Copper-catalyzed, palladium-free carbonylative Sonogashira coupling reaction of aliphatic and aromatic alkynes with iodoaryls

Article abstract of DOI:10.1055/s-2008-1042897

Copper bis(2,2,6,6-tetramethyl-3,5-heptanedionate) catalyzed carbonylative Sonogashira coupling reactions of aliphatic/aromatic alkynes with iodoaryls are reported for the first time. The protocol eliminates the use of a toxic, air-sensitive, and expensiv

Full text of DOI:10.1055/s-2008-1042897

886
LETTER
Copper-Catalyzed, Palladium-Free Carbonylative Sonogashira Coupling
Reaction of Aliphatic and Aromatic Alkynes with Iodoaryls
Coupling
R
eac
a
tionof
A
li
w
phatic and
A
romat
a
ic
A
lkynes
n
w
ithIodoaryls J. Tambade, Yogesh P. Patil, Nitin S. Nandurkar, Bhalchandra M. Bhanage*
Department of Chemistry, Institute of Chemical Technology (Autonomous), University of Mumbai,
N. Parekh Marg, Matunga, Mumbai 400 019, India
Fax +91(22)24145614; E-mail: bhalchandra_bhanage@yahoo.com
Received 1 November 2007
gashira coupling reaction has not yet been explored. Thus
Abstract: Copper bis(2,2,6,6-tetramethyl-3,5-heptanedionate) cat-
alyzed carbonylative Sonogashira coupling reactions of aliphatic/
aromatic alkynes with iodoaryls are reported for the first time. The
protocol eliminates the use of a toxic, air-sensitive, and expensive
there is a need to develop a chemically well-defined, sta-
ble transition-metal complex, which could overcome the
above disadvantages and could directly catalyze carbony-
Pd–phosphine-based catalytic system, and provides high yields of lative Sonogashira couplings of both aliphatic and aro-
desired products.
matic alkynes. This paper reports the first example of the
use of a copper-based catalytic system for the carbonyla-
tive Sonogashira coupling reaction under milder condi-
tions.
Key words: Sonogashira, carbonylation, iodoaryls, alkynes, copper
Alkynyl ketones have attracted considerable biological
interest due to their utility as synthetic intermediates, par-
ticularly for the synthesis of heterocyclic systems.1 One of
the routes to prepare these compounds involves the reac-
tion of alkynyl organometallic reagents such as sodium,2
lithium,3 cadmium,4 zinc,5 copper,6 and tin7 with acid
chlorides. However, these methods require use of dry sol-
vents in an inert atmosphere. Alternatively, alkynyl ke-
tones can be synthesized using transition-metal-catalyzed
coupling of terminal alkynes with organic halides in the
presence of carbon monoxide (carbonylative Sonogashira
coupling). Sonogashira coupling is a well-known reaction
catalyzed by palladium–ligand-based8 catalytic systems.
More recently, the use of copperinstead of palladium was
found to be an effective catalyst for this transformation.9
However, the carbonylative Songashira coupling reaction
has been explored only with Pd-based catalysts such as
Pd(OAc)2/CuI,10 PdCl2 [1,1¢-bis(diphenylphosphino)fer-
rocene],11 [(PPh3)Pd (Ph)(m-OH2)]2,12 PdCl2(PPh3)2/aq
NH3,13 or PdCl2/PPh3 in water.14 Recently, Ryu et al. have
reported a Pd/N-heterocyclic carbene (NHC)-catalyzed
carbonylative Sonogashira coupling reaction using a mul-
tiphase microwflow system.15 In spite of significant ad-
vances in this area, all the above reports involve use of a
palladium source along with toxic, air-sensitive, and ex-
pensive phosphine-based ligands, and the use of stoichio-
metric amounts of copper salt additives. However,
palladium-free, copper-catalyzed carbonylative Sono-
Previously, we had reported metal/TMHD (2,2,6,6,-tet-
ramethyl-3,5-heptanedionate)-based catalytic systems for
various transformations.16 Herein, we report a facile car-
bonylative Sonogashira coupling reaction of aliphatic and
aromatic alkynes with iodoaryls using a preformed
Cu(TMHD)2 complex (Scheme 1). The ease of prepara-
tion of this complex,17 its high solubility in organic sol-
vents, indefinite shelf life, and stability towards air makes
it an ideal complex for the carbonylative Sonogashira cou-
pling reaction.
