Sonogashira reactions catalyzed by a new and efficient copper(I) catalyst incorporating N-benzyl DABCO chloride

Article abstract of DOI:10.1016/j.tetlet.2014.03.120

A new and effective catalytic system using [N-benzyl DABCO] ⁺[Cu₄Cl₅]^- was developed for the palladium-free Sonogashira cross-coupling reactions of phenylacetylene with a variety of aryl halides. In this homogeneous catalytic system, 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride, a quaternary ammonium salt containing a coordinating center, plays an important role and increases the efficiency of Cu(I) species during the reaction. A number of internal alkynes were produced in moderate to excellent yields, in short reaction times in DMF at 135 °C.

Full text of DOI:10.1016/j.tetlet.2014.03.120

Accepted Manuscript
Sonogashira reactions catalyzed by a new and efficient copper(I) catalyst in-
corporating N-benzyl DABCO chloride
Abdol R. Hajipour, Fatemeh Mohammadsaleh
PII:
S0040-4039(14)00552-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.03.120
TETL 44442
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
10 December 2013
7 March 2014
27 March 2014
Please cite this article as: Hajipour, A.R., Mohammadsaleh, F., Sonogashira reactions catalyzed by a new and
efficient copper(I) catalyst incorporating N-benzyl DABCO chloride, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.03.120
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Sonogashira reactions catalyzed
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by a new and efficient copper(I) catalyst
incorporating N-benzyl DABCO chloride
Abdol R. Hajipour*, Fatemeh Mohammadsaleh

1
Tetrahedron Letters
journal homepage: www.els evier.com
Sonogashira reactions catalyzed by a new and efficient copper(I) catalyst
incorporating N-benzyl DABCO chloride
Abdol R. Hajipoura,b∗, Fatemeh Mohammadsaleha
a Pharmaceutical Research Laboratory, Department of Chemistry, Isfahan University of Technology, Isfahan 84156, IR of Iran
b Department of Pharmacology, University of Wisconsin, Medical School, 1300 University Avenue, Madison, 53706-1532, WI, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
A new and effective catalytic system using [N-benzyl DABCO]+[Cu4Cl5]‾ was developed for the
palladium-free Sonogashira cross-coupling reactions of phenylacetylene with a variety of aryl
halides. In this homogeneous catalytic system, 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octane
chloride, a quaternary ammonium salt containing a coordinating centre, plays an important role
and increases the efficiency of Cu(I) species during the reaction. A number of internal alkynes
were produced in moderate to excellent yields, in short reaction times in DMF at 135 ˚C.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Coupling reactions
Sonogashira reaction
N-Benzyl DABCO chloride
Copper(I) chloride
Catalyst
A variety of useful methods for the formation of aryl-
nucleophile bonds using various sources of C-, O-, N-, P-, and S-
nucleophiles have been developed in cross-coupling chemistry.1-6
Combinations of transition metals and ligands have been reported
as highly efficient catalytic systems for the synthesis of C-C, C-
N, and C-O bonds.1-6 High catalytic activity and selectivity are
important parameters for new catalytic systems.
been reported as catalysts for Sonogashira-type coupling
reactions. Copper-based catalysts are powerful in C-N, C-O, C-S,
and some C-C bond-forming reactions.22 Recent attention has
been concerned with employing copper-only catalytic systems in
coupling reactions, in particular, for Sonogashira-type couplings.
A number of copper-based catalytic systems have been proposed,
including nanoparticles,23 supported copper complexes,24 a bis(µ-
iodo)bis[(-)-sparteine]dicopper(I) catalyst,25 Cu(I)/amino acid,26
CuI/DABCO27 and Cu(I)/diamine.28 Miura and co-workers
suggested a Cu(I)/Cu(III) mechanistic pathway for copper-
catalyzed coupling reactions.29 The development of a new
catalytic system that is eco-friendly, readily available, mild and
easily separable would be useful in modern synthesis.
Quaternary ammonium and phosphonium salts (Q+ X–) have been
highly successful in enhancing the reactivity and selectivity of
metal-catalyzed organic reactions.30-32 The efficiency of these
systems is due to the involvement of metal nanoparticles
stabilized by quaternary salts and/or the formation of new
catalytic systems.
The formation of carbon-carbon bonds is important in the
synthesis of pharmaceuticals, and natural and industrial
products.7-10 The Sonogashira coupling reaction is a powerful
synthetic procedure for the construction of C(sp)-C(sp2) bonds by
the introduction of a triple bond into aromatic systems via cross-
coupling of aryl/alkyl halides and terminal alkynes.11,12 Alkynes
are building blocks for a wide range of pharmaceuticals, natural
products and materials.13 The original and general catalytic
systems for Sonogashira coupling reactions involve the use of
palladium-ligand (often a phosphine ligand) complexes as
catalysts and a copper(I) salt as a co-catalyst.14,15 The role of the
copper co-catalyst is to generate a copper-acetylide intermediate
that subsequently transmetallates at the palladium centre. In view
of modern organic synthesis, the use of expensive palladium
catalysts and the requirement for a copper(I) salt as a co-catalyst
is less attractive, in particular, for industrial scale synthesis. A
number of important studies have focused on the development of
new catalytic systems with high catalytic activity including
In continuation of our studies on the synthesis and
development of catalysts containing quaternary ammonium and
phosphonium salts,32-34 we introduce the new and interesting
catalytic system of [N-benzyl DABCO]+[Cu4Cl5]‾ as an efficient
catalyst for Sonogashira-like reactions of aryl halides with
phenylacetylene giving quantitative yields.
phosphine- and palladium-free conditions.
catalytically active metals have been developed for the
Sonogashira coupling reactions.
Numerous
Dimeric palladium(II) ammonium and phosphonium
complexes have been previously reported as catalysts for
chemical reactions;35-37 however, only a few reports are available
for the preparation of copper(I) complexes containing ammonium
salts and Cu4Cl5.38-40
Salts or nanoparticles of iron,16 cobalt,17 nickel,18 silver,19
gold20 and ruthenium21 in combination with various ligands have
———
∗ Corresponding author: Tel.: + 98 311 391 3262; fax: + 98 311 391 2350; e-mail: haji@cc.iut.ac.ir.

