Photooxidative Coupling of Thiols Promoted by Bromo(trichloro)methane in a Basic Aqueous Medium

Abstract

A transition-metal- and organic-solvent-free oxidative coupling of thiols catalyzed by BrCCl₃ and NaOH in an aqueous medium with oxygen as a green oxidant was established The facile and green method has a broad substrate scope in converting thiols into the corresponding disulfides with medium to excellent yields (up to 91%). This method could potentially be used to construct bioactive molecules containing disulfide bonds and to label bioactive molecules with disulfide bonds.

Key words

photocatalysis - coupling - free radicals - photooxidation - thiols - disulfides

The disulfide bond (–S–S–) is present in many natural products and drugs.[1] The construction of a disulfide bond as a covalent linker is also one of the most important approaches in biomolecular labeling and drug delivery.[2] In recent decades, numerous methods have been developed to prepare disulfide compounds.[3] Among these, oxidative coupling is one of the most convenient and most straightforward approaches. However, at the current stage, many reactions require harsh reagents such as stoichiometric strong oxidants or strong acids, including Br₂,[4] I₂,[5] DDQ,[6] Cr(IV) salts,[7] or HNO₃ [8] (Scheme [1]A). In metal-based reactions, residues of toxic metals such as Cr,[7] Cu,[9] Mn,[10] Ni,[11] Fe–Ru,[12] or Co[13] may be present (Scheme [1]B). Many metal-based photocatalytic systems have also been developed for the oxidative coupling of thiols, such as CdSe quantum dots,[14] an Ir complex,[15] Pd@Cu/MoS₂ nanostructures,[16] or a diaryl telluride co-catalyst[17] (Scheme [1]C). Furthermore, most of these reactions involve organic solvents, posing a serious environmental problem. Therefore, the development of a transition-metal- and organic-solvent-free reaction is a meaningful objective.

Scheme 1 Approaches to the oxidative coupling of thiols

Bromo(trichloro)methane (BrCCl₃) has been widely used in organic reactions.[18] For example, it has been used to oxidize the α-carbon of amines[18b] [19] and ethers[20] to generate iminium and oxonium ions as active intermediates that undergo various subsequent cascade reactions. A BrCCl₃–DBU system has been used to dehydrate heterocycles to prepare heteroaromatic systems;[21] a modified version of this reaction uses a BrCCl₃–NaH system.[22] We recently developed a metal- and catalyst-free photo-oxidative coupling of thiols in the presence of BrCCl₃ (3 equiv) and tetrahydrofuran (THF) as reagent and solvent, respectively (Scheme [1]D).[23] We found BrCCl₃ is readily photolyzed to generate radicals that initiate the process. We therefore hypothesized that a catalytic amount of BrCCl₃ might promote the reaction. Here, we reported a transition-metal- and organic-solvent-free oxidative coupling of thiols catalyzed by BrCCl₃ and NaOH in the presence of oxygen as a terminal oxidant in an aqueous medium.

On the basis of a survey of the literature and our hypothesis, we decided to investigate appropriate conditions for the reaction (Table [1]). Under irradiation by a 23 W white-light compact fluorescent lamp (CFL), a catalytic amount of BrCCl₃ (10 mol%) in a basic aqueous medium (aq NaOH, 25 mol%) at 60 °C (Table [1], entry 2) promoted the coupling reaction of 4-bromobenzenethiol (1a) to give disulfide 2a with the best performance (83% yield). Decreasing (5 mol%) or increasing (25 mol%) the amounts of BrCCl₃ produced no improvement in the yield (57 and 78%, respectively) (entries 1 and 3). We then examined the effect of changing the amount of NaOH; 10 mol% of NaOH gave a yield of 60%, whereas more NaOH (50 mol%) induced a slight decrease in the yield to 80% (entries 4 and 5). Because the volume of solvent might influence the yield through a change in the concentrations of the reactants and catalyst, we tested 0.20 mL and 1.0 mL of water and obtained yields of 75 and 56%, respectively (entries 6 and 7). Next, we optimized the reaction temperature; decreasing the temperature to room temperature or 35 °C induced an obvious decrease in the yield to 36 and 40%, respectively (entries 8 and 9). Finally, blue and UV lights were also tested, but gave lower yields of 2a (63 and 38%, respectively) (entries 10 and 11).

