Microwave-promoted copper-free Sonogashira-Hagihara couplings of aryl imidazolylsulfonates in water

Article abstract of DOI:10.1002/adsc.201200629

Aryl imidazol-1-ylsulfonates have been efficiently cross-coupled with aryl-, alkyl-, and silylacetylenes in neat water under copper-free conditions at 110 °C assisted by microwave irradiation. Using 0.5mol% of an oxime palladacycle as precatalyst, 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl (SPhos, 2mol%) as ligand, hexadecyltrimethylammonium bromide (CTAB) as additive, and triethylamine (TEA) as base, a wide array of disubstituted alkynes has been prepared in good to high yields in only 30min. Copyright

Full text of DOI:10.1002/adsc.201200629

FULL PAPERS
DOI: 10.1002/adsc.201200629
Microwave-Promoted Copper-Free Sonogashira–Hagihara
Couplings of Aryl Imidazolylsulfonates in Water
Josꢀ F. Cꢁvicos,a Diego A. Alonso,a,* and Carmen Nꢂjeraa,*
a
Departamento de Quꢁmica Orgꢂnica and Instituto de Sꢁntesis Orgꢂnica (ISO), Facultad de Ciencias, Universidad de
Alicante, Apartado 99, 03080 Alicante, Spain
Fax : (+34)-96-590-3549; e-mail: diego.alonso@ua.es or cnajera@ua.es
Received: July 18, 2012; Revised: October 19, 2012; Published online: January 4, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200629.
Abstract: Aryl imidazol-1-ylsulfonates have been ef- monium bromide (CTAB) as additive, and triethyl-
ficiently cross-coupled with aryl-, alkyl-, and silylace-
ACHTUNGTRENaNUNG mine (TEA) as base, a wide array of disubstituted
tylenes in neat water under copper-free conditions at alkynes has been prepared in good to high yields in
1108C assisted by microwave irradiation. Using only 30 min.
0.5 mol% of an oxime palladacycle as precatalyst,
2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl
Keywords: cross-coupling; microwave chemistry; pal-
(SPhos, 2 mol%) as ligand, hexadecyltrimethylam- ladacycles; Sonogashira–Hagihara reaction; water
Introduction
presence of a copper salt as cocatalyst, and employing
organic solvents as reaction medium (Scheme 1). Very
The palladium-catalyzed Sonogashira–Hagihara reac- recently, we have disclosed a phosphane-free oxime-
tion is one of the most important and widely used palladacycle[10,11]-catalyzed Suzuki cross-coupling reac-
methods for preparing aryl- and alkylacetylenes as tion of aryl imidazol-1-ylsulfonates[12] with arylboronic
well as conjugated enynes,[1] which are precursors for acids and potassium aryl trifluoroborates in aqueous
natural products, pharmaceuticals, and optical and methanol, a reaction which can be performed using
electronic materials.[1,2] Although aryl and alkenyl hal-
ides are most commonly employed as the electrophilic
partner in the Sonogashira reaction, considerable ef-
forts have recently been directed to search for alter-
native electrophiles. O-based electrophiles are partic-
ularly attractive partners in cross-coupling reactions
due to their high stability and the ubiquitous presence
of hydroxylated compounds both in nature and in syn-
thetic systems. Hydroxyarene derivatives offer a valua-
ble alternative given that phenols are typically inex-
pensive and readily available materials.[3,4] Although
triflates have shown high performance as electro-
philes in the Pd-catalyzed Sonogashira reaction, their
limited stability has focused recent studies on the de-
velopment of less common but still stable phenol-
based electrophiles.[5] Among them, good results have
been reported for the palladium-catalyzed coupling of
terminal alkynes with aryl mesylates,[6] tosylates,[6,7]
phosphonium salts,[8] and imidazolylsulfonates.[9] How-
ever, these couplings have all been performed using
high catalyst loadings (2–10 mol% Pd), usually in the philes.
Scheme 1. Sonogashira coupling of phenol-derived electro-
Adv. Synth. Catal. 2013, 355, 203 – 208
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203

Josꢀ F. Cꢁvicos et al.
