Palladium-free copper-catalyzed Sonogashira cross-coupling at room temperature

Article abstract of DOI:10.1055/s-2008-1067127

We have developed an efficient method for the palladium-free copper-catalyzed Sonogashira cross-coupling of o-iodoacetanilide derivatives with alkynes at room temperature; the corresponding coupling products were obtained in good to excellent yields using copper(I) iodide/N-methylpyrrolidine- 2-carboxamide as the catalyst. This inexpensive catalyst system has high tolerance towards various functional groups in the substrates. This represents the lowest reaction temperatures for copper-catalyzed Sonogashira cross-coupling thus far. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067127

PAPER
2417
Palladium-Free Copper-Catalyzed Sonogashira Cross-Coupling at Room
Temperature
C
opper-Catalyzed
u
Sonogashira
i
Cross-
m
C
oupling in Jiang,a,b Hua Fu,*a Renzhong Qiao,*b Yuyang Jiang,*a,c Yufen Zhao*a
a
b
c
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62781695; E-mail: fuhua@mail.tsinghua.edu.cn
Department of Pharmaceutical Engineering, College of Life Science and Technology, Beijing University of Chemical Technology,
Beijing 100029, P. R. of China
E-mail: qiaorz@mail.buct.edu.cn
Key Laboratory of Chemical Biology (Guangdong Province), Graduate School of Shenzhen, Tsinghua University, Shenzhen 518057,
P. R. of China
Received 18 March 2008; revised 16 April 2008
tion of C(sp2)–C(sp) bonds. However, the drawbacks of
the catalyst systems, such as air sensitivity, high cost, and
toxicity, limit their applications for industrial processes,
hence it is highly desirable to develop readily available
Abstract: We have developed an efficient method for the palladi-
um-free copper-catalyzed Sonogashira cross-coupling of o-iodo-
acetanilide derivatives with alkynes at room temperature; the
corresponding coupling products were obtained in good to excellent
yields using copper(I) iodide/N-methylpyrrolidine-2-carboxamide and inexpensive catalyst systems instead of palladium cat-
as the catalyst. This inexpensive catalyst system has high tolerance
alysts to promote the coupling of terminal alkynes and
towards various functional groups in the substrates. This represents
aryl or vinyl halides.
the lowest reaction temperatures for copper-catalyzed Sonogashira
cross-coupling thus far.
During the last decade, several examples involving nick-
el-5 and copper-catalyzed6 Sonogashira reactions have
been reported, but high temperatures (80–130 °C) and
long times were required. In particular, cyclic indoles
were the major products and only small amounts of
o-alkynyltrifluoroacetanilides were obtained when o-halo-
trifluoroacetanilides were used as the starting materials
[Scheme 1 (a)].6e–h In fact, the o-alkynyltrifluoroacetanil-
ides are important intermediates for the construction of di-
verse novel molecules, for example palladium-catalyzed
Key words: Sonogashira reaction, cross-coupling, copper cataly-
sis, N,N-ligand, room temperature
Many antimycotics,1 antibiotics,2 liquid crystals, poly-
mers, and optical or electronic materials3 have been syn-
thesized via the Sonogashira reaction4 of terminal alkynes
and aryl or vinyl halides; this palladium and copper co-
catalyzed coupling is a popular strategy for the construc-
O
O
H
NH
X
CF3
+
NH
CF3
N
[Cu]/L
heat
R1
R1
R1
(a)
R2
R2
+
R2
major
minor
R2
X = I, Br
R2
R1
R2
Br
O
[Pd]
(1) [Pd]
(2) H2O
+
R1
(b)
(c)
R1
NHCOCF3
N
H
N
H
O
Ar
[Pd]
NHCOCF3
+
ArI
+
CO
N
N
NHCOCF3
F3C
Scheme 1 (a) Copper-catalyzed coupling of o-halotrifluoroacetanilides with terminal alkynes; palladium-catalyzed synthesis of (b) 2-substi-
tuted 3-alkynylindoles or 2-substituted 3-acylindoles7a and (c) 12-acylindolo[1,2-c]quinazolines7b using o-alkynyltrifluoroacetanilides as the
starting materials
SYNTHESIS 2008, No. 15, pp 2417–2426
x
x.
x
x
.
2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1067127; Art ID: F06408SS
© Georg Thieme Verlag Stuttgart · New York

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H. Jiang et al.
