S1

Supporting Information

6π-Electrocyclization in Water: Microwave-Assisted Synthesis of Polyheterocyclic-Fused Quinoline-2-Thiones

Xiao-Yun Li,†a Yan Liu,†ab Xiao-Lan Chen,*a Xin-Yuan Lu,a Xing-Xing Liang,a Shan-Shan Zhu,a Chuan-Wan Wei,c Ling-Bo Qu,a and Bing Yu*a

a College of Chemistry, Green Catalysis Centre, Zhengzhou University, Zhengzhou 450001, Henan Province, China. E-mail: chenxl@zzu.edu.cn, bingyu@zzu.edu.cn

b College of Biological and Pharmaceutical Engineering, Xinyang Agriculture & Forestry University, Xinyang, 464000, China

c School of Chemistry and Chemical Engineering, University of South China, Hengyang 421001, China

† These authors contributed equally.

Table of Contents

1. General Information ........................................................................................S2

2. Experimental Procedures ................................................................................S2

3. Crystal Data and Structure Refinement for 3q...........................................S12

4. Characterization Data ...................................................................................S13

5. 1H NMR, 13C NMR and 19F NMR Spectra ..................................................S22

Electronic Supplementary Material (ESI) for Green Chemistry.This journal is © The Royal Society of Chemistry 2020

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1. General InformationAll reagents were purchased and used without further purification. TLC was performed on silica gel plates (F254, 200-300 mesh) using UV light (254/366 nm) for detection and column chromatography was performed on silica gel (200-300 mesh). 1H, 13C and 19F NMR spectra were measured on a Bruker Avance 400 MHz spectrometer operating at 400 MHz, 101 MHz and 376 MHz, respectively. All NMR spectra were recorded in CDCl3 or DMSO at room temperature (20 ± 2 °C). To display multiplicities and signal forms correctly the following abbreviations were used: s = singlet, d = doublet, t = triplet, m = multiplet. 1H and 13C chemical shifts are quoted in parts per million downfield from TMS. High resolution mass spectra (HRMS) were obtained with a Waters Micromass Q-Tof Micro instrument using the ESI technique. X-ray single-crystal diffraction data were collected on a Bruker SMART1000 CCD diffractometer with Mo-Kα radiation (λ = 0.71073 Å) at variable temperatures. Microwave-assisted reactions were conducted in the microwave reactor (2.45 GHz, maximum power 300 W) using a focused single-mode microwave synthesis system (Discover, CEM, USA) (Figure S1).

Figure S1. Pictures of 10 mL microwave reaction vial (Left) and 30 mL microwave reaction vial (Center) used in the experiment and the irradiation by microwave reactor (Right).

2. Experimental Procedures

2.1 Preparation of Starting Materials

2.1.1 General Procedures for the Synthesis of 2-(imidazo[1,2-a]pyridin-2-yl)anilines (1a-r and 1t-v)1

NO2

O

EtOH80 °C, 10 h

SnCl2, N2

EtOH, 2 h

1a-r and 1t-v

N

NHet

O2N

N

NHet

H2N

NHet

NH2 Br

A solution of 2-amino-pyridine (7.0 mmol, 0.66 g) and 2-bromo-1-(2-nitrophenyl)ethan-1-one (7.0 mmol, 1.70 g) in ethanol (28.0 mL) were added to the sealed tube for 10 h. Afterward, the mixture was basified to pH 8 with NaHCO3 solution and extracted with DCM (60.0 mL). The organic layer

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was washed with water (30.0 mL) and brine (30.0 mL) and dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (70/30, v/v) to afford the expected product. A solution of 2-(2-nitrophenyl)imidazo[1,2-a]pyridine (5.0 mmol, 1.19 g) and SnCl2 (25.0 mmol, 4.74 g) in ethanol (100.0 mL) was refluxed under nitrogen for 2 h. After cooled to room temperature, the residue was basified to pH 8 with NaHCO3 solution and extracted with EtOAc (100.0 mL), and it was filtered through a bed of celite. The organic layer was finally washed with water (80.0 mL) and brine (80.0 mL) and dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (75/25, v/v) to afford 2-(imidazo[1,2-a]pyridin-2-yl)anilines (1a-r and 1t-v).

2.1.2 General Procedures for the Synthesis of 2-(indolizin-2-yl)aniline (1s)2

N

H2N

NO2N

N

NO2 OBr

3 h

Et3N (5 equiv)

CH3CN, 60 °C16 h

1s

Acetone, 90 °CO

N

O2N

SnCl2EtOH, 80 °C, 2 h

Br

To a mixture of 2-bromo-1-(2-nitrophenyl)ethan-1-one (5.0 mmol, 1.21 g) in acetone (10.0 mL), 2-methylpyridine (6.5 mmol, 0.60 g) was added to the sealed tube. Then, the reaction mixture stirred at 90 °C for 3 h. After cooled to room temperature, the reaction mixture was suction-filtered and washed with CH2Cl2 (15.0 mL). The solid was used directly for the next step without further purification. To a mixture of indolizinium salt (5.0 mmol, 1.68 g) and Et3N (25.0 mmol) in CH3CN (20.0 mL) were stirred at 60 °C for 16 h. After cooled to room temperature, solvent was removed under reduced pressure. The residue was purified by column chromatography to afford the expected product. A solution of 2-(2-nitrophenyl)indolizine (5.0 mmol, 1.19 g) and SnCl2 (25.0 mmol, 4.74 g) in ethanol (100.0 mL) was refluxed under nitrogen for 2 h. The solution was allowed to cool down, and then the pH was made slightly basic (pH 8) by addition of saturated NaHCO3 solution. EtOAc (100.0 mL) was added to the mixture, and it was filtered through a bed of celite. The organic layer was finally washed with water (80.0 mL) and brine (80.0 mL) and dried over anhydrous Na2SO4. The organic layer was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (80/20, v/v) to afford 2-(indolizin-2-yl)aniline (1s).

2.2 General Procedures for the Synthesis of 2-(imidazo[1,2-a]pyridin-2-yl)aniline with Different Protecting Groups (6a-6d)

2.2.1 General Procedures for the Synthesis of 2-(imidazo[1,2-a]pyridin-2-yl)-N-methylaniline (6a)3

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N

N

H2N

1a

N

N

NN

N

HN6a

N

N

HN

O6c

AC2O/Et3N

CH2Cl2

MeI/NaHTHF

r.t., 30 min

10% HCl

ethylene glycolreflux, 30 min

O

A solution of acetic anhydride (1.2 mmol) was added dropwise over 15 min to a magnetically stirred solution of 2-(imidazo[1,2-a]pyridin-2-yl)aniline 1a (1.0 mmol) and triethylamine (1.2 mmol) in dry CH2Cl2 (15.0 mL). The reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure. Water was added to wash the resulting solid, and the mixture was filtered to give the N-(2-(imidazo[1,2-a]pyridin-2-yl)phenyl)acetamide 6c. Sodium hydride (1.2 mmol) was added to the magnetically stirred N-(2-(imidazo[1,2-a]pyridin-2-yl)phenyl)acetamide (6c, 1.0 mmol) in anhydrous THF, and iodomethane (1.2 mmol) was added dropwise to the mixture, which was maintained below 5 °C for 0.5 h, and stirred at room temperature. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was extracted between saturated aqueous NH4Cl and ethyl acetate for three times. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether/ethyl acetate to give the N-(2-(imidazo[1,2-a]pyridin-2-yl)phenyl)-N-methylacetamide. Concentrated HCl (0.25 mL) was added to a stirred solution of N-(2-(imidazo[1,2-a]pyridin-2-yl)phenyl)-N-methylacetamide (1.0 mmol) in ethylene glycol (0.75 mL). The reaction mixture was heated to reflux and the reaction was monitored by TLC. When the reaction was completed, the reaction mixture was extracted between water and ethyl acetate. The combined organic layers, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether/ethyl acetate to give 2-(imidazo[1,2-a]pyridin-2-yl)-N-methylaniline (6a).

N

N

HN6a

2-(imidazo[1,2-a]pyridin-2-yl)-N-methylaniline (6a): white solid (34.81 mg, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.55 (m, J = 6.7, 1.1 Hz, 1H), 8.34 (s, 1H), 8.26 (m, J = 4.8 Hz, 1H), 7.65 – 7.60 (m, 2H), 7.27 (m, J = 9.0, 6.8, 1.2 Hz, 1H), 7.20 – 7.15 (m, 1H), 6.95 (m, J = 6.8, 1.1 Hz, 1H), 6.69 – 6.61 (m, 2H), 2.88 (d, J = 5.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 147.96, 146.11, 143.85, 129.46, 127.98, 126.78, 125.10, 116.61, 115.98, 115.51, 113.05, 110.65, 109.38, 30.11. HRMS Calcd for C14H14N3 [M + H]+: 224.1182, found: 224.1181.

