), 2916 (w), 2854 (w), 2722 (w), 1607 (m), 1576 (w), 1536 (m), 1476 (m), 1413 (m), 1315 (m), 1170 (s), 1064 (m), 1044 (m), 1018 (w), 958 (m), 918 (m), 890 (m), 813 (s), 712 (m), 569 (s) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 2.38 (s, 3 H, CH₃), 7.29 (d, ³ J = 7.9 Hz, 2 H, ArH), 7.63 (dd, J = 9.1, 2.1 Hz, 1 H, ArH), 7.97–8.02 (m, 4 H, ArH), 9.22 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 21.4 (CH₃), 127.4 (2 CH), 128.0 (CH), 129.9 (2 CH), 130.7 (CH), 131.2 (CH), 133.5 (C), 134.9 (C), 140.7 (C), 140.8 (C), 141.7 (C), 144.1 (CH), 151.9 (C).

GC-MS (EI, 70 eV): m/z (%) = 254 (100) [M⁺], 227 (20), 192 (10), 165 (9), 116 (11).

HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₁ClN₂: 254.06053; found: 254.06064.

6-Chloro-2-(2,6-dimethylphenyl)quinoxaline (3d)

Starting with 1 (0.1 g, 0.5 mmol), 2d (0.097 g, 1.3 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), K₃PO₄ (0.212 g, 2 equiv), and THF (4 mL), 3d was isolated as a brownish, heavy oil; yield: 0.050 g (37%).

IR (ATR): 3063 (w), 3020 (w), 2919 (w), 2855 (w), 2735 (w), 2516 (w), 2392 (w), 2230 (w), 1932 (w), 1865 (w), 1748 (w), 1667 (w), 1602 (m), 1546 (m), 1505 (w), 1474 (s), 1451 (w), 1377 (w), 1293 (m), 1199 (w), 1169 (s), 1131 (w), 1091 (w), 1062 (m), 1042 (s), 1029 (w), 960 (m), 914 (w), 899 (s), 829 (s), 786 (w), 731 (m), 673 (m), 626 (m), 584 (s), 541 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 2.00 (s, 6 H, 2 CH₃), 7.07–7.10 (m, 2 H, ArH), 7.17–7.23 (m, 1 H, ArH), 7.65 (dd, J = 8.9, 2.3 Hz, 1 H, ArH), 7.98–8.08 (m, 2 H, ArH), 8.72 (s, 1 H, ArH).

¹³C NMR (75.46 MHz, CDCl₃): δ = 20.4 (2 CH₃), 128.1 (2 CH), 128.3 (CH), 129.1 (CH), 130.8 (CH), 131.3 (CH), 135.7 (C), 136.3 (2 C), 136.7 (C), 140.9 (C), 141.5 (C), 147.2 (CH), 155.7 (C).

GC-MS (EI, 70 eV): m/z (%) = 268 (39) [M⁺], 267 (100), 253 (6), 232 (6), 190 (2), 133 (3).

HRMS (EI): m/z [M + H]⁺ calcd for C₁₆H₁₄ClN₂: 269.08431; found: 269.08432.

6-Chloro-2-(3,5-dimethylphenyl)quinoxaline (3e)

Starting with 1 (0.1 g, 0.5 mmol), 2e (0.097 g, 1.3 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), K₃PO₄ (0.212 g, 2 equiv), and THF (4 mL), 3e was isolated as a white solid; yield: 0.12 g (90%); mp 178–179 °C.

IR (ATR): 3042 (w), 3010 (w), 2916 (w), 2858 (w), 2735 (w), 1936 (w), 1880 (w), 1798 (w), 1755 (w), 1606 (m), 1573 (w), 1536 (m), 1494 (w), 1453 (w), 1416 (w), 1398 (w), 1371 (w), 1312 (m), 1258 (w), 1172 (s), 1088 (m), 997 (m), 966 (m), 867 (m), 828 (s), 782 (m), 706 (s), 674 (m), 626 (m), 590 (m), 542 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 2.35 (s, 6 H, 2 CH₃), 7.06 (s, 1 H, ArH), 7.59 (dd, J = 8.9, 2.3 Hz, 1 H, ArH), 7.66 (s, 2 H, ArH), 7.95–7.99 (m, 2 H, ArH), 9.17 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 21.4 (2 CH₃), 125.3 (2 CH), 128.0 (CH), 130.7 (CH), 131.2 (CH), 132.1 (CH), 134.9 (C), 136.3 (C), 138.8 (2 C), 140.8 (C), 141.7 (C), 144.4 (CH), 152.2 (C).

GC-MS (EI, 70 eV): m/z (%) = 268 (100) [M⁺], 241 (13), 226 (4), 190 (6).

HRMS (EI): m/z [M⁺] calcd for C₁₆H₁₃ClN₂: 268.07618; found: 268.07635.

6-Chloro-2-(2,4,6-trimethylphenyl)quinoxaline (3f)

Starting with 1 (0.12 g, 0.6 mmol), 2f (0.121 g, 1.3 equiv), Pd(PPh₃)₄ (0.035 g, 0.05 equiv), K₃PO₄ (0.254 g, 2 equiv), and THF (4 mL), 3f was isolated as a yellowish solid; yield: 0.163 g (96%); mp 100 °C.

IR (ATR): 3076 (w), 3042 (m), 2964 (w), 2916 (m), 2854 (w), 1818 (w), 1727 (w), 1610 (m), 1567 (w), 1539 (m), 1470 (w), 1446 (m), 1417 (w), 1373 (m), 1330 (w), 1317 (w), 1295 (m), 1266 (w), 1163 (m), 1125 (m), 1042 (m), 964 (m), 892 (s), 846 (s), 828 (s), 788 (s), 688 (m), 588 (m), 572 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 1.97 (s, 6 H, 2 CH₃), 2.25 (s, 3 H, CH₃), 6.90 (s, 2 H, ArH), 7.62 (dd, J = 8.9, 2.3 Hz, 1 H, ArH), 7.96–8.06 (m, 2 H, ArH), 8.70 (s, 1 H, ArH).

¹³C NMR (75.46 MHz, CDCl₃): δ = 19.2 (2 CH₃), 20.1 (CH₃), 127.2 (CH), 127.8 (2 CH), 129.7 (CH), 130.1 (CH), 132.9 (C), 134.5 (C), 135.1 (2 C), 137.8 (C), 139.9 (C), 140.3 (C), 146.4 (CH), 154.8 (C).

GC-MS (EI, 70 eV): m/z (%) = 282 (40) [M⁺], 281 (100), 267 (9), 246 (4), 128 (2), 115 (5).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₆ClN₂: 283.09869; found: 283.10003.

6-Chloro-2-(2-methoxyphenyl)quinoxaline (3g)

Starting with 1 (0.1 g, 0.5 mmol), 2g (0.099 g, 1.3 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), K₃PO₄ (0.212 g, 2 equiv), and THF (4 mL), 3g was isolated as a white solid; yield: 0.097 g (72%); mp 143 °C.

IR (ATR): 3069 (w), 2973 (w), 2838 (w), 1939 (w), 1754 (w), 1600 (s), 1544 (w), 1493 (m), 1459 (s), 1392 (w), 1296 (w), 1239 (s), 1173 (m), 1117 (m), 1060 (s), 1020 (m), 962 (m), 930 (m), 901 (m), 876 (m), 834 (s), 741 (s), 702 (m), 641 (m), 583 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 3.83 (s, 3 H, OCH₃), 6.98 (d, ³ J = 8.3 Hz, 1 H, ArH), 7.08 (dt, J = 7.5, 0.9 Hz, 1 H, ArH), 7.38–7.44 (m, 1 H, ArH), 7.61 (dd, J = 8.9, 2.5 Hz, 1 H, ArH), 7.81 (dd, J = 7.6, 1.7 Hz, 1 H, ArH), 7.98–8.03 (m, 2 H, ArH), 9.27 (s, 1 H, ArH).

¹³C NMR (75.46 MHz, CDCl₃): δ = 54.6 (OCH₃), 110.4 (CH), 120.5 (CH), 125.1 (C), 126.9 (CH), 129.7 (2 CH), 130.5 (CH), 130.7 (CH), 133.9 (C), 140.2 (C), 140.3 (C), 147.1 (CH), 151.3 (C), 156.4 (C).

GC-MS (EI, 70 eV): m/z (%) = 270 (100) [M⁺], 253 (55), 241 (48), 213 (17), 178 (14), 165 (27), 151 (8), 118 (11), 110 (14), 103 (9), 90 (11), 75 (24).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₂ClN₂O: 271.06327; found: 271.06367.

6-Chloro-2-(4-methoxyphenyl)quinoxaline (3h)

Starting with 1 (0.1 g, 0.5 mmol), 2h (0.099 g, 1.3 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), K₃PO₄ (0.212 g, 2 equiv), and THF (4 mL), 3h was isolated as a yellowish white solid; yield: 0.086 g (63%); mp 144–146 °C.

