Nickel-Catalyzed Sonogashira C(sp)-C(sp2) Coupling through Visible-Light Sensitization

Article abstract of DOI:10.1021/acs.joc.0c01177

An efficient method for visible-light-initiated, nickel-catalyzed Sonogashira C(sp)-C(sp2) coupling has been developed via an energy-transfer mode. Thioxanthen-9-one as a photosensitizer could significantly accelerate the arylation of alkynes with a wide

Full text of DOI:10.1021/acs.joc.0c01177

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Article
Nickel-Catalysed Sonogashira C(sp)–C(sp2)
Coupling Through Visible-Light Sensitization
Da-Liang Zhu, Ruijie Xu, Qi Wu, Hai-Yan Li, Jian-Ping Lang, and Hong-Xi Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01177 • Publication Date (Web): 12 Jun 2020
Downloaded from pubs.acs.org on June 14, 2020
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Nickel-Catalysed Sonogashira C(sp)–C(sp ) Coupling
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Through Visible-Light Sensitization
†
‡
†
§
†
,†
Da-Liang Zhu, Ruijie Xu, Qi Wu, Hai-Yan Li, Jian-Ping Lang, and Hong-Xi Li*
†College of Chemistry, Chemical Engineering and Materials Science, Soochow
University, Suzhou 215123, People’s Republic of China
‡College of Overseas Education, Nanjing Tech University, Nanjing 211816, People’s
Republic of China
§Analysis and Testing Center, Soochow University, Suzhou 215123, People’s Republic
of China
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_
_____________________________________________________________________________
PC
Ni
X
R
R
R
R
Zn(II), visible light
4
7 examples
X = Cl, Br, I
PC = thioxanthen-9-one
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up to 94%
ABSTRACT: An efficient method for visible light-initiated, nickel-catalyzed Sonogashira
2
C(sp)–C(sp ) coupling has been developed via an energy transfer mode. Thioxanthen-
9
-one as a photosensitizer could significantly accelerate the arylation of alkynes with a
wide range of (hetero)aryl halides in high yields. The cross-coupling reaction undergoes
the stepwise oxidative addition of an arylhalide to nickel(0), transmetalation of the
resulting aryl–Ni(II) halide species with Zn(II) acetylide into aryl–Ni(II) acetylide species,
energy transfer from the excited-state of thioxanthen-9-one to aryl–Ni(II) acetylide and
reductive elimination to the aryl alkyne.
_
_____________________________________________________________________________
INTRODUCTION
Aryl alkynes are important building blocks that widely occur in numerous natural
products, pharmaceuticals, agrochemicals, and functional materials.1-4 To date, the
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palladium-catalyzed Sonogashira reaction of terminal alkynes with aryl halides with or
without copper co-catalyst is a popular method to access these complexes.5-9 Much
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effort has also been devoted to the employment of copper,10-13 cobalt,14,15 iron,16-18 and
ruthenium19,20 complexes or nanoparticles as catalysts for the arylation of alkynes.21-24
Due to its cheap availability and high catalytic activity, nickel catalyst has been used in
such conversions.25-32 In these Ni-catalyzed cases, CuI as a co-catalyst, phosphines as
auxiliary ligands and high temperatures were used.
In recent years, initiated by Molander33 and MacMillan,34,35 the synergistic
combination of metal catalysis with photocatalysis has provided a powerful approach to
achieve new chemical reactions.36-41 In the dual catalysis, nickel catalysts have been
2
3
42-52
2
2 53-
commonly used in cross-coupling reactions to forge C(sp )–C(sp ),
C(sp )–C(sp ),
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3
3 56-60
and C(sp )–C(sp )
bonds (Scheme 1). MacMillan, Wu and Chu et al.
demonstrated the hydroalkylation or alkylarylation of alkynes using nickel and
photoredox dual catalysis.61-63 However, there is no report on nickel-catalysed C(sp)–
2
C(sp ) cross-coupling under visible light irradiation. By far, expensive ruthenium and
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iridium polypyridyl complexes still dominate as photoactive species in the dual-
catalysis.42-65 The utility of cheap and commercially available organic photocatalysts has
received much attention in the pursuit of sustainable and green photochemical
processes.66-73 Diarylketones are suitable alternatives due to that their photoexcited
states can undergo energy transfer (EnT),74,75 hydrogen-atom transfer (HAT),76-81 or
electron transfer (ET)82,83 process. Nevertheless, their applications in combination with
nickel catalysts to construct C-C bonds remain significantly limited.84-87 Herein, we
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report the nickel-catalysed C(sp)–C(sp ) coupling of alkynes and (hetero)aryl halides
using thioxanthen-9-one (TXO) as a visible-light photosensitizer.