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Table 1 Copper-Catalyzed Sonogashira Cross-Coupling Reaction of N-(2-Iodophenyl)trifluoro- (1a) and N-(2-Iodophenyl)acetamide (1d)
with Phenylacetylene (2a): Optimization of the Catalysis Conditionsa
O
O
catalyst, ligand
base, DMF
H
NH
I
R
NH
R
N
+
Ph
+
Ph
r.t., 6 h
2a
1a,d
4a
3a,m
Ph
HO
COOH
NH HN
COOH
Ligand =
COOH
N
N
N
A
B
C
D
H
H
.
HCl
NHMe
O
OH
OH
N
COOH
N
H
H
E
G
F
Entry
R
Catalyst
Ligand
Base
Isolated yield (%)
3a
30
42
45
41
75
0
4a
1
2
3
4
5
6
7
8
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Me
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
A
B
C
D
E
F
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
0
0
0
0
trace
0
0
G
G
90
10
0
0
93b
9
10
11
12
13
14
15
16
17
18
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CuIc
Gc
Gc
G
G
G
G
G
G
G
G
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K3PO4
52
0
traced
CuIc
76e
0
CuBr
CuCl
CuSO4
75
78
0
0
0
Cu(OAc)2
CuCl2
CuI
25
20
trace
63
61
0
0
0
CuI
0
CuI
K2CO3
0
a Reaction conditions: o-iodoacetanilide derivative 1 (0.5 mmol), phenylacetylene (2a, 0.75 mmol), catalyst (0.15 mmol), ligand (0.5 mmol),
base (1.25 mmol), solvent (2 mL), N2, 25 °C, 6 h.
b Reaction temperature: 40 °C.
c Catalyst (0.05 mmol), ligand (0.1 mmol).
d Reaction time: 12 h.
e Reaction temperature: 80 °C.
Synthesis 2008, No. 15, 2417–2426 © Thieme Stuttgart · New York

PAPER
Copper-Catalyzed Sonogashira Cross-Coupling
2419
Ph
O
O
I
NH
CF3
NH
CF3
Ph
PdCl2, PPh3
Et3N, DMF
MeOOC
MeOOC
r.t., 16 h, 78%
3k
5
Scheme 2 Palladium-catalyzed coupling of 3k with phenylacetylene to give 5
R3
NH
R2
O
NHMe
R1
O
N
NH
R2
CuI, base
R3
O
HI
H
N
R1
I
L
H
N
Me
3
O
Cu
II
Cu
Cu
H
CuI
L
I
I
R3
III
R3
Scheme 3 Possible mechanism of N-methylpyrrolidine-2-carboxamide-promoted copper-catalyzed Sonogashira cross-coupling of o-halo-
acetanilides with alkynes
synthesis of 2-substituted 3-alkynylindoles or 2-substitut- per(I) iodide and 20 mol% N-methylpyrrolidine-2-
ed 3-acylindoles [Scheme 1 (b)]7a and 12-acylindolo[1,2- carboxamide (relative to o-iodotrifluoroacetanilide 1a)
c]quinazolines [Scheme 1 (c)].7b Herein, we report an easy were used as the catalyst/ligand system with a reaction
and inexpensive N-methylpyrrolidine-2-carboxamide- time of 12 hours, the coupling of the substrates 1a and 2a
promoted copper-catalyzed Sonogashira cross-coupling gave compound 3a in 52% yield together with a trace
of substituted o-iodoacetanilide derivatives with alkynes amount of 4a (entry 9). Increasing the reaction tempera-
to give o-alkynylacetanilides at room temperature.
ture to 80 °C led to complete transformation of 3a to 4a
(entry 10). We attempted various reaction temperature
and times and amounts of copper salt and ligand and the
results showed that an increase in temperature, extended
time, and reduction in the amount of catalyst/ligand im-
proved the yield of cyclic product 4a. In contrast, a rea-
sonable amount of catalyst/ligand, lower temperatures,
and shorter reaction times could inhibit transformation of
3a to 4a. We studied the effect of copper salts (compare
entries 7 and 11–15) and copper(I) iodide was found to be
the best catalyst. The base also influences the reaction
process and cesium carbonate provided the highest yields
(compare entries 7 and 16–18). Other solvents (DMSO,
toluene, dioxane, and THF) were also investigated and the
results showed that N,N-dimethylformamide was a suit-
able solvent. After the optimization process of catalysts,
ligands, bases, solvents, amount of catalysts and ligands,
the following cross-coupling reactions were performed
under our standard conditions, 30 mol% copper(I) iodide
as the catalyst, 1 equivalent of N-methylpyrrolidine-2-car-
boxamide as the ligand relative to the aryl halide, N,N-
dimethylformamide as the solvent, and 2.5 equivalents of
cesium carbonate as the base.
