Oxydifluoromethylation of Alkenes by Photoredox Catalysis: Simple Synthesis of CF₂H‐Containing Alcohols

Abstract

We have developed a novel and simple protocol for the direct incorporation of a difluoromethyl (CF₂H) group into alkenes by visible‐light‐driven photoredox catalysis. The use of fac‐[Ir(ppy)₃] (ppy=2‐pyridylphenyl) photocatalyst and shelf‐stable Hu's reagent, N‐tosyl‐S‐difluoromethyl‐S‐phenylsulfoximine, as a CF₂H source is the key to success. The well‐designed photoredox system achieves synthesis of not only β‐CF₂H‐substituted alcohols but also ethers and an ester from alkenes through solvolytic processes. The present method allows a single‐step and regioselective formation of C(sp³)–CF₂H and C(sp³)−O bonds from C=C moiety in alkenes, such as hydroxydifluoromethylation, regardless of terminal or internal alkenes. Moreover, this methodology tolerates a variety of functional groups.

Organofluorine compounds continue to increase in importance in the fields of pharmaceuticals, agrochemicals and functional materials, because installation of fluorine atoms frequently influences the medicinal action as well as the chemical and physical properties.1 Thus, considerable research efforts have been made so far towards the development of new methodologies for the selective incorporation of fluorine atoms or fluoroalkyl groups. There have been great advances in catalytic methods for the fluorination and trifluoromethylation in the past few years.2, 3 In contrast, simple and widely applicable introduction of a difluoromethyl (CF₂H) group to various carbon skeletons is still underdeveloped,4 even though the CF₂H group is an intriguing structural motif, especially in medicinal chemistry.5, 6 In the past decade, multistep strategies for the preparation of CF₂H‐containing compounds, that is, incorporation of a difluoroalkyl unit (CF₂‐PG: PG=a protective group) into the carbon skeletons followed by deprotection, have been well‐developed. However, a direct difluoromethylation is still highly desirable.5, 7

Alkenes are fundamental carbon feedstock and functionality, but the direct difluoromethylation of alkenes has been limited.8 In 1994, Chen and co‐workers reported a radical iododifluoromethylation using CF₂HI, which is a gaseous and hard to prepare reagent (Scheme 1 a).8a More recently, Dolbier and co‐workers exploited CF₂HSO₂Cl as a difluoromethyl radical source and developed alkene difluoromethylation, for example, chloro‐, carbo‐ and aminodifluoromethylation (Scheme 1 b).8b–8e Furthermore, the groups of Tan and Hu developed a silver‐catalyzed intramolecular carbodifluoromethylation with difluoromethylsulfinate salts, (CF₂HSO₂)_nM, such as (CF₂HSO₂)₂Zn and CF₂HSO₂Na (Scheme 1 c).8f,8g

Scheme 1.

Direct difluoromethylation of alkenes for the construction of C(sp³)–CF₂H bond.

For the past several years, our group has been extensively developing a photoredox‐catalyzed trifluoromethylative difunctionalization9, 10 of alkenes and alkynes using electrophilic trifluoromethylating reagents, such as Umemoto's11 and Togni's reagent.12 We envisaged that the appropriate choice of a difluoromethylating reagent could open an unprecedented photoredox‐catalyzed difluoromethylation of alkenes. Herein, we describe the first example of a photocatalytic oxydifluoromethylation of alkenes with shelf‐stable and easy‐to‐handle N‐tosyl‐S‐difluoromethyl‐S‐phenylsulfoximine (1 a), so‐called Hu's reagent, which has been previously reported to be a useful difluorocarbene source by Hu and co‐workers (Scheme 1 d).13, 14 This protocol allows us simple and versatile access to a wide range of CF₂H alcohols through regioselective installation of the CF₂H group and an oxygen nucleophile onto alkenes.