Scheme 1. Visible-Light-Mediated C-C Formations with Nickel and Photoredox Dual
Catalysis
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Previous works:
2
3
(
a) C(sp )-C(sp ) bond formation
Ar = Aryl, vinyl, acyl; X = halide;
R1
R1
R2
1 2
R R CY = alkyltrifluoroborates,
alkylsilicates, carboxylates,
photocatalyst
Ni catalyst
Ar-X +
Y
Ar
R2
3
C(sp )-H, 1,4-dihydropyridines
3
3
(
b) C(sp )-C(sp ) bond formation
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R1
R1
Ir photocatalyst
Ni catalyst
R-Br +
Y
R
R = alkyl; Y = H, COOH
R2
R2
2
2
(
c) C(sp )-C(sp ) bond formation
carbazolyl dicyanobenzene
Ni catalyst
Ar-X + K2CO3
ArCO H
2
EtO
carbazolyl dicyanobenzene
Ni catalyst
Ar-X +
ArCHO
CO H
2
EtO
Ar = aryl, vinyl;
R' = aryl, alkyl;
X = halide
Ir photocatalyst
Ar-X + R'COCO H
2
Ar-COR'
Ni catalyst
This work:
d) C(sp)-C(sp ) bond formation
2
(
Ni catalyst
O
Ar X +
R
Ar
R
S
RESULTS AND DISCUSSION
In 2016, Glorius and coworkers described the arylation of alkyl and aromatic alkynes
with diazonium salts by a dual photocatalytic system of Au catalyst and
88
[
Ru(bpy) ](PF ) . In 2017, MacMillan et al. used Ir(ppy) as a triplet photosensitizer to
3
6 2
3
photosensitize nickel-catalyzed aryl esterification.89 The two dual-catalytic systems
required the use of expensive polypyridyl Ru(II) or Ir(III) complexes. Very recently, we
have used commercially available thioxanthen-9-one (TXO) as a triplet photosensitizer
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to promote the nickel-catalyzed esterification of carboxylic acids with aryl bromides to
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provide aryl esters under visible light. Those results stimulated us to explore TXO to
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accelerate Sonogashira C(sp)–C(sp ) cross-coupling reactions. Our initial investigations
focused on the coupling of 4-bromobenzonitrile (1a) with 1-ethynyl-4-methylbenzene
(
2a) in N,N-dimethylformamide (DMF) with TXO, Ni(OAc) ·4H O, 4,4-di-tert-butyl-2,2-
2
2
bipyridine (dtbbpy), and t-BuNH(i-Pr). The irradiation of the mixture with a household 45
W compact fluorescent lamp (45W-CFL, Figure S1) for 24 h resulted in the formation of
the desired product 4-(p-tolylethynyl)benzonitrile (3aa) in 3% yield with 54% conversion
(entry 1, Table 1). The addition of anhydrous Zn(OTf)2 (25 mol%, OTf =
trifluoromethylsulfonate) drastically increased the conversion of 1a and the yield of 3aa
(up to 92%) (entry 2). The in situ formed zinc(II) acetylide might increase
transmetallation to form alkynyl nickel species.91,92 Reducing the amount of TXO to 10
mol% (entry 3) gave a lower, but still respectable yield (85%). The same cross-coupling
reaction gave an 83% yield in DMSO, 23% yield in MeCN, and 11% yield in dioxane
(
entries 1-3, Table S1). The reaction did not work in CHCl , n-hexane (entries 4 and 5,
3
Table S1). NiBr ·3H O, Ni(NO ) ·6H O, NiCl , Ni(acac) (acac = acetylacetonate), or
2
2
3 2
2
2
2
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Ni(COD) (COD = 1,5-cyclooctadiene) were subsequently examined, and lower yields
2
were observed (entries 4-8, Table 1). For various bases (t-BuNH(i-Pr), Et N, 1,8-
3
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diazabicyclo[5.4.0]undec-7-ene (DBU), (i-Pr) NEt, Cs CO , Na CO , K PO , NaF)
2
2
3
2
3
3
4
(entries 6-12, Table S1), t-BuNH(i-Pr) was found to be the best one (entry 2, Table 1).
The decreasing of Zn(OTf) led to the lower yield (entries 13 and 14, Table S1). Control
2
experiments indicated photosensitizer, base, nickel catalyst, dtbbpy, and light irradiation
were crucial for the cross coupling (entries 9-13, Table 1). No desired product was
observed when the reaction was setup at 60 °C under the exclusion of light (entry 14,
Table 1). Under the irradiation of a 300-W Xe lamp equipped with a 400 nm cut-off filter,
the same reaction afforded 3aa in 90% yield (entry 15, Table 1). Visible light could
effectively promote this Sonogashira reaction.
Table 1. Optimization of Sonogashira Cross-Coupling Reactionsa
TXO (20 mol%), Ni cat (5 mol%)
dtbbpy (6 mol%)
NC
Br
NC
Zn(OTf) (25 mol%)
2
t-BuNH(i-Pr) (2 equiv.)
DMF (3 mL), 45W-CFL, r.t.
3aa
1a
2a
Entry Cat.
