Copper-catalyzed Sonogashira-type reactions under mild palladium-free conditions

Article abstract of DOI:10.1021/ol801025u

(Chemical Equation Presented) We have developed an inexpensive catalytic system using a readily available copper/ligand combination for the Sonogashira-type cross-coupling of aryl iodides and phenyl- and hexyl-acetylene which affords disubstituted alkynes

Full text of DOI:10.1021/ol801025u

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3203-3206
Copper-Catalyzed Sonogashira-Type
Reactions Under Mild Palladium-Free
Conditions
Florian Monnier,* Franc¸ois Turtaut, Leslie Duroure, and Marc Taillefer*
´
Ecole Nationale Supe´rieure de Chimie de Montpellier, Institut Charles Gerhardt
Montpellier, CNRS UMR 5253, Architectures Mole´culaires et Mate´riaux
Nanostrucuture´s, 8 rue de l’Ecole Normale, 34296 Montpellier, Cedex 05 France
florian.monnier@enscm.fr; marc.taillefer@enscm.fr
Received May 12, 2008
ABSTRACT
We have developed an inexpensive catalytic system using a readily available copper/ligand combination for the Sonogashira-type cross-
coupling of aryl iodides and phenyl- and hexyl-acetylene which affords disubstituted alkynes in good to excellent yields.
After a spectacular resurgence of interest at the turn of this century,
Ullmann-type coupling in its catalytic version is becoming a very
competitive method for synthesis of aryl-nucleophile bonds with
various sources of C-, O-, N-, P-, and S-nucleophiles.1 Since 2001,
we have demonstrated in previous reports2 and patents3 that
combinations of copper salts and ligands (oximes, Schiff bases,
bipyridines, phenanthrolines, diketones, butadienyl phosphines) are
highly efficient catalytic systems for the formation of aryl-hetero-
atom bonds such as C-O, C-N, and also C-C bonds. To the
best of our knowledge, these methods are often among the mildest
ever described in the literature. As part of our goal of developing
a “tool box” of copper-based catalysts for cross-coupling reactions,
we are very much interested in suitable methods for C-C bond
formation between aryl halides and terminal aryl- and alkyl-alkynes
to afford the corresponding disubstituted alkynes.4 Here we report
an efficient catalysis of such reactions with a Cu(acac)2/ꢀ-diketone
catalyst in DMF at 90-120 °C using K2CO3 as an inexpensive
base (Scheme 1).
(1) For general reviews on Ullmann-type reaction, see: (a) Ley, S. V.;
Thomas, A. W. Angew.Chem., Int. Ed. 2003, 42, 5400. (b) Beletskaya, I. P.;
Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337. (c) Corbet, J.-P.;
Mignani, G. Chem. ReV. 2006, 106, 2651. (d) Monnier, F.; Taillefer, M.
Angew.Chem., Int. Ed. 2008, 47, 3096.
(2) For applications of our copper-based catalytic systems, see: (a)
Taillefer, M.; Xia, N.; Ouali, A. Angew. Chem., Int. Ed. 2007, 47, 934. (b)
Ouali, A.; Taillefer, M.; Spindler, J.-F.; Jutand, A. Organometallics 2007,
26, 65. (c) Ouali, A.; Spindler, J.-F.; Jutand, A.; Taillefer, M. AdV. Synth.
Catal. 2007, 349, 1906. (d) Ouali, A.; Laurent, R.; Caminade, A.-M.;
Majoral, J.-P.; Taillefer, M. J. Am. Chem. Soc. 2006, 128, 15990. (e)
Taillefer, M.; Ouali, A.; Renard, B.; Spindler, J.-F. Chem. Eur. J. 2006,
12, 5301. (f) Cristau, H.-J.; Ouali, A.; Spindler, J.-F.; Taillefer, M. Chem.
Eur. J. 2005, 11, 2483. (g) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.;
Taillefer, M. Eur. J. Org. Chem. 2004, 695. (h) Cristau, H.-J.; Cellier, P. P.;
Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10, 5607.
Scheme 1. Reactions of Aryl Iodides with Terminal Alkynes
Catalyzed by a Copper/Ligand Combination
(3) For patents, see: (a) Taillefer, M.; Cristau, H.-J.; Cellier, P. P.;
Spindler, J.-F. Fr 2833947-WO 0353225 (Pr. Nb. Fr 01 16547). 2001; Chem.
Abstr. 2003, 139, 69290. (b) Taillefer, M.; Cristau, H.-J.; Cellier, P. P.;
Spindler, J.-F.; Ouali, A. 2840303-WO 03101966 (Pr. Nb. Fr 02 06717),
2002; Chem. Abstr. 2004, 140, 16744. (c) Taillefer, M.; Kaddouri, H.;
Ouazzani, F. FR 0706826, 2007. (d) Taillefer, M.; Xia, N. FR 0706827,
2007.
This novel method is economically attractive since, in
contrast to almost all of the traditional Pd/Cu-cocatalyzed
Sonogashira coupling reactions, it does not use any palladium.5
10.1021/ol801025u CCC: $40.75
Published on Web 06/28/2008
2008 American Chemical Society

