An efficient copper(I) complex catalyzed Sonogashira type cross-coupling of aryl halides with terminal alkynes

Article abstract of DOI:10.1016/j.tetlet.2009.03.146

A wide range of arylated alkynes are synthesized from the corresponding aryl halides and terminal alkynes through Sonogashira type cross-coupling reactions through C(aryl)-C bond formation in the presence of a catalytic amount of N,N′-dibenzyl BINAM-CuI complex under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2009.03.146

Tetrahedron Letters 50 (2009) 2865–2869
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An efficient copper(I) complex catalyzed Sonogashira type cross-coupling
of aryl halides with terminal alkynes
*
K. G. Thakur, E. A. Jaseer, Ajay B. Naidu, Govindasamy Sekar
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600 036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A wide range of arylated alkynes are synthesized from the corresponding aryl halides and terminal
alkynes through Sonogashira type cross-coupling reactions through C(aryl)–C bond formation in
Received 1 January 2009
Revised 16 March 2009
Accepted 23 March 2009
Available online 26 March 2009
the presence of
conditions.
a
catalytic amount of N,N0-dibenzyl BINAM–CuI complex under mild reaction
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Copper catalyst
Coupling reaction
Arylated alkynes
C–C bond formation
Sonogashira coupling
Acetylinic compounds constitute a very important class of or-
ganic compounds playing a significant role in a number of natural
products and bioactive molecules.1 Palladium-catalyzed synthesis
of internal acetylenes from corresponding aryl halides and termi-
nal acetylenes used to be the method of choice (Sonogashira cou-
pling).2 However, the high costs of palladium salts, requirement
of copper as co-catalyst, high oxophillicity associated with phos-
phine ligands and tedious multistep processes involved in the syn-
thesis of these phosphine ligands have rendered Pd unpopular,
particularly for large scale reactions.
phine with some special phosphines to enhance the catalytic
efficiency3 and employing less expensive nickel instead of
palladium.4 However, the former suffers from the requirement
of less conveniently available phosphines, while the latter
still needs two metals, which makes catalyst recovery more
difficult.
On the other hand, although it has been known for decades
that aryl halides could couple with copper(I) acetylides to give
aryl acetylenes,6 there have been a few reports concerning the
use of copper(I) alone as the catalyst for coupling of aryl halides
with terminal alkynes.7 Although in these reports copper is used
as catalyst, high oxophillic phosphines are used as ligands.7a–e,k
Later on, oxophillic phosphine ligands are replaced by nitrogen
ligand to carry out the C–C bond forming Sonogashira coupling
reaction.7f–j Recently, Sonogashira coupling reaction was carried
out under microwave conditions using poly(ethylene glycol)s as
solvent.7h Very recently, DABCO was used as ligand with CuI
for the C–C bond formation between arylhalides and terminal
alkynes.7j However, this advance in the field of Sonogashira
coupling is not sufficient as most of the reactions need dry
and oxygen free reaction conditions due to phosphine ligands
and in some cases high catalytic loading (even super stoichiom-
etric amounts of ligands are needed). Therefore a mild, eco-
nomic and efficient catalytic system is still desirable for this
process.
OH
NR1R2
NR1R2
N
N
OH
L1: R1 = R2 = H
L2: R1 = H; R2 = Me L4: R1 = H; R2 = Bn
L3: R1 = R2 =Me
L5
In order to overcome the drawbacks a great number of efforts
have been directed to explore new catalytic systems recently.3–5
Successful examples include the replacement of triphenylphos-
As a part of our ongoing research towards copper-catalyzed oxi-
dation chemistry,8 very recently we reported 1,10-binaphthyl-2,20-
diamine (BINAM)9–Cu as an efficient catalyst for the synthesis of
diaryl ethers and aryl alkyl ethers via Ullmann coupling.10 In this
* Corresponding author. Tel.: +91 44 2257 4229; fax: +91 44 2257 4202.
E-mail address: gsekar@iitm.ac.in (G. Sekar).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.146

