Cobalt(II)-Catalyzed electrooxidative C H amination of arenes. with alkylamines

Cobalt(II)-Catalyzed electrooxidative C H amination of arenes with alkylamines Xinlong Gao,, Pan Wang,, Li Zeng, Shan Tang and Aiwen Lei*, The Institute for Advanced Studies (IAS), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, Hubei, P. R. China. E-mail: aiwenlei@whu.edu.cn Contents General information..... S2 General procedure.......s3 Detail descriptions for products....s7 References..........S6 Copies of product NMR spectra....... S7 S

General information All glassware was oven dried at 0 o C for hours and cooled down under vacuum. Aminoquinoline amides were synthesized according to literature procedures. Unless otherwise noted, materials were obtained from commercial suppliers and used without further purification. The instrument for electrolysis is dual display potentiostat (DJS-292B) (made in China). Cyclic voltammograms were obtained on a CHI 605E potentiostat. The anodic electrode was carbon cloth (5 mm 5 mm 0.36 mm) and cathodic electrode was nickel plate (5 mm 5 mm.0 mm). Thin layer chromatography (TLC) employed glass 0.25 mm silica gel plates. Flash chromatography columns were packed with 200-300 mesh silica gel in petroleum (bp. 60-90 o C). H and data were recorded with Bruker Advance III (400 MHz) spectrometers with tetramethylsilane as an internal standard. All chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz. All chemical shifts were reported relative to tetramethylsilane (0 ppm for H), CDCl 3 (77.0 ppm for C) and DMSO (2.50 ppm for H, 39.52 ppm for C), respectively. High resolution mass spectra (HRMS) were recorded on DIONEX UltiMate 3000 & Bruker Compact QTOF. S2

General procedure Electrooxidative C-H bond amination between Aryl amides and alkylamines: The electrolysis was carried out in an oven-dried H-type divided cell equipped with one stir bar at anode. Carbon cloth (5 mm 5 mm 0.36 mm) was used as the anode and nickel plate (5 mm 5 mm.00 mm) was used as the cathode, which were separated by a AMI-700-30 membrane. The anodic chamber was added with amide (0.25 mmol), Co(OAc) 2 4H 2O (0.05 mmol, 2.5 mg), NaOPiv H 2O (0.25 mmol, 35.5 mg) and n Bu 4NBF 4 (0.50 mmol, 64.5 mg) while the cathodic chamber was added with NaOPiv H 2O (0.50 mmol, 7.0 mg) and HOPiv (2.00 mmol, 204.3 mg) and no additional supporting electrolyte was added. A balloon filled with nitrogen ( atm) was connected to electrolysis system and purged three times. Subsequently, MeCN (0.0 ml) and MeOH (0.0 ml) were added to the anodic chamber and cathodic chamber respectively. Subsequently, alkylamine (0.50 mmol) was added into anodic chamber. Then electrolysis system was stirred at a constant current of 0 ma at 65 o C for 3.0 or 3.5 h. When the reaction was finished and cooled to room temperature, the reaction mixture of the anodic chamber was washed with water (0.0 ml) and extracted with diethyl ether (0.0 ml 3). The organic layers were combined, dried over Na 2SO 4 and concentrated. The pure product was obtained by flash column chromatography on silica gel (petroleum: ethyl acetate = 5:). General procedure for the gram-scale reaction via anodic oxidation: In a 50 ml H-type divided cell equipped with a stir bar respectivel, N-(quinolin-8-yl)thiophene-2-carboxamide (5.00 mmol,.27 g), Co(OAc) 2 4H 2O (.00 mmol, 249.0 mg), NaOPiv H 2O (5.00 mmol, 70.0 mg), n Bu 4NBF 4 (5.00 mmol,.75 g) were added into anode chamber while the cathodic chamber was added with NaOPiv H 2O (5.00 mmol, 70.0 mg) and HOPiv (30.00 mmol, 3.06 g) and no additional supporting electrolyte was added. The divided cell was equipped with carbon cloth anode (20 mm 20 mm 0.36 mm) and Ni plate cathode (5 mm 5 mm.00 mm), which were separated by a AMI-700-30 membrane. A balloon filled nitrogen ( atm.) was connected to two chamber of divided cell by the side tube and purged three times. Then MeCN (50.0 ml) and H 2O (50.0 ml) were added to the anodic chamber and cathodic chamber respectively. Subsequently, morpholine (0.00 mmol, 440.0 mg) was added into anodic chamber. Then electrolysis system was stirred at a constant current of 20 ma at 65 o C for 30.0 h. When the reaction was finished and cooled to room temperature, the reaction mixture of the anodic chamber was washed with water (50.0 ml) and extracted with diethyl S3

