Practical synthesis of unsymmetrical diarylacetylenes from propiolic acid and two different aryl bromides

Article abstract of DOI:10.1002/ejoc.201101770

A palladium catalyst that mediates the one-pot sequential Sonogashira and decarboxylative coupling of propiolic acid with two different aryl bromides has been developed. Selective coupling of the first aryl bromide was achieved in the presence of a copper-free, monometallic catalyst generated in situ from allylpalladium chloride dimer and SPhos with tetra-n-butylammonium fluoride as the base in an N-methyl-2-pyrrolidone/water solvent mixture. Upon addition of another aryl bromide and raising the temperature from 50 to 80°C, the intermediate arylpropiolic acid underwent decarboxylative coupling to give the corresponding diarylacetylene. Thus, the new system permits a one-pot three-component synthesis of unsymmetrical diarylacetylenes from widely available aryl bromides, rather than expensive aryl iodides, and propiolic acid, rather than (trimethylsilyl)acetylene, as an inexpensive and easy-to-handle acetylene synthon. The process is highly selective, modular, and gives access to a wide range of unsymmetrical diarylacetylenes in good yields. A palladium-catalyzed three component synthesis of diaryl acetylenes has been optimized. Several disubstituted alkynes have been prepared from two different arylbromides and propiolic acid in good yields. Copyright

Full text of DOI:10.1002/ejoc.201101770

FULL PAPER
DOI: 10.1002/ejoc.201101770
Practical Synthesis of Unsymmetrical Diarylacetylenes from Propiolic Acid
and Two Different Aryl Bromides
Stefano Tartaggia,[a] Ottorino De Lucchi,*[a] and Lukas J. Gooßen*[b]
Keywords: Synthesis design / Palladium / Alkynes / Decarboxylative coupling
A palladium catalyst that mediates the one-pot sequential
Sonogashira and decarboxylative coupling of propiolic acid
with two different aryl bromides has been developed. Selec-
tive coupling of the first aryl bromide was achieved in the
presence of a copper-free, monometallic catalyst generated
in situ from allylpalladium chloride dimer and SPhos with
tetra-n-butylammonium fluoride as the base in an N-methyl-
2-pyrrolidone/water solvent mixture. Upon addition of an-
other aryl bromide and raising the temperature from 50 to
80 °C, the intermediate arylpropiolic acid underwent de-
carboxylative coupling to give the corresponding diaryl-
acetylene. Thus, the new system permits a one-pot three-
component synthesis of unsymmetrical diarylacetylenes from
widely available aryl bromides, rather than expensive aryl
iodides, and propiolic acid, rather than (trimethylsilyl)acetyl-
ene, as an inexpensive and easy-to-handle acetylene syn-
thon. The process is highly selective, modular, and gives ac-
cess to a wide range of unsymmetrical diarylacetylenes in
good yields.
lyst. In copper-free protocols, palladium has the dual role
to acidify the acetylenic proton and perform the cross-cou-
pling.
Introduction
The Cassar–Sonogashira coupling of aryl or alkynyl hal-
ides with terminal alkynes is the most effective and widely
used method for the formation of C(sp)–C(sp2) bonds.[1] It
has found application in the synthesis of functional materi-
als,[2] pharmaceuticals, and natural products.[3] Tradition-
ally, bimetallic Cu/Pd catalysts are used. The function of
the copper cocatalyst is to promote C(sp)–H bond cleavage
so that mild amine bases suffice for the generation of alk-
ynyl–metal species. The palladium catalyst promotes the ac-
tual cross-coupling by oxidative addition of the aryl halide,
transmetallation with the alkynyl–copper species, and re-
ductive elimination of the product.
In Sonogashira couplings (Scheme 1), the use of expens-
ive aryl iodides as aryl electrophiles is still the rule rather
than the exception, but an increasing number of catalysts
allow the use of aryl bromides, triflates, and even chlorides.
Examples for such state-of-the-art systems have been de-
scribed by Herrmann, Plenio, Fu, Buchwald, and Hua,
which all feature combinations of palladium precursors
with bulky, electron-rich phosphanes.[10]
Four decades after its discovery, the efficiency of Sonoga-
shira catalysts has reached an impressive level. A variety of
reaction variants have been developed, which include palla-
dium-free,[4] amine-free,[5] and solvent-free[6] conditions and
reactions in aqueous media.[7] A particular focus was set
on the development of efficient, reusable Pd catalysts[8] and
copper-free reaction protocols[9] as copper promotes un-
wanted Glaser coupling, and the difficult separation of the
two metals complicates the recycling of the palladium cata-
Scheme 1. Standard vs. decarboxylative Sonogashira couplings.
Sonogashira reactions can also be used for the synthesis
of diarylacetylenes from aryl halides and arylacetylenes.
