A copper- and amine-free Sonogashira coupling reaction promoted by a ferrocene-based phosphinimine-phosphine ligand at low catalyst loading

Article abstract of DOI:10.1016/j.tetlet.2004.03.194

A palladium(II) complex containing a ferrocene-based phosphinimine- phosphine ligand was applied to the amine- and copper-free Sonogashira coupling of aryl iodides and aryl bromides with terminal alkynes using 1equiv of tetrabutylammonium acetate as an activator. The corresponding disubstituted alkynes were obtained in high yields and TONs using 0.1mol% Pd-catalyst.

Full text of DOI:10.1016/j.tetlet.2004.03.194

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4337–4340
A copper- and amine-free Sonogashira coupling reaction promoted
by a ferrocene-based phosphinimine-phosphine ligand at low
catalyst loading
*
*
~
Antonio Arques, David Aunon and Pedro Molina
ꢀ
ꢀ
ꢀ
Departamento de Quımica Organica, Facultad de Quımica, Campus de Espinardo, Universidad de Murcia, 30071 Murcia, Spain
Received 4 March 2004; revised 30 March 2004; accepted 31 March 2004
Abstract—A palladium(II) complex containing a ferrocene-based phosphinimine-phosphine ligand was applied to the amine- and
copper-free Sonogashira coupling of aryl iodides and aryl bromides with terminal alkynes using 1 equiv of tetrabutylammonium
acetate as an activator. The corresponding disubstituted alkynes were obtained in high yields and TONs using 0.1 mol % Pd-cat-
alyst.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The Sonogashira reaction, palladium and copper
co-catalyzed coupling of terminal alkynes with various
organic halides, is the most straightforward and
powerful method of the construction of C(sp2)–C(sp)
bonds.1 It provides an efficient route to aryl (heteroaryl)
alkynes, which are interesting intermediates for the
preparation of a wide variety of target compounds with
applications ranging from natural products2 to molec-
ular organic materials.3
Recently, three amine- and copper-free methodologies
for the Sonogashira reaction have been presented, the
first one is based on the use of stoichiometric amounts of
silver(I) oxide for aryl iodides, and tetrabutylammonium
fluoride or tetrabutylammonium hydroxide for aryl
bromides as activators.7 The second one is based on the
use of an oxime palladacycle and tetrabutylammonium
acetate as an additive.8 In the third one, which allows
the use of aryl chlorides as coupling partners, a
bulky electron-rich ortho-biphenylphosphane ligand is
employed.9 Interestingly, the use of a copper co-catalyst
inhibits the reaction. Sonogashira cross-coupling reac-
tion catalyzed by heterogeneous copper-free Pd-com-
plexes have been also reported.10
The original protocol of the Sonogashira reaction, a
dimetallic-mediated process, which is typically carried
out in the presence of catalytic amounts of a palla-
dium(II) complex as well as CuI in an amine as solvent
or in large excess, has been repeatedly modified and
improved to overcome several significant limitations.
The most important improvement concerned the elimi-
nation of CuI, which is used as co-catalyst, since it can
induce homocoupling reactions of terminal alkynes to
diynes in the presence of oxygen (Glaser-type reactions).
Copper-free approaches to the Sonogashira reaction
must involve the use of an amine, such as piperidine or
triethylamine, as solvent4 or in large excess.5 A copper-
free coupling of aryl iodides with terminal alkynes has
also been reported using an ionic liquid as solvent.6
P,N-Donor bidentate ligands exhibit hemilabile behav-
iour when coordinated to a soft metal centre such as
palladium. The soft phosphorus atom coordinates very
strongly to palladium whereas the hard nitrogen donor
is weakly bound.11 A distinguished family of hemilabile
ligands results by combining a phosphine and imine
COOEt
Ph
N
P
Ph
Cl
Fe
Pd
P
Cl
Ph2
Keywords: Sonogashira reaction; Copper-free; Palladium; Catalysis;
Alkynes.
1
* Corresponding authors. Tel.: +34-968-367496; fax: +34-968-364149;
e-mail: pmolina@um.es
Figure 1.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.194

