Palladium-Catalyzed Direct Arylation of Azine and Azole N-Oxides: Reaction Development, Scope, and Applications in Synthesis. Supporting Information

Transcription

1 S1 Palladium-Catalyzed Direct Arylation of Azine and Azole -xides: Reaction Development, Scope, and Applications in Synthesis Louis-Charles Campeau, David R. Stuart, Jean-Philippe Leclerc, Mégan Bertrand- Laperle, Elisia Villemure, Ho-Yan Sun, Sandrine Lasserre, icolas Guimond, lanie Lecavallier, Keith Fagnou* Center for Catalysis Research and Innovation, Department of Chemistry, University of ttawa, 10 Marie Curie, ttawa, (CAADA) K1 65 Supporting Information General thods: All experiments were carried out under an argon atmosphere unless otherwise stated. 1 H and 13 C MR spectra were recorded in CDCl 3 or (CD 3 ) 2 C solutions on a Bruker AVACE 300 or 400 MHz spectrometer or an IVA 500 MHz spectrometer. High-resolution mass spectra were obtained on a Kratos Concept IIH. Infra-Red analysis was performed with a Bruker EQUIX 55. HPLC Grade THF, Et 2, benzene, toluene and CH 2 Cl 2 are dried and purified via MBraun SP Series solvent purification system. Triethylamine was freshly distilled from ah before every use. Dimethylacetamide and sitylene were degassed with Argon before every use. Phosphonium salts were either synthesized according to literature procedures 1 or purchased from Strem, stored in a dessicator and used without further purification. Palladium sources were stored in a dessicator and were weighed out to air unless otherwise specified. All other reagents and solvents were used as is from commercial sources. Characterization data is provided for all new compounds, unless noted below, all other compounds have been reported in the literature or are commercially available. Table of Contents: General procedures for the oxidation of azines Characterization data for new -oxides General procedure for preparation of imidazole -oxides Characterization data for new imidazole -oxides Representative procedure for the direct arylation of quinoline -oxide Characterization data for 2-arylquinoline -oxides General procedure for the direct arylation of 4- and 2-substituted pyridine -oxides S3 S3 S4 S4 S8 S8 S16

2 S2 Characterization data for new 2-arylpyridine -oxides General procedure for the direct arylation of isoquinoline -oxides Characterization data for new 1- and 3-arylisoquinoline -oxides General procedure for the reduction of mixtures of 1- and 3-aryl Isoquinoline -oxides Characterization data for new 1-arylisoquinolines General procedure for the direct arylation of 3-substituted pyridine -oxides Characterization data for 3-substituted-2(or 6-)-arylpyridine -oxides General procedure for the C2 direct arylation of thiazole -oxides Characterization data for C2-arylthiazole -oxides General procedure for the C5 direct arylation of thiazole -oxides Characterization data for C5-arylthiazole -oxides General procedure for the C4 direct arylation of thiazole -oxides Characterization data for C4-arylthiazole -oxides General procedure for the C2 direct arylation of imidazole -oxides Characterization data for C2-arylimidazole -oxides General procedure for the C4 direct arylation of imidazole -oxides Characterization data for C4-arylimidazole -oxides General procedures for the reduction of azine and azole -oxides Characterization data for aryl azine and azoles Procedures and characterization data for the synthesis of 1 Procedures and characterization data for the synthesis of 2 Complete manuscript references S16 S22 S22 S24 S24 S27 S27 S30 S30 S35 S35 S37 S37 S38 S38 S50 S50 S53 S53 S61 S64 S65

3 S3 xidation of azines and azoles: xidation Procedure A: Prefered method for preparation using an adapted methyltrioxorhenium oxidation protocol first reported by Sharpless and co-workers. 2 Easily scalable with limited by products. The azine is dissolved in reagent grade CH 2 Cl 2 (2.5M). This this mixture is added Re 3 (1-4mol%) which usually results in a significant color change to deep yellow. This solution is then capped with a rubber septa which is pierced with a small needle as a vent and placed in an ice bath. To the cold solution is added dropwize a 50w% aqueous solution of H 2 2 (2 equiv.). nce all peroxide has been added, the reaction is allowed to warm to room temperature where it is stirred for 12-24h. After consumption of starting material, a small amount of Mn 2 (5-10mg) is added to destroy unreacted peroxyde. After stirring this solution of 1-2 hours (until bubbling stops) the mixture is poured into an extraction funnel where the phases are seperated. The aqueous phase is washed with two volumes of CH 2 Cl 2 and the organic are combined, dried with MgS 4, filtered and concentrated under reduced pressure. The -oxides were then purified via silica gel column chromatography using the individually specified solvent system as the eluent to afford the corresponding -oxide. xidation Procedure B: Produces large amounts of waste m-chlorobenzoic acid, not recommended for large scale. Compatible with diazines. Azine (1 eq.) and m-chloroperoxybenzoic acid (1.2 eq.) are dissolved in reagent grade dichloroethane (0.5M). The reaction is allowed to stir at room temperature overnight from which precipitates a white solid (m-chlorobenzoic acid). The solvent is then evaporated under reduced pressure and the crude reaction mixture is purified by column chromatography on silica gel using the individually specified solvent system as the eluent to afford the corresponding -oxide. xidation Procedure C: Caution, this reaction is in water. Azines with limited solubility in water showed diminished reactivity in these systems. Also, azine -oxides which were highly water soluble were difficult to isolate. Azine (1 eq.) is dissolved in acetone (2.5M) in a three neck round bottom flask and phosphate buffer is added (0.25M). ne neck is fitted with an addition funnel carrying oxone (2.4 eq.) in distilled water (0.3M). A second neck is fitted with a solution of 2M ah. Both solutions are added dropwise simultaneously at room temperature and the ph of the reaction in monitored and kept between 7-8. Typically reactions are complete within 3 hours. The mixture is extracted twice with CH 2 Cl 2 and once with CHCl 3. The organic layer is then dried over MgS 4, filtered and evaporated under reduced pressure to afford the pyridine -oxide, often in analytically pure form. 3 Table 1, entries 1 10: These compounds are currently commercially available or have been characterized previously in the literature. See Table 1 for specific oxidation conditions.

4 S4 Table 1, entry 11: The above compound was prepared according oxidation procedure B and was isolated in 68% yield. 1 H MR (400 MHz, CDCl 3, 293 K): δ 9.06 (d, J = 8.0 Hz, 1H), 8.75 (d, J = 8.3 Hz, 1 H), 8.51 (d, J = 6.5 Hz, 1H), 8.00 (d, J = 6.5 Hz, 1H), (m, 2H), 4.02 (s, 3H). 13 C MR (100 MHz, CDCl 3, 293 K): δ 165.1, 142.3, 134.4, 130.4, 130.2, 128.4, 126.8, 124.4, 122.9, 119.8, FTIR: 3080, 1716, 1556, 1514, 783, 771 cm -1. HRMS (EI): calculated for C 11 H 9 3 (M + ) ; found for C 11 H 9 3 (M + ) lting point (acetone/hexanes): C. R f (10% acetone in dichloromethane): Table 1, entry 13 19: These compounds have been characterized previously in the literature. 4 specific oxidation conditions. See Table 1 for General procedure for the preparation of α-ketooximes: A solution of substituted acetophenone (1 equiv.) in DMF was added to a suspension of ah (2 equiv.) at 0 o C in DMF to resulting concentration of 0.3 M. The mixture was stirred for ~1 h at 0 o C before the addition of tert-butylnitrite (1.1 equiv.) at 0 o C. The reaction mixture was then stirred at room temperature until completion by TCL analysis, after which ice cold water was added and the mixture was extracted with 3 portions of EtAc. The organic layer was dried with MgS 4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography. Table 2, entry 1 (α-ketooxime): H The compound was synthesized according to general procedure for the synthesis of α- ketoaldoximes and was purified via silica gel column chromatography using a gradient from 10% to 15% EtAc/Hexane. The desired product was obtained as a yellow solid (61 %).