However, due to the limited availability of the latter, a more
effective synthetic entry consists of the sequential coupling
of a first aryl halide with an acetylene synthon and subse-
quent coupling of the resulting arylacetylene with a second
aryl halide. The sequential arylation of acetylene itself is
problematic as the intermediate arylacetylenes tend to react
faster than the starting acetylene so that product mixtures
are obtained, see Scheme 2, (a).[11] The established synthesis
of unsymmetrical diarylalkynes thus involves the use of tri-
methylsilyl (TMS)-acetylene as the acetylene synthon, see
Scheme 2, (b). This arylation/deprotection/arylation se-
quence can be performed in one pot.[12] In the first step,
[a] Dipartimento di Scienze Molecolari e Nanosistemi, Università
Ca’ Foscari Venezia,
Dorsoduro 2137, 30123 Venice, Italy
E-mail: delucchi@unive.it
[b] FB Chemie – Organische Chemie, TU Kaiserslautern,
Erwin-Schrödinger-Straße, Geb. 54, 67663 Kaiserslautern,
Germany
Fax: +49-631-205-3921
E-mail: goossen@chemie.uni-kl.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101770.
Eur. J. Org. Chem. 2012, 1431–1438
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Tartaggia, O. De Lucchi, L. J. Gooßen
FULL PAPER
TMS-acetylate is coupled with an aryl halide under anhy- Upon raising the temperature to 80 °C, the resulting aryl-
drous conditions. Subsequent addition of water leads to the propiolic acid underwent decarboxylative coupling with the
cleavage of the TMS group, which permits further coupling aryl bromide to yield the corresponding diarylacetylene, see
with a second aryl halide. In a related strategy, inexpensive Scheme 2, (d).
2-methylbut-3-yn-ol is used as the acetylene synthon
Although this process demonstrates that inexpensive prop-
[Scheme 2, (c)], but in this case the deprotection step re- iolic acid can serve as an acetylene synthon in diarylacetyl-
quires harsh conditions and fresh catalyst has to be added ene synthesis, its practicability is limited by the fact that
for the second coupling step.[13]
only aryl iodides can be employed in the first coupling step.
In order to realize the full potential of this coupling strat-
egy, an extension to the widely available substrate class of
aryl bromides is highly desirable.
Herein we present an efficient method for the synthesis
of unsymmetrical diarylacetylenes from two different aryl
bromides and propiolic acid (Scheme 3).
Scheme 3. One-pot synthesis of diarylacetylenes from aryl brom-
ides and propiolic acid.
Scheme 2. Concepts for the synthesis of unsymmetrical diaryl-
acetylenes by Sonogashira coupling.
The concept of decarboxylative cross-coupling has re-
cently opened opportunities for a less costly alternative to
these established processes.[14] In redox-neutral decarbox-
Results and Discussion
In order to establish a sequential one-pot Sonogashira
ylative cross-coupling, nucleophilic organometallic species and decarboxylative coupling of propiolic acid starting
are generated by the extrusion of CO2 from carboxylate from aryl bromides, we first needed to identify a catalyst
salts. This strategy was originally described in the context system that would allow the coupling of propiolic acid with
of biaryl synthesis[15] and has subsequently been extended an aryl bromide at temperatures sufficiently low to prevent
to the formation of carbon–heteroatom bonds,[16] ketone[17] competitive protodecarboxylation and decarboxylative cou-
and imine[18] syntheses, (conjugate) addition reactions,[19] pling.
and recently Sonogashira couplings.[20] Propiolic acids ex-
As a model for this first coupling step, we chose the Son-
trude CO2 at low temperatures,[21] which has recently been ogashira reaction of propiolic acid (2) and bromobenzene
shown to be reversible.[22] In contrast to most other decar- (1a) to give phenylpropiolic acid (3a, Table 1). The forma-
boxylative couplings, decarboxylative Sonogashira reac- tion of tolane (4a) was indicative of unwanted decarbox-
tions can thus be performed at remarkably low tempera- ylative coupling.
tures. Lee and coworkers have demonstrated that various
As the starting point for catalyst development, the stan-
propiolic acids can be coupled with aryl bromides and iod- dard conditions reported for the Sonogashira coupling of
ides at 80 °C using a monometallic palladium catalyst.[23] aryl iodides [5 mol-% of tris(dibenzylideneacetone)dipalla-
An alternative procedure for decarboxylative coupling of dium(0) (Pd2dba3) and a triarylphosphane as the catalyst,
arylpropiolic acids with aryl bromides, iodides, and triflates tetra-n-butylammonium fluoride (TBAF) as the base in N-
using silver and lithium salts as additives has been reported methyl-2-pyrrolidone (NMP)] were employed (Table 1).[20]
by Kim and Lee.[24] An optimized protocol for decarbox- However, no conversion was seen at room temperature for
ylative coupling of alkynyl carboxylic acids with aryl and our aryl bromide substrate and only unsatisfactory yields
benzyl halides with low catalyst loading[25] and a Pd-free were reached at 60 °C (Entries 1–4). At higher tempera-
decarboxylative cross-coupling catalyzed by copper[26] have tures, rapid protodecarboxylation of 2 and 3a took place,
also been reported.
