Alkyl- and aryl-thioalkylation of olefins with organotrifluoroborates by photoredox catalysis

Abstract

A facile and environmentally benign protocol for alkyl- and aryl-thioalkylation of olefins has been developed. Photoredox catalysis with an Ir photocatalyst, [Ir(dF(CF₃)ppy)₂(bpy)](PF₆) (dF(CF₃)ppy: 5-trifluoromethyl-2-(2,4-difluorophenyl)pyridine, bpy: 2,2′-bipyridine), induces efficient oxidation of a variety of alkyl- and aryl-thioalkyltrifluoroborates under visible light irradiation at room temperature, leading to the generation of α-thioalkyl radicals via deboronation. The generated α-thioalkyl radicals smoothly react with electron-deficient olefins to afford addition products in good yields. The present photocatalytic method provides us with simple and new access to a range of alkylsulphides under mild reaction conditions.

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Introduction

Recently, visible-light-induced single electron transfer (SET) processes mediated by well-defined ruthenium(II) polypyridine complexes and the relevant cyclometalated iridium(III) derivatives have been recognized as a useful redox protocol from the viewpoint of radical chemistry and green chemistry.¹ In particular, use of oxidatively generated α-aminoalkyl radicals from various nitrogen-containing compounds by photoredox catalysis has become a powerful method for the synthesis of useful nitrogen-containing building blocks.^2,9d The nucleophilic α-aminoalkyl radicals can react with electron-deficient moieties such as unsaturated bonds and arenes to enable functionalization of a carbon atom adjacent to the nitrogen atom. Further expansion into functionalization of ether derivatives advances steadily.^3,9b In contrast, reaction of α-sulfur atom substituted alkyl radicals, i.e. α-thioalkyl radicals,⁴ by photoredox catalysis has not been reported yet, though it can become a new strategy for the synthesis of organic sulphides. In addition, sulphides are known as important functional groups in the field of medicinal chemistry and materials chemistry.⁵

Herein we describe the first example of photoredox-catalyzed thioalkylation of olefins through generation of α-thioalkyl radicals via oxidation of alkyl- and aryl-thioalkyltrifluoroborates (Scheme 1(a)). So far, a few examples of synthesis of sulphides by photoredox catalysis have been reported.⁶ In 1978 and 1979, Kellog et al. presented pioneering studies about reductive formation of sulphides from reaction of organosulfonium salts with Hantzsch ester in the presence of [Ru(bpy)₃]Cl₂ (bpy = 2,2′-bipyridine).^6a,b In 2012, Zheng and co-workers showed coupling reaction of N-methylindoles and arylsulfonyl chlorides via reduction of sulfonyl chlorides (Scheme 1(b)).^6c In 2013, Wang, Cuny and Noël described a one-pot Stadler–Ziegler type reaction by photoredox catalysis in a continuous microflow system (Scheme 1(c)).^6d Furthermore, radical thiol–ene reactions involved in [Ru(bpz)₃]²⁺ (bpz = 2,2′-bipyrazine) and [Ru(bpy)₃]²⁺ were reported by the groups of Yoon and Stephenson, respectively (Scheme 1(d)).^6e,f,g Their proposed reactive intermediates are different from α-thioalkyl radicals.

Scheme 1 Synthesis of sulphides by photoredox catalysis.

Organoborates are widely used in synthetic chemistry because of their easy-to-handle properties and compatibility with a variety of functional groups including sulphides.⁷ In addition, generation of organic radicals by oxidation of organoborates has been well-documented so far.⁸ Recently, our group and the groups of Chen and Molander reported on photocatalytic reactions using organoborates.^9,10 In particular, we have extensively developed redox-neutral α-heteroatom methylation such as radical aminomethylation^9d and radical alkoxymethylation^9b of olefins using the corresponding organotrifluoroborates by photoredox catalysis. Although radical thioalkylation is the subject of the present article, the reaction of potassium 1,3-dithian-2-yltrifluoroborate (1a) can be regarded as a synthetic equivalent of formylation (Scheme 1(a)). Because 1,3-dithianes represent protected acyl groups for useful transformations,¹¹ nucleophilic 1,3-dithian-2-yl radicals can be utilized as acyl anion equivalents. Thus, radical dithianylation can be connected to nucleophilic acylation.^4d,f,g

Results and discussion

We initially examined the visible-light reaction of potassium 1,3-dithian-2-yltrifluoroborate (1a) with 1 equivalent of acrylonitrile (2a) in the mixed solvent system, acetone-d₆ and CD₃OD (1/1), in the presence of Ir photocatalyst 4, [Ir(dF(CF₃)ppy)₂(bpy)](PF₆) (dF(CF₃)ppy: 5-(trifluoromethyl)-2-(2,4-difluorophenyl)pyridine), which can serve as a strong oxidant (E_1/2 = +0.91 V vs. Cp₂Fe) when photochemically excited.¹²

As a result, hydrodithianylated product 3aa was obtained in a 56% NMR yield together with the formation of 2-deuterated-1,3-dithiacyclohexane 1a′ (33%) and 1,3-dithianyl dimer 1a″ (10%) (entry 1 in Table 1). The formation of these by-products suggests that the 1,3-dithian-2-yl radical is involved in the present photocatalytic reaction. Next, the use of 2 equivalents of acrylonitrile (2a) dramatically increased the yield of 3aa (90% NMR yield) and suppressed the side reactions (entry 2). Other photocatalysts, [Ir(dF(CF₃)ppy)₂(dtbbpy)](PF₆) (5) (dtbbpy: 4,4′-di-tert-butyl-2,2′-bipyridine) and [Ru(bpy)₃](PF₆)₂ (6),¹³ resulted in lower yields (entries 3 and 4). CD₃OD and the mixed solvent system, acetone-d₆ and CD₃OD, turned out to be appropriate solvent systems (entries 5–8). Furthermore, the present reaction required both visible-light irradiation and the photocatalyst (entries 9 and 10).

Table 1 Optimization of the photocatalytic radical reaction of 1a with 2a^a

Entry	1a : 2a	Photocat.	Solvent	NMR yield of /%
				3aa	1a′	1a″
a Reaction conditions: a reaction mixture of 1a (0.05 mmol), 2a (0.05 mmol or 0.10 mmol), photocatalyst (1.0 μmol), SiEt4 (an internal standard) and solvent (0.40 mL) was irradiated by using 3 W blue LEDs (λ = 425 ± 15 nm) at room temperature for 24 h. b The reaction was conducted in the dark.
1	1 : 1	4	Acetone-d6–CD3OD (1/1)	56	33	10
2	1 : 2	4	Acetone-d6–CD3OD (1/1)	90	6	3
3	1 : 2	5	Acetone-d6–CD3OD (1/1)	73	17	2
4	1 : 2	6	Acetone-d6–CD3OD (1/1)	79	15	1
5	1 : 2	4	CD3OD	93	5	1
6	1 : 2	4	Acetone-d6	10	12	1
7	1 : 2	4	CD3CN	17	11	0
8	1 : 2	4	DMSO-d6	10	10	5
9^b	1 : 2	4	CD3OD	0	0	0
10	1 : 2	None	CD3OD	0	0	0

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With the optimal reaction conditions in hand, the preparative scale hydrodithianylation of olefins was performed (Table 2). The reactions of typical electron-deficient alkenes, acrylonitrile (2a), 3-buten-2-one (2b) and methyl acrylate (2c), proceeded smoothly to give the corresponding products (3aa–3ac) in good yields (71–80%) (entries 1–3). 1,1-Disubstituted olefins such as methacrylonitrile (2d), α-methylene-γ-butyrolactone (2e) and methyl 2-(trifluoromethyl)acrylate (2f) could also be applied to the present reaction (3ad–3af: 64–80% yields) (entries 4–6). However, olefins with a substituent at the reaction site, 2-cyclopenten-1-one (2g) and diethyl ethylidenemalonate (2h), resulted in low conversions of the olefins and significant formation of deborohydrogenated by-product 1a′ (entries 7 and 8). In contrast, the reaction of fumaronitrile (2i) afforded the hydrodithianylated product (3ai) in an 86% yield (entry 9). These results suggest that the present photocatalytic dithianylation is effective for terminal olefins bearing electron-withdrawing groups and highly electron-deficient internal olefins.

Table 2 The scope of the present photocatalytic hydrodithianylation^a

Entry	Olefin 2	Product 3	Isolated yield/%
a Reaction conditions: a reaction mixture of 1a (0.25 mmol), olefin 2 (0.50 mmol), Ir photocatalyst 4 (5.0 μmol), and degassed MeOH (2.0 mL) was irradiated by using 3 W blue LEDs (λ = 425 ± 15 nm) at room temperature for 24 h.
1			80
2			78
3			71
4			64
5			78
6			80
7			—
8			—
9			86

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Next, the scope of aryl- and alkyl-thiomethyltrifluoroborates was examined (Scheme 2). The reactions of potassium phenylthiomethyltrifluoroborate (1b), potassium 4-methoxyphenylthiomethyltrifluoroborate (1c), and potassium 4-trifluoromethylphenylthiomethyltrifluoroborate (1d) with acrylonitrile (2a) afforded the corresponding arylthiomethylated products (3ba–da) in moderate yields (15–43%) due to the formation of a considerable amount of arylthiomethanes 1′ as a by-product. Notably, the electron-withdrawing CF₃ group hinders the formation of the byproduct. These results suggest that the electron-withdrawing group stabilizes the generated arylthiomethyl radical under these reaction conditions. In contrast, potassium phenethylthiomethyltrifluroborate (1e) gave the alkylthiomethylated product 3ea in an excellent yield (84% yield). In addition, the reaction of 1e did not require an excess amount of olefin.

Scheme 2 Examination of substituents on the sulphur atom in thiomethyltrifluoroborates.

In the light of high reactivity and selectivity of potassium phenethylthiomethyltrifluoroborate (1e), the scope of olefins was investigated (Table 3). Electron-deficient olefins (2b–e, 2i) were also applicable to the present reaction. It should be noted that the reaction with 1e enabled alkylthiomethylation of olefins with a substituent at the reaction site, 2-cyclopenten-1-one (2g) and diethyl ethylidenemalonate (2h), which could not be applied to the reaction with 1avide supra. The alkylthiomethylated products were obtained in 41% (3eg) and 62% yields (3eh) with the use of an excess amount of borate and 5 mol% of Ir catalyst 4. These results suggest that the phenethylthiomethyl radical serves as a species more nucleophilic than the 1,3-dithian-2-yl radical and arylthiomethyl radicals presumably due to steric and electronic reasons.

Table 3 The scope of the present photocatalytic phenethylthiomethylation^a,b

a Reaction conditions: a reaction mixture of 1a (0.25 mmol), olefin 2 (0.25 mmol), Ir photocatalyst 4 (5.0 μmol), degassed acetone (1.0 mL) and MeOH (1.0 mL) was irradiated by using 3 W blue LEDs (λ = 425 ± 15 nm) at room temperature for 24 h. b Isolated yields. c 1e:2 = 2 : 1, 5 mol% of Ir catalyst 4 was used.

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Utilization of sunlight as a light source for photoreaction is promising in terms of green and sustainable chemistry. Thus, sunlight-driven photocatalytic alkylthiomethylation of 2a with 1e was performed. As a result, the reaction proceeded more efficiently (8 h) than the reaction irradiated by using blue LEDs (eqn (1)).

To gain an insight into the reaction mechanism, electrochemical analysis of organoborates and luminescence quenching experiments were carried out (see the ESI†). Oxidation potentials for all the above-mentioned α-thioalkylborates (1a–1e) were less than +0.72 V vs. Cp₂Fe, indicating that they can be easily oxidized by the photoactivated Ir photocatalyst 4 (E_1/2 = +0.91 V vs. Cp₂Fe). In addition, potassium phenethylthiomethyltrifluoroborate (1e) strongly quenched luminescence from the triplet excited state of 4, supporting that the first SET event occurs between the excited Ir species and 1.

A plausible reaction mechanism is illustrated in Scheme 3. Visible light irradiation induces the excitation of the Ir photocatalyst (Ir^III) into the photoactivated state (*Ir^III), which serves as a strong oxidant. One-electron oxidation of alkyl- or aryl-thioalkylborate 1 by *Ir^III generates an α-thioalkyl radical via deboronation accompanying the formation of the highly reduced Ir species, Ir^II. Subsequent addition of the α-thioalkyl radical to electron-deficient olefins 2 affords the radical intermediate 3′, which undergoes a second SET event from Ir^II to be converted into carboanionic intermediate 3⁻. Finally, protonation by the solvent produces alkyl- or aryl-thioalkylated product 3. A control experiment in CD₃OH revealed that the H atom in the product 3 does not result from hydrogen abstraction from the CD₃ group but from protonation with the OH group (see the ESI†). At present, we cannot rule out the radical propagation mechanism at all. But the present reaction required continuous irradiation of visible light to proceed steadily (see the ESI†). Therefore, the radical propagation process is not the major reaction pathway, if any.

Scheme 3 A plausible reaction mechanism.

Conclusions

We have developed alkyl- and aryl-thioalkylation of olefins using the corresponding organotrifluoroborates by visible-light-induced photoredox catalysis. The present photocatalytic protocol enables facile generation of α-thioalkyl radicals and access to a new range of alkylsulphides without any additives under mild reaction conditions: room temperature and visible light irradiation including natural sunlight. Now our effort is directed to the synthesis of new useful compounds through photoredox processes.

Acknowledgements

The financial support from the Japanese government (Grants-in-Aid for Scientific Research: no. 26288045) is gratefully acknowledged. Y.L. also gratefully acknowledges financial support from the Japanese Government (Monbukagakusho: MEXT) Scholarship (no. 121540).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and spectral data. See DOI: 10.1039/c4qo00352g

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