5 S5 1 H MR (400MHz, CDCl 3, 293K, TMS): δ 3.96 (3H, s), 7.24 (1H, dd, J = 9.0, 2.5 Hz), 7.38 (1H, d, J = 2.5 Hz), 7.88 (1H, d, J = 8.7 Hz), 7.97 (1H, d, J = 9.0 Hz), 8.04 (1H, dd, J = 8.7, 1.7 Hz), 8.07 (1H, s), 8.69 (1H, d, J = 0.9 Hz), (1H, broad). 13 C MR (100MHz, CDCl 3, 293K, TMS): δ 56.9 (CH 3 ), (CH), (CH), (CH), (CH), (C), (CH), (C), (CH), (C), (CH), (C), (C). IR (v max /cm -1 ): 858, 986, 1207, 1267, 1480, 1622, 2845, 2931, 3059, HRMS calculated for C 13 H 11 3 (M + ): ; Found: lting point ( C): (100% Acetone) R f : 0.21 on silica gel (25% EtAc/Hexane) Table 2, entry 2 (α-ketooxime): H The compound was synthesized according to general procedure for the synthesis of α- ketoaldoximes and was purified via silica gel column chromatography using 20% Acetone/Hexane. The desired product was obtained as a white solid (76% yield). The product was isolated as a 1.5:1 anti:syn mixture in which the major product is unknown. 1 H MR (400MHz, CDCl 3, 293K, TMS): δ 3.88 (2.1H, s), 3.92 (3H, s), 6.94 (1.3H, ddd, J = 2.8, 4.9, 9.8 Hz), 7.01 (2H, ddd, J = 2.8, 4.9, 9.8 Hz), 8.01 (2H, ddd, J = 2.8, 4.9, 9.8 Hz), 8.05 (0.6H, s), 8.09 (1.3H, ddd, J = 2.8, 4.9, 9.8 Hz), 8.21 (1H, s). 13 C MR (100 MHz, CDCl 3, 293K, TMS): δ 55.5 (CH 3 ), 55.8 (CH 3 ), (CH), (CH), (C), (C), (CH), (CH), (CH), (CH), (C), (C), (C), (C). IR (v max /cm -1 ): 841, 1021, 1269, 1471, 1596, 1665, HRMS calculated for C 9 H 9 3 (M+) ; Found: lting point ( C): (100% CHCl 3 ) R f : 0.18 on silica gel (20% Acetone/Hexane) Table 2, entry 3 (α-ketooxime): H 2 The compound was synthesized according to general procedure for the synthesis of α- ketoaldoximes and was purified via silica gel column chromatography using 20% Acetone/Hexane. The desired product was obtained as a yellow solid (21% yield). 1 H MR (400MHz, CD 6 C, 293K): δ 7.98 (1H, s), 8.25 (2H, d, J = 8.6 Hz), 8.35 (2H, d, J = 8.6 Hz).

6 S6 13 C MR (100 MHz, CD 6 C, 293K): δ (CH), (CH), (C), (CH), (C). (1 missing peak, 2 C peaks overlap) IR (v max /cm -1 ): 1340, 1523, 1636, 2868, 2985, HRMS calculated for C 8 H (M+) ; Found: lting point ( C): (100% Acetone) R f : 0.25 on silica gel (20% Acetone/Hexane) Table 2, entry 4 (α-ketooxime): H The compound was synthesized according the following procedure. Hydroxylamine hydrochloride (1 equiv.) was added to a solution of methylglyoxal 40% in water (1 equiv.) in THF. The reaction mixture was then stirred at room temperature until completion by TCL analysis, after which water was added and the mixture was extracted with 3 portions of EtAc. The organic layer was washed with brine once, dried with MgS 4 and concentrated under reduced pressure. The crude mixture was purified via silica gel column chromatography using 20% Acetone/Hexane. The desired product was obtained as a white solid (65% yield). The product was isolated as a ~15:1syn:anti mixture in which the major product is unknown. 1 H MR (400MHz, CDCl 3, 293K, TMS): δ 2.25 (0.21H, s), 2.41 (3H, s), 7.28 (0.05H, s), 7.60 (1H, s), 9.46 (1H, broad). 13 C MR (100 MHz, CDCl 3, 293K, TMS): δ 25.5 (CH 3 ), 31.0 (CH 3 ), (CH), (C). IR (v max /cm -1 ): 994, 1019, 1243, 1450, 1655, 1705, 2754, 2889, 2998, HRMS calculated for C 3 H 5 2 (M+) ; Found: lting point ( C): (100% CHCl 3 ) R f : 0.29 on silica gel (20% Acetone/Hexane) General procedure for the preparation of imidazole -oxides: α-ketoaldoxime (1 equiv.) and the appropriate 1,3,5-trialkylhexahydro-1,3,5-triazine (1.1 equiv.) were stirred at room temperature until the reaction was complete by TLC. AcH was removed under vacuum after which a minimum amount of a saturated ahc 3 solution was added to obtain a solution at ph 8. The mixture was extracted with 5-10 portions of a mixture of 20% H/DCM. The organic layer was dried with MgS 4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography. Table 2, entry 1 (imidazole -oxide):

7 S7 The compound was synthesized according to general procedure for the preparation of imidazole -oxides and was purified via silica gel column chromatography using a gradient from 15% to 20% H/DCM. The desired product was obtained as a white solid (83 % yield). 1 H MR (400MHz, CDCl 3, 293K, TMS): δ 3.68 (3H, s), 3.96 (3H, s), 7.18 (1H, d, J = 2.4 Hz), 7.23 (2H, m), 7.39 (1H, dd, J = 1.7, 8.5 Hz), 7.79 (3H, m), 7.97 (1H, d, J = 1.7 Hz). 13 C MR (100MHz, CDCl 3, 293K, TMS): δ 33.5 (CH 3 ), 55.4 (CH 3 ), (CH), (CH), (CH), (C), (CH), (CH), (CH), (C), (CH), (CH), (C), (C), (C). IR (v max /cm -1 ): 856, 1034, 1202, 1270, 1391, 1501, 1628, 2846, HRMS calculated for C 15 H (M + ): ; Found: lting point ( C): (100% CHCl 3 ) R f : 0.15 on silica gel (10% H/CHCl 3 ) Table 2, entry 2 (α-ketooxime): The compound was synthesized according to general procedure for the preparation of imidazole -oxides and was purified via silica gel column chromatography using a gradient from 10% to 20% H/CHCl 3. The desired product was obtained as a white solid (61% yield). 1 H MR (400MHz, CDCl 3, 293K, TMS): δ 3.61 (3H, s), 3.86 (3H, s), 7.00 (2H, d, J = 8.7 Hz), 7.13 (1H, d, J = 1.6 Hz), 7.29 (2H, d, J = 8.7 Hz), 7.98 (1H, s). 13 C MR (100 MHz, CDCl 3, 293K, TMS): δ 33.3 (CH 3 ), 55.5 (CH 3 ), (CH), (C), (CH), (CH), (CH), (C), (C). IR (v max /cm -1 ): 1040, 1181, 1254, 1327, 1509, 1651, 2879, HRMS calculated for C 11 H (M+) ; Found: lting point ( C): (100% CHCl 3 ) R f : 0.11 on silica gel (20% H/CHCl 3 ) Table 2, entry 3 (imidazole -oxide):