which precluded selective product formation. In the litera-
Lee and coworkers have utilized decarboxylative Sonoga- ture, only one report of the successful coupling of an aryl
shira coupling for the one-pot synthesis of unsymmetrical bromide with 2 was found: Buchwald disclosed that a
diarylacetylenes.[27] When heating a mixture of an aryl iod- highly engineered, water-soluble dialkyl-biaryl-phosphane
ide, an aryl bromide, and propiolic acid to 50 °C in the pres- ligand permits the synthesis of 3-methoxyphenylpropiolic
ence of a palladium catalyst, the aryl iodide exclusively re- acid from the corresponding aryl bromide under special,
acts with the propiolic acid under C–H functionalization. aqueous conditions.[28] We thus tested various related elec-
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Synthesis of Unsymmetrical Diarylacetylenes
Table 1. Synthesis of 3a from 2 and 1a.[a]
The reaction conditions were further optimized to im-
prove the yield and selectivity of the reaction (Table 2). The
yields dropped in solvents other than NMP (Entries 1–3)
and when other bases were used (Entries 4–5), even though
these solvents and bases are successfully employed in the
Sonogashira coupling of aryl iodides. Other sources of fluo-
ride were also ineffective (Entry 6). A definite improvement
was achieved by the addition of water as a cosolvent (En-
tries 7–9). In a mixture of 9:1 NMP/water, 3a was obtained
in 92% yield along with only 5% of 4a (Entry 8). Further
experiments showed that other proton sources such as
methanol were less effective cosolvents than water (Entry
10).
Entry Ligand
[mol-%]
“Pd”
[mol-%]
T
Time
Yield [%]
[°C] [h]
3a
4a
1
2
3
4
5
6
7
8
PPh3 (20)
P(oTol)3 (20) Pd2dba3 (10)
P(pTol)3 (20) Pd2dba3 (10)
Pd2dba3 (10)
60
60
60
60
60
60
60
60
60
50
50
50
40
50
50
50
4
4
4
4
4
4
4
4
17
38
14
26
43
49
54
45
51
42
59
71
61
40
79
47
0
0
0
0
4
6
6
23
4
0
2
7
5
4
6
14
dppf (10)
L1 (15)
L2 (15)
L3 (15)
L4 (15)
L3 (7.5)
L3 (7.5)
L3 (7.5)
L3 (7.5)
L3 (7.5)
L3 (7.5)
L3 (7.5)
L3 (7.5)
Pd2dba3 (10)
Pd2dba3 (10)
Pd2dba3 (10)
Pd2dba3 (10)
Pd2dba3 (10)
Pd2dba3 (5)
Pd2dba3 (5)
Pd2dba3 (5)
Pd2dba3 (5)
Pd2dba3 (5)
Pd(OAc)2 (5)
[allylPdCl]2 (5)
PdCl2 (5)
9
4
4
Table 2. Effect of different bases, additives, and cosolvents on the
10
11
12
13
14
15
16
synthesis of 3a.[a]
10
16
16
16
16
16
Entry Base
[equiv.]
Solvent Cosolvent
[%]
Conv. 1 Yield [%]
[%]
3a
4a
1
2
3
4
5
6
7
8
9
10
TBAF (6) NMP
–
–
–
–
–
–
100
35
45
56
74
32
100
99
79
11
0
traces
traces
4
84
92
6
1
0
0
0
8
3
5
5
12
TBAF (6) THF[b]
TBAF (6) DMSO[c]
Cs2CO3 (6) NMP
[a] Reaction conditions: 1a (0.50 mmol),
2
(0.55 mmol),
NEt3 (6)
CsF (6)
NMP
NMP
TBAF·3H2O (3.00 mmol), NMP (2.5 mL). Yields were determined
by GC using n-tetradecane as an internal standard after converting
3a into the methyl ester with MeOTf/K2CO3.
TBAF (6) NMP
TBAF (6) NMP
TBAF (6) NMP
TBAF (6) NMP
H2O (5)
H2O (10)
H2O (15)
92
58
62
MeOH (10) 88
tron-rich, sterically demanding dialkyl-biaryl-phosphanes
(Figure 1). With these ligands, the activity of the catalyst
was substantially improved (Entries 5–8). The highest yield
of 3a was obtained with L3 (SPhos). L4 (XPhos) led to a
higher conversion of 1a, but a lower selectivity for 3a over
4a.