Base
Solvent
Conversio
Yield
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n
1b
2
Ni(OAc) ·4H O
t-BuNH(i-Pr)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
54%
93%
87%
85%
78%
76%
60%
57%
trace
0
3%
92%
85%
73%
76%
59%
54%
47%
trace
0
2
2
Ni(OAc) ·4H O
t-BuNH(i-Pr)
t-BuNH(i-Pr)
t-BuNH(i-Pr)
t-BuNH(i-Pr)
t-BuNH(i-Pr)
t-BuNH(i-Pr)
t-BuNH(i-Pr)
t-BuNH(i-Pr)
-
2
2
0
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0
3c
4
Ni(OAc) ·4H O
2
2
NiCl2
NiBr ·3H O
5
2
2
6
Ni(NO ) ·6H O
3
2
2
7
Ni(acac)2
Ni(COD)2
8
9d
Ni(OAc) ·4H O
2
2
1
1
1
1
1
0
Ni(OAc) ·4H O
2
2
1
-
t-BuNH(i-Pr)
t-BuNH(i-Pr)
t-BuNH(i-Pr)
t-BuNH(i-Pr)
t-BuNH(i-Pr)
0
0
2e
3f
4g
Ni(OAc) ·4H O
7%
0
<5%
0
2
2
Ni(OAc) ·4H O
2
2
Ni(OAc) ·4H O
0
0
2
2
15h
Ni(OAc) ·4H O
94%
90%
2
2
a1a (0.2 mmol, 1 equiv.), 2a (0.4 mmol, 2 equiv.), Ni(OAc) ·4H O (0.01 mmol, 5 mol%), dtbbpy
2
2
(
0.012 mmol, 6 mol%), t-BuNH(i-Pr) (0.4 mmol, 2.0 equiv.), Zn(OTf) (25 mol%), TXO (20 mol%), in
2
3
mL DMF under an N atmosphere, irradiation under 45W-Compact Fluorescent Lamp (CFL) for 24
2
h with cooling by fan, HPLC conversion and yield (HPLC = high performance liquid
b
c
d
e
f
chromatography). Without Zn(OTf) . TXO (10 mol%). Without TXO. Without dtbbpy. At room
2
g
h
temperature and in dark. At 60 ℃ and in dark. Under 300-W Xe lamp equipped with a 400 nm cut-
off filter.
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With the optimized conditions in hand, the scopes of the coupling reaction with
regard to both alkynes (Table 2) and aryl halides (Table 3) were investigated. Aryl
alkynes with electron-deficient and electron-rich groups at para- or meta-positions of
phenyl ring efficiently proceeded to produce diaryl alkynes 3aa-3al in 84−93% yields.
Substrates 2m and 2n possessing ortho substituents were well tolerated, as evidenced
by isolation of 3am and 3an in 68-73% yields. The reaction of 2-ethynylnaphthalene with
1
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1a afforded 3ao in 62% isolated yield. Heteroatom-containing alkynes such as 2-
ethynylthiophene (2p), 4-ethynylpyridine (2q) and 5-ethynylpyrimidine (2r) gave arylated
products 3ap-3ar in good yields (55-63%). Treatment of primary alkyl, secondary alkyl,
or hydroxylsubstituted alkynes (2s-2v) with 1a enabled the corresponding coupling in
83-92% yields. Ethynyltrimethylsilane (2w) was successfully transformed into 4-
((trimethylsilyl)ethynyl)benzonitrile (3aw) with 82% yield. To further investigate the
synthetic applicability of this method, ethisterone (2x) or levonorgestrel (2y) reacted with
1a to give the desired products 3ax and 3ay under the standard reaction conditions.
Table 2. Cross-Coupling Reactions of 1a with Alkynes (2).
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TXO (20 mol%)
Ni(OAc) •4H O (5 mol%)
2
2
dtbbpy (6 mol%)
NC
Br
R
NC
R
Zn(OTf) (25 mol%)
2
1a
2
t-BuNH(i-Pr) (2 equiv.)
DMF (3 mL), 45W-CFL, r.t.
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Entrya
1
Alkyne
Product
Yield
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
3aa 91%
3ab 90%
3ac 87%
3ad 88%
3ae 86%
2
3
4
5
6
7
8
9
OMe
OMe
tBu
Et
tBu
Et
namyl
Ph
namyl
Ph
3af
87%
3ag 84%
3ah 93%
F
F
Cl
Cl
3ai
3aj
91%
92%
1
0
1
CO2Me
CO2Me
1
3ak 86%
NC
F
F
12
3al
88%
NC
NC
13
3am 68%
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F
F
1
4
5
3an 73%
3ao 62%
NC
1
NC
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
S
S
1
6
7
NC
3ap 63%
3aq 55%
1
N
NC
NC
N
N
N
N
18
3ar
59%
N
19
NC
NC
NC
NC
NC
3as 91%
3at 89%
2
0
1
2
3au 92%
3av 83%
3aw 82%
22
OH
OH
2
3
4
Si
Si
H
H
H
H
NC
NC
H
HO
HO
H
2
O
HO
HO
3ax 45%
3ay 47%
O
H
H
H
H
H
25
H
O
H
O
H
a1a (0.2 mmol), 2 (0.4 mmol), Ni(OAc) ·4H O (5 mol%), dtbbpy (6 mol%), t-BuNH(i-Pr) (0.4 mmol),
2
2
Zn(OTf) (25 mol%), TXO (20 mol%), 3 mL DMF, N , 45W-CFL for 24 h with cooling by fan and
2
2
isolated yields.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
We next examined the reactivity of (hetero)aryl halides with 2a (Table 3). Aryl
bromides (1a–1e, 1g–1l) bearing electron-deficient groups, including nitrile, carbonyl,
fluoro, carboxylic ester or trifluoromethyl at the para- or/and meta-positions of phenyl
ring, offered the products (3aa–3ea, 3ga–3la) in 70–91% yields. The electron-rich aryl
bromide 1f was treated with 2a to yield 3fa in 49% yield. Moderate yield was achieved
when the substituent was on the ortho-position of the benzene ring (3ma). Treatment of
1n with 2a afforded 3na in 67% isolated yield. 2-Bromonaphthalene (1o) was smoothly
converted into 3oa. Pyridine substrates 1p-1v proved to be competent for this
transformation and provided products 3pa-3va in a 66–81% yield range.