2866
K. G. Thakur et al. / Tetrahedron Letters 50 (2009) 2865–2869
Table 1
CuI catalyzed Sonogashira coupling with different ligands
I
Cu complex
K2CO3
DMF, 140-145 oC
I
Ligand (20 mol%)
CuI (20 mol%)
+
+
R
R'
MeO
R
K2CO3
R'
DMF, 140-145 oC
OMe
Scheme 1.
Entry
Ligand
Time (h)
Yielda (%)
1
2
3
4
5
L1
L2
L3
L4
L5
20
24
24
06
24
85
45
89
99
76
Letter we report our initial finding about easily available N,N0-
dibenzyl BINAM–CuI complex catalyzed C(aryl)–C bond formation
reaction (Sonogashira coupling) for the synthesis of internal al-
kynes from corresponding aryl halides and terminal alkynes
(Scheme 1). This procedure is very simple, mild, clean and works
efficiently without any additives.
a
Isolated yield.
In the preliminary studies, we used 20 mol % BINAM ligand L1
with 20 mol % of CuI in the presence of K2CO3 (3 equiv) for the cou-
pling of p-methoxy iodobenzene with phenyl acetylene in DMF at
140 °C. The reaction provided 85% isolated yield of the 1-methoxy-
4-(phenylethynyl)benzene in 20 h through C(aryl)–C bond forma-
tion (Table 1, entry 1). When the ligand L1 was replaced with li-
gand L2, the isolated yield was reduced to 45%. Replacing the
ligand L2 by L3, the yield was increased to 89%. Surprisingly, the
N,N0-dibenzyl BINAM ligand L4 with CuI catalyzed the Sonogashira
cross-coupling reaction of p-methoxy iodobenzene with phenyl
acetylene in DMF at 140 °C and provided quantitative yield for
the expected product in just 6 h (entry 4). Usage of Salen ligand
L5 instead of L4 provided only 76% yield in one day for the coupling
reaction.
The reaction was screened with several copper salts, solvents
and bases to increase the efficiency of the cross-coupling reac-
tions and the results are summarized in Table 2. Although several
copper salts catalyzed the coupling reaction, CuI and Cu(OTf)2
turned out to be the copper salts of choice in view of yield as well
as reaction time (Table 2, entries 1 and 2). The low cost of CuI
over Cu(OTf)2 encouraged us to proceed the coupling reaction
with CuI. Similarly, DMF was the best solvent among those exam-
ined. K2CO3 was found to be the most effective base compared to
Na2CO3 and Cs2CO3. Next, the reaction was carried out with dif-
ferent ratios of L4 and CuI and it was found that 20 mol % of
L4-copper combination was the most effective catalytic system.
When the reaction was carried out only with CuI without L4,
the reaction provided only 39% yield for the coupling reaction,
which shows that ligand L4 is mandatory for quantitative yield
of the product.
Table 2
Effect of Cu salts, solvents and bases
I
L4 (20 mol%)
Cu salt (20 mol%)
+
MeO
K2CO3
solvent, 140-145 oC
OMe
Entry
Cu salt
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CuI
DMF
06
06
24
24
24
24
24
24
24
24
24
24
24
24
24
99
99
92
72
96
91
83
Cu(OTf)2
Cu(OAc)2
Cu(SO4)2ꢀ5H2O
CuBr
DMF
DMF
DMF
DMF
CuCl2ꢀ2H2O
DMF
DMF
CuCl
CuI
CuI
CuI
CuI
CuI
CuI
CuI
DMSO
MeCN
Dioxane
Xylene
Toluene
DMF
85
20b
29b
00
00b
46c
50d
23e
DMF
DMF
CuI
a
Isolated yield.
b
c
Reaction was carried out at boiling temperature of corresponding solvent.
Na2CO3 was used as base.
Cs2CO3 was used as base.
d
e
K3PO4 was used as base.
Using the above-mentioned optimized conditions, we initiated
our investigations into the scope of the N,N0-dibenzyl BINAM L4–
CuI catalyzed Sonogashira type cross-coupling and the results are
summarized in Table 3. Various aryl iodides and terminal alkynes
reacted to give the corresponding arylated acetylenes. We found
that iodobenzene containing electron-releasing groups such as
methoxy group (entries 7–11) as well as electron-withdrawing
group such as trifluoromethyl group (entries 20 and 21) reacted
with terminal acetylenes to provide arylated alkynes in very high
isolated yields. Highly sterically hindered ortho-substituted iodo-
benzenes also provided very good yields by reacting with termi-
nal alkynes in the presence of L4–CuI complex (entries 16 and
17). The reaction condition tolerated acid sensitive functional
groups. For example, OTHP ether containing terminal alkyne
(2-(prop-2-ynyloxy)tetrahydro-2H-pyran) reacted with iodoben-
zene and p-methyl iodobenzene to provide corresponding
arylated product in good yield without cleavage of acid sensitive
-OTHP ether group (entries 3 and 6). Terminal alkyne containing
heterocycle also reacted with aryl iodide in the presence of L4–
CuI complex to provide corresponding arylated product in excel-
lent isolated yield (entry 9). Under our optimized reaction condi-
tions, aryl bromides also reacted with terminal alkynes to provide
the corresponding C-arylated alkynes (entries 22–24). Using
BINAM as ligand with copper has one advantage over other re-
ported ligands as it can be used in enantiomerically pure form
for the asymmetric Sonogashira coupling (non-enzymatic kinetic
resolution) reaction.11
In summary, we have developed an efficient, and experimen-
tally simple N,N0-dibenzyl BINAM–CuI complex catalyzed C-aryla-
tion of terminal alkynes with aryl iodides through C(aryl)–C bond
formation reaction. Both the electron-releasing as well as elec-
tron-withdrawing groups containing aryl iodides react with termi-
nal alkynes to provide arylated alkyne products in high yields. The
reaction condition is very mild as OTHP ether is untouched during
the entire reaction time. Efforts to expand the utility of our new
catalyst to other class of nucleophiles will be reported in due
course.