4338
A. Arques et al. / Tetrahedron Letters 45 (2004) 4337–4340
Table 1. Sonogashira reaction: reaction conditions studya
1 (1 mol%)
+
X
Ph
C
CH
C
C Ph
piperidine, CuI
R
R
Entry
R
X
CuI(mol %)
T (ꢁC)b
tR (h)
Yieldc
9700
9900
TONd
A
B
C
D
E
F
3-H3CO
3-H3CO
I1.5
I1.5
Br
25
80
0.4
0.25
97
99
4-H3CO
4-H3CO
1.5
1.5
1.5
3
25
80
80
80
4
6
6
6
<1
61
58
52
Br
Br
6100
5800
5200
4-H3C–CO
4-H3C–CO
Br
a Reactions were run using 1 mol % of 1, 1 mmol of aryl halide, 1.2 mmol of phenylacetylene in piperidine as solvent.
b The reaction mixture was placed in an oil bath at stated temperature and held there for the allotted time.
c Isolated product after work-up.
d TON (turnover number) ¼ mol product mol PdÀ1
.
Table 2 (continued)
groups (phosphine-imine ligands), which have been
attracting considerable attention in the past few years as
an important class of P,N-ligands.12 In spite of the
fact that iminophosphoranes have been shown to
coordinate to transition metals via the approximately
sp2-hybridized nitrogen atom to give stable complexes,13
Entry
i
Halide
Alkyne
Yield (%)b
Ph–CBCH
96 (90)
99
Br
S
j
Ph–CBCH
H3C
Br
functionalized iminophosphoranes that contain
a
phosphino group as a second donor site have received
very little attention as ligands for homogeneous
catalysis.14
OCH3
I
C
CH
k
>99 (97)
Fe
Some years ago, we reported15 the preparation and
structural characterization of the palladium(II) complex
1 (Fig. 1), containing a ferrocene-based phosphinimine-
phosphine ligand. We wish now to report its efficient use
C
C
CH
CH
l
>99 (98)
65 (64)
Fe
Fe
H3C
NC
I
m
Br
a Reactions were run using 0.1 mol % of 1, 1 mmol of aryl halide,
1.2 mmol of phenylacetylene in NMP as solvent in the presence of
TBAOAc (1.5 mmol) at 110 ꢁC for 1 h.
Table 2. Amine- and copper-free Sonogashira coupling of aryl- and
heteroaryl halides catalyzed by 1a
b Conversion determinated by GC using decane as internal standard
and based on starting halide. In brackets, isolated product yields after
workup, which gave satisfactory spectroscopic data (1H and 13C
NMR and MS).
Entry
Halide
Alkyne
Yield (%)b
H3CO
a
Ph–CBCH
99
I
OCH3
I
in an easy, quick, amine- and copper-free methodology
for the Sonogashira reaction.
b
c
Ph–CBCH
Ph–CBCH
98 (96)
As a starting point for the development of the metho-
dology, we chose as model reactions the coupling be-
tween the ‘deactivated’ 3-methoxy-iodobenzene and
4-methoxy-bromobenzene and the ‘activated’ 4-bromo-
acetophenone with phenylacetylene in the presence of
catalyst 1 (1 mmol % of Pd) in piperidine as solvent. As
illustrated by Table 1, the coupling reaction between
3-methoxy-iodobenzene and phenylacetylene provided
an excellent yield (87%) in the presence of CuIas
co-catalyst (1.5 mol %) at 25 ꢁC. The transformation
of the related 4-methoxy-bromobenzene and 4-bromo-
acetophenone necessitated a reaction temperature of
80 ꢁC and longer reaction time (entries d and e).
Increasing the co-catalyst loading to 3 mol % had a
negligible effect on the yield (entry f). These results
demonstrate clearly the applicability of the complex 1 in
the Sonogashira cross-coupling reaction, however, the
success of these examples remains linked to the use of
CuIas co-catalyst. The use of N-methylpyrrolidinone
>99 (99)
H3C
I
I
d
Ph–CBCH
96 (94)
e
f
Ph–CBCH
Ph–CBCH
>99 (97)
84 (83)
I
S
CH3
Br
O
g
Br
Ph–CBCH
Ph–CBCH
94 (92)
72 (70)
H3C
CHO
Br
h