2.2.2 General Procedures for the Synthesis of Boc-, Ac- and Ts- Protecting 2-(imidazo[1,2-

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a]pyridin-2-yl)aniline (exampled by 6b)4

N

N

H2N

+ N

N

HN

MW

H2O

1a OO

6b

OOO

OO

A mixture of 2-(imidazo[1,2-a]pyridin-2-yl)aniline 1a (0.2 mmol, 41.82 mg), di-tert-butyl dicarbonate (0.22 mmol) and H2O (0.5 mL) were added to a 10 mL microwave reaction vial and the reaction mixture was heated to 80 °C by using a focused single-mode microwave synthesis system (Discover, CEM, USA) under air and then irradiated a further 10 minutes. Afterward, the product was suction-filtered and washed with CH2Cl2 (3×5.0 mL) without further purification.

N

N

HNO

O6b

tert-butyl (2-(imidazo[1,2-a]pyridin-2-yl)phenyl)carbamate (6b): white solid (59.37 mg, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.60 (d, J = 6.7 Hz, 1H), 8.47 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.81 (dd, J = 7.8, 1.2 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.38 – 7.28 (m, 2H), 7.10 – 7.05 (m, 1H), 7.04 – 6.98 (m, 1H), 1.50 (s, 9H). 13C NMR (101 MHz, DMSO-d6) δ 153.06, 144.25, 143.92, 137.54, 128.92, 127.99, 127.26, 126.26, 122.52, 119.80, 119.29, 116.72, 113.60, 110.75, 79.67, 28.50. HRMS Calcd for C18H20N3O2 [M + H]+: 310.1550, found: 310.1558.

N

N

HN

O6c

N-(2-(imidazo[1,2-a]pyridin-2-yl)phenyl)acetamide (6c): green solid (45.70 mg, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.63 – 8.57 (m, 1H), 8.48 (d, J = 8.7 Hz, 2H), 7.87 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.33 (m, J = 18.1, 7.6 Hz, 2H), 7.14 (t, J = 7.3 Hz, 1H), 7.01 (t, J = 6.5 Hz, 1H), 2.20 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.51, 144.00, 128.78, 127.90, 127.27, 126.24, 123.57, 120.94, 120.52, 116.90, 113.62, 110.96, 25.46. HRMS Calcd for C15H14N3O [M + H]+: 252.1131, found: 252.1128.

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N

N

HNS

OO6d

N-(2-(imidazo[1,2-a]pyridin-2-yl)phenyl)-4-methylbenzenesulfonamide (6d): purple solid (69.72 mg, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.58 (d, J = 6.8 Hz, 1H), 8.38 (s, 1H), 7.78 – 7.71 (m, 2H), 7.56 – 7.49 (m, 3H), 7.41 (m, J = 9.0, 6.8, 1.1 Hz, 1H), 7.30 – 7.25 (m, 1H), 7.17 – 7.10 (m, 3H), 7.05 (m, J = 6.8, 1.0 Hz, 1H), 2.24 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 143.81, 143.27, 136.58, 135.97, 129.90, 129.14, 127.96, 127.34, 127.04, 126.79, 124.57, 121.56, 120.61, 116.72, 113.89, 110.85, 21.33. HRMS Calcd for C20H18N3O2S [M + H]+: 364.1114, found: 364.1117.

2.3 General Procedure for the Synthesis of imidazopyridine fused quinoline-2-thiones (exampled by 3a)

N

NCS2

140 °C, 30 min

1a 2a

N

N

NH

S3a

MW

H2OH2N

A mixture of 2-(imidazo[1,2-a]pyridin-2-yl)aniline 1a (0.2 mmol, 41.82 mg), carbon disulfide 2a (0.4 mmol) and H2O (1.0 mL) were added to a 10 mL microwave reaction vial and the reaction mixture was heated to 140 °C by using a focused single-mode microwave synthesis system (Discover, CEM, USA) under air and then irradiated a further 30 minutes. Afterward, the product was isolated by simple filtration and dried in a vacuum drying oven.

2.4 General Procedure for Gram-scale Reaction

A mixture of 2-(imidazo[1,2-a]pyridin-2-yl)aniline 1a (4.5 mmol, 0.94 g), carbon disulfide 2a (9.0 mmol) were added in a 30 mL microwave reaction vial. Then, H2O (20.0 mL) was added into this reaction system. The reaction vial was sealed under air and stirred under irradiation of microwave at 140 °C for 30 min. Afterward, the product was isolated by simple filtration and dried in a vacuum drying oven.

2.5 General Procedure for the Synthesis of 6-(methylthio)pyrido[2',1':2,3]imidazo[4,5-c]quinoline (4)5

Pyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione 3a (0.3 mmol, 75.30 mg), MeI (0.36 mmol), K2CO3 (0.45 mmol, 62.20 mg), EtOH (1.0 mL) was added by dropper and the mixture was stirred at 80 °C for 5 h. And the progress of the reaction was monitored by TLC (silica gel). After completion of the reaction, mixture was cooled to ambient temperature, quenched by addition of saturated NH4Cl (2.0 mL), and extracted with DCM (3×10.0 mL). The organic layers were combined and dried with

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anhydrous Na2SO4 and concentrated in vacuo, the resulting residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (20:1) as eluent to afford the product.

2.6 General Procedure for the Synthesis of 6-(piperidin-1-yl)pyrido[2',1':2,3]imidazo[4,5-c]quinoline (5)6

Pyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione 3a (0.3 mmol, 75.30 mg), and piperidine (1.2 mmol) in DMA (2.0 mL) was stirred under an oxygen atmosphere at 110 °C for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature and then added H2O (5.0 mL). The aqueous solution was extracted with DCM (3×10.0 mL) and the combined extracts were dried with anhydrous Na2SO4. The solvent was removed under reduced pressure by rotary evaporation. Then, the pure product was obtained by flash column chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 20:1).

2.7 General Procedure for the Synthesis of 2-((1H-pyrrol-1-yl)methyl)aniline （7）7

N

O2NNO2

Br pyrrole

n-Bu4NBr, NaOHCH2Cl2, 0 °C to r.t.

N

H2N7

Zn, NH4ClTHF

A mixture of 1-(bromomethyl)-2-nitrobenzene (5.0 mmol, 1.08 g), pyrrole (10.0 mmol) and tetrabutylammonium bromide (10.0 mmol) were added in 10.0 mL CH2Cl2. Then, NaOH (10.0 mmol) was added into this reaction system for 30 min. The reaction vessel was stirred at 25 °C for 2 h. Afterward, the mixture was extracted with DCM and water. The organic layers were combined, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure by rotary evaporation. Then, the pure product was obtained by flash column chromatography on silica gel. A suspension of 1-(2-nitrobenzyl)-1H-pyrrole (5.0 mmol, 1.01 g), zinc powder (45.0 mmol, 2.93 g) and ammonium chloride (30.0 mmol, 1.60 g) in THF (45.0 mL) were refluxed for 10 h under N2 atmosphere. The resulting suspension was filtered and the solid was washed with dichloromethane. The organic layer was then dried over Na2SO4, concentrated under reduced pressure to give crude product. The crude product was purified through silica gel column chromatography using petroleum ether/ethyl acetate as eluent to give pure 2-((1H-pyrrol-1-yl)methyl)aniline (7).

N

H2N7

2-((1H-pyrrol-1-yl)methyl)aniline (7): white solid (28.22 mg, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.01 – 6.95 (m, 1H), 6.79 (t, J = 2.1 Hz, 2H), 6.66 (d, J = 8.0 Hz, 2H), 6.53 – 6.47 (m, 1H), 6.02 (t, J = 2.1 Hz, 2H), 5.03 (s, 2H), 4.95 (s, 2H). 13C NMR (101 MHz, DMSO-d6) δ 146.24, 128.69, 128.59, 122.39, 121.50, 116.62, 115.37, 108.10, 49.23. HRMS Calcd for C11H13N2 [M + H]+: 173.1073, found: 173.1081.

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2.8 General Procedure for the Synthesis of (2-(imidazo[1,2-a]pyridin-2-yl)phenyl)carbamodithioate （9）8

N

N

HNS

S9

N

N

H2N1a

1) CS2, DABCO

2) BTC

Under an ambient atmosphere, a 25 mL round-bottom flask was charged with 2-(imidazo[1,2-a]pyridin-2-yl)aniline 1a (2.0 mmol, 0.42 g), DABCO (8.0 mmol, 0.90 g), and toluene (4.0 mL) with stirring. CS2 (4.0 mmol) was added dropwise. The mixture was kept at room temperature overnight. The precipitates were filtered, washed with toluene (3×3.0 mL), and dissolved in CHCl3 (5.0 mL) with stirring. Then, a solution of BTC (1.0 mmol, 0.30 g) in CHCl3 (2.5 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 1 h and heated at reflux for 2 h. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of petroleum ether and ethyl acetate as eluents to afford (2-(imidazo[1,2-a]pyridin-2-yl)phenyl)carbamodithioate (9).

