SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2020, 31, 349–354 letter 349 en Syn lett Y.-Z. Ji et al. Letter TMSOTf-Promoted Sulfinylation of Electron-Rich Aromatics with Sodium Arylsulfinates Yuan-Zhao Jia 2 R1 Hui-Jing Li*a,b R X a Hao-Ran Yang 2 R = OMe, OH, Me ArSO2Na, TMSOTf X = NMe, NBn, NPh, NH, S a Zheng-Yan Zhang 1 R = F, Br, Me, OMe, NO2, CN O air, room temperature Li-Jun Xiea O S S Ar Yan-Chao Wu*a,b 0000-0002-0111-7484 Ar R2 12 examples 34 examples R1 a School of Marine Science and Technology, Harbin Institute of X yield up to 95% Technology, 2 Wenhuaxi Road, Weihai 264209, P. R. of China yield up to 90% b Weihai Institute of Marine Biomedical Industrial Technology, Wendeng District, Weihai 264400, P. R. of China [email protected] [email protected] Received: 03.10.2019 quently, we reported a TMSOTf-promoted thiolation of in- Accepted after revision: 16.12.2019 doles with sodium arylsulfinates by in situ overreduction of Published online: 09.01.2020 DOI: 10.1055/s-0039-1691563; Art ID: st-2019-k0654-l the new generated, sulfinylated intermediates (Scheme 1b, left).15b We envisioned that the sulfoxide reduction process Abstract A new transition-metal-free route for the direct sulfinylation might be obviated by carefully controlling the reaction con- of electron-rich aromatics with sodium arylsulfinates in the presence of ditions, and thus could facilitate a practical sulfoxide syn- TMSOTf is reported. Various electron-rich aromatics, including pyrroles, thiophenes, indoles, and electron-rich arenes, with sodium arylsulfi- thesis. We report herein the realization of this strategy by nates are converted into the corresponding sulfoxides in moderate to shortening the reaction time (i.e., 12 h vs. 0.5–1 h) and si- excellent yields. This protocol possesses many advantages such as readily multaneously decreasing the amount of TMSOTf (i.e., 4 available and stable starting materials, broad substrate scopes, and equiv vs. 2 equiv), which provide a facile synthetic protocol transition-metal-free reaction conditions. to sulfoxides from electron-rich arenes and heteroarenes Key words sulfinylation, pyrroles, indoles, sulfoxides, sodium arylsulfi- with sodium arylsulfinates (Scheme 1b, right). nates a) Sulfinate syntheses15a O TMSCl O Downloaded by: Kevin Chang. Copyrighted material. Sulfoxides are prevalent in important and high-value R–OH S + S chemical structures1 such as the natural products,2 phar- Ar ONa Ar OR 3 4 5 maceutically active compounds, ligands, organocatalysis, b) Thioether15b and sulfoxide syntheses 6 and functional materials. Traditionally, sulfoxides could be TMSOTf TMSOTf O O 7 S (4 equiv) 2 (2 equiv) prepared by oxidation of sulfides or nucleophilic substitu- 1 2 S + Ar –H S Ar Ar 1 1 2 tion of sulfinyl derivatives with organometallic reagents.8 12 h Ar ONa 0.5–1.0 h Ar Ar this work In addition, other synthetic approaches to sulfoxides, such Ar2 = indoles Ar2 = indoles, pyrroles, thiophenes, as transition-metal-catalyzed arylation of sulfenate an- electron-rich arenes ions,9 have also been reported.10 In recent years, direct Scheme 1 Synthetic application of sodium arylsulfinates sulfinylation of electron-rich arenes and heteroarenes has been developed by using sulfinic acids,11 sulfinates,12 and Reaction of sodium p-toluenesulfinate (1a) with N-Me- sulfinamides13 as the sulfinylating reagents. Despite these pyrrole (2a) was used as a probe for evaluating the reaction advances, the direct synthesis of the sulfoxides, using easy- conditions (Table 1). Following our previous procedure (2 15a to-handle reagents under mild reaction conditions, remains equiv of TMSCl, CH2Cl2, rt), reaction of sodium p-toluene- in demand. sulfinate (1a) with N-Me-pyrrole (2a, 1.5 equiv) afforded 2- On the other hand, sodium arylsulfinates are stable, sulfinylpyrrole 3a and 3-sulfinylpyrrole 4a in 6% and 55% odorless, and easy-to-handle sulfur compounds, and thus yields, respectively (Table 1, entry 1). Subsequently, DMSCl, have been widely used as desirable starting materials TIPSCl, TBDMSCl, TMSOTf, BF3·Et2O, CF3SO3H, p-TsOH·H2O, for the synthesis of organosulfur compounds.14,15 We have and AcOH were further investigated for this reaction, and reported the advantages of using sodium arylsulfinates/ TMSOTf is found to be the most efficient promoter for this TMSCl system with oxygenated nucleophiles for obtaining reaction (Table 1, entries 1–9). The reaction did not work 15a sulfinates under mild conditions (Scheme 1a). Subse- when it was performed in DMF, DMSO, H2O (Table 1, entries © 2020. Thieme. All rights reserved. Synlett 2020, 31, 349–354 Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany 350 Syn lett Y.