Table 1 Optimization of the Reaction Conditions^a

Entry	BrCCl3 (mol%)	NaOH (mol%)	H2O (mL)	Temp (°C)	Light	Yieldb (%)
1	5	25	0.50	60	whitec	57
2	10	25	0.50	60	white	83
3	25	25	0.50	60	white	78
4	10	10	0.50	60	white	60
5	10	50	0.50	60	white	80
6	10	25	0.20	60	white	75
7	10	25	1.0	60	white	56
8	10	25	0.50	r.t.	white	36
9	10	25	0.50	35	white	40
10	10	25	0.50	60	blued	63
11	10	25	0.50	60	UVe	38

^a Reaction conditions: 4-bromobenzenethiol (1a; 0.4 mmol), BrCCl₃, NaOH, water, irradiation, 12 h, in air.

^b Isolated yield after column chromatography.

^c 23 W CFL.

^d 60 W blue light

^e 7 W UV light (214 nm).

With the optimized conditions in hand, we next investigated the substrate scope for the arenethiols 1a–p (Scheme [2]). Substrates 1b–f and 1n bearing electron-donating groups such as methyl, hydroxy, or methoxy gave the corresponding disulfides 2 in yields of 34 to 85%. Substrates 1g–m and 1o bearing electron-withdrawing groups such as chloro, bromo, carboxylic acid, or trifluoromethyl gave the corresponding disulfides 2 in yields from 42 to 87%. The ortho-substituents on substrates 1b, 1g, 1j, 1m, and 1n appeared to have a negative effect on the performance of the reaction, whereas the para-substituents on substrates 1d, 1f, 1i, and 1l appeared to promote a better performance. The system was also applied to heteroaromatic thiol 1p, and afforded the corresponding disulfide 2p in an excellent 91% yield.

Scheme 2 Substrate scope of the aryl thiol. Reaction conditions: aryl thiol 1 (0.4 mmol, 1 equiv), BrCCl₃ (0.04 mmol, 10 mol%), NaOH (0.10 mmol, 25 mol%), H₂O (0.50 mL), irradiation by a 23 W white light, 60 °C, 12 h, in air. The products were isolated by column chromatography.

Then, the reactions of the benzylic thiols 3a–q were studied (Scheme [3]). Substrates 3b–f bearing electron-donating groups such as methyl, methoxy, or tert-butyl gave the corresponding disulfides 4 in yields of 44 to 69%. Substrates 3g–q bearing electron-withdrawing groups such as fluoro, chloro, bromo, cyano, or trifluoromethyl gave the corresponding disulfides in yields of 40 to 80%. No obvious effect on the yield was observed as a result of ortho-, meta-, or para-substitutions by methyl, fluoro, chloro, or bromo groups on the aromatic ring (4b–d, 4g–i, 4j–l, and 4m–o). A bulky tert-butyl group did not show an obvious steric effect (4f). There was no obvious difference in the influence of electron-donating groups and that of electron-withdrawing groups.

Scheme 3 Substrate scope of benzylic thiols. Reaction conditions: benzylic thiol 3 (0.4 mmol, 1 equiv.), BrCCl₃ (0.04 mmol, 10 mol%), NaOH (0.10 mmol, 25 mol%), H₂O (0.50 mL), irradiation by a 23 W white light, 60 °C, 12 h, air. The products were isolated by column chromatography.

Finally, our system also could be applied to aliphatic thiols 5a–d (Scheme [4]). Coupling of linear octane-1-thiol (5a) gave disulfide 6a in an excellent 90% yield. The reaction tolerated the hydroxy group in 2-sulfanylethanol (5b). Cyclohexanethiol (5c) was oxidized to afford the disulfide 6c in 75% yield. The oxidative coupling of 2-phenylethanethiol (5d) gave disulfide 6d in 48% yield. In general, this reaction therefore has a broad substrate scope that includes aryl, benzyl, and aliphatic thiols.

