Electrophilic Vinylation of Thiols under Mild and Transition Metal‐Free Conditions

Abstract The iodine(III) reagents vinylbenziodoxolones (VBX) were employed to vinylate a series of aliphatic and aromatic thiols, providing E‐alkenyl sulfides with complete chemo‐ and regioselectivity, as well as excellent stereoselectivity. The methodology displays high functional group tolerance and proceeds under mild and transition metal‐free conditions without the need for excess substrate or reagents. Mercaptothiazoles could be vinylated under modified conditions, resulting in opposite stereoselectivity compared to previous reactions with vinyliodonium salts. Novel VBX reagents with substituted benziodoxolone cores were prepared, and improved reactivity was discovered with a dimethyl‐substituted core.

Step-wise synthesis of Core-Substituted VBX

One-pot synthesis of VBX reagents
VBX reagents with unsubstituted benziodoxolone core were prepared by employing our reported one-pot synthesis. [2] General procedure S1: 2-iodobenzoic acid (1 equiv) was added to a round bottom flask followed by DCM. mCPBA (85%, 1.1 equiv) was added, and the mixture was cooled to 0 °C followed by the addition of TfOH (1.5 equiv). The mixture was stirred at RT for 15 minutes and then cooled to 0 °C for 5 minutes. The corresponding boronic acid (1.4 equiv) was added in one portion and rinsed down with DCM (1-5 mL). The mixture was stirred at room temperature for 1 h. Saturated NaHCO3 was added and the mixture was stirred vigorously at rt for 1 h. The reaction mixture was transferred to a separation funnel, diluted with DCM and H2O. Note: dilution helped to avoid emulsions in the separation. The layers were separated the aqueous phase was extracted three times with DCM. The combined organic phases were washed with H2O and brine and then dried over Na2SO4. The drying agent was filtered off and the solvent was removed in vacuo. Et2O was added to the white precipitate and the mixture was stirred vigorously at RT for approx. 30 min. The solid was filtered off (glass filter funnel, porosity 3) and washed with Et2O to obtain VBX reagents.

Step-wise synthesis of Core-Substituted VBX
The core-substituted VBX 2b-2f and 2l were synthetized using Nachtsheim's two-step procedure [3] since our one-pot procedure is optimized for 2-iodobenzoic acid and yields of vinylbenziodoxolones with substituted iodobenzoic acid varied considerably.
General procedure S2: [3] To a suspension of 2-iodosylbenzoic acid 11 (0.6-2.0 mmol, 1 equiv) in dry DCM or MeCN (10-20 mL) was added TMSOTf (0.67-2.30 mmol, 1.15 equiv) dropwise over 10 min and stirred for 30 min at room temperature. Afterwards (E)-styrylboronic acid (0.67-2.30 mmol, 1.15 equiv) was added over 5 min and the reaction mixture was stirred for 1.5 h at room temperature. Pyridine (1.15 equiv) was added and after further 10 min stirring the solvent was removed under reduced pressure. The residue was dissolved in DCM and washed with a solution of HCl 1M. The aqueous phase was extracted three times with DCM and the combined organic phases were washed with a saturated solution of NaHCO3, dried over Na2SO4, filtered and concentrated under reduce pressure. The residue was dissolved in a minimum amount of DCM and precipitate in Et2O, stirred vigorously for 30 min and stored at 4 °C for 2-16 h. The precipitate was filtered and washed with Et2O to afford the corresponding core-substituted VBX reagent. The iodosyl compounds required for this procedure were prepared following literature procedures: 11a, [3] 11b, [5] 11c, [6] 11d, [7] 11e, [5] 11f. [8] (

Optimization on Thiols
Optimization of thiols were performed on thiophenol 1a. All reactions were carried out in anhydrous solvents. It was established two different procedures on setting up the reactions. The thiophenol (0.1 mmol, 1.0 equiv) was dissolved in the solvent of choice followed by the addition of the base (1.0 equiv). After 5 minutes the VBX 2a (1.1equiv, if not otherwise stated) was added to the reaction mixture and stirred at indicated time. Adding the base at the end showed less amount of the product 4a. Differently, thiophenol (0.1 mmol, 1.0 equiv) was dissolved in the solvent of choice, subsequently VBX 2a (1.1equiv, if not otherwise stated) was added followed by the addition of the base (1.0 equiv).

