Efficient coupling reactions of arylalkynes and aldehydes leading to the synthesis of enones

Article abstract of DOI:10.1002/hlca.200490276

Ionic liquids such as 1-butyl-3-methyl-1H-imidazolium 4- methylbenzenesulfonate (BmimOTs) and its 1-ethyl analogue EmimOTs are novel effective and recyclable media for acid-catalyzed coupling reaction, of aromatic alkynes with aldehydes affording (E)-enones (Scheme 1, Table) with simple recovery and easy workup due to the absence of volatile organic solvents. This transformation avoids the use of moisture-sensitive and heavy-metal Lewis acids.

Full text of DOI:10.1002/hlca.200490276

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Helvetica Chimica Acta ± Vol. 87 (2004)
Efficient Coupling Reactions of Arylalkynes and Aldehydes Leading to the
Synthesis of Enones
a
b
a
a
a
by Li-Wen Xu ) ), Lyi Li ), Chun-Gu Xia* ), and Pei-Qing Zhao )
a) State Key Laboratory of Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou, 730000, P. R. China
(
fax: ‡ 86-931-8277088, e-mail: licpxulw@hotmail.com and cgxia@ns.lzb.ac.cn)
b) School of Chemistry and Material Sciences, Wenzhou University, Wenzhou, 325035, P. R. China
Ionic liquids such as 1-butyl-3-methyl-1H-imidazolium 4-methylbenzenesulfonate (BmimOTs) and its 1-
ethyl analogue EmimOTs are novel effective and recyclable media for acid-catalyzed coupling reactions of
aromatic alkynes with aldehydes affording (E)-enones (Scheme 1, Table) with simple recovery and easy workup
due to the absence of volatile organic solvents. This transformation avoids the use of moisture-sensitive and
heavy-metal Lewis acids.
Introduction. ± In past decades, the addition of alkynylmetal or alkyne reagents to
aldehydes and ketones resulting in the formation of propargyl alcohols (ˆ prop-2-yn-1-
ols) has been extensively studied [1][2]. However, the novel reaction between alkynes
and carbonyl compounds to give conjugated enones has received less attention. To the
best of our knowledge, few descriptions of coupling of alkynes and aldehydes to enones
have been reported [3]. Unfortunately, the reported methodology for the coupling
reaction was found to be unsatisfactory and needed improvement.
During the last decade, the increasing environmental consciousness of the chemical
community has led to the search for more efficient and environmentally friendly
methods for organic synthesis [4]. One of the related significant progresses has been
made by the application of ionic liquids in catalytic processes due to their very low
vapor pressure and their capacity to dissolve easily many organic and inorganic
substances [5]. Application of ionic liquids as novel media for catalytic hydrogenation,
Suzuki-type and other cross-coupling reactions, oxidation reactions, etc., has rapidly
expanded [6]. Recently, the use of ionic liquids as Lewis acid catalysts and reaction
media has developed into a very important field [7]. Recent work has demonstrated
unique catalytic properties of ionic liquids in alkylation reactions, Friedel ± Crafts
reactions, and other reactions [8]. Compared to transition metal salts Lewis acid
catalysts, ionic liquids have not been extensively explored as Lewis acid catalysts.
Herein, we report the first use of ionic liquids, such as 1-butyl-3-methyl-1H-
imidazolium 4-methylbenzenesulfonate (BmimOTs), as a novel medium to promote
the coupling reaction of alkyne and aldehydes.
Results and Discussion. ± The ionic liquid BmimOTs was synthesized by using
procedures similar to those used to prepare BmimBF [9]. We first investigated the
4
miscibility of BmimOTs with other chemicals (solvents). Thus, BmimOTs is miscible
with H O, EtOH, amines, and aldehydes but immiscible with Et O, AcOEt, and
2
2
ꢀ
2004 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta ± Vol. 87 (2004)
3081
toluene. The coupling of phenylacetylene and benzaldehyde in BmimOTs at 1008 for
1
2
1
2 h was used as test reaction (Scheme 1; R ˆ R ˆ H). The results showed that the use
of 1.2 equiv. of alkyne and 1.0 equiv. of aldehyde led in good yields to the (E)-enone.
The (E)-configuration of the enone was determined by comparison of NMR and
GCMS data with reported ones [3]. The 1-ethyl-3-methyl-1H-imidazolium 4-methyl-
benzenesulfonate (EmimOTs) is also an effective ionic liquid in this coupling reaction.
However, when the reaction was run in H O (or DMF) and TsOH or HBr was used as a
2
catalyst (20 mol-%) under reflux (1008), only minimal reaction took place, even after
longer reaction periods. Similarly, no coupling product was obtained when the reaction
was performed in other ionic liquids, such as BmimBF or BmimPF . According to the
4
6
above findings and the analysis of by-products, we propose that traces of HBr were
probably responsible for the catalytic effect because BmimOTs was difficult to obtain
free of HBr.
Scheme 1
Upon completion of the reaction, addition of H O to the reaction mixture
2
precipitated the product, which was recovered in high yield by simple filtration. After
evaporation of the residual H O, the ionic liquid was recycled and reused for the next
2
run. The recycled ionic liquid BmimOTs with a drop of HBr per 1 mmol of
benzaldehyde substrate could be reused five times without appreciable loss of activity
for the coupling reaction of benzaldehyde and phenylacetylene. However, the ionic
liquid without additional HBr led to only moderate yields after five runs.
A variety of aldehydes and alkynes were then examined for this ionic-liquid-
promoted coupling reaction (see Scheme 1 and the Table). Most of the obtained enones
are interesting in organic synthesis and pharmacological industries [10]. Aromatic
aldehydes with electron-donating and electron-withdrawing groups, including those
bearing an alkoxy, chloro, bromo, or nitro substituent, were able to undergo the
corresponding coupling reaction and displayed high conversions to the thermodynami-
cally favored (E)-enones (Entries 4 ± 10). The decreased yields for aliphatic aldehydes
are due to the oxidation of the aliphatic aldehydes and resulted in the formation of the
corresponding acids (Entry 11). With aliphatic alkynes or diphenylacetylene as the
starting material, no reaction occurred, even after prolonged reaction periods
(
Entries 2 and 3).
When enolizable ketones and aromatic aldehydes in a 1:1 ratio were used as
substrates in BmimOTs under the same conditions, high yields of enones were also
achieved, as exemplified in Scheme 2. It is of interest to note that enones were also
formed in high yields on coupling aromatic imines and phenylacetylene under the same
conditions; no imine was detected in the final reaction mixture because of the poor
stablility of imines in BmimOTs due to trace amounts of HBr, which might convert the
imine to the aldehyde. The similarity of the alkyne and ketone coupling with aromatic