N

N

HNS

S9

ethyl (2-(imidazo[1,2-a]pyridin-2-yl)phenyl)carbamodithioate (9): white solid (16.28 mg, 26% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 8.59 (d, J = 6.8 Hz, 1H), 8.47 (s, 1H), 8.25 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 9.1 Hz, 1H), 7.38 – 7.30 (m, 2H), 7.13 – 7.08 (m, 1H), 7.01 (m, J = 6.8, 3.4 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 153.86, 144.08, 143.97, 137.12, 129.04, 128.03, 127.27, 126.42, 122.93, 119.98, 119.41, 116.72, 113.90 – 113.31 (m), 110.95 – 110.58 (m), 60.88, 15.00. HRMS Calcd for C16H16N3S [M + H]+: 314.0780, found: 314.0786.

2.9 General Procedure for the Synthesis of 1-(2-isocyanophenyl)-1H-pyrrole (11)9

N

CN11

N

H2N

N

HNHCOOAc

DCM

POCl3

Et3N, THF

OH

To a stirring solution of 2-(1H-pyrrol-1-yl)aniline (3.0 mmol, 0.47 g) in DCM (6.0 mL) was added dropwise acetic formic anhydride (7.8 mmol, 0.62 mL) at 0 °C. The mixture was stirred for 2 h at

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room temperature. Then, the mixture was quenched with saturated Na2CO3 solution and extracted with DCM for three times. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude formamides. The crude product was used for next dehydration without further purification. The formamides and Et3N (3.0 mL) were dissolved in THF (6.0 mL) under nitrogen atmosphere. POCl3 (5.2 mmol, 0.49 mL) in THF (1.0 mL) was added slowly to the solution via syringe for a period of 1 h at 0 °C. The reaction mixture was then stirred for another 2 h at 0 °C. After that, the reaction mixture was diluted with 5.0 mL ethyl acetate at 0 °C and slowly quenched with saturated Na2CO3 solution with continuous stirring for another 30 min. The crude products were then purified through silica gel column chromatography using petroleum ether/ethyl acetate as eluent to give 1-(2-isocyanophenyl)-1H-pyrrole (11).

N

CN11

1-(2-isocyanophenyl)-1H-pyrrole (11): yellow oil (16.28 mg, 36% yield). 1H NMR (600 MHz, Chloroform-d) δ 7.41 – 7.33 (m, 2H), 7.27 – 7.20 (m, 2H), 6.91 (d, J = 2.0 Hz, 2H), 6.31 – 6.26 (m, 2H). 13C NMR (151 MHz, Chloroform-d) δ 169.14 – 167.84 (m), 136.07, 129.31, 127.60, 126.18, 125.14, 120.29, 109.51. HRMS Calcd for C11H9N2 [M + H]+: 169.0760, found: 169.0766.

2.10 Calculation for E-factor and EcoScale Score

Table S1. E-factor of Synthesis of Quinoline-2-Thiones SystemItem Reactant 1 Reactant 2 Product

1a 2a 3aMmol 0.2 mmol 0.4 mmol 0.198 mmolMW 209.09 76.14 251.05Mass 41.82 mg 30.46 mg 49.71 mg

E-factor =

ΣMW of stiochiometric reactants + ΣMW of desired productsΣMW of desired products

=

41.82 + 30.46 - 49.7149.71

= 0.45 Table S2. Penalty Points for the Synthesis of Quinoline-2-Thiones SystemEcoScale penalty points Factor Penalty

1.yield 99% 0.52.price 2-(imidazo[1,2-a]pyridin-2-yl)aniline 0

carbon disulfide 0H2O 0

3.safety 2-(imidazo[1,2-a]pyridin-2-yl)aniline 0carbon disulfide (F, T) 10H2O 0

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4.technical setup microwave heating 25.temperature/time heating, <1 h 26.workup and purification simple filtration 0total penalty points 14.5EcoScale score 85.5

2.11 Mechanistic Studies

N

NCS2

1a 2a 3a

N

N

NH

S

Radical scavenger(1.0 equiv)

Standard conditions

a)

H2N

Radicalscavenger

TEMPOBHT

Yield of 3a(%)

9485

N

NCS2

6 2a 3a

N

N

NH

SStandard conditions

b)

HNPG

Me-Ts-Boc-Ac-

Yield of 3a(%)

003226

PG =

N

NHN

SSEt

3a, 23% yeild

N

N

NH

S

N

H2NCS2

Standard conditionsN

NH

HH H H

S

d)

e)N

NHS

Saturated aq. NaOH

c)

7 8not detected

S8, Et3N

100 °C

3x, 65% yield11

1,4-Dioxanereflux

9

N

CN

N

NHN

SSH

N

NC

S

10

12

Scheme S1. Mechanistic Studies

In order to have a deeper mechanistic insight into this microwave-assisted cyclization reaction, several control experiments were carried out (Scheme S1). Initially, when the well-known radical scavengers, i.e., 2, 2, 6, 6-tetramethylpiperidine 1-oxyl (TEMPO) or 2, 6-di-tert-butyl-4-methylphenol (BHT) was added to the model reaction under standard conditions, no obvious declines in yields were observed, ruling out the radical process in this transformation (Scheme S1a). Afterward, the reactivities of N-protected 2-(imidazo[1,2-a]pyridin-2-yl)anilines 6 were tested. When N-methyl and -Ts substituted substates were reacted with CS2 under standard conditions, no desired product 3a was detected. While, the N-Boc and -Ac protected ones only provided deprotected product 3a in significantly decreased yields of 32% and 26%, respectively, which implying the condensation of amino group with carbon disulfide could be hindered by N-protected groups (Scheme S1b). Next,

S11

the 2-((1H-pyrrol-1-yl)methyl)aniline 7 with the insertion of a methylene group between benzene and pyrrole was synthesized to block the 6π-electron conjugated system. Predictably, it failed to give any desired seven-membered cyclic product 8 when reacting with CS2 under standard conditions (Scheme S1c). Despite considerable efforts have been made to synthesize the key intermediates A and B which are involved in our proposed mechanism, unfortunately, we are not yet able to obtain them, and there are no previous literatures reporting the successful cases of preparing them. However, a one-pot formation of the cyclization products 3a and 3x was observed during the synthesis of corresponding intermediates carbamodithioic acid 10 and thioisocyanate 12 from ethyl carbamodithioate 9 and isocyanide 11 (Scheme S1d-e), which evidently supports our proposed mechanism that the formation of intermediates carbamodithioic acid and thioisocyanate is necessary in this reaction.

Reference1. Sharma, S.; Saha, B.; Sawant, D.; Kundu, B., Synthesis of Novel N-Rich Polycyclic Skeletons Based on Azoles and Pyridines. J. Comb. Chem. 2007, 9, 783-792.2. Kumar, K. S.; Rajesham, B.; Kumar, N. P.; Ramulu, M. S.; Dandela, R., A Ligand/Additive/Base-Free C(sp2)-H Activation and Isocyanide Insertion in PEG-400: Synthesis of Indolizine/Imidazoline-Fused Heterocycles. ChemistrySelect 2018, 3, 4581-4585.3. Peng, Y.-Y.; Liu, H.-L.; Tang, M.; Cai, L.-S.; Pike, V., Highly Efficient N-Monomethylation of Primary Aryl Amines. Chin. J. Chem. 2009, 27, 1339-1344.4. Nardi, M.; Cano, N. H.; Costanzo, P.; Oliverio, M.; Sindona, G.; Procopio, A., Aqueous MW eco-friendly protocol for amino group protection. RSC Adv. 2015, 5, 18751-18760.5. Wang, T.-L.; Liu, X.-J.; Huo, C.-D.; Wang, X.-C.; Quan, Z.-J., Base-catalyzed thio-lactamization of 2-(1-arylvinyl)anilines with CS2 for the synthesis of quinoline-2-thiones. Chem. Commun. 2018, 54, 499-502.6. Lv, Z.-C.; Wang, H.-M.; Quan, Z.-C.; Gao, Y.; Lei, A.-W., Dioxygen-triggered oxidative cleavage of the C–S bond towards C–N bond formation. Chem. Commun. 2019, 55, 12332-12335.7. Gao, K.; Wu, B.; Yu, C.-B.; Chen, Q.-A.; Ye, Z.-S.; Zhou, Y.-G., Iridium Catalyzed Asymmetric Hydrogenation of Cyclic Imines of Benzodiazepinones and Benzodiazepines. Org. Lett. 2012, 14, 3890-3893.8. Zhao, C.-L.; Han, Q.-Y.; Zhang, C.-P., TfOH-Promoted Transition-Metal-Free Cascade Trifluoroethylation/Cyclization of Organic Isothiocyanates by Phenyl(2,2,2-trifluoroethyl)iodonium Triflate. Org. Lett. 2018, 20, 6480-6484.9. Liu, Y.; Li, S.-J.; Chen, X.-L.; Fan, L.-L.; Li, X.-Y.; Zhu, S.-S.; Qu, L.-B.; Yu, B., Mn(III)-Mediated Regioselective 6-endo-trig Radical Cyclization of o-Vinylaryl Isocyanides to Access 2-Functionalized Quinolines. Adv. Synth. Catal. 2020, 362, 688-694.