ether (50.0 ml 3). The organic layers were combined, dried over Na 2SO 4, and concentrated. The pure product was obtained by flash column chromatography on silica gel (petroleum: ethyl acetate = 5:). White soild (.0 g) was obtained in 59% isolated yield. Intermolecular kinetic isotope effect (KIE) experiment: The electrolysis was carried out in an oven-dried H-type divided cell equipped with one stir bar at anode. Carbon cloth (5 mm 5 mm 0.36 mm) was used as the anode and nickel plate (5 mm 5 mm.00 mm) was used as the cathode, which were separated by a AMI-700-30 membrane. The anodic chamber was added N- (quinolin-8-yl)benzamide (0.25 mmol, 3.0 mg), N-(quinolin-8-yl)benzamide-d 5 (0.25 mmol, 3.6 mg), Co(OAc) 2 4H 2O (0.05 mmol, 2.5 mg), NaOPiv H 2O (0.25 mmol, 35.5 mg) and n Bu 4NBF 4 (0.50 mmol, 64.5 mg) while the cathodic chamber was added with NaOPiv H 2O (0.50 mmol, 7.0 mg) and HOPiv (2.00 mmol, 204.3 mg) and no additional supporting electrolyte was added. A balloon filled with nitrogen ( atm) was connected to electrolysis system and purged three times. Subsequently, MeCN (0.0 ml) and MeOH (0.0 ml) were added to the anodic chamber and cathodic chamber respectively. Subsequently, morpholine (0.50 mmol, 44.0 mg) was added into anodic chamber. Then electrolysis system was stirred at a constant current of 0 ma at 65 o C for 60 min. When the reaction was finished and cooled to room temperature, the reaction mixture of the anodic chamber was washed with water (0.0 ml) and extracted with diethyl ether (0.0 ml 3). The organic layers were combined, dried over Na 2SO 4 and concentrated. The pure product was obtained by flash column chromatography on silica gel (petroleum: ethyl acetate = 5:) to afford 24% combined amination products. The ratio was k H: k D =.: determined by spectrum. S4

Intramolecular kinetic isotope effect (KIE) experiment: The electrolysis was carried out in an oven-dried H-type divided cell equipped with one stir bar at anode. Carbon cloth (5 mm 5 mm 0.36 mm) was used as the anode and nickel plate (5 mm 5 mm.00 mm) was used as the cathode, which were separated by a AMI-700-30 membrane. The anodic chamber was added N- S5

(quinolin-8-yl)benzamide-d (0.25 mmol, 62.3 mg), Co(OAc) 2 4H 2O (0.05 mmol, 2.5 mg), NaOPiv H 2O (0.25 mmol, 35.5 mg) and n Bu 4NBF 4 (0.50 mmol, 64.5 mg) while the cathodic chamber was added with NaOPiv H 2O (0.50 mmol, 7.0 mg) and HOPiv (2.00 mmol, 204.3 mg) and no additional supporting electrolyte was added. A balloon filled with nitrogen ( atm) was connected to electrolysis system and purged three times. Subsequently, MeCN (0.0 ml) and MeOH (0.0 ml) were added to the anodic chamber and cathodic chamber respectively. Subsequently, morpholine (0.50 mmol, 44.0 mg) was added into anodic chamber. Then electrolysis system was stirred at a constant current of 0 ma at 65 o C for 60 min. When the reaction was finished and cooled to room temperature, the reaction mixture of the anodic chamber was washed with water (0.0 ml) and extracted with diethyl ether (0.0 ml 3). The organic layers were combined, dried over Na 2SO 4 and concentrated. The pure product was obtained by flash column chromatography on silica gel (petroleum: ethyl acetate = 5:) to afford 25% combined amination products. The ratio was k H: k D =.70: determined by spectrum. S6

General Procedure for cyclic voltammerty (CV): Cyclic voltammerty was performed in a three electrode cell connected to a schlenk line under nitrogen at room temperature. The working S7

Current/ ma electrode was a steady glassy carbon disk electrode; the counter electrode was a platinum wire. The reference was a Ag/AgCl electrode submerged in saturated aqueous KCl solution and was seperated from reaction by a salt bridge. 0.0 ml of MeCN containing M n Bu 4NBF 4 was poured into the electrochemical cell in all experiments. The scan rate is 0.05 V/s, ranging from 0 V to 2.0 V. Figure S Cyclic voltammogram. 0.005 0.000-0.005-0.00-0.05-0.020 Blank e Co+NaOPiv e+co+naopiv -0.025 2.0.6.2 0.8 0.4 0.0 Potential (V vs Ag/AgCl) Calibration the Ep into E 0 : To explain the real oxidation behavior of the reaction mixture, we calibrate the Ep of [Co] into E ºby known procedure for intrinsically irreversible inorganic complexes. As predicted by the quadratic nature of Marcus theory, α exhibits the potential dependence defined as follow: α = 0.5 + F 2λ (E app E 0 ) () where E app is the effective or applied potential and λ is the reorganization energy. The transfer coefficient is determined experimentally as follow: α = 47.4 δe pc (mv) (2) where δe pc is the voltammetric peak width, E pc/2 is the potential at the half-height of the peak, and E app is defined as follow: δe pc = E pc E pc/2 (3) E app = E pc+e pc/2 2 (4) S8