A. Arques et al. / Tetrahedron Letters 45 (2004) 4337–4340
4339
Table 3. Amine- and copper-free Sonogashira reaction of trialkylsilyl-protected acetylenes
R
+
or
C
C
X
R'3Si
C
CH
C
C
SiR'3
R
R
R
2
3
Entry
R
X
R0
tR (h)
Product
Yield (%)a
a
b
c
d
e
f
4-H3CO
4-H3C
IMe
1
1
2
2
2
76 (72)
97 (93)
85
IMe
IMe
I
2-Thienyl
4-H3C
2
i-Pr
i-Pr
i-Pr
i-Pr
1
3
3
3
3
99 (93)
99 (85)
97 (75)
95
2-H3CO
4-H3CCO
4-CN
I
1
Br
Br
1.5
1.5
g
a Conversion determinated by GC using decane as internal standard and based on starting halide. In brackets, isolated product yields after workup,
which gave satisfactory spectroscopic data (1H and 13C NMR and MS).
(NMP) as solvent and tetrabutylammonium acetate
(TBAOAc) as additive, allows that this alkynylation
process can be performed under very convenient amine-
and copper-free conditions.
In conclusion, we have shown that the readily available
palladium(II) complex, is an efficient and versatile cat-
alyst for amine- and copper-free Sonogashira reactions
of aryl(heteroaryl) iodides and aryl(heteroaryl) bro-
mides with a variety of terminal alkynes. The catalyst
system is highly active using very low loading conditions
(0.1 mol % of Pd).
The coupling reaction between 2-methoxy-iodobenzene
and phenylacetylene led to a product yield of 85% when
NMP was used as solvent in the presence of TBAOAc as
additive at 25 ꢁC for 27 h using 1 mol % of 1. Increasing
the reaction temperature to 110 ꢁC improved the yields
to 99% after 1 h. Under these conditions coupling of
4-bromoacetophenone with phenylacetylene provided
the product in 99% yield. With this in mind, we inves-
tigated the effects of decreasing the catalyst loading. We
found that reduction of the catalyst loading to 0.1 mol %
led in the reaction of 2-methoxy-iodobenzene and
4-bromoacetophenone with phenylacetylene to a prod-
uct yield of 99% and 94%, respectively.
Typical experimental procedure. In a 25 mL flask was
placed N-methylpyrrolidinone (8 mL), 4-iodotoluene
(545 mg, 2.5 mmol), phenylacetylene (312 mg, 3 mmol),
tetrabutylammonium acetate (1130 mg, 3.75 mmol) and
the catalyst 1 (2.1 mg, 2.5 10À3 mmol). The resulting
solution was placed in a sand bath pre-heated to 110 ꢁC
and stirred for 1 h. After this time, the solution was
poured into 5% v/v hydrochloric acid (20 mL) and then
extracted with diethyl ether (4 · 15 mL). The combined
organic layers were washed with brine (20 mL) and
water (20 mL) before being dried over anhydrous
MgSO4. After filtration the solvent was removed and the
crude product was chromatographed on a silica gel
column, using 1:12 EtOAc/hexanes as eluent to give
4-methyl-1-phenylethynyl benzene (475 mg, 90%).
With our optimized reaction conditions in hand, we
screened a range of aromatic and heteroaromatic iodides
and bromides in the coupling reaction with phenyl- and
ferrocenylacetylene (Table 2). The results show that the
procedure is applicable to a range of aryl iodides and
activated aryl bromide substrates, with good product
yields being obtained. The method is found to be rela-
tively insensitive to the steric hindrance of the starting
halide (entries b, f and k), and it also shows good
functional group compatibility. For example, 2-bromo-
benzaldehyde is not destroyed during the course of the
reaction (entry h).
Acknowledgements
ꢀ
ꢀ
We thank the Direccion General de Investigacion
(MCyT Spain) project BQU2001-0014, for financial
support.
In an effort to explore the scope of the method, we have
screened the coupling of representative aryl iodides and
aryl bromides with trialkylsilyl-protected acetylenes,
which are known to be much more difficult to couple as
compared to phenylacetylene in Sonogashira copper-
free protocols. While we found that the use of trimeth-
ylsilylacetylene was inefficient due to the significant
desilylation of the product that takes place under our
reaction condition to give symmetrically disubstituted
alkynes 2 (Table 3 entries a–c), the use of triisopropyl-
silylacetylene was a suitable surrogate and the mono-
arylacetylenes 3 were obtained (entries d–g) in excellent
yields.
References and notes
1. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467–4470; (b) Sonogashira, K. In Metal-
Catalyzed Cross-Coupling Reactions; Stang, P. J., Diede-
rich, F., Eds.; Wiley-VCH: Weinheim, 1998; pp 203–229;
(c) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46–
49.
2. (a) Paterson, I.; Davies, R. D. M.; Marquez, R. Angew.
Chem., Int. Ed. 2001, 40, 603–607; (b) Toyota, M.;
Komori, C.; Ihara, M. J. Org. Chem. 2000, 65, 7110–
7113; (c) Yoshimura, F.; Kawata, S.; Hirama, M.

