Efficient and General Protocol for the Copper-Free Sonogashira Coupling of Aryl Bromides at Room Temperature

Article abstract of DOI:10.1021/ol035632f

(Equation presented) A mild and general protocol for the copper-free Sonogashira coupling of aryl bromides with acetylenes has been developed. The use of (AllylPdCl)₂ and P(t-Bu)₃ provides the active Pd(0) catalyst that allows subseq

Full text of DOI:10.1021/ol035632f

ORGANIC
LETTERS
2003
Vol. 5, No. 22
4191-4194
Efficient and General Protocol for the
Copper-Free Sonogashira Coupling of
Aryl Bromides at Room Temperature
Arash Soheili,* Jennifer Albaneze-Walker, Jerry A. Murry, Peter G. Dormer, and
David L. Hughes
Department of Process Research, Merck Research Laboratories, Merck & Co., Inc.,
P.O. Box 2000, Rahway, New Jersey 07065
arash_soheili@merck.com
Received August 27, 2003
ABSTRACT
A mild and general protocol for the copper-free Sonogashira coupling of aryl bromides with acetylenes has been developed. The use of
(AllylPdCl)2 and P(t-Bu)3 provides the active Pd(0) catalyst that allows subsequent coupling of various alkynes at room temperature with good
to excellent yields.
We recently required an efficient and general method to
effect the Sonogashira coupling1 of terminal acetylenes with
aryl bromides. We desired conditions that would be practical,
amenable to large-scale synthesis and allow for substrate
generality. Typical literature procedures for Sonogashira
couplings utilize catalytic palladium with a metal cocatalyst
and a base.2 The most widely employed cocatalysts are cop-
per salts, which can suffer from Glaser-type homocoupling
of the alkyne.3 This is a major problem when the supply of
acetylene is limited or expensive. In our hands, this was a
significant issue that could not be overcome by manipulating
the reaction conditions. The use of other metal cocatalysts
such as zinc, tin, boron, or aluminum have been developed
to address this issue.4 Unfortunately, most of these procedures
require stoichiometric metal, which is a concern in terms of
toxicity, cost, and product purity. Additionally, these condi-
tions usually require low temperature and strong bases, which
limits the functionality that can be present in the coupling
partners.
cal procedure that involved utilizing the Fu catalyst (gener-
ated from Pd2dba3 and P(t-Bu)3 in a 1:1 ratio) in neat
triethylamine.5c In our hands, we observed extensive oligo-
merization of the acetylene when employing these conditions
(2) For recent advances in Sonogashira coupling, see: (a) Hundertmark,
T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729-
1731. (b) Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002, 4, 1411-
1414. (c) Mori, A.; Shimada, T.; Kondo, T.; Sekiguch, A. Synlett 2001,
649-651. (d) Bumagin, N. A.; Sukhomlinova, L. I.; Luzikova, E. V.;
Tolstaya, T. P.; Beletsdaya, I. P. Tetrahedron Lett. 1996, 37, 897-900. (e)
Radhakrishnan, U.; Stang, P. J. Org. Lett. 2001, 3, 859-860. (f) Mori, A.;
Ahmed, M. S. M.; Sekiguchi, A.; Masui, K.; Koike, T. Chem. Lett. 2002,
756-757. (g) Alammi, M.; Crousse, B.; Ferri, F. J. Organomet. Chem.
2001, 624, 114-123. (h) Crisp, G. T.; Turner, P. D.; Stephens, K. A. J.
Organomet. Chem. 1998, 570, 219-224. (i) Negishi, E.; Anastasia, L. Org.
Lett. 2003, 5, 1597-1600. (j) Langille, N. F.; Dakin, L. A.; Panek, J. S.
Org. Lett. 2002, 4, 2485-2488. (k) Gelman, D.; Tsvelikhovsky, D.;
Molander, G. A.; Blum, J. J. Org. Chem. 2002, 67, 6287-6290. (l) Yang,
C.; Nolan, P. Organometallics 2002, 21, 1020-1022. (m) Kollhofer, A.;
Pullmann, T.; Plenio, H. Angew. Chem., Int. Ed. Engl. 2003, 42, 1056-
1057. (n) Novak, Z.; Szabo, A.; Repasi, J.; Kotschy, A. J. Org. Chem. 2003,
68, 3327-3329. (o) Elangovan, A.; Wang, Y.; Ho, T. Org. Lett. 2003, 5,
1841-1844. (p) Mori, Y.; Seki, M. J. Org. Chem. 2003, 68, 1571-1574.
(q) Choudary, B. M.; Madhi, S.; Chowdari, N. S. J. Am. Chem. Soc. 2002,
124, 14127-14136. For an analogous Ni-catalyzed Sonogashira, see: (r)
Beletskaya, I. P.; Latyshev, G. V.; Tsvetkov, A. V.; Lukashev, N. V.
Tetrahedron Lett. 2003, 44, 5011-5013.
Sonogashira reactions that do not utilize cocatalysts have
been reported.5 Herrmann and co-workers disclosed a practi-
(3) (a) Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 42-424 (b) Hay, A.
S. J. Org. Chem. 1962, 27, 3320-3321. (c) Rossi, R.; Carpita, A.; Begelli,
C. Tetrahedron Lett. 1985, 26, 523-526. (d) Liu, Q.; Burton, D. J.
Tetrahedron Lett. 1997, 38, 4371-4374. (e) For a review of alkyne coupling,
see: Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed.
2000, 39, 2632-2657.
(1) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467-4470. (b) Takahashi, K.; Kuroyama, Y.; Sonogashira, K.;
Hagihara, N. Synthesis 1980, 627-630. (c) For a general review, see:
Sonogashira, K. In Metal Catalyzed Cross-Coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter 5.
10.1021/ol035632f CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/27/2003