α Because the [Co] is irreversible, E pc, E pc/2, E app and the voltammetric peak broadens (δe pc) were changed while the scan rate υ is increased. These changes create the potential dependence of α, which is predicted to display a linear dependence. Table S E pc and E pc/2 of Co(OAc) 2 4H 2O + NaOPiv H 2O Figure S2 Electron transfer coefficients, α, plotted as a function of E app for Co(OAc) 2 4H 2O + NaOPiv H 2O 0.60 y = -.432x + 2.374 R 2 =0.9324 0.55 0.50 0.45 0.40.26.28.30 E app (V vs. Ag/AgCl) As predicted by α = 0.5 + F 2λ (E app E 0 ), E app becomes E 0 when α = 0.5, suggesting estimated standard oxidation potential of.269 V vs Ag/AgCl for Co(OAc) 2 4H 2O + NaOPiv H 2O. The same strategy for e + Co(OAc) 2 4H 2O + NaOPiv H 2O was also been carried out. The standard oxidation potential of.460 V vs AgAgCl for e + Co(OAc) 2 4H 2O + NaOPiv H 2O was figured out when α equalled to 0.5. Table S2 E pc and E pc/2 of e + Co(OAc) 2 4H 2O + NaOPiv H 2O S9

α Figure S3 Electron transfer coefficients, α, plotted as a function of E app for e + Co(OAc) 2 4H 2O + NaOPiv H 2O 0.8 y = -6.75x+0.3556 R 2 =0.95988 0.7 0.6 0.5.42.44.46 E app (V vs Ag/AgCl) General Procedure for chronoamperometry (CA): Chronoamperometry was performed in a three electrode divided cell which were separated by a AMI-700-30 membrane and connected to a schlenk line under nitrogen at room temperature. The working electrode was a carbon cloth electrode (5 mm*5 mm*0.36 mm) and the reference was a Ag wire. the counter electrode was nickel plate (5 mm*5 mm*mm). In blank experiment, NaOPiv H 2O (0.25 mmol, 35.5 mg) and n Bu 4NBF 4 (0.50 mmol, 64.5 mg) was dissolved in MeCN (0 ml) at anodic chember. At cathodic chember, NaOPiv H 2O (0.50 mmol, 7.0 mg) and HOPiv (2.00 mmol, 204.3 mg) was added to MeOH (0 ml). As a comparison experiment, Co(OAc) 2 4H 2O (0.05 mmol, 2.5 mg) was added to anodic chember additionally. The scan rate is 50 mv/s, the fixed potential is 0.9V vs Ag/Ag +. S0

Detail descriptions for products 3-Morpholino-N-(quinolin-8-yl)thiophene-2-carboxamide (3aa): 2 white solid was obtained in 74 % isolated yield. (400 MHz, DMSO-d 6) δ 2.59 (s, H), 8.97 (dd, J = 4.4,.6 Hz, H), 8.89 (dd, J = 7.6,.2 Hz, H), 8.44 (dd, J = 8.4,.6 Hz, H), 7.88 (d, J = 5.2 Hz, H), 7.70 7.67 (m, 2H), 7.63 7.59 (m, H), 7.44 (d, J = 5.6 Hz, H), 4.02 4.00 (m, 4H), 3.04 3.02 (m, 4H). (0 MHz, DMSO-d 6) δ 59.74, 52.97, 48.68, 7.94, 6.75, 5.4,.22, 28.58, 28.00, 27.2, 23.49, 22.35, 2.93, 6.97, 65.68, 53.90. 3-Morpholino-N-(quinolin-8-yl)furan-2-carboxamide (3ba): white solid was obtained in 32 % isolated yield. (400 MHz, CDCl 3) δ.4 (s, H), 8.95 (dd, J = 7.6,.6 Hz,.2H), 8.90 (dd, J = 4.0,.6 Hz, H), 8.8 (dd, J = 8.4,.6 Hz, H), 7.59 7.47 (m, 4H), 6.54 (d, J = 2.0 Hz, H), 4.08 3.99 (m, 4H), 3.24 3.5 (m, 4H). (0 MHz, CDCl 3) δ 56.98, 48.04, 44.32, 44.05, 8.66, 6.30, 6.07, 5.0, 28.03, 27.43, 2.53, 2.33, 6.86, 06.38, 66.62, 52.63. HRMS (ESI) calculated for C 8H 7N 3O 3 [M+Na] + : 346.62; found: 346.67. 3-Morpholino-N-(quinolin-8-yl)benzo[b]thiophene-2-carboxamide (3ca): white solid was obtained in 52 % isolated yield. (400 MHz, CDCl 3) δ.02 (s, H), 9. (dd, J = 6.8, 2.0 Hz, H), 8.97 (dd, J = 4.4,.6 Hz, H), 8.23 8.9 (m, 2H), 7.89 7.87 (m, H), 7.6 7.54 (m, 2H), 7.52 (dd, J = 8.4, 4.4 Hz, H), 7.45 7.37 (m, 2H), 4.36 4.35 (m, 4H), 3.54 (s, 4H). (0 MHz, CDCl 3) δ 6.06, 47.80, 43.69, 9.35, 8.9, 6.47, 5.96, 5.45, 5.5, S