8 S8 2 The compound was synthesized according to general procedure for the preparation of imidazole -oxides and was purified via silica gel column chromatography using a gradient from 10% to 20% H/CHCl 3. The desired product was obtained as a yellow/brown solid (84% yield). 1 H MR (400MHz, CD 3 D, 293K): δ 3.81 (3H, s), 7.52 (1H, d, J = 1.4 Hz), 7.81 (2H, d, J = 8.9 Hz), 8.37 (2H, d, J = 8.9 Hz), 8.47 (1H, d, J = 1.4 Hz, exchangeable). 13 C MR (100 MHz, CD 3 D, 293K): δ 34.6 (CH 3 ), (CH), (CH), (C), (CH), (C), (C). (1 missing peak because of exchangeable CH) IR (v max /cm -1 ): 748, 867, 1234, 1330, 1645, 2937, 3013, HRMS calculated for C 10 H (M+) ; Found: lting point ( C): (100% CHCl 3 ) R f : 0.17 on silica gel (15% H/CHCl 3 ) Table 2, entry 4 (imidazole -oxide): Ph The compound was synthesized according to general procedure for the preparation of imidazole -oxides but 0.5 equiv. of 1,3,5-Tribenzylhexahydro-1,3,5-triazine was used. The crude product was purified via silica gel column chromatography using a gradient from 10% to 15% H/CHCl 3. The desired product was obtained as a white solid (67% yield). 1 H MR (400MHz, CDCl 3, 293K, TMS): δ 2.13 (3H, s), 5.01 (2H, s), 6.95 (1H, s), 7.12 (2H, m), 7.37 (3H, m), 7.83 (1H, s). 13 C MR (100 MHz, CDCl 3, 293K, TMS): δ 9.4 (CH 3 ), 49.5 (CH 2 ), (CH), (C), (CH), (CH), (CH), (CH), (C). IR (v max /cm -1 ): 703, 1045, 1308, 1414, 1630, 2954, HRMS calculated for C 11 H 12 2 (M+) ; Found: lting point ( C): (100% CHCl 3 ) R f : 0.24 on silica gel (15% H/CHCl 3 ) Representative procedure for the direct arylation of quinoline -oxide: A 0.3 M solution of 4-bromotoluene was prepared in dry toluene and degassed with argon. Palladium (II) acetate ( g, mmol, 5 mol %), di-tertbutylmethylphosphonium tetrafluoroborate ( g, mmol, 5 mol %), K 2 C 3

9 S9 (0.083 g, mmol, 2 eq), and quinoline -oxide (0.131 g, mmol, 3 eq) were weighed out in air into a round botton flask and fitted with a reflux condenser capped with a septa. This system was evacuated and refilled with argon to sufficiently purge the system of oxygen (~ 5 times). The aryl halide solution (1.0 ml, 0.3 mmol) was transferred via syringe to the round bottom flask, and the reaction was heated to 110 C for 16 hours under an atmosphere of argon. The cooled reaction mixture was filtered over celite and washed with acetone and dichloromethane. The solvent was removed under vacuum and the resulting residue subjected to column chromatography on silica gel. Table 3, entry 7: The above procedure was followed and the residue was subjected to column chromatography on silica gel (7 x 3 cm) with 15% acetone in dichloromethane as the solvent to afford the title compound in 96% yield. 1 H MR (400 MHz, CDCl 3, 293 K): δ 8.86 (d, J = 9.0 Hz, 1H), 7.90 (d, J = 8.2 Hz, 2 H), 7.85 (d, J = 8.2 Hz, 1H), 7.77 (dd, J = 7.8 = 7.8 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.62 (dd, J = 7.8 = 7.8 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 8.2 Hz, 2H), 2.43 (s, 3H). 13 C MR (75 MHz, CDCl 3, 293 K): δ 145.1, 142.3, 139.7, 136.6, 130.5, 129.5, 129.4, 129.0, 128.2, 127.9, 125.2, 123.3, 120.3, FTIR: 3059, 1608, 1556, 1499, 806, 734 cm -1. HRMS (EI): calculated for C 16 H 13 (M + ) ; found for C 16 H 13 (M + ) lting point (acetone/dcm): C. R f (15% acetone in dichloromethane): Table 4, entry 1: The above procedure was followed and the residue was subjected to column chromatography on silica gel (7 x 3 cm) with 10% acetone in dichloromethane as the solvent to afford the title compound in 89% yield. 1 H MR (300 MHz, CDCl 3, 293 K): δ 8.86 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 8.1 Hz, 2 H), 7.85 (d, J = 8.1 Hz, 1H), (m, 2H), 7.62 (dd, J = J = 7.4 Hz, 1H), (m, 4H).

10 S10 13 C MR (75 MHz, CDCl 3, 293 K): δ 144.9, 142.2, 133.5, 130.5, 129.6, 129.5, 129.5, 128.4, 128.3, 128.0, 125.2, 123.3, FTIR: 3054, 1560, 1491, 764 cm -1. HRMS (EI): calculated for C 15 H 11 (M + ) ; found for C 15 H 11 (M + ) lting point (acetone/hexanes): C. R f (10% acetone in dichloromethane): Table 4, entry 2: t Bu The above procedure was followed and the residue was subjected to column chromatography on silica gel (7 x 3 cm) with 15% acetone in dichloromethane as the solvent to afford the title compound in 94% yield. 1 H MR (400 MHz, CDCl 3, 293 K): δ 8.87 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 8.6 Hz, 2 H), 7.87 (d, J = 8.2 Hz, 1H), 7.78 (dd, J = 8.2 = 8.2 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.63 (dd, J = 7.8 = 7.8 Hz, 1H), (m, 3H, overlapping signals), 1.38 (s, 9H). 13 C MR (100 MHz, CDCl 3, 293 K): δ 152.8, 147.1, 145.0, 144.7, 142.3, 130.5, 129.3, 128.3, 127.9, 125.3, 125.2, 123.3, 120.3, 34.9, FTIR: 2965, 1597, 1563, 1499, 806, 738 cm -1. HRMS (EI): calculated for C 19 H 19 (M + ) ; found for C 19 H 19 (M + ) lting point (acetone/dcm): C. R f (15% acetone in dichloromethane): Table 4, entry 3 The above procedure was followed and the residue was subjected to column chromatography on silica gel (7 x 3 cm) with 15% acetone in dichloromethane as the solvent to afford the title compound in 87% yield. 1 H MR (400 MHz, CDCl 3, 293 K): δ 8.85 (d, J = 8.9 Hz, 1H), 8.03 (d, J = 8.7 Hz, 2 H), 7.84 (d, J = 8.4 Hz, 1H), 7.77 (ddd, J = 8.5, J = 7.0, J = 1.6 Hz, 1H), 7.71 (d, J = 9.1 Hz, 1H), 7.61 (ddd, J = 7.9. J = unresolved, J = 1.0 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 8.5 Hz, 2H), 3.88 (s, 3H). 13 C MR (100 MHz, CDCl 3, 293 K): δ 160.5, 144.7, 142.3, 131.2, 130.5, 129.3, 128.1, 127.9, 125.7, 125.2, 123.1, 120.2, 113.7, FTIR: 3064, 1605, 1560, 1501, 806, 732 cm -1.

11 S11 HRMS (EI): calculated for C 16 H 13 2 (M + ) ; found for C 16 H 13 2 (M + ) lting point (acetone/dcm): C. R f (15% acetone in dichloromethane): Table 4, entry 4: C 2 Et The above procedure was followed and the residue was subjected to column chromatography on silica gel (7 x 3 cm) with 10% acetone in dichloromethane as the solvent to afford the title compound in 61% yield. 1 H MR (300 MHz, CDCl 3, 293 K): δ 8.85 (d, J = 8.7 Hz, 1H), 8.20 (d, J = 8.1 Hz, 2 H), 8.07 (d, J = 8.7 Hz, 2H), 7.90 (d, J = 8.1 Hz, 1H), (m, 2H), 7.68 (dd, J = J = 6.8 Hz, 1H), 7.5 (d, J = 8.7 Hz, 1H), 4.43 (q, J = 7.4 Hz, 2H), 1.43 (t, J = 7.4 Hz, 3H). 13 C MR (75 MHz, CDCl 3, 293 K): δ 166.1, 144.0, 142.3, 137.7, 131.1, 130.8, 129.8, 129.6, 129.5, 128.8, 128.1, 125.4, 123.1, 120.3, 61.2, FTIR: 3074, 1710, 1612, 1558, 1501, 818, 734 cm -1. HRMS (EI): calculated for C 18 H 15 3 (M + ) ; found for C 18 H 15 3 (M + ) lting point (acetone/dcm): C. R f (10% acetone in dichloromethane): Table 4, entry 5: The above procedure was followed with the addition of Ag 2 C 3 (0.5 eq) and the residue was subjected to column chromatography on silica gel (7 x 3 cm) with 10% acetone in dichloromethane as the solvent to afford the title compound in 70% yield. 1 H MR (300 MHz, CDCl 3, 293 K): δ 8.85 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1 H), (m, 2H), 7.66 (dd, J = J = 8.1 Hz, 1H), (m, 5H), 2.27 (s, 3H). 13 C MR (75 MHz, CDCl 3, 293 K): δ 146.7, 142.0, 137.7, 133.9, 130.4, 130.1, 129.9, 129.3, 129.1, 128.4, 128.0, 125.9, 124.6, 123.8, 120.3, FTIR: 3064, 1603, 1561, 1514, 812, 735 cm -1. HRMS (EI): calculated for C 16 H 13 (M + ) ; found for C 16 H 13 (M + ) lting point (acetone/dcm): C. R f (10% acetone in dichloromethane): 0.31.

