One-pot synthesis of monosubstituted aryl(hetaryl)acetylenes by direct introduction of the C≡CH residue into arenes and hetarenes

Article abstract of DOI:10.1016/j.tet.2004.05.093

A convenient one-pot synthesis of aryl(hetaryl)acetylenes by cross-coupling of aryl(hetaryl)iodides with acetylene in presence of PdCl₂(Ph ₃)₂, CuI and K₂CO₃ in DMF has been developed.

Full text of DOI:10.1016/j.tet.2004.05.093

Tetrahedron 60 (2004) 6685–6688
One-pot synthesis of monosubstituted aryl(hetaryl)acetylenes
by direct introduction of the CuCH residue into arenes
and hetarenes
a,*
a
Sergei F. Vasilevsky, Svetlana V. Klyatskaya and Jose Elguero
b,*
´
a
Institute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of Science,
6
30090 Novosibirsk, Russian Federation
b
Instituto de Qu ´ı mica M e´ dica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain
Received 13 February 2004; revised 30 March 2004; accepted 21 May 2004
Available online 25 June 2004
Abstract—A convenient one-pot synthesis of aryl(hetaryl)acetylenes by cross-coupling of aryl(hetaryl)iodides with acetylene in presence of
PdCl (Ph , CuI and K CO in DMF has been developed.
q 2004 Elsevier Ltd. All rights reserved.
2
3
)
2
2
3
1. Introduction
The diverse and high reactivity of the CuC bond and the
unusually high CH-acidity of monosubstituted acetylenes
has determined an unabated interest on 1-alkynes for many
1
–4
years.
The CuCH moiety is susceptible of nucleophilic,
electrophilic, radical and cycloaddition reactions, and can
be used both for functionalizing and building up C–C
bonds. In fact, terminal acetylenes are very important key-
5
6
compounds in the widely applied Mannich, Hay, Cadiot-
7
8
Chodkiewicz, and Sonogashira-Heck reactions for pre-
paring the corresponding propargyl-amines, symmetrical
and unsymmetrical 1,3-diynes and disubstituted acetylenes.
Scheme 1.
However, a review of the publications dealing with the
study of the transformations of vinylic or ketonic groups
into acetylenes under the action of bases indicates the
sensitivity of these reactions to experimental conditions,
the structure of the starting substrate and the nature of the
Ethynyl derivatives occupy a special place, because
monosubstituted acetylenes have not only a reactive triple
bond but also an active hydrogen which allows to carry out
various transformations of the molecule with preservation
of the multiple bond. The properties of such compounds as
C–H acids are used for functionalization and construction
of C–C bonds.
1
0,11
base.
ethynylpyridine and ethynylquinoline obtained by the
Thus, the yields of all possible isomers of
1
0
dehydrohalogenation varied from 0.1 to 33%. An attempt
to dehydrobrominate a pyrrolo-dibromoderivative under the
1
0
12
Usually classical methods for preparing aryl(hetaryl)alk-1-
ynes involve the sequence halogenation–dehalogenation of
action of sodium ethoxide failed. The present authors
found that pyrazolylvinylchlorides, which are not substi-
tuted at the nitrogen of the ring, under the effect of sodium
amide lead to complex mixtures.
9
vinyl aromatic compounds or halogenation–dehydro-
halogenation of dihaloderivatives from vinylarenes(hetar-
1
0
enes) or methylaryl(hetaryl)-ketones (Scheme 1).
In the last three decades, beginning from the discovery of
Japanese chemists who found new effective catalysts for the
cross-coupling reaction of arylhalides with monosubstituted
acetylenes, this method has become the main one for
producing not only disubstituted, but also monosubstituted
arylacetylenes. This approach involves protecting one end
Keywords: Cross-coupling; Monosubstituted acetylenes; Homogeneous
catalysis.
1
0
*
Corresponding authors. Tel.: þ34-91-4110874; fax: þ34-91-5644853;
e-mail addresses: vasilev@ns.kinetics.nsc.ru; iqmbe17@iqm.csic.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.093