28.8, 27.48, 25.96, 24.53, 23.96, 22., 2.58, 8.67, 66.44, 5.47. HRMS (ESI) calculated for C 22H 29N 3O 2S [M+Na] + : 42.090; found: 42.087. 2-Morpholino-N-(quinolin-8-yl)benzamide (3da): 2 white solid was obtained in 6 % isolated yield. (400 MHz, DMSO-d 6) δ 2.69 (s, H), 9.0 (dd, J = 7.6,.6 Hz, H), 8.95 (dd, J = 4.0,.6 Hz, H), 8.44 (dd, J = 8.0,.6 Hz, H), 8.03 (dd, J = 8.0, 2.0 Hz, H), 7.7 7.6 (m, 3H), 7.60 7.56 (m, H), 7.39 7.36 (m, H), 7.30 7.26 (m, H), 3.84 3.8 (m, 4H), 3.05 3.03 (m, 4H). (0 MHz, DMSO-d 6) δ 64.68, 5.08, 48.84, 7.90, 6.75, 5.06, 2.77,.42, 28.07, 27.9, 27.27, 24.06, 22.32, 22.00, 9.89, 6.83, 65.28, 53.6. 4-Methyl-2-morpholino-N-(quinolin-8-yl)benzamide (3ea): 2 white solid was obtained in 60 % isolated yield. (400 MHz, CDCl 3) δ 2.70 (s, H), 9. (dd, J = 7.6,.2 Hz, H), 8.87 (dd, J = 4.0,.6 Hz, H), 8.8 (dd, J = 8.0,.6 Hz, H), 8.09 (d, J = 7.6 Hz, H), 7.6 7.45 (m, 3H), 7.08 7.05 (m, 2H), 3.99 3.96 (m, 4H), 3.5 3. (m, 4H), 2.42 (s, 3H). (0 MHz, CDCl 3) δ 65.70, 5.05, 48.0, 42.87, 8.74, 6.32, 5.66, 2.2, 28.25, 27.5, 25.94, 25.0, 2.56, 2.53, 9.89, 7.64, 66.09, 53.88, 2.60. 2-Methyl-6-morpholino-N-(quinolin-8-yl)benzamide (3fa): 2 white solid was obtained in 55 % isolated yield. (400 MHz, CDCl 3) δ 0.62 (s, H), 9.00 (dd, J = 7.6,.6 Hz, H), 8.77 (dd, J = 4.4,.6 Hz, H), 8.9 (dd, J = 8.4,.6 Hz, H), 7.62 7.54 (m, 2H), 7.46 (dd, J = 8.4, 4.4 Hz, H), 7.3 (t, J = 7.6 Hz, H), 7.02 6.97 (m, 2H), 3.58 3.55 (m, 4H), 3.09 3.07 (m, 4H), 2.50 (s, 3H). (0 MHz, CDCl 3) δ 67.82, 49.93, 48., 8.4, 8.25, 6.34, 4.89,.7, 0.07, 28.5, 27.49, 25.8, 2.65, 2.62, 6.48, 6.33, 66.82, 52.95, 20.34. S2

