A Ni(OAc)2·4H2O-catalysed Sonogashira-type coupling reaction of aryl iodides and terminal alkynes in the presence of CuI

Article abstract of DOI:10.3184/174751912X13379433093990

An effective and promising Ni/Cu catalytic system for the coupling of aryl iodides with various terminal alkynes has been developed. For the first time the readily available chiral amino alcohol has been employed as the ligand for the Pd-free Sonogashira

Full text of DOI:10.3184/174751912X13379433093990

JOURNAL OF CHEMICAL RESEARCH 2012
JULY, 437–440
RESEARCH PAPER 437
A Ni(OAc) ·4H O-catalysed Sonogashira-type coupling reaction of aryl
2
2
iodides and terminal alkynes in the presence of CuI
Hailong Yang, Yan Zhu, Peng Sun, Hong Yan, Linhua Lu, Shouguo Wang and Jincheng Mao*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow
University, Suzhou 215123, P. R. China
An effective and promising Ni/Cu catalytic system for the coupling of aryl iodides with various terminal alkynes has
been developed. For the first time the readily available chiral amino alcohol has been employed as the ligand for the
Pd-free Sonogashira coupling reaction.
Keywords: aryl iodides, terminal alkynes, Sonogashira coupling, cross-coupling, palladium-free
2
1
It is well known that transition metal-catalysed cross-coupling
reactions are very powerful processes for the formation of
could show the best catalytic activity. We now report that
readily available Ni(OAc) ·4H O has proved to be a promising
2
2
1,3
carbon–carbon bonds Among them, the Sonogashira-type
coupling between terminal alkynes and aryl or vinyl halides
is one of the important and widely used procedures for the
synthesis of molecules containing an acetylenic moiety, which
is found in many fine chemicals and biologically active
catalyst for the Sonogashira coupling reaction together with
CuI and with chiral amino alcohol (12) (Scheme 1) as the
ligand.
Experimental
4
5
substances. For example, compound 1 was synthesised for
All reactions were carried out under an argon atmosphere. Solvents
were dried and degassed by standard methods and all aryl halides
were purchased from Aldrich or Alfa. Aryl alkynes and various nickel
resources were purchased from Aldrich, Acros or Alfa. Flash column
chromatography was performed using silica gel (300–400 mesh).
Analytical TLC was performed using glass plates pre-coated with
00–300 mesh silica gel impregnated with a fluorescent indicator
254 nm). NMR spectra were recorded in CDCl3 on a Varian
Inova-400 NMR spectrometer (400 MHz) with TMS as an internal
reference. Products were characterised by comparison with H NMR,
the research on three-dimensional metal-organic frameworks
6
(
MOFs) and compound 2 and its derivatives were proved to be
potential hepatitis C virus (HCV) inhibitors (Fig. 1).
The traditional Sonogashira coupling is carried out in the
presence of PdCl (PPh ) , PdCl /PPh , or Pd(PPh ) together
2
3
2
2
3
3 4
2
(
with CuI as the cocatalyst and larger amount of amines as the
7
solvents or cosolvents. In the past decades, many efficient
modified protocols have been developed, such as copper-
1
8
–12
13
14
free, Pd/Ni bimetallic systems, Au complex and Ru/Al O
13
22–24
2
3
C NMR and TOF-MS data in the literatures.
15
systems. However, they were limited in industrial use due to
the expensive cost. Thus, the alternative way to solve this