S12

3. Crystal Data and Structure Refinement for 3qIdentification code 1967133Empirical formula C17H15F3N3OS2

Formula weight 398.44Temperature/K 298.15Crystal system triclinicSpace group P-1a/Å 7.1450(6)b/Å 10.3161(9)c/Å 12.2769(11)α/° 101.410(3)β/° 103.927(3)γ/° 93.498(2)Volume/Å3 855.32(13)Z 2ρcalcg/cm3 1.547μ/mm-1 0.354F(000) 410.0Crystal size/mm3 0.42 × 0.21 × 0.13Radiation MoKα (λ = 0.71073)2Θ range for data collection/° 5.912 to 50.196Index ranges -8 ≤ h ≤ 8, -12 ≤ k ≤ 12, -14 ≤ l ≤ 14Reflections collected 4416Independent reflections 3001 [Rint = 0.0303, Rsigma = 0.0458]Data/restraints/parameters 3001/0/238Goodness-of-fit on F2 1.029Final R indexes [I>=2σ (I)] R1 = 0.0520, wR2 = 0.1399Final R indexes [all data] R1 = 0.0629, wR2 = 0.1501Largest diff. peak/hole / e Å-3 0.52/-0.36

Figure S1. ORTEP view (30% ellipsoid contour probability) of X-crystal structure of 3q.

S13

4. Characterization Data

N

N

NH

S3a

Pyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3a): red solid (49.70 mg, 99% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.37 (s, 1H), 10.85 (d, J = 6.9 Hz, 1H), 8.42 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 9.1 Hz, 1H), 7.88 (dd, J = 17.3, 8.0 Hz, 2H), 7.71 (t, J = 7.7 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 6.9 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 169.26, 162.74, 150.54, 144.60, 138.24, 132.26, 130.59, 127.72, 124.54, 123.32, 122.21, 117.75, 117.30, 114.03. HRMS Calcd for C14H10N3S [M + H]+: 252.0590, found: 252.0595.

3b

N

N

NHS

9-methylpyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3b): red solid (51.95 mg, 98% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H), 10.67 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 9.1 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 2.51 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.19, 149.52, 144.46, 138.12, 135.02, 130.52, 125.28, 124.57, 123.54, 123.27, 122.01, 117.80, 117.26, 116.62, 18.50. HRMS Calcd for C15H12N3S [M + H]+: 266.0746, found: 266.0752.

3c

N

N

NHSMeO

9-methoxypyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3c): pink solid (55.09 mg, 98% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 10.66 (d, J = 2.3 Hz, 1H), 8.37 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 9.7 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.72 – 7.66 (m, 2H), 7.50 (t, J = 7.3 Hz, 1H), 3.94 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.31, 149.23, 147.37, 144.43, 138.04, 130.37, 126.14, 124.61, 123.12, 122.72, 118.07, 117.55, 117.34, 110.05, 56.77. HRMS Calcd for C15H12N3OS [M + H]+: 282.0696, found: 282.0701.

S14

3d

N

N

NH

SN

N

9-(4-methylpiperazin-1-yl)pyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3d): red solid (68.43 mg, 98% yield), mp 277.2 - 278.5 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 10.46 (s, 1H), 8.35 (d, J = 7.5 Hz, 1H), 7.89 (s, 2H), 7.81 (d, J = 8.3 Hz, 1H), 7.68 – 7.63 (m, 1H), 7.48 (t, J = 7.5 Hz, 1H), 3.23 – 3.17 (m, 4H), 2.59 – 2.54 (m, 4H), 2.27 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.15, 146.90, 144.26, 140.56, 138.04, 130.22, 127.42, 124.50, 123.09, 122.57, 118.14, 117.29, 116.89, 112.29, 54.74, 49.48, 46.13. HRMS Calcd for C19H20N5S [M + H]+: 350.1434, found: 350.1429.

3e

N

N

NH

S

9-phenylpyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3e): red solid (62.79 mg, 96% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 11.21 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.20 (dd, J = 9.4, 1.8 Hz, 1H), 8.06 (d, J = 9.4 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 7.4 Hz, 2H), 7.71 – 7.66 (m, 1H), 7.58 (t, J = 7.6 Hz, 2H), 7.49 (m, J = 7.8 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 169.26, 149.75, 145.07, 138.29, 136.54, 131.81, 130.70, 129.90, 128.74, 127.12, 126.84, 124.66, 124.56, 123.35, 122.35, 117.84, 117.37, 117.33. HRMS Calcd for C20H14N3S [M + H]+: 328.0903, found: 328.0906.

3f

N

N

NH

S

9,11-dimethylpyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3f): yellow solid (37.95 mg, 68% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 10.51 (s, 1H), 8.39 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.70 – 7.64 (m, 1H), 7.55 – 7.46 (m, 2H), 2.67 (s, 3H), 2.43 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.33, 149.71, 144.00, 138.10, 133.64, 130.39, 126.13, 124.51, 123.30, 123.10, 122.54, 117.98, 117.26, 18.52, 17.19. HRMS Calcd for C16H14N3S [M + H]+: 280.0903, found: 280.0907.

S15

3g

N

N

NHSNC

6-thioxo-5,6-dihydropyrido[2',1':2,3]imidazo[4,5-c]quinoline-9-carbonitrile (3g): red solid (52.45 mg, 95% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.61 (s, 1H), 11.28 (s, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.10 (s, 2H), 7.84 (d, J = 8.3 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 7.4 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 169.38, 149.87, 145.64, 138.47, 133.40, 131.82, 131.37, 125.01, 123.47, 121.97, 118.31, 117.47, 117.35, 117.11, 98.47. HRMS Calcd for C15H9N4S [M + H]+: 277.0542, found: 277.0534.

3h

N

N

NHSF3C

9-(trifluoromethyl)pyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3h): white solid (52.96 mg, 83% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.64 (s, 1H), 11.40 (s, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.23 – 8.12 (m, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.80 – 7.73 (m, 1H), 7.57 (t, J = 7.6 Hz, 1H). 13C NMR (151 MHz, DMSO-d6) δ 169.54, 150.49, 145.77, 138.49, 131.29, 127.55, 126.50, 125.07, 123.51, 122.45, 118.60, 117.64, 117.55, 115.93, 55.38. 19F NMR (376 MHz, DMSO-d6) δ -60.07. HRMS Calcd for C15H9F3N3S [M + H]+: 320.0464, found: 320.0461.

3i

N

N

NHSF

9-fluoropyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3i): green solid (46.27 mg, 86% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.45 (s, 1H), 10.94 (dd, J = 4.7, 2.5 Hz, 1H), 8.40 (d, J = 7.7 Hz, 1H), 8.11 (dd, J = 9.8, 5.3 Hz, 1H), 8.04 – 7.99 (m, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.74 – 7.69 (m, 1H), 7.53 (t, J = 7.4 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 169.56, 152.64 (d, J = 234.6 Hz), 148.30, 145.25, 138.22, 130.80, 124.83, 123.63 (d, J = 25.4 Hz), 123.28, 122.75, 118.20 (d, J = 8.9 Hz), 117.88, 117.45, 114.42 (d, J = 45.2 Hz). 19F NMR (376 MHz, DMSO-d6) δ -136.90. HRMS Calcd for C14H9FN3S [M + H]+: 270.0496, found: 270.0497.

S16

3j

N

N

NHSCl

9-chloropyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3j): yellow solid (45.60 mg, 80% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.48 (s, 1H), 10.98 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 9.6 Hz, 1H), 7.97 – 7.92 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 169.42, 148.96, 144.92, 138.24, 132.75, 130.91, 125.09, 124.86, 123.36, 122.01, 120.39, 118.22, 117.68, 117.43. HRMS Calcd for C14H9ClN3S [M + H]+: 286.0200, found: 286.0193.

3k

N

N

NH

SBr

9-bromopyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3k): red solid (61.18 mg, 93% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H), 11.08 (s, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 2.0 Hz, 2H), 7.86 (d, J = 8.3 Hz, 1H), 7.76 – 7.71 (m, 1H), 7.54 (t, J = 7.5 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 169.37, 149.06, 144.72, 138.25, 134.93, 130.97, 127.21, 124.92, 123.41, 121.86, 118.48, 117.65, 117.44, 107.39. HRMS Calcd for C14H9BrN3S [M + H]+: 329.9695, found: 329.9691.

3l

N

N

NH

S

10-methylpyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3l): red solid (51.95 mg, 98% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.28 (s, 1H), 10.67 (d, J = 7.0 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 6.9 Hz, 1H), 2.55 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.76, 151.05, 144.86, 143.73, 138.28, 130.55, 126.87, 124.50, 123.34, 122.20, 117.81, 117.30, 116.37, 115.82, 21.82. HRMS Calcd for C15H12N3S [M + H]+: 266.0746, found: 266.0745.