5-Methyl-2-morpholino-N-(quinolin-8-yl)benzamide (3ga): 2 white solid was obtained in 38 % isolated yield. (400 MHz, CDCl 3) δ 2.80 (s, H), 9.4 (dd, J = 7.6,.2 Hz, H), 8.88 (dd, J = 4.4,.6 Hz, H), 8.9 (dd, J = 8.0,.6 Hz, H), 8.03 8.02 (m, H), 7.60 (t, J = 8.0 Hz, H), 7.56 7.53 (m, H), 7.49 (dd, J = 8.0, 4.0 Hz, H), 7.32 7.29 (m, H), 7.7 (d, J = 8.4 Hz, H), 3.99 3.97 (m, 4H), 3.4 3. (m, 4H), 2.39 (s, 3H). (0 MHz, CDCl 3) δ 65.86, 48.77, 48., 8.89, 6.43, 5.73, 4.05, 2.95, 2.57, 28.50, 28.35, 27.6, 2.76, 2.63, 9.38, 7.85, 66.22, 54.05, 20.74. 3-Morpholino-N-(quinolin-8-yl)-[,'-biphenyl]-2-carboxamide (3ha): white solid was obtained in 67 % isolated yield. (400 MHz, DMSO-d 6) δ 0.53 (s, H), 8.88 (dd, J = 4.0,.6 Hz, H), 8.52 8.50 (m, H), 8.4 (dd, J = 8.4,.6 Hz, H), 7.69 7.6 (m, 2H), 7.58 7.5 (m, 2H), 7.44 7.4 (m, 2H), 7.33 7.25 (m, 4H), 7.5 7.2 (m, H), 3.44 3.42 (m, 4H), 3.0 2.99 (m, 4H). (0 MHz, DMSO-d 6) δ 66.58, 49.97, 48.98, 4.53, 40.74, 7.76, 6.68, 4.33,.58, 0.46, 28.32, 28.4, 27.90, 27.7, 25.47, 22.32, 2.98, 8.94, 5.94, 66.5, 52.73. HRMS (ESI) calculated for C 26H 23N 3O 2 [M+Na] + : 432.682; found: 432.678. 4-Fluoro-2-morpholino-N-(quinolin-8-yl)benzamide (3ia): 2 white solid was obtained in 5 % isolated yield. (400 MHz, DMSO-d 6) δ 2.49 (s, H), 8.99 8.96 (m, 2H), 8.45 (dd, J = 8.4,.6 Hz, H), 8.06 (dd, J = 8.8, 7.2 Hz, H), 7.73 7.6 (m, 3H), 7.23 (dd, J =.2, 2.4 Hz, H), 7.4 7.09 (m, H), 3.82 3.80 (m, 4H), 3.08 3.05 (m, 4H). (0 MHz, DMSO-d 6) δ 64.55 (d, J C-F = 25.5 Hz), 63.80, 53.45 (d, 3 J C-F = 8. Hz), 48.92, 7.83, 6.80, 4.89, 3.86 (d, 3 J C-F = 0. Hz), 28.07, 27.29, 24.42 (d, 4 J C-F = 2.9 Hz), 22.39, 22.0, 6.78, 0.74 (d, 2 J C-F = 2.9 Hz), 07.43 (d, 2 J C-F = 23.5 Hz), 65.7, 53.43. 9 F NMR (377 MHz, DMSOd 6) δ -06.45. S

4-Chloro-2-morpholino-N-(quinolin-8-yl)benzamide (3ja): 2 white solid was obtained in 5 % isolated yield. (400 MHz, DMSO-d 6) δ 2.47 (s, H), 8.97 8.94 (m, 2H), 8.43 (dd, J = 8.4,.6 Hz, H), 7.99 (d, J = 8.0 Hz, H), 7.72 7.60 (m, 3H), 7.38 (d, J = 2.0 Hz, H), 7.32 (dd, J = 8.4, 2.0 Hz, H), 3.8 3.79 (m, 4H), 3.06 3.04 (m, 4H). (0 MHz, DMSO-d 6) δ 63.75, 52.30, 48.90, 7.82, 7.7, 6.79, 4.78, 3.2, 28.05, 27.26, 26.73, 23.95, 22.38, 22.20, 20., 6.87, 65.6, 53.35. 4-Bromo-2-morpholino-N-(quinolin-8-yl)benzamide (3ka): 2 white solid was obtained in 50 % isolated yield. (400 MHz, DMSO-d 6) δ 2.48 (s, H), 8.98 8.86 (m, 2H), 8.46 (dd, J = 8.0,.2 Hz, H), 7.92 (d, J = 8.4 Hz, H), 7.74 7.62 (m, 3H), 7.53 (d, J =.6 Hz, H), 7.49 (dd, J = 8.4, 2.0 Hz, H), 3.82 3.80 (m, 4H), 3.09 3.06 (m, 4H). (0 MHz, DMSO-d 6) δ 63.86, 52.27, 48.93, 7.8, 6.80, 4.75, 3.23, 28.05, 27.26, 27., 26.96, 26.08, 22.97, 22.39, 22.22, 6.86, 65.6, 53.35. 4-Methoxy-2-morpholino-N-(quinolin-8-yl)benzamide (3la): 3 white solid was obtained in 57 % isolated yield. (400 MHz, CDCl 3) δ 2.63 (s, H), 9. (dd, J = 7.6,.2 Hz, H), 8.88 (dd, J = 4.4,.6 Hz, H), 8.20 8.7 (m, 2H), 7.59 (d, J = 8.0 Hz, H), 7.54 7.52 (m, H), 7.48 (dd, J = 8.0, 4.0 Hz, H), 6.79 6.76 (m, 2H), 3.99 3.97 (m, 4H), 3.88 (s, 3H), 3.5 3. (m, 4H). C NMR (0 MHz, CDCl 3) δ 65.37, 62.78, 52.92, 48.00, 8.73, 6.34, 5.73, 3.99, 28.26, 27.53, 2.53, 2.47, 2.36, 7.59, 08.20, 06.07, 66.02, 55.43, 53.87. 2-Morpholino-N-(quinolin-8-yl)-4-(trifluoromethyl)benzamide (3ma): 2 white solid was S4

