CC BY ND NC 4.0 · Synlett 2019; 30(04): 511-514
DOI: 10.1055/s-0037-1612230
letter
Copyright with the author

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

,
Daisuke Moriyama
,
Yuuta Funakoshi
,
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan   Email: tmiura@sbchem.kyoto-u.ac.jp   Email: murakami@sbchem.kyoto-u.ac.jp
› Author Affiliations
This work was supported by JSPS KAKENHI [Scientific Research (S) (15H05756) and (C) (16K05694)]
Further Information

Publication History

Received: 22 December 2018

Accepted after revision:23.01.2019

Publication Date:
13 February 2019 (eFirst)

 

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.


#

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.

Zoom Image
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.

Zoom Image
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 3bg 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]).

Zoom Image
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).

Zoom Image
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]


#

Acknowledgment

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

Supporting Information

  • References and Notes


    • For reviews, see:
    • 1a Narayanam JM. R, Stephenson CR. J. Chem. Soc. Rev. 2011; 40: 102
    • 1b Skubi KL, Blum TR, Yoon TP. Chem. Rev. 2016; 116: 10035
    • 1c Romero NA, Nicewicz DA. Chem. Rev. 2016; 116: 10075
    • 1d Twilton J, Le C, Zhang P, Shaw MH, Evans RW, MacMillan DW. C. Nat. Rev. Chem. 2017; 1: 0052
    • 1e Lee KN, Ngai M.-Y. Chem. Commun. 2017; 53: 13093
    • 1f Marzo L, Pagire SK, Reiser O, König B. Angew. Chem. Int. Ed. 2018; 57: 10034

      For photoinduced reactions using phosphonium salts as the radical source, see:
    • 2a Lin Q.-Y, Xu X.-H, Zhang K, Qing F.-L. Angew. Chem. Int. Ed. 2016; 55: 1479
    • 2b Panferova LI, Tsymbal AV, Levin VV, Struchkova MI, Dilman AD. Org. Lett. 2016; 18: 996

      For 1,2-bromo[(ethoxycarbonyl)methylation] of alkenes with BrCH(R)CO2Et as the radical source, see:
    • 3a Nguyen JD, Tucker JW, Konieczynska MD, Stephenson CR. J. J. Am. Chem. Soc. 2011; 133: 4160
    • 3b Arceo E, Montroni E, Melchiorre P. Angew. Chem. Int. Ed. 2014; 53: 12064
    • 3c Cheng J, Cheng Y, Xie J, Zhu C. Org. Lett. 2017; 19: 6452
    • 3d Magagnano G, Gualandi A, Marchini M, Mengozzi L, Ceroni P, Cozzi PG. Chem. Commun. 2017; 53: 1591

    • For a recent review, see:
    • 3e Courant T, Masson G. J. Org. Chem. 2016; 81: 6945
  • 4 Miura T, Funakoshi Y, Nakahashi J, Moriyama D, Murakami M. Angew. Chem. Int. Ed. 2018; 57: 15455
  • 5 For the use of thiols as sources of electrophilic hydrogen atoms and the subsequent reactions between the resulting thiyl radicals and ascorbate anions, see: Guo X, Wenger OS. Angew. Chem. Int. Ed. 2018; 57: 2469
  • 6 For a similar photoinduced elongation of alkenes using BrCH2CO2Et as the radical source, see: Sumino S, Fusano A, Ryu I. Org. Lett. 2013; 15: 2826
  • 7 For a review on 1,2-addition reactions with alkanenitriles as radical sources, see: Chu X.-Q, Ge D, Shen Z.-L, Loh T.-P. ACS Catal. 2018; 8: 258

    • For 1,2-hydro(cyanomethylation) of alkenes by using CH3CN as the radical source, see:
    • 8a Li Z, Xiao Y, Liu Z.-Q. Chem. Commun. 2015; 51: 9969

    • See also:
    • 8b Bruno JW, Marks TJ, Lewis FD. J. Am. Chem. Soc. 1981; 103: 3608
    • 8c Sonawane HR, Bellur NS, Shah VG. J. Chem. Soc., Chem. Commun. 1990; 1603