IR (ATR): 3048 (m), 3015 (w), 2930 (w), 2894 (w), 2039 (w), 1915 (w), 1882 (w), 1651 (w), 1604 (s), 1580 (w), 1519 (m), 1463 (w), 1398 (w), 1315 (s), 1269 (w), 1250 (s), 1183 (w), 1167 (s), 1114 (m), 1024 (s), 955 (m), 921 (m), 898 (m), 823 (s), 783 (m), 689 (m), 633 (m), 570 (s) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 3.81 (s, 3 H, OCH₃), 6.98 (d, ³ J = 9.1 Hz, 2 H, ArH), 7.58 (dd, J = 9.1, 2.5 Hz, 1 H, ArH), 7.92–7.98 (m, 2 H, ArH), 8.06 (d, ³ J = 8.9 Hz, 2 H, ArH), 9.18 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 55.4 (OCH₃), 114.6 (2 CH), 128.0 (CH), 128.8 (C), 128.9 (2 CH), 130.6 (CH), 131.1 (CH), 134.6 (C), 140.8 (C), 141.4 (C), 143.8 (CH), 151.5 (C), 161.6 (C).

GC-MS (EI, 70 eV): m/z (%) = 270 (100) [M⁺], 255 (17), 243 (10), 227 (8), 200 (7), 192 (4), 133 (11), 110 (5).

HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₁ClN₂O: 270.05544; found: 270.05544.

6-Chloro-2-(2,3-dimethoxyphenyl)quinoxaline (3i)

Starting with 1 (0.12 g, 0.6 mmol), 2i (0.142 g, 1.3 equiv), Pd(PPh₃)₄ (0.035 g, 0.05 equiv), K₃PO₄ (0.254 g, 2 equiv), and THF (4 mL), 3i was isolated as a white solid; yield: 0.118 g (65%); mp 124 °C.

IR (ATR): 2996 (w), 2951 (m), 2840 (m), 1582 (m), 1542 (m), 1484 (m), 1466 (s), 1428 (m), 1397 (w), 1320 (m), 1266 (s), 1234 (m), 1175 (m), 1110 (m), 1086 (m), 1041 (s), 994 (s), 934 (m), 918 (m), 850 (m), 834 (s), 783 (m), 765 (m), 741 (s), 690 (m), 679 (m), 623 (m), 597 (s), 534 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 3.69 (s, 3 H, OCH₃), 3.86 (s, 3 H, OCH₃), 7.00 (dd, J = 8.1, 1.5 Hz, 1 H, ArH), 7.15 (t, J = 7.9 Hz, 1 H, ArH), 7.38 (dd, J = 7.7, 1.5 Hz, 1 H, ArH), 7.62 (dd, J = 8.9, 2.3 Hz, 1 H, ArH), 7.98–8.04 (m, 2 H, ArH), 9.27 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 56.0 (OCH₃), 61.4 (OCH₃), 114.3 (CH), 122.7 (CH), 124.8 (CH), 128.0 (CH), 130.8 (CH), 130.9 (CH), 131.2 (C), 135.3 (C), 141.2 (C), 141.4 (C), 147.6 (C), 147.8 (CH), 151.9 (C), 153.1 (C).

GC-MS (EI, 70 eV): m/z (%) = 300 (100) [M⁺], 285 (47), 283 (91), 271 (34), 257 (23), 242 (13), 213 (11), 179 (18), 165 (26), 142 (6), 120 (7), 110 (13), 100 (7), 75 (20).

HRMS (EI): m/z [M⁺] calcd for C₁₆H₁₃ClN₂O₂: 300.06601; found: 300.06569.

6-Chloro-2-(2,6-dimethoxyphenyl)quinoxaline (3j)

Starting with 1 (0.12 g, 0.6 mmol), 2j (0.142 g, 1.3 equiv), Pd(PPh₃)₄ (0.035 g, 0.05 equiv), K₃PO₄ (0.254 g, 2 equiv), and THF (4 mL), 3j was isolated as a yellow solid; yield: 0.175 g (97%); mp 135–137 °C.

IR (ATR): 3079 (w), 2985 (w), 2831 (w), 1621 (w), 1586 (m), 1538 (m), 1497 (s), 1464 (w), 1425 (m), 1394 (w), 1336 (w), 1304 (s), 1259 (m), 1225 (m), 1208 (m), 1181 (s), 1154 (m), 1060 (m), 1021 (s), 965 (m), 883 (m), 832 (s), 795 (s), 786 (m), 732 (s), 700 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 3.78 (s, 6 H, 2 OCH₃), 6.93–6.94 (m, 2 H, ArH), 7.40 (d, J = 2.8 Hz, 1 H, ArH), 7.61 (dd, J = 8.9, 2.3 Hz, 1 H, ArH), 7.98–8.02 (m, 2 H, ArH), 9.29 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 55.9 (OCH₃), 56.3 (OCH₃), 113.0 (CH), 115.9 (CH), 117.5 (CH), 126.6 (C), 127.9 (CH), 130.7 (2 CH), 135.1 (C), 141.1 (C), 141.3 (C), 148.0 (CH), 151.8 (C), 152.0 (C), 154.3 (C).

GC-MS (EI, 70 eV): m/z (%) = 300 (100) [M⁺], 285 (64), 283 (88), 269 (14), 257 (12), 242 (16), 214 (7), 179 (13), 165 (24), 148 (13), 120 (7), 110 (11), 100 (5), 75 (14).

HRMS (EI): m/z [M⁺] calcd for C₁₆H₁₃ClN₂O₂: 300.06601; found: 300.06590.

6-Chloro-2-(2,3,4-trimethoxyphenyl)quinoxaline (3k)

Starting with 1 (0.12 g, 0.6 mmol), 2k (0.165 g, 1.3 equiv), Pd(PPh₃)₄ (0.035 g, 0.05 equiv), K₃PO₄ (0.254 g, 2 equiv), and THF (4 mL), 3k was isolated as a yellowish solid; yield: 0.105 g (53%); mp 106–108 °C.

IR (ATR): 3052 (w), 2943 (m), 2848 (w), 1601 (s), 1542 (m), 1494 (w), 1460 (m), 1433 (w), 1414 (s), 1335 (w), 1309 (m), 1280 (m), 1210 (m), 1171 (m), 1133 (w), 1106 (s), 1087 (m), 1014 (s), 969 (m), 949 (w), 928 (m), 902 (m), 853 (m), 823 (m), 774 (s), 597 (m), 544 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 3.79 (s, 3 H, OCH₃), 3.86 (s, 3 H, OCH₃), 3.87 (s, 3 H, OCH₃), 6.78 (d, ³ J = 8.7 Hz, 1 H, ArH), 7.55–7.61 (m, 2 H, ArH), 7.94–8.00 (m, 2 H, ArH), 9.24 (s, 1 H, ArH).

¹³C NMR (75.46 MHz, CDCl₃): δ = 56.2 (OCH₃), 61.0 (OCH₃), 61.6 (OCH₃), 108.2 (CH), 123.8 (C), 125.9 (CH), 128.0 (CH), 130.6 (CH), 130.8 (CH), 134.9 (C), 141.1 (C), 141.2 (C), 142.3 (C), 147.6 (CH), 151.7 (C), 152.5 (C), 155.7 (C).

GC-MS (EI, 70 eV): m/z (%) = 330 (100) [M⁺], 315 (51), 313 (40), 299 (12), 287 (14), 272 (15), 257 (13), 229 (12), 215 (15), 203 (10), 201 (26), 178 (10), 163 (14), 153 (11), 135 (8), 110 (6), 100 (7).

HRMS (EI): m/z [M⁺] calcd for C₁₇H₁₅ClN₂O₃: 330.07657; found: 330.07637.

6-Chloro-2-(3-fluorophenyl)quinoxaline (3l)

Starting with 1 (0.1 g, 0.5 mmol), 2l (0.09 g, 1.3 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), K₃PO₄ (0.212 g, 2 equiv), and THF (4 mL), 3l was isolated as a white solid; yield: 0.03 g (23%); mp 172–173 °C.

IR (ATR): 3087 (w), 3065 (w), 2923 (w), 2850 (w), 1953 (w), 1815 (w), 1704 (w), 1590 (m), 1495 (w), 1435 (m), 1402 (w), 1314 (m), 1203 (m), 975 (s), 865 (s), 831 (s), 789 (s), 695 (s), 670 (s), 596 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 7.13–7.19 (m, 1 H, ArH), 7.43–7.50 (m, 1 H, ArH), 7.67 (dd, J = 8.9, 2.3 Hz, 1 H, ArH), 7.85–7.89 (m, 2 H, ArH), 8.00–8.05 (m, 2 H, ArH), 9.23 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 113.5 (d, ² J _CF = 23.3 Hz, CH), 116.4 (d, ² J _CF = 21.1 Hz, CH), 122.0 (d, ⁴ J _CF = 2.7 Hz, CH), 127.1 (CH), 129.8 (d, ³ J _CF = 8.2 Hz, CH), 129.9 (CH), 130.6 (CH), 134.7 (C), 137.6 (d, ³ J _CF = 7.8 Hz, C), 139.7 (C), 141.0 (C), 142.8 (CH), 149.5 (d, ⁴ J _CF = 2.7 Hz, C), 162.4 (d, ¹ J _CF = 247.2 Hz, C).