12 S12 Table 4, entry 6 Cl The above procedure was followed with the addition of Ag 2 C 3 (0.5 eq) and the residue was subjected to column chromatography on silica gel (7 x 3 cm) with 10% acetone in dichloromethane as the solvent to afford the title compound in 70% yield. 1 H MR (300 MHz, CDCl 3, 293 K): δ 8.84 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), (m, 2H), 7.67 (dd, J = J = 8.1 Hz, 1H), (m, 2H), (m, 3H). 13 C MR (75 MHz, CDCl 3, 293 K): δ 143.9, 142.0, 133.8, 133.2, 131.0, 130.6, 130.5, 130.1, 129.8, 128.8, 128.1, 126.3, 124.6, 123.6, FTIR: 3058, 1561, 811, 739 cm -1. HRMS (EI): calculated for C 15 H 10 Cl (M + ) ; found for C 15 H 10 Cl (M + ) lting point (acetone/dcm): C. R f (10% acetone in dichloromethane): Table 4, entry 7: The above procedure was followed and the residue was subjected to column chromatography on silica gel (7 x 3 cm) with 15% acetone in dichloromethane as the solvent to afford the title compound in 87% yield. 1 H MR (400 MHz, CDCl 3, 293 K): δ 8.86 (d, J = 8.6 Hz, 1H), 7.86 (dd, J = 8.2, 1.2 Hz, 1 H), 7.78 (ddd, J = 8.2, 6.7, 1.2 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.64 (ddd, J = 7.8, 6.7, 0.8 Hz, 1H), (m, 1H, overlapping signals), 7.50 (d, J = 9.0, 1H), 7.47 (ddd, J = 7.4, 1.2, 1.2, 1H), 7.43 (dd, J = 7.8 = 7.8 Hz, 1H), 7.02 (ddd, J = 7.8, 2.7, 1.2 Hz, 1H), 3.88 (s, 3H). 13 C MR (100 MHz, CDCl 3, 293 K): δ 159.4, 144.9, 142.3, 134.8, 130.6, 129.6, 129.4, 128.5, 128.0, 125.2, 123.4, 122.0, 120.3, 115.8, 114.7, FTIR: 3061, 1596, 1580, 1486, 1341, 1042, 804, 770 cm -1. HRMS (EI): calculated for C 16 H 13 2 (M + ) ; found for C 16 H 13 2 (M + ) lting point (acetone/dcm): C. R f (15% acetone in dichloromethane): Table 4, entry 8:

13 S13 The above procedure was followed and the residue was subjected to column chromatography on silica gel (7 x 3 cm) with 15% acetone in dichloromethane as the solvent to afford the title compound in 92% yield. 1 H MR (400 MHz, CDCl 3, 293 K): δ 8.86 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.78 (dd, J = 7.8 = 7.8 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.63 (dd, J = 7.4 = 7.4 Hz, 1H), 7.56 (s, 2H), 7.48 (d, J = 8.6 Hz, 1H), 7.11 (s, 1H), 2.40 (s, 6H). 13 C MR (75 MHz, CDCl 3, 293 K): δ 145.5, 142.3, 137.9, 133.4, 131.2, 130.5, 129.5, 128.3, 127.9, 127.2, 125.1, 123.5, 120.3, FTIR: 3060, 1599, 1561, 1509, 810, 732 cm -1. HRMS (EI): calculated for C 16 H 13 (M + ) ; found for C 16 H 13 (M + ) lting point (acetone/dcm): C. R f (15% acetone in dichloromethane): Table 4, entry 9 The above procedure was followed and the residue was subjected to column chromatography on silica gel (7 x 3 cm) with 10% acetone in dichloromethane as the solvent to afford the title compound in 73% yield. 1 H MR (300 MHz, CDCl 3, 293 K): δ 8.89 (d, J = 8.7 Hz, 1H), 8.46 (s, 1H), 8.10 (dd, J = 8.7, J = 1.9 Hz, 1H), (m, 4H), (m, 2H), (m, 4H). 13 C MR (75 MHz, CDCl 3, 293 K): δ 145.0, 142.3, 133.6, 133.0, 131.0, 130.6, 129.6, 129.6, 128.6, 128.5, 128.0, 127.7, 127.1, 126.4, 126.3, 125.3, 123.5, There is one overlapping carbon signal as 1 peak is missing even with prolonged scans. FTIR: 3122, 1560, 1496, 803, 730 cm -1. HRMS (EI): calculated for C 19 H 13 (M + ) ; found for C 19 H 13 (M + ) lting point (acetone/dcm): C. R f (10% acetone in dichloromethane): Table 4, entry 10:

14 S14 The above procedure was followed with the addition of Ag 2 C 3 (0.5 eq) and the residue was subjected to column chromatography on silica gel (7 x 3 cm) with 10% acetone in dichloromethane as the solvent to afford the title compound in 83% yield. 1 H MR (300 MHz, CDCl 3, 293 K): δ 8.88 (d, J = 9.3 Hz, 1H), (m, 3H), (m, 2H), 7.69 (ddd, J = 8.1, J = 6.8, J = 1.2 Hz, 1H), 7.60 (d, J = 5.6 Hz, 2H), (m, 4H). 13 C MR (75 MHz, CDCl 3, 293 K): δ 145.6, 142.1, 133.4, 132.1, 130.7, 130.5, 130.1, 129.9, 128.6, 128.6, 128.1, 127.7, 126.9, 126.2, 125.4, 125.4, 124.7, 124.5, FTIR: 3057, 1592, 1561, 1503, 890, 774, 731 cm -1. HRMS (EI): calculated for C 19 H 13 (M + ) ; found for C 19 H 13 (M + ) lting point (acetone/hexanes): C. R f (10% acetone in dichloromethane): Representative Procedure for the direct arylation of 6-methoxyquinoline -oxides: This was analogous to the general procedure for the direct arylation of unsubstituted quinoline -oxides, however dioxane was used as the reaction solvent instead of toluene. Table 4, entry 11: The above procedure was followed and the residue was subjected to column chromatography on silica gel (7 x 3 cm) with 10% acetone in dichloromethane as the solvent to afford the title compound in 72% yield. 1 H MR (300 MHz, CDCl 3, 293 K): δ 8.76 (d, J = 9.3 Hz, 1H), 7.95 (d, J = 7.4 Hz, 2 H), 7.64 (d, J = 8.7 Hz, 1H), (m, 4H), 7.40 (dd, J = 9.9 Hz, J = 2.5 Hz 1H), 7.11 (d, J = 2.5 Hz, 1H), 3.96 (s, 3H). 13 C MR (75 MHz, CDCl 3, 293 K): δ 159.2, 143.2, 137.8, 133.5, 131.0, 129.5, 129.2, 128.2, 124.3, 123.8, 122.6, 122.0, 105.8, FTIR: 3058, 1616, 1567, 1489, 850, 764 cm -1. HRMS (EI): calculated for C 16 H 13 2 (M + ) ; found for C 16 H 13 2 (M + ) lting point (acetone/dcm): C. R f (10% acetone in dichloromethane): Table 4, entry 12:

