A Practical and Versatile Method for the C–H Sulfenylation of Imidazo[1,2-a]pyridines

^◊ Current address: Department of Chemistry, Mustansiriyah University, Baghdad, Iraq

Abstract

Imidazo[1,2-a]pyridines are an important class of heterocycles that are prevalent in many bioactive small molecules. We report the direct introduction of a broad selection of aromatic, heteroaromatic, or alkyl fragments connected by a thioether group into these important heterocycles by using readily prepared thiosulfate salts.

Key words

imidazopyridines - coupling reaction - C–H functionalization - thioethers - regioselectivity - sulfenylation

• References and Notes

• 1 Couty F, Evano G. In Comprehensive Heterocyclic Chemistry III, Vol. 11. Katritzky A, Ramsden CA, Scriven EF. V, Taylor RJ. K. Elsevier; Oxford: 2008. Chap. 11.10,; 40
• 2 Swainston Harrison T, Keating GM. CNS Drugs 2005; 19: 65
• 3a Semwal R, Ravi C, Saxena S, Adimurthy S. J. Org. Chem. 2019; 84: 14151
• 3b Sharma P, Jain N. J. Org. Chem. 2019; 84: 13045
• 3c Gan Z, Yan Q, Li G, Li Q, Dou X, Li G.-Y, Yang D. Adv. Synth. Catal. 2019; 361: 4558
• 3d Deng J.-C, Zhang J.-R, Li M.-H, Huang J.-C, Lai Z.-S, Tong X.-Y, Cui Z.-N, Tang R.-Y. Org. Biomol. Chem. 2019; 17: 7854
• 3e Tian L.-L, Lu S, Zhang Z.-H, Huang E.-L, Yan H.-T, Zhu X, Hao X.-Q, Song M.-P. J. Org. Chem. 2019; 84: 5213
• 4a Hu S, Du S, Yao Y, Yang Z, Ren H, Chen Z. Synlett 2019; 30: 625
• 4b Gao Y.-C, Huang Z.-B, Xu L, Li Z.-D, Laia Z.-S, Tang R.-Y. Org. Biomol. Chem. 2019; 17: 2279
• 4c Kong D, Wang Q, Huang T, Liang M, Lin Q, Wu M. Tetrahedron 2019; 75: 1457
• 4d Reddy RJ, Shankar A, Kumari AH. Asian J. Org. Chem. 2019; 8: 2269
• 5 Al-Saedy MA. E, Nassoy A.-CM. A, Harrity JP. A. Synlett 2018; 29: 349