[a] Reaction conditions: 1a (0.50 mmol),
2
(0.55 mmol),
TBAF·3H2O (3.0 mmol), [allylPdCl]2 (2.5 mol-%), L3 (7.5 mol-%),
solvent (2.5 mL), 16 h, 50 °C. Conversions and yields were deter-
mined by GC using n-tetradecane as an internal standard after con-
verting 3a into the methyl ester with MeOTf/K2CO3. [b] THF =
tetrahydrofuran. [c] DMSO = dimethyl sulfoxide.
We next investigated whether this optimized system,
which contained [allylPdCl]2/L3 as the catalyst, TBAF as
the base, and a 9:1 mixture of NMP/H2O, would also pro-
mote the second step of our proposed diarylacetylene syn-
thesis: the decarboxylative cross-coupling of arylpropiolic
acids. We were delighted to find that the reaction of 3a and
4-bromotoluene (1b) to the desired unsymmetrical diaryl-
acetylene 6a took place at 70 °C. The yield could be in-
creased to 84% by raising the temperature to 80 °C and
Figure 1. Dialkyl biaryl phosphanes used in this study.
A reduction of the catalyst amount to 2.5 mol-% extending the reaction time to 14 h (Table 3). Longer reac-
Pd2(dba)3 and 7.5 mol-% L3 did not significantly affect the tion times and higher temperatures did not improve the
yield (Entry 9). The selectivity for 3a over 4a was improved yield any further.
when the temperature was reduced to 50 °C (Entry 10). At
The final step was to combine the two reactions opti-
this temperature, complete conversion of the substrate was mized separately into a one-pot protocol (Table 4). Thus,
achieved within 16 h, and 3a was obtained in 71% yield we stirred 1a with 2 at 50 °C for 16 h in NMP/water (9:1)
(Entries 11 and 12). Lower temperatures further slowed the in the presence of [allylPdCl]2/L3 and TBAF, then added
reaction without improving the selectivity (Entry 13). A 1b, raised the temperature to 80 °C, and continued to stir
change of the palladium source to allyl palladium chloride for 14 h. Under these conditions, the unsymmetrical diaryl-
dimer was beneficial, whereas other precursors had a detri- acetylene 5a was obtained in high yield (77%) along with
mental effect on yield or selectivity (Entries 14–16).
only small amounts of the undesired symmetrical products
After this first round of optimization, 79% of the prod- 4a and 6a. Control experiments confirmed that such high
uct along with 6% of 4a were obtained using a catalyst conversions and selectivities were only be achieved when
generated from allyl palladium chloride dimer (2.5 mol-%) using [allylPdCl]2 as the catalyst precursor (Entries 1–4), L3
and L3 (7.5 mol-%) with TBAF as the base in NMP at as the ligand (Entries 1 and 5), and NMP/water (9:1) as
50 °C in 16 h (Entry 15).
the solvent (Entries 1 and 6–8). Under these conditions, the
Eur. J. Org. Chem. 2012, 1431–1438
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S. Tartaggia, O. De Lucchi, L. J. Gooßen
Table 5. Synthesis of unsymmetrical diaryl alkynes.[a]
FULL PAPER
Table 3. Palladium-catalyzed decarboxylative coupling reaction of
3a and 1b.[a]
Entry
T
[°C]
Time
[h]
Conversion
1b [%]
Yield
5a [%]
1
2
3
4
70
80
90
80
10
10
10
14
69
82
91
92
45
71
55
84
[a] Reaction conditions: 3a (0.50 mmol), 1b (0.50 mmol),
TBAF·3H2O (3.00 mmol), NMP/H2O (2.5 mL, 9:1), [allylPdCl]2
(2.5 mol-%), L3 (7.5 mol-%). Conversions and yields were deter-
mined by GC using n-tetradecane as the internal standard.
formation of butadiynes, which is a common side reaction
in conventional Sonogashira coupling reactions, was not
observed. The reason for the positive influence of water on
the reaction outcome could not be unambiguously clarified.
Table 4. One-pot synthesis of 5a.[a]
Entry Ligand “Pd”
H2O Conv. [%]
Yield [%]
[%]
1a
1b
5a
4a
6a
1
2
3
4
5
6
7
L3
L3
L3
L4
L3
L3
L3
[allylPdCl]2
[allylPdCl]2
[allylPdCl]2
[allylPdCl]2
PdCl2
10
0
5
10
10
10
10
100 98
77
48
61
39
37
59
39
7
7
5
3
18
19
1
91
97
90
84
36
26
13
14
26
100 92
99 95
100 88
99 94
Pd(OAc)2
Pd2(dba)3
0
14
[a] Reaction conditions: 1a (0.50 mmol), 2 (0.55 mmol), Pd source
(5 mol-%), ligand (7.5 mol-%), TBAF·3H2O (3.0 mmol), NMP/
H2O (2.5 mL), 1b (0.50 mmol). Conversions and yields were deter-
mined by GC using n-tetradecane as the internal standard.