15 S15 The above procedure was followed and the residue was subjected to column chromatography on silica gel (7 x 3 cm) with 10% acetone in dichloromethane as the solvent to afford the title compound in 85% yield. 1 H MR (300 MHz, CDCl 3, 293 K): δ 8.76 (d, J = 9.9 Hz, 1H), 7.87 (d, J = 8.1 Hz, 2 H), 7.62 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.39 (dd, J = 9.9 Hz, J = 3.1 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 2.5 Hz, 1H), 3.95 (s, 3H), 2.43 (s, 3H). 13 C MR (75 MHz, CDCl 3, 293 K): δ 159.1, 143.4, 139.4, 137.9, 130.8, 130.6, 129.4, 129.0, 124.3, 123.8, 122.4, 122.0, 105.9, 55.7, FTIR: 3030, 1615, 1575, 1498, 801, 723 cm -1. HRMS (EI): calculated for C 17 H 15 2 (M + ) ; found for C 17 H 15 2 (M + ) lting point (acetone/dcm): C. R f (10% acetone in dichloromethane): Table 4, entry 13: The above procedure was followed and the residue was subjected to column chromatography on silica gel (7 x 3 cm) with 10% acetone in dichloromethane as the solvent to afford the title compound in 77% yield. 1 H MR (300 MHz, CDCl 3, 293 K): δ 8.76 (d, J = 9.3 Hz, 1H), 7.98 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.39 (dd, J = 9.3 Hz, J = 2.5 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 7.03 (d, J = 9.3 Hz, 2H), 3.95 (s, 3H), 3.88 (s, 3H). 13 C MR (75 MHz, CDCl 3, 293 K): δ 160.3, 159.1, 143.0, 137.9, 131.1, 130.6, 125.8, 124.3, 123.6, 122.4, 121.9, 113.6, 105.9, 55.7, FTIR: 2962, 1618, 1604, 1564, 1495, 834, 722 cm -1. HRMS (EI): calculated for C 17 H 15 3 (M + ) ; found for C 17 H 15 3 (M + ) lting point (acetone/dcm): C. R f (10% acetone in dichloromethane): Table 4, entry 14:

16 S16 Cl Column chromatography was performed on silica gel (7 x 3 cm) with 5% acetone in dichloromethane as the solvent to afford the title compound in 55% yield. 1 H MR (300 MHz, CDCl 3, 293 K): δ 8.74 (d, J = 9.6 Hz, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.8 Hz, 1H), 7.40 (dd, J = 9.5 Hz, J = 2.6 Hz, 1H), 7.11 (d, J = 2.6 Hz, 1H), 3.96 (s, 3H). 13 C MR (75 MHz, CDCl 3, 293 K): δ 159.4, 142.1, 137.9, 135.3, 131.9, 131.1, 131.0, 128.5, 124.4, 123.4, 122.7, 122.0, 105.9, FTIR: 2999, 1620, 1574, 1567, 1487, 828 cm -1. HRMS (EI): calculated for C 16 H 12 2 Cl (M + ) ; found for C 16 H 12 2 Cl (M + ) lting point (acetone/dcm): C. R f (5% acetone in dichloromethane): Table 4, entry 15: The general procedure for the arylation of quinoline -oxides was followed and the residue was subjected to column chromatography on silica gel (7 x 3 cm) with 10% acetone in dichloromethane as the solvent to afford the title compound in 91% yield. 1 H MR (400 MHz, CDCl 3, 293 K): δ 9.01 (dd, J = 8.5 Hz, J = 0.9 Hz, 1H), 8.85 (d, J = 8.6 Hz, 0.9 Hz, 1H), 8.22 (s, 1H), 7.88 (d, J = 8.2, 2H), 7.78 (ddd, J = J = 8.4 Hz, J = 1.4 Hz, 1H), 7.70 (ddd, J = J = 8.4 Hz, J = 1.4 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 4.00 (s, 3H), 2.43 (s, 3H). 13 C MR (100 MHz, CDCl 3, 293 K): δ 165.4, 144.1, 143.1, 140.1, 130.4, 129.8, 129.5, 129.4, 129.1, 127.1, 126.7, 126.6, 122.2, 120.3, 52.6, FTIR: 2951, 1719, 1556, 1502, 1437, 786, 740 cm -1. HRMS (EI): calculated for C 18 H 15 3 (M + ) ; found for C 18 H 15 3 (M + ) lting point (acetone/dcm): C. R f (2% acetone in dichloromethane): General procedure for the arylation of 4- and 2-substituted pyridine -oxides:

17 S17 Pd(Ac) 2 (5 mol%), P t Bu 3. HBF 4 (6 mol%), potassium carbonate powder (K 2 C 3, 1.5 equiv.), aryl halide (1 equiv.) and proper azine -oxide (1.1-4 equiv.) are weighed to air and placed inside the flask. The flask is then fitted with a reflux condenser which is capped with a rubber septum. The whole setup is then evacuated under vacuum and refilled with Argon four times. Toluene (0.15M) is then added under a steady flow of argon. After addition, the reaction is immersed in the oil bath. Stirring is commenced and the heating source is turned on (set to 125ºC). The reaction is left stirring for hours (overnight), then allowed to cool, diluted with DCM and filtered over celite. The residues are then purified using silica gel chromatography. Table 5, entry 1: C 2 Purified with 5% Acetone in DCM (Rf~0.25) light yellow solid 1 H MR (400MHz, CDCl 3, 293K, TMS): 2.38 (6H, s), 3.95 (3H, s), 7.12 (1H, br), 7.38 (2H, s), 7.78 (1H, dd, J=6.7Hz & 2.4Hz), 8.01 (1H, d, J=2.7Hz), 8.32 (1H, d, J=7.1Hz); 13 C MR (100MHz, CDCl 3, 293K, TMS): 21.3, 52.7, 124.2, 126.1, 126.8, 127.7, 131.7, 138.0, 140.6, 149.9, 150.7, 164.2; IR (ν max /cm -1 ): 2951, 1721, 1269, 1238, 1113, 768; HRMS calculated for C 15 H 15 3 (M+) ; Found: ; m.p. (CHCl 3 ): ºC Table 5, entry 2: C 2 Purified with 5% Acetone in DCM (Rf~0.25) tan solid 1 H MR (400MHz, CDCl 3, 293K, TMS): 3.87 (3H, s), 3.95 (3H, s), 7.02 (2H, d, J=9.0), 7.75 (1H, dd, J=6.7Hz & 2.4Hz), 7.82 (2H, d, J=9.0Hz), 8.04 (1H, d, J=62.4Hz), 8.31 (1H, d, J=6.7Hz); 13 C MR (100MHz, CDCl 3, 293K, TMS): 52.8, 55.4, 113.8, 123.7, 124.0, 126.2, 127.2, 130.8, 140.7, 149.1, 160.9, 164.3; IR (ν max /cm -1 ): 2953, 1722, 1305, 1256, 1113, 768; HRMS calculated for C 14 H 13 4 (M+) ; Found: ; m.p. (CHCl 3 ): ºC