FULL PAPERS
conventional or microwave heating, under conditions Results and Discussion
with low catalyst loading (1 mol% Pd).[13] This cou-
pling can be also performed in neat water by using Initially, we investigated the microwave-promoted So-
the cationic surfactant[14] hexadecyltrimethylammoni- nogashira coupling of naphthalen-1-yl 1H-imidazole-
um bromide (CTAB) as additive, which has allowed 1-sulfonate (2aa, 1 equiv.) with phenylacetylene
us to cross-couple aryl imidazol-1-ylsulfonates with (1.5 equiv.) in water in the presence of CTAB (3a),
potassium aryl- and alkenyltrifluoroborates under mi- which was the best surfactant in the Suzuki reac-
crowave heating (40 W, 1108C) using 0.5 mol% of tion,[13] and TEA (2 equiv.) as base (Scheme 2). With
oxime palladacycle 1a.[15]
an initial microwave irradiation of 40 W, the reaction
To date, no examples have been reported for transi- temperature was maintained at 1108C for 30 min. As
tion-metal catalyzed Sonogashira cross-coupling of catalyst, oxime palladacycle 1a (1 mol% Pd) was se-
phenol derivatives in neat water (Scheme 1).[16] In this lected to perform the initial screening due to the high
contribution, we present the first Sonogashira cou- activity of this complex as precatalyst in different
pling of aryl imidazolylsulfonates performed in neat cross-coupling and Heck-type reactions in aqueous
water using oxime palladacycle 1a as precatalyst medium.[11,13,14] Unfortunately, under these conditions,
under microwave irradiation (Scheme 1).
the alkynylation did not take place and starting mate-
rials were mostly recovered (Scheme 2). Since we
have previously demonstrated the improvement of
the activity of oxime palladacycles using phosphanes
in the Suzuki arylation[17a] and alkenylation[17b] reac-
tions of the challenging deactivated aryl chlorides, we
assembled a small catalyst library prepared in situ by
mixing 1a (1 mol% Pd) and different electron-rich
and sterically demanding ligands (2 mol%). As de-
picted in Scheme 2, the most active catalytic system
was obtained when using Buchwaldꢄs ligands 9 and
10, especially the tertiary electron-rich and sterically
hindered SPhos ligand 10, which led to an excellent
96% isolated yield for 4a. Other mono- and bidentate
phosphane-derived ligands such as 5–12 as well as the
sterically hindered phosphate 13 and the imidazolini-
um NHC ligand 14 always led to lower yields in the
process (Scheme 2).
Having identified SPhos as the optimal ligand for
the copper-free Sonogashira reaction in water, further
optimization of the reaction conditions was carried
out in order to improve the efficiency of the catalytic
system (Table 1).[18]
Initially, the efficiency of the microwave irradiation
was demonstrated since only a 48% yield was ob-
tained for 4a when the reaction was performed under
conventional thermal conditions (1308C, 24 h,
Table 1, entry 1). Regarding the catalyst, a 58% yield
of 1-(phenylethynyl)naphthalene was obtained under
the optimized reaction conditions when oxime palla-
dacycle 1b (1 mol% Pd) was employed as catalyst
(Table 1, entry 2). This result confirmed the facility of
palladacycle 1a in cross-coupling reactions in aqueous
medium. Other Pd sources such as Pd
ACHTUNGRTEN(NUNG OAc)2 and
Pd2A(dba)3 were also less effective than 1a affording
CTHUNGTRENNUNG
lower yields of 4a as shown in entries 3 and 4.
With respect to the base (Table 1, entries 5–9),
good isolated yields were obtained with other organic
(pyrrolidine, 89%) and inorganic bases (K2CO3 and
K3PO4, 75 and 78%, respectively), although these ex-
periments did not improve the ability of TEA in this
process.
Scheme 2. Sonogashira coupling in water: ligands study.
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Microwave-Promoted Copper-Free Sonogashira–Hagihara Couplings of Aryl Imidazolylsulfonates
Table 1. Sonogashira alkynylation of 2 in water; reaction conditions study.