2
Tetrahedron Letters
Our first goal was the synthesis and characterization of [N-
benzyl DABCO]+[Cu4Cl5]‾ (Catalyst A).41 The preparation of 1-
benzyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride ([N-benzyl
DABCO]Cl) has been reported in our previous work.42 [N-Benzyl
DABCO]Cl was reacted with freshly recrystallized CuCl in
methanol at reflux temperature under an N2 atmosphere to give
the catalyst A. The compound synthesized was characterized by
elemental analysis (CHN), inductively coupled plasma analysis
(ICP), UV–vis spectroscopy and thermogravimetric analysis
(TGA). In 2003, Mys’kiv et al. reported the [Cu4Cl5]– species as a
counteranion for the quaternary ammonium cation, N,N'-
diallylmorpholinium.38 Also, Flonani et al. have introduced a
structure for the anion [Cu4Cl5]–.40 These reports, and also the
results obtained from the CHN and ICP analysis of our
compound helped us to suggest the formula, [N-benzyl
DABCO]+[Cu4Cl5]‾, for catalyst A. This compound is stable in
air for several months and is insoluble in common organic
solvents such as methanol, ethanol, acetonitrile and ethyl acetate,
but is soluble in DMF.
Figure 2. TGA thermograms
Screening of different bases such as K2CO3, KOH and t-
BuOK revealed K2CO3 as the most effective base (Table 1,
entries 7, 8, 11). The concentration of K2CO3 was also found to
be important in this reaction system (Table 1, entry 6). Among
the different solvents tested such as H2O, MeCN, DMF, NMP
and DMSO, DMF gave the best result. It is noteworthy that the
reaction temperature plays an important role in this reaction. The
yield of the model reaction increased when the reaction was
conducted at 135 ˚C (Table 1, entries 3 and 9).
The optical absorption properties of the catalyst A were
investigated by UV–vis spectroscopy in DMF solution at room
temperature. Figure 1 shows the absorbance spectra of [N-benzyl
DABCO]Cl, CuCl and the catalyst A.
We also examined catalyst loadings for the title reaction
(Table 1), employing various amounts under optimized
conditions. A catalyst loading of 5 mol% was found to be optimal
with respect to the yield and short reaction times (Table 1, entries
3, 10, 11). A lower catalyst concentration usually led to slow
reactions, and increasing the amount of catalyst shortened the
reaction time. However, increasing the catalyst concentration to
10 mol% did not have any further significant effect on the yield
or reaction time.
As shown in Table 1 (entries 13 and 14), we also investigated
the efficiency of CuCl as the catalyst in this reaction. Without the
aid of any ligands, treatment of 4-iodonitrobenzene with
phenylacetylene, CuCl (10 mol%), and K2CO3 (2 equiv) in DMF
afforded only a trace amount of the corresponding Sonogashira
product (5%). Under the same reaction conditions, adding [N-
benzyl DABCO]Cl (5 mol%) to the reaction mixture improved
the yield slightly (up to 10%).
According to the experimental results, the optimized
conditions were obtained using N,N-dimethyl formamide (DMF)
as solvent and K2CO3 (2 eq) as a base at 135 °C. Under these
conditions 4-nitro-1-phenylethynylbenzene was obtained as the
desired product in 99% yield with only a trace amount of 1,4-
diphenylbuta-1,3-diyne as a by-product formed via the homo-
coupling of phenylacetylene.
Having optimized the reaction conditions, catalyst A was
applied to the Sonogashira coupling of various aryl halides with
phenylacetylene. We examined electronic effects on the resulting
yields and conversion times. This catalytic system was
compatible with a wide range of functional groups such as nitro,
cyano, methoxy, halogen, and carbonyl on the aryl halides.
Electron-poor aryl halides, in comparison to electron-rich aryl
halides, gave better conversions in shorter reaction times. As
shown in Table 2, all the aryl iodides were rapidly converted into
the corresponding Sonogashira products in excellent yields. Aryl
bromides also reacted with phenylacetylene to afford the
corresponding Sonogashira products (Table 2. entries 7–11).
However, the reactivity of aryl bromides was lower than that of
the aryl iodides and they required longer times giving lower
yields.
Figure 1. UV–vis absorption spectra
The UV–vis spectrum of [N-benzyl DABCO]Cl shows a sharp
absorption band at 270 nm. In the spectrum of CuCl and catalyst
A two absorption bands at around 276 nm and 284 nm were
observed. The band in the 436-434 nm wavelength range also
appeared in the UV–vis spectrum of catalyst A.
The thermal stability of catalyst A was investigated by
thermogravimetric analysis with a heating rate of 10 ˚C min−1
under an N2 atmosphere. Figure 2 shows TGA thermograms of
weight loss as a function of temperature for pure [N-benzyl
DABCO]Cl and catalyst A. TGA results indicate that the catalyst
A is stable up to 200 ˚C; and a total of 45.8% weight loss
occurred by 800 ˚C.
The efficiency of this catalytic system was evaluated in the
Sonogashira cross-coupling reactions of aryl halides and
phenylacetylene.43 In order to optimize the reaction conditions,
we examined the effect of various reaction parameters such as
solvent, base and temperature on the yields and reaction times of
a series of screening experiments carried out for the cross-
coupling of 4-iodonitrobenzene with phenylacetylene as a model
reaction (Table 1).