to electron-rich aryl bromides. Slow addition of the acetylene
to the reaction mixture minimizes this side reaction, which
is in agreement with the observations of Herrmann. More
recently, Andrus has described a Pd carbene complex that
also catalyzes a copper-free version of this reaction.5i Despite
these recent advances, there still remained a need for a
general protocol that would efficiently broaden the scope of
this important reaction. In this manuscript, we disclose the
results of a systematic investigation of the copper-free Sono-
gashira reaction and a general procedure for the coupling of
a variety of aryl bromides with terminal acetylenes.
Table 1. Base-Dependent Conversion in the Copper-Free
Sonogashira Coupling of Phenylacetylene and
Bromoacetophenonea
entry
base
timeb
yield (%)c
6
Initial results revealed that Pd[P(t-Bu)3]2 and 2 equiv of
1
2
3
4
5
6
7
8
9
10
11
12
15
16
Bu-NH2
t-Bu-NH2
46 h
9 h
7 h
4 h
8 h
3 h
4 h
5 h
1.5 h
0.5 h
5 days
24 h
24 h
2 h
51
95
99
99
99
99
30
79
99
99
85
0
amine base in DMF afforded coupled products at room
temperature with activated aryl bromides. Due to the thermal
instability of the isolated palladium complex,7 we required
a robust method for the in situ formation of the active
catalyst. We were pleased to find that we could obtain the
same catalytic activity as the isolated Pd complex with a
solution of (AllylPdCl)2 and P(t-Bu)3 in a 1:2 ratio of Pd to
phosphine.
Utilizing a DMF solution of catalyst prepared in this man-
ner, we next examined the effect of base in the model coup-
ling of phenylacetylene with bromoacetophenone in DMF.
Several bases ranging from primary to tertiary amines
afforded excellent yields (entries 2-6 and 9-10). Reaction
rates were noted to increase with more hindered bases such
as tert-butylamine and tetramethyl piperidine (entry 1 vs 2
and entry 3 vs 4). Employing Herrmann’s conditions (entries
7 and 8), we observed decomposition of the phenylacetylene8
before all of the aryl halide was consumed. DABCO and
quinuclidine afforded the fastest reaction rates, with complete
conversion in 1.5 and 0.5 h, respectively. Cesium carbonate
also resulted in rapid conversion and good yield (entry 16).
We were also pleased to discover that the reaction proceeds
in excellent conversion in a variety of solvents ranging from
nonpolar toluene to amide solvents and even in an alcoholic
solvent such as ethanol.
piperidine
tetramethyl piperidine
morpholine
(i-pr)2NH
(i-pr)2EtN
Et3N
DABCO
quinuclidine
tetramethyl guanidine
DBU
HMDS
Cs2CO3
49
90
a All reactions were run in 0.92 M DMF with 1 equiv of aryl halide, 1.1
equiv of acetylene, 2.5 mol % (AllylPdCl)2, 10 mol % phosphine, and 2
equiv of base. b Complete consumption of aryl halide by HPLC. c HPLC
assay yield.
excellent yields with both aryl and alkyl acetylenes (entries
1-5). We were also able to couple bromobenzene and even
bromoanisole with aryl and alkyl acetylenes using DABCO11
(entries 6-9). Sterically demanding 2-bromoxylene coupled
with phenylacetylene in excellent yield (entry 10). In
addition, heterocyclic compounds such as 3-bromopyridine
and 3-bromothiophene coupled with phenylacetylene in good
yield (entry 11 and 13). Notably, 3-bromopyridine-N-oxide
coupled in excellent yield without reduction to the pyridine
(entry 12). We have also investigated the coupling of
activated aryl chlorides and observed that the reaction can
proceed at 80 °C with slow addition of the acetylene (entry
14). Decomposition of the alkyne is currently a limitation
of the methodology for coupling of aryl chlorides.
Next, we chose to investigate the coupling of a variety of
terminal acetylenes with aryl bromides in acetonitrile9 (Table
2).10 Electron-deficient aryl bromides coupled with good to
(4) (a) For recent reviews on alkyne cross-coupling, see: (a) Sonogashira,
K. J. Organomet. Chem. 2002, 653, 46-49. (b) Tykwinski, R. R. Angew.
Chem., Int. Ed. 2003, 42, 1566-1568. (c) Negishi, E.; Anastasia, L. Chem.
ReV. 2003, 103, 1979-2017.
With a viable protocol in hand, we turned our attention
toward the mechanism of this reaction. Although the copper-
(5) (a) Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993,
34, 6403-6406. (b) Nguefack, J.; Bolitt, V.; Sinou, D. Tetrahedron Lett.
1996, 37, 5527-5530. (c) Herrmann, W. A.; Bohm Volker, P. W. Eur. J.
Org. Chem. 2000, 22, 3679-3681. (d) Ryu, I.; Fukuyama, T.; Shinmen,
M.; Nishitani, S.; Sato, M. Org. Lett. 2002, 4, 1691-1694. (e) Pal, M.;
Parasuraman, K.; Gupta, S.; Yeleswarapu, K. R. Synlett 2002, 12, 1976-
1982. (f) Alonso, D.; Najera, C.; Pacheco, M. C. Tetrahedron Lett. 2002,
43, 9365-9368. (g) Fu, X.; Zhang, S.; Yin, J.; Schumacher, D. P.
Tetrahedron Lett. 2002, 43, 6673-6676. (h) Uozumi, Y.; Kobayashi, Y.
Heterocycles 2003, 59, 71-74. (i) Ma, Y.; Song, C.; Jiang, W.; Wu, Q.;
Wang, Y.; Liu, X.; Andrus, M. B. Org. Lett. 2003, ASAP.
(9) Due to convenient workup, we chose acetonitrile in preference to
DMF to continue our investigation.
(10) Typical Procedure (Table 2, entry 2). Methyl 4-bromobonzoate
(0.46 g, 2.12 mmol) and (AllylPdCl)2 (0.019 g, 0.053 mmol) was added to
a dry Schlenk tube and sealed with a rubber septum. The vessel was
degassed then backfilled with nitrogen in three repetitions followed by
addition of acetonitrile (2.5 mL). Then, P(t-Bu)3 (0.64 mL of a 10 wt %
solution in hexanes, 0.21 mmol), phenylacetylene (0.26 mL, 2.33 mmol),
and piperidine (0.42 mL, 4.24 mmol) were added in that order via a syringe
to the stirred reaction mixture. During the reaction, the precipitation of
piperidine bromide salt was observed. After completion of reaction, as
determined by complete HPLC consumption of aryl halide, EtOAc (10 mL)
and water (5 mL) were added to the reaction mixture. The layers were
separated, and the aqueous layer was extracted with 2 × 10 mL of EtOAc.
The organic layers were combined and then washed with brine, dried with
sodium sulfate, and concentrated. Purification by flash chromatography (95:5
hexanes/EtOAc) furnished the desired product (0.46 g, 92%) as a solid.
(11) Prolonged reaction times (2 days) and incomplete conversion
(∼90%) was observed when using piperidine as the base.
(6) Purchased from Strem Chemicals. For use of Pd[P(t-Bu)3]2 in
palladium cross-coupling reactions, see: (a) Littke, A. F.; Schwarz, L.; Fu,
G. C. J. Am. Chem. Soc. 2002, 124, 6343-6348. (b) Netherton, M. R.; Fu,
G. C. Org. Lett. 2001, 3, 4295-4298.(c) Dai, C.; Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 2719-2724. (d) Littke, A. F.; Dai, C.; Fu, G. C. J. Am.
Chem. Soc. 2000, 122, 4020-4028.
(7) Gray/brown discoloration of catalyst over time was observed when
stored in the glovebox or in the freezer.
(8) Attempts to identify the product of acetylene decomposition by HPLC,
1H, and 13C NMR revealed only poorly resolved polymeric material.
4192
Org. Lett., Vol. 5, No. 22, 2003