Entry
2
Surfactant[a]
Pd catalyst
Base
Yield [%][b]
1
2
3
4
5
6
7
8
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2ab
2ac
2ad
2ae
2af
CTAB (3a)
CTAB (3a)
CTAB (3a)
CTAB (3a)
CTAB (3a)
CTAB (3a)
CTAB (3a)
CTAB (3a)
CTAB (3a)
TBAOH (3b)
SDS (3c)
MAXEMUL6112 (3d)
PTS (3e)
SPAN80 (3f)
ZONYL 9361 (3g)
ZONYL FSN (3h)
CTAB (3a)
CTAB (3a)
CTAB (3a)
CTAB (3a)
CTAB (3a)
1a
1b
TEA
TEA
TEA
TEA
pyrrolidine
K2CO3
KOH
CsOH
K3PO4
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
96 (48)[c]
58
75
24
89
75
31
26
78
76
85
91
67
73
86
72
Pd
Pd
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
G
N
9
10
11
12
13
14
15
16
17
18
19
20
21
<5
<5
<5
<5
<5
TEA
TEA
TEA
[a]
CTAB: hexadecyltrimethylammonium bromide; TBAOH: tetrabutylammonium hydroxide; SDS: sodium dodecyl sul-
phate; PTS: polyoxyethanyl-a-tocopheryl sebacate; for the rest of surfactant acronyms, see the Supporting Information.
Isolated yield after flash chromatography.
[b]
[c]
Isolated yield when the reaction was performed under conventional thermal conditions (1308C, 24 h).
The effect of the surfactant on the activity of the tion with the imidazol-1-ylsulfonate 2aa under the op-
catalytic system was also studied (Table 1, entries 10– timized reaction conditions (Table 2). Thus, naphtha-
16). Regardless of the ionic character of the additive, len-1-yl 1H-imidazole-1-sulfonate (2aa) was coupled
lower yields were observed for the alkynylation reac- with 4-tolyl- and 4-methoxyphenylacetylenes in excel-
tion, with the exception of the anionic phosphate lent 96 and 87% yields, respectively (Table 2, entries 2
ester-derived surfactant MAXEMUL 6112, which af- and 3). Lower yields were achieved in the coupling
forded 4a in a 91% isolated yield (Table 1, entry 12). with the electron-poor 4-(trifluoromethyl)phenyl-,
Finally, we also tested the reactivity of the electro- and 2-pyridylacetylenes (Table 2, entries 4 and 5), re-
philes 2ab–2af in the process under the optimized re- sults which were also observed for alkyl-substituted
action conditions. As depicted in Table 1 (entries 17– acetylenes such as cyclohexylacetylene (63%, entry 6)
21), none of these derivatives showed any reactivity and 1-butyne (40%, entry 7). In the case of using tri-
and only starting material was recovered from the methylsilylacetylene as nucleophile, a double aryla-
crude reaction mixtures.
tion process was observed affording 1,2-di(naphtha-
To test the effectiveness of the catalytic system in len-1-yl)ethyne (15) as major product in a 45% isolat-
the Pd-catalyzed Sonogashira coupling in water, ed yield (Table 2, entry 8). Unfortunately, this yield
a range of terminal alkynes was examined in the reac- could not be improved by using two equivalents of
Adv. Synth. Catal. 2013, 355, 203 – 208
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Josꢀ F. Cꢁvicos et al.
FULL PAPERS
Table 2. Sonogashira cross-coupling reaction: nucleophile
scope.
such as o-tolyl 1H-imidazole-1-sulfonate (2ga) and
2,6-dimethylphenyl 1H-imidazole-1-sulfonate (2ha),
reactions which afforded the corresponding cross-cou-
pled products in yields ranging from 41 to 95%
(Table 3, entries 6–10). Finally, the heterocyclic pyri-
din-2-yl 1H-imidazole-1-sulfonate (2ia) led to com-
pound 4u in a modest 45% yield after reaction with
phenylacetylene (Table 3, entry 11).
Conclusions
Entry
R
No.
Yield [%][a]
1
2
3
4
5
6
7
8
9
Ph
4a
4b
4c
4d
4e
4f
4g
15
15
4j
96
96
87
59
52
63
40
We have disclosed a copper-free oxime palladacycle-
catalyzed Sonogashira cross-coupling reaction of elec-
tron-rich, electron-poor, and sterically hindered aryl
imidazol-1-ylsulfonates with aryl- and alkyl-substitut-
ed terminal alkynes using water as solvent under mi-
crowave irradiation. This reaction is carried out in the
presence of SPhos as ligand (2 mol%), hexadecyltri-
methylammonium bromide as additive, and using
only 1 mol% Pd of bench stable oxime palladacycle
1a as precatalyst. Further studies to demonstrate the
ability of imidazolylsulfonates as electrophiles in
cross-coupling reactions in water are underway in the
group.