Scheme 4 The substrate scope of aliphatic thiols. Reaction conditions: thiol 5 (0.4 mmol, 1 equiv), BrCCl₃ (0.04 mmol, 10 mol%), NaOH (0.10 mmol, 25 mol%), H₂O (0.50 mL), irradiation by a 23 W white light, 60 °C, 12 h, in air. The products were isolated by column chromatography.

Control experiments were carried out to verify the role of each item in the reaction conditions (Table [2]). Reactions without BrCCl₃ or NaOH showed an obvious decrease in yield (34 and 24%, respectively) (Table [2], entries 2 and 3). The yield also dropped markedly in the absence of light or air (oxygen) (entries 4 and 5). These control experiments showed that BrCCl₃, NaOH, a light source, and oxygen are all necessary for the reaction.

Table 2 Control Experiments^a

Entry	Conditions	Yieldb (%)
1	standard conditionsa	83
2	no BrCCl3	34
3	no NaOH	24
4	no light	40
5	N2 (no air)	38

^a Reaction conditions: 4-bromobenzenethiol (1a; 0.4 mmol, 1 equiv), BrCCl₃(0.04 mmol, 10 mol%), NaOH (0.10 mmol, 0.25 equiv), H₂O (0.50 mL), irradiation by a 23 W white light, 60 °C, 12 h, in air.

^b Isolated yield by column chromatography.

As a consequence, the reaction mechanism had to be confirmed. When TEMPO was added, the reaction was inhibited and the thiol radical was captured and could be identified by HRMS (see the Supporting Information, Figure S1). In accordance with the control experiments (Table [2]) and the validation experiments, we propose the possible mechanism shown in Scheme [5]. BrCCl₃ (A) is converted into a bromine radical B and a trichloromethane radical C by homolytic cleavage in presence of light irradiation. Both radicals B and C abstract protons from the thiol 1, 3, or 5 by hydrogen-atom transfer (HAT) to generate the radical D, which self-couples to afford the corresponding disulfide product 2, 4, or 6, together with HBr and chloroform as byproducts. These byproducts are oxidized by oxygen in the presence of NaOH to restore radicals B and C, with the formation of water and sodium peroxide E. The latter reacts with water to generate O₂ and NaOH. Overall, this catalytic cycle promotes the oxidative coupling reaction. Volatile substances, such as the HBr and chloroform intermediates and residual BrCCl₃, are easily removed from the system, which minimizes possible contamination of the products. Furthermore, a green medium (water) as the solvent and the use of oxygen as a green oxidant in the reaction system extend the green credentials of this transition-metal-free reaction.

Scheme 5 Proposed mechanism

In conclusion, we have developed an oxidative coupling reaction of thiols to prepare disulfides.[24] This reaction is catalyzed by a base and BrCCl₃ in an aqueous medium, and has a broad scope of substrates. The organic-solvent- and transition-metal-free system will help to relieve serious environmental and safety concerns in drug discovery. This method provides a useful supplement to the current methods for the construction of bioactive molecules and for tag-labeling of bioactive molecules with a disulfide bond.[25] Further studies on the applications of the reaction are now in progress in our laboratory.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors would like to thank Professor Yifeng Wang (USTC, China) for discussions on the mechanism. We also thank the analytical and testing center of SCME, Nanjing Tech University, for the NMR and HRMS measurements.

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• 24 Disulfides 2, 4, and 6; General ProcedureA round-bottomed flask was charged with the appropriate thiol 1, 3, or 5 (0.4 mmol), BrCCl₃ (0.04 mmol), NaOH (0.1 mmol), and H₂O (0.5 mL). The mixture was then irradiated by a 23 W CFL with stirring at 60 °C for 12–18 h. When the reaction was complete, volatiles were removed in vacuo to give the crude product, which was purified by chromatography (silica gel).Diphenyl Disulfide¹ (2a)White solid; yield: 24.5 mg (61%), R_f = 0.71 (PE). ¹H NMR (400 MHz, CDCl₃): δ = 7.50–7.46 (m, 4 H), 7.30–7.23 (m, 4 H), 7.23–7.16 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 137.09, 129.17, 127.54, 127.24.
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Publication History

Received: 14 January 2023

Accepted: 17 February 2023

Article published online:
31 March 2023