problem was raised by using cheaper and lower-toxicity metal
instead of palladium, for example, copper-catalysed coupling
reactions in the presence of ligands
lytic system for the reaction. Recently, we reported a highly
efficient example of Fe/Cu co-catalysed alkynylation of aryl
halides in the absence of any ligands. As an extension of this
work, we have tried to find other efficient palladium-free cata-
lytic systems for the Sonogashira coupling reaction. In 2005,
Wang and Li reported that an ultrafine particle nickel(0) could
Sonogashira reaction of alkynes and halides;general procedure
A flask was charged with Ni(OAc) ·4H O (0.075 mmol), (–)-ephe-
drine (12) (0.15 mmol), CuI (0.075 mmol), BuOK (1.0 mmol) and any
remaining solids (aryl halide). The flask was evacuated and backfilled
with argon (this procedure was repeated three times). Aryl iodides
2
2
t
1
6–18
or an iron-based cata-
19
(
0.5 mmol, if liquid), alkyne (0.6 mmol), and DMSO (2 mL) were
added to the flask under an argon atmosphere. The flask was sealed
and the mixture was stirred at the shown temperature for the indicated
period of time. At the end of the reaction, the reaction mixture was
cooled to room temperature, diluted with diethyl ether and washed
with water. The combined organic phase was dried over anhydrous
Na SO . The solvent of the filtrate was removed with the aid of a
rotary evaporator, and the residue was purified by column chromato-
graphy on silica gel, using a mixed solvent (petroleum ether/ethyl
acetate) as eluent to provide the desired product.
2
0
2
4
catalyse this coupling in the presence of CuI with PPh as the
3
ligand. They also found that Ni(0) of a special size (ca 100 nm)
1
-(2-(4-Methoxyphenyl)ethynyl)benzene (3): Yellow solid; m.p.
22 1
5
7–59 °C (lit. 59–60 °C); H NMR (400 MHz, CDCl ) δ 7.52–7.50
3
(
m, 2H, ArH), 7.47 (d, J = 8.8 Hz, 2H, ArH), 7.36–7.32 (m, 3H, ArH),
+
6
.88 (d, J = 8.8 Hz, 2H, ArH), 3.83 (s, 3H, CH ); HRMS (ESI ): Calcd.
3
+
for [C H O] requires m/z 208.0888, found 208.0896.
15
12
1
-(2-Phenylethynyl)naphthalene (4) [22]: Yellow solid. m.p. 74–
1
7
5 °C; H NMR (400 MHz, CDCl ) δ 8.45 (d, J = 8.0 Hz, 1H, ArH),
3
7
.86 (t, J = 8.0 Hz, 2H, ArH), 7.77 (d, J = 0.8 Hz, 1H, ArH), 7.67 (d,
J = 0.2 Hz, 1H, ArH), 7.65 (d, J = 0.2 Hz, 1H, ArH), 7.59 (d, J =
6
.8 Hz, 1H, ArH), 7.56 (d, J = 0.8 Hz, 1H, ArH), 7.53 (d, J = 0.8 Hz,
+
+
1
H, ArH), 7.48–7.39 (m, 3H, ArH); HRMS (ESI ): Calcd for [C H ]
18 12
requires m/z 228.0939; found 228.0938.
1
-Fluoro-4-(2-phenylethynyl)benzene (5): Yellow solid; m.p. 108–
2
3
1
1
09 °C (lit. 105–109 °C); H NMR (400 MHz, CDCl ) δ 7.53–7.50
3
(
m, 4H, ArH), 7.36–7.34 (m, 3H, ArH), 7.05 (t, J = 8.6 Hz, 2H, ArH);
13
C NMR (100 MHz, CDCl3) δ 165.4 (d, J = 249.5 Hz, C), 135.2 (d,
J = 8.3 Hz, CH), 133.2 (CH), 130.0 (d, J = 3.7 Hz, CH), 124.7 (C),
21.0 (d, J = 3.4 Hz, CH), 117.4 (C), 117.2 (C), 90.7 (C), 89.2 (C);
1
+
+
HRMS (ESI ): Calcd for [C H F] requires m/z 196.0688; found
14
9
1
96.0690.
,2-Diphenylethyne (6): White solid; m.p. 58–59 °C lit. 63–
23
1
Fig. 1 Examples for structures containing the arylene-ethynyl-
ene motif.
1
6
4 °C); H NMR (300 MHz, CDCl ) (δ, ppm):7.25–7.35 (m, 6H),
3
13
7
.52–7.54 (m, 4H); C NMR (100 MHz, CDCl ) (δ, ppm): 89.84,
3
+ +
1
28.87. 129.69, 132.09, 132.98; HRMS (ESI ): Calcd for [C H ]
14 10
*
Correspondent. E-mail: jcmao@suda.edu.cn
requires m/z 178.0783; found 178.0791.