¹⁹F NMR (282.40 MHz, CDCl₃): δ = –111.56 (ArF).

GC-MS (EI, 70 eV): m/z (%) = 258 (100) [M⁺], 231 (31), 196 (21), 169 (4), 129 (4), 110 (15), 100 (4), 75 (23), 63 (1), 50 (4).

HRMS (EI): m/z [M⁺] calcd for C₁₄H₈ClFN₂: 258.03546; found: 258.03571.

6-Chloro-2-(4-fluorophenyl)quinoxaline (3m)

Starting with 1 (0.1 g, 0.5 mmol), 2m (0.09 g, 1.3 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), K₃PO₄ (0.212 g, 2 equiv), and THF (4 mL), 3m was isolated as a yellowish white solid; yield: 0.08 g (62%); mp 165–168 °C.

IR (ATR): 3054 (w), 3012 (w), 2914 (w), 1600 (s), 1558 (w), 1514 (m), 1478 (m), 1305 (m), 1237 (s), 1162 (m), 1047 (m), 957 (m), 901 (m), 872 (m), 828 (s), 790 (m), 720 (m), 691 (m), 571 (s) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 7.13–7.21 (m, 2 H, ArH), 7.64 (dd, J = 9.1, 2.5 Hz, 1 H, ArH), 7.96–8.02 (m, 2 H, ArH), 8.07–8.14 (m, 2 H, ArH), 9.20 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 116.3 (d, ² J _CF = 21.5 Hz, 2 CH), 128.1 (CH), 129.5 (d, ³ J _CF = 8.7 Hz, 2 CH), 130.7 (CH), 131.4 (CH), 132.5 (d, ⁴ J _CF = 3.2 Hz, C), 135.3 (C), 140.7 (C), 141.7 (C), 143.7 (CH), 150.8 (C), 164.4 (d, ¹ J _CF = 251.31 Hz, C).

¹⁹F NMR (282.40 MHz, CDCl₃): δ = –110.01 (ArF).

GC-MS (EI, 70 eV): m/z (%) = 258 (100) [M⁺], 233 (11), 231 (33), 196 (20), 169 (5).

HRMS (EI): m/z [M⁺] calcd for C₁₄H₈ClFN₂: 258.03546; found: 258.03559.

6-Chloro-2-(2-thienyl)quinoxaline (3n)

Starting with 1 (0.1 g, 0.5 mmol), 2n (0.082 g, 1.3 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), K₃PO₄ (0.212 g, 2 equiv), and THF (4 mL), 3n was isolated as a yellow solid; yield: 0.056 g (45%); mp 154–156 °C.

IR (ATR): 3095 (w), 3064 (w), 3011 (w), 2007 (w), 1941 (w), 1887 (w), 1746 (w), 1693 (w), 1593 (m), 1541 (s), 1474 (m), 1433 (w), 1414 (m), 1369 (w), 1311 (m), 1269 (w), 1176 (s), 1131 (m), 1062 (s), 1002 (s), 942 (s), 872 (m), 832 (s), 789 (m), 709 (s), 588 (s), 558 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 7.11–7.14 (m, 1 H, ArH), 7.48 (dd, J = 5.1, 1.1 Hz, 1 H, ArH), 7.59 (dd, J = 8.9, 2.5 Hz, 1 H, ArH), 7.77 (dd, J = 3.8, 1.1 Hz, 1 H, ArH), 7.89–7.96 (m, 2 H, ArH), 9.13 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 127.2 (CH), 128.1 (CH), 128.6 (CH), 130.2 (CH), 130.3 (CH), 131.4 (CH), 134.8 (C), 140.6 (C), 141.5 (C), 141.8 (C), 142.8 (CH), 147.5 (C).

GC-MS (EI, 70 eV): m/z (%) = 246 (100) [M⁺], 219 (29), 184 (12), 140 (10), 110 (11), 100 (3), 84 (2), 75 (12).

HRMS (EI): m/z [M⁺] calcd for C₁₂H₇ClN₂S: 246.00130; found: 246.00147.

6-Chloro-2-(4-ethylphenyl)quinoxaline (3o)

Starting with 1 (0.1 g, 0.5 mmol), 2o (0.098 g, 1.3 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), K₃PO₄ (0.212 g, 2 equiv), and THF (4 mL), 3o was isolated as a white solid; yield: 0.13 g (96%); mp 104 °C.

IR (ATR): 3068 (w), 3039 (w), 2955 (m), 2865 (w), 1607 (s), 1537 (s), 1504 (w), 1477 (s), 1445 (w), 1416 (m), 1334 (w), 1313 (s), 1281 (m), 1225 (w), 1173 (s), 1053 (s), 1014 (m), 957 (s), 922 (m), 908 (s), 871 (m), 825 (s), 720 (m), 689 (m), 628 (m), 582 (s), 569 (m), 540 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 1.21 (t, ³ J = 7.7 Hz, 3 H, CH₃), 2.65 (q, J = 7.5 Hz, 2 H, CH₂), 7.29 (d, ³ J = 8.5 Hz, 2 H, ArH), 7.59 (dd, J = 9.1, 2.3 Hz, 1 H, ArH), 7.94–8.02 (m, 4 H, ArH), 9.19 (s, 1 H, ArH).

¹³C NMR (75.46 MHz, CDCl₃): δ = 15.4 (CH₃), 28.8 (CH₂), 127.5 (2 CH), 128.1 (CH), 128.8 (2 CH), 130.8 (CH), 131.2 (CH), 133.8 (C), 134.9 (C), 140.8 (C), 141.7 (C), 144.1 (CH), 147.1 (C), 151.9 (C).

GC-MS (EI, 70 eV): m/z (%) = 268 (100) [M⁺], 255 (26), 253 (79), 226 (4), 190 (7), 163 (2), 116 (18), 110 (8), 89 (7), 84 (1), 75 (11).

HRMS (EI): m/z [M⁺] calcd for C₁₆H₁₃ClN₂: 268.07618; found: 268.07642.

2-(4-tert-Butylphenyl)-6-chloroquinoxaline (3p)

Starting with 1 (0.1 g, 0.5 mmol), 2p (0.106 g, 1.3 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), K₃PO₄ (0.212 g, 2 equiv), and THF (4 mL), 3p was isolated as a white solid; yield: 0.115 g (77%); mp 99–102 °C.

IR (ATR): 3093 (w), 3063 (w), 2955 (m), 2867 (w), 1601 (m), 1569 (w), 1537 (m), 1504 (w), 1474 (m), 1455 (w), 1404 (m), 1392 (w), 1360 (m), 1333 (w), 1316 (m), 1270 (m), 1200 (m), 1174 (m), 1147 (w), 1093 (m), 1045 (m), 1012 (m), 957 (s), 920 (s), 897 (s), 879 (m), 841 (s), 826 (s), 739 (m), 694 (w), 672 (m), 577 (s), 539 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 1.30 (s, 9 H, 3 CH₃), 7.50 (d, ³ J = 8.7 Hz, 2 H, ArH), 7.60 (dd, J = 9.1, 2.5 Hz, 1 H, ArH), 7.95–8.04 (m, 4 H, ArH), 9.21 (s, 1 H, ArH).

¹³C NMR (75.46 MHz, CDCl₃): δ = 31.2 (3 CH₃), 34.9 (C), 126.2 (2 CH), 127.3 (2 CH), 128.1 (CH), 130.8 (CH), 131.2 (CH), 133.6 (C), 134.9 (C), 140.9 (C), 141.7 (C), 144.1 (CH), 151.9 (C), 153.9 (C).

GC-MS (EI, 70 eV): m/z (%) = 296 (31) [M⁺], 281 (100), 265 (5), 253 (11), 218 (1), 203 (1), 163 (4), 140 (2), 116 (7), 110 (4), 75 (5), 39 (1).

HRMS (EI): m/z [M⁺] calcd for C₁₈H₁₇ClN₂: 296.10748; found: 296.10752.

6-Chloro-2-[4-(trifluoromethyl)phenyl]quinoxaline (3q)

Starting with 1 (0.1 g, 0.5 mmol), 2q (0.123 g, 1.3 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), K₃PO₄ (0.212 g, 2 equiv), and THF (4 mL), 3q was isolated as a white solid; yield: 0.081 g (52%); mp 128–130 °C.

IR (ATR): 3043 (w), 1928 (w), 1809 (w), 1617 (w), 1604 (m), 1538 (m), 1519 (w), 1478 (m), 1414 (m), 1326 (s), 1260 (w), 1195 (w), 1174 (w), 1157 (m), 1107 (s), 1068 (s), 1015 (m), 960 (m), 927 (m), 899 (m), 850 (m), 832 (s), 800 (w), 651 (m), 598 (s), 568 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 7.67 (dd, J = 8.9, 2.3 Hz, 1 H, ArH), 7.75 (d, ³ J = 8.1 Hz, 2 H, ArH), 8.01–8.06 (m, 2 H, ArH), 8.23 (d, ³ J = 8.1 Hz, 2 H, ArH), 9.26 (s, 1 H, ArH).