-Z. Ji et al. Letter a 10–12). With the use of MeNO2, MeCN, THF, 1,4-dioxane, Table 1 Optimization of the Reaction Conditions and toluene in comparison to (ClCH2)2, lower yields were found (Table 1, entries 13–18). No reaction took place in the O O O promoter N S S S (X equiv) absence of TMSOTf (Table 1, entry 19). Further parameters + + ONa N solvent optimization identified the most effective TMSOTf loading rt, 0.5 h N as 2.0 equiv (Table 1, entries 13 and 20–24). The reaction was also performed under argon atmosphere, and the same 1a 2a 3a 4a yield was observed (Table 1, entries 13 and 25), which indi- Entry Promoter Solvent Yield of 3a Yield of cated that noble gas atmosphere is not necessary for this re- (X equiv) (%)b 4a (%)b action. 1 TMSCl (2.0) CH Cl 655 The optimized sulfinylation reaction conditions proved 2 2 to be effective for various sodium arylsulfinates 1 and 2 DMSCl (2.0) CH2Cl2 422 pyrroles/thiophenes 2 (Scheme 2). With the aromatic ring 3 TIPSCl (2.0) CH2Cl2 220 bearing hydrogen atoms, electron-withdrawing and elec- 4 TBDMSCl (2.0) CH2Cl2 362 tron-donating groups, sodium arylsulfinates 1 reacted 5 TMSOTf (2.0) CH2Cl2 076 smoothly with N-Me-pyrrole (2a) in the presence of 6BF3·Et2O (2.0) CH2Cl2 060 TMSOTf (2 equiv) in (ClCH ) at 25 °C to afford sulfoxides 2 2 7CFSO H (2.0) CH Cl 066 4a–l in 31–84% yields within 0.5 h. 1-Naphthyl-, 2-naphth- 3 3 2 2 yl-, 2-thienyl-, and cyclopropyl-substituted sodium sulfi- 8 p-TsOH·H2O (2.0) CH2Cl2 023 nates reacted with pyrrole 2a to generate the sulfoxides 9 AcOH (2.0) CH2Cl2 N.D. N.D. 4m–p in 45–77% yields. N-Substituted pyrroles with benzyl 10 TMSOTf (2.0) DMF N.D. N.D. and phenyl reacted with sodium p-toluenesulfinate (1a) to 11 TMSOTf (2.0) DMSO N.D. N.D. afford the sulfoxides 4q and 4r in 90% and 89% yields, re- 12 TMSOTf (2.0) H2O N.D. N.D. spectively. Treatment of 1-tosyl-1H-pyrrole with sodium 13 TMSOTf (2.0) (ClCH ) 0 88 (83c) arylsulfinate 2a failed to give the desired sulfoxide 4s. The 2 2 reaction of 1H-pyrrole and 2,5-dimethyl-1H-pyrrole with 14 TMSOTf (2.0) MeNO2 060 sodium arylsulfinate 2a went smoothly to generate the de- 15 TMSOTf (2.0) MeCN 0 81 sired sulfoxides 4t and 4u in 41% and 36% yields, respective- 16 TMSOTf (2.0) THF 0 74 ly. 17 TMSOTf (2.0) 1,4-dioxane 0 50 Reaction of 3-ethyl-2,5-dimethyl-1H-pyrrole with sodi- 18 TMSOTf (2.0) toluene 0 77 um arylsulfinate 2a is complex under the standard condi- 19 – (ClCH ) N.R. N.R. tions and the expected sulfoxides 4v was not observed. In- 2 2 terestingly, treatment of 1-(1-benzyl-1H-pyrrol-2-yl)ethan- 20 TMSOTf (0.5) (ClCH2)2 610 Downloaded by: Kevin Chang. Copyrighted material. 1-one, an electron-deficient pyrrole, with sodium arylsulfi- 21 TMSOTf (1.0) (ClCH2)2 438 nate 2a under the standard conditions did not afford the 22 TMSOTf (1.5) (ClCH2)2 073 corresponding thermodynamic product 3-sulfinylpyrrole. 23 TMSOTf (3.0) (ClCH2)2 074 Instead, kinetic product 2-sulfinylpyrrole 3w was obtained 24 TMSOTf (4.0) (ClCH ) 064 in 13% yield, whose structure has been determined from 2 2 d the observed different chemical shifts and coupling con- 25 TMSOTf (2.0) (ClCH2)2 088 stant between H /H ( = 5.54 ppm, = 5.50 ppm, J = J = a General conditions: 1a (0.2 mmol), 2a (0.3 mmol), and promoter (0–0.8 a b a b ab ba mmol) in solvent (1.0 mL) at rt for 0.5 h. DMS = dimethylsilyl; TIPS = triiso- 15.0 Hz, Scheme 2). Ethyl 1-benzyl-2,4-dimethyl-1H-pyr- propylsilyl; TBDMS = tert-butyldimethylsilyl; N.D. = no detection; N.R. = no role-3-carboxylate, an electron-deficient pyrrole with its 3- reaction. b The yield was determined by 1H NMR spectroscopy using 0.2 mmol of positions possessing substituents, was also investigated, CH2Br2 as a standard. which reacted with sodium arylsulfinate 2a to generate the c Isolated yield. d overreduction product 5x in 47% yield. The reaction of thio- Under argon. phene, 3-hexylthiophene with sodium arylsulfinate 2a went smoothly to afford sulfoxides 4y and 4z in 23% and (ClCH2)2 at 25 °C to afford sulfoxides 4a (5.32 g) in 81% yield 63% yields, respectively. within 0.5 h. This result showed the great potential of this To prove the synthetic utility of this synthetic method, sulfinylation reaction in practical synthesis. gram-scale reaction was carried out under the standard To glean insight into the sulfinylation reaction mecha- sulfinylation conditions (Scheme 3). The reaction of sodium nism, a control experiment was carried out in Scheme 4.