Initially, we chose as a model reaction for method
development the coupling of 4′-iodoacetophenone 1 with
phenylacetylene 2 where we found that in the absence of
supporting ligand L the reaction gave 1,4-diphenylbuta-1,3-
diyne 2′ as the only product from homocoupling of 2 through
a Glaser-type reaction (Table 1, entry 1).6
coupling. Similarly, the ꢀ-hydroxy ketone L8 and acetylac-
etone L3 also give disappointing results. On the other hand,
other ꢀ-diketones such as L4-L77 are active for this
Sonogashira cross-coupling reaction. Moreover, 1,3-diphe-
nylpropane-1,3-dione L7 easily appears to be the most
efficient of the ligands tried. Moreover, Cu(acac)2 showed
the best activity compared with other copper sources such
as CuI and Cu(OAc)2 (entries 8, 16, and 24). In a second
set of experiments (Table 2), we examined the influence of
Table 1. Reaction of Phenylacetylene 2 with
4′-Iodoacetophenone 1 Catalyzed by Different Cu/L
Combinations
Table 2. Influence of the Base on the Cross-Coupling between
4′-Iodoacetophenone 1 and Phenylacetylene 2
entry
basea
3b
1
2
3
4
5
6
K2CO3
Cs2CO3
K3PO4
NaOH
pyridine
94
48
75
7
0
96
c
K2CO3
a All reactions except entry 6 were performed with: 1 (0.5 mmol), 2
(0.75 mmol), [Cu(acac)2] (0.05 mmol), L7 (0.15 mmol), base (1 mmol), 1
mL of DMF, 24 h, 120 °C. b Yields established by GC-MS with
1,3-dimethoxybenzene as internal standards. c 1 (0.55 mmol), 2 (0.5 mmol),
[Cu(acac)2] (0.05 mmol), L7 (0.15 mmol), base (1 mmol), 1 mL of DMF,
24 h, 90 °C.
entry
[Cu]a
L
3b
0c
1
2
3
4
5
6
7
8
Cu(acac)2
Cu(acac)2
–
L1
L2
L3
L4
L5
L6
L7
L8
L1
L2
L3
L4
L5
L6
L7
L8
L1
L2
L3
L4
L5
L6
L7
L8
40
52
28
66
81
78
94
41
36
47
10
50
70
65
80
>50
40
48
11
54
75
60
84
45\
“
“
“
“
“
“
“
altering the base on the best result from Table 1. This
confirms that K2CO3 was the best of the bases tried for both
yield and selectivity. Protic and organic bases such as NaOH
and pyridine were totally inefficient. In addition, the solvents
DMF, toluene, acetonitrile (at 80 °C), and dioxane were tried,
affording 94, 0, 10, and 5%, respectively, of the desired
coupling product 3.
At this stage in the investigation, we were pleased to have
found an efficient system for cross-coupling aryl iodides with
terminal alkynes. However, we were also seeking more
attractive reaction conditions in terms of elapsed time and
temperature.
Further research demonstrated that good yields could be
maintained at significantly lower temperatures simply by
reversing the reagent in excess (Table 2, entry 6): a slight
excess of aryl iodide 1 (1.1 equiv for every 1 equiv of
terminal alkyne 2, instead of the previous ratio of 1:1.5)
affords a similar yield of 3 at only 90 °C.
Next, we explored the breadth of application of this new
method. By using the conditions optimized on the model
reaction, we were able to apply this new method to a broad
range of targets, including terminal aryl- and alkylacetylenes
and also aryl iodides substituted by electron-withdrawing and
electron-donating groups (Table 3). Aryl iodides activated
by electron-withdrawing groups are coupled with terminal
alkynes at 90 °C (entries 1-8) in good to excellent yields,
while iodobenzene and aryl iodides deactivated by donating
substituents require higher temperatures around 120 °C
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
CuI
“
“
“
“
“
“
“
Cu(OAc)2
“
“
“
“
“
“
“
a All reactions were performed with: 4′-iodoacetophenone (0.5 mmol),
phenylacetylene (0.75 mmol), [Cu] (0.05 mmol), L (0.15 mmol), K2CO3
(1 mmol), 1 mL of DMF, 24 h. b Yields established by GC-MS with 1,3-
dimethoxybenzene as the internal standard. c Isolated yield of 1,4-diphe-
nylbuta-1,3-diyne 2′ (resulting from the homocoupling of 2): 70%.
Then we examined the efficiency of using various copper
salts in combination with ligands L1-L8 and K2CO3 at 120
°C. Table 1 demonstrates that ligands L1-L2, which are
usually highly efficient for C-N and C-O coupling reac-
tions,2,3 gave only moderate yields for alkyne C-C cross-
3204
Org. Lett., Vol. 10, No. 15, 2008

