Double arylation of diynes and alkynylation of functionalized heteroaryl halides by a practical heck reaction in an ionic liquid

Article abstract of DOI:10.1055/s-0031-1289861

The efficient palladium-catalyzed alkynylation of electron-rich bromoheteroarenes, incorporating deactivating electron-donating methyl and methoxy groups, and the (hetero)arylation of diynes, take place in the imidazolium ionic liquid [BMIM][BF₄

Full text of DOI:10.1055/s-0031-1289861

2844
LETTER
Double Arylation of Diynes and Alkynylation of Functionalized Heteroaryl
Halides by a Practical Heck Reaction in an Ionic Liquid
Heck
R
eaction
a
inan Ionic
m
Liquid er Saleh, Michel Picquet, Philippe Meunier, Jean-Cyrille Hierso*
Université de Bourgogne, Institut de Chimie Moléculaire de l’Université de Bourgogne UMR-CNRS 5260,
9 avenue Alain Savary, 21078 Dijon, France
Fax +33(0)380393682; E-mail: jean-cyrille.hierso@u-bourgogne.fr
Received 14 July 2011
Dedicated to Professor Richard Heck for his Nobel Prize awarded in 2010
[Pd(OAc)2(PPh3)2], in an amine solvent at 100 °C. The
Abstract: The efficient palladium-catalyzed alkynylation of elec-
tron-rich bromoheteroarenes, incorporating deactivating electron-
donating methyl and methoxy groups, and the (hetero)arylation of
diynes, take place in the imidazolium ionic liquid [BMIM][BF4], as
major limitation of the system, underlined by the author,
was that halides with strongly electron-donating substitu-
ents do not react well. Following this ground-breaking
a highly polar non-volatile solvent. This method may constitute a work, much progress has been accomplished in this aspect
and others.4–8 However, only a few catalytic systems, that
sustainable alternative to classical solvents such as dioxane, DMF,
NMP, or DMAc. New enynes are formed in the presence of a sys-
are generally not easy to access have been reported for the
tem encompassing a copper-free palladium catalyst, triphenylphos-
coupling of a wide range of heteroaryl halides that include
phine as ligand, and various inexpensive bases. The enyne
in their scope N-, O-, and S-heteroarenes,2 especially
molecules reported are selectively synthesized in high yields and
when compared to systems focused on aryl halides. Re-
ports that address the issue of extending arene alkynyla-
tion into more attractive solvents such as ambient-
temperature ionic liquids (ILs) are mainly based on the
coupling of expensive aryl iodides, thus precluding indus-
trial applications.9–11 Nevertheless, many palladium alky-
nylation reactions are conducted in potentially harmful
polar organic solvents,1 and more sustainable alternatives
need to be investigated for further industrial progress. Due
to their low vapor pressure, ease of handling, and potential
for recycling, ILs have shown great promise.12 As reaction
media, their compatibility with transition metals and lim-
ited miscibility with classical organic solvents enable easy
organic product separation, and possibly immobilization
of the catalytic species. We herein report our efforts to de-
velop efficient conditions for the Heck alkynylation of
heteroaryl bromides functionalized with electron-donat-
ing groups in 1-n-butyl-3-methylimidazolium tetrafluo-
roborate ([BMIM][BF4]; Table 1). We additionally report
an efficient double (hetero)arylation of terminal diynes
using the same simple methodology. Until now, this type
of simultaneous double cross-coupling reaction has only
been rarely investigated in isolated examples, even though
the products obtained have shown great potential in me-
dicinal chemistry and materials science.13
are mostly unprecedented.