K. G. Thakur et al. / Tetrahedron Letters 50 (2009) 2865–2869
2867
Table 3
Cross-coupling reaction of aryl halides with terminal alkynes in the presence of L4–CuI catalysta
L4 (20 mol%)
CuI (20 mol%)
I
+
K2CO3
R
R'
R
R'
DMF, 140-145 oC
Entry
1
Aryl halide
Alkynes
Time (h)
20
Productb
Yieldc (%)
75
I
I
I
2
3
4
5
6
7
8
9
6
20
6
90
75
79
88
73
99
72
70
OTHP
OTHP
I
I
I
20
20
6
OTHP
OTHP
MeO
MeO
MeO
I
I
I
MeO
24
24
MeO
MeO
N
N
10
11
14
20
77
93
MeO
MeO
I
I
MeO
MeO
12
13
14
8
24
14
99
96
94
I
I
I
I
15
20
99
(continued on next page)

2868
K. G. Thakur et al. / Tetrahedron Letters 50 (2009) 2865–2869
Table 3 (continued)
Entry
Aryl halide
Alkynes
Time (h)
14
Productb
Yieldc (%)
92
OMe
OMe
16
17
I
OMe
OMe
20
14
80
86
I
I
I
18
19
20
21
22
23
20
8
99
85
81
51
42
35
I
I
F3C
F3C
F3C
F3C
13
24
48
48
Br
Br
24
Br
a
1.5 equiv of alkyne, 1 equiv of haloarene and 3 equiv of K2CO3 in 3 mL DMF was treated with 20 mol % of L4–CuI complex.
b
c
All the alkynes gave satisfactory spectral data.
Isolated yield.12
5. For Sonogashira-type couplings using microwave heating, see: Leadbeater, N.
E.; Macro, M.; Tominack, B. J. Org. Lett. 2003, 5, 3919–3922.
Acknowledgements
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Synthesis 2005, 1706–1712; (d) Tang, B. X.; Wang, F.; Li, J. H.; Xie, Y. X.; Zhang,
M. B. J. Org. Chem. 2007, 72, 6294–6297; (e) Gujadhar, R. K.; Bates, C. G.;
Venkataraman, D. Org. Lett. 2001, 3, 4315–4317; (f) Ma, D.; Liu, F. Chem.
Commun. 2004, 1934–1935; (g) He, H.; Wu, Y. J. Tetrahedron Lett. 2004, 45,
3237–3239; (h) Colacino, E.; Daich, L.; Martinez, J.; Lamaty, F. Synlett 2007,
1279–1283; (i) Chinchilla, R.; Na´jera, C. Chem. Rev. 2007, 107, 874–922; (j) Li, J.-
H.; Li, J.-L.; Wang, D.-P.; Pi, S.-F.; Xie, Y.-X.; Zhang, M.-B.; Hu, X.-C. J. Org. Chem.
2007, 72, 2053–2057; (k) Guan, J. T.; Yu, G.-A.; Chen, L.; Weng, T. Q.; Yuan, J. J.;
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We thank DST (Project No. SR/S1/OC-06/2008), New Delhi for
the financial support. K.G.T. and E.A.J. thank CSIR and ABN thanks
UGC for senior research fellowship. We thank DST, New Delhi,
for the funding towards the 400 MHz NMR machine to the Depart-
ment of Chemistry, IIT-Madras under the IRPHA scheme and ESI-
MS facility under the FIST programme.
References and notes
1. Theil, F. Angew. Chem., Int. Ed. 1999, 38, 2345–2347.
2. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467–
4470; (b) Sonogashira, K. In Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1999; Vol. 3, p 521; (c) Kawanami, H.; Matsushima,
K.; Sato, M.; Ikushima, Y. Angew. Chem., Int. Ed. 2007, 46, 5129–5132; (d) Yi, W.
B.; Chi, C.; Wang, X. Eur. J. Org. Chem. 2007, 3445–3448; (e) Li, J. H.; Liang, Y.;
Xie, Y. X. J. Org. Chem. 2005, 70, 4393–4396.
3. (a) Feuerstein, M.; Doucet, H.; Satelli, M. Tetrahedron Lett. 2004, 45, 1603–1606;