Disappointingly, 5-bromobenzo[d][1,3]dioxole (1w) was not found to be a viable
substrate for this conversion. However, the arylation of 2a with 5-
iodobenzo[d][1,3]dioxole produced 3wa in 62% yield. Aryl iodides showed higher
reactivity than the corresponding aryl bromides (2a, 2w). Reaction of 2a with 4-
chlorobenzonitrile also offered 3aa in 40% yield. Noteworthy, 3aa was obtained in 72%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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yield (0.9378 g, 4.32 mmol) when the cross-coupling of 1a (1.092 g, 6.0 mmol) with 2a
(1.392 g, 12.0 mmol) was performed on a gram scale under the irradiation of 2  45 W-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CFL (Figure S1c) for 72 h.
Table 3. Cross-Coupling Reactions of Aryl Halides (1) with 2a.
TXO (20 mol%)
Ni(OAc) •4H O (5 mol%)
2
2
dtbbpy (6 mol%)
Ar
X
Ar
Zn(OTf) (25 mol%)
2
1
t-BuNH(i-Pr) (2 equiv.)
DMF (3 mL), 45W-CFL, r.t.
3
2a
Entrya
1
Aryl halide
Product
Yield
94%
NC
I
2
3
4
5
6
7
8
NC
Br
Cl
NC
3aa 91%
40%
NC
F3C
Br
F3C
3ba 85%
3ca 89%
3da 87%
3ea 89%
MeOC
MeO2C
EtO2C
MeO
Br
MeOC
MeO2C
EtO2C
MeO
Br
Br
Br
3fa
49%
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
F3C
F3C
Br
Br
9
3ga 76%
3ha 70%
F3C
NC
F3C
NC
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10
F3C
F3C
Br
1
1
2
3ia
3ja
81%
77%
NC
NC
Br
Br
1
MeOC
MeOC
NC
NC
13
3ka 76%
F3C
F3C
F
Br
F
1
4
5
3la
75%
NC
NC
CN
CN
Br
1
3ma 50%
F3C
Br
F3C
1
6
7
3na 67%
3oa 62%
1
Br
Br
18
3pa 67%
N
N
MeOC
MeOC
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Page 15 of 74
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Br
19
3qa 66%
N
N
F3C
F3C
Br
2
0
1
3ra
72%
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
NC
N
NC
2
Br
Br
N
3sa 73%
N
Br
N
22
3ta
81%
F3C
F3C
N
N
2
3
4
5
3ua 69%
3va 72%
3wa 62%
2
Br
N
N
I
O
O
O
O
2
a
1 (0.2 mmol), 2a (0.4 mmol), Ni(OAc) ·4H O (5 mol%), dtbbpy (6 mol%), t-BuNH(i-Pr) (0.4 mmol),
2
2
Zn(OTf) (25 mol%), TXO (20 mol%), 3 mL DMF, N , 45W-CFL for 24 h with cooling by fan and
2
2
isolated yields.
We then moved on to examine the mechanism of this reaction system. Cyclic
voltammetry (CV) of TXO revealed a reduction potential at E = -1.66 V vs. saturated
calomel electrode (SCE) in DMF (Figure S2). Based on the electrochemical and
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
spectroscopic data of TXO (Figure S3 and S4), the redox potentials of excited-states
TXO* is estimated to be +1.34 V vs. SCE. So TXO* could engage one electron from
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
II
III
II
35
III
(
dtbbpy)-arylNi acetylide (E(Ni /Ni ) = 0.83 V vs. SCE ) to generate a (dtbbpy)Ni -aryl
•−
34,35
acetylide and TXO . The Ni(III) species may then undergo reductive elimination
to
I
afford an expected product and a (dtbbpy)Ni intermediate. The Ni(I) species would be
readily reduced to [(dtbbpy)Ni ] (E(Ni /Ni ) = −1.20 V vs. SCE34,35) by TXO•−
0
II
0
•−
(
E(TXO/TXO ) = -1.66 V vs. SCE in DMF). Such Ni-catalyzed coupling reaction might
undergo electron transfer process (Scheme S1). To test this pathway, we performed a
series of experiments with some other photocatalysts (entries 1-5, Table 4). The
utilization of Eosin Y or Rose Bengal with similar oxidizing potentials instead of TXO
drastically reduced the efficacy of the C−C cross coupling in our model system (entries
+
3 and 4). 9-Mesityl-10-methylacridinium perchlorate [Mes -Acr]ClO with a much higher
4
oxidizing potential than TXO (entry 5) did not provide any product under the identical
conditions. These experiments suggest that a mechanism involving oxidation of Ni(II) to
Ni(III) may not be operative in this transformation.