Key words: arylation, diynes, heteroarenes, palladium, ionic liquid
The development of metal-catalyzed methods for incor-
porating alkynes into organic molecules has attracted
growing interest in the recent years. Alkynes are recurring
building blocks in a wide range of industrial intermediates
and biologically active products.1 In addition, the reactiv-
ity of the alkyne function opens the way to many valuable
subsequent chemical transformations such as cyclization
through hydroamination. Since significant numbers of
current pharmaceutical and agrochemical compounds are
based on heterocyclic scaffolds, the direct alkynylation of
heteroaromatics can be a key synthetic step in the conver-
gent and efficient construction of a range of complex mol-
ecules (Scheme 1).2
R1
R2
N
or
[Pd]/L
HetAr-X
+
H
R2
E
X = I, Br, Cl
E = S, NR
R1, R2 = aryl, alkyl
R1
R2
Alkynylation of five- and six-membered electron-rich
heteroaryl bromides incorporating one nitrogen or sulfur
heteroatom proceeded satisfactorily. Good selectivity and
excellent yields were obtained when phenylacetylene was
coupled with 3-bromo-5-methoxypyridine (91% in 4 h;
Table 1, entry 1), 3-bromo-6-methoxypyridine (90% in
4 h; entry 2), and with 3-bromo-6-methylpyridine (91% in
4 h; entry 3). Excellent yield was also obtained under the
same conditions for the sterically deactivated substrate,
3-bromo-4-methylpyridine (92% in 4 h; entry 4). Only
small amounts of side-product due to dimerization of the
excess of phenylacetylene were detected, but this side re-
Scheme 1 Palladium-catalyzed alkynylation of heteroaryl halides
In the 1970s, Heck described the alkynylation of aryl-,
vinyl-, and heterocyclic halides using either aromatic
or aliphatic terminal alkynes.3 The reactions were con-
ducted in the presence of catalytic amounts of
SYNLETT 2011, No. 19, pp 2844–2848
Advanced online publication: 09.11.2011
DOI: 10.1055/s-0031-1289861; Art ID: D22511ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

LETTER
Heck Reaction in an Ionic Liquid
2845
action did not hamper in any way the coupling of the het- chain aliphatic acetylenes (1-hexyne and 1-decyne).
eroaryl bromides. Having demonstrated the efficient Yields above 90% were achieved in four hours for the
coupling of phenylacetylene with a variety of electron- coupling of methoxybromopyridines with 1-decyne
rich pyridinyl bromides, we examined the alkynylation (Table 1, entries 5–7). As observed with phenylacetylene,
reaction with other terminal alkynes. A selection of the position of the methoxy or methyl groups does not in-
electron-rich heterocycles was reacted with short or long fluence the course of the reaction. Additionally, bromides
Table 1 Copper-Free Palladium-Catalyzed Alkynylation of Functionalized Heteroarenes Bearing Electron-Donor Groups in an Ionic Liquida
Entry
1
Heteroaryl bromide
Time (h)
4
Product
Yield (%)b
91
MeO
MeO
Br
N
N
1
2
MeO
2
3
4
4
90
91
MeO
Me
Br
N
N
N
Me
Br
N
3
Me
Me
4
5
4
4
92
91
Br
N
N
4
MeO
MeO
n-octyl
Br
N
N
5
6
MeO
n-octyl
6
7
4
4
93
91
MeO
Br
N
N
n-octyl
N
Me
Br
N
Me
7
8
Me
Me
8
4
94
n-octyl
Br
S
S
N
MeO
MeO
9
10
11
7
7
7
95
94
70
n-Bu
Br
N
9
MeO
n-Bu
MeO
Br
N
N
10
Me
Me
n-Bu
S
Br
S
11
a Reaction conditions: [Pd(allyl)Cl]2 catalyst (0.5 mol%), Ph3P (3 mol%), aryl bromide (1.0 equiv), alkyne (1.2 equiv, 3.42 mmol), base (1.2
equiv), [BMIM][BF4] (3 mL), 100 °C.
b Average yields of two runs, based on aryl bromide; isolated yields obtained after chromatography on silica column.
Synlett 2011, No. 19, 2844–2848 © Thieme Stuttgart · New York

2846
S. Saleh et al.
LETTER
R
Y
S
(CH2)n
or
Y
S
[Pd] (1 mol%)
[BMIM][BF4]
R
R
(Het)Ar-X
+
H
(CH2)n
H
E
X = Br, Cl; Y = CH, N
E = CH, N
(CH2)
n
E
R
R = aryl, alkyl
n = 3–4
Scheme 2 Palladium-catalyzed double arylation of terminal diynes
substituted at positions 2- and 3- with respect to the tion would modify the course of the second alkynylation.
heteroatom were equally efficiently coupled. The sterical- In this case, interesting unsymmetrical double alkynyla-
ly deactivated 2-methyl-3-bromothiophene was also suc- tion products might be envisaged. Additionally, the result-
cessfully coupled (94% in 4 h; entry 8). Longer reaction ing heteroarylated diynes may be interesting precursors
times were needed to couple the more volatile 1-hexyne, for further annulation leading to indoles and carbazoles,
but good to excellent yields were obtained (70 to 95%; en- for instance by catalyzed hydroamination.14 Table 2 sum-
tries 9–11).
marizes the successful results obtained under conditions
similar to those optimized for the simple arylation of
monoalkynes.