18 S18 Table 5, entry 3: Purified with 2% Acetone, 3% H in DCM (Rf~0.25) tan oil 1 H MR (400MHz, CDCl 3, 293K, TMS): 2.35 (3H, s), 3.84 (3H, s), 6.99 (3H, m), 7.22 (1H, d, J=2.3Hz), 7.80 (2H, d, J=8.9Hz), 8.19 (1H, d, J=6.6Hz); 13 C MR (100MHz, CDCl 3, 293K, TMS): 29.0, 55.3, 113.6, 124.8, 124.9, 127.6, 130.8, 137.5, 139.8, 148.1, 160.5; IR (ν max /cm -1 ): 3384, 1607, 1476, 1251, 1180, 785; HRMS calculated for C 13 H 13 2 (M+) ; Found: ; Table 5, entry 4: Purified with 5% H in DCM (Rf~0.25) tan solid 1 H MR (400MHz, CDCl 3, 293K, TMS): 2.36 (3H, s), 7.13 (1H, dd, J=6.6Hz & 2.5Hz), 7.21 (1H, d, J=2.5Hz), 7.50 (5H, m), 7.88 (1H, d, J=8.2Hz), 7.94 (1H, d, J=8.1Hz), 8.28 (1H, d, J=6.7Hz); 13 C MR (100MHz, CDCl 3, 293K, TMS): 29.1, 125.3, 125.4, 126.1, 126.2, 126.8, 127.7, 128.5, 129.4, 130.0, 131.0, 131.3, 133.4, 136.9, 139.6, 148.9; IR (ν max /cm -1 ): 3395, 1478, 1460, 1235, 821, 784; HRMS calculated for C 16 H 13 1 (M+) ; Found: ; m.p. (CHCl 3 ): ºC Table 5, entry 5: Purified with 5% H in DCM (Rf~0.25) 1 H MR (400MHz, CDCl 3, 293K, TMS): 3.83 (3H, s), 6.91 (2H, m) 7.52 (5H, m), 7.90 (1H, d, J=7.1Hz), 7.95 (1H, d, J=8.0Hz), 8.30 (1H, d, J=7.2Hz);

19 S19 13 C MR (100MHz, CDCl 3, 293K, TMS): 56.1, 111.7, 113.7, 125.2, 125.4, 126.3, 126.9, 127.6, 128.5, 130.1, 130.8, 131.3, 133.4, 140.9, 150.2, 157.1; IR (ν max /cm -1 ): 3377, 1484, 1421, 1219, 1028, 782; HRMS calculated for C 16 H 13 2 (M+) ; Found: ; Table 5, entry 6: C 2 Et Purified with 3% Acetone, 4% H in DCM (Rf~0.25) white solid 1 H MR (400MHz, CDCl 3, 293K, TMS): 1.41 (3H, t), 2.39 (3H, s), 4.41 (2H, q), 7.07 (1H, dd, J=6.7Hz & 2.2Hz), 7.25 (1H, d, J=2.5Hz), 7.91 (2H, d, J=8.6Hz), 8.13 (2H, d, J=8.6), 8.22 (1H, d, J=6.7Hz); 13 C MR (100MHz, CDCl 3, 293K, TMS): 14.3, 29.1, 61.1, 125.9, 128.0, 129.3, 129.4, 131.1, 137.0, 137.3, 139.9, 147.5, 166.1; IR (ν max /cm -1 ): 3391, 1715, 1277, 1246, 1125, 771; HRMS calculated for C 15 H 15 3 (M+) ; Found: ; m.p. (CHCl 3 ): ºC Table 5, entry 7: Ph C 2 Et Purified with 20% Acetone in DCM (Rf~0.25) tan solid 1 H MR (400MHz, CDCl 3, 293K, TMS): 1.41 (3H, t), 4.39 (2H, q, J=7.2Hz), 7.47 (4H, m), 7.61 (2H, d, J=7.2Hz), 7.66 (1H, d, J=2.7Hz), 7.94 (2H, d, J=8.3Hz), 8.15 (2H, d, J=8.4Hz), 8.37 (1H, d, J=6.9Hz); 13 C MR (100MHz, CDCl 3, 293K, TMS): 14.3, 61.2, 122.8, 125.0, 126.4, 129.2, 129.3, 129.4, 129.5, 131.3, 136.2, 136.9, 138.5, 140.5, 148.1, 166.0; IR (ν max /cm -1 ): 3396, 1713, 1470, 1276, 1106, 762; HRMS calculated for C 20 H 17 3 (M+) ; Found: ; m.p. (CHCl 3 ): ºC Table 5, entry 8 9: These compounds have been characterized previously in the literature. 5

20 S20 Table 6, entry 1: This compound has been previously characterized in the literature. 6 Table 6, entry 2: btained in 34% yield as a off-white solid. 1 H MR (500MHz, CDCl 3, 293K, TMS: 2.37 (3H, s), 2.40 (3H, s), 2.55 (3H, s), 7.07 (1H, d, J=8.3Hz), 7.17 (1H, d, J=8.3Hz), 7.25 (2H, d, J=8.3Hz), 7.66 (2H, d, J=8.3Hz); 13 C MR (100MHz, CDCl 3, 293K, TMS): 14.4, 19.7, 21.4, 123.3, 126.5, 128.7, 129.3, 130.9, 133.1, 139.0, 147.0, 148.9; IR (ν max /cm -1 ): 2925, 1490, ; HRMS calculated for C 14 H 15 (M+) ; Found: ; m.p. : ºC (CHCl 3 ) Rf: 0.19 (2%H, 10% 2 C, DCM) Table 6, entry 3: C btained in 74% yield as a white solid. 1 H MR (500MHz, CDCl 3, 293K, TMS: 2.42 (3H, s), 2.59 (3H, s), (3H, m), 7.47 (1H, d, J=8.1Hz), 7.53 (2H, d, J=8.2Hz); 13 C MR (100MHz, CDCl 3, 293K, TMS): 19.0, 21.6, 110.9, 115.4, 125.1, 126.7, 127.4, 129.3, 129.6, 141.0, 152.5, 154.6, ; IR (ν max /cm -1 ): 2919, 2231, 1348, 1269, 815; HRMS calculated for C 14 H 12 2 (M+) ; Found: ; m.p. : ºC (CH 2 Cl 2 ) Rf: 0.20 (1%H, 5% 2 C, DCM) Table 6, entry 4: This compound has been previously characterized in the literature. 6 Table 6, entry 5:

21 S21 p-tol btained in 74% yield as a yellow solid. 1 H MR (500MHz, CDCl 3, 293K, TMS: 2.36 (6H, s), 2.40 (3H, s), 7.06 (1H, s), (3H, m), (2H, m), 7.24 (2H, s, br), 7.74 (2H, d, J=8.2Hz); 13 C MR (100MHz, CDCl 3, 293K, TMS): 21.3, 21.4, 124.8, 125.8, 125.8, 127.2, 128.7, 129.5, 130.5, 130.9, 133.3, 137.6, 139.4, 150.0, 150.3; IR (ν max /cm -1 ): 2916, 1362, 1245, 780; HRMS calculated for C 20 H 19 (M+) ; Found: ; m.p. : ºC (CH 2 Cl 2 ) Rf: 0.27 (0.5%H, 1% 2 C, DCM) Table 6, entry 6: C C 2 Et Purified with 1% Acetone in DCM (Rf~0.25) light yellow solid 1 H MR (400MHz, CDCl 3, 293K, TMS): 1.42 (3H, t, J=14.3Hz & 7.2Hz), 4.42 (2H, q, J=7.2Hz), 7.40 (1H, m), 7.68 (2H, m), 7.87 (2H, d, J=8.4Hz), 8.13 (2H, d, J=8.4Hz); 13 C MR (100MHz, CDCl 3, 293K, TMS): 14.3, 61.4, 112.1, 124.6, 127.1, 129.2, 129.5, 130.3, 130.6, 132.1, 134.9, 149.4, 165.8; IR (ν max /cm -1 ): 3074, 1711, 1378, 1281, 1105, 769; HRMS calculated for C 15 H (M+) ; Found: ; m.p. (CHCl 3 ): ºC. Table 6, entry 7: C Purified with 1.5% Acetone in DCM (Rf~0.25) light yellow solid 1 H MR (400MHz, CDCl 3, 293K, TMS): 3.85 (3H, s), 6.97 (2H, d, J=8.9Hz), 7.33 (1H, dd, J=16.0Hz & 7.9Hz), 7.58 (1H, dd, J=7.8Hz & 2.0Hz), 7.62 (1H, dd, J=8.0Hz & 2.1Hz), 7.80 (2H, d, J=8.9Hz); 13 C MR (100MHz, CDCl 3, 293K, TMS): 55.4, 112.5, 113.8, 122.9, 124.7, 126.8, 129.4, 129.8, 130.8, 149.9, 161.2; IR (ν max /cm -1 ): 3073, 1611, 1379, 1262, 1183, 783;