6686
S. F. Vasilevsky et al. / Tetrahedron 60 (2004) 6685–6688
Scheme 2.
of acetylene, introduction of 1-alkyne via coupling at the
free end of acetylene, followed by deprotection of the
acetylenic moiety of aryl- or hetarylacetylenes (Scheme 2).
achieving our aim we changed the traditional conditions of
a reaction of cross-coupling. In this paper we describe full
experimental conditions and new additional examples.
A usual way for ethynylarene synthesis involves the
cleavage of the tertiary acetylenic alcohols or trimethyl-
silylacetylene derivatives by treatment with a catalytic
amount of alkali. However, the starting reagent, trimethyl-
silylacetylene, is rather expensive and gives only trimethyl-
silyl derivatives. On the other hand, the second method—
base-induced cleavage of a-acetylenic alcohols into carbo-
nyl and ethynyl compounds (the reverse Favorsky reaction)
requires hard reaction conditions (strong alkali, high
temperature) and cannot be applied for obtaining labile
acetylenic compounds.
We have proposed that it is necessary to have a large excess
of acetylenes in the reaction mixture for diminishing the
competition reaction of the iodoarene with the initially
generated ethynylarene. Thus, we decided to use a solvent
with high boiling point and which dissolves large amounts
of acetylene. Dimethylformamide is a solvent, which
has just such properties. Below is given the solubility of
HCuCH at 20 8C and 760 mm Hg in different solvents:
volumes of HCuCH per 1 volume of solvent: ether 5.5,
THF 18.5, DMF 33–37. To increase additionally the high
concentration of HCuCH we used a relatively large amount
of DMF (the weight ratio iodide/DMF¼1:200).
1
5
In 1980 Japanese chemists tried to carry out cross-coupling
of aryliodides with acetylene itself using the typical
catalytic system PdCl (PPh ) –CuI–R N for preparing of
It is also known that the application of stronger bases in
cross-coupling substantially increases the reaction rate, thus
we used potassium carbonate instead of the usual di- and
trialkylamines. Taking into account the facts mentioned
above, we carried out cross-coupling of a series of iodo-
arenes and -hetarenes in an acetylene current in the presence
of catalytic amounts of PdCl (PPh ) , CuI and excess of
2
3 2
3
ethynylarenes (Scheme 3). But their attempts were unsuc-
cessful; the main products being tolanes as a result of the
reaction of the arylalk-1-yne formed with the starting iodo
1
,13
component.
2
3 2
We supposed that this negative result was related with using
volatile amines, having high vapor pressure, which decrease
partial pressure of acetylene and therefore its concentration.
Nevertheless, we undertook a first attempt to carry out the
cross-coupling of acetylene with iodoarenes and -hetarenes
K CO in DMF at 50–55 8C (Scheme 4).
2 3
Iodoarenes and hetarenes with low reactivity like p-iodo-
aniline, 4-iodo-1,3,5-trimethylpyrazole, 4-iodo-3-ethoxy-
carbonyl-1,2,5-trimethylpyrrole, due to the strong þM-effect
of the nitrogen atom underwent ethynylation in low yields
1
4
for preparing the desired monosubstituted acetylenes. For
Scheme 3.
Scheme 4.