¹³C NMR (75.46 MHz, CDCl₃): δ = 123.9 (q, ¹ J _CF = 272.35 Hz, CF₃), 126.1 (q, ³ J _CF = 3.30 Hz, 2 CH), 127.8 (2 CH), 128.2 (CH), 130.2 (q, ² J _CF = 32.46 Hz, C), 130.9 (CH), 131.7 (CH), 136.0 (C), 139.6 (C), 140.7 (C), 142.2 (C), 143.8 (CH), 150.3 (C).

¹⁹F NMR (282.40 MHz, CDCl₃): δ = –62.81 (ArCF₃).

GC-MS (EI, 70 eV): m/z (%) = 308 (100) [M⁺], 281 (24), 246 (9), 226 (8), 212 (2), 177 (4), 152 (6), 136 (2), 110 (17), 100 (4), 75 (20), 50 (3).

HRMS (EI): m/z [M⁺] calcd for C₁₅H₈ClF₃N₂: 308.03226; found: 308.03178.

6-Chloro-2-(4-vinylphenyl)quinoxaline (3r)

Starting with 1 (0.1 g, 0.5 mmol), 2r (0.096 g, 1.3 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), K₃PO₄ (0.212 g, 2 equiv), and THF (4 mL), 3r was isolated as a yellow solid; yield: 0.04 g (30%); mp 113–115 °C.

IR (ATR): 3046 (w), 2921 (m), 2851 (w), 1606 (m), 1568 (w), 1536 (m), 1475 (m), 1445 (w), 1411 (m), 1333 (w), 1314 (m), 1210 (w), 1172 (s), 1047 (m), 957 (m), 899 (m), 825 (s), 782 (w), 731 (m), 572 (s) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 5.29 (d, J = 11.3 Hz, 1 H, =CH₂), 5.79 (d, J = 17.6 Hz, 1 H, =CH₂), 6.65–6.75 (m, 1 H, =CH), 7.49 (d, ³ J = 8.3 Hz, 2 H, ArH), 7.61 (dd, J = 8.9, 2.3 Hz, 1 H, ArH), 7.95–8.00 (m, 2 H, ArH), 8.06 (d, ³ J = 8.5 Hz, 2 H, ArH), 9.21 (s, 1 H, ArH).

¹³C NMR (75.46 MHz, CDCl₃): δ = 114.6 (=CH₂), 125.9 (2 CH), 126.6 (2 CH), 127.0 (CH), 129.7 (CH), 130.3 (CH), 134.1 (C), 134.5 (C), 135.1 (CH), 138.6 (C), 139.8 (C), 140.7 (C), 142.9 (CH), 150.3 (C).

GC-MS (EI, 70 eV): m/z (%) = 266 (100) [M⁺], 238 (14), 204 (10), 177 (3), 129 (12).

HRMS (EI): m/z [M⁺] calcd for C₁₆H₁₁ClN₂: 266.06053; found: 266.06088.

6-Chloro-2-(2-chlorophenyl)quinoxaline (3s)

Starting with 1 (0.12 g, 0.6 mmol), 2s (0.121 g, 1.3 equiv), Pd(PPh₃)₄ (0.035 g, 0.05 equiv), K₃PO₄ (0.254 g, 2 equiv), and THF (4 mL), 3s was isolated as a white solid; yield: 0.129 g (78%); mp 177 °C.

IR (ATR): 3091 (w), 3047 (m), 2982 (w), 1921 (w), 1807 (w), 1621 (w), 1598 (s), 1543 (m), 1504 (w), 1476 (s), 1447 (w), 1429 (m), 1397 (w), 1356 (w), 1324 (w), 1311 (m), 1265 (w), 1248 (m), 1176 (s), 1147 (w), 1137 (m), 1093 (w), 1075 (m), 1040 (s), 961 (s), 935 (s), 921 (w), 898 (s), 833 (s), 791 (m), 748 (s), 723 (m), 686 (m), 676 (m), 579 (m), 538 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 7.34–7.40 (m, 2 H, ArH), 7.44–7.49 (m, 1 H, ArH), 7.62–7.68 (m, 2 H, ArH), 8.00–8.07 (m, 2 H, ArH), 9.13 (s, 1 H, ArH).

¹³C NMR (75.46 MHz, CDCl₃): δ = 126.5 (CH), 127.2 (CH), 129.3 (CH), 129.8 (CH), 129.9 (CH), 130.3 (CH), 130.9 (CH), 131.5 (C), 134.9 (C), 135.1 (C), 139.8 (C), 140.6 (C), 145.9 (CH), 151.5 (C).

GC-MS (EI, 70 eV): m/z (%) = 274 (100) [M⁺], 247 (20), 241 (30), 239 (93), 212 (21), 177 (31), 137 (18), 110 (20), 102 (12), 100 (9).

HRMS (EI): m/z [M⁺] calcd for C₁₄H₈Cl₂N₂: 274.00591; found: 274.00546.

6-Chloro-2-(3-chlorophenyl)quinoxaline (3t)

Starting with 1 (0.1 g, 0.5 mmol), 2t (0.1 g, 1.3 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), K₃PO₄ (0.212 g, 2 equiv), and THF (4 mL), 3t was isolated as a white solid; yield: 0.035 g (25%); mp 167 °C.

IR (ATR): 3080 (w), 3048 (m), 1937 (w), 1822 (w), 1712 (w), 1602 (w), 1537 (m), 1475 (m), 1371 (w), 1311 (s), 1258 (w), 1175 (m), 1106 (w), 1065 (m), 1048 (w), 966 (s), 940 (m), 904 (m), 831 (m), 791 (s), 755 (m), 700 (s), 671 (m), 638 (w), 586 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 7.41–7.43 (m, 2 H, ArH), 7.65 (dd, J = 8.9, 2.3 Hz, 1 H, ArH), 7.93–8.04 (m, 3 H, ArH), 8.13–8.14 (m, 1 H, ArH), 9.20 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 125.4 (CH), 127.6 (CH), 128.1 (CH), 130.4 (2 CH), 130.9 (CH), 131.6 (CH), 135.4 (C), 135.7 (C), 138.1 (C), 140.7 (C), 142.0 (C), 143.7 (CH), 150.4 (C).

GC-MS (EI, 70 eV): m/z (%) = 275 (17), 274 (100) [M⁺], 247 (18), 239 (26), 212 (21), 177 (23), 137 (14), 110 (18), 100 (6), 84 (2), 75 (28), 63 (2), 50 (6).

HRMS (EI): m/z [M⁺] calcd for C₁₄H₈Cl₂N₂: 274.00591; found: 274.00535.

Synthesis of 4a–f; General Procedure

A 1,4-dioxane soln (8 mL) of 2,6-dichloroquinoxaline (1, 1.0 equiv), an arylboronic acid 2 (2.5 equiv), 2 M K₂CO₃ (2 mL), and Pd(PPh₃)₄ (5 mol%) was heated at 120 °C for 12 h. The reaction mixture was cooled to r.t., then H₂O (100 mL) was added and the mixture was extracted with CH₂Cl₂ (100 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (gradient elution, n-heptane–EtOAc).

2,6-Di(o-tolyl)quinoxaline (4a)

Starting with 1 (0.1 g, 0.5 mmol), 2a (0.169 g, 2.5 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), 2 M K₂CO₃ (1 mL), and 1,4-dioxane (4 mL), 4a was isolated as a white solid; yield: 0.1 g (64%); mp 139 °C.

IR (ATR): 3092 (w), 3019 (w), 2921 (w), 2854 (w), 2735 (w), 1954 (w), 1822 (w), 1539 (m), 1494 (w), 1481 (m), 1434 (m), 1349 (w), 1314 (m), 1268 (w), 1164 (m), 1060 (m), 1029 (m), 977 (w), 961 (m), 848 (s), 791 (w), 757 (s), 728 (s), 705 (w), 666 (m), 626 (m), 600 (w), 564 (w), 546 (w), 535 (w) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 2.28 (s, 3 H, CH₃), 2.41 (s, 3 H, CH₃), 7.22–7.33 (m, 7 H, ArH), 7.47–7.50 (m, 1 H, ArH), 7.71 (dd, J = 8.7, 2.1 Hz, 1 H, ArH), 8.02–8.12 (m, 2 H, ArH), 8.95 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 20.4 (CH₃), 20.6 (CH₃), 126.1 (CH), 126.4 (CH), 128.0 (CH), 128.9 (CH), 129.1 (CH), 129.4 (CH), 129.9 (CH), 130.0 (CH), 130.6 (CH), 131.3 (CH), 132.2 (CH), 135.4 (C), 136.6 (C), 137.2 (C), 140.5 (C), 140.9 (C), 141.0 (C), 143.7 (C), 146.2 (CH), 154.9 (C).

GC-MS (EI, 70 eV): m/z (%) = 310 (48) [M⁺], 309 (100), 190 (2), 165 (8), 153 (4), 115 (10), 89 (3), 75 (1), 65 (2), 51 (1), 39 (1).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₁₉N₂: 311.15428; found: 311.15435.

