The use of calcium carbide in one-pot synthesis of symmetric diaryl ethynes

Article abstract of DOI:10.1039/b607809e

An efficient Pd-catalyzed copper and amine free coupling reaction of acetylene and aryl bromides was achieved with calcium carbide as an acetylene source, using inorganic base and easily prepared, air-stable aminophosphine ligand in common organic solvents, providing symmetric diaryl ethynes in one-pot with yields ranged from moderate to excellent. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b607809e

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The use of calcium carbide in one-pot synthesis of symmetric diaryl
ethynes{
Weiwei Zhang, Huayue Wu, Zhiqing Liu, Ping Zhong, Lin Zhang, Xiaobo Huang and Jiang Cheng*
Received (in Cambridge, UK) 2nd June 2006, Accepted 13th September 2006
First published as an Advance Article on the web 2nd October 2006
DOI: 10.1039/b607809e
An efficient Pd-catalyzed copper and amine free coupling
reaction of acetylene and aryl bromides was achieved with
calcium carbide as an acetylene source, using inorganic base
and easily prepared, air-stable aminophosphine ligand in
common organic solvents, providing symmetric diaryl ethynes
in one-pot with yields ranged from moderate to excellent.
to give diaryldiacetylenes when exposed to air or an oxidant, which
7
is known as the Glaser coupling. The methods mentioned above
have the following disadvantages: 1) The yield is often not very
high. 2) By-products are generally difficult to separate from the
desired products. 3) The copper acetylide is potentially an
8
explosive reagent. 4) The use of amine as solvent is not
environmental friendly. 5) Only the expensive, highly active aryl
iodides are proper substrates when acetylene gas is employed. 6)
This procedure, especially in a large scale preparation, is not
experimentally facile because acetylene is a gas. Considering this,
we explored the use of the inexpensive, easily handled and
commercially available calcium carbide as the acetylene source to
synthesize some biaryl ethynes. Herein, we report a copper and
amine free alkynylation reaction between aryl bromides and
acetylene, which was derived from calcium carbide in situ,
affording the biaryl ethynes in one-pot with moderate to excellent
yields. Aminophosphines were employed as ligands in the
procedure, which were air-stable, easily prepared and showed
high activity in the Suzuki reaction as well as in copper and amine
Palladium-catalyzed coupling of terminal alkynes with aryl or
alkenyl halides is one of the most straightforward methods for the
1,2
preparation of aryl alkynes and conjugated enynes (Scheme 1).
Such reactions can not only serve as a powerful synthetic
method in constructing complex systems including natural
3
products, but also as a powerful tool to synthesize conjugated
oligomers or polymers with interesting physical properties in
4
material science. Such a method for efficient synthesis of
diarylacetylenes has also been applied for supramolecular self-
4
assembly construction. Usually, biaryl ethynes can be obtained by
5
two ways. One is by using a protected acetylene (Scheme 2).
However, this three-step procedure is circuitous and often leads to
modest overall yields of the desired diaryl ethyne. The other one is
using acetylene gas, which is a very economical way to deliver a
9
free alkynylation reaction.
At the very beginning, we noted that two molecules of HBr were
released in the alkynylation reaction cycle. So we reasoned, if the
released HBr could react with calcium carbide to produce
acetylene, the added base would remain untouched. Thus, the
alkynylation reaction of aryl bromides with acetylene (derived
from calcium carbide in situ) would run in the presence of only a
6
triplet C–C bond moiety to organic substrates. But it often
requires Cu(I) salt or amine to synthesize biaryl ethyne from
acetylene gas and the procedures are not well documented. The
Cu(I) acetylides formed in situ can undergo oxidative dimerization
catalytic amount of base and water (Scheme 3). We first chose
i
p-bromoanisole as a substrate and Pr
2
NPPh
2
(L1) as a ligand to
investigate the alkynylation reaction in the absence of a copper
salt.
Much to our disappointment, treatment with a mixture of
calcium carbide 1 (256 mg, 4 mmol), p-bromoanisole 2h (374 mg,
Scheme 1
2
mmol), Pd(OAc)
0 mol%) and L1 (43 mg, 0.15 mmol) in undried THF (5 mL) at
5 uC under an inert atmosphere for 12 hours only afforded the
2 2 3
(11 mg, 0.05 mmol), K CO (10 mol% and
5
6
Scheme 2
College of Chemistry & Material Science, Wenzhou University, Mid.
Xueyuan Rd., Wenzhou, 325027, China.
E-mail: shchengjiang@yahoo.com.cn; Fax: 86-577-88156826;
Tel: 86-577-88156826
{
Electronic supplementary information (ESI) available: Screen of the
reaction conditions, analytical data and copies of spectra for the cross-
coupling products. See DOI: 10.1039/b607809e
Scheme 3
4
826 | Chem. Commun., 2006, 4826–4828
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desired product 3h in 32% and 36% yields, respectively. Therefore,
we tested a series of parameters, which may play important roles in
the reaction. Firstly, we studied the influence of the ratio of the
base. It was pleasing to find that the combination of 1 (256 mg,
Table 1 Alkynylation reaction of aryl bromides and acetylene using
calcium carbide as acetylene source
a
4
2
mmol), 2h (374 mg, 2 mmol), Pd(OAc) (11 mg, 0.05 mmol),
K
2
CO (552 mg, 4 mmol) and L1 (43 mg, 0.15 mmol) in undried
3
10
THF (5 mL) gave the product in 79% yield. When the amount of
K CO was increased to 300 mol%, the product was obtained in
Yield
(%)
b
2
3
Entry
Aryl bromide
Product
80% yield. Since no significant increase in the yield was found by
1
2
3
4
5
6
7
8
9
Bromobenzene (2a)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
83
97
75
76
78
69
62
79
67
56
14
72
44
56
N. R.
56
65
increasing the amount of base, we chose to use 200 mol% of
K CO in the reaction to reduce the waste. We then turned our
1-Bromonaphthalene (2b)
o-Bromotoluene (2c)
m-Bromotoluene (2d)
2
3
attention to the screening of ligands. On considering the electronic
effect and steric hindrance in ligand designing in the transition
p-Bromotoluene (2e)
11
2,6-Dimethylphenyl bromide (2f)
2,4,6-Trimethylphenyl bromide (2g)
p-Bromoanisole (2h)
metal catalyzed-coupling reaction,
we tested some other
aminophosphine ligands, which are all easily synthesized (Fig. 1).
Only a trace amount of desired product was detected when L2,
which was a high activity ligand in the Suzuki reaction, was
employed. The ligand L3 gave 30% yield of the product. Since an
increase of the electron density in the P atom usually facilitates the
oxidative addition step in the catalytic cycles, we introduced
methoxy group in the para position of the phenyl in L1. However,
the yield was only slightly increased to 82% when L4 was applied
instead of L1. We therefore decided to use the easily prepared
ligand L1 in the reaction and optimized the base and solvent
conditions by screening. Finally the optimized reaction conditions
were as follows: 1 (256 mg, 4 mmol), 2h (374 mg, 2 mmol),
m-Bromoanisole (2i)
10
11
12
3-Bromobenzaldehyde (2j)
4-Bromobenzaldehyde (2k)
3-Bromopyridine (2l)
13
3-Bromothiophene (2m)
14
15
16
5-Bromobenzo[d][1,3]dioxole (2n)
1-Bromo-4-nitrobenzene (2o)
2-(4-Bromophenyl)-1,3-dioxolane (2p)
4-Bromo N, N-dimethylaniline (2q)
17
a
All reactions were run with aryl bromide (2 mmol), CaC
4 mmol), Pd(OAc)
CO
2
(236 mg,
2
(11 mg, 0.05 mmol), L1 (43 mg, 0.15 mmol) and
(552 mg, 4 mmol) in 5 ml of undried THF at 65 uC for 12 h.
K
2
3
b
Isolated yield.
Pd(OAc)
43 mg, 0.15 mmol) in undried THF (5 mL). With the optimized
reaction conditions in hand, a series of aryl bromides were tested
2 2 3
(11 mg, 0.05 mmol), K CO (552 mg, 4 mmol) and L1
(
the general considerations in the transition metal catalyzed
coupling reaction. We propose that the reactions proceed in two
steps: 1) The aryl acetylene’s formation. 2) The Sonogashira
reaction of aryl acetylene with aryl bromide (Scheme 4).
12
under these conditions. The results are summarized in Table 1.
The aryl bromide substrates worked well under the reaction
conditions in the absence of CuI or amine. For example, although
aryl bromides containing electron-donating substituents were
usually found to be reluctant in taking part in oxidative addition
to Pd(0), yet in our system, products 3b, 3h, 3i were obtained in
When p-nitrobromobenzene (2o) was used as the substrate, the
reaction could not proceed and the starting materials were almost
quantitatively recovered without the formation of product 4. This
implies that during the course of forming symmetric diarylacety-
lenes, the second reaction serves as the driving force for the first
reaction. Although p-nitrobromobenzene may take part in the first
reaction more facilely than p-bromoanisole, in the primary product
97%, 79% and 67% isolated yield, respectively (Table 1, Entries 2,
8, 9). The ortho group in the aryl bromide was found to have some
effect in the reaction, and the yields were slightly decreased to 75%
for o-bromotoluene (2c), 69% for 2,6-dimethylphenyl bromide (2f)
and 62% for 2,4,6-trimethylphenyl bromide (2g) (Table 1, Entries
4, the terminal triple bond in p-nitrophenylacetylene (4o) has much
less electron density than in p-methoxyphenylacetylene (4h) owing
to the presence of the strongly electron withdrawing nitro group. It
is known that in Sonogashira reactions, alkynes with low electron
density in the terminal triple bond are less active. For example,
trifluoromethylethyne and ethyl propionate are not good sub-
3, 6, 7). As for the 3-bromothiophene (2m), maybe owing to the
possibility of the sulfur atom coordinating with the palladium
atom, the yield was slightly decreased to 44% (Table 1, Entry 13).
It is noteworthy that the aryl bromides containing electron-
withdrawing substituents afford the desired products in low yield.
A 56% yield of the product was obtained for 3-bromobenzalde-
hyde (2j) and no reaction takes place for 1-bromo-4-nitrobenzene
1
3
strates in Sonogashira reactions. We suspected that this electron
deficiency in the terminal triple bond in 4o was the reason for the
1
4
lack of reactivity of 2o in the reactions mentioned above. To
support this hypothesis, we have found in control experiments that
p-bromoanisole (2h) reacts with p-methoxyphenylacetylene
smoothly in the presence of palladium acetate and the ligand L1
to give the symmetric diarylethyne in 77% yield, while 2o can not
react with p-nitrophenyl acetylene under the same conditions
(2o) (Table 1, Entries 10, 15). However, when the carbonyl group
in 4-bromobenzaldehyde (2k) was protected by ethylene glycol, the
yield of the coupling product 3p dramatically increased to 56%
(Table 1, Entry 16). This seems to be somewhat contradictory to
(Scheme 5).
Fig. 1 The screened ligands.
Scheme 4
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 4826–4828 | 4827

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pp 179–225; (f) K. Sonogashira, in Metal-Catalyzed Cross-Coupling
Reactions, ed. F. Diederich and P. J. Stang, Wiley-VCH, Weinheim,
Germany, 1998, pp 203–229.
3
4
(a) Z. Nov a´ k, G. Timari and A. Kotschy, Tetrahedron, 2003, 59, 7509;
(b) Z. Nov a´ k, A. Szab o´ , J. R e´ p a´ si and A. Kotschy, J. Org. Chem., 2003,
68, 3327; (c) U. Beutler, J. Mazacek, G. Penn, B. Schenkel and
D. Wasmuth, Chimia, 1996, 50, 154.
S. C. Johannessen, R. G. Brisbois, J. P. Fischer, P. A. Grieco,
A. E. Counterman and D. E. Clemmer, J. Am. Chem. Soc., 2001, 123,
Scheme 5
3818.
In conclusion, we have developed an efficient, copper and amine
free alkynylation reaction using calcium carbide and aryl bromides
with easily prepared, air-stable aminophosphine as ligand. The
mild reaction conditions, the use of undried solvent, the obviation
of copper salt as co-catalyst and amine as solvent, as well as the
utilization of cheap inorganic base and calcium carbide all
contribute to making this a most attractive reaction.