Initially, the effects of various catalysts, solvents, and
bases were investigated for the carbonylative Sonogashira
coupling reaction of phenyl acetylene with iodobenzene at
90 °C under 20 atm of carbon monoxide (Table 1). Cop-
per salts, such as Cu(OAc)2, CuCl2, CuI, were found to be
less effective due to their poor solubility in organic sol-
vents. The N- or P-containing ligands, such as EDA and
PPh3, and metal complexes, such as copper bis(2,2,6,6,-
tetramethyl-3,5-heptanedionate) [Cu(TMHD)2], copper
bis(acetylacetonate) [Cu(acac)2], and copper bis(ethyl
acetoacetonate) [Cu(eaa)2], were also tested, and among
them Cu(TMHD)2 was found to be the most effective cat-
alyst providing an excellent yield of 80%.
The reactivity trend could result from the fact that a better
balance exists between the electronic and steric effects in
the Cu(TMHD)2 complex. The effect of various solvents
on the reaction system was investigated. It was observed
O
Cu(TMHD)2
toluene, Et3N, 90 °C
ArI
CO
R
H
+
+
Ar
R
R = Ph, n-Bu, n-Hex
Scheme 1
SYNLETT 2008, No. 6, pp 0886–0888
x
x.
x
x.
2
0
0
8
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042897; Art ID: D35907ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Coupling Reaction of Aliphatic and Aromatic Alkynes with Iodoaryls
887
that the reaction was more favorable in nonpolar solvents proceeded smoothly under the present conditions giving
such as toluene, as compared to polar solvents such as wa- 68% yield (entry 5). The reaction also works well with a
ter, DMF, or THF. The probable reason may be due to the heterocyclic iodoaryl such as 2-iodothiophene, providing
high solubility and stability of the catalyst in nonpolar sol- a moderate yield of 67% (entry 6).
vents providing higher yield. In order to evaluate the ef-
Table 2 Carbonylative Sonogashira Coupling of Phenyl Acetylene
fect of base, various organic and inorganic bases, such as
K2CO3, Cs2CO3, KOt-B, and Et3N, were studied. Out of
with Aryl Iodidesa
them, Et3N was found to be the most effective, providing
an 80% yield of the desired product at three equivalents
loading relative to the aryl iodide.
Entry
Ar
R
Yield (%)b
8015
1
2
3
4
5c
6
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
4-MeOC6H4
2-MeC6H4
4-O2NC6H4
thien-2-yl
7814
Table 1 Effect of Catalyst, Solvent, and Base for the Carbonylative
Sonogashira Coupling Reaction of Phenyl Acetylene with Iodoben-
zenea
7613
7315
Entry
Catalyst
Solvent
Base
Yield (%)
6811
Effect of catalyst
6711
1
2
3
4
5
6
7
8
Cu(OAc)2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
38
44
35
80
62
58
68
08
a Reaction conditions: aryl iodide (2.0 mmol), phenylacetylene (3.0
mmol), Cu(TMHD)2 (5 mol%), Et3N (6.0 mmol), toluene (10 mL),
CO (20 atm), 14 h, 90 °C.
CuCl2
b Yields of isolated product.
CuI
c Reaction time: 18 h.
Cu(TMHD)2
Cu(acac)2
Cu(eaa)2
To check the generality of the process, the catalytic sys-
tem was extended for the carbonylative coupling reaction
of aliphatic alkynes with aryl iodides (Table 3).18 Aliphat-
ic alkynes, such as 1-hexyne, were found to react smooth-
ly with iodobenzene under the present conditions,
providing a 74% yield of the desired product (entry 1).