3
Table 1. Optimization of the reaction conditions for the Sonogashira-like coupling a
Temp
(°C)
Conversion
(%)b
Entry
Solvent
Base
Catalyst (mol%)
1
2
H2O
MeCN
DMF
NMP
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
t-BuOK
KOH
A, (5)
100
80
-
A, (5)
-
3
A, (5)
135
135
135
135
135
135
115
135
135
135
135
135
99
48
50
50
90
85
7
4
A, (5)
5
6c
A, (5)
A, (5)
7
A, (10)
8
A, (10)
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
A, (5)
10
11
12
13
14
A, (2.5)
25
99
0
A, (10)
-
CuCl, (10)
5
CuCl, (10) / [N-benzyl DABCO]Cl, (5)
10
aReaction conditions: 4-nitroiodobenzene (0.1 mmol), phenylacetylene (0.12 mmol), 30 min.
bGC conversion.
c0.15 mmol K2CO3.
Substituent effects in the aryl iodides were less significant
than those in the aryl bromides, and the reactivities of aryl
bromides with electron-withdrawing substituents were higher
than those of aryl bromides with electron donating substituents.
For example, coupling of 4-bromoanisole with phenylacetylene
(Table 2, entry 8) was slow. Aryl chlorides were inactive in this
system.
.
Table 2. Sonogashira-like coupling reactions of aryl halides with phenylacetylene using catalyst Aa
Time
(h)
Conversion
(%)b
Yield
(%)c
Entry
1
Ar–X
Sonogashira product
0.5
99
95
2
3
4
5
4.5
97
99
98
60
90
2
1.5
3
96
91
55