2,6-Di(p-tolyl)quinoxaline (4b)

Starting with 1 (0.1 g, 0.5 mmol), 2c (0.169 g, 2.5 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), 2 M K₂CO₃ (1 mL), and 1,4-dioxane (4 mL), 4b was isolated as a white solid; yield: 0.08 g (51%); mp 203–205 °C.

IR (ATR): 3020 (w), 2913 (w), 2856 (w), 2726 (w), 1614 (m), 1503 (w), 1402 (w), 1322 (w), 1275 (w), 1186 (w), 1167 (m), 1118 (w), 1054 (m), 975 (w), 931 (m), 849 (w), 816 (s), 723 (m), 691 (w), 606 (m), 587 (w), 554 (w) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 2.35 (s, 3 H, CH₃), 2.37 (s, 3 H, CH₃), 7.25 (d, ³ J = 7.9 Hz, 2 H, ArH), 7.29 (d, ³ J = 7.9 Hz, 2 H, ArH), 7.60 (d, ³ J = 8.1 Hz, 2 H, ArH), 7.95 (dd, J = 8.7, 1.9 Hz, 1 H, ArH), 8.03 (d, ³ J = 8.1 Hz, 2 H, ArH), 8.08–8.21 (m, 2 H, ArH), 9.24 (s, 1 H, ArH).

¹³C NMR (75.46 MHz, CDCl₃): δ = 21.2 (CH₃), 21.5 (CH₃), 126.1 (CH), 127.3 (2 CH), 127.4 (2 CH), 129.7 (CH), 129.80 (CH), 129.83 (2 CH), 129.9 (2 CH), 134.1 (C), 136.9 (C), 137.5 (C), 138.1 (C), 140.5 (C), 141.7 (C), 142.0 (C), 143.6 (CH), 151.5 (C).

GC-MS (EI, 70 eV): m/z (%) = 310 (100) [M⁺], 295 (2), 268 (1), 166 (14), 139 (1), 116 (15), 91 (1), 63 (1).

HRMS (EI): m/z [M⁺] calcd for C₂₂H₁₈N₂: 310.14645; found: 310.14679.

2,6-Bis(3,5-dimethylphenyl)quinoxaline (4c)

Starting with 1 (0.1 g, 0.5 mmol), 2e (0.186 g, 2.5 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), 2 M K₂CO₃ (1 mL), and 1,4-dioxane (4 mL), 4c was isolated as a yellow solid; yield: 0.16 g (94%); mp 190–192 °C.

IR (ATR): 3012 (w), 2913 (m), 2854 (w), 2734 (w), 1597 (m), 1538 (w), 1435 (w), 1373 (w), 1316 (m), 1286 (w), 1217 (w), 1164 (m), 1087 (m), 1037 (m), 967 (m), 938 (w), 842 (s), 788 (m), 771 (w), 711 (m), 681 (s), 628 (m), 569 (w), 544 (w) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 2.33 (s, 6 H, 2 CH₃), 2.36 (s, 6 H, 2 CH₃), 6.97 (s, 1 H, ArH), 7.05 (s, 1 H, ArH), 7.29 (s, 2 H, ArH), 7.70 (s, 2 H, ArH), 7.93 (dd, J = 8.7, 2.1 Hz, 1 H, ArH), 8.01–8.19 (m, 2 H, ArH), 9.20 (s, 1 H, ArH).

¹³C NMR (75.46 MHz, CDCl₃): δ = 20.4 (4 CH₃), 124.3 (2 CH), 124.4 (2 CH), 125.4 (CH), 128.6 (CH), 128.7 (CH), 128.9 (CH), 130.8 (CH), 135.7 (C), 137.6 (2 C), 137.7 (2 C), 138.6 (C), 140.5 (C), 140.7 (C), 141.3 (C), 142.9 (CH), 150.8 (C).

GC-MS (EI, 70 eV): m/z (%) = 338 (100) [M⁺], 311 (2), 296 (1), 180 (7), 154 (2), 130 (8), 115 (4), 77 (1).

HRMS (EI): m/z [M⁺] calcd for C₂₄H₂₂N₂: 338.17775; found: 338.17749.

2,6-Bis(2-methoxyphenyl)quinoxaline (4d)

Starting with 1 (0.1 g, 0.5 mmol), 2g (0.19 g, 2.5 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), 2 M K₂CO₃ (1 mL), and 1,4-dioxane (4 mL), 4d was isolated as a yellow solid; yield: 0.085 g (49%); mp 128–129 °C.

IR (ATR): 3066 (w), 3024 (w), 2938 (w), 2838 (w), 1599 (m), 1489 (m), 1440 (w), 1336 (w), 1268 (m), 1233 (s), 1163 (m), 1116 (m), 1060 (m), 1039 (w), 1016 (s), 960 (m), 904 (m), 842 (w), 828 (m), 784 (m), 741 (s), 695 (w), 666 (m), 617 (m), 576 (m), 562 (w), 541 (w) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 3.75 (s, 3 H, OCH₃), 3.80 (s, 3 H, OCH₃), 6.93–6.97 (m, 2 H, ArH), 6.99–7.09 (m, 2 H, ArH), 7.26–7.40 (m, 3 H, ArH), 7.82 (dd, J = 7.5, 1.7 Hz, 1 H, ArH), 7.89 (dd, J = 8.7, 2.1 Hz, 1 H, ArH), 8.05–8.18 (m, 2 H, ArH), 9.25 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 55.5 (OCH₃), 55.6 (OCH₃), 111.4 (CH), 111.5 (CH), 121.1 (CH), 121.5 (CH), 126.7 (C), 128.6 (CH), 129.0 (CH), 129.4 (C), 129.5 (CH), 131.1 (CH), 131.3 (CH), 131.6 (CH), 132.1 (CH), 140.0 (C), 140.9 (C), 141.8 (C), 147.3 (CH), 151.8 (C), 156.6 (C), 157.4 (C).

GC-MS (EI, 70 eV): m/z (%) = 342 (100) [M⁺], 341 (58), 325 (48), 313 (29), 297 (10), 270 (4), 237 (19), 207 (3), 193 (4), 164 (6), 139 (15), 131 (7), 118 (8), 90 (4), 77 (3), 63 (3), 39 (1).

HRMS (EI): m/z [M⁺] calcd for C₂₂H₁₈N₂O₂: 342.13628; found: 342.13586.

2,6-Bis(4-ethylphenyl)quinoxaline (4e)

Starting with 1 (0.1 g, 0.5 mmol), 2o (0.188 g, 2.5 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), 2 M K₂CO₃ (1 mL), and 1,4-dioxane (4 mL), 4e was isolated as a white solid; yield: 0.08 g (47%); mp 150 °C.

IR (ATR): 3025 (w), 2931 (w), 2874 (w), 1614 (m), 1513 (w), 1452 (m), 1300 (w), 1203 (w), 1165 (m), 1121 (w), 1057 (m), 1015 (m), 960 (m), 914 (w), 829 (s), 798 (w), 684 (w), 633 (w), 609 (m), 590 (w), 553 (w) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 1.22 (t, ³ J = 7.2 Hz, 3 H, CH₃), 1.24 (t, ³ J = 7.5 Hz, 3 H, CH₃), 2.65 (q, J = 7.5 Hz, 2 H, CH₂), 2.67 (q, J = 7.5 Hz, 2 H, CH₂), 7.27 (d, ³ J = 8.5 Hz, 2 H, ArH), 7.32 (d, ³ J = 8.5 Hz, 2 H, ArH), 7.62 (d, ³ J = 8.3 Hz, 2 H, ArH), 7.95 (dd, J = 8.7, 2.1 Hz, 1 H, ArH), 8.05 (d, ³ J = 8.3 Hz, 2 H, ArH), 8.08–8.21 (m, 2 H, ArH), 9.23 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 15.4 (CH₃), 15.5 (CH₃), 28.6 (CH₂), 28.8 (CH₂), 126.1 (CH), 127.4 (2 CH), 127.5 (2 CH), 128.6 (2 CH), 128.7 (2 CH), 129.7 (CH), 129.8 (CH), 134.3 (C), 137.1 (C), 141.6 (C), 141.7 (C), 142.0 (C), 143.7 (CH), 144.4 (C), 146.7 (C), 151.5 (C).

GC-MS (EI, 70 eV): m/z (%) = 338 (100) [M⁺], 323 (55), 308 (13), 190 (2), 154 (13), 115 (5), 102 (1), 90 (1), 51 (1).

HRMS (EI): m/z [M⁺] calcd for C₂₄H₂₂N₂: 338.17775; found: 338.17782.

2,6-Bis(4-tert-butylphenyl)quinoxaline (4f)

Starting with 1 (0.1 g, 0.5 mmol), 2p (0.223 g, 2.5 equiv), Pd(PPh₃)₄ (0.029 g, 0.05 equiv), 2 M K₂CO₃ (1 mL), and 1,4-dioxane (4 mL), 4f was isolated as a white solid; yield: 0.052 g (26%); mp 265–267 °C.

