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

Article abstract of DOI:10.1055/s-0037-1612230

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.

Full text of DOI:10.1055/s-0037-1612230

SYNLETT
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Georg Thieme Verlag Stuttgart · New York
2019, 30, 511–514
letter
511
en
T. Miura et al.
Letter
Synlett
Photoinduced 1,2-Hydro(cyanomethylation) of Alkenes with a
Cyanomethylphosphonium Ylide
Tomoya Miura*
0
0
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3-2
4
9
3-
0
1
8
4
blue LEDs
Ph3P CHCN
+
R
R
CN
Daisuke Moriyama
Yuuta Funakoshi
cat. fac-Ir(ppy)3
cat. C6F5SH
up to 88%
ascorbic acid
Masahiro Murakami*
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2-9
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3-3
4
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2
R
= -(CH2)2Ph, -(CH2)2Ac, -(CH2)3CO2H, -(CH2)3CN,
-(CH2)4OH, -(CH2)4OBz, -(CH2)5Cl
Department of Synthetic Chemistry and Biological Chemistry, Kyoto
University, Katsura, Kyoto 615-8510, Japan
tmiura@sbchem.kyoto-u.ac.jp
ppy = 2-phenylpyridinato
murakami@sbchem.kyoto-u.ac.jp
Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue
Received: 22.12.2018
Accepted after revision:23.01.2019
Published online: 13.02.2019
species is not as electrophilic as the original cyanomethyl
radical, and can therefore abstract a hydrogen atom from a
sulfanyl group5 to form an elongated aliphatic nitrile.
Initially, we applied the conditions optimized for the re-
action of an ester-stabilized phosphonium ylide4 to the re-
action of the cyanomethylphosphonium ylide 2 with 4-
phenylbut-1-ene (1a), and we obtained 6-phenylhexane-
nitrile (3a) as expected. The yield, however, was moderate
(43% by NMR), which led us to adapt the reaction condi-
tions 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.
DOI: 10.1055/s-0037-1612230; Art ID: st-2018-b0826-l
License terms:
Abstract An efficient method has been developed for the 1,2-hy-
dro(cyanomethylation) of alkenes, in which a cyanomethyl radical spe-
cies 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.
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 vari-
ety of reagents are now available as competent precursors
to radical species. We recently reported that an ester-stabi-
lized phosphonium ylide2 can act as a precursor to an
(alkoxycarbonyl)methyl radical species3 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 cyanomethylphosphoni-
um ylide instead of an ester-stabilized phosphonium ylide.
The former act as the precursor of a cyanomethyl radical
species7–10 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 (alkoxy-
carbonyl)methyl radical.3,4,6 The appended alkyl radical
fac-Ir(ppy)3 (1.0 mol%)
Ph
1a
C6F5SH (20 mol%)
+
Ph
CN
ascorbic acid (10 equiv)
KHSO4 (3.0 equiv)
CH3CN/H2O (1:1)
Ph3P CHCN
3a
2 (2.0 equiv)
94% (NMR)
80% (isolated)
r.t., 40 h, blue LEDs
Scheme 1 1,2-Hydro(cyanomethylation) of alkene 1a with phosphoni-
um ylide 2
The formation of the product 3a can be reasonably ex-
plained 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
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, 511–514