4
Tetrahedron
6
1.5
97
95
7d
8
6
7
7
7
69
1
61
0
9
55
74
49
65
10
11
12
3.5
97
85
12
-
aReaction conditions: aryl halide (0.2 mmol), phenylacetylene (0.22 mmol), K2CO3 (0.4 mmol), DMF, 135 ˚C, 5 mol% catalyst A, N2
atmosphere.
bGC conversion.
cIsolated yield.
dIn DMSO solvent
was investigated by inductively coupled plasma (ICP) analysis,
and no Pd-impurity was observed in any of the samples.
The selectivity of the procedure was examined using 1-bromo-
4-iodobenzene and 1,4-diiodobenzene. In these reactions iodide
acted as the better leaving group (Scheme 1).
The absence of Pd contamination in the starting materials,
including the bases (K2CO3, KOH, t-BuOK) and the Cu complex
Scheme. 1. Reaction selectivity of 1-bromo-4-iodobenzene and 1,4-diiodobenzene with phenylacetylene.
conclusion, we have synthesized [N-benzyl
In
DABCO]+[Cu4Cl5]‾ and employed it as an efficient and stable
catalyst in Sonogashira-like cross-coupling reactions. Using this
palladium-free catalytic system, a variety of substituted aromatic
alkynes were prepared in good to excellent yields.
References and notes
1. Ranu, B. C.; Dey, R.; Chatterjee, T.; Ahammed, S.
ChemSusChem. 2012, 5, 22.
2. Yang, C.-T.; Zhang, Z.-Q.; Liu, Y.-C.; Liu, L. Angew.
Chem. Int. Ed. 2011, 50, 3904.
Acknowledgments
3. Seechurn, C. C. C. J.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062.
4. Furuya, T., Klein, J. E. M. N., Ritter, T. Synthesis 2010,
1804.
5. Meijere, A. In Metal-Catalysed Cross-Coupling
Reactions; Diederich, F., Ed., 2nd ed.; Wiley-VCH:
Weinheim, 2004.
We gratefully acknowledge the funding support received for
this project from the Isfahan University of Technology (IUT), IR
of Iran, and Isfahan Science and Technology Town (ISTT), IR of
Iran. Further financial support from the Center of Excellence in
Sensor and Green Chemistry Research (IUT) is gratefully
acknowledged.
6. Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev.
2004, 248, 2337.
7. Ghasemi, H.; Antunes, L. M.; Organ, M. G. Org. Lett.
2004, 6, 2913.