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In light of the above experiments, we suspected that a mechanism involving
triplet−triplet energy transfer from the excited-state of TXO (TXO*) to the Ni(II) complex
might be operative. As displayed in Table 4, the reactivity was correlated with triplet
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
state energy (E ) of photocatalysts rather than with excited-state oxidation potential.
T
-1
TXO with highest E (63.4 kcal·mol ) proved most effective (entry 1). Ir(ppy) with E of
T
3
T
-1
5
5.2 kcal·mol was a moderately efficient photocatalyst in combination with the nickel
-1
+
catalyst (entry 2). Rose Bengal (40.9 kcal·mol ) and [Mes -Acr]ClO with lower triplet
4
energy almost shut down the arylation reaction. On this basis of the information, this
cross coupling possibly proceeded via an EnT manner.
Table 4. The Effect of Photosensitizer on the Coupling of 1a and 2a.
photosensitizer(20 mol%)
Ni(OAc) •4H O (5 mol%)
2
2
Br
dtbbpy (6 mol%)
Zn(OTf) (25 mol%)
t-BuNH(i-Pr) (2 equiv.)
2
NC
NC
1a
DMF (3 mL), 45W-CFL, r.t.
3aa
2a
Photosensitize E* M/M (V)
r
Yield
Entrya
E (nm) E (kcal/mol)
m
T
1
2
TXO
1.34
0.31
414
518
63.4
55.2
92%
44%
Ir(ppy)3
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
4
5
Eosin Y
1.18
0.99
539
559
590
-
40.9
-
6%
<1%
0
Rose Bengal
+
[Mes -Acr]ClO 2.05
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a1a (0.2 mmol), 2a (0.4 mmol), Ni(OAc) ·4H O (5 mol%), dtbbpy (6 mol%), t-BuNH(i-Pr) (0.4 mmol),
2
2
Zn(OTf) (25 mol%), photosensitizer (20 mol%), 3 mL DMF, N , 45W-CFL for 24 h with cooling by
2
2
fan and HPLC yields.
To further verify the EnT mechanism, we carried out the reaction of Ni(COD) and
2
dtbbpy with 1a to offer (dtbbpy)-4-cyanophenylnickel(II) bromide (4). Compound 4
shows only a weak absorption at wavelengths of more than 400 nm (Figure S5). The
visible light irradiation of the cross-coupling reaction of 4 and 2a in the absence of TXO
resulted in no conversion, suggesting that the operative triplet state is not accessible
from the excited state of Ni(II) intermediate (eq 1, Scheme 2). UV irradiation (λ = 365
nm) of 4 and 2a for 24 h led to the formation of the cross-coupling product 3aa in 24%
yield. In addition, the irradiation of the reaction of 1a and 2a in DMF without TXO under
45W-CFL for 24 h could not afford 3aa. Only 11% yield of 3aa could be achieved by
prolonging the irradiation time to 120 h. The same reaction offered 3aa in 16% yield
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after 24 h of λ = 365 nm irradiation (eq 2, Scheme 2). These experiments suggest a
mechanism involving an energy-transfer pathway in which an excited-state of (dtbbpy)-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4-cyanophenyl-(p-tolylethynyl)nickel(II) species (confirmed by electrospray ionization
mass spectrometry (Figure S7)) underwent reductive elimination to form the desired
product 3aa. As discussed above, the 47% yield of 3aa was achieved using Ni(COD)2
as a catalyst (entry 8, Table 1), thus suggesting the involvement of a Ni(0) species in
this transformation. These above results implied that the excited-state Ni(II) species
generated by energy transfer from excited TXO underwent reductive elimination to form
aryl alkyne and a reactive Ni(0) intermediate.
Scheme 2. The Studies of Reductive Elimination
t-Bu
Br
Zn(OTf)2 (0.25 eq.)
t-BuNH(i-Pr) (2.0 eq.)
N
N
NiII
+
(1)
hv, r.t.
CN
t-Bu
NC
4
2a
3aa
trace under 45W-CFL for 24 h
3% under 45W-CFL for 120 h
1
24% under 365 nm for 24 h
Ni(OAc)2·4H2O (5 mol%)
dtbbpy (6 mol%)
Br
+
(
2)
NC
t-BuNH(i-Pr) (2.0 eq.)
Zn(OTf)2 (0.25 eq.), hv, r.t. NC
1a
2a
3aa
trace under 45W-CFL for 24 h
1
1% under 45W-CFL for 120 h
6% under 365 nm for 24 h
1
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Based on the combination of above experiments and literature reports,37,74,75,90-93
a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
plausible catalytic cycle is delineated in Scheme 3. The initial oxidative addition of
0
[
dtbbpyNi ] (A) with aryl halide gives aryl-Ni(II)-halide complex B. Transmetallation of B
with Zn(II) acetylide affords aryl-Ni(II) acetylide C. Simultaneously, the irradiation of
TXO produces the triplet photoexcited state TXO* under visible light. The subsequent
triplet-triplet energy transfer can occur between TXO* and C, affording the excited state
of C. The resulting excited-state Ni(II) species (D) undergoes the reductive elimination
to generate 3 and A, thereby completing the catalytic cycle.