IR (ATR): 3062 (w), 2964 (m), 2863 (w), 2707 (w), 1614 (m), 1504 (w), 1455 (m), 1361 (m), 1301 (w), 1265 (m), 1202 (w), 1138 (w), 1047 (m), 976 (w), 930 (m), 890 (m), 823 (s), 742 (w), 694 (w), 640 (w), 610 (m), 566 (s), 545 (w) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 1.32 (s, 18 H, 6 CH₃), 7.47 (d, ³ J = 8.5 Hz, 2 H, ArH), 7.52 (d, ³ J = 8.7 Hz, 2 H, ArH), 7.65 (d, ³ J = 8.5 Hz, 2 H, ArH), 7.97 (dd, J = 8.7, 2.1 Hz, 1 H, ArH), 8.06 (d, ³ J = 8.5 Hz, 2 H, ArH), 8.09–8.23 (m, 2 H, ArH), 9.25 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 31.2 (3 CH₃), 31.3 (3 CH₃), 34.7 (C), 34.9 (C), 126.0 (2 CH), 126.1 (CH), 126.2 (2 CH), 127.1 (2 CH), 127.2 (2 CH), 129.7 (CH), 129.8 (CH), 134.1 (C), 136.8 (C), 141.6 (C), 141.7 (C), 141.9 (C), 143.7 (CH), 151.3 (C), 151.5 (C), 153.5 (C).

GC-MS (EI, 70 eV): m/z (%) = 394 (63) [M⁺], 380 (31), 379 (100), 363 (10), 335 (3), 295 (2), 182 (11), 154 (10), 102 (1), 41 (3).

HRMS (EI): m/z [M⁺] calcd for C₂₈H₃₀N₂: 394.24035; found: 394.24046.

Synthesis of 5a–g; General Procedure

A 1,4-dioxane soln (8 mL) of a 2-aryl-6-chloroquinoxaline 3 (1.0 equiv), an arylboronic acid 2 (1.3 equiv), 2 M K₂CO₃ (2 mL), and Pd(PPh₃)₄ (5 mol%) was heated at 120 °C for 8 h. The reaction mixture was cooled to r.t., then H₂O (100 mL) was added and the mixture was extracted with CH₂Cl₂ (100 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (gradient elution, n-heptane–EtOAc).

6-(3,5-Dimethylphenyl)-2-(p-tolyl)quinoxaline (5a)

Starting with 3c (0.05 g, 0.2 mmol), 2e (0.039 g, 1.3 equiv), Pd(PPh₃)₄ (0.012 g, 0.05 equiv), 2 M K₂CO₃ (1 mL), and 1,4-dioxane (4 mL), 5a was isolated as a light yellow solid; yield: 0.045 g (70%); mp 168 °C.

IR (ATR): 3030 (w), 2913 (m), 2727 (w), 1601 (m), 1555 (w), 1463 (w), 1427 (w), 1370 (w), 1276 (w), 1184 (w), 1164 (w), 1075 (w), 1049 (m), 960 (m), 929 (w), 881 (w), 818 (s), 776 (w), 717 (m), 682 (m), 640 (w), 624 (w), 614 (s), 569 (w), 555 (w), 536 (w) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 2.34 (s, 6 H, 2 CH₃), 2.37 (s, 3 H, CH₃), 6.99 (s, 1 H, ArH), 7.28 (s, 1 H, ArH), 7.30 (s, 3 H, ArH), 7.95 (dd, J = 8.7, 2.1 Hz, 1 H, ArH), 8.03 (d, ³ J = 8.1 Hz, 2 H, ArH), 8.08 (d, ³ J = 8.7 Hz, 1 H, ArH), 8.20 (d, J = 2.1 Hz, 1 H, ArH), 9.23 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 21.4 (3 CH₃), 125.4 (2 CH), 126.4 (CH), 127.4 (2 CH), 129.6 (CH), 129.7 (CH), 129.8 (2 CH), 129.9 (CH), 134.0 (C), 138.6 (2 C), 139.7 (C), 140.4 (C), 141.6 (C), 141.7 (C), 142.3 (C), 143.6 (CH), 151.5 (C).

GC-MS (EI, 70 eV): m/z (%) = 324 (100) [M⁺], 309 (5), 297 (5), 180 (42), 162 (20), 130 (27), 115 (11), 77 (1), 65 (1), 63 (1).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₁N₂: 325.16993; found: 325.17059.

6-(4-tert-Butylphenyl)-2-(p-tolyl)quinoxaline (5b)

Starting with 3c (0.05 g, 0.2 mmol), 2p (0.046 g, 1.3 equiv), Pd(PPh₃)₄ (0.012 g, 0.05 equiv), 2 M K₂CO₃ (1 mL), and 1,4-dioxane (4 mL), 5b was isolated as a light yellow solid; yield: 0.054 g (78%); mp 185–187 °C.

IR (ATR): 3061 (w), 3032 (w), 2902 (w), 2865 (w), 1916 (w), 1614 (m), 1514 (w), 1450 (m), 1397 (w), 1362 (m), 1269 (w), 1186 (w), 1166 (m), 1143 (w), 1109 (w), 1048 (w), 1009 (w), 958 (m), 925 (m), 889 (w), 842 (w), 819 (s), 740 (w), 718 (m), 687 (w), 672 (w), 628 (w), 606 (m), 564 (w), 558 (m), 547 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 1.31 (s, 9 H, 3 CH₃), 2.37 (s, 3 H, CH₃), 7.28 (d, ³ J = 7.9 Hz, 2 H, ArH), 7.46 (d, ³ J = 8.7 Hz, 2 H, ArH), 7.65 (d, ³ J = 8.5 Hz, 2 H, ArH), 7.95 (dd, J = 8.9, 1.9 Hz, 1 H, ArH), 8.03 (d, ³ J = 8.3 Hz, 2 H, ArH), 8.09 (d, J = 8.7 Hz, 1 H, ArH), 8.22 (d, J = 1.5 Hz, 1 H, ArH), 9.23 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 21.4 (CH₃), 31.3 (3 CH₃), 34.7 (C), 126.0 (2 CH), 126.1 (CH), 127.1 (2 CH), 127.4 (2 CH), 129.7 (CH), 129.8 (CH), 129.9 (2 CH), 134.0 (C), 136.7 (2 C), 140.4 (2 C), 141.7 (C), 141.9 (C), 143.6 (CH), 151.3 (C).

GC-MS (EI, 70 eV): m/z (%) = 352 (100) [M⁺], 309 (25), 297 (9), 178 (10), 152 (7), 141 (15), 65 (1), 39 (1).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₅N₂: 353.20123; found: 353.20151.

6-(2-Methoxyphenyl)-2-(p-tolyl)quinoxaline (5c)

Starting with 3c (0.05 g, 0.2 mmol), 2g (0.04 g, 1.3 equiv), Pd(PPh₃)₄ (0.012 g, 0.05 equiv), 2 M K₂CO₃ (1 mL), and 1,4-dioxane (4 mL), 5c was isolated as a light yellow solid; yield: 0.03 g (47%); mp 125–127 °C.

IR (ATR): 3063 (w), 3002 (w), 1916 (w), 2834 (w), 1613 (w), 1567 (w), 1518 (w), 1464 (m), 1415 (w), 1322 (w), 1283 (w), 1243 (m), 1182 (w), 1119 (m), 1059 (w), 1025 (m), 977 (w), 932 (m), 900 (m), 833 (s), 823 (s), 754 (s), 716 (w), 636 (w), 616 (w), 609 (m), 576 (w), 543 (w) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 2.35 (s, 3 H, CH₃), 3.77 (s, 3 H, OCH₃), 6.94–7.04 (m, 2 H, ArH), 7.26–7.33 (m, 3 H, ArH), 7.39 (dd, J = 7.5, 1.7 Hz, 1 H, ArH), 7.91 (dd, J = 8.7, 1.9 Hz, 1 H, ArH), 8.01–8.17 (m, 4 H, ArH), 9.21 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 21.4 (CH₃), 55.6 (OCH₃), 111.4 (CH), 121.1 (CH), 127.4 (2 CH), 128.6 (CH), 129.0 (CH), 129.3 (C), 129.5 (CH), 129.9 (2 CH), 131.1 (CH), 132.6 (CH), 134.1 (C), 139.9 (C), 140.4 (C), 141.4 (C), 141.5 (C), 143.3 (CH), 151.5 (C), 156.6 (C).

GC-MS (EI, 70 eV): m/z (%) = 326 (100) [M⁺], 311 (20), 284 (20), 182 (9), 163 (12), 139 (12), 131 (5), 115 (2), 102 (1), 63 (1), 39 (1).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₁₉N₂O: 327.14919; found: 327.15004.

6-(4-Fluorophenyl)-2-(4-methoxyphenyl)quinoxaline (5d)

Starting with 3h (0.08 g, 0.3 mmol), 2m (0.054 g, 1.3 equiv), Pd(PPh₃)₄ (0.017 g, 0.05 equiv), 2 M K₂CO₃ (1 mL), and 1,4-dioxane (4 mL), 5d was isolated as a white solid; yield: 0.074 g (76%); mp 187–189 °C.