S17

3m

N

N

NH

S

MeO

10-methoxypyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3m): red solid (55.08 mg, 98% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 10.60 (d, J = 7.6 Hz, 1H), 8.34 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.07 (dd, J = 7.6, 2.4 Hz, 1H), 3.99 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 172.61, 158.00, 150.07, 143.05, 135.20, 133.37, 133.05, 129.18, 127.98, 126.93, 122.40, 122.04, 112.51, 100.58, 61.51. HRMS Calcd for C15H12N3OS [M + H]+: 282.0696, found: 282.0692.

3n

N

N

NH

F3C

S

10-(trifluoromethyl)pyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3n): yellow solid (48.49 mg, 76% yield), mp 286.2 - 287.5 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.53 (s, 1H), 10.95 (d, J = 7.3 Hz, 1H), 8.46 (s, 1H), 8.36 (d, J = 7.4 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.73 – 7.64 (m, 2H), 7.53 – 7.49 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 170.03, 148.87, 145.32, 138.28, 131.07, 128.97, 124.88, 123.36, 122.42, 117.50, 117.40, 115.34, 115.30, 109.33, 109.30. 19F NMR (376 MHz, DMSO-d6) δ -61.88. HRMS Calcd for C15H9F3N3S [M + H]+: 320.0464, found: 320.0468.

3o

N

N

NH

S

11-methylpyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3o): yellow solid (48.77 mg, 92% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 10.72 (d, J = 6.8 Hz, 1H), 8.46 – 8.43 (m, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.73 – 7.68 (m, 2H), 7.54 – 7.50 (m, 1H), 7.31 (t, J = 7.0 Hz, 1H), 2.74 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.42, 150.80, 144.16, 138.25, 130.85, 130.57, 126.93, 125.53, 124.60, 123.41, 122.76, 117.93, 117.33, 114.01, 17.33. HRMS Calcd for C15H12N3S [M + H]+: 266.0746, found: 266.0744.

S18

3p

N

N

NH

S

MeO

11-methoxypyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3p): yellow solid (55.08 mg, 98% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 10.42 (dd, J = 6.2, 1.6 Hz, 1H), 8.42 (d, J = 7.0 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.72 – 7.67 (m, 1H), 7.54 – 7.49 (m, 1H), 7.33 – 7.26 (m, 2H), 4.08 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.67, 148.43, 144.73, 143.60, 138.21, 130.51, 124.69, 123.30, 123.07, 120.27, 118.04, 117.29, 114.08, 109.03, 56.70. HRMS Calcd for C15H12N3OS [M + H]+: 282.0696, found: 282.0697.

3q

N

N

NH

S

F3C

11-(trifluoromethyl)pyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3q): yellow solid (59.98 mg, 94% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.61 (s, 1H), 11.10 (d, J = 6.9 Hz, 1H), 8.47 – 8.44 (m, 1H), 8.35 (d, J = 7.3 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.78 – 7.74 (m, 1H), 7.58 – 7.52 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 169.74, 146.08, 144.83, 138.45, 131.43, 131.20, 126.11, 124.99, 123.60, 122.39, 117.52, 117.44, 112.89, 55.37. 19F NMR (376 MHz, DMSO-d6) δ -61.55. HRMS Calcd for C15H9F3N3S [M + H]+: 320.0464, found: 320.0464.

3r

N

N

NH

SMe

8-methylpyrido[2',1':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3r): brown solid (49.30 mg, 93% yield), mp 291.8 – 293.1 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 7.77 (dd, J = 4.5, 3.0 Hz, 3H), 7.68 – 7.63 (m, 1H), 7.47 – 7.42 (m, 1H), 7.15 – 7.11 (m, 1H), 3.34 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 171.44, 153.24, 146.82, 142.89, 138.69, 132.85, 130.81, 126.36, 124.14, 123.46, 117.59, 116.84, 116.68, 114.70, 27.00. HRMS Calcd for C15H12N3S [M + H]+: 266.0746, found: 266.0754.

S19

3s

NNH

S

indolizino[3,2-c]quinoline-6(5H)-thione (3s): brown solid (49.30 mg, 99% yield), mp >300 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 11.29 (d, J = 7.2 Hz, 1H), 8.32 (d, J = 7.3 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.61 – 7.56 (m, 1H), 7.50 – 7.41 (m, 3H), 7.11 (m, J = 7.0, 1.2 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 185.51, 168.24, 140.89, 136.20, 129.25, 128.77, 127.08, 126.50, 124.72, 124.07, 119.05, 118.34, 117.00, 112.13, 93.62. HRMS Calcd for C15H11N2S [M + H]+: 251.0637, found: 251.0628.

3t

N

S N

NHS

benzo[4',5']thiazolo[2',3':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3t): green solid (18.42 mg, 30% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.48 (s, 1H), 10.77 – 10.74 (m, 1H), 8.32 – 8.28 (m, 1H), 8.16 (dd, J = 7.9, 1.1 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.64 (m, J = 22.5, 8.5, 7.3, 1.4 Hz, 2H), 7.56 – 7.48 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 168.47, 159.00, 147.62, 138.03, 134.42, 130.44, 130.39, 129.13, 126.32, 126.08, 125.19, 124.88, 122.90, 120.58, 117.56, 116.99. HRMS Calcd for C16H10N3S2 [M + H]+: 308.0311, found: 308.0324.

3u

N

N

NH

S

isoquinolino[1',2':2,3]imidazo[4,5-c]quinoline-6(5H)-thione (3u): gray solid (49.98 mg, 83% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.51 (s, 1H), 10.54 (d, J = 7.4 Hz, 1H), 8.88 – 8.83 (m, 1H), 8.53 – 8.48 (m, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.89 (m, J = 14.6, 7.2, 3.7 Hz, 3H), 7.74 – 7.67 (m, 2H), 7.59 – 7.54 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 169.51, 148.99, 143.26, 138.07, 131.98, 131.36, 130.35, 129.14, 127.91, 125.01, 124.83, 123.97, 123.83, 123.16, 122.28, 118.00, 117.38, 113.73. HRMS Calcd for C18H12N3S [M + H]+: 302.0746, found: 302.0745.

S20

3v

N

N

NH

S

imidazo[1,2-a:5,4-c']diquinoline-6(5H)-thione (3v): yellow solid (54.79 mg, 91% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.42 (s, 1H), 9.60 (d, J = 8.5 Hz, 1H), 8.43 (d, J = 7.3 Hz, 1H), 8.29 (d, J = 9.3 Hz, 1H), 8.13 – 8.09 (m, 1H), 7.89 (dd, J = 8.8, 5.9 Hz, 2H), 7.78 (m, J = 8.6, 7.2, 1.5 Hz, 1H), 7.74 – 7.64 (m, 2H), 7.55 – 7.50 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 171.01, 151.76, 146.28, 138.48, 134.76, 133.28, 130.63, 128.75, 128.31, 127.51, 126.03, 125.21, 125.03, 124.59, 123.29, 117.68, 116.91, 116.70. HRMS Calcd for C18H12N3S [M + H]+: 302.0746, found: 302.0754.

HN

NH

S3w

5,11-dihydro-6H-indolo[3,2-c]quinoline-6-thione (3w): white solid (35.01 mg, 70% yield), mp 270.4 – 271.3 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 12.90 (s, 1H), 9.09 (d, J = 7.9 Hz, 1H), 8.36 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.70 – 7.63 (m, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H).13C NMR (101 MHz, DMSO-d6) δ 176.69, 139.02, 138.17, 137.83, 130.30, 125.64, 125.62, 124.03, 122.82, 122.76, 121.70, 117.36, 116.01, 113.80, 112.12. HRMS Calcd for C15H11N2S [M + H]+: 251.0637, found: 251.0631.

N

NHS3x

pyrrolo[1,2-a]quinoxaline-4(5H)-thione (3x): white solid (9.20 mg, 23% yield), mp 208.0 – 209.2 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.36 (dd, J = 2.5, 1.5 Hz, 1H), 8.17 – 8.12 (m, 1H), 7.61 – 7.57 (m, 1H), 7.41 – 7.35 (m, 2H), 7.32 (dd, J = 3.9, 1.3 Hz, 1H), 6.84 – 6.80 (m, 1H).13C NMR (101 MHz, DMSO-d6) δ 174.53, 129.73, 128.14, 126.38, 125.20, 124.60, 119.02, 117.56, 116.17, 115.73, 114.97. HRMS Calcd for C11H9N2S [M + H]+: 201.0481, found: 201.0484.

S21

N

N

N

S4

6-(methylthio)pyrido[2',1':2,3]imidazo[4,5-c]quinoline (4): white solid (48.51 mg, 61% yield), mp 123.4 – 124.2 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J = 6.9 Hz, 1H), 8.49 (d, J = 7.6 Hz, 1H), 7.96 (dd, J = 19.0, 8.7 Hz, 2H), 7.75 – 7.69 (m, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.28 (t, J = 6.8 Hz, 1H), 2.87 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 148.97, 146.68, 145.64, 144.87, 130.75, 129.13, 128.70, 128.13, 125.70, 122.80, 120.33, 120.28, 117.77, 113.75, 12.46. HRMS Calcd for C15H12N3S [M + H]+: 266.0746, found: 266.0745.