obtained in 29 % isolated yield. (400 MHz, DMSO-d 6) δ 2.43 (s, H), 8.97 8.94 (m, 2H), 8.44 (dd, J = 8.4,.6 Hz, H), 8.5 (d, J = 7.6 Hz, H), 7.74 7.59 (m, 5H), 3.80 3.78 (m, 4H), 3.2 3.09 (m, 4H). (0 MHz, DMSO-d 6) δ 63.59, 5.40, 48.99, 7.79, 6.80, 4.5, 2.52, 2.40 (q, 2 J C-F = 3.9 Hz),.52, 28.98, 28.04, 27.24, 23.7 (q, J C-F = 273.7 Hz), 22.43, 20.30 (q, 3 J C-F = 3.7 Hz), 6.9, 6.47 (q, 3 J C-F = 3.7 Hz), 65.6, 53.6. 9 F NMR (377 MHz, DMSO-d 6) δ -6.40. 4-Acetyl-2-morpholino-N-(quinolin-8-yl)benzamide (3na): 2 white solid was obtained in 45 % isolated yield. (400 MHz, CDCl 3) δ 2.60 (s, H), 9. (dd, J = 7.2,.6 Hz, H), 8.88 (dd, J = 4.4, 2.0 Hz, H), 8.25 (d, J = 8.0 Hz, H), 8.2 (dd, J = 8.4,.6 Hz, H), 7.84 (d, J =.6 Hz, H), 7.78 (dd, J = 8.0,.6 Hz, H), 7.63 7.57 (m, 2H), 7.5 (dd, J = 8.4, 4.0 Hz, H), 3.97 3.85 (m, 4H), 3.2 3.9 (m, 4H), 2.67 (s, 3H). (0 MHz, CDCl 3) δ 97.57, 64.72, 5.7, 48.25, 9.75, 8.63, 6.43, 5.06, 2.73, 2.49, 28.25, 27.49, 24.4, 22.4, 2.73, 8.32, 7.74, 65.97, 53.66, 26.87. Methyl 3-morpholino-4-(quinolin-8-ylcarbamoyl)benzoate (3oa): 3 white solid was obtained in 47 % isolated yield. (400 MHz, CDCl 3) δ 2.60 (s, H), 9. (dd, J = 7.6,.6 Hz, H), 8.88 (dd, J = 4.4,.6 Hz, H), 8.22 (d, J = 8.0 Hz, H), 8.9 (dd, J = 8.0,.6 Hz, H), 7.9 7.88 (m, 2H), 7.62 7.55 (m, 2H), 7.50 (dd, J = 8.4, 4.4 Hz, H), 3.97 3.95 (m, 7H), 3.20 3.8 (m, 4H). (0 MHz, CDCl 3) δ 66.26, 64.72, 50.86, 48.8, 8.59, 6.38, 5.06, 3.25, 2.62, 2.8, 28.20, 27.45, 24.94, 22.05, 2.66, 20.28, 7.7, 65.93, 53.66, 52.39. 2-Morpholino-N-(quinolin-8-yl)--naphthamide (3pa): white solid was obtained in 48 % isolated yield. (400 MHz, CDCl 3) δ 0.67 (s, H), 9. (dd, J = 7.6,.2 Hz, H), 8.73 (dd, J = 4.4,.6 Hz, H), 8.29 (dd, J = 8.8, 0.8 Hz, H), 8.8 (dd, J = 8.4,.6 Hz, H), 7.94-7.92 (m, H), 7.83- S5