Scheme 1. Proposed Catalytic Cycle of Copper-Free
Table 2. Copper-Free Sonogashira Coupling of Various Aryl
Bromides with Aryl and Alkyl Acetylenes
Sonogashira Coupling
Drawing from the literature, we envisioned the following
catalytic cycle (Scheme 1).
The cycle is proposed to initiate by the generation of
palladium complex I followed by oxidative addition with
the aryl bromide to complex II. Then, ligand dissociation
followed by complexation with acetylene leads to complex
III with subsequent deprotonation to provide intermediate
IV. This species undergoes isomerization followed by
reductive elimination to provide product and turn over the
catalytic cycle.
We desired evidence about the formation of active catalyst
generated by the in situ protocol. Although this procedure
has been previously employed,13 details of the active cata-
lyst have not been described. We decided to probe the
catalyst formation utilizing NMR spectroscopy. Upon mixing
(AllylPdCl)2 and phosphine in a 1:2 ratio of Pd/phosphine
in CD3CN,14 we observed the immediate precipitation of a
white solid, which was identified as the Pd[P(t-Bu)3]2 com-
plex15 (Scheme 2). In the yellow supernatant solution was
observed the allylphosphonium salt16 3 and free P(t-Bu)3 by
31P NMR. Therefore, we rationalize that initially the phos-
(12) For mechanism of the copper-catalyzed Sonogashira coupling, see:
(a) Osakada, K.; Sakata, R.; Yamamoto, T. Organometallics 1997, 16,
5354-5364. (b) Espinet, P.; Fornies, J.; Martinez, F.; Sotes, M.; Lalinde,
E.; Moreno, M. T.; Ruiz, A.; Welch, A. J. J. Organomet. Chem. 1991,
403, 253-267.
(13) Denmark, S. E.; Wu, Z. Org. Lett. 1999, 1, 1495-1498.
(14) In a glovebox P(t-Bu)3HBF4 (17.7 mg, 0.060 mmol), (AllylPdCl)2
(5.6 mg, 0.015 mmol), and DABCO (7.0 mg, 0.060 mmol) were charged
to a dry NMR tube followed by addition of CD3CN (0.6 mL). The solution
immediately turned yellow with the precipitation of a white solid. The NMR
tube was then sealed and removed from the glovebox.
(15) Both 1H and 31P NMR matched the commercially purchased material
from Strem Chemicals. Pd[P(t-Bu)3]2 is not soluble in acetonitrile or DMF
but has high solubility in toluene and benzene.
a Complete consumption of aryl halide by HPLC. b Isolated yield of
product with g98% purity. c Performed with 1.4 equiv of acetylene.
d Performed with 2 equiv of acetylene in DMAc at 80 °C.
(16) Allychloride and P(t-Bu)3 react in acetonitrile to make allylphos-
phonium chloride only at elevated temperatures. No reaction is observed
at room temperature. This suggests that the formation of allylphosphonium
chloride in the reaction comes from a π-allyl Pd species that is more
activated for nucleophilic attack by the phosphine.
catalyzed Sonogashira has been investigated,12 the mecha-
nism of the copper-free variant has not been described.
Org. Lett., Vol. 5, No. 22, 2003
4193