N

N

N

N 5

6-(piperidin-1-yl)pyrido[2',1':2,3]imidazo[4,5-c]quinoline (5): white solid (48.04 mg, 53% yield), mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 6.9 Hz, 1H), 8.52 – 8.47 (m, 1H), 7.95 (dd, J = 14.6, 8.7 Hz, 2H), 7.78 – 7.66 (m, 2H), 7.59 – 7.54 (m, 1H), 7.38 – 7.32 (m, 1H), 3.18 (d, J = 4.3 Hz, 4H), 1.90 – 1.54 (m, 6H). 13C NMR (101 MHz, DMSO-d6) δ 152.65, 148.78, 147.97, 144.42, 130.25, 128.90, 128.43, 128.24, 124.86, 122.59, 120.84, 117.60, 115.48, 113.58, 51.26, 25.66, 24.42. HRMS Calcd for C19H19N4 [M + H]+: 303.1604, found: 303.1605.

S22

5. 1H NMR, 13C NMR and 19F NMR Spectra1H NMR spectrum of 6a

-1012345678910111213141516f1 (ppm)

0

5000

10000

15000

20000

25000

3.00

2.03

1.00

1.00

1.01

2.00

0.95

1.00

0.99

2.88

2.89

6.62

6.62

6.64

6.64

6.66

6.66

6.66

6.68

6.93

6.93

6.95

6.95

6.96

6.97

7.16

7.16

7.18

7.20

7.20

7.25

7.25

7.27

7.27

7.27

7.27

7.29

7.29

7.61

7.61

7.63

7.63

7.64

7.64

8.25

8.26

8.27

8.28

8.34

8.54

8.54

8.54

8.55

8.56

8.56

N

N

HN6a

13C NMR spectrum of 6a

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

110

30.1

1

109.

3811

0.65

113.

0511

5.51

115.

9811

6.61

125.

1012

6.78

127.

9812

9.46

143.

8514

6.11

147.

96

N

N

HN6a

S23

1H NMR spectrum of 6b

-1012345678910111213141516f1 (ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

30000

32000

34000

36000

9.01

1.00

1.02

2.07

0.99

1.00

0.95

1.00

1.00

1.00

1.50

6.99

6.99

7.01

7.01

7.03

7.03

7.06

7.06

7.08

7.10

7.10

7.29

7.29

7.31

7.33

7.35

7.35

7.35

7.37

7.37

7.61

7.64

7.80

7.80

7.82

7.82

8.26

8.28

8.47

8.59

8.60

11.8

4

N

N

HNO

O6b

13C NMR spectrum of 6b

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-5

0

5

10

15

20

25

30

35

40

45

28.5

0

79.6

7

110.

7511

3.60

116.

7211

9.29

119.

8012

2.52

126.

2612

7.26

127.

9912

8.92

137.

5414

3.92

144.

25

153.

06

N

N

HNO

O6b

S24

1H NMR spectrum of 6c

-1012345678910111213141516f1 (ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

3.06

1.01

1.02

2.08

0.99

1.00

1.90

1.00

1.01

2.20

6.99

7.01

7.03

7.12

7.14

7.16

7.29

7.31

7.33

7.36

7.38

7.69

7.72

7.86

7.88

8.47

8.49

8.59

8.61

12.5

1

N

N

HN

O6c

13C NMR spectrum of 6c

N

N

HN

O6c

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

25.4

6

110.

9611

3.62

116.

9012

0.52

120.

9412

3.57

126.

2412

7.27

127.

9012

8.78

144.

00

168.

51

S25

1H NMR spectrum of 6d

-1012345678910111213141516f1 (ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

3.01

1.00

3.00

1.03

1.01

3.00

2.03

1.01

1.00

0.97

2.24

7.03

7.03

7.05

7.05

7.06

7.07

7.11

7.11

7.13

7.15

7.25

7.26

7.27

7.29

7.30

7.39

7.39

7.41

7.41

7.41

7.41

7.43

7.43

7.51

7.53

7.55

7.55

7.72

7.74

7.76

7.77

8.38

8.57

8.59

12.7

1

N

N

HNS

OO6d

13C NMR spectrum of 6d

N

N

HNS

OO6d

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

18021

.33

110.

8511

3.89

116.

7212

0.61

121.

5612

4.57

126.

7912

7.04

127.

3412

7.96

129.

1412

9.90

135.

9713

6.58

143.

2714

3.81

S26

1H NMR spectrum of 3a

-1012345678910111213141516f1 (ppm)

-200

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2800

1.02

1.02

1.01

2.02

0.98

0.99

1.00

1.00

7.39

7.41

7.43

7.51

7.53

7.55

7.70

7.72

7.73

7.85

7.87

7.90

7.91

8.01

8.04

8.41

8.43

10.8

410

.86

13.3

7

N

N

NHS3a

13C NMR spectrum of 3a

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

0

100

200

300

400

500

600

700

800

900

114.

0311

7.30

117.

7512

2.21

123.

3212

4.54

127.

7213

0.59

132.

2613

8.24

144.

6015

0.54

162.

74

169.

26

N

N

NHS3a

S27

1H NMR spectrum of 3b

-1012345678910111213141516f1 (ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

3.00

1.02

1.07

1.03

1.00

1.00

1.00

1.00

1.00

2.51

7.48

7.49

7.51

7.66

7.68

7.70

7.73

7.75

7.82

7.84

7.90

7.92

8.36

8.38

10.6

7

13.2

6

3b

N

N

NHS

13C NMR spectrum of 3b

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

190018

.50

116.

6211

7.26

117.

8012

2.01

123.

2712

3.54

124.

5712

5.28

130.

5213

5.02

138.

1214

4.46

149.

52

169.

19

3b

N

N

NHS

S28

1H NMR spectrum of 3c

-1012345678910111213141516f1 (ppm)

0

500

1000

1500

2000

2500

3000

3500

3.00

1.00

2.00

1.00

1.00

1.00

1.00

1.00

3.94

7.49

7.50

7.52

7.66

7.66

7.68

7.69

7.70

7.70

7.71

7.72

7.82

7.84

7.95

7.98

8.36

8.38

10.6

610

.66

13.3

0

3c

N

N

NHS

MeO

13C NMR spectrum of 3c

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-20

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300

320

56.7

7

110.

0511

7.34

117.

5511

8.07

122.

7212

3.12

124.

6112

6.14

130.

3713

8.04

144.

4314

7.37

149.

23

169.

31

3c

N

N

NHS

MeO

S29

1H NMR spectrum of 3d

-1012345678910111213141516f1 (ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

3.00

4.00

4.00

1.00

1.01

1.00

2.00

1.00

1.00

1.00

2.27

2.55

2.56

2.57

3.19

3.20

3.21

7.46

7.48

7.50

7.64

7.64

7.66

7.68

7.68

7.80

7.82

7.89

8.34

8.36

10.4

6

13.2

1

3d

N

N

NHS

N

N

13C NMR spectrum of 3d

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-20

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300

320

340

360

46.1

349

.48

54.7

4

112.

2911

6.89

117.

2911

8.14

122.

5712

3.09

124.

5012

7.42

130.

2213

8.04

140.

5614

4.26

146.

90

169.

15

3d

N

N

NHS

N

N

S30

1H NMR spectrum of 3e

-1012345678910111213141516f1 (ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

2.05

2.02

1.00

2.00

1.00

1.00

1.00

1.00

1.02

1.00

7.46

7.48

7.50

7.52

7.56

7.58

7.60

7.67

7.67

7.69

7.70

7.71

7.77

7.79

7.82

7.84

8.05

8.07

8.19

8.19

8.21

8.22

8.37

8.39

11.2

1

13.3

8

3e

N

N

NHS

13C NMR spectrum of 3e

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

117.

3311

7.37

117.

8412

2.35

123.

3512

4.56

124.

6612

6.84

127.

1212

8.74

129.

9013

0.70

131.

8113

6.54

138.

2914

5.07

149.

75

169.

26

3e

N

N

NHS

S31

1H NMR spectrum of 3f

-1012345678910111213141516f1 (ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000

19000

3.00

3.00

2.02

1.00

1.00

1.00

1.00

1.00

2.43

2.67

7.46

7.47

7.48

7.50

7.50

7.54

7.65

7.65

7.67

7.67

7.69

7.69

7.81

7.83

8.38

8.40

10.5

1

13.2

4

3f

N

N

NHS

13C NMR spectrum of 3f

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-20

0

20

40

60

80

100

120

140

160

180

200

220

240

260

28017.1

918

.52

117.

2611

7.98

122.

5412

3.10

123.

3012

4.51

126.

1313

0.39

133.

6413

8.10

144.

0014

9.71

169.

33

3f

N

N

NHS

S32

1H NMR spectrum of 3g

-1012345678910111213141516f1 (ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

1.06

1.05

1.00

2.00

1.03

1.00

1.00

7.53

7.55

7.57

7.73

7.75

7.77

7.77

7.85

7.87

8.13

8.38

8.40

11.3

1

13.6

4

3g

N

N

NHSNC

13C NMR spectrum of 3g

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

98.4

7

117.