Having thus found an effective protocol for the synthesis
of unsymmetrical diarylacetylenes from propiolic acid and
two different aryl bromides, we next explored its scope. As
can be seen from Table 5, the one-pot process is broadly
applicable with regard to both aryl bromide coupling part-
ners. Various aryl bromides were successfully employed as
substrates for the first arylation step, which include elec-
tron-rich, electron-poor, sterically crowded, and heterocy-
clic derivatives. The best yields were obtained with bromo-
benzene itself (5a–k) and with arenes that bear electron-
rich substituents (5a, 5b, 5m, 5o, 5r). Substrates that bear
electron-withdrawing groups (5f, 5g, 5l, 5k) gave slightly
lower yields.
[a] Aryl groups Ar1 that originate from the first arylation are de-
picted on the left. Reaction conditions: Ar1Br (0.50 mmol), 2
(0.55 mmol), [allylPdCl]2 (2.5 mol-%), L3 (7.5 mol-%), TBAF·
3H2O (3.00 mmol), NMP (2.5 mL), 50 °C, 16 h, then addition of
Ar2Br (0.50 mmol), 80 °C, 14 h. Yields refer to isolated products.
Variation of the aryl bromide in the second arylation step
revealed that this step also has a broad substrate scope.
Interestingly, this decarboxylative coupling seems to be
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Synthesis of Unsymmetrical Diarylacetylenes
CDCl3 as solvent. Mass spectra were acquired with a Trace GC–
MS 2000 ThermoQuest instrument. Melting points were measured
with a Büchi 535 apparatus, and IR spectra with a Perkin–Elmer
FTIR Spectrum ONE (HeNe 633 nm Ͻ 0.4 mW).
more effective with electron-poor than with electron-rich
aryl bromides. For the synthesis of unsymmetrical diaryl-
acetylenes with one electron-rich and one electron-poor ar-
ene ring, it is thus advisable to introduce the electron-rich
arene in the Sonogashira coupling step and the electron-
poor one in the decarboxylative coupling step. Performing
the coupling steps in reverse usually led to decreased yields.
A few substrates, among them aryl bromides that bear nitro
or cyano groups, did not give satisfactory yields in the non-
decarboxylative coupling with propiolic acid. As a further
limitation to our protocol, we found that when using very
similar bromoarenes in both steps, e.g. 2-bromotoluene in
the first step and bromobenzene in the second, the separa-
tion of the desired product from the symmetrical alkynes,
which were obtained in small quantities as side products,
was problematic.
However, as can be seen from the examples in Table 5,
diarylacetylenes that bear various functional groups were
tolerated, which include ester, ether, hydroxy, trifluorome-
thyl, chloro, nitro, and even basic amino groups. Although
a lower Pd-loading was employed, the scope and yields are
comparable to related methods starting from expensive aryl
iodides.[27]
General Procedure for the Preparation of Diarylacetylenes 5a–s: A
20 mL Schlenk tube equipped with a magnetic stirrer bar and a
rubber septum was charged with allylpalladium(II) chloride dimer
(0.025 mmol) and 2-dicyclohexylphosphanyl-2Ј,6Ј-dimethoxybi-
phenyl (0.0375 mmol). Aryl bromide 1a–c, 1e, 1g, 1h, or 1m–r
(0.50 mmol), 2 (36 μL, 0.55 mmol), and a degassed solution of
TBAF·3H2O (0.95 g, 3 mmol) in NMP/H2O (9:1, 2.5 mL) were
added by syringe. The reaction mixture was stirred at 50 °C for
16 h before aryl bromide 1a–m (0.50 mmol) was added by syringe
(solid aryl bromides were added as solution in degassed NMP).
The resulting mixture was stirred at 80 °C for 14 h, cooled to room
temperature, and diluted with diethyl ether (20 mL). The resulting
solution was washed successively with saturated aqueous NH4Cl
solution (20 mL) and brine (20 mL), dried with MgSO4, filtered,
and the solvents were removed in vacuo. The crude product was
purified by column chromatography (SiO2, diethyl ether/cyclohex-
ane gradient) to afford 5a–s.
1-Methyl-4-(2-phenylethynyl)benzene (5a): Compound 5a was syn-
thesized according to the general procedure from bromobenzene
(53 μL, 0.50 mmol) and 4-bromotoluene (62 μL, 0.50 mmol). After
purification by flash column chromatography (SiO2, cyclohexane),
5a was isolated as a white solid (68.3 mg, 71%); m.p. 68–70 °C. The
NMR spectroscopic data matched those reported in the literature
for 1-methyl-4-(2-phenylethynyl)benzene [CAS number 3287-02-3].