With regard to the results obtained in the arylation of ter-
minal alkynes, we investigated the double arylation of ter-
minal diynes using the same methodology (Scheme 2).
One objective was to examine whether the first alkynyla-
Table 2 Copper-Free Palladium-Catalyzed Double Arylation of Diynes in an Ionic Liquida
Entry Haloarene
Base
Time (h)
5
Product
Yield (%)d
98
N
N
N
1
pyrrolidine
Br
N
12
Br
N
S
2
pyrrolidine
5
91
N
13
14
3
pyrrolidine
5
5
93
54
S
Br
S
S
N
N
N
S
4
Et3N
S
Br
15
16
Br
5b
pyrrolidine
5
92
N
N
N
Synlett 2011, No. 19, 2844–2848 © Thieme Stuttgart · New York

LETTER
Heck Reaction in an Ionic Liquid
2847
Table 2 Copper-Free Palladium-Catalyzed Double Arylation of Diynes in an Ionic Liquida (continued)
Entry Haloarene
Base
Et3N
Time (h)
5
Product
Yield (%)d
N
N
N
N
6
80
Cl
N
N
17
S
N
N
S
N
S
7
Et3N
5
69
Cl
18
19
20
21
22
Br
MeOC
8c
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
40
40
40
40
30
64
51
50
COMe
MeOC
Br
9c
Br
MeO
10c
11c
OMe
MeO
Br
Me
Me
Me
a Reaction conditions: [Pd(allyl)Cl]2 (0.5 mol%), Ph3P (3 mol%), aryl bromide (or chloride) (1.0 mmol), 1,7-octadiyne (0.55 mmol), base (1.2
mmol), [BMIM][BF4] (3 mL), 100 °C.
b 1,6-Heptadiyne.
c 130 °C.
d Isolated yields obtained after chromatography on silica column.
3-Bromopyridine was quantitatively coupled to 1,7- and 2-chlorobenzothiazole coupled to 1,7-octadiyne
octadiyne to give 1,8-di(pyridin-3-yl)octa-1,7-diyne (Table 2, entries 6 and 7). These interesting results
(98% in 5 h; Table 2, entry 1).15,16 3-Bromoquinoline and prompted us to extend the study of the double arylation re-
3-bromothiophene were also efficiently coupled to 1,7- action by using functionalized aryl bromides (electron-
octadiyne, with yields around 90%, under the same condi- rich activated and electron-poor deactivated substrates).
tions (Table 2, entries 2 and 3). A limitation appeared for Moderate to good conversions were obtained for the aryl-
the coupling of diheteroaromatic 2-bromothiazole since, ation of 1,7-octadiyne with the electronically activated 4-
in the presence of pyrrolidine, coupling of this base to bro- bromoacetophenone (30%; Table 2, entry 8) and the unac-
mothiazole was mainly observed. Conversely, 1,8-di(thi- tivated bromobenzene (64%; Table 2, entry 9), although
azol-2-yl)octa-1,7-diyne was obtained in 54% isolated increased temperature and time was required (130 °C for
yield using a tertiary base (Et3N; Table 2, entry 4). Excel- 40 h). Fairly good results were obtained with electronical-
lent yield was also obtained when 3-bromoquinoline was ly deactivated substrates, with 4-bromanisole being con-
reacted with the slightly shorter chain substrate 1,6-hep- verted in 51% yield (Table 2, entry 10) and 4-
tadiyne under the same conditions (Table 2, entry 5). We bromotoluene in 50% yield (Table 2, entry 11), albeit in
also tested the reaction using heteroaryl chlorides, which much longer reaction times (40 h). In these latter cases,
are substrates that are more challenging but clearly more we detected a competitive oligomerization of the diynes
valuable from a sustainability and economic point of (present in excess), which diminished the final yield rela-
view. Good yields were obtained with 2-chloropyrazine tive to enyne. Attempts to make unsymmetrical arylated
Synlett 2011, No. 19, 2844–2848 © Thieme Stuttgart · New York

2848
S. Saleh et al.
LETTER
(5) (a) Nakamura, K.; Okubo, H.; Yamaguchi, M. Synlett 1999,
549. (b) Mery, D.; Heuze, K.; Astruc, D. Chem. Commun.