Scheme 3. Proposed Mechanism
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Zn2+
Zn
R
H
R
t-BuNH(i-Pr)
t-Bu
t-Bu
R
t-Bu
N
N
NiII
X
N
N
NiII
Ar
Ar
(C)
(
B)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
t-Bu
TXO*
Energy
Transfer
Nickel-catalytic
Cycle
Photocatalytic
Cycle
Ar-X
TXO
t-Bu
N
N
t-Bu
R *
0
Ni (solvent)
N
NiII
(A)
t-Bu
N
Ar
t-Bu
(
D)
Ar
R
CONCLUSIONS
2
In summary, we have shown the Ni-catalyzed C(sp)–C(sp ) couplings of alkynes with
(
hetero)aryl halides using the quite inexpensive photosensitizer thioxanthen-9-one as an
energy transfer agent at ambient temperature and under the illumination of a household
light bulb. The arylation of alkynes are compatible with a wide range of functional
groups to provide aryl alkynes in moderate to excellent yields. The combination of a
cheap, readily available organic photocatalyst with an earth-abundant metal catalyst
provides a highly economical route to construct C-C and C-heteroatom bonds.
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EXPERIMENTAL SECTION
General Information. All reagents were used as purchased without further
purification. All solvents were obtained from commercial sources and were purified
according to standard procedures. Column chromatography was performed on silica
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gel. H and C NMR spectra were recorded at ambient temperature on a Varian UNITY
plus-400 spectrometer. The LC-MS (liquid chromatography mass spectroscopy) was
recorded using a Rapid Resolution HT-3 chromatographic column on an Agilent 1260
Infinity Liquid Chromatograph with 6120 Quadrupole Mass Spectrometer and MeCN as
mobile phase. High performance liquid chromatography (HPLC) was conducted on a
LC-20AT with MeOH and H O as the mobile phase. High resolution mass spectra
2
(HRMS) were obtained with a GCT Premier (Micromass UK Limited) chemical ionization
time-of-flight mass spectrometer (CI-TOF). The IR spectra (KBr disc) were recorded on
−
1
a Nicolet MagNa-IR550 FT-IR spectrometer (4000-400 cm ).
Preparation of (dtbbpy)-4-cyanophenylnickel(II) bromide (4). This complex was
synthesized by adapting the literature report.90 In a nitrogen filled glove box, an oven-
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dried 10 mL test tube was charged with Ni(COD) (0.0550 g, 0.2 mmol), dtbbpy (0.0536
2
g, 0.2 mmol) and THF (3 mL). The mixture was stirred for 2 h at room temperature and
the color of solution was turned into deep purple. 4-Bromobenzonitrile (0.1092 g, 0.6
mmol) was added and the reaction was left to stir for 20 min. The resulting dark red
solution was triturated with pentane (10 mL). The precipitate was collected on a frit,
rinsed with pentane and residual solvent was removed under vacuum to give an orange
powder. The product was used without further purification. The complex was stored in a
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nitrogen filled glove box at -35 ºC. H NMR (400 MHz, CD Cl , ppm) δ = 9.18 (s, 1H),
2
2
7.82 (m, 4H), 7.55 (d, J = 5.6, 1H), 7.18 (s, 4H), 1.41 (s, 9 H), 1.35 (s, 9H).
The Studies of Reductive Elimination. The (dtbbpy)-4-cyanophenylnickel(II)
bromide (4) (0.1521 mg, 0.3 mmol) and 6 mL dried, degassed DMF, t-BuNH(i-Pr)
(0.0690 mg, 0.6 mmol) and 1-ethynyl-4-methylbenzene (0.1044 g, 0.9 mmol) were
added. The suspension was then stirred for 15min and 2 mL of this mixture was
weighed into the other two 10 mL test tubes. These three test tubes were added with
Zn(OTf) (0.0092 g, 25 mol%) independently. The resulting mixture was stirred under
2
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5W-CFL (Philips) and 365 nm irradiation for 24 h or 120 h with cooling by fan. Next,
biphenyl was added as an internal standard, followed by water (10 mL) and the
aqueous solution extracted with ethyl acetate (3 × 10 mL). The combined extracts were
dried over anhydrous Na SO , and concentrated in vacuum. The crude product was
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dissolved in acetonitrile for monitoring by HPLC.
Experimental Procedures and Analytical Data. Typical Reaction (Table 1, Entry 2).