Conclusions
Compound 5a was also prepared according to the general pro-
cedure from 4-bromotoluene (62 μL, 0.50 mmol) and bromobenz-
ene (53 μL, 0.50 mmol). After purification by flash column
chromatography (SiO2, cyclohexane), 5a was isolated as a white
solid (70.2 mg, 73%); m.p. 68–70 °C.
A copper-free, monometallic catalyst generated in situ
from allylpalladium chloride dimer and L3 allows the syn-
thesis of unsymmetrical diarylacetylenes from propiolic ac-
ids and two different aryl bromides in the presence of
TBAF as the base in an NMP/water solvent mixture. The
first step of this one-pot reaction sequence consists of
1-Methyl-3-(2-phenylethynyl)benzene (5b): Compound 5b was syn-
thesized according to the general procedure from bromobenzene
a Sonogashira coupling of the first aryl bromide with (53 μL, 0.50 mmol) and 3-bromotoluene (61 μL, 0.50 mmol). After
purification by flash column chromatography (SiO2, cyclohexane),
5b was isolated as a white solid (66.3 mg, 69%); m.p. 28–30 °C. The
NMR spectroscopic data matched those reported in the literature
for 1-methyl-3-(2-phenylethynyl)benzene [CAS number 14635-91-
7].
propiolic acid to selectively give an arylpropiolic acid.
Upon addition of another aryl bromide and raising the
temperature from 50 to 80 °C, the corresponding diaryl-
acetylene is formed by decarboxylative coupling. The mild
reaction conditions are compatible with various functional
groups so that a wide range of diversely substituted diaryl-
acetylenes are conveniently accessible in good yields.
Compound 5b was also prepared according to the general pro-
cedure from 3-bromotoluene (61 μL, 0.50 mmol) and bromo-
benzene (53 μL, 0.50 mmol). After purification by flash column
chromatography (SiO2, cyclohexane), 5b was isolated as a white
solid (69.2 mg, 72%); m.p. 28–30 °C.
Experimental Section
1-Methyl-2-(2-phenylethynyl)benzene (5c): Compound 5c was syn-
thesized according to the general procedure from bromobenzene
(53 μL, 0.50 mmol) and 2-bromotoluene (60 μL, 0.50 mmol). After
purification by flash column chromatography (SiO2, cyclohexane),
5c was isolated as a colorless oil (64.4 mg, 67%). The NMR spec-
troscopic data matched those reported in the literature for 1-
methyl-2-(2-phenylethynyl)benzene [CAS number 14309-60-5].
General Methods: Chemicals and solvents were either purchased
from commercial suppliers (puriss. p.A.) or purified by standard
techniques. All reactions, if not stated otherwise, were performed
in oven-dried glassware under an argon atmosphere with a teflon-
coated stirrer bar and dry septum. All reactions were monitored by
GC using tetradecane as an internal standard. Response factors of
the products with regard to tetradecane were obtained experimen-
tally by analyzing known quantities of the substances. GC analyses
were carried out using an HP-5 capillary column (phenyl methyl
1-(2-Phenylethynyl)naphthalene (5d): Compound 5d was synthe-
sized according to the general procedure from bromobenzene
(53 μL, 0.50 mmol) and 1-bromonaphthalene (70 μL, 0.50 mmol).
siloxane, 30 m ϫ320ϫ0.25, 100/2.3–30–300/3, 2 min at 50 °C, After purification by flash column chromatography (SiO2, cyclo-
heating rate 25 °C/min, 3 min at 250 °C). Column chromatography
was performed with 230–400 mesh silica gel. NMR spectra were
obtained with a Bruker AC 200 spectrometer (200 MHz) using
hexane), 5d was isolated as a colorless oil (94.7 mg, 83%). The
NMR spectroscopic data matched those reported in the literature
for 1-(2-phenylethynyl)naphthalene [CAS number 4044-57-9].
Eur. J. Org. Chem. 2012, 1431–1438
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Tartaggia, O. De Lucchi, L. J. Gooßen
FULL PAPER
Compound 5d was also prepared according to the general pro-
cedure from 1-bromonaphthalene (70 μL, 0.50 mmol) and bromo-
benzene (53 μL, 0.50 mmol). After purification by flash column
chromatography (SiO2, cyclohexane), 5d was isolated as a colorless
oil (93.6 mg, 82%).
low solid (37.9 mg, 34%); m.p. 119–121 °C. The NMR spectro-
scopic data matched those reported in the literature for 1-nitro-4-
(2-phenylethynyl)benzene [CAS number 1942-30-9].
1-Nitro-3-(2-phenylethynyl)benzene (5j): Compound 5j was synthe-
sized according to the general procedure from bromobenzene
(53 μL, 0.50 mmol) and 1-bromo-3-nitrobenzene (101 mg,
0.50 mmol). After purification by flash column chromatography
(SiO2, diethyl ether/cyclohexane, 1:9), 5j was isolated as a pale yel-
low solid (58.0 mg, 52%); m.p. 66–68 °C. The NMR spectroscopic
data matched those reported in the literature for 1-nitro-3-(2-phen-
ylethynyl)benzene [CAS number 29338-47-4].