Although several examples involving copper-catalyzed
coupling of o-halotrifluoroacetanilide derivatives with
alkynes have been reported as described above, the cou-
pling reactions predominately gave the corresponding cy-
clic indoles [Scheme 1 (a)].6e–h We believe that the choice
of a suitable catalyst system (including copper sources,
ligands, bases, solvents, amount of catalysts, and ligands)
and reaction temperature could promote the coupling of o-
halotrifluoroacetanilide derivatives with alkynes to give
o-alkynyltrifluoroacetanilides and inhibit the cyclization
of the internal alkynes to indoles, hence, we initialized the
optimization of the catalysis conditions as shown in Table
1. Several ligands, N,N¢-dimethylethylenediamine A
(entry 1),8 amino acids B–E (entries 2–5),9 rac-BINOL F
(entry 6),10 and N-methylpyrrolidine-2-carboxamide hy-
drochloride G11 (entry 7) (1 equiv relative to o-iodotri-
fluoroacetanilide) were screened using 30 mol% copper(I)
iodide as the copper source, cesium carbonate as the base
and N,N-dimethylformamide as the solvent. N-Meth-
ylpyrrolidine-2-carboxamide exhibited the best activity
(90% yield of 3a, entry 7). No cyclic product 4a was ob-
served in the reaction of N-(2-iodophenyl)trifluoroacet-
amide (1a) with phenylacetylene (2a) even when the As shown in Table 2, the copper-catalyzed Sonogashira
reaction time was extended to 12 hours under the same cross-coupling of o-iodotrifluoroacetanilide 1a with vari-
conditions (entry 7). The coupling yield greatly decreased ous alkynes [phenylacetylene (2a), pent-1-yn-3-ol (2b),
to 10% when the NHCOCF3 group in o-iodotrifluoroacet- 1-ethynylcyclohexene (2c), oct-1-yne (2d), and cyclopro-
anilide 1a was replaced with NHCOMe to give o-iodo- pylacetylene (2e)] gave good to excellent yields of 3a–e
acetanilide 1d at 25 °C for six hours, fortunately, the (entries 1–5). It is worthwhile to note that o-iodotrifluoro-
coupling reaction gave a 93% yield of 3m when tempera- acetanilide 1a using cyclopropylacetylene (2e) as the part-
ture was increased to 40 °C (entry 8). When 10 mol% cop- ner could not completely transfer into the corresponding
Synthesis 2008, No. 15, 2417–2426 © Thieme Stuttgart · New York

2420
H. Jiang et al.
PAPER
products when one equivalent of ligand was used. Howev- ucts (entries 8–10). The result showed that addition of the
er, the coupling rate of o-iodotrifluoroacetanilide 1a with first alkyne to 2,6-diiodotrifluoroacetanilide derivative 1c
cyclopropylacetylene (2e) was very fast in the presence of decreased the activity of the second C–I bond in the
two equivalents of the ligand and the reaction was com- monosubstituted products. The monosubstituted product
plete within 30 minutes giving 3e together with a small 3k could be coupled with another alkyne to give internal
amount of cyclization product 4e (entry 5). Unfortunately, dialkyne 5 under palladium catalysis (Scheme 2), which
o-bromoacetanilide 1e reacted with phenylacetylene (2a) provides an opportunity for the construction of diverse
and oct-1-yne (2d) to provide lower yields of 3a and 3d molecules. In addition, the inexpensive catalyst system
even at 40 °C (entries 13 and 14); the yield of the corre- (CuI/N-methylpyrrolidine-2-carboxamide) has a high tol-
sponding cyclic products gradually increased when tem- erance towards various functional groups in the sub-
perature was continuously raised. We investigated the strates, for example ester, amide, and hydroxy groups.
ortho effect of o-halotrifluoroacetanilides; the coupling of
2,4-diiodotrifluoroacetanilide derivative 1b with alkynes
A possible coupling mechanism of N-methylpyrrolidine-
2-carboxamide-promoted copper-catalyzed Sonogashira
selectively occurred at the ortho position (entries 6 and 7),
cross-coupling of o-haloacetanilides with alkynes has
and these result showed that the NHCOCF3 group in 2,4-
been suggested (Scheme 3). The reaction of a terminal
alkyne with copper(I) iodide in the presence of a base
(Cs2CO3) formed copper acetylide I, the complex of I
with the ligand (Pro-NHMe) yields II, oxidative addition
diiodotrifluoroacetanilide derivative 1b could promote
the Sonogashira cross-coupling. We also attempted the
coupling of 2,6-diiodotrifluoroacetanilide derivative 1c
with phenylacetylene (2a), pent-1-yn-3-ol (2b), and 1-
of II to the haloacetanilide gives III. Release of copper(I)
ethynylcyclohexene (2c), in all cases this gave the corre-
iodide provides the target product 3. The ortho-substituent
sponding monosubstituted products 3h, 3j, and 3k as the
effect was previously identified by Ma’s group.12
major product with small amount of disubstituted prod-
Table 2 N-Methylpyrrolidine-2-carboxamide-Promoted Copper-Catalyzed Sonogashira Cross-Coupling of Substituted o-Haloacetanilide
Derivatives with Alkynesa
O
O
CuI (30 mol%)
L (100 mol%)
H
R2
R2
R3
NH
X
NH
N
R1
R3
R3
R1
+
R1
+
DMF, Cs2CO3, r.t.