Electron-donating substituents at the ortho- or para-posi-
tions of the iodobenzene were tolerated. However, the re-
action of 2-iodothiophene was found to be sluggish
providing a 52% yield of coupled product. 1-Octyne was
also found to react efficiently with iodoaryls providing
good to excellent yields (70–77%) of the desired product.
Cu(OAc)2/PPh3
Cu(OAc)2/EDA
Effect of solvent
9
10
11
12
Cu(TMHD)2
H2O
DMF
THF
none
Et3N
Et3N
Et3N
Et3N
05
08
24
10
Cu(TMHD)2
Cu(TMHD)2
Cu(TMHD)2
Table 3 Carbonylative Sonogashira Coupling of Alkynes with Aryl
Effect of base
Iodidesa
13
14
15
16b
Cu(TMHD)2
toluene
toluene
toluene
toluene
K2CO3
Cs2CO3
KOt-Bu
Et3N
08
10
35
70
Entry
1c
Ar
R
Yield (%)b
7414
Cu(TMHD)2
Cu(TMHD)2
Cu(TMHD)2
Ph
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Hex
n-Hex
n-Hex
2c
4-MeC6H4
4-MeOC6H4
2-MeC6H4
thien-2-yl
Ph
7214
3c
6814
a Reaction conditions: iodobenzene (2.0 mmol), phenylacetylene (3.0
mmol), catalyst (5 mol%), base (6.0 mmol), solvent (10 mL), CO (20
atm), 14 h, 90 °C.
4c
6314
5c
5214
b Base (3.0 mmol).
6d
7714
7d
4-MeC6H4
4-MeOC6H4
7313
Thus, using Cu(TMHD)2 as the preferred catalyst, toluene
as solvent, and Et3N as base, the carbonylative Sonogash-
ira coupling of phenyl acetylene with various electron-do-
nating and electron-withdrawing iodoaryls was studied
(Table 2).18 Electron-donating substituents such as Me
and OMe on the iodoarene were well tolerated (entries 2
and 3). No significant steric electronic effect was ob-
served for ortho or para substituents. The reaction of de-
activated substrates such as 4-iodonitrobenzene also
8d
7013
a Reaction conditions: aryl iodide (2.0 mmol), alkyne (3.0 mmol),
Cu(TMHD)2 (5 mol%), Et3N (6.0 mmol), toluene (10 ml), CO (20
atm), 14 h, 90 °C.
b Yields of isolated product.
c Alkyne = 1-hexyne.
d Alkyne = 1-octyne.
Synlett 2008, No. 6, 886–888 © Thieme Stuttgart · New York

888
P. J. Tambade et al.
LETTER
(11) Kobayashi, T.; Tanaka, M. J. Chem. Soc., Chem. Commun.
1981, 333.
(12) Delaude, L.; Masdeu, A. M.; Alper, H. Synthesis 1994, 1149.
(13) Mohamed Ahmed, M. S.; Mori, A. Org. Lett. 2003, 5, 3057.
(14) Liang, B.; Huang, M.; You, Z.; Xiong, Z.; Lu, K.; Fathi, R.;
Chen, J.; Yang, Z. J. Org. Chem. 2005, 70, 6097.
In summary, several important features are demonstrated
in this study. The Cu(TMHD)2 complex was found to be
an excellent alternative to the toxic, air-sensitive, and ex-
pensive palladium–phosphine catalyst systems; the ease
of preparation of this complex, its high solubility in organ-
ic solvents, indefinite shelf life, and stability towards air
make it an ideal complex for the carbonylative Sonogash-
ira coupling reaction; the system works well with a wide
variety of iodoaryls with different steric and electronic
properties.
(15) Rahman, M. T.; Fukuyama, T.; Kamata, N.; Sato, M.; Ryu,
I. Chem. Commun. 2006, 2236.
(16) (a) Nandurkar, N. S.; Bhanushali, M. J.; Bhor, M. D.;
Bhanage, B. M. Tetrahedron Lett. 2007, 48, 6573.
(b) Nandurkar, N. S.; Bhanushali, M. J.; Bhor, M. D.;
Bhanage, B. M. Tetrahedron Lett. 2008, 49, 1045.
