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: [email protected], [email protected]
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
S3
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