Photoinduced 1,2-Hydro(cyanomethylation) of Alkenes with a Cyanomethylphosphonium Ylide

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

An efficient method has been developed for the 1,2-hydro(cyanomethylation) of alkenes, in which a cyanomethyl radical species is generated from a cyanomethylphosphonium ylide by irradiation with visible light in the presence of an iridium complex, a thiol, and ascorbic acid. The cyanomethyl radical species then adds across the C=C double bond of an alkene to form an elongated alkyl radical species that accepts a hydrogen atom from the thiol to produce an elongated aliphatic nitrile. The ascorbic acid acts as the reductant to complete the catalytic cycle.

 

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Key words

alkenes - nitriles - photocatalysis - radicals - phosphonium ylides - hydro(cyanomethylation)

Radical chemistry has undergone a renaissance since the introduction of photoredox catalysis,[1] and a wide variety of reagents are now available as competent precursors to radical species. We recently reported that an ester-stabilized phosphonium ylide[2] can act as a precursor to an (alkoxycarbonyl)methyl radical species[3] when irradiated with visible light in the presence of an iridium catalyst, a thiol, and ascorbic acid.[4] The radical species, substituted by an electron-withdrawing alkoxycarbonyl group, adds across the C=C double bond of an alkene to generate an elongated alkyl radical. Subsequently, the thiol delivers a hydrogen atom to the radical,[5] producing an elongated aliphatic ester.[6]

We also examined the use of a cyanomethylphosphonium ylide instead of an ester-stabilized phosphonium ylide. The former act as the precursor of a cyanomethyl radical species[7] [8] [9] [10] that, due to the electron-withdrawing nature of the cyano group, is sufficiently electrophilic to attach to a C=C double bond of an alkene, as in the case of an (alkoxycarbonyl)methyl radical.[3,4,6] The appended alkyl radical species is not as electrophilic as the original cyanomethyl radical, and can therefore abstract a hydrogen atom from a sulfanyl group[5] to form an elongated aliphatic nitrile.

Initially, we applied the conditions optimized for the reaction of an ester-stabilized phosphonium ylide[4] to the reaction of the cyanomethylphosphonium ylide 2 with 4-phenylbut-1-ene (1a), and we obtained 6-phenylhexanenitrile (3a) as expected. The yield, however, was moderate (43% by NMR), which led us to adapt the reaction conditions slightly to fit the ylide 2. The elongated nitrile 3a was produced in 94% NMR yield and 80% isolated yield when 1a (0.50 mmol) was treated with 2 (1.0 mmol, 2.0 equiv) in 1:1 CH₃CN/H₂O (0.1 M) under irradiation by blue light-emitting diodes (LEDs; 470 nm, 23 W) in the presence of fac-Ir(ppy)₃ (1.0 mol%; ppy = 2-phenylpyridinato), C₆F₅SH (20 mol%), ascorbic acid (10 equiv), and KHSO₄ (3.0 equiv) at room temperature for 40 hours (Scheme [1]). No product resulting from 1,2-addition in the opposite direction was observable within the detection limits of ¹H NMR (400 MHz). A larger-scale experiment using 925 mg (7.0 mmol) of 1a also gave a comparable yield of 3a (83% isolated yield), indicating the scalability of the present reaction.

Scheme 1 1,2-Hydro(cyanomethylation) of alkene 1a with phosphonium ylide 2

The formation of the product 3a can be reasonably explained by assuming the radical mechanism depicted in Scheme [2], which is similar to that proposed in the case of ester-stabilized phosphonium ylides.[4] First, an acid/base ­reaction of 2 (pK _aH = 6.9)[11] with ascorbic acid (AscH₂; pK _a= 4.0)[12] generates the phosphonium ascorbate [Ph₃PCH₂CN]⁺[AscH]^– (4). This has an energetically low-lying σ* orbital for the C–P linkage. The Ir catalyst [fac-Ir(ppy)₃] [Ir(III)] is photoexcited by visible light to form the excited species [Ir(III)]*. This then transfers a single electron to the σ* orbital of the phosphonium ascorbate 4, giving rise to the cyanomethyl radical species 5, along with PPh₃ and [Ir(IV)]⁺[AscH]^–. Electrophilic addition of 5 to the C=C double bond of alkene 1a affords the elongated secondary alkyl radical species 6, which is less electrophilic than 5. Hydrogen-atom transfer from C₆F₅SH to 6 produces 3a and a thiyl radical (C₆F₅S^•).[5] The [Ir(IV)]⁺ species and C₆F₅S^• are reduced back to the [Ir(III)] species and C₆F₅SH, respectively, by the action of the ascorbate anion [AscH]^–,[13] [14] which ultimately becomes dehydroascorbic acid (DHA).[15] The additive KHSO₄ might act by suppressing undesirable formation of a thiolate anion (C₆F₅S^–) from C₆F₅SH.