IR (ATR): 3062 (w), 3014 (w), 2970 (w), 2843 (w), 1600 (m), 1545 (w), 1510 (m), 1454 (w), 1401 (w), 1306 (w), 1253 (m), 1226 (m), 1178 (w), 1115 (w), 1100 (w), 1027 (m), 960 (m), 902 (w), 890 (w), 826 (s), 785 (w), 720 (w), 696 (w), 640 (m), 631 (w), 589 (m), 554 (w), 534 (m) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 3.84 (s, 3 H, OCH₃), 7.02 (d, ³ J = 9.1 Hz, 2 H, ArH), 7.13 (t, J = 8.7 Hz, 2 H, ArH), 7.62–7.69 (m, 2 H, ArH), 7.90 (dd, J = 8.7, 2.1 Hz, 1 H, ArH), 8.07–8.16 (m, 4 H, ArH), 9.23 (s, 1 H, ArH).

¹³C NMR (75.46 MHz, CDCl₃): δ = 55.5 (OCH₃), 114.6 (2 CH), 116.0 (d, ² J _CF = 22.0 Hz, 2 CH), 126.4 (CH), 128.9 (2 CH), 129.1 (d, ³ J _CF = 8.3 Hz, 2 CH), 129.3 (C), 129.6 (CH), 129.8 (CH), 135.9 (d, ⁴ J _CF = 3.3 Hz, C), 140.8 (C), 141.4 (C), 141.6 (C), 143.6 (CH), 151.3 (C), 161.5 (C), 163.0 (d, ¹ J _CF = 247.59 Hz, C).

¹⁹F NMR (282.40 MHz, CDCl₃): δ = –114.27 (ArF).

GC-MS (EI, 70 eV): m/z (%) = 330 (100) [M⁺], 315 (14), 287 (10), 260 (2), 195 (2), 170 (12), 120 (20), 103 (1), 90 (1), 75 (1), 65 (1), 63 (1).

HRMS (EI): m/z [M⁺] calcd for C₂₁H₁₅FN₂O: 330.11629; found: 330.11615.

6-(3,5-Dimethylphenyl)-2-(4-fluorophenyl)quinoxaline (5e)

Starting with 3m (0.07 g, 0.3 mmol), 2e (0.058 g, 1.3 equiv), Pd(PPh₃)₄ (0.017 g, 0.05 equiv), 2 M K₂CO₃ (1 mL), and 1,4-dioxane (4 mL), 5e was isolated as a white solid; yield: 0.055 g (63%); mp 163–165 °C.

IR (ATR): 3339 (s), 2919 (w), 2859 (w), 2735 (w), 1599 (m), 1538 (w), 1469 (w), 1410 (w), 1343 (w), 1298 (w), 1264 (w), 1225 (m), 1142 (w), 1048 (m), 960 (m), 911 (w), 839 (m), 827 (s), 789 (w), 722 (m), 684 (m), 634 (w), 612 (s), 573 (w), 552 (w), 541 (w) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 2.34 (s, 6 H, 2 CH₃), 6.99 (s, 1 H, ArH), 7.16 (t, J = 8.7 Hz, 2 H, ArH), 7.29 (s, 2 H, ArH), 7.95 (dd, J = 8.7, 1.9 Hz, 1 H, ArH), 8.04–8.20 (m, 4 H, ArH), 9.19 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 20.4 (2 CH₃), 115.2 (d, ² J _CF = 21.97 Hz, 2 CH), 124.4 (2 CH), 125.4 (CH), 128.3 (CH), 128.5 (d, ³ J _CF = 8.2 Hz, 2 CH), 128.8 (CH), 129.2 (CH), 131.9 (d, ⁴ J _CF = 3.2 Hz, C), 137.6 (2 C), 138.6 (C), 140.5 (C), 140.7 (C), 141.6 (C), 142.2 (CH), 149.3 (C), 163.2 (d, ¹ J _CF = 250.8 Hz, C).

¹⁹F NMR (282.40 MHz, CDCl₃): δ = –110.61 (ArF).

GC-MS (EI, 70 eV): m/z (%) = 328 (100) [M⁺], 313 (3), 180 (13), 164 (3), 130 (9), 115 (5), 94 (1), 75 (1).

HRMS (EI): m/z [M⁺] calcd for C₂₂H₁₇FN₂: 328.13703; found: 328.13668.

6-(3,5-Dimethylphenyl)-2-(2-thienyl)quinoxaline (5f)

Starting with 3n (0.05 g, 0.2 mmol), 2e (0.039 g, 1.3 equiv), Pd(PPh₃)₄ (0.012 g, 0.05 equiv), 2 M K₂CO₃ (1 mL), and 1,4-dioxane (4 mL), 5f was isolated as a yellow solid; yield: 0.058 g (91%); mp 152 °C.

IR (ATR): 3106 (w), 3012 (w), 2913 (m), 2858 (w), 2722 (w), 1602 (m), 1573 (w), 1539 (m), 1454 (w), 1417 (m), 1371 (w), 1321 (m), 1238 (w), 1161 (w), 1132 (m), 1064 (w), 1006 (m), 935 (w), 919 (m), 891 (w), 819 (s), 786 (w), 775 (m), 750 (w), 703 (m), 682 (s), 625 (w), 615 (s), 606 (w), 561 (w), 537 (w) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 2.33 (s, 3 H, CH₃), 2.34 (s, 3 H, CH₃), 6.98 (s, 1 H, ArH), 7.10–7.13 (m, 1 H, ArH), 7.29 (s, 2 H, ArH), 7.46 (dd, J = 5.1, 1.1 Hz, 1 H, ArH), 7.77 (dd, J = 3.8, 1.1 Hz, 1 H, ArH), 7.90–8.16 (m, 3 H, ArH), 9.15 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 21.4 (2 CH₃), 125.3 (2 CH), 126.4 (CH), 126.8 (CH), 128.5 (CH), 129.2 (CH), 129.7 (CH), 129.8 (CH), 130.2 (CH), 138.6 (3 C), 139.6 (C), 141.4 (C), 141.6 (C), 142.2 (C), 142.4 (CH), 147.0 (C).

GC-MS (EI, 70 eV): m/z (%) = 316 (100) [M⁺], 301 (4), 180 (19), 158 (7), 130 (14), 115 (5), 69 (1), 63 (1), 57 (1).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₁₇N₂S: 317.11070; found: 317.11119.

2-(4-Ethylphenyl)-6-(p-tolyl)quinoxaline (5g)

Starting with 3o (0.07 g, 0.3 mmol), 2c (0.053 g, 1.3 equiv), Pd(PPh₃)₄ (0.017 g, 0.05 equiv), 2 M K₂CO₃ (1 mL), and 1,4-dioxane (4 mL), 5g was isolated as a yellowish solid; yield: 0.046 g (54%); mp 152–154 °C.

IR (ATR): 3021 (w), 2962 (m), 2854 (w), 2729 (w), 1915 (w), 1822 (w), 1727 (w), 1613 (m), 1513 (w), 1452 (m), 1336 (w), 1276 (w), 1209 (w), 1165 (m), 1080 (w), 1015 (w), 960 (m), 932 (m), 894 (w), 835 (m), 817 (s), 788 (w), 722 (w), 665 (w), 608 (m), 588 (w), 554 (w), 542 (w) cm^–1.

¹H NMR (300.13 MHz, CDCl₃): δ = 1.21 (t, ³ J = 7.5 Hz, 3 H, CH₃), 2.33 (s, 3 H, CH₃), 2.65 (q, J = 7.7 Hz, 2 H, CH₂), 7.22 (d, ³ J = 7.7 Hz, 2 H, ArH), 7.29 (d, ³ J = 8.3 Hz, 2 H, ArH), 7.57 (d, ³ J = 8.1 Hz, 2 H, ArH), 7.92 (dd, J = 8.7, 2.1 Hz, 1 H, ArH), 8.02–8.18 (m, 4 H, ArH), 9.21 (s, 1 H, ArH).

¹³C NMR (62.89 MHz, CDCl₃): δ = 15.4 (CH₃), 21.2 (CH₃), 28.8 (CH₂), 126.1 (CH), 127.3 (2 CH), 127.5 (2 CH), 128.7 (2 CH), 129.7 (2 CH), 129.8 (2 CH), 134.3 (C), 136.8 (C), 138.1 (C), 141.6 (C), 141.7 (C), 141.9 (C), 143.7 (CH), 146.7 (C), 151.5 (C).

GC-MS (EI, 70 eV): m/z (%) = 324 (100) [M⁺], 309 (36), 254 (1), 166 (8), 154 (7), 116 (11), 103 (1), 91 (2), 77 (1), 51 (1).

HRMS (EI): m/z [M⁺] calcd for C₂₃H₂₀N₂: 324.16210; found: 324.16206.