4340
A. Arques et al. / Tetrahedron Letters 45 (2004) 4337–4340
Tetrahedron Lett. 1999, 40, 8281–8285; (d) Miller, M. W.;
9. Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003,
42, 5993–5996.
Johnson, C. R. J. Org. Chem. 1997, 62, 1582–1583; (e)
Sakai, A.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1999,
40, 4211–4214; (f) Graham, A. E.; McKerrecher, D.;
Davies, D. H.; Taylor, R. J. K. Tetrahedron Lett. 1996, 37,
7445–7448.
ꢀ
ꢀ
10. (a) Heuze, K.; Mery, D.; Gauss, D.; Astruc, D. Chem.
Commun. 2003, 2274–2275; (b) Djakovitch, L.; Rollet, P.
Tetrahedron Lett. 2004, 45, 1367–1370.
11. Jeffrey, J. C.; Rauchfuss, T. B. Inorg. Chem. 1979, 18,
2658–2666.
3. (a) Bunz, U. H. F. Chem. Rev. 2000, 100, 1605–1644; (b)
Tour, J. M. Acc. Chem. Res. 2000, 33, 791–804.
12. (a) Espinet, P.; Soulantica, K. Coord. Chem. Rev. 1999,
193–195, 499–556; (b) Shirakawa, E.; Hiyama, T. J. Orga-
nomet. Chem. 1999, 576, 169–178; (c) Hu, X.; Dai, H.; Hu,
X.; Chen, H.; Wang, J.; Bai, C.; Zheng, Z. Tetrahedron:
Asymmetry 2002, 13, 1687–1693.
13. (a) Dehnicke, K.; Krieger, M.; Massa, W. Coord. Chem.
Rev. 1999, 182, 19–65; (b) Witt, M.; Roesky, H. W. Chem.
Rev. 1994, 94, 1163–1181.
ꢀ
ꢀ
4. (a) Mery, D.; Heuze, K.; Astruc, D. Chem. Commun. 2003,
1934–1935; (b) Alami, M.; Ferri, F.; Linstrumelle, G.
Tetrahedron Lett. 1993, 34, 6403–6406; (c) Pal, M.;
Parasuraman, K.; Gupta, S.; Yeleswarapu, K. R. Synlett
2002, 1976–1982; (d) Fu, X.; Zhang, S.; Yin, J.;
Schumacher, D. P. Tetrahedron Lett. 2002, 43, 6673–
6676.
€
5. (a) Bohm, V. P. W.; Herrmann, W. A. Eur. J. Org. Chem.
2000, 3679–3681; (b) Heidenreich, R. G.; Kohler, K.;
Krauter, J. G. E.; Pietsch, J. Synlett 2002, 1118–1122.
6. Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu,
I. Org. Lett. 2002, 4, 1691–1694.
14. (a) Spencer, L. P.; Altwer, R.; Wei, P.; Gelmini, L.; Gauld,
J.; Stephan, D. W. Organometallics 2003, 22, 3841–3854;
(b) Wu, H.-R.; Liu, Y.-H.; Peng, S.-M.; Liu, S.-T. Eur. J.
€
ꢀ
Inorg. Chem. 2003, 3152–3159; (c) Sauthier, M.; Fornies-
Camer, J.; Toupet, L.; Reau, R. Organometallics 2000, 19,
ꢀ
ꢀ
7. Mori, A.; Kawashima, J.; Shimada, T.; Suguro, M.;
Hirabayashi, K.; Nishihara, Y. Org. Lett. 2000, 2, 2935–
2937.
553–562.
15. (a) Molina, P.; Arques, A.; Garcıa, A.; Ramırez de
ꢀ
ꢀ
Arellano, M. C. Tetrahedron Lett. 1997, 38, 7613–7616;
ꢀ
ꢀ
(b) Molina, P.; Arques, A.; Garcıa, A.; Ramırez de
Arellano, M. C. Eur. J. Inorg. Chem. 1998, 1359–1368.
ꢀ
8. Alonso, D. A.; Najera, C.; Pacheco, M. C. Tetrahedron
Lett. 2002, 43, 9365–9368.