For related examples see:
• 6a Qi H, Zhang T, Wan K, Luo M. J. Org. Chem. 2016; 81: 4262
• 6b Li J, Cai Z.-J, Wang S.-Y, Ji S.-J. Org. Biomol. Chem. 2016; 14: 9384
• 7 For a review, see: Biswas K, Basu B. Curr. Organocatal. 2018; 5: 182
• 8 Aliphatic Thiosulfate Salts 1a–g; General Procedure The appropriate alkyl halide (1–2 equiv) was added to a stirred solution of Na₂S₂O₃·5H₂O (1 equiv) in 4:1 MeOH–H₂O OH (0.5 M) at r.t., and the mixture was stirred at reflux for 1 d. The solvent was removed in vacuo, and the crude residue was dissolved in acetone, filtered, and concentrated in vacuo to furnish the pure alkyl thiosulfate as a solid. Sodium S-(1,3-Dioxolan-2-ylmethyl) Thiosulfate (1d) Prepared by following the general procedure from Na₂S₂O₃·5H₂O (2.545 g, 10.25 mmol) and 2-bromomethyl-1,3-dioxolane (0.856 g, 5.13 mmol) as a colourless solid; yield: 1.114 g (quant); mp 188–189 ℃. FTIR (neat): 2696 (s), 2890 (s), 1475 (m), 1423 (s), 1376 (s), 1222 (m), 1140 (s), 1087 (s), 1039 (s), 816 (s) cm^–1. ¹H NMR (400 MHz, D₂O): δ = 5.24 (t, J = 4.5 Hz, 1 H), 4.00–3.87 (m, 4 H), 3.26 (d, J = 4.5 Hz, 2 H). ¹³C NMR (101 MHz, D₂O): δ = 101.5, 65.2, 37.1. HRMS (ESI-TOF): m/z [M – Na]^– calcd for C₄H₇O₅S₂: 198.9740; found: 198.9742.
• 9 Zhang H, Wei Q, Wei S, Qu J, Wang B. Eur. J. Org. Chem. 2016; 3373
• 10 Jansa P, Čechová L, Dračínský M, Janeba Z. RSC Adv. 2013; 3: 2650
• 11 Indole Thiosulfate Salts 2a–d; General Procedure Step 1: NCS (1.5 equiv) and NaSCN (2.0 equiv) were added to a mixture of the appropriate indole (1 equiv) in EtOH (0.25 M) at 0 °C, and the mixture was stirred at r.t. until the starting material was consumed. The solvent was evaporated in vacuo and the crude product was purified by column chromatography [silica gel, PE to 30% EtOAc–PE (gradient)]. Step 2: To a solution of the resulting 3-indole thiocyanate (1 equiv) in 4:1 EtOH–H₂O (0.02 M) was added Na₂SO₃ (2 equiv), and the mixture was stirred at r.t. for 24 h. The solvents were evaporated in vacuo, and the residue was dissolved in MeOH. The solution was filtered to remove insoluble inorganic salts and then concentrated in vacuo. Sodium S-(6-Chloro-1H-indol-3-yl) Thiosulfate (2b) By following the general procedure (Step 1) using 6-chloroindole (0.773 g, 5.10 mmol), NaSCN (0.827 g, 10.20 mmol), and NCS (1.022 g, 7.65 mmol), 6-chloro-1H-indol-3-yl thiocyanate was obtained as a brown solid; yield: 0.862 g (81%); mp 126–127 ℃. By following the general procedure (Step 2) using 6-chloro-1H-indol-3-yl thiocyanate (1.022 g, 4.90 mmol) and Na₂SO₃ (1.234 g, 9.79 mmol), the desired product 2b was obtained as a beige solid; yield: 1.312 g (94%); mp 113–114 ℃. FTIR (neat): 3395 (br), 3050 (w), 1624 (w), 1566 (w), 1456 (s), 1447 (s), 1413 (m), 1314 (m), 1264 (s), 1127, 1093 (s), 1065 (s), 876 (m), 800 (s) cm^–1. ¹H NMR (400 MHz, D₂O): δ = 7.53 (d, J = 8.5 Hz, 1 H), 7.49 (s, 1 H), 7.33 (d, J = 1.5 Hz, 1 H), 7.07 (dd, J = 8.5, 1.5 Hz, 1 H). ¹³C NMR (101 MHz, D₂O): δ = 136.3, 134.2, 127.7, 127.0, 121.1, 119.8, 111.8, 99.5. HRMS (ESI-TOF): m/z [M – Na]^– calcd for C₈H₅ ³⁵ClNO₃S₂: 261.9405; found: 261.9409.
• 12 Full experimental procedures and spectra are provided in the Supporting Information.
• 13 Coupling of Bunte Salts to Imidazo[1,2-a]pyridines; General Procedure A flame-dried Schlenk tube equipped with a magnetic stirring bar was charged with imidazo[1,2-a]pyridine (1 equiv), the appropriate Bunte salt (1.5 equiv), and I₂ (20 mol%). The tube was sealed with a rubber septum, and placed under an atmosphere of argon. DMSO (0.15 M) was added from a syringe and the septum was replaced by a Teflon screw cap under flowing argon. The mixture was stirred at 80 °C for 24 h then cooled to r.t. Sat. aq Na₂S₂O₃ was added, and the mixture was extracted with EtOAc. The combined organic layers were washed with H₂O and brine, dried (MgSO₄), filtered, and concentrated in vacuo. The product was purified by crystallisation from pentane or by flash chromatography [silica gel, PE to 30% EtOAc–PE ­(gradient)]. 3-[(1,3-Dioxolan-2-ylmethyl)sulfanyl]imidazo[1,2-a]pyridine (4f) Prepared by following the general procedure using imidazo[1,2-a]pyridine (33 mg, 35 μL, 0.34 mmol), sodium S-(1,3-dioxolan-2-yl)methyl thiosulfate (1d; 115 mg, 0.52 mmol), and I₂ (17 mg, 0.07 mmol) as a brown gum; yield: 70 mg (86%). FTIR (neat): 3099 (w), 2974 (br), 2888 (s), 1632 (m), 1506 (s), 1497 (s), 1377 (w), 1340 (s), 1292 (s), 1233 (m), 1144 (s), 1037 (m), 977 (w), 758 (s) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.50 (dt, J = 7.0, 1.0 Hz, 1 H), 7.83 (s, 1 H), 7.64 (dt, J = 9.0, 1.0 Hz, 1 H), 7.28 (ddd, J = 9.0, 7.0, 1.0 Hz, 1 H), 6.94 (td, J = 7.0, 1.0 Hz, 1 H), 5.00 (t, J = 4.5 Hz, 1 H), 4.03–3.94 (m, 2 H), 3.92–3.84 (m, 2 H), 2.85 (d, J = 4.5 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 147.4, 141.3, 125.5, 124.4, 117.9, 116.4, 112.8, 102.7, 65.3, 39.6. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₁₃N₂O₂S: 237.0692; found: 237.0691.
• 14 CCDC 1534461 contains the supplementary crystallographic data for compound 4i. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.