1
2
4
X = I, Br
2 = CF3, Me
3
For R2 = CF3
.
HCl
NHMe
R
L =
N
O
H
Entry
1
Aryl halide
Acetylene
Time (h)
Product
Yieldb (%)
O
O
NH
CF3
Ph
R3 = Ph
2a
NH
CF3
6
90
82
I
1a
3a
O
NH
CF3
R3 = CH(OH)Et
2b
2
1a
6
Et
OH
3b
O
NH
CF3
R3 = cyclohex-1-
3
1a
enyl
6
78
2c
3c
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PAPER
Copper-Catalyzed Sonogashira Cross-Coupling
2421
Table 2 N-Methylpyrrolidine-2-carboxamide-Promoted Copper-Catalyzed Sonogashira Cross-Coupling of Substituted o-Haloacetanilide
Derivatives with Alkynesa (continued)
O
O
CuI (30 mol%)
L (100 mol%)
H
R2
R3
NH
X
R2
NH
N
R1
R3
R3
R1
+
R1
+
DMF, Cs2CO3, r.t.
1
2
4
X = I, Br
2 = CF3, Me
3
For R2 = CF3
.
HCl
NHMe
R
L =
N
O
H
Entry
4
Aryl halide
Acetylene
Time (h)
Product
Yieldb (%)
O
NH
CF3
R3 = n-hexyl
2d
1a
6
71
(CH2)5Me
3d
O
NH
CF3
R3 = cyclopropyl
2e
5
1a
0.5
60c
3e
4e
H
N
20c
O
CO2Me
NH
O
CO2Me
CF3
NH
CF3
6
7
8
2a
2b
2a
20
20
20
83
I
I
I
Ph
1b
3f
O
CO2Me
NH
CF3
1b
71
46
I
Et
OH
3g
O
I
O
I
NH
CF3
Ph
NH
I
CF3
MeOOC
MeOOC
1c
3h
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H. Jiang et al.
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Table 2 N-Methylpyrrolidine-2-carboxamide-Promoted Copper-Catalyzed Sonogashira Cross-Coupling of Substituted o-Haloacetanilide
Derivatives with Alkynesa (continued)
O
O
CuI (30 mol%)
L (100 mol%)
H
R2
R3
NH
X
R2
NH
N
R1
R3
R3
R1
+
R1
+
DMF, Cs2CO3, r.t.
1
2
4
X = I, Br
2 = CF3, Me
3
For R2 = CF3
.
HCl
NHMe
R
L =
N
O
H
Entry
Aryl halide
Acetylene
Time (h)
Product
Yieldb (%)
Ph
O
NH
CF3
Ph
18
62
53
MeOOC
3i
O
I
NH
CF3
9
1c
2b
20
MeOOC
Et
OH
3j
O
I
NH
CF3
10
1c
2c
20
MeOOC
3k
O
29
NH
CF3
MeOOC
3l
O
O
N
Me
Ph
NH
Me
H
11
2a
6
93d
I
1d
3m
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Copper-Catalyzed Sonogashira Cross-Coupling
2423
Table 2 N-Methylpyrrolidine-2-carboxamide-Promoted Copper-Catalyzed Sonogashira Cross-Coupling of Substituted o-Haloacetanilide
Derivatives with Alkynesa (continued)
O
O
CuI (30 mol%)
L (100 mol%)
H
R2
R3
NH
X
R2
NH
N
R1
R3
R3
R1
+
R1
+
DMF, Cs2CO3, r.t.
1
2
4
X = I, Br
2 = CF3, Me
3
For R2 = CF3
.
HCl
NHMe
R
L =
N
O
H
Entry
12
Aryl halide
Acetylene
Time (h)
Product
Yieldb (%)
O
NH
Me
1d
2b
6
78d
Et
OH
3n
3a
O
NH
Br
CF3
13
14
2a
2d
20
20
27
33
1e
1e
3d
a Reaction conditions: o-haloacetanilide 1 (0.5 mmol), alkyne 2 (0.75 mmol, 1.25 mmol for entry 10), CuI (0.15 mmol), ligand (0.5 mmol),
Cs2CO3 (1.25 mmol), DMF (2 mL), N2.
b Isolated yield.
c Ligand (2 equiv) was used.
d Reaction temperature (40 °C).