4-MeC6H4
4-MeOC6H4
4-CF3C6H4
2-pyridyl
cyclohexyl
C3H7
TMS
CO2H
ACHTUNGTRENNUNG(CH3)2C(OH)
45[b,c]
37[b,d]
38
10
[a]
Isolated yield after flash chromatography.
Isolated yield for 1,2-di(naphthalen-1-yl)ethyne (15).
A 7% yield (GC) of trimethyl(naphthalen-1-ylethynyl)-
ACHTUNGTRENNUNGsilane (4h) was also detected in the crude reaction mix-
[b]
[c]
ture.
[d]
A 7% yield (GC) of 3-(naphthalen-1-yl)propiolic acid
(4i) was also detected in the crude reaction mixture.
Experimental Section
Typical Procedure for the Sonogashira Coupling in
water under MW Irradiation Conditions
A 10-mL MW vessel was charged with 2-cyanophenyl 1H-
imidazole-1-sulfonate (0.050 g, 0.2 mmol, 1 equiv.), p-tolyl-
AHCTUNGRTEGNUNaN cetylene (0.038 mL, 0.3 mmol), Et3N (0.056 mL, 0.4 mmol),
electrophile, conditions which afforded 15 in a poor
15% yield. When 2aa was allowed to react with pro-
piolic acid, the double coupling process was also ob-
served affording 15 in a 37% yield (Table 2, entry 9).
However, the alkynylation of 2aa with 2-methylbut-3-
yn-2-ol, led to the monoarylated compound 4j in
a 38% yield (Table 2, entry 10).
Regarding the electrophilic component, moderate
to high yields (45–95%) were obtained in the micro-
wave-assisted 1a/S-Phos-catalyzed cross-coupling of
different terminal acetylenes with neutral, electron-
rich, and electron-poor phenylimidazol-1-ylsulfonates
(Table 3). Thus, phenyl 1H-imidazole-1-sulfonate
(2ba) as well as the electron-rich 4-methoxyphenyl
hexadecyltrimethylammonium bromide (0.03 g, 40 mol%),
catalyst 1a (0.6 mg, 1 mol% Pd), H2O (1.7 mL) and SPhos
(0.0017 g, 2 mol%). The vessel was sealed with a pressure
lock, and the mixture was heated in air at 1308C for 30 min
with the aid of an initial 40 W MW irradiation in a CEM
Discover MW reactor. After cooling to room temperature,
the reaction mixture was extracted with EtOAc (3ꢅ10 mL),
and the organic layers were washed with H2O (3ꢅ10 mL),
dried over MgSO4, and concentrated under reduced pres-
sure. The crude residue was purified by flash chromatogra-
phy (hexane) to obtain compound 4o; yield: 0.040 g (94%).
1H-imidazole-1-sulfonate (2ca) and 3,5-dimethylphen- Acknowledgements
yl 1H-imidazole-1-sulfonate (2da) reacted with phe-
Financial support from the MICINN (Projects CTQ2007-
nylacetylene to afford compounds 4k, 4l, and 4m in
89, 78, and 55% yields, respectively (Table 3, en-
tries 1–3). High yields were also observed for the cou-
pling of the activated electrophiles 2ea and 2fa with
phenylacetylene and 4-tolylacetylene, respectively
(Table 3, entries 4 and 5). The process was also effec-
tive for the coupling of 2-aryl- and 2-alkylacetylenes
with deactivated and sterically hindered electrophiles
62771/BQU, CTQ2010-20387 and Consolider INGENIO
2010 CSD2007-00006), FEDER, from the Generalitat Va-
lenciana (Project PROMETEO/2009/038), and the University
of Alicante is acknowledged.
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Microwave-Promoted Copper-Free Sonogashira–Hagihara Couplings of Aryl Imidazolylsulfonates
Table 3. Sonogashira cross-coupling reaction: substrate scope.
[a]
Isolated yield after flash chromatography.
A 7% yield (GC) of 1,4-bis(phenylethynyl)benzene (16) was also detected in the crude reaction mixture.
A 6% yield (GC) of 1,2-di-o-tolylethyne (17) was also detected in the crude reaction mixture.
A 5% yield (GC) of 1,2-bis(2,6-dimethylphenyl)ethyne (18) was also detected in the crude reaction mix-
[b]
[c]
[d]
ture.
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