A 10 mL test tube was weighted with 1a (0.2 mmol), 2a (0.4 mmol), Ni(OAc) ·4H O
2
2
(2.49 mg, 0.01 mmol), dtbbpy (3.22 mg, 0.012 mmol) and TXO (8.4 mg, 0.04 mmol), t-
BuNH(i-Pr) (46.0 mg, 0.4 mmol), and Zn(OTf) (18.2 mg, 25 mol%) in 3 mL degased,
2
dried DMF. The reaction was stirred under a nitrogen atmosphere and irradiated with a
household 45W CFL (Philips) for 24 h with cooling by fan. Next, 3 mL water was added
and the mixture was extracted three times with ethyl acetate (3 × 5 mL). The combined
organic layer was washed with brine, dried over anhydrous Na SO and concentrated
2
4
under reduced pressure. The pure product was obtained by flash column
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chromatography on silica gel using petroleum ether and ethyl acetate (EtOAc) as the
eluent.
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-(p-Tolylethynyl)benzonitrile (3aa).94 3aa was obtained in 91% yield (39.5 mg)
based on 4-bromobenzonitrile, 94% yield (40.8 mg) based on 4-iodobenzonitrile, 40%
yield (17.4 mg) based on 4-chlorobenzonitrile according to the general procedure
1
(petroleum ether/EtOAc, 100:1): white solid. H NMR (400 MHz, CDCl , ppm) δ = 7.60
3
(q, J = 8.2 Hz, 4H), 7.44 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 2.38 (s, 3H).
13
1
C{ H}NMR (151 MHz, CDCl , ppm) δ = 139.7, 132.2, 132.2, 131.9, 129.5, 128.7,
3
+
+
1
19.3, 118.8, 111.4, 94.3, 87.4, 21.8. QTOF-MS m/z [M + Na] Calcd for C H NNa
16
11
240.0784; Found 240.0792.
4
-(Phenylethynyl)benzonitrile (3ab).95 3ab was obtained in 90% yield (36.5 mg)
1
according to the general procedure (petroleum ether/EtOAc, 100:1): white solid. H
NMR (400 MHz, CDCl , ppm): δ 7.61 (q, J = 8.3 Hz, 4H), 7.58–7.52 (m, 2H), 7.43–7.34
3
1
(
m, 3H). 13C{ H}NMR (151 MHz, CDCl , ppm): δ 132.2, 132.2, 132.0, 129.3, 128.7,
3
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The Journal of Organic Chemistry
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28.4, 122.4, 118.7, 111.6, 94.0, 87.9. QTOF-MS m/z [M + Na] Calcd for C H NNa
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226.0627; Found 226.0645.
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-((4-Methoxyphenyl)ethynyl)benzonitrile (3ac).96 3ac was obtained in 87% yield
(40.6 mg) according to the general procedure (petroleum ether/EtOAc, 100:1): white
1
solid. H NMR (400 MHz, CDCl , ppm): δ 7.58 (dd, J = 17.6, 8.3 Hz, 4H), 7.48 (d, J =
3
13
1
8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 3.83 (s, 3H). C{ H}NMR (151 MHz, CDCl , ppm):
3
δ 160.4, 133.5, 132.1, 132.0, 128.8, 118.8, 114.4, 114.3, 111.1, 94.3, 86.9, 55.5. QTOF-
+
+
MS m/z [M + Na] Calcd for C H NONa 256.0733; Found 256.0721.
16
11
97
4
-((4-(Tert-butyl)phenyl)ethynyl)benzonitrile (3ad). 3ad was obtained in 88% yield
(
45.6 mg) according to the general procedure (petroleum ether/EtOAc, 100:1): white
1
solid. H NMR (400 MHz, CDCl , ppm): δ 7.64–7.61 (m, 2H), 7.60–7.57 (m, 2H), 7.51–
3
13
1
7
.47 (m, 2H), 7.43–7.38 (m, 2H), 1.34 (s, 9H). C{ H}NMR (151 MHz, CDCl , ppm): δ
3
1
52.7, 132.2, 132.2, 131.7, 128.7, 125.7, 119.3, 118.7, 111.4, 94.4, 87.4, 35.1, 31.3.
+
+
QTOF-MS m/z [M + Na] Calcd for C H NNa 282.1253; Found 282.1260.
19
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-((4-Ethylphenyl)ethynyl)benzonitrile (3ae). 3ae was obtained in 86% yield (39.7
mg) according to the general procedure (petroleum ether/EtOAc, 100:1): white solid, mp
1
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1
1
1
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1
1
1
1
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=
105.8−106.3 ℃. H NMR (400 MHz, CDCl , ppm): δ 7.34 (q, J = 8.1 Hz, 4H), 7.21 (d,
3
J = 7.8 Hz, 2H), 6.95 (d, J = 7.8 Hz, 2H), 2.42 (q, J = 7.5 Hz, 2H), 0.99 (t, J = 7.5 Hz,
1
3
1
3
1
2
H). C{ H}NMR (151 MHz, CDCl , ppm): δ 145.9, 132.2, 132.2, 132.0, 128.7, 128.3,
3
-1
19.6, 118.8, 111.4, 94.4, 87.4, 29.1, 15.5. IR (KBr disc, cm ): 2957, 2926, 2852, 2225,
213, 1918, 1640, 1597, 1511, 1459, 1407, 1377, 1271, 1177, 1133, 1105, 1060, 1017,
+
+
973, 835, 556, 543. QTOF-MS m/z [M + Na] Calcd for C H NNa 254.0940; Found
17
13
2
54.0955.