The trifluoroacetyl group in the o-alkynyltrifluoroacet- carried at room temperature and increasing the amount of
anilides is readily removed to yield o-alkynylanilides.13 For the catalyst (CuI) and the ligand (N-methylpyrrolidine-2-
example treatment of 2,2,2-trifluoro-N-[2-(phenylethy- carboxamide) improved the efficiency of the Sonogashira
nyl)phenyl]acetamide (3a) with methanol–water/sodium cross-coupling of o-haloacetanilide derivatives with
carbonate at 70 °C for 12 hours gave 2-(phenylethy- alkynes and inhibited the cyclization of the o-alkynylacet-
nyl)aniline (6) in 71% yield (Scheme 4). o-Alkynylanil- anilides. The inexpensive catalyst system has a high toler-
ides are important intermediates in organic synthetic ance towards various functional groups in the substrates.
chemistry and medicinal chemistry14 and they provide This convenient and efficient approach to o-alkynylaceta-
many opportunities for the synthesis of diverse com- nilides provides opportunities for the synthesis of diverse
pounds.
molecules.
In summary, we have developed an efficient method for
synthesis of o-alkynylacetanilides; this protocol used in-
expensive copper(I) iodide/N-methylpyrrolidine-2-car-
boxamide as the catalyst and various o-haloacetanilide
derivatives as the substrates. The coupling reactions were
All reactions were carried out under an N2 atmosphere. DMF was
dried over CaH2 and freshly distilled before use. 1H and 13C NMR
spectra were recorded with TMS as internal standard in CDCl3 (1H
NMR: TMS, d = 0.00, CDCl3, d = 7.24; 13C NMR: CDCl3, d = 77.0).
Compounds 1a–c were synthesized according to the known litera-
ture.15
O
N-[2-(Ethynyl)phenyl]acetamides 3a–n; General Procedure
A flask was charged with CuI (29 mg, 0.15 mmol), N-methylpyrro-
lidine-2-carboxamide hydrochloride (83 mg, 0.5 mmol), Cs2CO3
(407 mg, 1.25 mmol), haloacetanilide 1 (0.5 mmol), alkyne 2 (0.75
mmol for all examples in Tables 1 and 2 except Table 2, entry 10,
1.25 mmol ), and DMF (2 mL). The mixture was stirred under N2 at
r.t. (25 °C or 40 °C) for the period indicated in Tables 1 and 2. After
completion of the coupling reaction (TLC), the mixture was diluted
with EtOAc, the soln was filtered, and the inorganic salts were re-
MeOH–H2O
Na2CO3, 70 °C
NH
NH2
CF3
12 h, 71%
6
Ph
Ph
3a
Scheme 4 Deprotection of the trifluoroacetyl group in 2,2,2-trifluo-
ro-N-[2-(phenylethynyl)phenyl]acetamide (3a) to give 2-(phenyl-
ethynyl)aniline (6)
Synthesis 2008, No. 15, 2417–2426 © Thieme Stuttgart · New York

2424
H. Jiang et al.
PAPER
moved. The solvent of the filtrate was removed with the aid of a ro-
tary evaporator, and the residue was purified by flash column
chromatography (silica gel, petroleum ether–EtOAc, 40:1 to 4:1) to
provide the desired product.
HRMS: m/z [M + H]+ calcd for C13H11F3NO: 254.0793; found:
254.0788.
Methyl 5-Iodo-3-(phenylethynyl)-2-(trifluoroacetamido)ben-
zoate (3f)
White solid; yield: 83%; mp 129–130 °C.
2,2,2-Trifluoro-N-[2-(phenylethynyl)phenyl]acetamide (3a)16
White solid; yield: 90%; mp 121–122 °C.
1H NMR (300 MHz, CDCl3): d = 8.87 (s, 1 H), 8.35 (d, J = 8.2 Hz,
1 H), 7.50–7.53 (m, 4 H), 7.37–7.39 (m, 3 H), 7.18 (t, J = 8.1 Hz, 1
1H NMR (300 MHz, CDCl3): d = 9.81 (s, 1 H), 8.26 (d, J = 1.6 Hz,
1 H), 8.11 (d, J = 1.6 Hz, 1 H), 7.35–7.49 (m, 5 H), 3.94 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 165.4, 154.7, 145.1, 139.0, 135.3,
131.6, 129.3, 128.4, 125.5, 122.8, 121.8, 115.8 (J = 143.1 Hz), 98.5,
90.2, 83.1, 53.1.