4
38 JOURNAL OF CHEMICAL RESEARCH 2012
Scheme 1 The ligands evaluated in the study.
1
-Chloro-4-(2-phenylethynyl)benzene (7): Yellow solid; m.p. 83–
t
K CO , K PO , KOH, NaOH, BuOLi, KF, Na CO , NaOAc,
24
1
2
3
3
4
2
3
8
7
4 °C (lit. 83–84 °C); H NMR (400 MHz, CDCl ) δ 7.53 (t, J =
.6 Hz, 2H, ArH), 7.46 (d, J = 8.4 Hz, 2H, ArH), 7.36–7.34 (m, 4H,
ArH), 7.32 (s, 1H,ArH); HRMS (ESI ): Calcd for [C H Cl] requires
t
3
LiOAc, LiOAc, Bu NOAc, TMSNLi and BuOK had remark-
able effect on the coupling reactions (Table 1, entries 1–12),
and BuOK was the best among the bases. In addition, an
4
+
35
+
14
9
t
m/z 212.0393; found 212.0396.
-Methyl-4-(2-phenylethynyl)benzene (8): White solid; m.p. 113–
organic base (triethylamine) was also employed, but here the
coupling did not occur (Table 1, entry 13). Furthermore, sev-
eral commonly-used solvents, including dimethylformamide
(DMF), PEG-400 (poly(ethylene)glycol), NMP (N-methyl-2-
pyrrolidone), toluene, dioxane, isopropanol and acetonitrile,
were screened in the model reaction under suitable tempera-
tures (Table 1, entries 14–20). The results suggested that
DMSO was the best solvent.
Then different additives were employed in the coupling
reaction between iodoanisole and phenylacetylene as shown in
Table 2. Firstly, 15 mol% of CuI showed an obvious accelera-
tion role in the reaction and an enhanced yield of the desired
1
24
1
1
(
7
15 °C (lit. 113–114 °C); H NMR (400 MHz, CDCl ) δ 7.54–7.52
m, 2H, ArH), 7.43 (d, J = 8.0 Hz, 2H, ArH), 7.37–7.33 (m, 3H, ArH),
3
+
.16 (d, J = 8.0 Hz, 2H, ArH), 2.37 (s, 3H, CH ); HRMS (ESI )Calcd
3
+
for [C H ] requires m/z 192.0939, found 192.0926.
15
12
Results and discussion
Firstly, various commercially available ligands (3–22) were
directly employed into the model coupling between p–iodoan-
isole and phenylacetylene in the presence of Ni(OAc) ·4H O
as the catalyst precursor, BuOK as the base and DMSO (dimethyl
sulfoxide) as the solvent, at 130 °C for 24 h. As shown in
Scheme1,theseligandsincludeL-proline(3),1,10-phenanthro-
line (4), N,N′-dimethylethylenediamine (5), hippuric acid (6),
2
2
t
8-hydroxyquinoline(7),2,2′-bipyridine(8),rac-1,1′-bi-2-naph-
thol (9), 2-aminophenol (10), (1R,2S)-2-amino-1,2-diphenyl-
ethanol (11), (–)-ephedrine (12), diphenyl [(S)-pyrrolidin-2-yl]
methanol (13), DABCO (1,4-diazabicycol[2.2.2]octane) (14),
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (15), N,N-dimeth-
ylglycine (16), N-methyl-(–)-ephedrine (17), 2,2-(diacetamido)
propionic acid (18), triethylamine (19), TMEDA (tetrameth-
ylethylenediamine) (20), (1R, 2S)-1-amino-2-indanol (21) and
L-prolinol (22). The results were shown in Fig. 2. Recently, we
have reported that inexpensive hippuric acid (6) is a novel
ligand for amination of nitrogen-containing heterocycles with
2
5
various aryl halides in moderate to excellent yields. In our
screening experiment, hippuric acid also showed good cata-
lytic effect in the Sonogashira coupling reaction. From Fig. 2,
it can be seen that (–)-ephedrine (12) afforded the desired
product in highest yield.
Fig. 2 The relationship between ligands and catalytic effect.
Thus, 12 was considered as the best ligand for the following
screening experiments. The results are listed in Table 1. As
shown, various widely used inorganic bases such as Cs CO ,
The catalytic reaction conditions: iodoanisole (0.5 mmol),
t
2 2
phenylacetylene (0.6 mmol), BuOK (2 equiv.), Ni(OAc) ·4H O
(15 mol %), ligand (30 mol%), DMSO (2 mL), 130 °C, 24 h, Ar.
2
3

JOURNAL OF CHEMICAL RESEARCH 2012 439
Table 1 Screening different bases and solvents in the nickel-
The results that we obtained encouraged us to investigate
the applied scope of this catalytic system summarised in Table
a
catalysed Sonogashira reaction
3
. The reaction times were 24 h and 48 h, respectively. It can
be seen that the Ni/Cu system efficiently promotes cross-
coupling reactions between aryl iodides and terminal alkynes.
Generally, the longer reaction time resulted in higher yields of
the corresponding products (Table 3, entries 2, 4, 6, 8, 10, 12,
14 and 16). Furthermore, for the aryl idodides, unsubstituted
examples usually afforded better results than substituted ones
Entry
Cat.
Ni(OAc) ·4H
Base
Cs CO
Solvent (T/°C) Yield/%b
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
3
DMSO (130)
DMSO (130)
DMSO (130)
DMSO (130)
DMSO (130)
DMSO (130)
DMSO (130)
DMSO (130)
DMSO (130)
NR
NR
13
10
7
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
·4H
·4H
·4H
·4H
·4H
·4H
·4H
·4H
·4H
·4H
·4H
·4H
·4H
·4H
·4H
·4H
·4H
·4H
·4H
K
2
CO
KOH
NaOH
3
(
Table 3, entries 3–4, 7–8).
t
BuOLi
KF
2 2
Table 3 Ni(OAc) ·4H O-catalysed Sonogashira coupling of
a
NR
8
alkynes and aryl iodides
2 3
Na CO
NaOAc
LiOAc
9
6
10
11
12
13
14
15
16
17
18
19
20
Bu
4
NOAc DMSO (130)
5
TMSNLi
DMSO (130)
DMSO (130)
DMSO (130)
DMF (130)
PEG-400 (130)
NMP (130)
10
34
NR
13
9
t
BuOK
Et N
3
Entry
RX
R′C≡CH
Product Time Yield
t
t
t
t
t
t
t
BuOK
BuOK
BuOK
BuOK
BuOK
BuOK
BuOK
b
/h
/%
8
Toluene (100)
Dioxane (100)
Trace
5
25
NR
1
2
25
25
24
48
53
CH
3
CN (100)
i
PrOH (100)
56
45
a
The catalytic reaction conditions: aryl iodide (0.5 mmol), alkyne
0.6 mmol), base (2 equiv), Ni(OAc) ·4H O (15 mol%), 12
30 mol%), solvent (2 mL), 130 °C, 24 h, Ar.
(
(
2
2
3
4
26
26
24
48
b
Isolated yield.
product was obtained (Table 2, entry 1). Varying the reaction
temperature from 130 to 140 °C, we got a higher isolated yield
55
(
53%) (Table 2, entry 2). The control experiment suggested
that CuI alone afforded the corresponding product in low yield
Table 2, entry 3). Therefore, it can be seen that the combina-
tion of Ni(OAc) ·4H O and CuI showed higher catalytic activ-
5
6
27
27
28
28
29
29
30
30
30
30
27
27
24
48
24
48
24
48
24
48
24
48
24
48
33
35
54
66
30
35
44
56
51
52
36
43
(
2
2
ity. In addition, other types of additives were studied in the
coupling reaction, including iodine, TBAB (tetra-n-butylam-
monium bromide), LiCl, zinc powder, copper powder and
sodium borohydride. However, we did not observe enhanced
results (Table 2, entries 4–9). Various nickel resources were
also used in the coupling reactions and the results were still
disappointing (Table 2, entries 10–12). The lower temperature
led to a decreased yield of the desired product (Table 2, entry
7
8
9
1
3). In order to avoid to generating homocoupling product of
alkynes, all of the experiments were conducted under an argon
atmosphere.
10
11
Table 2 Screening different additives and nickel sources in
a
the nickel-catalysed Sonogashira reaction
Entry
Cat.
Additive/mol% Temp./°C Yield/%b
12
1
2
3
4
5
6
7
8
9
Ni(OAc)
Ni(OAc)
–
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
Ni(OAc)
2
·4H
2
2
O
O
CuI (15)
CuI (15)
CuI (15)
130
140
140
130
130
130
130
130
130
130
130
130
110
44
53
·4H
2
1
1
1
3
4
5
6
28
2
·4H
2
·4H
2
·4H
2
·4H
2
·4H
2
·4H
2
O
2
O
2
O
2
O
2
O
2
O
I
2
(100)
NR
13
Trace
23
36
TBAB (100)
LiCl (100)
Zn (30)
Cu (30)
NaBH
4
(150)
Trace
30
10
11
12
13
NiCl
NiCl ·6H
Ni(acac)
Ni(OAc) ·4H
2
CuI (15)
CuI (15)
CuI (15)
CuI (15)
2
2
O
32
1
2
20
2
2
O
43
a
The catalytic reaction conditions: aryl halide (0.5 mmol),
a
t
The catalytic reaction conditions: aryl iodide (0.5 mmol),
2 2
alkyne (0.6 mmol), BuOK (2 equiv), Ni(OAc) ·4H O (15 mol %),
t
alkyne (0.6 mmol), BuOK (2 equiv), Ni cat. (15 mol %), 12
CuI (15 mol%) 12 (30 mol%), DMSO (2 mL), 140 °C, 24–48 h,
(
30 mol%), DMSO (2 mL), 130 °C, 24 h, Ar.
Isolated yield.
Ar.
b
b
Isolated yield.

4
40 JOURNAL OF CHEMICAL RESEARCH 2012
Conclusions
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2
3
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Received 17 January 2012; accepted 2 May 2012
Paper 1201114 doi: 10.3184/174751912X13379433093990
Published online: 26 June 2012
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