S. F. Vasilevsky et al. / Tetrahedron 60 (2004) 6685–6688
6687
Table 1. Ethynylarenes and -hetarenes
Compound
Time, h Yield, % (%, from copper salt) Boiling points (melting points), 8C Literature
2
2
o-Ethynylcarbomethoxybenzene (12)
p-Ethynylnitrobenzene (13)
o-Ethynylnitrobenzene (14)
12
12.5
8
17
17
17
73.2 (56.4)
76.4
64.4
80–85/1 Torr n
146.5–147.5
79.5–81
d
¼1.5550
14
19
19
21
19
19
19
19
11
22
4-Ethynylpyridine (15)
60.2
96–97
44/23 Torr n
17
Phenylacetylene (16)
p-Ethynylanisole (17)
p-Ethynylaniline (18)
o-Ethynylaniline (19)
60.0 (56.4)
64.2 (50.0)
(10.0)
(47.4)
24.0 (20.3)
35.4 (20.0)
d
¼1.5507
27–28 96–98/14 Torr
99–100
99–101/13 Torr
45.5–56.5
87.5–88.5
4-Ethynyl-1,3,5-trimethyl-1H-pyrazole (20)
4-Ethynyl-1,2,5-trimethyl-3-carbomethoxy-1H-pyrrole (21)
36
(
15–35%). Iodobenzene and even p-methoxyiodobenzene
tube was tightly placed on the flask, the air was replaced by
acetylene (purified from acetone passing through water and
then sulfuric acid). The flask was charged with 260 mL of
DMF, powdered potassium carbonate (2 g, 15 mmol),
PdCl (Ph P) (50 mg) and CuI (25 mg). After the mixture
gave monoarylated products in moderate yields (50–55%).
Iodoarenes (hetarenes) with electron withdrawing sub-
stituents gave the desired ethynyl derivatives in high yields
(
65–75%).
2
3
2
was additionally saturated with acetylene with vigorous
stirring, the temperature was raised up to 50 8C and a
solution of iodides 1–10 (10 mmol) in 30–40 mL of DMF
(also previously saturated with acetylene) was slowly added
during 5–6 h. Reaction was carried out at 50–55 8C and
under a permanent stream of acetylene up to completion of
the reaction (TLC control).
The different behavior of p- and o-iodoaniline is note-
worthy. The yield in the case of the deactivated o-iodo-
aniline was rather high (50%). We explain this fact by
the proximity of the amino group in ortho-position to the
halogeno atom, which assist the formation of the complex of
palladium salt followed by the introduction of palladium
between carbon and iodine atoms—the first step of the
cross-coupling. We had already observed the same trends
After cooling the reaction mixture to room temperature,
700 mL of ether (or 700 mL of chloroform) and then 800–
1
6
for other analogous cases.
9
00 mL of water was added. The aqueous layer was
Our studies on the one-pot synthesis of aryl(hetaryl)alk-1-
ynes from iodoarenes(hetarenes) show that target com-
pounds can be prepared in moderate yields (60–75%) for
activated iodides and in low yields (15–35%) from halo
derivatives with low reactivity. Unusual results were
obtained for o- and p-iodoanilines. For the experimental
details of the synthesis as well as physical constants and
yields of ethynyl derivatives see Section 2 and Table 1.
extracted twice with ether [or CHCl (2£100 mL)]. The
3
combined organic solutions were washed three times with
200 mL of water in order to remove as much as possible of
the DMF and were dried over MgSO . After filtering the
4
solution through a thick layer of neutral Al O (3£2 cm) on
2
3
a sintered-glass funnel, the solvent was removed to dryness
under reduced pressure. The desired acetylenes were
purified by distillation or by recrystallization. Time of
reaction, yields and melting point of compounds are
reported in Table 1.
2. Experimental
2
.1. General procedures
Acknowledgements
Melting points were determined with a hot-stage micro-
scope. Column chromatography was performed on silica gel
This work was supported by RFBR grant No 02-03-32229,
grant CRDF No 008-XI.
(
aluminium backed TLC plates of silica gel 60 F254 (Merck,
Merck 60, 70–230 mesh). The R values were measured on
f
1
0
.2 mm) with the indicated eluent. H NMR spectra were
recorded on a Bruker DRX 400 (9.4 T, 400.13 MHz)
References and notes
spectrometer. Chemical shifts (d in ppm) are given from
internal CHCl (7.24 ppm). Coupling constants (J in Hz) are
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3
accurate to ^0.2 Hz. Mass spectra (HRMS) were measured
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1
7
18
19
additional purification. Iodides 1, 9, 10 were prepared
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2
0
the published procedure.
5
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2
.2. General procedures of ethynylation
6
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