HRMS: m/z [M + H]+ calcd for C18H12F3INO3: 473.9814; found:
473.9811.
H).
13C NMR (75 MHz, CDCl3): d = 154.5 (J = 18.3 Hz), 136.1, 131.7,
131.5, 129.9, 129.4, 128.7, 125.6, 121.7, 119.7, 115.8 (J = 143.4
Hz), 113.6, 98.1, 82.9.
HRMS: m/z [M + H]+ calcd for C16H11F3NO: 290.0793; found:
290.0796.
Methyl 3-(3-Hydroxypent-1-ynyl)-5-iodo-2-(trifluoroacetami-
do)benzoate (3g)
2,2,2-Trifluoro-N-[2-(3-hydroxypent-1-ynyl)phenyl]acetamide
Red solid; yield: 71%; mp 110–112 °C.
(3b)
1H NMR (300 MHz, CDCl3): d = 9.87 (s, 1 H), 8.24 (d, J = 2.1 Hz,
1 H), 7.99 (d, J = 2.1 Hz, 1 H), 4.51 (t, J = 6.5 Hz, 1 H), 3.93 (s, 3
H), 2.39 (s, 1 H), 1.78 (m, 2 H), 1.03 (t, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 165.3, 154.6 (J = 18.6 Hz), 145.4,
139.3, 135.7, 125.3, 122.2, 115.7 (J = 123.1 Hz), 99.4, 90.2, 78.8,
63.9, 53.0, 30.4, 9.3.
White solid; yield: 82%; mp 90–91 °C.
1H NMR (300 MHz, CDCl3): d = 8.71 (s, 1 H), 8.31 (d, J = 8.2 Hz,
1 H), 7.35–7.45 (m, 2 H), 7.16 (t, J = 8.5 Hz, 1 H), 4.62 (t, J = 6.5
Hz, 1 H), 2.17 (s, 1 H), 1.86 (m, 2 H), 1.09 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 154.5 (J = 18.6 Hz), 136.2, 131.9,
129.9, 125.4, 119.6, 115.7 (J = 143.4 Hz), 112.8, 98.9, 78.7, 64.0,
30.8, 9.3.
HRMS: m/z [M + H]+ calcd for C15H14F3INO4: 455.9920; found:
455.9916.
HRMS: m/z [M + H]+ calcd for C13H13F3NO: 272.0898; found:
272.0896.
Methyl 3-Iodo-5-(phenylethynyl)-4-(trifluoroacetamido)ben-
zoate (3h)
N-[2-(Cyclohex-1-enylethynyl)phenyl]-2,2,2-trifluoroacet-
amide (3c)
White solid; yield: 78%; mp 75–76 °C.
White solid; yield: 46%; mp 124–126 °C.
1H NMR (300 MHz, CDCl3): d = 8.38–8.42 (m, 1 H), 8.12–8.20 (m,
2 H), 7.33–7.45 (m, 5 H), 3.92 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.2, 154.4 (J = 16.1 Hz), 140.1,
139.9, 133.6, 131.6, 131.0, 129.3, 128.4, 123.0, 121.6, 115.8
(J = 143.4 Hz), 97.2, 96.7, 83.6, 52.7.
HRMS: m/z [M + H]+ calcd for C18H12F3INO3: 473.9814; found:
473.9811.
1H NMR (300 MHz, CDCl3): d = 8.80 (s, 1 H), 8.32 (d, J = 8.2 Hz,
1 H), 7.42 (d, J = 7.9 Hz, 1 H), 7.34 (t, J = 7.6 Hz, 1 H), 7.14 (t,
J = 7.6 Hz, 1 H), 6.27 (s, 1 H), 2.16–2.22 (m, 4 H), 1.61–1.72 (m, 4
H).
13C NMR (75 MHz, CDCl3): d = 154.3 (J = 18.6 Hz), 137.0, 135.8,
131.3, 129.1, 125.3, 119.7, 119.3, 115.7 (J = 143.4 Hz), 113.9,
100.1, 80.3, 28.9, 25.8, 22.1, 21.2.
Methyl 3,5-Bis(phenylethynyl)-4-(trifluoroacetamido)benzoate
(3i)
HRMS: m/z [M + H]+ calcd for C16H15F3NO: 294.1106; found:
294.1110.
White solid; yield: 18%; mp 176–178 °C.
1H NMR (300 MHz, CDCl3): d = 8.34 (s, 1 H), 8.18 (s, 2 H), 7.35–
2,2,2-Trifluoro-N-[2-(oct-1-ynyl)phenyl]acetamide (3d)
White oil; yield: 71%.