5
8. Hansen, T. M.; Engler, M. M.; Forsyth, C. J. Bioorg.
Med. Chem. Lett. 2003, 13, 2127.
9. Hiroya, K.; Matsumoto, S.; Sakamoto, T. Org. Lett.
2004, 6, 2953.
10. Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem. 2005, 117, 4516.
11. Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
12. Doucet, H.; Hierso, J.-C. Angew. Chem. 2007, 119, 850.
13. Tykwinski, R. R. Angew. Chem. Int. Ed., 2003, 42,
1566.
37. Baig, S.; Richard, B.; Serp, P.; Mijoule, l.; Hussein,
K.; Guihe´ry, N.; Barthelat, J.; Kalck, P. Inorg. Chem.
2006,45, 1935.
38. Goreshnik, E. A.; Mys’kiv, M. G. Russ. J. Coord.
Chem. 2003, 29, 505.
39. Jeannin, Y.; Sécheresse, F.; Bernès, S.; Robert, F.
Inorg. Chim. Acta. 1992, 198–200, 493.
40. Angelis, S. D.; Solan, E.; Flonani, C.; Chiesi-Villa, A.;
Rizzoli, C. J. Am. Chem. Soc. 1994, 116, 5702.
41. Procedure for the synthesis
of
[N-benzyl
14. Sonogashira, K. In Comprehensive Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: Oxford, 1999; Vol.
3, p 521.
15. Prabakaran, K.; Khan, F. N.; Jin, S. Tetrahedron Lett.
2011, 52, 2566.
DABCO]+[Cu4Cl5]‾: In a round-bottom flask, CuCl (1
mmol, 0.099 g), freshly recrystallized from HCl, was
mixed with MeOH (10 mL). The resulting mixture was
treated with [N-benzyl DABCO]Cl (2 mmol, 0.47 g in
10 mL of MeOH). A yellow solid formed immediately.
The mixture was stirred for 30 min at room temperature
and then heated at 65 ˚C with stirring for about 4 h
under an N2 atmosphere. The yellow solid product was
isolated by filtration and washed with methanol. Anal.
Calcd for C13H19Cl5Cu4N2: Cu, 40.04; C, 24.60; H,
3.02; N, 4.41. Found: C, 24.59; H, 3.50; N, 4.37. The
16. Carril, M.; Correa, A.; Bolm, C. Angew. Chem. 2008,
120, 4940.
17. Feng, L.; Liu, F.; Sun, P.; Bao, J. Synlett 2008, 1415.
18. Wang, L.; Li, P.; Zhang, Y. Chem. Commun. 2004, 514.
19. Li, P.; Wang, L. Synlett 2006, 2261.
20. GonzKlez-Arellano, C.; Abad, A.; Corma, A.; García,
H.; Iglesias, M.; Sánchez, F. Angew. Chem. 2007, 119,
1558.
21. Park, S.; Kim, M.; Koo, D. H.; Chang, S. Adv. Synth.
Catal. 2004, 346, 1638.
22. Monnier, F.; Taillefer, M. Angew. Chem. 2008, 120,
3140.
23. Tang, B. X.; Wang, F.; Li, J. H.; Xie, Y. X.; Zhang, M.
B. J. Org.Chem. 2007, 72, 6294.
24. Biffis, A.; Scattolin, E.; Ravasio, N.; Zaccheria, F.
Tetrahedron Lett. 2007, 48, 8761.
25. Priyadarshini, S.; Joseph, P. J. A.; Srinivas, P.;
Maheswaran, H.; Kantam, M. L.; Bhargava, S.
Tetrahedron Lett. 2011, 52, 1615.
copper content of
a
100 ppm solution of
C13H19Cl5Cu4N2 is 40.07% as analyzed by the ICP
technique.
42. Hajipour, A.R.; Mahboubghah, N., J. Chem. Research
(S), 1998, 122.
43. General Procedure for Sonogashira Cross-Coupling:
Aryl halide (0.2 mmol) and K2CO3 (0.4 mmol) were
added to a mixture of DMF (2 mL) and catalyst A (5
mol%) in a round-bottom flask equipped with a
condenser and under an N2 atmosphere. The mixture
was heated in an oil bath at 135 °C and then
phenylacetylene (0.22 mmol) was added in two
portions. The mixture was stirred continuously during
26. Liu, F.; Ma, D. J. Org. Chem. 2007, 72, 4844.
27. 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.
28. Wang, Y. F.; Deng, W.; Liu, L.; Guo, Q. X. Chin.
Chem. Lett. 2005, 16, 1197.
29. Okuro, K.; Furuune, M.; Enna, M.; Miura, M.; Nomura,
M. J. Org. Chem. 1993, 58, 4716.
30. Calo, V.; Nacci, A.; Monopoli, A.; Ieva, E.; Cioffi, N.
Org. Lett. 2005, 7, 617.
31. Jeffery, T. Tetrahedron. 1996, 52, 10113.
32. Hajipour, A. R.; Azizi, G.; Ruoho, A. E. Synlett 2013,
24, 254.
33. Hajipour, A. R.; Najafi, N.; Rafieea, F. Appl.
Organomet. Chem. 2013, 27, 228.
34. Hajipour, A. R.; Mahboobi Dehbane, I.; Rafiee, F. Appl.
Organomet. Chem. 2012, 26, 743.
35. Zawartka, W.; Gniewek, A.; Trzeciaka, A.M.;
Zilkowski, J.J.; Pernak, J. J. Mol. Catal. A: Chem.
2009, 304, 8.
the
reaction
and monitored
by thin-layer
chromatography (TLC) and gas chromatography (GC).
After the reaction was complete, the mixture was
cooled to room temperature and diluted with EtOAc and
H2O. The product was extracted with EtOAc and the
organic phase dried over MgSO4, filtered and
concentrated. The arylalkynes obtained could be
purified by silica gel column chromatography
(hexane:EtOAc). The arylalkyne products were known
1
compounds and were characterized from their IR, H
NMR
phenylethynyl)benzene (Table 2, entry 2): FT-IR (KBr,
and
GC-MS.
1-Methoxy-(4-
cm-1): 3052, 2214, 1593, 1509, 1245, 1137,1028. H-
1
NMR (400 MHz, ppm, CDCl3): δ = 7.42 (m, 2H), 7.38
(d, J = 8.8 Hz, 2H), 7.25 (m, 3H), 6.79 (d, J = 8.8 Hz,
2H), 3.73 (s, 3H). MS (EI): m/z (%): 208 [M]+ (100),
193 (57), 165 (60).
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36. Zawartka, W.; Trzeciak, A.M.; Ziłkowski, J.J.; Lis, T.;
Ciunik, Z.; Pernak, J. Adv. Synth. Catal. 2006, 348,
1689.