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Helvetica Chimica Acta ± Vol. 87 (2004)
Table. BmimOTs-Promoted Coupling Reaction of Alkynes and Aldehydes (cf. Scheme 1)a)
Entry
Aldehyde
Alkyne
Yield [%]b)
1
2
3
4
5
6
7
8
9
PhCHO
PhCHO
PhCHO
PhCꢀCH
PhCꢀCPh
90
trace
trace
84
95
94
78
60
78
89
Me(CH
2
)
3
CꢀCH
4-MeC
4-ClC
6
H
H
4
CHO
CHO
PhCꢀCH
PhCꢀCH
PhCꢀCH
PhCꢀCH
PhCꢀCH
PhCꢀCH
PhCꢀCH
PhCꢀCH
6
4
4-NO
2-ClC
2
C
6
H
4
CHO
6
H
4
CHO
2-MeOC
3-MeOC
6
H
H
4
CHO
CHO
6
4
1
1
0
1
4-BrC
PhCH
6
H
4
CHO
2
CH CHO
2
65
a
)
)
Reaction conditions: aldehyde (2 mmol) and alkyne (2.4 mmol) in BmimOTs (3ml) at 100 8 for 12 h.
Yield of isolated material.
b
aldehydes showed that hydrolysis of the alkyne might be a reasonable mechanism
under the acidic conditions.
Scheme 2
It is known that the addition of HBr to acetylene is difficult and requires a catalyst
[
11]. However, we found that acetophenone (3) was formed on hydrolysis of
phenylacetylene (1) alone under the coupling conditions described above (Scheme 3).
On the basis of these results, we suggest that in the coupling reaction, the enone was not
formed by isomerization of the 1,3-di-arylpropargyl alcohol (ˆ1,3-diaryprop-1-yn-1-
ol), an intermediate that was not observed under the coupling conditions. Instead, we
propose a reasonable mechanism involving as the first step the addition HBr to the
alkyne, promoted by the ionic liquid (Scheme 3). The intermediate 2 could then be
hydrated by H O to form the corresponding acetophenone (3), which reacts with the
2
aldehyde to give the corresponding enone. Thus, acetophenones could be the crucial
intermediates. The proposed mechanism is supported by the formation of trace
amounts of intermediate 2 and ketone 3 as detected by GCMS.
In conclusion, we showed that ionic liquids such as BmimOTs and EmimOTs are
good recyclable media in promoting the acid-catalyzed coupling reaction between an
arylalkyne and an aromatic aldehyde affording the thermodynamically favored (E)-
enone. This interesting process compares favorably with earlier reported method-
ologies, especially in terms of simple recovery, easy workup, absence of volatile organic
solvents, and avoidance of moisture-sensitive and heavy metal Lewis acids.
This study was supported in part by the Natural Science Foundation of China (project No. 29933050).

Helvetica Chimica Acta ± Vol. 87 (2004)
3083
Scheme 3
Experimental Part
General. All solvents and reagents were used without purification. All the products were fully characterized
by GC/MS (Agilent-6890N-GC/5973N and HP-5 spectrometers) and usual spectral methods. TLC: silica gel F254
plates; visualization under ultraviolet light. Flash column chromatography (FC): silica gel (100 ± 200 mesh). IR
1
13
spectra: FT-IR apparatus. H- and C-NMR spectra: 400 and 100 MHz, resp., referenced to the internal solvent
signals.
1
-Butyl-3-methyl-1H-imidazolium 4-Methylbenzenesulfonate (BmimOTs). To BmimBr at r.t., a small
amount of H O was added with stirring, and then TsOH (1 equiv.) was added slowly. The mixture was stirred for
an additional period of 4 h. Then the H O was evaporated at 708 to give BmimOTs.
2
2
Coupling Reaction of Alkynes with Aldehydes, General Procedure. To a mixture of aldehyde (2.0 mmol) and
arylalkyne (2.4 mmol), the ionic liquid BmimOTs (3ml) was added, and strirring was continued at 100 8 for 12 h.
After completion of the reaction, H O (10 ml) was added at r.t., and the precipitated product filtrated. The
2
crude product was purified by FC (silica gel, petroleum ether/AcOEt 15 :1).
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[
Received August 3, 2004