We initially explored CF₂H reagent 1 for the photocatalytic hydroxydifluoromethylation of 4‐methylstyrene (2 a) at room temperature under visible‐light irradiation with blue LEDs (λ _max=425 nm; Table 1). Taking account of the reaction conditions of the photocatalytic hydroxytrifluoromethylation reported by us,10a we conducted the reaction in a mixed solvent system of [D₆]acetone and D₂O (9:1) in the presence of fac‐[Ir(ppy)₃] (ppy=2‐pyridylphenyl) (5 mol %), which serves as a strong reducing agent when photoexcited (E _1/2=−2.14 V versus. [Cp₂Fe]).15 Under these reaction conditions, sulfone‐based commercially available CF₂H reagents, CF₂HSO₂Ph (1 b) and CF₂HSO₂Py (1 c; Py=2‐pyridyl), were tested (entries 1 and 2). Reagent 1 b was scarcely converted. In contrast, 1 c gave the corresponding CF₂H alcohol 3 a in 29 % NMR yield together with a mixture of unidentified products. Encouraged by these results, we continued to examine the analogous CF₂H reagent (sulfoximine‐based CF₂H reagent 1 a).16 To our delight, hydroxydifluoromethylation proceeded in a regioselective manner to afford 3,3‐difluoro‐1‐tolylpropanol (3 a) as a sole regioisomer in 88 % NMR yield (entry 3). Next, the examination of typical photocatalysts revealed that fac‐[Ir(ppy)₃] was the best catalyst (entries 3–5).15 Finally, the present photocatalytic reaction did not proceed at all either in the dark or in the absence of photocatalyst (entries 6 and 7), indicating that photoactivated species is involved in the present transformation.

Table 1.

Optimization of the photocatalytic hydroxydifluoromethylation of 4‐methylstyrene (2 a).^[a]

Entry	Photocatalyst	CF2H reagent 1	Yield of 3 a [%][b]
1	fac‐[Ir(ppy)3]	1 b	0
2	fac‐[Ir(ppy)3]	1 c	29
3	fac‐[Ir(ppy)3]	1 a	88
4	[Ru(bpy)3][PF6]2	1 a	0
5	[Ir(ppy)2(dtbbpy)][PF6]	1 a	0
6[c]	fac‐[Ir(ppy)3]	1 a	0
7	none	1 a	0

[a] For detailed reaction conditions, see the Supporting Information. [b] Yields were determined by ¹H NMR spectroscopy using Si(Et)₄ as an internal standard. [c] In the dark. LED=light‐emitting diode.

The scope of the present photocatalytic hydroxydifluoromethylation of alkenes is summarized in Table 2. Styrenes with various functional groups on the benzene ring, such as alkyls (2 a, b), halogens (2 d–f), Boc‐protected amino (2 g), boronic acid ester (2 h), and cyanomethyl (2 i) groups, smoothly produced the corresponding CF₂H‐containing alcohols (3 a–i) in good yields (50–84 %, 2–24 h). In contrast, the reaction of styrene with an electron‐donating group on the benzene ring, 4‐methoxystyrene (2 j), required longer time, but the corresponding product 3 j was obtained in good yield (88 %, 72 h). In addition, α‐methylstyrene (2 k) and the aliphatic alkene, 1,1‐dicyclohexylethene (2 l), were also successfully applied to the present photocatalytic reaction, leading to the corresponding CF₂H alcohols (3 k, l) in 87 and 32 % yields, respectively.

Table 2.

Scope of the photocatalytic hydroxydifluoromethylation.^[a]

3 a: 67 %[b,c]	3 b: 65 %	3 c: 72 %[b,d]
3 d: 83 %[b,d]	3 e: 50 %	3 f: 73 %[e]
3 g: 84 %	3 h: 56 %	3 i: 64 %
3 j: 88 %[f]	3 k: 87 %[e,g]	3 l: 32 %[g]
3 m: 43 %, 1:1.2 d.r.[d,g]	3 n: 53 %, 1:3.3 d.r.[g]	3 o: 64 %, 1:1.6 d.r.
3 p: 67 %, 1:1.3 d.r.	3 q: 63 %, 1:3.3 d.r.[d,e,g]	3 r: 43 %, 1:1.1 d.r.[d,e,g]

[a] For detailed reaction conditions, see the Supporting Information; diastereomer ratios (d.r.) were determined by ¹H NMR spectra of crude reaction mixtures; yields were obtained after purification. [b] Ir photocatalyst (0.5 mol %) was used. [c] Reaction time=2 h. [d] The ratio of 2 and 1 a was 1.5:1; yields were calculated on the basis of starting 1 a. [e] Ir photocatalyst (5 mol %) was used. [f] Reaction time=72 h. [g] Reaction time=36 h.