      For 1,2-difunctionalization of alkenes by using CH3CN as the radical source, see:
    • 9a Bunescu A, Wang Q, Zhu J. Angew. Chem. Int. Ed. 2015; 54: 3132
    • 9b Chatalova-Sazepin C, Wang Q, Sammis GM, Zhu J. Angew. Chem. Int. Ed. 2015; 54: 5443
    • 9c Lan X.-W, Wang N.-X, Bai C.-B, Lan C.-L, Zhang T, Chen S.-L, Xing Y. Org. Lett. 2016; 18: 5986
    • 9d Wu X, Riedel J, Dong VM. Angew. Chem. Int. Ed. 2017; 56: 11589
    • 9e Liu Y.-Y, Yang X.-H, Song R.-J, Luo S, Li J.-H. Nat. Commun. 2017; 8: 14720

      For 1,2-bromo(cyanomethylation) of alkenes by using BrCH2CN as the radical source, see:
    • 10a Voutyritsa E, Triandafillidi I, Kokotos CG. ChemCatChem 2018; 10: 2466
    • 10b Voutyritsa E, Nikitas NF, Apostolopoulou MK, Gerogiannopoulou AD. D, Kokotos CG. Synthesis 2018; 50: 3395 ; See also refs. 3 (b) and 3 (d)
  • 11 Zhang X.-M, Bordwell FG. J. Am. Chem. Soc. 1994; 116: 968
  • 12 Creutz C. Inorg. Chem. 1981; 20: 4449
  • 13 Warren JJ, Mayer JM. J. Am. Chem. Soc. 2010; 132: 7784

    • For photocatalytic reactions using ascorbic acid as the reductant, see:
    • 14a Maji T, Karmakar A, Reiser O. J. Org. Chem. 2011; 76: 736
    • 14b Wallentin C.-J, Nguyen JD, Finkbeiner P, Stephenson CR. J. J. Am. Chem. Soc. 2012; 134: 8875
    • 14c Supranovich VI, Levin VV, Struchkova MI, Dilman AD. Org. Lett. 2018; 20: 840 ; See also ref. 5
  • 15 Kerber RC. J. Chem. Educ. 2008; 85: 1237
  • 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.

  • References and Notes


    • For reviews, see:
    • 1a Narayanam JM. R, Stephenson CR. J. Chem. Soc. Rev. 2011; 40: 102
    • 1b Skubi KL, Blum TR, Yoon TP. Chem. Rev. 2016; 116: 10035
    • 1c Romero NA, Nicewicz DA. Chem. Rev. 2016; 116: 10075
    • 1d Twilton J, Le C, Zhang P, Shaw MH, Evans RW, MacMillan DW. C. Nat. Rev. Chem. 2017; 1: 0052
    • 1e Lee KN, Ngai M.-Y. Chem. Commun. 2017; 53: 13093
    • 1f Marzo L, Pagire SK, Reiser O, König B. Angew. Chem. Int. Ed. 2018; 57: 10034

      For photoinduced reactions using phosphonium salts as the radical source, see:
    • 2a Lin Q.-Y, Xu X.-H, Zhang K, Qing F.-L. Angew. Chem. Int. Ed. 2016; 55: 1479
    • 2b Panferova LI, Tsymbal AV, Levin VV, Struchkova MI, Dilman AD. Org. Lett. 2016; 18: 996

      For 1,2-bromo[(ethoxycarbonyl)methylation] of alkenes with BrCH(R)CO2Et as the radical source, see:
    • 3a Nguyen JD, Tucker JW, Konieczynska MD, Stephenson CR. J. J. Am. Chem. Soc. 2011; 133: 4160
    • 3b Arceo E, Montroni E, Melchiorre P. Angew. Chem. Int. Ed. 2014; 53: 12064
    • 3c Cheng J, Cheng Y, Xie J, Zhu C. Org. Lett. 2017; 19: 6452
    • 3d Magagnano G, Gualandi A, Marchini M, Mengozzi L, Ceroni P, Cozzi PG. Chem. Commun. 2017; 53: 1591