5 Z. Nov a´ k, P. Names and A. Kotschy, Org. Lett., 2004, 6, 4917.
6
7
(a) C. J. Li, D. L. Chen and C. Costello, Org. Process Res. Dev., 1997, 1,
25; (b) M. Pal and N. G. Kundu, J. Chem. Soc., Perkin Trans. 1, 1996,
49.
P. Siemsen, R. C. Livingston and F. Diederich, Angew. Chem., Int. Ed.,
2000, 39, 2632.
3
4
8 Copper-free Sonogasgira coupling reactions, see: (a) B. Liang, M. Dai,
J. Chen and Z. Yang, J. Org. Chem., 2005, 70, 391 and reference therein;
(b) A. R. Gholap, K. Venkatesan, R. Pasricha, T. Daniel, R. J. Lahoti
and K. V. Srinivasan, J. Org. Chem., 2005, 70, 4869.
9 (a) J. Cheng, F. Wang, J. Xu, Y. Pan and Z. Zhang, Tetrahedron Lett.,
We thank the National Natural Science Foundation of China
(20504023, 20572079), the Natural Science Foundation of
2
003, 44, 7095; (b) J. Cheng, Y. Sun, F. Wang, J. Xu, Y. Pan and
Z. Zhang, J. Org. Chem., 2004, 69, 5428.
0 See Supporting Material{.
1 A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed., 2002, 41, 4176.
Zhejiang Province (No. Y404039, No.Y405015) and the
Scientific Research Fund of Zhejiang Provincial Education
Department (grant No. 20051292) for financial support.
1
1
12 General procedure: Under nitrogen atmosphere, a Schlenk reaction tube
was charged with calcium carbide 1 (236 mg, 4 mmol), aryl bromide 2
Notes and references
(
2 mmol), K
ligand (0.15 mmol) and undried THF (5 mL). The reaction tube was
purged with N under a dry ice bath. After the mixture was heated at
2 3 2
CO (552 mg, 4 mmol), Pd(OAc) (11 mg, 0.05 mmol),
1
(a) K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett.,
975, 16, 4467; (b) L. Cassar, J. Organomet. Chem., 1975, 93, 253; (c)
1
2
H. A. Dieck and F. R. Heck, J. Organomet. Chem., 1975, 93, 259.
For reviews, see: (a) K. Sonogashira, in Comprehensive Organic
Synthesis, ed. B. M. Trost and I. Fleming, Pergamon Press, New
York, 1991, Vol. 3, pp. 521–549; (b) R. Rossi, A. Carpita and F. Bellina,
Org. Prep. Proced. Int., 1995, 27, 129–169; (c) J. Tsuji, Palladium
Reagents and Catalysts, Wiley, Chichester, UK, 1995, pp 168–171; (d)
K. C. Nicolaou and E. J. Sorensen, Classics in Total Synthesis, VCH,
Weinheim, Germany, 1996, pp 582–586; (e) L. Brandsma,
S. F. Vasilevsky and H. D. Verkruijsse, Application of Transition
Metal Catalysts in Organic Synthesis, Springer, Berlin, 1998,
65 uC for 12 h, the solvent was evaporated under reduced pressure and
the residue was purified by flash column chromatography on a silica gel
2
1
to give the product 3. 3h 1,2-bis(4-methoxyphenyl)ethyne H NMR
(300 MHz, CDCl
3
): d 7.44 (d, J = 9.0 Hz, 4H), 6.85 (d, J = 9.0 Hz, 4H),
3.81 (s, 6H). C NMR (75 MHz, CDCl ): d 159.4, 132.8, 115.8, 114.0,
87.9, 55.3.
13
3
13 E. Negishi and L. Anastasia, Chem. Rev., 2003, 103, 1978.
14 The charge of the terminal carbon atom is calculated to be 20.272825
and 20.227259 for 4h and 4o, respectively by DFT method at the
B3LYP-6-31G level (Gaussian 98).
4
828 | Chem. Commun., 2006, 4826–4828
This journal is ß The Royal Society of Chemistry 2006