1111

7.35

117.

4711

8.31

121.

9712

3.47

125.

0113

1.37

131.

8213

3.40

138.

4714

5.64

149.

87

169.

38

3g

N

N

NHS

NC

S33

1H NMR spectrum of 3h

-1012345678910111213141516f1 (ppm)

-200

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

1.00

1.00

1.00

2.00

1.00

1.00

1.00

7.55

7.57

7.59

7.74

7.74

7.76

7.78

7.78

7.87

7.89

8.13

8.13

8.15

8.16

8.20

8.22

8.43

8.45

11.4

0

13.6

4

3h

N

N

NHS

F3C

13C NMR spectrum of 3h

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

55.3

8

115.

9311

7.55

117.

6411

8.60

122.

4512

3.51

125.

0712

6.50

127.

5513

1.29

138.

49

145.

77

150.

49

169.

54

3h

N

N

NHS

F3C

S34

19F NMR spectrum of 3h

-135-130-125-120-115-110-105-100-95-90-85-80-75-70-65-60-55-50-45-40-35-30-25f1 (ppm)

-2

-1

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

3.00

-60.

073h

N

N

NHS

F3C

1H NMR spectrum of 3i

-1012345678910111213141516f1 (ppm)

-200

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2800

3000

0.99

0.99

0.94

0.97

0.97

0.96

0.95

0.93

7.51

7.53

7.55

7.70

7.70

7.72

7.74

7.74

7.84

7.86

7.99

7.99

8.01

8.02

8.03

8.04

8.09

8.10

8.12

8.13

8.39

8.41

10.9

310

.93

10.9

410

.94

13.4

5

3i

N

N

NHS

F

S35

13C NMR spectrum of 3i

3i

N

N

NHS

F

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500

550

600

650

114.

1911

4.64

117.

4511

7.88

118.

1511

8.24

122.

7512

3.28

123.

5012

3.75

124.

8313

0.80

138.

2214

5.25

148.

3015

1.47

153.

80

169.

56

19F NMR spectrum of 3i

-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1 (ppm)

-2

-1

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

1.00

-136

.90

3i

N

N

NHS

F

S36

1H NMR spectrum of 3j

-1012345678910111213141516f1 (ppm)

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

1.05

1.00

1.00

1.00

1.00

1.00

0.98

1.00

7.51

7.53

7.55

7.70

7.72

7.74

7.83

7.86

7.93

7.93

7.94

7.96

7.96

7.96

8.04

8.06

8.37

8.39

10.9

8

13.4

8

3j

N

N

NHS

Cl

13C NMR spectrum of 3j

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-40

-20

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300

320

340

360

380

400

117.

4311

7.68

118.

2212

0.39

122.

0112

3.36

124.

8612

5.09

130.

9113

2.75

138.

2414

4.92

148.

96

169.

42

3j

N

N

NHS

Cl

S37

1H NMR spectrum of 3k

-1012345678910111213141516f1 (ppm)

0

500

1000

1500

2000

2500

3000

3500

4000

4500

1.05

1.03

1.00

2.02

1.00

1.00

1.00

7.52

7.54

7.56

7.71

7.71

7.73

7.75

7.75

7.85

7.87

8.00

8.02

8.03

8.05

8.05

8.40

8.42

11.0

8

13.5

0

3k

N

N

NHS

Br

13C NMR spectrum of 3k

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-20

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300

320

340

360

380

400

107.

39

117.

4411

7.65

118.

4812

1.86

123.

4112

4.92

127.

2113

0.97

134.

9313

8.25

144.

7214

9.06

169.

37

3k

N

N

NHS

Br

S38

1H NMR spectrum of 3l

-1012345678910111213141516f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

3.00

1.00

1.00

1.00

1.00

1.00

0.99

1.00

1.00

2.55

7.25

7.26

7.49

7.50

7.52

7.67

7.69

7.71

7.80

7.83

7.85

8.38

8.40

10.6

610

.68

13.2

8

3l

N

N

NHS

13C NMR spectrum of 3l

3l

N

N

NHS

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

0

50

100

150

200

250

300

350

400

45021

.82

115.

8211

6.36

117.

3011

7.81

122.

2012

3.35

124.

5012

6.87

130.

5413

8.28

143.

7314

4.86

151.

04

168.

75

S39

1H NMR spectrum of 3m

-1012345678910111213141516f1 (ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

3.00

1.00

1.00

1.00

1.00

1.00

1.00

1.00

1.01

3.99

7.06

7.07

7.08

7.09

7.40

7.40

7.47

7.49

7.51

7.66

7.68

7.70

7.82

7.84

8.33

8.35

10.5

910

.61

13.2

1

3m

N

N

NHS

MeO

13C NMR spectrum of 3m

0102030405060708090100110120130140150160170180190200f1 (ppm)

-20

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300

320

340

61.5

1

100.

58

112.

51

122.

0412

2.40

126.

9312

7.98

129.

1813

3.05

133.

3713

5.20

143.

05

150.

07

158.

00

167.

15

172.

61

3m

N

N

NHS

MeO

S40

1H NMR spectrum of 3n

-1012345678910111213141516f1 (ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000

19000

1.06

2.00

1.00

1.00

0.98

1.00

1.01

7.49

7.49

7.51

7.53

7.64

7.65

7.66

7.66

7.69

7.69

7.71

7.72

7.73

7.82

7.84

8.36

8.37

8.46

10.9

410

.96

13.5

3

3n

N

N

NH

F3C

S

13C NMR spectrum of 3n

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-200

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

2000

2100

2200

109.

3010

9.33

115.

3011

5.34

117.

4011

7.50

122.

4212

3.36

124.

8812

8.97

131.

0713

8.28

145.

3214

8.87

170.

03

3n

N

N

NH

F3C

S

S41

19F NMR spectrum of 3n

-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1 (ppm)

-5

0

5

10

15

20

25

30

35

40

45

50

55

60

65

3.00

-61.

88

3n

N

N

NH

F3C

S

1H NMR spectrum of 3o

-1012345678910111213141516f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

3.00

1.02

1.02

2.01

1.00

1.00

1.00

1.00

2.74

7.30

7.31

7.33

7.50

7.50

7.52

7.54

7.54

7.68

7.69

7.71

7.71

7.72

7.73

7.85

7.87

8.44

8.44

8.44

8.46

8.46

10.7

110

.72

13.3

4

3o

N

N

NHS

S42

13C NMR spectrum of 3o

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-20

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300

320

17.3

3

114.

0111

7.33

117.

9312

2.76

123.

4112

4.60

125.

5312

6.93

130.

5713

0.85

138.

2514

4.16

150.

80

169.

42

3o

N

N

NHS

1H NMR spectrum of 3p

-1012345678910111213141516f1 (ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

3.00

2.12

1.05

1.03

1.00

1.00

1.00

1.02

4.08

7.27

7.29

7.30

7.31

7.33

7.33

7.49

7.49

7.51

7.53

7.53

7.67

7.67

7.69

7.69

7.71

7.71

7.83

7.85

8.41

8.42

10.4

110

.41

10.4

310

.43

13.3

5

3p

N

N

NHS

MeO

S43

13C NMR spectrum of 3p

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-20

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300

320

340

360

56.7

0

109.

0311

4.08

117.

2911

8.04

120.

2712

3.07

123.

3012

4.69

130.

5113

8.21

143.

6014

4.73

148.

43

169.

67

3p

N

N

NHS

MeO

1H NMR spectrum of 3q

-1012345678910111213141516f1 (ppm)

-200

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

2600

2800

3000

2.08

1.05

1.01

1.00

1.00

1.00

1.00

7.52

7.54

7.56

7.57

7.58

7.74

7.74

7.76

7.76

7.78

7.78

7.88

7.90

8.34

8.36

8.44

8.45

8.46

8.47

11.0

911

.11

13.6

1

3q

N

N

NHS

F3C

S44

13C NMR spectrum of 3q

3q

N

N

NHS

F3C

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

0

50

100

150

200

250

30055.3

7

112.

8911

7.44

117.

5212

2.39

123.

6012

4.99

126.

1113

1.20

131.

4313

8.45

144.

8314

6.08

169.

74

19F NMR spectrum of 3q

-210-200-190-180-170-160-150-140-130-120-110-100-90-80-70-60-50-40-30-20-10010f1 (ppm)

-5

0

5

10

15

20

25

30

35

-61.

55

3q

N

N

NHS

F3C

S45

1H NMR spectrum of 3r

3r

N

N

NHSMe

-1012345678910111213141516f1 (ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

30000

32000

34000

36000

38000

40000

42000

3.00

1.00

1.05

1.05

3.00

1.00

1.00

3.34

7.12

7.13

7.14

7.42

7.43

7.44

7.46

7.46

7.63

7.64

7.65

7.66

7.67

7.67

7.76

7.77

7.77

7.78

8.33

8.35

13.0

7

13C NMR spectrum of 3r

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

190

200

210

220

230

27.0

0

114.