(c) Purecha, V. H.; Nandurkar, N. S.; Bhanage, B. M.;
Nagarkar, J. M. Tetrahedron Lett. 2008, 49, 1384.
(17) Typical Procedure for the Preparation of Cu(TMHD)2
NaOH (22 mmol) was dissolved in MeOH (20 mL) with
stirring and the resulting solution was cooled to r.t., followed
by addition of TMHD (20 mmol). To the mixture, a solution
obtained by dissolving Cu(NO3)2·6H2O (10 mmol) in MeOH
(20 mL) was added over a period of 30 min. The reaction
mixture was stirred for 6 h and the resulting precipitate was
filtered and dried. Yield 93%, mp 196–198 °C.
Acknowledgment
The financial assistance from Technical Education Quality Impro-
vement Programme (TEQIP), Government of India is kindly ack-
nowledged.
References and Notes
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(18) General Procedure
To an 100 mL autoclave, phenylacetylene (3.0 mmol),
iodobenzene (2.0 mmol), Cu(TMHD)2 (0.1 mmol), toluene
(10 mL) and Et3N (6.0 mmol) were added. The mixture was
first stirred for 10 min, then the vessel pressures 8–20 atm of
CO and the reaction mixture was heated at 90 °C for 14 h.
After the reaction was complete, the mixture was extracted
with EtOAc (3 × 10 mL), the combined organic extracts
were dried over Na2SO4, and the solvent was removed under
vacuum. The residue obtained was purified by column
chromatography (silica gel, 60–120 mesh) using PE
(60:80)–EtOAc as eluent to afford the pure products. All the
compounds are known and were characterized by GC–MS
(Shimadzu) and NMR (Varian 300 MHz).
Spectroscopic Data of Representative Compounds
Table 2, Entry 1: GC-MS: m/z (%) = 206 [M+], 178, 129
(100). 1H NMR (300 MHz, CDCl3, 25 °C): d = 7.49–7.54
(m, 5 H), 7.61–7.63 (m, 1 H), 7.68–7.70 (m, 2 H), 8.23 (ddd,
J = 8.4, 2.1, 1.2, 2 H) ppm. 13C NMR (70 MHz, CDCl3,
25 °C): d = 87.0, 93.2, 120.2, 128.8, 128.8, 129.2, 130.9,
133.2, 134.3, 137.0, 178.1 ppm.
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2007, 1279. (b) Saejueng, P.; Bates, C. G.; Venkataraman,
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Table 2, Entry 2: GC-MS: m/z (%) = 220 [M+], 192 (100),
165, 129. 1H NMR (300 MHz, CDCl3, 25 °C): d = 2.44 (s, 3
H), 7.29–7.44 (m, 5 H), 7.67 (d, J = 8.4 Hz, 2 H), 8.11 (d,
J = 8.4 Hz, 2 H) ppm. 13C NMR (70 MHz, CDCl3, 25 °C ):
d = 21.9, 87.0, 92.7, 120.3, 128.8, 129.4, 129.9, 130.8, 133.1,
134.7, 145.3, 177.8 ppm.
Table 3, Entry 1: GC-MS: m/z (%) = 186 [M+], 105 (100),
77. 1H NMR (300 MHz, CDCl3, 25 °C): d = 0.98 (t, J = 2.8,
4.8, 7.2, 3 H), 1.26–1.33 (m, 2 H), 1.63–1.69 (m, 2 H), 2.51
(t, J = 7.2, 6.8, 2 H), 7.460–7.59 (m, 3 H), 8.12–8.15 (m, 2
H) ppm. 13C NMR (70 MHz, CDCl3, 25 °C): d = 13.7, 19.1,
22.7, 29.9, 80.0, 97.0, 128.6, 129.7, 131.8, 134.0, 178.1 ppm.
(10) Kang, S. K.; Lim, K. H.; Ho, P. S.; Kim, W. Y. Synthesis
1997, 874.
Synlett 2008, No. 6, 886–888 © Thieme Stuttgart · New York