7.8 (m, H), 7.64 (t, J = 8.0 Hz, H), 7.58 7.49 (m, 2H), 7.45 7.38 (m, 3H), 3.63 3.6 (m, 4H), 3.24 3.22 (m, 4H). (0 MHz, CDCl 3) δ 67.47, 48., 47.3, 8.36, 6.33, 4.88,.57,.22, 0.22, 28.2, 27.87, 27.48, 27.39, 26.69, 24.87, 24.78, 2.76, 2.66, 8.59, 6.57, 66.89, 52.8. HRMS (ESI) calculated for C 24H 2N 3O 2 [M+Na] + : 406.526; found: 406.526. 3-(Piperidin--yl)-N-(quinolin-8-yl)thiophene-2-carboxamide (3ab): white solid was obtained in 42 % NMR yield. (400 MHz, CDCl 3) δ 2.73 (s, H), 9.04 (dd, J = 7.6,.2 Hz, H), 8.86 (dd, J = 4.0, 2.0 Hz, H), 8.7 (dd, J = 8.4,.6 Hz, H), 7.59 7.55 (m, H), 7.53 7.45 (m, 3H), 7.8 (d, J = 5.2 Hz, H), 3.04 3.0 (m, 4H), 2.02.96 (m, 4H),.69.63 (m, 2H). C NMR (0 MHz, CDCl 3) δ 6.07, 54.29, 47.67, 9.03, 6.23, 5.98, 29.63, 29.22, 28.2, 27.54, 22.33, 2.52, 2.50, 7.98, 55.78, 25.48, 24.5. HRMS (ESI) calculated for C 9H 9N 3OS [M+Na] + : 360.4; found: 360.40. N-(quinolin-8-yl)-3-thiomorpholinothiophene-2-carboxamide (3ac): white solid was obtained in 5 % isolated yield. (400 MHz, DMSO-d 6) δ 2.69 (s, H), 9.00 8.99 (m, H), 8.9 8.89 (m, H), 8.46 8.43 (m, H), 7.87 7.85 (m, H), 7.72 7.68 (m, 2H), 7.63 7.59 (m, H), 7.45 7.43 (m, H), 3.24 3.2 (m, 4H), 3. 3.09 (m, 4H). (0 MHz, DMSO-d 6) δ 59.77, 53.65, 48.5, 7.76, 6.89, 5.23,.9, 29.03, 28.03, 27.28, 24.00, 22.45, 2.92, 6.90, 55.66, 26.56. HRMS (ESI) calculated for C 8H 7N 3OS 2 [M+Na] + : 378.0705; found: 378.070. S6

3-(3,4-Dihydroisoquinolin-2(H)-yl)-N-(quinolin-8-yl)thiophene-2-carboxamide (3ad): white solid was obtained in 40 % isolated yield. (400 MHz, CDCl 3) δ 2.99 (s, H), 8.96 (dd, J = 7.6,.2 Hz, H), 8.00 (dd, J = 8.4,.6 Hz, H), 7.53 7.49 (m, 3H), 7.44 7.42 (m, H), 7.24 7. (m, 5H), 7.06 7.04 (m, H), 4.33 (s, 2H), 3.39 (t, J = 6.0 Hz, 2H), 3.5 (t, J = 6.0 Hz, 2H). (0 MHz, CDCl 3) δ 60.48, 52.34, 47.49, 9.00, 5.63, 4.54, 4.3, 0.73, 29.84, 28.70, 27.80, 27.7, 26.3, 26.7, 25.93, 22.78, 2.35, 2.2, 7.35, 55.77, 5.92, 29.47. HRMS (ESI) calculated for C 23H 9N 3OS [M+Na] + : 408.4; found: 408.50. N-(Quinolin-8-yl)-3-(,4-dioxa-8-azaspiro[4.5]decan-8-yl)thiophene-2-carboxamide (3ae): white solid was obtained in 72 % isolated yield. (400 MHz, CDCl 3) δ 2.85 (s, H), 9.09 (dd, J = 7.6,.6 Hz, H), 8.98 (dd, J = 4.0,.6 Hz, H), 8.5 (dd, J = 8.4,.6 Hz, H), 7.58-7.54 (m, H), 7.52 7.47 (m, 3H), 7.23 7.22 (m, H), 4.04 (s, 4H), 3.5 (t, J = 5.6 Hz, 4H), 2.25 (s, 4H). (0 MHz, CDCl 3) δ 60.80, 52.78, 47.99, 8.85, 6.5, 5.86, 0.36, 29.74, 28.09, 27.37, 22.54, 2.63, 2.54, 7.76, 06.98, 64.34, 52.84, 34.78. HRMS (ESI) calculated for C 2H 2N 3O 3S [M+Na] + : 48.96; found: 48.206. Ethyl -(2-(quinolin-8-ylcarbamoyl)thiophen-3-yl)piperidine-4-carboxylate (3af): white solid was obtained in 63 % NMR yield. (400 MHz, CDCl 3) δ 2.62 (s, H), 9.06 (dd, J = 7.6,.6 Hz, H), 8.99 (dd, J = 4.0,.6 Hz, H), 8.6 (dd, J = 8.4,.6 Hz, H), 7.58 7.46 (m, 4H), 7.8 7.6 (m, H), 4.9 (q, J = 7.2 Hz, 2H), 3.34 3.29 (m, 2H), 2.88 2.83 (m, 2H), 2.50 2.46 (m, 2H), 2.08 2.04 (m, 2H),.28 (t, J = 7.2 Hz, 3H). (0 MHz, CDCl 3) δ 75.7, 60.74, 53.02, 48.33, 8.86, 6., 5.7, 29.85, 29.77, 28.08, 27.3, 22., 2.57, 2.5, 7.77, 60.43, 54.22, 4.0, 27.95, 4.25. HRMS (ESI) calculated for C 22H 23N 3O 3S [M+Na] + : 432.52; found: 432.52. S7