4-(2-Phenylethynyl)phenol (5e): Compound 5e was synthesized ac-
cording to the general procedure from bromobenzene (53 μL,
0.50 mmol) and 4-bromophenol (86.5 mg, 0.50 mmol). After purifi-
cation by flash column chromatography (SiO2, diethyl ether/cyclo-
hexane, 2:8), 5e was isolated as a pale yellow solid (62.1 mg, 64%);
m.p. 121–123 °C. The NMR spectroscopic data matched those re-
ported in the literature for 4-(2-phenylethynyl)phenol [CAS number
1849-26-9].
3-(2-Phenylethynyl)pyridine (5k): Compound 5k was synthesized
according to the general procedure from bromobenzene (53 μL,
0.50 mmol) and 3-bromopyridine (48 μL, 0.50 mmol). After purifi-
cation by flash column chromatography (SiO2, diethyl ether/cyclo-
hexane, 3:7), 5k was isolated as a pale yellow solid (62.7 mg, 70%);
m.p. 49–51 °C. The NMR spectroscopic data matched those re-
ported in the literature for 3-(2-phenylethynyl)pyridine [CAS
number 1328-38-5].
1-Chloro-4-(2-phenylethynyl)benzene (5f): Compound 5f was syn-
thesized according to the general procedure from bromobenzene
(53 μL, 0.50 mmol) and 1-bromo-4-chlorobenzene (95.7 mg,
0.50 mmol). After purification by flash column chromatography
(SiO2, cyclohexane), 5f was isolated as a white solid (52.2 mg,
49%); m.p. 80–82 °C. The NMR spectroscopic data matched those
reported in the literature for 1-chloro-4-(2-phenylethynyl)benzene
[CAS number 5172-02-1].
Compound 5k was also prepared according to the general pro-
cedure from 3-bromopyridine (48 μL, 0.50 mmol) and bromobenz-
ene (53 μL, 0.50 mmol). After purification by flash column
chromatography (SiO2, diethyl ether/cyclohexane, 3:7), 5k was iso-
lated as a pale yellow solid (40.3 mg, 45%); m.p. 49–51 °C.
Compound 5f was also prepared according to the general pro-
cedure from 1-bromo-4-chlorobenzene (95.7 mg, 0.50 mmol) and
bromobenzene (53 μL, 0.50 mmol). After purification by flash col-
umn chromatography (SiO2, cyclohexane), 5f was isolated as a
white solid (58.6 mg, 55%); m.p. 80–82 °C.
1,3-Dimethoxy-5-(2-phenylethynyl)benzene (5m): Compound 5m
was synthesized according to the general procedure from 1-bromo-
3,5-dimethoxybenzene (108.5 mg, 0.50 mmol) and bromobenzene
(53 μL, 0.50 mmol). After purification by flash column chromatog-
raphy (SiO2, diethyl ether/cyclohexane, 1:9), 5m was isolated as a
pale yellow oil (75.1 mg, 63%). The NMR spectroscopic data
matched those reported in the literature for 1,3-dimethoxy-5-(2-
1-Fluoro-4-(2-phenylethynyl)benzene (5g): Compound 5g was syn-
thesized according to the general procedure from bromobenzene
(53 μL, 0.50 mmol) and 1-bromo-4-fluorobenzene (55 μL,
0.50 mmol). After purification by flash column chromatography
(SiO2, cyclohexane), 5g was isolated as a white solid (67.7 mg,
69%); m.p. 108–110 °C. The NMR spectroscopic data matched phenylethynyl)benzene.
those reported in the literature for 1-fluoro-4-(2-phenylethynyl)-
1-Methoxy-4-(2-phenylethynyl)benzene (5n): Compound 5n was
benzene [CAS number 405-29-8].
synthesized according to the general procedure from 4-bromoan-
isole (63 μL, 0.50 mmol) and bromobenzene (53 μL, 0.50 mmol).
After purification by flash column chromatography (SiO2, diethyl
ether/cyclohexane, 1:9), 5n was isolated as a pale yellow solid
(53.1 mg, 51%); m.p. 53–55 °C. The NMR spectroscopic data
matched those reported in the literature for 1-methoxy-4-(2-phenyl-
ethynyl)benzene [CAS number 7380-78-1].
Compound 5g was also prepared according to the general pro-
cedure from 1-bromo-4-fluorobenzene (55 μL, 0.50 mmol) and
bromobenzene (53 μL, 0.50 mmol). After purification by flash col-
umn chromatography (SiO2, cyclohexane), 5g was isolated as a
white solid (38.3 mg, 39%); m.p. 108–110 °C.