    • For a recent review, see:
    • 3e Courant T, Masson G. J. Org. Chem. 2016; 81: 6945
  • 4 Miura T, Funakoshi Y, Nakahashi J, Moriyama D, Murakami M. Angew. Chem. Int. Ed. 2018; 57: 15455
  • 5 For the use of thiols as sources of electrophilic hydrogen atoms and the subsequent reactions between the resulting thiyl radicals and ascorbate anions, see: Guo X, Wenger OS. Angew. Chem. Int. Ed. 2018; 57: 2469
  • 6 For a similar photoinduced elongation of alkenes using BrCH2CO2Et as the radical source, see: Sumino S, Fusano A, Ryu I. Org. Lett. 2013; 15: 2826
  • 7 For a review on 1,2-addition reactions with alkanenitriles as radical sources, see: Chu X.-Q, Ge D, Shen Z.-L, Loh T.-P. ACS Catal. 2018; 8: 258

    • For 1,2-hydro(cyanomethylation) of alkenes by using CH3CN as the radical source, see:
    • 8a Li Z, Xiao Y, Liu Z.-Q. Chem. Commun. 2015; 51: 9969

    • See also:
    • 8b Bruno JW, Marks TJ, Lewis FD. J. Am. Chem. Soc. 1981; 103: 3608
    • 8c Sonawane HR, Bellur NS, Shah VG. J. Chem. Soc., Chem. Commun. 1990; 1603

      For 1,2-difunctionalization of alkenes by using CH3CN as the radical source, see:
    • 9a Bunescu A, Wang Q, Zhu J. Angew. Chem. Int. Ed. 2015; 54: 3132
    • 9b Chatalova-Sazepin C, Wang Q, Sammis GM, Zhu J. Angew. Chem. Int. Ed. 2015; 54: 5443
    • 9c Lan X.-W, Wang N.-X, Bai C.-B, Lan C.-L, Zhang T, Chen S.-L, Xing Y. Org. Lett. 2016; 18: 5986
    • 9d Wu X, Riedel J, Dong VM. Angew. Chem. Int. Ed. 2017; 56: 11589
    • 9e Liu Y.-Y, Yang X.-H, Song R.-J, Luo S, Li J.-H. Nat. Commun. 2017; 8: 14720

      For 1,2-bromo(cyanomethylation) of alkenes by using BrCH2CN as the radical source, see:
    • 10a Voutyritsa E, Triandafillidi I, Kokotos CG. ChemCatChem 2018; 10: 2466
    • 10b Voutyritsa E, Nikitas NF, Apostolopoulou MK, Gerogiannopoulou AD. D, Kokotos CG. Synthesis 2018; 50: 3395 ; See also refs. 3 (b) and 3 (d)
  • 11 Zhang X.-M, Bordwell FG. J. Am. Chem. Soc. 1994; 116: 968
  • 12 Creutz C. Inorg. Chem. 1981; 20: 4449
  • 13 Warren JJ, Mayer JM. J. Am. Chem. Soc. 2010; 132: 7784

    • For photocatalytic reactions using ascorbic acid as the reductant, see:
    • 14a Maji T, Karmakar A, Reiser O. J. Org. Chem. 2011; 76: 736
    • 14b Wallentin C.-J, Nguyen JD, Finkbeiner P, Stephenson CR. J. J. Am. Chem. Soc. 2012; 134: 8875
    • 14c Supranovich VI, Levin VV, Struchkova MI, Dilman AD. Org. Lett. 2018; 20: 840 ; See also ref. 5
  • 15 Kerber RC. J. Chem. Educ. 2008; 85: 1237
  • 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.

 
Zoom Image
Scheme 1 1,2-Hydro(cyanomethylation) of alkene 1a with phosphonium ylide 2
Zoom Image
Scheme 2 Plausible mechanism for the formation of 3a from alkene 1a and phosphonium ylide 2
Zoom Image
Scheme 3 The addition reaction to 1-benzofuran (7)
Zoom Image
Scheme 4 The reaction with the α-cyanoethylphosphonium ylide 9