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T. Miura et al.
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reaction of 2 (pKaH = 6.9)11 with ascorbic acid (AscH2;
pKa= 4.0)12 generates the phosphonium ascorbate
[Ph3PCH2CN]+[AscH]– (4). This has an energetically low-ly-
ing 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 dou-
ble bond of alkene 1a affords the elongated secondary alkyl
radical species 6, which is less electrophilic than 5. Hydro-
gen-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 thio-
late anion (C6F5S–) from C6F5SH.
species (entry 13). Even the tetrasubstituted alkene 1n un-
derwent the reaction (entry 14). The 1,2-adduct 3o was ob-
tained in 18% NMR yield from styrene (1o), and the final re-
action mixture contained various products, probably as a
result of the high reactivity of the benzylic radical interme-
diates (entry 15).16
Table 1 1,2-Hydro(cyanomethylation) of Various Alkenes 1 with Phos-
phorus Ylide 2a
Entry Alkene 1
Product 3
Yieldb (%)
76
O
O
3b
1b
1
( )
2
( )
CN
2
HO2C
HO2C
3c
( )
1c
2
3
4
( )
82
74
88
CN
3
3
NC
HO
Ph
NC
( )
1d
3d
3e
( )
( )
CN
CN
3
3
HO
( )
1e
4
4
OH
OH
O
i)
Ph
Cl
O
( )
O
O
( )
[Ph3PCH2CN]+[AscH]–
4
CN
+
Ph3P CHCN
4
5
6
3f
77
88
1f
2
4
O
O
HO
OH
AscH2
Cl
1g
3g
( )
( )
CN
5
5
ii)
H
hν
CN
[Ir(III)]* [Ir(IV)]+[AscH]–
[Ir(III)]
3h
R
CN
7
8
73
77
1h
3a
C6F5S
[Ph3PCH2CN]+[AscH]–
PPh3
+
CN
C6F5SH
R
3i
1i
4
1a
CH2CN
dr = 10:1
R
+
CN
5
H3C
CH3
H3C
CH3
6
electrophilic radical
[Ir(III)] = fac-Ir(ppy)3
iii)
CN
9
59
79
1j
3j
[Ir(IV)]+[AscH]–
+
+
[Ir(III)]
C6F5S
C6F5SH
DHA
Scheme 2 Plausible mechanism for the formation of 3a from alkene 1a
and phosphonium ylide 2
10
1k
3k
CN
Various alkenes 1 were subjected to the 1,2-hydro(cy-
anomethylation) reaction with 2 (Table 1). A wide range of
functional groups were tolerated to afford the correspond-
ing 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 disubsti-
tuted alkenes 1j and 1k afforded the corresponding prod-
ucts 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 diastereo-
mers of 3m was formed through nonstereoselective trans-
fer of a hydrogen atom to an intermediate tertiary radical
n-Pr
n-Pr
CN
11
12
28
3l
3l
n-Pr
n-Pr
n-Pr (Z)-1l
n-Pr
n-Pr
n-Pr
CN
29c
(E)-1l
CN
1m
3m
13
45
dr = 7:3
CH3
CH3
CH3
CH3
CH3
14
15
1n
56c
18c
3n
H3C
Ph
H3C
CN
H3C
CH3
CH3
1o
3o
CN
Ph
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.
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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).
References and Notes
(1) For reviews, see: (a) Narayanam, J. M. R.; Stephenson, C. R. J.
Chem. Soc. Rev. 2011, 40, 102. (b) Skubi, K. L.; Blum, T. R.; Yoon,
T. P. Chem. Rev. 2016, 116, 10035. (c) Romero, N. A.; Nicewicz, D.
A. Chem. Rev. 2016, 116, 10075. (d) Twilton, J.; Le, C.; Zhang, P.;
Shaw, M. H.; Evans, R. W.; MacMillan, D. W. C. Nat. Rev. Chem.
2017, 1, 0052. (e) Lee, K. N.; Ngai, M.-Y. Chem. Commun. 2017,
53, 13093. (f) Marzo, L.; Pagire, S. K.; Reiser, O.; König, B. Angew.
Chem. Int. Ed. 2018, 57, 10034.
(2) For photoinduced reactions using phosphonium salts as the
radical source, see: (a) Lin, Q.-Y.; Xu, X.-H.; Zhang, K.; Qing, F.-L.
Angew. Chem. Int. Ed. 2016, 55, 1479. (b) Panferova, L. I.;
Tsymbal, A. V.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. Org.
Lett. 2016, 18, 996.
O
fac-Ir(ppy)3 (1.0 mol%)
CN
7
O
C6F5SH (20 mol%)
+
ascorbic acid (10 equiv)
KHSO4, CH3CN/H2O
Ph3P CHCN
8 50%
2 (2.0 equiv)
r.t., 40 h, blue LEDs
Scheme 3 The addition reaction to 1-benzofuran (7)
(3) For 1,2-bromo[(ethoxycarbonyl)methylation] of alkenes with
BrCH(R)CO2Et as the radical source, see: (a) Nguyen, J. D.;
Tucker, J. W.; Konieczynska, M. D.; Stephenson, C. R. J. J. Am.
Chem. Soc. 2011, 133, 4160. (b) Arceo, E.; Montroni, E.;
Melchiorre, P. Angew. Chem. Int. Ed. 2014, 53, 12064. (c) Cheng,