7011

6.68

116.

8411

7.59

123.

4612

4.14

126.

3613

0.81

132.

8513

8.69

142.

8914

6.82

153.

24

171.

44

3r

N

N

NHSMe

S46

1H NMR spectrum of 3s

-1012345678910111213141516f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

1.04

3.21

1.08

1.02

1.01

1.00

1.00

1.00

7.10

7.10

7.11

7.12

7.13

7.13

7.41

7.42

7.43

7.43

7.45

7.47

7.47

7.48

7.48

7.49

7.49

7.57

7.57

7.59

7.59

7.61

7.61

7.78

7.80

7.90

7.92

8.31

8.33

11.2

811

.30

12.8

7

3s

NNH

S

13C NMR spectrum of 3s

3s

NNH

S

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-20

0

20

40

60

80

100

120

140

160

180

200

220

24093.6

2

112.

1311

7.00

118.

3411

9.05

124.

0712

4.72

126.

5012

7.08

128.

7712

9.25

136.

2014

0.89

168.

24

185.

51

S47

1H NMR spectrum of 3t

-1012345678910111213141516f1 (ppm)

-200

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

2000

2100

2200

2300

2400

2.25

2.38

1.03

1.02

1.02

1.01

1.00

7.48

7.48

7.50

7.51

7.52

7.52

7.52

7.53

7.55

7.55

7.60

7.60

7.61

7.62

7.62

7.64

7.64

7.65

7.66

7.67

7.67

7.68

7.69

7.69

7.83

7.85

8.15

8.15

8.17

8.17

8.29

8.29

8.31

8.31

10.7

410

.75

10.7

710

.77

13.4

8

3t

N

S N

NHS

13C NMR spectrum of 3t

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

0

50

100

150

200

250

300

350

400

450116.

9911

7.56

120.

5812

2.90

124.

8812

5.19

126.

0812

6.32

129.

1313

0.39

130.

4413

4.42

138.

0314

7.62

159.

00

168.

47

3t

N

S N

NHS

S48

1H NMR spectrum of 3u

-1012345678910111213141516f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

1.00

2.02

3.07

1.00

1.00

1.00

1.00

1.00

7.54

7.54

7.56

7.58

7.68

7.70

7.71

7.72

7.73

7.74

7.85

7.85

7.86

7.87

7.88

7.89

7.89

7.90

7.90

7.91

7.92

7.93

8.09

8.10

8.49

8.49

8.51

8.51

8.84

8.84

8.86

10.5

310

.55

13.5

1

3u

N

N

NHS

13C NMR spectrum of 3u

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

0

50

100

150

200

250

300

350

400

113.

7311

7.38

118.

0012

2.28

123.

1612

3.83

123.

9712

4.83

125.

0112

7.91

129.

1413

0.35

131.

3613

1.98

138.

0714

3.26

148.

99

169.

51

3u

N

N

NHS

S49

1H NMR spectrum of 3v

-1012345678910111213141516f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

1.04

2.13

1.03

2.02

1.02

1.00

1.00

1.00

1.03

7.51

7.51

7.53

7.55

7.55

7.64

7.64

7.66

7.68

7.68

7.69

7.70

7.71

7.72

7.73

7.73

7.76

7.77

7.78

7.78

7.79

7.80

7.80

7.87

7.89

7.90

7.91

8.10

8.10

8.12

8.12

8.28

8.31

8.42

8.44

9.59

9.61

13.4

2

3v

N

N

NHS

13C NMR spectrum of 3v

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

0

50

100

150

200

250

300

350

400

116.

7011

6.91

117.

6812

3.29

124.

5912

5.03

125.

2112

6.03

127.

5112

8.31

128.

7513

0.63

133.

2813

4.76

138.

4814

6.28

151.

76

171.

01

3v

N

N

NHS

S50

1H NMR spectrum of 3w

-1012345678910111213141516f1 (ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

1.00

2.02

2.11

1.01

1.00

1.00

1.00

1.00

7.35

7.37

7.38

7.47

7.49

7.50

7.64

7.66

7.68

7.70

7.84

7.86

8.35

8.37

9.08

9.10

12.9

013

.07

HN

NH

S3w

13C NMR spectrum of 3w

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

190

200

210

220

230

240

112.

1211

3.80

116.

0111

7.36

121.

7012

2.76

122.

8212

4.03

125.

6212

5.64

130.

3013

7.83

138.

1713

9.02

176.

69

HN

NH

S3w

S51

1H NMR spectrum of 3x

-1012345678910111213141516f1 (ppm)

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

1.00

1.00

2.11

1.02

1.00

1.00

1.00

6.81

6.82

6.82

6.83

7.31

7.32

7.32

7.33

7.35

7.36

7.37

7.38

7.39

7.39

7.40

7.57

7.57

7.58

7.58

7.59

7.59

7.60

7.61

8.13

8.14

8.14

8.15

8.15

8.15

8.16

8.17

8.35

8.36

8.36

8.36

12.9

2

N

NHS3x

13C NMR spectrum of 3x

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

190

200

210

220

230

114.

9711

5.73

116.

1711

7.56

119.

0212

4.60

125.

2012

6.38

128.

1412

9.73

174.

53

N

NHS3x

S52

1H NMR spectrum of 4

N

N

N

S4

-1012345678910111213141516f1 (ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

30000

32000

3.00

1.00

1.00

2.03

2.02

1.00

1.00

2.87

7.27

7.28

7.30

7.58

7.60

7.62

7.70

7.70

7.71

7.72

7.72

7.73

7.75

7.93

7.95

7.97

8.00

8.48

8.50

9.16

9.18

13C NMR spectrum of 4

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

18012

.46

113.

7511

7.77

120.

2812

0.33

122.

8012

5.70

128.

1312

8.70

129.

1313

0.75

144.

8714

5.64

146.

6814

8.97

N

N

N

S4

S53

1H NMR spectrum of 5

N

N

N

N 5

-1012345678910111213141516f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

6.01

4.18

1.07

1.06

2.18

2.09

1.00

1.00

1.64

1.66

1.71

1.72

1.86

1.87

1.89

3.17

3.18

7.33

7.33

7.35

7.35

7.37

7.37

7.55

7.55

7.57

7.58

7.59

7.67

7.67

7.69

7.69

7.71

7.71

7.73

7.73

7.75

7.75

7.77

7.77

7.92

7.95

7.96

7.98

8.48

8.49

8.50

8.51

8.87

8.89

13C NMR spectrum of 5

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

17024.4

225

.66

51.2

6

113.

5811

5.48

117.

6012

0.84

122.

5912

4.86

128.

2412

8.43

128.

9013

0.25

144.

4214

7.97

148.

7815

2.65

N

N

N

N 5

S54

1H NMR spectrum of 7

-1012345678910111213141516f1 (ppm)

-2000

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

12000

13000

14000

15000

16000

17000

18000

19000

20000

21000

22000

23000

24000

25000

1.99

2.00

2.01

0.97

2.00

2.00

1.00

4.95

5.03

6.01

6.02

6.02

6.48

6.48

6.50

6.50

6.52

6.52

6.65

6.67

6.79

6.79

6.80

6.96

6.96

6.98

7.00

7.00

N

H2N7

13C NMR spectrum of 7

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

0

50

100

150

200

250

300

350

400

49.2

3

108.

10

115.

3711

6.62

121.

5012

2.39

128.

5912

8.69

146.

24

N

H2N7

S55

1H NMR spectrum of 9

-1012345678910111213141516f1 (ppm)

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

11000

3.10

2.19

1.00

1.02

2.14

1.00

1.00

0.99

1.00

1.00

0.95

1.25

1.27

1.28

4.14

4.16

4.18

4.20

7.00

7.00

7.01

7.02

7.03

7.09

7.09

7.11

7.12

7.13

7.31

7.31

7.33

7.34

7.34

7.35

7.35

7.35

7.36

7.36

7.38

7.38

7.64

7.67

7.82

7.84

8.24

8.26

8.47

8.58

8.60

11.9

6

N

N

HNS

S9

13C NMR spectrum of 9

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-10

0

10

20

30

40

50

60

70

80

90

100

11015.0

0

60.8

8

110.

8211

3.68

116.

7211

9.41

119.

9812

2.93

126.

4212

7.27

128.

0312

9.04

137.

1214

3.97

144.

08

153.

86

N

N

HNS

S9

S56

1H NMR spectrum of 11

-1012345678910111213141516f1 (ppm)

-5000

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

50000

55000

2.00

2.00

2.03

2.03

6.28

6.28

6.29

6.91

6.91

7.21

7.21

7.22

7.23

7.23

7.25

7.25

7.26

7.34

7.34

7.35

7.35

7.36

7.37

7.38

7.40

N

CN11

13C NMR spectrum of 11

N

CN11

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

-2000

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

30000

32000

34000

36000

38000

40000

42000

109.

51

120.

2912

5.14

126.

1812

7.60

129.

3113

6.07

168.

76