A Continuous-Flow Protocol for the Synthesis of Alkenyl Thioethers Based on the Photochemical Activation of Halogen-Bonding Complexes

Abstract

We report a useful flow protocol for the preparation of alkenyl thioethers from alkenyl bromides and thiols in basic media with visible-light irradiation. The reactions exhibit a wide functional-group tolerance, proceed under mild conditions, are stereoselective, and do not require the use of catalysts. The transformations can be successfully scaled up to 5 mmol scale without compromising the yield. The key to the success of these reactions is the photochemical excitation of halogen-bonding complexes to form alkenyl and sulfur-centered radicals, a protocol recently developed in our laboratories.

Key words

photochemistry - flow chemistry - thioetherification - scale-up

Publication History

Received: 03 May 2024

Accepted after revision: 14 June 2024

Accepted Manuscript online:
15 June 2024

Article published online:
02 July 2024

• References and Notes


For recent reviews on C–S bond formation, see:
• 1a Lee C.-F, Basha RS, Badsara SS. Top. Curr. Chem. 2018; 376: 25
• 1b Annamalai P, Liu K.-C, Badsara SS, Lee C.-F. Chem. Rec. 2021; 21: 3674
• 1c Beletskaya IP, Ananikov VP. Chem. Rev. 2022; 122: 16110

For recent reviews on visible-light-driven construction of C–S bonds, see:
• 2a Wu Z, Pratt DA. Nat. Rev. Chem. 2023; 7: 573
• 2b Feng J, Zhang Y, Wang X, Liu J, Benazzi V, Lu K, Zhao X, Protti S. Adv. Synth. Catal. 2023; 365: 3413

For selected recent examples, see:
• 3a Burykina JV, Shlapakov NS, Gordeev EG, König B, Ananikov VP. Chem. Sci. 2020; 11: 10061
• 3b Burykina JV, Kobelev AD, Shlapakov NS, Kostyukovich AY, Fakhrutdinov AN, König B, Ananikov VP. Angew. Chem. Int. Ed. 2022; 61: e202116888
• 3c Jiang T, Chen L, Wen S, Zhang L, Wang T, Xiong F. J. Org. Chem. 2024; 89: 1296
• 4a Ilardi EA, Vitaku E, Njardarson JT. J. Med. Chem. 2014; 57: 2832
• 4b Wang B.-W, Jiang K, Li J.-X, Luo S.-H, Wang Z.-Y, Jiang H.-F. Angew. Chem. Int. Ed. 2020; 59: 2338
• 4c Liu X.-S, Tang Z, Li Z, Li M, Xu L, Liu L. Nat. Commun. 2021; 12: 7298

For selected examples, see:
• 5a Sahharova LT, Gordeev EG, Eremin DB, Ananikov VP. ACS Catal. 2020; 10: 9872
• 5b Fragis M, Deobald JL, Dharavath S, Scott J, Magolan J. Org. Lett. 2021; 23: 4548
• 5c Nie Z, Lv H, Yang T, Su M, Luo W, Liu Q, Guo C. Adv. Synth. Catal. 2022; 364: 2989

For recent reviews, see:
• 6a Sideri IK, Voutyritsa E, Kokotos CG. Org. Biomol. Chem. 2018; 16: 4596
• 6b Crespi S, Fagnoni M. Chem. Rev. 2020; 120: 9790
• 6c Protti S, Ravelli D, Fagnoni M. Trends Chem. 2022; 4: 305
• 6d Das A, Thomas KR. J. Chem. Eur. J. 2024; e202400193
• 6e Piedra HF, Plaza M. Photochem. Photobiol. Sci. 2024; 23: 1217
• 7 Lang Y, Li C.-J, Zeng H. Org. Chem. Front. 2021; 8: 3594
• 8 Sempere Y, Morgenstern M, Bach T, Plaza M. Photochem. Photobiol. Sci. 2022; 21: 719
• 9 Crisenza GE. M, Mazzarella D, Melchiorre P. J. Am. Chem. Soc. 2020; 142: 5461
• 10 Piedra HF, Valdés C, Plaza M. Chem. Sci. 2023; 14: 5545
• 11 Cavallo G, Metrangolo P, Milani R, Pilati T, Priimagi A, Resnati G, Terraneo G. Chem. Rev. 2016; 116: 2478