2003, 1934. (c) Hundertmark, T.; Littke, A. F.; Buchwald,
S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729.
(6) (a) Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551.
(b) Alonso, D. A.; Najera, C.; Pacheco, M. C. Tetrahedron
Lett. 2002, 43, 9365.
(7) (a) Hierso, J.-C.; Fihri, A.; Amardeil, R.; Meunier, P.;
Doucet, H.; Santelli, M.; Ivanov, V. V. Org. Lett. 2004, 6,
3473. (b) Feuerstein, M.; Berthiol, F.; Doucet, H.; Santelli,
M. Org. Biomol. Chem. 2003, 1, 2235.
(8) (a) Kollhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem.
Int. Ed. 2003, 42, 1056. (b) Gelman, D.; Buchwald, S. L.
Angew. Chem. Int. Ed. 2003, 42, 5993.
diynes either in one pot or stepwise, remained unsuccess-
ful, giving mixtures of products. This suggests that, con-
trary to our initial expectations, the first alkynylation has
little influence on the remaining terminal alkyne.
In summary, we have reported the efficiency of a simple
system [Pd/3PPh3] (1 mol%) in the ionic liquid
[BMIM][BF4] for the coupling of a variety of electron-
rich functionalized heteroaryl bromides with phenylacet-
ylene and the aliphatic 1-hexyne and 1-decyne terminal
alkynes.15 A double arylation of bifunctional terminal
diynes can be efficiently performed using the same cata-
lytic system. Depending on the heterocycle, a primary or
tertiary amine can be used as soluble base. Both aryl and
heteroaryl bromides are suitable substrates, as well as 2-
chloroheteroarenes. The accessibility of the system,
which features inexpensive ligands, organic base, and IL
solvent, make these results of interest for further develop-
ment of Heck and Sonogashira type coupling reactions in
ionic liquids. Importantly, we have shown that, as well as
iodoarenes, aryl and heteroaryl bromides and some chlo-
rides are suitable substrates for copper-free palladium
alkynylation in ionic liquid.
(9) Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I.
Org. Lett. 2002, 4, 1691.
(10) Park, S. B.; Alper, H. Chem. Commun. 2004, 1306.
(11) (a) Gholap, A. R.; Venkatesan, K.; Pasricha, R.; Daniel, T.;
Lahoti, R. J.; Srinivasan, K. V. J. Org. Chem. 2005, 70,
4869. (b) Corma, A.; Garcia, H.; Leyva, A. Tetrahedron
2005, 61, 9848. (c) Hierso, J.-C.; Picquet, M.; Cattey, H.;
Meunier, P. Synlett 2006, 3005. (d) Hierso, J.-C.; Boudon,
J.; Picquet, M.; Meunier, P. Eur. J. Org. Chem. 2007, 583.
(e) Saleh, S.; Fayad, E.; Azouri, M.; Hierso, J.-C.; Andrieu,
J.; Picquet, M. Adv. Synth. Catal. 2009, 351, 1621.
(f) Saleh, S.; Picquet, M.; Meunier, P.; Hierso, J.-C.
Tetrahedron 2009, 65, 7146.
(12) (a) Welton, T. Chem. Rev. 1999, 99, 2071. (b) Dupont, J.;
de Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102,
3667. (c) Wasserscheid, P.; Keim, W. Angew. Chem. Int. Ed.
2000, 39, 3772. (d) Sheldon, R. Chem. Commun. 2001,
2399. (e) Dyson, P. J. Transition Met. Chem. 2002, 27, 353.