General Procedure A for Vinylation of Thiols.
Thiol 1 (1.0 equiv, 0.3 mmol) was placed in an oven-dried microwave vial with magnetic stirring bar under argon, followed by the addition of dry and degassed THF (2.0 mL). Subsequently, VBX 2 (1.1 equiv) was added followed by tBuOK (1.0 equiv) and the vial rinsed with THF (1.0 mL), the mixture rapidly turns yellow and it was stirred at RT for 2 h. The reaction was quenched with water (2.0 mL) and the aqueous phase was extracted with DCM (2 x 10 mL) and the combined organic phases were dried over Na2SO4, filtered and concentrated under reduce pressure. The reaction crude was purified via column chromatography.

Recovery of Iodoarene
The formed iodobenzoic acid can be recovered and reused in formation of VBX, thus increasing the sustainability and economy of the process both when we use the normal VBX 2a and the Me2VBX 2e after acid work-up and extraction with DCM.

Mechanistic studies
To investigate if the reaction proceeds through radical species, the radical scavengers (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) and 1,1-diphenylethylene (DPE) were added to the reaction mixture. As displayed in Table S2, a lower yields and E:Z ratios were obtained with TEMPO. Instead with DPE the yields were almost the same as in standard condition but a slightly lower E:Z-ratios were obtained. Based on these results a radical mechanism does not seem to be operating. To investigate the formation of an arene species from the VBX reagent, 5.0 equivalents of furan were added under the optimized reaction conditions. This would allow for trapping the alkyne species through a [4+2] cycloaddition. 1 H-NMR of the crude reaction did not show any new products being formed.

Reaction of silyl protected thiophenol
Having demonstrated the scope with thiols, the vinylation of silyl-protected thiol was investigated to allow for facile functionalization of complex substrates. Indeed, treatment of 7 with VBX 2a in the absence of base resulted in 29% yield of 3a, which could be increased to 77% NMR yield by in situ-deprotection with TBAF.
Procedure: thiohenol 1 (0.1 mmol, 1.0 equiv) was placed in an oven-dried microwave vial with magnetic stirring bar under argon, followed by the addition of dry and degassed THF (0.75 mL). Subsequently, VBX 2a (1.1 equiv) was added followed by addition drop by drop of TBAF (1.0 equiv) and the vial rinsed with THF (0.25 mL), the mixture rapidly turns yellow and it was stirred at RT for 2 h. The reaction was quenched with water (2.0 mL) and the aqueous phase was extracted with DCM (2 x 10 mL) and the combined organic phases were dried over Na2SO4, filtered and concentrated under reduce pressure giving 77% NMR yield with an E:Z ratio > 20:1. The yield was calculated employing TBD as internal standard. The crude was purified on column chromatography (pentane) and 3a was isolated as colorless oil in 76% yield (16 mg), E:Z>20:1.

Optimization on Mercaptothiazoles and byproduct formation
Vinylation of tautomers of thioamides required further optimization, which was performed on 2-mercaptothiazole (8). All reactions were carried out in anhydrous and degassed solvents. The mercaptothiazole (0.1 mmol, 1.0 equiv) was dissolved in the solvent of choice, subsequently, VBX 2a (1.1 equiv, if not otherwise stated) was added, finally the base (1.0 equiv) was added. After the indicated time, the reaction was concentrated at the rotavapor, followed by the addition of water (1.0 mL) and DCM, followed by extraction with DCM (3x5.0 mL). The combined organic phases were dried over Na2SO4. Afterwards, the reaction was concentrated at the rotavapor. The reaction crude was purified via column chromatography. NMR yields were determined with TMP as internal standard. The standard conditions for thiol vinylation did not work in case of 2-mercaptothiazole (Table S3; entry 1). Increasing the temperature to 60° C afforded 44% yield (entry 2). We applied the conditions previously reported in our group for arylation of thioamides [10] by exchanging the solvent from THF to toluene and increasing the temperature to 80 °C, which proved beneficial (entry 3). Increasing the temperature to 110 °C did not improve the yields (entry 5). Exchanging the base did not increase the yield (entries 6-9). We observed the formation of side product 10 at higher temperature, so we tried increasing the equivalents of VBX (entry 10) but it did not influence the outcome positively. We could not observe the formation of the N-vinylated product. The E/Z ratio was consistent around 9:1 towards the E product.