For selected examples, see:
• 12a Kandukuri SR, Bahamonde A, Chatterjee I, Jurberg ID, Escudero-Adán EC, Melchiorre P. Angew. Chem. Int. Ed. 2015; 54: 1485
• 12b Cuadros S, Rosso C, Barison G, Costa P, Kurbasic M, Bonchio M, Prato M, Filippini G, Dell’Amico L. Org. Lett. 2022; 24: 2961
• 12c Kato N, Nanjo T, Takemoto Y. ACS Catal. 2022; 12: 7843
• 12d Zhang C, Zuo H, Lee GY, Zou Y, Dang Q.-D, Houk KN, Niu D. Nat. Chem. 2022; 14: 686
• 12e Mountanea OG, Mantzourani C, Kokotou MG, Kokotos CG, Kokotos G. Eur. J. Org. Chem. 2023; 26: e202300046
• 12f Bourboula A, Mountanea OG, Krasakis G, Mantzourani C, Kokotou MG, Kokotos CG, Kokotos G. Eur. J. Org. Chem. 2023; 26: e202300008
• 12g Li Y, Hou J, Zhang P, Dai P, Gu Y, Xia Q, Zhang W. Chem. Eur. J. 2024; e202400237
• 12h Guo P, Pu G, Wang G, Zeng L.-Y, Li W.-P, Li X, Zhou P.-P, He C.-Y. Org. Lett. 2024; 26: 3097
• 12i Pu G, Song S.-Y, Yang J, Guo P, Jia J, Liu P, Li X, Liu P, He C.-Y. Org. Chem. Front. 2024; 11: 3320
• 12j Yamaguchi E, Murai M, Itoh A. J. Org. Chem. 2024; 89: 6555
• 13 Piedra HF, Plaza M. Chem. Sci. 2023; 14: 650
• 14 Piedra HF, Gebler V, Valdés C, Plaza M. Chem. Sci. 2023; 14: 12767
• 15a Jiang Z, You K, Wu H, Xu M, Wang T, Luo J. Org. Lett. 2024; 26: 636
• 15b Piedra HF, Valdés C, Plaza M. Adv. Synth. Catal. 2024; 366: 1422

For reviews on continuous-flow photochemistry, see:
• 16a Cambié D, Bottecchia C, Straathof NJ. V, Hessel V, Noël T. Chem. Rev. 2016; 116: 10276
• 16b Buglioni L, Raymenants F, Slattery A, Zondag SD. A, Noël T. Chem. Rev. 2022; 122: 2752
• 16c Capaldo L, Wen Z, Noël T. Chem. Sci. 2023; 14: 4230
• 17 Thioethers 3aa–ia; General Procedure A solution of the appropriate vinyl bromide 1 (0.52 mmol), thiol 2 (0.8 mmol), and NaOH (0.8 mmol) in anhyd DMSO (4 mL) was prepared and loaded into a syringe. The syringe was connected to a high-pressure pump and a photoreactor (see SI for a detailed description). The solution was continuously pumped through the system at 4 mL/h and illuminated by a Kessil lamp (PRL160; λ = 427 nm). DMSO was used to drive the reacting mixture into a collector flask as the solution entered the reactor. The reaction was quenched by adding H₂O (10 mL), and the resulting mixture was diluted with Et₂O (15 mL), and transferred to a separatory funnel. The aqueous phase was extracted with Et₂O (3 × 15 mL), and the combined organic phase was washed with brine (20 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane–EtOAc). [(E)-2-(Phenylsulfanyl)vinyl]benzene (3aa) Prepared from vinyl bromide 1a (67 μL, 0.52 mmol), PhSH (2a; 82 μL, 0.80 mmol), and freshly ground NaOH (32 mg, 0.80 mmol) by following the general procedure, and purified by flash chromatography [silica gel, hexane–EtOAc (50:1)] to give a colorless oil; yield: 72 mg (65%, dr 5.5:1 trans/cis). For simplicity, the integrals in the ¹H NMR spectra have been adjusted to the major (trans) isomer: the signals for the corresponding cis-isomer have also been analyzed. ¹H NMR (300 MHz, CDCl₃, 300 K): δ = 7.59–7.21 (m, 10 H + cis-isomer), 6.91 (d, J = 15.4 Hz, 1 H), 6.76 (d, J = 15.5 Hz, 1 H), 6.62 (d, J = 10.8 Hz, cis-isomer), 6.53 (d, J = 10.7 Hz, cis-isomer). ¹³C NMR (75 MHz, CDCl₃, 300 K): δ = 136.6 (C), 135.3 (C), 131.8 (CH), 129.9 (CH), 129.2 (CH), 128.7 (CH), 127.6 (CH), 127.0 (CH), 126.0 (CH), 123.4 (CH).