1-(2-Phenylethynyl)-4-(trifluoromethyl)benzene (5h): Compound 5h
was synthesized according to the general procedure from bromo-
4-N,N-Dimethyl-4-(2-phenylethynyl)aniline (5o): Compound 5o was
benzene (53 μL, 0.50 mmol) and 1-bromo-4-(trifluoromethyl)benz- synthesized according to the general procedure from 4-bromo-N,N-
ene (70 μL, 0.50 mmol). After purification by flash column
chromatography (SiO2, cyclohexane), 5h was isolated as a white
solid (94.7 mg, 77%); m.p. 101–103 °C. The NMR spectroscopic
data matched those reported in the literature for 1-(2-phenyleth-
ynyl)-4-(trifluoromethyl)benzene [CAS number 370-99-0].
dimethylaniline (100 mg, 0.50 mmol) and bromobenzene (53 μL,
0.50 mmol). After purification by flash column chromatography
(SiO2, diethyl ether/cyclohexane, 3:7), 5o was isolated as a pale yel-
low solid (78.6 mg, 71%); m.p. 107–109 °C. The NMR spectro-
scopic data matched those reported in the literature for 4-N,N-di-
methyl-4-(2-phenylethynyl)aniline [CAS number 14301-08-7].
Methyl 4-(2-Phenylethynyl)benzoate (5i): Compound 5i was synthe-
sized according to the general procedure from bromobenzene
4-(2-Phenylethynyl)aniline (5p): Compound 5p was synthesized ac-
(53 μL, 0.50 mmol) and methyl 4-bromobenzoate (107.5 mg, cording to the general procedure from 4-bromoaniline (86 mg,
0.50 mmol). After purification by flash column chromatography
(SiO2, diethyl ether/cyclohexane, 2:8), 5i was isolated as a pale yel-
low solid (85.1 mg, 72%); m.p. 117–119 °C. The NMR spectro-
scopic data matched those reported in the literature for methyl 4-
(2-phenylethynyl)benzoate [CAS number 42497-80-3].
0.50 mmol) and bromobenzene (53 μL, 0.50 mmol). After purifica-
tion by flash column chromatography (SiO2, diethyl ether/cyclohex-
ane, 4:6), 5p was isolated as a pale yellow solid (48.3 mg, 50%);
m.p. 125–127 °C. The NMR spectroscopic data matched those re-
ported in the literature for 4-(2-phenylethynyl)aniline [CAS number
1849-25-8].
1-Nitro-4-(2-phenylethynyl)benzene (5l): Compound 5l was synthe-
sized according to the general procedure from bromobenzene
(53 μL, 0.50 mmol) and 1-bromo-4-nitrobenzene (101 mg,
0.50 mmol). After purification by flash column chromatography
(SiO2, diethyl ether/cyclohexane, 2:8), 5l was isolated as a pale yel-
3-(2-Phenylethynyl)aniline (5q): Compound 5q was synthesized ac-
cording to the general procedure from 3-bromoaniline (54 μL,
0.50 mmol) and bromobenzene (53 μL, 0.50 mmol). After purifica-
tion by flash column chromatography (SiO2, diethyl ether/cyclohex-
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Synthesis of Unsymmetrical Diarylacetylenes
1850; d) B. H. Lipshutz, D. W. Chung, B. Rich, Org. Lett. 2008,
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ane, 3:7), 5q was isolated as a pale yellow solid (58.2 mg, 61%);
m.p. 43–45 °C. The NMR spectroscopic data matched those re-
ported in the literature for 3-(2-phenylethynyl)aniline [CAS number
51624-44-3].
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3-[2-(4-Methylphenyl)ethynyl]pyridine (5r): Compound 5r was syn-
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ether/cyclohexane, 3:7), 5r was isolated as a white solid (75.3 mg,
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[CAS number 733035-88-6].
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3-[2-(Naphthalen-1-yl)ethynyl]pyridine (5s): Compound 5s was syn-
thesized according to the general procedure from 1-bromonaphth-
alene (70 μL, 0.50 mmol) and 3-bromopyridine (48 μL, 0.50 mmol).
After purification by flash column chromatography (SiO2, diethyl
ether/cyclohexane, 3:7), 5s was isolated as a pale yellow oil
(64.2 mg, 56%). The NMR spectroscopic data matched those re-
ported in the literature for 3-[2-(naphthalen-1-yl)ethynyl]pyridine
[CAS number 950824-89-2].
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Supporting Information (see footnote on the first page of this arti-
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Acknowledgments
We gratefully acknowledge Ministero dell’Università
e della
Ricerca (MIUR) within the national PRIN framework and Nano-
Kat for funding and Umicore for the generous donation of precious
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FULL PAPER
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Published Online: January 18, 2012
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Eur. J. Org. Chem. 2012, 1431–1438