4-((4-Pentylphenyl)ethynyl)benzonitrile (3af). 3af was obtained in 87% yield (47.5
mg) according to the general procedure (petroleum ether/EtOAc, 100:1): white solid, mp
1
77.5−78.3 ℃. H NMR (400 MHz, CDCl , ppm): δ 7.60 (q, J = 8.1 Hz, 4H), 7.46 (d, J =
3
7
.8 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 2.63 (t, J = 7.7 Hz, 2H), 1.63 (dd, J = 14.2, 7.2 Hz,
13
1
2
H), 1.33 (d, J = 3.1 Hz, 5H), 0.90 (t, J = 6.5 Hz, 3H). C{ H}NMR (151 MHz, CDCl ,
3
ppm): δ 144.7, 132.2, 132.1, 131.9, 128.8, 128.7, 119.5, 118.7, 111.4, 94.4, 87.4, 36.1,
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1
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1.6, 31.0, 22.7, 14.2. IR (KBr disc, cm ): 2958, 2926, 2856, 2217, 1910, 1674, 1600,
1
512, 1456, 1405, 1377, 1262, 1183, 1103, 1019, 838, 802, 727, 555, 544. QTOF-MS
0
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+
+
m/z [M + Na] Calcd for C H NNa 296.1410; Found 296.1410.
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4-([1,1'-Biphenyl]-4-ylethynyl)benzonitrile (3ag). 3ag was obtained in 84% yield
(
46.9 mg) according to the general procedure (petroleum ether/EtOAc, 100:1): white
1
solid, mp 177.8−178.7 ℃. H NMR (400 MHz, CDCl , ppm): δ 7.64 (d, J = 12.3 Hz, 9H),
3
.57–7.43 (m, 3H), 7.39 (t, J = 7.3 Hz, 1H). 13C{ H}NMR (151 MHz, CDCl , ppm): δ
1
7
3
142.0, 140.2, 133.6, 132.8, 132.4, 132.2, 129.1, 128.4, 128.1, 127.3, 127.2, 121.2,
-1
1
18.7, 111.6, 94.0, 88.6. IR (KBr disc, cm ): 2957, 2925, 2853, 2231, 2215, 1637,
1598, 1500, 1459, 1483, 1406, 1378, 1261, 1178, 1098, 1020, 841, 803, 765, 690, 554.
+
+
QTOF-MS m/z [M + Na] Calcd for C H NNa 302.0940; Found 302.0954.
21
13
4
-((4-Fluorophenyl)ethynyl)benzonitrile (3ah).96 3ah was obtained in 93% yield
(
41.1 mg) according to the general procedure (petroleum ether/EtOAc, 100:1): white
1
solid. H NMR (400 MHz, CDCl , ppm): δ 7.63 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz,
3
13
1
2
H), 7.56–7.49 (m, 2H), 7.07 (t, J = 8.5 Hz, 2H). C{ H}NMR (151 MHz, CDCl , ppm): δ
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63.1 (d, J = 252.2 Hz), 162.3, 133.9 (d, J = 8.5 Hz), 132.2, 132.1, 128.2, 118.6, 118.5
+
(d, J = 3.0 Hz), 116.1 (d, J = 21.1 Hz), 111.7, 92.8, 87.5. QTOF-MS m/z [M + Na] Calcd
1
1
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5
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2
3
4
5
6
7
8
9
0
+
for C H FNNa 244.0533; Found 244.0517.
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8
96
4-((4-Chlorophenyl)ethynyl)benzonitrile (3ai). 3ai was obtained in 91% yield (43.1
1
mg) according to the general procedure (petroleum ether/EtOAc, 100:1): white solid. H
NMR (400 MHz, CDCl , ppm): δ 7.63 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.49–
3
13
1
7.44 (m, 2H), 7.35 (d, J = 8.5 Hz, 2H). C{ H}NMR (151 MHz, CDCl , ppm): δ 135.4,
3
133.2, 132.2, 132.2, 129.1, 128.0, 120.9, 118.6, 111.9, 92.7, 88.8. QTOF-MS m/z [M +
+
+
Na] Calcd for C H ClNNa 260.0237; Found 260.0263.
15
8
Methyl 4-((4-cyanophenyl)ethynyl)benzoate (3aj). 3aj was obtained in 92% yield
(48.0 mg) according to the general procedure (petroleum ether/EtOAc, 100:1): yellow
1
solid, mp 149.0−149.8 ℃. H NMR (400 MHz, CDCl , ppm): δ 8.04 (d, J = 8.1 Hz, 2H),
3
13
1
7.71–7.54 (m, 6H), 3.93 (s, 3H). C{ H}NMR (151 MHz, CDCl , ppm): δ 166.6, 132.4,
3
132.3, 131.9, 130.5, 129.8, 127.8, 127.0, 118.6, 112.2, 92.9, 90.5, 52.5. IR (KBr disc,
-1
cm ): 2954, 2924, 2851, 2225, 1938, 1721, 1604, 1559, 1514, 1494, 1446, 1433, 1405,
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