(f) Olivier-Bourbigou, H.; Magna, L. J. Mol. Catal. A:
Chem. 2002, 182, 419. (g) Picquet, M.; Poinsot, D.;
Stutzmann, S.; Tkatchenko, I.; Tommasi, I.; Wasserscheid,
P.; Zimmermann, J. Top. Catal. 2004, 29, 139.
(13) (a) Zhang, Z.; Lockman, P. R.; Mittapalli, R. K.; Allen, D.
D.; Dwoskin, L. P.; Crooks, P. A. Bioorg. Med. Chem. Lett.
2008, 18, 5622. (b) Hay, C.; Hissler, M.; Fischmeister, C.;
Rault-Berthelot, J.; Toupet, L.; Nyulàszi, L.; Réau, R. Chem.
Eur. J. 2001, 7, 4222.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Thanks are due to S. Royer and J. Andrieu for their help. S.S.
sincerely thanks the French MESR for a grant. This work was sup-
ported by the ‘Conseil Régional de Bourgogne’ (PARI SMT8), the
‘Université de Bourgogne’ and the CNRS with the 3MIM program
(P4 project: ‘Palladium Methodology for Heterocycle Functionali-
zation’). This work was also supported by the CNRS CP2D pro-
gram ‘Chimie pour le Développement Durable’ ANR-09-CP2D-03
CAMELOT.
(14) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, 215.
(15) Typical procedure: The catalyst was prepared as a solid
mixture of [Pd(allyl)Cl]2 (6.3 mg, 0.034 mmol of Pd) and
Ph3P (26.9 mg, 0.102 mmol), and degassed for 15 min in a
20 mL Schlenk tube equipped with a magnetic stirrer bar and
a reflux condenser. Under argon, were added the heteroaryl
halide (either solid or liquid, 3.42 mmol) and [BMIM][BF4]
(3 mL). The mixture was further degassed under reduced
pressure for 10 min. The Schlenk tube was heated in an oil
bath at 60 °C to give a red solution. The vessel was removed
from the heating bath and, to the ionic liquid solution, was
then added pyrrolidine (0.35 mL, 292 mg, 4.1 mmol) and the
terminal alkyne (4.1 mmol). The resulting mixture was
heated at 100 °C for 4 h under argon and, after extraction
with diethyl ether (4 × 5 mL), the product was purified by
silica gel chromatography (ethyl acetate–heptane, 1:9) to
give the enyne compound. The recovered ionic liquid can be
reused without treatment for further catalytic couplings,
after removal of ether traces by simple evaporation under
vacuum. Reloading of triphenylphosphine may be necessary
after three runs due to a partial organic extraction, no amine
salt removal was done during this recycling.
References and Notes
(1) (a) Doucet, H.; Hierso, J.-C. Angew. Chem. Int. Ed. 2007, 46,
834. (b) Negishi, E.-I.; Anastasia, L. Chem. Rev. 2003, 103,
1979. (c) Tykwinski, R. R. Angew. Chem. Int. Ed. 2003, 42,
1566.
(2) (a) Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron
Lett. 2005, 46, 1717. (b) Feuerstein, M.; Doucet, H.;
Santelli, M. J. Mol. Catal. A: Chem. 2006, 256, 75.
(c) Yang, F.; Cui, X.; Li, Y.-N.; Ren, G.-R.; Wu, Y.
Tetrahedron Lett. 2007, 46, 1717. (d) Fleckenstein, C. A.;
Plenio, H. Green Chem. 2008, 10, 563. (e) Mehta, V. P.;
Sharma, A.; Van der Eycken, E. Org. Lett. 2008, 6, 1147.
(f) Wu, M.; Mao, J.; Guo, J.; Ji, S. Eur. J. Org. Chem. 2008,
4050. (g) Torborg, C.; Zapf, A.; Beller, M. ChemSusChem
2008, 1, 91. (h) Torborg, C.; Huang, J.; Schulz, T.;
Schäffner, B.; Zapf, A.; Spannenberg, A.; Börner, A.; Beller,
M. Chem. Eur. J. 2009, 15, 1329.
(3) Dieck, H. A.; Heck, F. R. J. Organomet. Chem. 1975, 93,
259.
(4) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
(16) Copies of 1H and 13C NMR spectra of products 1–22 and
detailed assignment are reported as Supporting Information.
Synlett 2011, No. 19, 2844–2848 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.