J.; Cheng, Y.; Xie, J.; Zhu, C. Org. Lett. 2017, 19, 6452.
(d) Magagnano, G.; Gualandi, A.; Marchini, M.; Mengozzi, L.;
Ceroni, P.; Cozzi, P. G. Chem. Commun. 2017, 53, 1591. For a
recent review, see: (e) Courant, T.; Masson, G. J. Org. Chem.
2016, 81, 6945.
Notably, even a branched -cyanoethyl group was at-
tached to the C=C double bond of 1a when -cyanoethyl-
phophorus ylide 9 was employed (Scheme 4).
fac-Ir(ppy)3 (2.0 mol%)
Ph
1a
C6F5SH (20 mol%)
CH3
CN
+
ascorbic acid (10 equiv)
KHSO4, CH3CN/H2O
CH3
CN
Ph
Ph3P
10 32%
r.t., 64 h, blue LEDs
9 (5.0 equiv)
(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 radi-
cals and ascorbate anions, see: Guo, X.; Wenger, O. S. Angew.
Chem. Int. Ed. 2018, 57, 2469.
(6) For a similar photoinduced elongation of alkenes using BrCH2-
CO2Et 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.
(8) For 1,2-hydro(cyanomethylation) of alkenes by using CH3CN as
the radical source, see: (a) Li, Z.; Xiao, Y.; Liu, Z.-Q. Chem.
Commun. 2015, 51, 9969. See also: (b) Bruno, J. W.; Marks, T. J.;
Lewis, F. D. J. Am. Chem. Soc. 1981, 103, 3608. (c) Sonawane, H.
R.; Bellur, N. S.; Shah, V. G. J. Chem. Soc., Chem. Commun. 1990,
1603.
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 potential-
ly hazardous conditions significantly limit the synthetic
value of the method. The present reaction uses cyanometh-
ylphosphonium ylide, which is stable and easily accessible,
as the radical source, thereby providing a convenient meth-
od for synthesizing elongated aliphatic nitriles from
alkenes.17
Funding Information
(9) For 1,2-difunctionalization of alkenes by using CH3CN as the
radical source, see: (a) Bunescu, A.; Wang, Q.; Zhu, J. Angew.
Chem. Int. Ed. 2015, 54, 3132. (b) Chatalova-Sazepin, C.; Wang,
Q.; Sammis, G. M.; Zhu, J. Angew. Chem. Int. Ed. 2015, 54, 5443.
(c) Lan, X.-W.; Wang, N.-X.; Bai, C.-B.; Lan, C.-L.; Zhang, T.; Chen,
S.-L.; Xing, Y. Org. Lett. 2016, 18, 5986. (d) Wu, X.; Riedel, J.;
Dong, V. M. Angew. Chem. Int. Ed. 2017, 56, 11589. (e) Liu, Y.-Y.;
Yang, X.-H.; Song, R.-J.; Luo, S.; Li, J.-H. Nat. Commun. 2017, 8,
14720.
This work was supported by JSPS KAKENHI [Scientific Research (S)
(15H05756) and (C) (16K05694)]
J
S
P
S
K
A
K
E
N
H
I
(1
5
H
0
5
7
5
6)J
S
P
S
K
A
K
E
N
H
I
(1
6
K
0
5
6
9
4)
Acknowledgment
We thank Mr. H. Nikishima (Kyoto University) for his experimental
contribution at a preliminary stage.
(10) For 1,2-bromo(cyanomethylation) of alkenes by using BrCH2CN
as the radical source, see: (a) Voutyritsa, E.; Triandafillidi, I.;
Kokotos, C. G. ChemCatChem 2018, 10, 2466. (b) Voutyritsa, E.;
Nikitas, N. F.; Apostolopoulou, M. K.; Gerogiannopoulou, A. D.
D.; Kokotos, C. G. Synthesis 2018, 50, 3395; See also refs. 3 (b)
and 3 (d).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612230.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
(11) Zhang, X.-M.; Bordwell, F. G. J. Am. Chem. Soc. 1994, 116, 968.
(12) Creutz, C. Inorg. Chem. 1981, 20, 4449.
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(14) For photocatalytic reactions using ascorbic acid as the reduc-
tant, see: (a) Maji, T.; Karmakar, A.; Reiser, O. J. Org. Chem. 2011,
76, 736. (b) Wallentin, C.-J.; Nguyen, J. D.; Finkbeiner, P.;
Stephenson, C. R. J. J. Am. Chem. Soc. 2012, 134, 8875.
(c) Supranovich, V. I.; Levin, V. V.; Struchkova, M. I.; Dilman, A.
D. Org. Lett. 2018, 20, 840; See also ref. 5.
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%).
(15) Kerber, R. C. 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.
IR (ATR): 2936, 2245, 1454 cm–1 1H NMR (400 MHz, CDCl3):
.
(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
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
C
12H15N: 173.1204; found: 173.1205.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, 511–514