22 S22 HRMS calculated for C 13 H (M+) ; Found: ; m.p. (CHCl 3 ): ºC Table 6, entry 8: C Purified with 0.2% Acetone in DCM (Rf~0.25) 1 H MR (400MHz, CDCl 3, 293K, TMS): 2.21 (3H, s), 7.21 (1H, dd, J=7.3Hz & 0.8Hz), 7.32 (4H, m), 7.49 (1H, dd, J=7.9Hz & 2.2Hz), 7.66 (1H, dd, J=7.8Hz & 2.1Hz); 13 C MR (100MHz, CDCl 3, 293K, TMS): 19.5, 112.2, 124.0, 126.0, 126.4, 129.4, 130.1, 130.3, 130.5, 131.0, 131.1, 137.9, 152.0; IR (ν max /cm -1 ): 3067, 1470, 1380, 1270, 1246, 761; HRMS calculated for C 13 H 10 2 (M+) ; Found: ; m.p. (CHCl 3 ): ºC Table 6, entry 9: This compound has been previously characterized in the literature. 7 Table 6, entry 10: This compound has been previously characterized in the literature. 6 General Procedure for direct arylation of Isoquinoline -xides: A 0.3 M solution of aryl halide was prepared in dry toluene and degassed with argon. Palladium (II) acetate ( g, mmol, 5 mol %), di-tert-butylmethylphosphonium tetrafluoroborate (0.030 mmol, 10 mol %), K 2 C 3 (0.599 mmol, 2 eq), and quinoline - oxide ( mmol, 3 eq) were weighed out in air into a round botton flask and fitted with a reflux condenser capped with a septa. This system was evacuated and refilled with argon to sufficiently purge the system of oxygen (~ 5 times). The aryl halide solution (1.0 ml, 0.3 mmol) was transferred via syringe to the round bottom flask, and the reaction was heated to 110 C for 12 hours under an atmosphere of argon. The cooled reaction mixture was filtered over celite and washed with acetone and dichloromethane. The solvent was removed under vacuum and the resulting residue subjected to column chromatography on silica gel. Table 8, entry 1 3 (-oxide):

23 S23 The above procedure was followed and column chromatography was performed on silica gel with H:acetone:DCM (2:20:78) as the solvent to afford the product as a mixture of isomers (6': 7' 13.5:1 by 1 H MR spectroscopy) in 98% yield. Isomer 6': 1 H MR (400 MHz, CDCl 3, 293 K): δ 8.28 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.54 (m, 1H), (m, 6H), 2.47 (s, 3H). 13 C MR (100 MHz, CDCl 3, 293 K): δ 146.3, 139.4, 137.4, 130.0, 129.7, 129.5, 129.1, 128.9, 128.2, 127.9, 126.8, 125.8, 123.1, FTIR: 3056, 1620, 1551, 1493, 817, 745 cm -1. HRMS (EI): calculated for C 16 H 13 (M + ) ; found for C 16 H 13 (M + ) lting point (acetone/dcm): C. R f (H:acetone:DCM (2:20:78)): Isomer 7': 1 H MR (400 MHz, CDCl 3, 293 K): δ 8.90 (s, 1H), (m, 2H), (m, 3H), (m, 2H), 7.31 (d, J = 7.9 Hz, 2H), 2.43 (s, 3H). 13 C MR (100 MHz, CDCl 3, 293 K): δ 147.3, 139.5, 137.0, 130.0, 129.6, 129.2, 128.9, 128.9, 128.7, 126.6, 124.5, 124.4, There is one overlapping carbon signal as 1 peak is missing even with prolonged scans. FTIR: 3029, 1635, 1560, 1487, 811, 746 cm -1. HRMS (EI): calculated for C 16 H 13 (M + ) ; found for C 16 H 13 (M + ) lting point (acetone/dcm): C. R f (H:acetone:DCM (2:20:78)): Table 8, entry 4 (-oxide): The above procedure was followed and column chromatography was performed on silica gel with H:acetone:DCM (2:20:78) as the solvent to afford the product as a mixture of isomers (6': 7' 12.4:1 by 1 H MR spectroscopy) in 92% yield. Structural proof based on reduction, see below.

24 S24 Table 8, entry 5 (-oxide): C 2 Et C 2 Et The above procedure was followed and column chromatography was performed on silica gel with H:acetone:DCM (2:20:78) as the solvent to afford the product as a mixture of isomers (6': 7' 15.8:1 by 1 H MR spectroscopy) in 95% yield. Structural proof based on reduction, see below. Table 8, entry 6 (-oxide): CH 3 CH 3 The above procedure was followed and column chromatography was performed on silica gel with H:acetone:DCM (2:20:78) as the solvent to afford the product as a mixture of isomers (6': 7' 13.5:1 by 1 H MR spectroscopy) in 96% yield. Structural proof based on reduction, see below. Table 8, entry 7 (-oxide): Cl Cl The above procedure was followed and column chromatography was performed on silica gel with H:acetone:DCM (2:20:78) as the solvent to afford the product as a mixture of isomers (6': 7' 14.1:1 by 1 H MR spectroscopy) in 63% yield. Structural proof based on reduction, see below. General procedure for the reduction of 1-aryl- and 3-arylisoquinoline -oxides 8 :

25 S25 The regioisomeric mixture of 1- and 3-arylisoquinoline -oxides (1 eq) and 10% Pd/C (10 mol% Pd) were weighed into a thick-walled test tube and sealed with a rubber septa and purged with argon. thanol (0.14 M in isoquinoline -oxide) was added and ammonium formate (14 eq) was then added to the the black reaction mixture which was heated to 40 C. The reaction was monitored by thin layer chromatography until it was observed that the -oxide had been completely consumed. The reaction was then filtered over celite and washed with DCM, the solvent was removed and the residue subjected to flash chromatography with an appropriate solvent system. Table 8, entry 1 (isoquinoline): The above procedure was followed and column chromatography was performed on silica gel with acetone:dcm (2:98) as the solvent to afford the title compound in 80% yield. MR data is consistent with that previously reported in the literature. 9 Table 8, entry 4 (isoquinoline): The above procedure was followed and column chromatography was performed on silica gel with acetone:dcm (1:99) as the solvent to afford the title compound in 73% yield. 1 H MR (400 MHz, CDCl 3, 293 K): δ 8.59 (d, J = 5.7 Hz, 1H), 8.12 (dd, J = 8.5 Hz, J = 0.8 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.66 (ddd, J = J = 8.1 Hz, J = 1.2 Hz, 1H), 7.61 (d, J = 5.6 Hz, 1H), 7.52 (ddd, J = J = 8.3 Hz, J = 1.3 Hz, 1H), 7.30 (s, 2H), 7.12 (s, 1H), 2.41 (s, 6H). 13 C MR (100 MHz, CDCl 3, 293 K): δ 161.1, 142.2, 139.5, 137.8, 136.8, 130.2, 129.9, 127.8, 127.7, 127.0, 126.9, 126.8, 119.7, FTIR: 2916, 1390, 825, 707 cm -1. HRMS (EI): calculated for C 17 H 15 (M + ) ; found for C 17 H 15 (M + ) lting point (acetone/dcm): C. R f (acetone:dcm (1:99)): Table 8, entry 5 (isoquinoline):