7.51 (m, 10 H), 3.94 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 165.0, 154.3 (J = 19.0 Hz), 138.6,
133.2, 132.4, 129.6, 129.2, 128.5, 121.8, 121.3, 115.9 (J = 143.41
Hz), 97.3, 83.5, 52.6.
HRMS: m/z [M + H]+ calcd for C26H17F3NO3: 448.1161; found:
448.1164.
1H NMR (300 MHz, CDCl3): d = 8.82 (s, 1 H), 8.33 (d, J = 8.3 Hz,
1 H), 7.42 (d, J = 7.6 Hz, 1 H), 7.34 (t, J = 7.2 Hz, 1 H), 7.13 (t,
J = 7.6 Hz, 1 H), 2.50 (t, J = 6.9 Hz, 2 H), 1.32–1.65 (m, 8 H), 0.90
(t, J = 6.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 154.4 (J = 18.3 Hz), 136.1, 131.6,
129.0, 125.2, 119.2, 115.7 (J = 143.1 Hz), 113.8, 99.7, 74.6, 31.2,
28.6, 28.5, 22.4, 19.4, 13.9.
Methyl 3-(3-Hydroxypent-1-ynyl)-5-iodo-4-(trifluoroacetami-
do)benzoate (3j)
White solid; yield: 62%; mp 109–110 °C.
HRMS: m/z [M + H]+ calcd for C16H19F3NO: 298.1419; found:
298.1417.
1H NMR (300 MHz, CDCl3): d = 8.49 (s, 1 H), 8.40 (d, J = 1.7 Hz,
1 H), 8.02 (d, J = 1.7 Hz, 1 H), 4.51 (t, J = 6.5 Hz, 1 H), 3.93 (s, 3
H), 2.66 (s, 1 H), 1.76 (m, 2 H), 1.01 (t, J = 7.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.2, 154.6 (J = 18.6 Hz), 140.5,
140.2, 133.9, 130.9, 122.4, 115.7 (J = 143.1 Hz), 97.9, 96.7, 79.3,
63.9, 52.8, 30.4, 9.3.
N-[2-(Cyclopropylethynyl)phenyl]-2,2,2-trifluoroacetamide
(3e)
White solid; yield: 60%; mp 66–67 °C.
1H NMR (300 MHz, CDCl3): d = 8.78 (s, 1 H), 8.30 (d, J = 8.3 Hz,
1 H), 7.40 (d, J = 7.6 Hz, 1 H), 7.33 (t, J = 8.2 Hz, 1 H), 7.14 (t,
J = 7.6 Hz, 1 H), 1.53 (m, 1 H), 0.98–0.84 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 154.3 (J = 18.3 Hz), 136.3, 131.6,
128.9, 125.3, 119.2, 115.7 (J = 143.4 Hz), 113.9, 102.7, 69.6, 9.1.
HRMS: m/z [M + H]+ calcd for C15H14F3INO4: 455.9920; found:
455.9927.
Synthesis 2008, No. 15, 2417–2426 © Thieme Stuttgart · New York

PAPER
Copper-Catalyzed Sonogashira Cross-Coupling
2425
Methyl 3-(Cyclohex-1-enylethynyl)-5-iodo-4-(trifluoroacetami-
do)benzoate (3k)
13C NMR (75 MHz, CDCl3): d = 141.6, 135.7, 128.6, 120.9, 119.7,
119.6, 110.1, 97.6, 8.7, 7.2.
White solid; yield: 53%.
1H NMR (300 MHz, CDCl3): d = 8.32–8.37 (m, 1 H), 8.00–8.18 (m,
2 H), 6.22 (s, 1 H), 3.92 (s, 3 H), 2.14 (m, 4 H), 1.64 (m, 4 H).
HRMS: m/z [M + H]+ calcd for C11H12N: 158.0970; found:
158.0965.
Methyl 3-(Cyclohex-1-enylethynyl)-5-(phenylethynyl)-4-(tri-
fluoroacetamido)benzoate (5)
White solid; yield: 78%.
1H NMR (300 MHz, CDCl3): d = 8.05–8.22 (m, 3 H), 7.33–7.48 (m,
5 H), 6.25 (m, 1 H), 3.9 (s, 3 H), 2.16–2.18 (m, 4 H), 1.62–1.67 (m,
4 H).
13C NMR (300 MHz, CDCl3): d = 164.4, 154.5 (J = 19.7 Hz), 149.9,
139.3, 137.8, 133.3, 130.8, 123.5, 119.8, 115.8 (J = 143.1 Hz), 99.4,
96.5, 81.2, 52.6, 28.5, 25.8, 22.0, 21.2.