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• 2f Suresh M, Lavanya P, Sudhakar D, Vasu K, Rao CV. J. Chem. Pharm. Res. 2010; 2: 497
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• 3a Sridevi C, Balaji K, Naidu A.  E-J. Chem. 2011; 8: 924
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• 3b Burguete A, Pontiki E, Litina DH, Ancizu S, Villar R, Solano B, Moreno E, Torres E, Perez S, Aldana I, Monge A. Chem. Biol. Drug Des. 2011; 77: 255
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For reviews, see:
• 8d Hussain A, Madhesia D. J. Pharm. Res. 2011; 4: 924
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• 8e Deepika Y, Nath PS, Sachin K, Shewta S. Int. J. Curr. Pharm. Rev. Res. 2011; 2: 33
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• 15e Bailly C, Waring MJ. Biochem. J. 1998; 330: 81
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• 16 Baek JB, Harris FW. J. Polym. Sci., Part A: Polym. Chem. 2005; 43: 78
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• 17a Dailey S, Feast WJ, Peace RJ, Sage IC, Till S, Wood EL. J. Mater. Chem. 2001; 11: 2238
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• 17b Wang H, Chen G, Liu Y, Hu L, Xu X, Ji S. Dyes Pigm. 2009; 83: 269
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• For reviews of site-selective palladium(0)-catalyzed cross-coupling reactions, see:

• 18a Schröter S, Stock C, Bach T. Tetrahedron 2005; 61: 2245
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• 18b Schnürch M, Flasik R, Khan AF, Spina M, Mihovilovic MD, Stanetty P. Eur. J. Org. Chem. 2006; 3283
• 18c Wang R, Manabe K. Synthesis 2009; 1405
  Thieme Connect

• The Suzuki cross-coupling reaction of 2,6-dichloro-quinoxaline with one Boc-protected pyrazolylboronic acid pinacol ester has been reported in a patent. Surprisingly, the authors state the opposite regioselectivity for this reaction; see:

• 19a Boyle RG, Walker DW. WO 2010136755 (A1), 2010

For other palladium-catalyzed reactions of 2,6-dichloroquinoxaline (Sonogashira reaction), see:
• 19b Armengol M, Joule JA. J. Chem. Soc., Perkin Trans. 1 2001; 154
• 19c Armengol M, Joule JA. J. Chem. Soc., Perkin Trans. 1 2001; 978
• 20 CCDC 865782 (3g) and 865783 (5e) contain all crystallographic details for this publication. The data are available, free of charge, at www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: +44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk]
• 21 Martin LJ, Marzinzik AL, Ley SV, Baxendale IR. Org. Lett. 2011; 13: 320
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• 2e Sridevi C, Balaji K, Naidu A, Sudhakaran R. E-J. Chem. 2009; 6: 866
  Search in Google Scholar
• 2f Suresh M, Lavanya P, Sudhakar D, Vasu K, Rao CV. J. Chem. Pharm. Res. 2010; 2: 497
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• 3a Sridevi C, Balaji K, Naidu A.  E-J. Chem. 2011; 8: 924
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• 3b Burguete A, Pontiki E, Litina DH, Ancizu S, Villar R, Solano B, Moreno E, Torres E, Perez S, Aldana I, Monge A. Chem. Biol. Drug Des. 2011; 77: 255
  CrossrefSearch in Google Scholar
• 4 Seitz LE, Suling WJ, Reynolds RC. J. Med. Chem. 2002; 45: 5604
  CrossrefPubMedSearch in Google Scholar
• 5 Budakoti A, Bhat AR, Azam A. Eur. J. Med. Chem. 2009; 44: 1317
  CrossrefSearch in Google Scholar
• 6 Chung HJ, Jung OJ, Chae MJ, Hong SY, Chung KH, Lee SK, Ryu CK. Bioorg. Med. Chem. Lett. 2005; 15: 3380
  CrossrefSearch in Google Scholar
• 7 Kurasawa Y, Kim HS. J. Heterocycl. Chem. 1998; 35: 1101
  CrossrefSearch in Google Scholar
• 8a Guillon J, Mouray E, Moreau S, Mullie C, Forfar I, Desplat V, Fabre SB, Pinaud N, Ravanello F, Le-Naour A, Leger JM, Gosmann G, Jarry C, Delaris G, Sonnet P, Grellier P. Eur. J. Med. Chem. 2011; 46: 2310
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• 8b Barea C, Pabon A, Castillo D, Zimic M, Quiliano M, Galiano S, Silanes SP, Monge A, Deharo E, Aldana I. Bioorg. Med. Chem. Lett. 2011; 21: 4498
  CrossrefSearch in Google Scholar
• 8c Guillon J, Forfar I, Desplat V, Fabre SB, Thiolat D, Massip S, Carrie H, Mossalayi D, Jarry C. J. Enzyme Inhib. Med. Chem. 2007; 22: 541
  CrossrefSearch in Google Scholar

For reviews, see:
• 8d Hussain A, Madhesia D. J. Pharm. Res. 2011; 4: 924
  Search in Google Scholar
• 8e Deepika Y, Nath PS, Sachin K, Shewta S. Int. J. Curr. Pharm. Rev. Res. 2011; 2: 33
  Search in Google Scholar
• 9 Sheng R, Xu Y, Weng Q, Xia Q, He Q, Yang B, Hu Y. Drug Discovery Ther. 2007; 1: 119
  Search in Google Scholar
• 10 Pradhan J, Sharma R, Goyal A. Int. J. Pharm. Res. Dev. 2010; 2 (06) Article No. 8
  Search in Google Scholar
• 11 Servam P, Chandramohan M, Pannecouque C, De Clercq E. Int. J. Pharm. Ind. Res. 2011; 1: 2
  Search in Google Scholar
• 12 Vicente E, Silanes SP, Lima LM, Ancizu S, Burguete A, Solano B, Villar R, Aldana I, Antonio M. Bioorg. Med. Chem. 2009; 17: 385
  CrossrefPubMedSearch in Google Scholar
• 13 Gazit A, Yee K, Uecker A, Bohmer FD, Sjoblom T, Ostman A, Waltenberger J, Golomb G, Banai S, Heinrich MC, Levitzki A. Bioorg. Med. Chem. 2003; 11: 2007
  CrossrefSearch in Google Scholar
• 14 You L, Cho EJ, Leavitt J, Ma LC, Montelione GT, Anslyn EV, Krug RM, Ellington A, Robertus JD. Bioorg. Med. Chem. Lett. 2011; 21: 3007
  CrossrefSearch in Google Scholar
• 15a Waring M, Makoff A. Mol. Pharmacol. 1974; 10: 214
  Search in Google Scholar
• 15b Kong D, Park EJ, Stephen AG, Galvani M, Cardellina JH, Monks A, Fisher RJ, Shoemaker RH, Melillo G. Cancer Res. 2005; 65: 9047
  CrossrefSearch in Google Scholar
• 15c Wakelin LP. G. Med. Res. Rev. 1986; 6: 275
  CrossrefSearch in Google Scholar
• 15d Lorenz KB, Diederichsen U. J. Org. Chem. 2004; 69: 3917
  CrossrefSearch in Google Scholar
• 15e Bailly C, Waring MJ. Biochem. J. 1998; 330: 81
  Search in Google Scholar
• 16 Baek JB, Harris FW. J. Polym. Sci., Part A: Polym. Chem. 2005; 43: 78
  CrossrefSearch in Google Scholar
• 17a Dailey S, Feast WJ, Peace RJ, Sage IC, Till S, Wood EL. J. Mater. Chem. 2001; 11: 2238
  CrossrefSearch in Google Scholar
• 17b Wang H, Chen G, Liu Y, Hu L, Xu X, Ji S. Dyes Pigm. 2009; 83: 269
  CrossrefSearch in Google Scholar

• For reviews of site-selective palladium(0)-catalyzed cross-coupling reactions, see:

• 18a Schröter S, Stock C, Bach T. Tetrahedron 2005; 61: 2245
  CrossrefSearch in Google Scholar
• 18b Schnürch M, Flasik R, Khan AF, Spina M, Mihovilovic MD, Stanetty P. Eur. J. Org. Chem. 2006; 3283
• 18c Wang R, Manabe K. Synthesis 2009; 1405
  Thieme Connect

• The Suzuki cross-coupling reaction of 2,6-dichloro-quinoxaline with one Boc-protected pyrazolylboronic acid pinacol ester has been reported in a patent. Surprisingly, the authors state the opposite regioselectivity for this reaction; see:

• 19a Boyle RG, Walker DW. WO 2010136755 (A1), 2010

For other palladium-catalyzed reactions of 2,6-dichloroquinoxaline (Sonogashira reaction), see:
• 19b Armengol M, Joule JA. J. Chem. Soc., Perkin Trans. 1 2001; 154
• 19c Armengol M, Joule JA. J. Chem. Soc., Perkin Trans. 1 2001; 978
• 20 CCDC 865782 (3g) and 865783 (5e) contain all crystallographic details for this publication. The data are available, free of charge, at www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: +44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk]
• 21 Martin LJ, Marzinzik AL, Ley SV, Baxendale IR. Org. Lett. 2011; 13: 320
  CrossrefPubMedSearch in Google Scholar