26 S26 C 2 Et The above procedure was followed and column chromatography was performed on silica gel with acetone:dcm (2:98) as the solvent to afford the title compound in 83% yield. 1 H MR (400 MHz, CDCl 3, 293 K): δ 8.63 (d, J = 5.7 Hz, 1H), 8.22 (d, J = 8.6 Hz, 2H), 8.03 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.5 Hz, 2H), (m, 2H), 7.55 (ddd, J = J = 8.3 Hz, J = 1.3 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H). 13 C MR (100 MHz, CDCl 3, 293 K): δ 166.4, 159.6, 143.9, 142.3, 136.8, 130.5, 130.2, 130.0, 129.6, 127.5, 127.1, 127.1, 126.6, 120.4, 61.1, FTIR: 2981, 1715, 1273, 1102, 827, 772, 707 cm -1. HRMS (EI): calculated for C 12 H 11 2 (M + ) ; found for C 12 H 11 2 (M + ) lting point (acetone/dcm): C. R f (acetone:dcm (2:98)): Table 8, entry 6 (isolquinoline): CH 3 The above procedure was followed and column chromatography was performed on silica gel with acetone:dcm (1:99) as the solvent to afford the title compound in 83% yield. MR data is consistent with that previously reported in the literature. 9 Table 8, entry 7 (isoquinoline): Cl

27 S27 The following alternate procedure was used. 10 The regioisomeric mixture of 1- and 3- arylisoquinoline -oxides (1 eq) was dissolved in THF:H 4 Cl(sat) (1:1 v/v) (0.03 M in isoquinoline -oxide). Zinc dust (5 eq) was added to this solution and it was stirred at room temp. for 1 hour. The reaction was filtered over celite, extracted with ether and the organic layer dried over MgS 4. The residue was subjected to column chromatography on silica gel with DCM:Pet. Ether (60:40) as the solvent to afford the title compound in 85% yield. 1 H MR (400 MHz, CDCl 3, 293 K): δ 8.60 (d, J = 5.7 Hz, 1H), 8.05 (dd, J = 8.5 Hz, J = 0.9 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.70 (ddd, J = J = 8.1 Hz, J = 1.2 Hz, 1H), (m, 3H), (m, 3H). 13 C MR (100 MHz, CDCl 3, 293 K): δ 159.4, 142.2, 138.0, 136.9, 134.8, 131.3, 130.1, 128.6, 127.4, 127.1, 127.1, 126.6, FTIR: 3051, 1488, 1028, 818 cm -1. HRMS (EI): calculated for C 15 H 10 Cl (M + ) ; found for C 15 H 10 Cl (M + ) lting point (acetone/dcm): C. R f (DCM: Pet. Ether (60:40)): General procedure for the arylation of 3-Substituted Pyridine -oxides: Pd(Ac) 2 ( mmol), ligand (0.009 mmol), K 2 C 3 (0.225 mmol) and appropriate pyridine -oxide (0.45 mmol) are weighed to air and placed in a 10mL Radley s testtube. A rubber septa is placed on the test-tube and the vessel is evacuated and purged with Argon. This cycle is repeated three times. 5-bromo-m-xylene (0.15 mmol) and degassed toluene (0.15M) are then added under Argon. The reaction is then placed in a oil bath and the heat source is set to 115ºC. The reaction is left stirring overnight (12-18hrs) after which it is allowed to cool. 1,3,5-trimethoxybenzene (0.05 mmol) is added and the reaction is diluted with DCM (5 ml). A small aliquot (1 ml) is then removed for MR analysis which provides the ratio of products and MR yield. Column chromatography on silica gel is used to separate the major isomer. Table 9, entry 1: Chromatography using 2% H, 10% Acetone in DCM; Isolated in 58% yield 1 H MR (400MHz, CDCl 3, 293K, TMS): 2.33 (3H, s), 2.37 (6H, s), 7.07 (1H, s), 7.11 (1H, d, J=7.8Hz), 7.28 (1H, d, J=7.8Hz), 7.37 (2H, s), 8.19 (1H, s); 13 C MR (400MHz, CDCl 3, 293K, TMS): 21.4, 27.1, 126.8, 126.9, 127.1, 131.1, 132.6, 134.9, 137.8, 140.2, 147.0, ; IR (ν max /cm -1 ): 2920, 1508, 1372, 1268, 816; HRMS calculated for C 14 H 15 (M+) ; Found: ;

28 S28 Table 9, entry 2: Ph Chromatography using 1% H, 10% Acetone in DCM; Isolated in 80% yield 1 H MR (400MHz, CDCl 3, 293K, TMS): 2.39 (6H, s), 7.09 (1H, s), (7H, m), (2H, m), 8.59 (1H, d, J=1.5Hz); 13 C MR (400MHz, CDCl 3, 293K, TMS): 21.4, 124.3, 126.8, 126.9, 127.2, 129.1, 129.3, 131.3, 132.3, 135.2, 137.9, 138.3, 138.5, 148.0, ; IR (ν max /cm -1 ): 3058, 2917, 1367, 1204, 760; HRMS calculated for C 19 H 17 (M+) ; Found: ; m. p. (CHCl 3 ): ºC Table 9, entry 3: Chromatography using 10% Acetone in DCM; Isolated in 74% yield 1 H MR (400MHz, CDCl 3, 293K, TMS): 2.37 (6H, s), 3.97 (3H, s), 7.11 (1H, s) 7.44 (2H, s), 7.47 (1H, d, J=8.2Hz), 7.83 (1H, dd, J=8.2Hz & 1.7Hz), 8.89 (1H, d, J=1.4Hz); 13 C MR (400MHz, CDCl 3, 293K, TMS): 21.3, 52.9, 125.7, 126.9, 127.1, 127.7, 131.7, 132.0, 138.0, 141.5, 152.9, 163.6; IR (ν max /cm -1 ): 2954, 1729, 1297, 1106, 758; HRMS calculated for C 15 H 15 3 (M+) ; Found: ; m. p. (CHCl 3 ): ºC Table 9, entry 5: Chromatography using 2% H, 15% Acetone in DCM ; Isolated in 79% yield

29 S29 1 H MR (300MHz, CDCl 3, 293K, TMS): 2.36 (6H, s), 3.78 (3H, s), 6.89 (1H, d, J=8.7Hz), 7.07 (3H, s), 7.15 (1H, dd, J=8.7Hz & 6.2Hz), 8.03 (1H, dd, J=6.8Hz & J=1.2Hz); 13 C MR (400MHz, CDCl 3, 293K, TMS): 21.4, 56.5, 108.5, 123.4, 127.5, 128.9, 131.1, 133.3, 137.8, 141.5, 156.0; IR (ν max /cm -1 ): 2938, 1561, 1414, 1221, 1080, 849; HRMS calculated for C 14 H 15 2 (M+) ; Found: m. p. (CHCl 3 ): ºC Table 9, entry 6: Chromatography using 2% H, 10% Acetone in DCM ; Isolated in 55% yield 1 H MR (300MHz, (CD 3 ) 2 C, 293K): 1.20 (6H, t, J=7.0Hz), 2.35 (6H, s), 3.47 (4H, br), 7.10 (1H, s), 7.31 (1H, dd, J=8.1Hz & 1.9Hz), 7.51 (2H, s), 7.59 (1H, d, 8.1Hz), 8.25 (1H, d, J=1.9Hz); 13 C MR (400MHz, CDCl 3, 293K, TMS): 14.0 (15.5 rotamer), 22.3, 41.0 (45.0 rotamer), 123.8, 128.8, 129.0, (br), 134.6, 137.0, 139.2, (br), 150.6, 167.3; IR (ν max /cm -1 ): 2974, 1634, 1436, 1293, 753; HRMS calculated for C 18 H (M+) ; Found: Table 9, entry 8: 2 Chromatography using 4% H, 30% Ethyl Acetate in PhH ; Isolated in 67% yield 1 H MR (500MHz, CDCl 3, 293K, TMS): 2.36 (6H, s), 7.03 (2H, s), 7.13 (1H, s), 7.37 (1H, dd, J=8.3Hz and 6.4Hz), 7.62 (1H, d, J=8.3Hz), 8.47 (1H, d, J=6.4Hz); 13 C MR (400MHz, CDCl 3, 293K, TMS): 21.3, 119.2, 124.0, 126.4, 127.3, 132.5, 138.6, 142.8, 145.8, 149.5; IR (ν max /cm -1 ): 2921, 1539, 1371, 1272, 811; HRMS calculated for C 13 H (M+) ; Found: ; m. p. (CHCl 3 ): ºC Table 9, entry 10: