Efficient iron/copper cocatalyzed alkynylation of aryl iodides with terminal alkynes

Article abstract of DOI:10.1021/jo801942h

(Equation Presented) We developed a highly efficient and practical protocol for the coupling of terminal alkynes with aryl iodides that is catalyzed by inexpensive and environmentally benign Fe/Cu. A broad spectrum of substrates can participate in the process effectively to produce desired products in good yields. The versatility, generality, low cost, and environmental friendliness, in combination with exceptionally high reaction rates, render this method particularly attractive for industrial applications.

Full text of DOI:10.1021/jo801942h

Efficient Iron/Copper Cocatalyzed Alkynylation of Aryl Iodides with
Terminal Alkynes
He Huang, Hualiang Jiang, Kaixian Chen, and Hong Liu*
Drug DiscoVery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences,
555 Zuchongzhi Road, Shanghai 201203, China
hliu@mail.shcnc.ac.cn
ReceiVed September 02, 2008
We developed a highly efficient and practical protocol for the coupling of terminal alkynes with aryl
iodides that is catalyzed by inexpensive and environmentally benign Fe/Cu. A broad spectrum of substrates
can participate in the process effectively to produce desired products in good yields. The versatility,
generality, low cost, and environmental friendliness, in combination with exceptionally high reaction
rates, render this method particularly attractive for industrial applications.
Introduction
with various aryl chlorides in the presence of a palladium
catalyst utilizing the P(Cy)2Ar as ligand to produce the coupling
product in good yields.6c However, the coupling reactions of
Cross-coupling reactions mediated by transition metals are
presently considered the cornerstones in the field of organic
synthesis.1 Reactions leading to C(sp)-C(sp2) bond formation
are often the key steps involved in a wide range of organic
processes.2 Among these, the Sonogashira-type reactions, which
involve the coupling of aryl or vinyl halides with terminal
alkynes, have been studied in detail as powerful tools for
preparing arylalkynes and conjugated enynes, which are the
precursors for natural products, pharmaceuticals, and molecular
organic materials.3 In the past decade, an effort was made to
develop efficient catalytic systems.4-7 A significant step toward
the development of the Sonogashira reaction was achieved by
Fu et al., who treated various aryl bromides with alkynes based
on the system (PhCN)2PdCl2/PtBu3/CuI at room temperature.5a
Gelman and Buchwald reported that phenylacetylene coupled
(4) For representative articles on the palladium-catalyzed Sonogashira cross-
coupling reactions, see: (a) Alonso, D. A.; Na´jera, C.; Pacheco, M. C. AdV. Synth.
Catal. 2003, 345, 1146. (b) Genin, E.; Amengual, R.; Michelet, V.; Savignac,
M.; Jutand, A.; Neuville, L.; Geneˆt, J. P. AdV. Synth. Catal. 2004, 346, 1733.
(c) Gil-Molto´, J.; Karlstro¨m, S.; Na´jera, C. Tetrahedron 2005, 61, 12168. (d)
Liang, B.; Dai, M.; Chen, J.; Yang, Z. J. Org. Chem. 2005, 70, 391. (e) Ko¨llhofer,
A.; Plenio, H. AdV. Synth. Catal. 2005, 347, 1295. (f) Soares do Re`go Barros,
O.; Favero, A.; Nogueira, C. W.; Menezes, P. H.; Zeni, G. Tetrahedron Lett.
2006, 47, 2179. (g) Li, P. H.; Wang, L. AdV. Synth. Catal. 2006, 348, 681. (h)
Guan, J. T.; Weng, T. Q.; Yu, G. A.; Liu, S. H. Tetrahedron Lett. 2007, 48,
7129.
(5) For representative articles on the palladium/copper system for the
Sonogashira cross-coupling reactions, see: (a) Hundertmark, T.; Littke, A. F.;
Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729. (b) Pal, M.; Subramanian,
V.; Parasuraman, K.; Yeleswarapu, K. R. Tetrahedron 2003, 59, 9563. (c) Nova´k,
Z.; Nemes, P.; Kotschy, A. Org. Lett. 2004, 6, 4917. (d) Dubbaka, S. R.; Vogel,
P. AdV. Synth. Catal. 2004, 346, 1793. (e) Tracey, M. R.; Zhang, Y.; Frederick,
M. O.; Mulder, J. A.; Hsung, R. P. Org. Lett. 2004, 6, 2209. (f) Garc´ıa, D.;
Cuadro, A. M.; Alvarez-Builla, J.; Vaquero, J. J. Org. Lett. 2004, 6, 4175. (g)
Zheng, S. L.; Reid, S.; Lin, N.; Wang, B. Tetrahedron Lett. 2006, 47, 2331. (h)
Mino, T.; Shirae, Y.; Saito, T.; Sakamoto, M.; Fujita, T. J. Org. Chem. 2006,
71, 9499. (i) Sessions, L. B.; Cohen, B. R.; Grubbs, R. B. Macromolecules 2007,
40, 1926.
(1) For recent reviews on this topic, see: (a) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. ReV. 2007, 107, 174. (b) Beccalli, E. M.; Broggini, G.;
Martinelli, M.; Sottocornola, S. Chem. ReV. 2007, 107, 5318. (c) Reetz, M. T.
Angew. Chem., Int. Ed. 2008, 47, 2556.
(2) For selected references, see: (a) Me´ry, D.; Heuze´, K.; Astruc, D. Chem.
Commun. 2003, 15, 1934. (b) Choudary, B. M.; Madhi, S.; Kantam, M. L.;
Sreedhar, B.; Iwasawa, Y. J. Am. Chem. Soc. 2004, 126, 2292. (c) Li, J. H.;
Zhang, X. D.; Xie, Y. X. Eur. J. Org. Chem. 2005, 4256. (d) Cwik, A.; Hell, Z.;
Figueras, F. Tetrahedron Lett. 2006, 47, 3023. (e) Ruiz, J.; Cutillas, N.; Lo´pez,
F.; Lo´pez, G.; Bautista, D. Organometallics 2006, 25, 5768. (f) Li, J. H.; Li,
J. L.; Wang, D. P.; Pi, S. F.; Xie, Y. X.; Zhang, M. B.; Hu, X. C. J. Org. Chem.
2007, 72, 2053. (g) Gonza´lez-Arellano, C.; Abad, A.; Corma, A.; Garc´ıa, H.;
Iglesias, M.; Sa´nchez, F. Angew. Chem., Int. Ed. 2007, 46, 1536.
(3) For recent reviews on the Sonogashira reaction, see: (a) Doucet, H.;
Hierso, J. C. Angew. Chem., Int. Ed. 2007, 46, 834. (b) Chinchilla, R.; Na´jera,
C. Chem. ReV. 2007, 107, 874. (c) Plenio, H. Angew. Chem., Int. Ed. 2008, 47,
6954.
(6) For representative articles on the Sonogashira cross-coupling reactions
of aryl chlorides with alkynes, see: (a) Eberhard, M. R.; Wang, Z. H.; Jensen,
C. M. Chem. Commun. 2002, 8, 818. (b) Choudary, B. M.; Madhi, S.; Chowdari,
N. S.; Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc. 2002, 124, 14127. (c)
Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42, 5993. (d)
Ko¨llhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem., Int. Ed. 2003, 42, 1056.
(e) Remmele, H.; Ko¨llhofer, A.; Plenio, H. Organometallics 2003, 22, 4098. (f)
Heuze´, K.; Me´ry, D.; Gauss, D.; Blais, J. C.; Astruc, D. Chem.-Eur. J. 2004,
10, 3936. (g) Protti, S.; Fagnoni, M.; Albini, A. Angew. Chem., Int. Ed. 2005,
44, 5675. (h) Yi, C. Y.; Hua, R. M. J. Org. Chem. 2006, 71, 2535. (i) Liang, Y.;
Xie, Y. X.; Li, J. H. J. Org. Chem. 2006, 71, 379. (j) Fleckenstein, C. A.; Plenio,
H. Organometallics 2007, 26, 2758. (k) Yi, W. B.; Cai, C.; Wang, X. Eur. J.
Org. Chem. 2007, 2007, 3445.
10.1021/jo801942h CCC: $40.75
Published on Web 10/21/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9061–9064 9061

Huang et al.
TABLE 1. Optimization of the Catalysis Conditions
entry
solvent
[Fe] cat.
[Cu] cat. (0.1 equiv)
liganda
yield (%)
1b
2c
3d
DMF
DMF
DMF
FeCl3
Fe2O3
Fe2O3
Cu(acac)2
Cu(acac)2
DMEDA
DMEDA
DMEDA
69
85
0
Fe(acac)3
4
DMF
DMF
DMF
DMF
DMF
toluene
DMSO
Cu(acac)2
DMEDA
DMEDA
48
0
5c
6c
7c
Fe2O3
Fe2O3
Fe2O3
Fe2O3
Fe2O3
Fe2O3
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
70
91
56
63
62
TMEDA
TMEDA
TMEDA
TMEDA
c e
,
8
9c
10c
a DMEDA ) N,N′-dimethylethylenediamine; TMEDA ) N,N,N′,N′-tetramethylethylenediamine. b 0.1 equiv of FeCl3 was used. c 0.1 equiv of Fe2O3
was used. d 0.1 equiv of Fe(acac)3 and 0.1 equiv of Fe2O3 were used. e NaOEt was used as base.
this type are usually performed using an expensive palladium
catalyst in the presence or absence of a copper(I) cocatalyst.
Iron complexes, which offer attractive industrial prospects in
terms of low price and environmentally benign features, used
alone or in combination with other metals,8,9 are rarely reported
to be used in the formation of this type of bond. Significant
progress in this field has been made very recently. Bolm et al.
demonstrated a novel iron-catalyzed arylation of terminal
alkynes by utilizing catalytic amounts of FeCl3 in conjunction
with N,N′-dimethylethylenediamine (DMEDA).8e Taillefer et al.
reported the Cu-catalyzed Sonogashira-type coupling using 0.3
equiv of 1,3-diphenylpropane-1,3-dione as the ligand.7b Vogel’s
group obtained similar results in the case of aryl iodides with
terminal alkynes catalyzed by Fe(acac)3 and CuI.10 Although
these methods are encouraging, there is a considerable scope
for improvement. For example, Bolm’s method requires long
reaction times (72 h), and the reaction of aliphatic alkyne was
less successful in this catalytic system. Furthermore, these
methods suffer from a relatively narrow scope of substrates.
No examples of the coupling of heterocyclic alkynes with aryl
halides or heterocyclic halides have been reported. Clearly, the
development of improved procedures in which more sustainable
catalysts and wide applications are used has remained an elusive
goal.
based on a simple and inexpensive method of iron-copper
cocatalysis. The reported reactions proceed in the presence of
a catalytic amount of [Cu(acac)2] (acac ) acetylacetonate) and
Fe2O3 to yield the products, and these conditions have been
employed for a wide range of substrates, including aliphatic
alkynes, heterocyclic alkynes, various substituted aryl alkynes,
and aryl iodides or heterocyclic iodides.
As reported in previous studies, the Sonogashira-type reaction
proceeded more rapidly in the presence of more electron-poor
halides.3 For our initial experiments, we chose to study the cross-
coupling of phenylacetylene and p-iodoanisole, a relatively
challenging test substrate because of its electron richness, as
the model reaction for screening the catalyst and optimizing
the reaction conditions. As illustrated in Table 1, the preliminary
survey was carried out in N,N-dimethylformamide (DMF) at
135 °C using cesium carbonate as a base. The coupling reaction
provided promising results in the presence of catalytic amounts
of both [Cu(acac)2] and FeCl3 (69% yield; Table 1, entry 1).
Remarkably, the yield afforded by Fe2O3 was better than that
afforded by FeCl3 (85% yield; Table 1, entry 2). We observed
that there was no coupling when [Cu(acac)2] was replaced by
[Fe(acac)3] (Table 1, entry 3). In the absence of an iron source,
catalytic amounts of [Cu(acac)2] afforded a moderate yield of
the coupling product (48% yield; Table 1, entry 4). However,
the catalytic amount of Fe2O3 was unable to promote the reaction
in the absence of a copper source (Table 1, entry 5), indicating
that the nature of the copper source had a pronounced impact
on this process (Table 1, entries 1-3 and 5). In addition, the
use of [Cu(acac)2] appears to be important for the reaction to
proceed (Table 1, entries 1-5). Remarkably, switching the
ligand DMEDA with cheaper tetramethylethylenediamine (TME-
DA) led to a superior yield (Table 1, entries 6 and 7). The more
effective base among those that we surveyed is Cs2CO3 (Table
1, entries 7 and 8). Previous studies indicated that toluene,
dimethyl sulfoxide (DMSO), and DMF were the most effective
solvents for the Sonogashira-type coupling reactions.2f,6d,7
Further optimization of these reaction conditions revealed that
DMF was superior to others solvents (Table 1, entries 7, 9, and
10).
Results and Discussion
In this study, we report a general and practical method for
the coupling of terminal alkynes with aryl iodides, which is
(7) For representative articles on the copper-catalyzed Sonogashira cross-
coupling reactions, see: (a) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D.
Org. Lett. 2001, 3, 4315. (b) Monnier, F.; Turtaut, F.; Duroure, L.; Taillefer, M.
Org. Lett. 2008, 10, 3203. (c) Bates, C. G.; Saejueng, P.; Murphy, J. M.;
Venkataraman, D. Org. Lett. 2002, 4, 4727. (d) Okuro, K.; Furune, M.; Enna,
M.; Miura, M.; Nomura, M. J. Org. Chem. 1993, 58, 4716. (e) Okuro, K.;
Furuune, M.; Miura, M.; Nomura, M. Tetrahedron Lett. 1992, 33, 5363.
(8) For recent representative articles on the Fe- or Fe/Cu-catalyzed coupling
reactions, see: (a) Taillefer, M.; Xia, N.; Ouali, A. Angew. Chem., Int. Ed. 2007,
46, 934. (b) Taillefer, M.; Xia, N.; Ouali, A. U.S. Patent 60/818,334, 2006. The
application field described also concerns C-C, C-O, C-S, and C-P bond
formation. (c) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008,
47, 2880. (d) Bistri, O.; Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47,
586. (e) Carril, M.; Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 4862.
(f) Volla, C. M. R.; Vogel, P. Angew. Chem., Int. Ed. 2008, 47, 1305.
(9) For representative reviews on iron-catalyzed coupling reactions, see: (a)
Correa, A.; Manchen˜o, O. G.; Bolm, C. Chem. Soc. ReV. 2008, 37, 110. (b)
Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104, 6217.
(10) Volla, C. M. R.; Vogel, P. Tetrahedron Lett. 2008, 49, 5961.
Under our optimized reaction conditions (0.1 equiv of
[Cu(acac)2], 0.1 equiv of Fe2O3, 0.2 equiv of TMEDA, 1.0 equiv
of Cs2CO3, and DMF, 135 °C, 16 h), we accomplished
9062 J. Org. Chem. Vol. 73, No. 22, 2008

Iron/Copper Cocatalyzed Alkynylation of Aryl Iodides
TABLE 2. Sonogashira-Type Coupling of Aryl Iodides ArI with Alkynes RCt CHa
a Reaction conditions: 0.1 equiv of [Cu(acac)2], 0.1 equiv of Fe2O3, 0.2 equiv of TMEDA, 1.0 equiv of Cs2CO3, DMF, 135 °C, 16 h.
Sonogashira-type cross-couplings of a wide array of electroni-
cally and structurally diverse aryl halides.
poor aryl iodides reacted with alkynes to provide excellent yields
of the reaction products. Remarkably, even extremely electron-
rich aryl iodides coupled efficiently with alkynes in the presence
of this catalytic system (Table 2, entries 2-4, 14, and 20).
Although sterically hindered substrates are often problematic,3
it is also tolerant of ortho substitution in aryl iodides without
any difficulty (Table 2, entries 4, 7, 10, 17, and 25). In further
As shown in Table 2, the corresponding products were
obtained in good to excellent yields. Consistent with the results
of previous studies, bromobenzene was found to be less efficient
than iodobenzene (Table 2, entry 1).3 The electronic effects on
the reactions were limited. Both electron-neutral and electron-
J. Org. Chem. Vol. 73, No. 22, 2008 9063

Huang et al.
experiments for establishing the scope of this method, we
investigated the cross-coupling of alkynes with heterocyclic
iodides, thus allowing access to heterocyclic alkyne derivatives
which are present in numerous appealing compounds. Pyridyl
iodide was found to afford excellent yields of the corresponding
products (Table 2, entries 11, 18, and 24). The use of less
reactive thienyl iodide resulted in moderate yields (Table 2,
entries 12 and 19). Notably, both the aryl alkynes and aliphatic
alkynes were effective in the formation of the C(sp)-C(sp2)
bond (Table 2, entries 1-19). More remarkable is the efficient
coupling between 2-ethynylpyridine and electron-rich, electron-
neutral, electron-deficient, and heterocyclic aryl iodides (Table
2, entries 20-24). Furthermore, sterically demanding ortho
substituents did not hamper the coupling, and good yields were
obtained (Table 2, entry 25). These successful reactions reveal
that the present catalytic system is also effective for the cross-
coupling reactions of aryl iodides with heterocyclic alkynes. In
general, it is remarkable that all reactions were very clean, and
the desired products were obtained in high yields without
undesirable amounts of alkyne homocoupling products, which
were often generated in the presence of copper(I).1
rates, render this method particularly attractive for industrial
applications.
Experimental Section
General Procedure for the Synthesis of 3a (Table 2, Entry
1). A mixture of 1-iodobenzene (51 µL), phenylacetylene (50 µL),
and Cs2CO3 (148 mg) was dissolved in DMF (1.5 mL). Subse-
quently, 0.1 equiv of Cu(acac)2, 0.1 equiv of Fe2O3, and 0.2 of
equiv TMEDA were added to this mixture. The vial was sealed,
and this mixture was then heated in an oil bath for 16 h at 135 °C.
The reaction was then cooled to ambient temperature, and the crude
reaction mixture was diluted with ethyl acetate and filtered through
celite. The filtrate was washed twice with brine, and the combined
aqueous phases were extracted with ethyl acetate. The organic layers
were dried using Na2SO4, concentrated, and purified by flash column
chromatography (petroleum ether/ethyl acetate) to yield the expected
1
product. The data obtained are as follows. H NMR (300 MHz,
CDCl3): δ 7.57-7.54 (m, 4H), 7.40-7.35 (m, 6H). 13C NMR (100
MHz, CDCl3): δ 131.5, 128.3, 128.2, 123.2, 89.351. MS (EI, m/z):
178 [M]+. HRMS (EI) calcd for C14H10 [M]+, 178.0783; found,
178.0791.
Acknowledgment. We gratefully acknowledge financial
support from the State Key Program of Basic Research of China
(Grant 2006BAI01B02), the National Natural Science Founda-
tion of China (Grants 20721003 and 20872153), and the 863
Hi-Tech Program of China (Grants 2006AA020602).
Conclusions
In summary, we developed a highly efficient and practical
protocol for the coupling of terminal alkynes with aryl iodides
that is catalyzed by the inexpensive and environmentally benign
Fe/Cu to create the C(sp)-C(sp2) bond. A broad spectrum of
substrates can participate in the process effectively under the
optimized conditions to produce good yields of the desired
products. The versatility, generality, low cost, and environmental
friendliness, in combination with exceptionally high reaction
Supporting Information Available: Detailed experimental
procedures and compound characterization data for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801942H
9064 J. Org. Chem. Vol. 73, No. 22, 2008