HRMS: m/z [M + H]+ calcd for C18H16F3INO2: 478.0127; found:
478.0121.
Methyl 3,5-Bis(cyclohex-1-enylethynyl)-4-(trifluoroacetami-
do)benzoate (3l)
White solid; yield: 29%; mp 179–180 °C.
1H NMR (300 MHz, CDCl3): d = 8.03–8.06 (m, 3 H), 6.24 (s, 2 H),
3.92 (s, 3 H), 2.1 (m, 8 H), 1.61–1.67 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 165.1, 154.2 (J = 19.0 Hz), 138.4,
137.5, 132.9, 132.7, 131.6, 129.4, 129.1, 128.4, 121.9, 121.7, 121.1,
129.9, 115.4 (J = 143.6 Hz), 99.6, 97.0, 83.8, 81.1, 52.5, 28.6, 25.8,
22.1, 21.2.
HRMS: m/z [M + H]+ calcd for C26H21F3NO3: 452.1474; found:
452.1471.
13C NMR (300 MHz, CDCl3): d = 165.2, 153.7 (J = 17.8 Hz), 138.1,
137.4, 132.5, 129.3, 121.4, 120.0, 115.0 (J = 143.1 Hz), 99.3, 81.3,
52.5, 28.6, 25.8, 22.1, 21.2.
HRMS: m/z [M + H]+ calcd for C26H25F3NO3: 456.1787; found:
456.1786.
2-(Phenylethynyl)aniline (6)19
White solid; yield: 71%; mp 80–82 °C (Lit.19 85–87 °C).
1H NMR (300 MHz, CDCl3): d = 7.31–7.52 (m, 7 H), 6.67–6.69 (m,
2 H), 4.13 (s, 2 H).
N-[2-(Phenylethynyl)phenyl]acetamide (3m)17
13C NMR (75 MHz, CDCl3): d = 147.6, 132.0, 131.4, 129.6, 128.3,
128.1, 123.2, 117.9, 114.3, 107.8, 94.6, 85.8.
White solid; yield: 93%; mp 121–122 °C (Lit.17 119–120 °C).
1H NMR (300 MHz, CDCl3): d = 8.39 (d, J = 8.3 Hz, 1 H), 7.98 (s,
1 H), 7.31–7.53 (m, 7 H), 7.13 (t, J = 8.2 Hz, 1 H), 2.21 (s, 3 H).
HRMS: m/z [M + H]+ calcd for C14H12N: 194.0970; found:
194.0973.
13C NMR (75 MHz, CDCl3): d = 168.0, 138.7, 131.5, 131.3, 129.5,
128.7, 128.4, 123.2, 122.2, 119.2, 111.7, 96.2, 84.2, 24.7.
HRMS: m/z [M + H]+ calcd for C16H14NO: 236.1075; found:
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (Grant No. 20672065, 20572008 and 20732004), Chi-
nese 863 Project (Grant No. 2007AA02Z160), Programs for New
Century Excellent Talents in University (NCET-05-0062) and
Changjiang Scholars and innovative Research Team in University
(PCSIRT) (No. IRT0404) in China and the Key Subject Foundation
from Beijing Department of Education (XK100030514).
236.1073.
N-[2-(3-Hydroxypent-1-ynyl)phenyl]acetamide (3n)
Yellow oil; yield: 78%.
1H NMR (300 MHz, CDCl3): d = 8.27 (d, J = 8.9 Hz, 1 H), 7.99 (s,
1 H), 7.24–7.36 (m, 2 H), 6.99 (t, J = 8.2 Hz, 1 H), 4.60 (t, J = 6.5
Hz, 1 H), 3.31 (s, 1 H), 2.16 (s, 3 H), 1.85–1.87 (m, 2 H), 1.09 (t,
J = 7.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 168.6, 138.7, 131.6, 129.5, 123.4,
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119.6, 111.7, 97.5, 79.8, 63.8, 30.8, 24.6, 9.5.
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2-Phenyl-1H-indole (4a)18
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White solid; yield: 76%; mp 179–182 °C (Lit.18 186–187 °C).
1H NMR (300 MHz, CDCl3): d = 8.25 (s, 1 H), 7.20–7.63 (m, 9 H),
6.80 (s, 1 H).
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White solid; yield: 20%.
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1 H), 7.02–7.21 (m, 3 H), 6.12 (s, 1 H), 1.83–1.88 (m, 1 H), 0.7–0.9
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Synthesis 2008, No. 15, 2417–2426 © Thieme Stuttgart · New York

2426
H. Jiang et al.
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Synthesis 2008, No. 15, 2417–2426 © Thieme Stuttgart · New York