Tert-butyl 4-(2-(quinolin-8-ylcarbamoyl)thiophen-3-yl)piperazine--carboxylate (3ag): white solid was obtained in 7 % isolated yield. (400 MHz, CDCl 3) δ 2.65 (s, H), 9.04 (dd, J = 7.6,.6 Hz, H), 8.79 (dd, J = 4.0,.6 Hz, H), 8.8 (dd, J = 8.4,.6 Hz, H), 7.60 7.50 (m, 3H), 7.47 (dd, J = 8.0, 4.0 Hz, H), 7.7 7.6 (m, H), 3.9 3.89 (m, 4H), 3.07 3.03 (m, 4H),.5 (s, 9H). (0 MHz, CDCl 3) δ 60.59, 54.90, 52.4, 47.80, 8.80, 6.47, 5.63, 0.32, 0., 28.23, 27.57, 22.9, 2.75, 2.65, 7.96, 80.0, 53.97, 45.79, 43.84, 42.96, 28.48. HRMS (ESI) calculated for C 23H 26N 4O 3S [M+Na] + : 46.68; found: 46.628. 3-(4-Hydroxypiperidin--yl)-N-(quinolin-8-yl)thiophene-2-carboxamide (3ah): white solid was obtained in 39 % isolated yield. (400 MHz, CDCl 3) δ 2.72 (s, H), 9.05 (dd, J = 7.6,.6 Hz, H), 8.94 (dd, J = 4.0,.6 Hz, H), 8.5 (dd, J = 8.0,.6 Hz, H), 7.58 7.54 (m, H), 7.52 7.43 (m, 3H), 7.8 7.7 (m, H), 4.02 3.97 (m, H), 3.29 3.23 (m, 2H), 2.93 2.87 (m, 2H), 2.29 2.2 (m, 4H), 2.02 (s, H). (0 MHz, CDCl 3) δ 60.94, 53.2, 48.04, 8.96, 6.27, 5.82, 29.85, 29.83, 28.20, 27.49, 22.37, 2.68, 2.64, 7.95, 67.44, 52.27, 33.83. HRMS (ESI) calculated for C 9H 9N 3O 2S [M+Na] + : 376.090; found: 376.084. 3-(Benzyl(methyl)amino)-N-(quinolin-8-yl)thiophene-2-carboxamide (3ai): white solid was obtained in 22 % isolated yield. (400 MHz, DMSO-d 6) δ.24 (s, H), 8.9 (dd, J = 4.4, 2.0 Hz, H), 8.78 (dd, J = 7.6,.2 Hz, H), 8.44 (dd, J = 8.4,.6 Hz, H), 7.77 (d, J = 5.2 Hz, H), 7.7 7.60 (m, 3H), 7.43 7.38 (m, 3H), 7.5 7. (m, 3H), 4.35 (s, 2H), 2.90 (s, 3H). (0 MHz, DMSO-d 6) δ 60.05, 53.0, 49.65, 8.96, 7.87, 7.05, 5.78, 0.83, 29.88, S8

29.59, 28.52, 27.76, 24.79, 22.75, 22.7, 6.73, 60.87, 46.0. HRMS (ESI) calculated for C 22H 9N 3OS [M+Na] + : 396.4; found: 396.5. S9

References () McCormick, M. C.; Keijzer, K.; Polavarapu, A.; Schultz, F. A.; Baik, M.-H. J. Am. Chem. Soc. 204, 6, 8992. (2) Yan, Q.; Chen, Z.; Yu, W.; Yin, H.; Liu, Z.; Zhang, Y. Org. Lett. 205, 7, 2482. (3) Tran, L. D.; Roane, J.; Daugulis, O. Angew. Chem. Int. Ed. 20, 52, 6043. S20

Copies of product NMR Spectra 3aa S2

3ba S22

3ca S23

3da S24

3ea S25

3fa S26

3ga S27

3ha S28

3ia S29

9 F NMR 3ja S30

3ka S3

3la S32

3ma S33

9 F NMR S34

3na S35

3oa S36

3pa S37

3ab S38

3ac S39

3ad S40

3ae S4

3af S42

3ag S43

3ah S44

3ai S45

S46