halide, acetylene, and base.18 Since a rate dependence on
aryl bromide is observed, we conclude that the resting state
of the catalyst is not complex II but rather a low-valent
Pd(0) coordination complex such as I. Also, since it has been
shown that oxidative insertion and ligand dissociation are
reversible pathways,19 we propose that the rate-limiting step
in the catalytic cycle is formation of the σ bound Pd(II)
acetylide complex IV. We are currently continuing to
investigate the mechanism of this reaction.
Scheme 2. Active Palladium Catalyst Formation
In conclusion, we have developed a practical and mild
copper-free Sonogashira coupling of aryl bromides at room
temperature. The reaction proceeds in excellent yield with
activated and electron-rich aryl bromides with aromatic and
aliphatic acetylenes. Current work is focused on extending
the scope to aryl chlorides and further probing the mechanism
of this important reaction.
phine reacts with the (AllylPdCl)2 to form the monophos-
phine Pd(II) species 1 that further reacts with another
phosphine to form allylphosphonium chloride and the active
Pd-L catalyst.17 In the presence of an aryl halide, oxidative
insertion provides the monophosphine Ar-Pd(II)-X com-
plex 2 (Scheme 2).
We have conducted preliminary kinetic experiments on
bromoacetophenone and phenylacetylene using DABCO and
observed a rate dependence on the concentration of aryl
Acknowledgment. We thank Prof. Greg Fu, Prof. Jack
Norton, Dr. Cecile Savarin, and Dr. Remy Angelaud for
helpful discussions and suggestions.
Supporting Information Available: Experimental pro-
cedures for products in Table 2 and kinetic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL035632F
(18) See Supporting Information for full details.
(19) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 1232-
1233.
(17) Pd-L species has been rationalized by Fu, Hartwig, Buchwald, and
others as the active species in many coupling reactions.
4194
Org. Lett., Vol. 5, No. 22, 2003