Furthermore, the present photocatalytic system enables the difluoromethylation of internal alkenes, including a trisubstituted alkene. Reactions of β‐methylstyrene (2 m), trans‐stilbene (2 n), indene (2 o), trans‐cinnamyl alcohol (2 p), trans‐cinnamic acid methyl ester (2 q), and α,β‐dimethylstyrene (2 r; E/Z=1:5.6) afforded the corresponding difluoromethylated products (3 m–r) in 43–67 % yields as sole regioisomers but mixtures of diastereomers. It should be noted that the present photocatalytic system with Hu's reagent 1 a is compatible for a wide variety of functionalities, such as hydroxyl, N‐protected amino, halogens, nitrile, ester, and boronic acid ester groups. Moreover a regiospecific addition of the CF₂H and OH groups, regardless of terminal or internal alkenes, is particularly significant. These results prompted us to investigate reactions of more structurally complex substrates. It was found that the present reaction system was amenable to the hydroxydifluoromethylation of vinylestrone (2 s) and vinyl‐N‐benzoyl‐l‐tyrosine ethyl ester (2 t), leading to the corresponding difluoromethylated alcohols (3 s: 61 %; 3 t: 73 %; Scheme 2). These results suggest that the present protocol would be valuable for the late‐stage difluoromethylation in a synthetic process.

Scheme 2.

Direct difluoromethylation of alkenes with estrone and amino acid skeleton.

Next, we examined other oxygen nucleophiles, ROH (4), such as alcohols and carboxylic acids, for the reaction of 4‐methylstyrene (2 a; Scheme 3). All reactions were conducted in dry CH₂Cl₂/ROH (9:1). It turned out that the alkoxydifluoromethylation and carboxydifluoromethylation smoothly proceeded regioselectively not only to introduce a CF₂H group but also to construct ether and ester functionalities onto the C=C bond. Reactions with MeOH (4 a) and tBuOH (4 b) gave the corresponding CF₂H ethers 5 a and 5 b in 69 and 54 % yields, respectively. Carboxylic acid substrate 4 c produced CF₂H‐containing ester 5 c in 54 % yield.

Scheme 3.

Oxydifluoromethylation of 4‐methylstyrene (2 a): simple synthesis of CF₂H ester and CF₂H ethers.

To gain insight into the reaction mechanism, the reaction of 1‐phenyl‐2‐(1‐phenylethenyl)cyclopropane (2 u) was examined (Scheme 4). As a result, the difluoromethylated alcohol 3 u was obtained in 83 % yield (E/Z=1:2.3) through a ring‐opening process of the cyclopropane unit. In addition, when photocatalytic hydroxydifluoromethylation of 2 a was conducted in the presence of 2,2,6,6‐tetramethylpiperidine N‐oxide (TEMPO), which is a radical scavenger, the hydroxydifluoromethylation was completely inhibited (See the Supporting Information for details). These results suggest that radical intermediates are involved in the present photocatalytic reaction.

Scheme 4.

Photocatalytic hydroxydifluoromethylation of 1‐phenyl‐2‐(1‐phenylethenyl)cyclopropane (2 u).

On the basis of these observations and our previous reports,10 a plausible reaction mechanism is shown in Scheme 5. First, the photocatalyst Ir ^III is excited by visible light to give the excited species *Ir ^III. The formed excited species *Ir ^III serves as a strong one‐electron reductant to undergo single‐electron transfer (SET) to Hu's reagent 1 a, leading to generation of the highly oxidized species Ir ^IV. Reduced 1 a fragmentizes into the CF₂H radical and sulfinamide 6. The generated CF₂H radical reacts with alkene 2 in a regioselective manner to afford the stabilized radical intermediate 7, which is then oxidized by the strongly oxidizing species Ir ^IV to generate α‐CF₂H carbocationic intermediate 8 together with regeneration of the photocatalyst Ir ^III of the ground state. Finally, the carbocationic intermediate 8 undergoes solvolysis by ROH to produce oxydifluoromethylated products 3 or 5.

Scheme 5.

A plausible reaction mechanism.

In conclusion, we have developed a novel photoredox‐catalyzed oxydifluoromethylation of alkenes. The present work is the first report to use Hu's reagent, N‐tosyl‐S‐difluoromethyl‐S‐phenylsulfoximine (1 a), as a CF₂H radical precursor. Visible‐light‐driven photoredox catalysis by the Ir photocatalyst, fac‐[Ir(ppy)₃], has opened a new possibility of radical difluoromethylation by the difluorocarbene source 1 a. The designed redox‐neutral reaction system enables step‐economical synthesis of β‐CF₂H‐substituted alcohols, ethers, and esters under mild reaction conditions. Remarkably, the present photocatalytic difluoromethylation system exhibits excellent functional group compatibility. A development of new synthetic methods for organofluorine compounds through a photoredox‐catalyzed fluoroalkylation is currently underway in our laboratory.

Supporting information

As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.

Supplementary

Y. Arai, R. Tomita, G. Ando, T. Koike, M. Akita, Chem. Eur. J. 2016, 22, 1262.