(b) Heuze, K.; Mery, D.; Gauss, D.; Astruc, D. Chem. Commun. 2003, 2274–2275;
(c) Mery, D.; Heuze, K.; Astruc, D. Chem. Commun. 2003, 1934–1935; (d) Soheili,
A.; Albaneze, W.; walker, J.; Murry, J. A.; Dormar, P. G.; Hughes, D. L. Org. Lett.
2003, 5, 4191–4194; (e) Mas-Marza, E.; Segqrrq, A. M.; Claver, C.; Peris, E.;
Fernandez, E. Tetrahedron Lett. 2003, 44, 6595–6599; (f) Leadbeater, N. E.;
Tominack, B. J. Tetrahedron Lett. 2003, 44, 8653–8656.
8. (a) Mannam, S.; Kumar, S. A.; Sekar, G. Adv. Synth. Catal. 2007, 349, 2253–2258;
(b) Mannam, S.; Sekar, G. Tetrahedron Lett. 2008, 49, 1083–1086; (c) Mannam,
S.; Sekar, G. Tetrahedron Lett. 2008, 49, 2457–2460.
9. BINAM is used as ligand in several reactions: (a) Guillena, G.; Hita, M. C.;
Na´jera, C. Tetrahedron: Asymmetry 2006, 17, 729–733. aldol condensation; (b)
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc.
1999, 121, 10219–10220. Baylis–Hillman reaction; (c) Takenaka, N.; Huang, Y.;
Rawal, V. H. Tetrahedron 2002, 58, 8299–8305. Diels–Alder reaction.
10. (a) Naidu, A. B.; Raghunath, O. R.; Prasad, D. J. C.; Sekar, G. Tetrahedron Lett.
2008, 49, 1057–1061; (b) Naidu, A. B.; Sekar, G. Tetrahedron Lett. 2008, 49,
3147–3151.
11. For asymmetric Sonogashira coupling, see Kanda, K.; Koike, T.; Endo, K.;
Shibata, T. Chem. Commun. 2009, 1870–1872.
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12. Typical representative experimental procedure: p-methoxy iodobenzene
(117 mg, 0.5 mmol), K2CO3 (207.3 mg, 1.5 mmol), N,N0-dibenzyl-BINAM

K. G. Thakur et al. / Tetrahedron Letters 50 (2009) 2865–2869
2869
(46.4 mg, 0.1 mmol) and CuI (19 mg, 0.1 mmol) were taken in a 15 mL reaction
tube capped with a septum. The reaction tube was evacuated and back-filled
with nitrogen. DMF (3 mL) was added to the reaction mixture at room
temperature and the resulting reaction mixture was heated to 140–145 °C.
room temperature and the solvent was evaporated. The crude residue was
directly purified by column chromatography on silica gel using ethyl acetate/
hexane as the eluent to afford 1-methoxy-4-(phenylethynyl)benzene7h
(103 mg, 99%) as a white solid; Rf 0.4 (in hexanes); FTIR (CH2Cl2): 1173,
Phenyl acetylene (82.5
lL, 0.75 mmol) was added to the reaction mixture at
1247, 2181, 2853, 2923, 2954 cmꢁ1 1H NMR (400 MHz, CDCl3) d 3.82 (s, 3H),
;
145 °C as two equal portions (41.3
lL) in 10 min intervals. The septum was
6.87 (dd, J = 7.2, 2 Hz, 2H), 7.27–7.39 (m, 3H), 7.42–7.56 (m, 4H); 13C NMR
(100 MHz, CDCl3) d 55.5, 88.2, 89.5, 114.2, 115.6, 123.8, 128.1, 128.5, 131.6,
133.2, 159.8; HRMS [M+1]+ Calcd for C15H12O: 209.0966. Found: 209.0960.
replaced with a glass stopper and the reaction mixture was heated for 6 h (the
progress of the reaction was followed by TLC). After complete disappearance of
p-methoxy iodobenzene (TLC), the reaction mixture was allowed to cool to