General Procedure B for Vinylation of Mercaptothiazoles:
The mercaptothiazole (1.0 equiv, 0.3 mmol) was placed in a oven-dried microwave vial with magnetic stirring bar under argon, followed by the addition of anhdrous and degassed toluene (2.0 mL). Subsequently, VBX 2a (1.1 equiv) was added followed by tBuOK (1.0 equiv) and the vial was rinsed with toluene (1.0 mL); then the mixture was stirred at 80 °C for 2 h. Afterwards, the reaction was concentrated at the rotavapor followed by addition of DCM (5.0 mL) and water (5 mL). The aqueous phase was extracted with DCM (2 x 10 mL) and the combined organic phases were dried over Na2SO4, filtered and concentrated under reduce pressure. The reaction crude was purified via column chromatography.
Interestingly, VBX reactions of 8a without base resulted in a different product according to 1 H NMR of the crude product, which formed the desired product 9a in 37% yield during isolation performed on column chromatography (Scheme S1). The crude product is believed to be the unusually stable iodine(III) species 11 with the nucleophile coordinated to iodine, as previously reported in certain reactions with diaryliodonium salts. [11] To the best of our knowledge, such intermediates remain unknown with benziodoxolone reagents. The crude 1 H NMR is given in Figure S2, and the spectra in CDCl3 of desired product 9a, VBX 2a, intermediate 11 and mercaptobenzothiazole are compared in Figure S3.
When the reaction was done with VBX 2e following a General Procedure A, 90% yield of the 3a was obtained. The crude did not need further purification.
When the reaction was done with VBX 2e following a General Procedure A, 77% yield of the 3i was obtained. The crude did not need further purification.
When the reaction was done with VBX 2e following a General Procedure A, 97% yield of the 3l was obtained. The crude did not need further purification.

Analytical data for E-3t
Mp

Unprotected Cysteine
Procedure: L-cysteine (1.0 equiv, 0.1 mmol) was placed in a oven-dried microwave vial with magnetic stirring bar under argon, followed by the addition of anhydrous and degassed THF (1.0 mL). Subsequently, VBX 2a (1.1 equiv) was added followed by tBuOLi (2.0 equiv) and the vial was rinsed with THF (1.0 mL); then the mixture was stirred at 80 °C o/n. Afterwards, the reaction was quenched with HCl 1M (2 mL) followed by addition of DCM. The organic phase was washed with H2O (2x2 mL) and the aqueous phase was dried at the rotavapor. The solid obtained was dissolved in MeOD and NMR yield was calculated using TMB as IS. NMR yield corresponds to 11% and the presence of the corresponding vinylated product has been confirmed with HRMS. HRMS(ESI) m/z: calcd for C11H13NO2SNa + [M+Na] + : 246.0559; found 246.0546.

1-thio-beta-D-glucose
Procedure: 1-thio-beta-D-glucose (1.0 equiv, 0.1 mmol) was placed in a oven-dried microwave vial with magnetic stirring bar under argon, followed by the addition of anhydrous and degassed THF (1.0 mL). Subsequently, VBX 2a (1.1 equiv) was added followed by tBuOK (1.0 equiv) and the vial was rinsed with THF (1.0 mL); then the mixture was stirred at 60 °C o/n. Afterwards, the reaction was quenched with water (2 mL) followed by addition of DCM. The aqueous phase was extracted with DCM (2x10 mL) and the organic phase was dried at the rotavapor. The solid obtained was dissolved in MeOD and NMR yield was calculated using TMB as IS. NMR yield corresponds to 18% and the presence of the corresponding vinylated product has been confirmed with HRMS. HRMS(ESI) m/z: calcd for C14H18NO5SNa + [M+Na] + : 321.0767; found 321.0729.