Scheme 2 Plausible mechanism for the formation of 3a from alkene 1a and phosphonium ylide 2

Various alkenes 1 were subjected to the 1,2-hydro(cyanomethylation) reaction with 2 (Table [1]). A wide range of functional groups were tolerated to afford the corresponding elongated aliphatic nitriles 3b–g in yields ranging from 74 to 88% (Table [1], entries 1–6). Not only monosubstituted alkenes, but also polysubstituted alkenes, participated in the reaction. Geminally disubstituted alkenes 1h and 1i were suitable substrates (entries 7 and 8). Cyclic disubstituted alkenes 1j and 1k afforded the corresponding products 3j and 3k in yields of 59 and 79%, respectively (entries 9 and 10). The reaction of the acyclic vicinally disubstituted alkenes (Z)- and (E)-1l was sluggish, and the reason for the low yield of product 3l is unclear (entries 11 and 12). In the case of trisubstituted alkene 1m, a mixture of diastereomers of 3m was formed through nonstereoselective transfer of a hydrogen atom to an intermediate tertiary radical species (entry 13). Even the tetrasubstituted alkene 1n underwent the reaction (entry 14). The 1,2-adduct 3o was obtained in 18% NMR yield from styrene (1o), and the final reaction mixture contained various products, probably as a result of the high reactivity of the benzylic radical intermediates (entry 15).[16]

Table 1 1,2-Hydro(cyanomethylation) of Various Alkenes 1 with Phosphorus Ylide 2 ^a

Entry	Alkene 1	Product 3	Yieldb (%)
1			76
2			82
3			74
4			88
5			77
6			88
7			73
8			77
9			59
10			79
11			28
12			29c
13			45
14			56c
15			18c

^a Reaction conditions: 1 (0.50 mmol), 2 (1.0 mmol), fac-Ir(ppy)₃ (1.0 mol%), C₆F₅SH (20 mol%), ascorbic acid (5.0 mmol), KHSO₄ (1.5 mmol), 1:1 CH₃CN/H₂O (5.0 mL), r.t., 40 h, blue LEDs (470 nm, 23 W).

^b Isolated yield.

^c NMR yield with 1,1,2,2-tetrachloroethane as internal standard.

In the case of 1-benzofuran (7), the cyanomethyl radical species added regioselectively to form a benzylic radical species, giving the 2-substituted 2,3-dihydro-1-benzofuran 8 (Scheme [3]).

Scheme 3 The addition reaction to 1-benzofuran (7)

Notably, even a branched α-cyanoethyl group was attached to the C=C double bond of 1a when α-cyanoethyl­phophorus ylide 9 was employed (Scheme 4).

Scheme 4 The reaction with the α-cyanoethylphosphonium ylide 9

A similar reaction to form elongated aliphatic nitriles from alkenes has been reported,[8] in which a cyanomethyl radical species is generated from CH₃CN by using an excess of dicumyl peroxide at a high temperature; these potentially hazardous conditions significantly limit the synthetic value of the method. The present reaction uses cyanomethylphosphonium ylide, which is stable and easily accessible, as the radical source, thereby providing a convenient method for synthesizing elongated aliphatic nitriles from alkenes.[17]

 

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Acknowledgment

We thank Mr. H. Nikishima (Kyoto University) for his experimental contribution at a preliminary stage.

• References and Notes


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• 16 The reactions of terminal alkynes such as 4-phenylbut-1-yne gave complex mixtures of products, in which the corresponding 1,2-hydro(cyanomethylation) product (a β,γ-unsaturated nitrile) was present in ~10% yield as a 1:1 mixture of E- and Z-isomers.
• 17 6-Phenylhexanenitrile (3a); Typical Procedure A vial (2–5 mL; Biotage, Fisher Scientific) equipped with a stirrer bar was charged with the phosphorus ylide 2 (302 mg, 1.00 mmol), fac-Ir(ppy)₃ (3.30 mg, 0.005 mmol, 1.0 mol%), ascorbic acid (882 mg, 5.00 mmol), and KHSO₄ (207 mg, 1.52 mmol). The vial was then flushed with argon gas and quickly capped with a Teflon septum. 4-Phenylbut-1-ene (1a, 67.6 mg, 0.51 mmol), C₆F₅SH (20.0 mg, 0.100 mmol, 20 mol%), distilled CH₃CN (2.5 mL), and H₂O (2.5 mL; degassed with argon gas for 30 min) were added from a syringe, and the mixture was stirred vigorously for 40 h under blue LED lights (470 nm, 23 W) while the vial was cooled with a fan. The mixture was then diluted with brine (25 mL) and extracted with CH₂Cl₂ (3 × 25 mL). The organic phase was dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography [silica gel, hexane/EtOAc (9:1)] to give a colorless oil; yield: 70.7 mg (0.41 mmol, 80%). IR (ATR): 2936, 2245, 1454 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.45–1.53 (m, 2 H), 1.63–1.73 (m, 4 H), 2.33 (t, J = 7.2 Hz, 2 H), 2.63 (t, J = 7.6 Hz, 2 H), 7.16–7.21 (m, 3 H), 7.26–7.31 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 17.1, 25.3, 28.3, 30.5, 35.5, 119.7, 125.8, 128.3, 141.9. HRMS (EI⁺): m/z [M]⁺ calcd for C₁₂H₁₅N: 173.1204; found: 173.1205.