Table 3. Coupling Products from Aryl Iodides with Aryl- and
Alkyl-alkynes
Figure 1. Possible working mechanism for the palladium-free
Sonogashira reaction.
intermediate (2). The latter would react by oxidative addition
with the aromatic halide to form a four-coordinated cop-
per(III) complex from which the cross-coupling product is
expelled and the catalytic active species is reformed by
reductive elimination. Note that the copper(III) intermediate
could be of neutral (3) or cationic (4) type.
Thus, we have discovered a mild and efficient catalysis
of Sonogashira-type reactions using an easily handled Cu/
ligand combination. This method is applicable to a wide
range of variously substituted aryl iodides for coupling
to both alkyl- and aryl-substituted terminal alkynes. This
novel catalytic system is tolerant, versatile, and signifi-
cantly less expensive than “traditional” Pd-Cu-catalyzed
(4) Sonogashira-type coupling catalyzed by copper, see: (a) Okuro, K.;
Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J. Org. Chem. 1993, 58,
4716. (b) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001,
3, 4315. (c) Thathagar, M. B.; Beckers, J.; Rothenberg, G. Green Chem.
2004, 6, 215. (d) Ma, D.; Liu, F. Chem. Commun. 2004, 1934. (e) Wang,
Y. F.; Deng, W.; Liu, L.; Guo, Q. X. Chin. Chem. Lett. 2005, 16, 1197. (f)
Saejueng, P.; Bates, C. G.; Venkataraman, D. Synthesis 2005, 1706. (g)
Xie, Y.-X.; Deng, C.-L.; Pi, S.-F.; Li, J.-H.; Yin, D.-L. Chin. J. Chem.
2006, 24, 1290. (h) Colacino, E.; Da¨ıch, L.; Martinez, J.; Lamaty, F. Synlett
2007, 1279. (i) Guo, S.-M.; Deng, C.-L.; Li, J.-H. Chin. Chem. Lett. 2007,
18, 13. (j) 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.
a Reaction conditions for entries 1-14: aryl iodides (2.2 mmol),
phenylacetylene or hexyne (2 mmol), [Cu(acac)2] (0.2 mmol), L7 (0.6
mmol), base (4 mmol), 4 mL of DMF. b Isolated yields.
(5) For reviews on the Sonogashira reaction: (a) Doucet, H.; Hierso,
J.-C. Angew.Chem., Int. Ed. 2007, 46, 834. (b) Chinchilla, R.; Najera, C.
Chem. ReV. 2007, 107, 874. (c) Negishi, E.-I.; Anastasia, L. Chem. ReV.
2003, 103, 1979.
(entries 9-14) to afford the desired products in moderate to
excellent yields. With the exception of work reported by
Ma,4d ours is the only efficient system under such mild
conditions (90-120 °C) compared to the harsher conditions
of 130-150 °C employed by other groups.4a–c,e–j
Concerning the mechanism, it is worth noting that in
copper-catalyzed Ullmann arylations few studies have been
performed.2b,c,8 In our case, we can only present a working
mechanism for this palladium-free Sonogashira reaction
(Figure 1).4a,g On the basis of previous studies, it seems
reasonable to propose copper(I) as a catalytic species (1),
with a ligand of diketone type coordinated to the metal. In
a first step, in the presence of base, the coordination/
deprotonationofthealkynecouldthengiveacopper(I)-acetylide
(6) For a review on acetylenic coupling, see: Siemsen, P.; Livingston,
R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632.
(7) Diketones used as a ligand in Ullmann-catalyzed reaction were
successfully described in C-N formation. See: (a) Shafir, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2006, 128, 8742. (b) de Lange, B.; Lambers-
Verstappen, M. H.; Schmieder-van de Vondervoort, L.; Sereinig, N.; de
Rijk, R.; de Vries, A. M.; de Vries, J. G. Synlett 2006, 3105. Diketones
were also used as ligands in Ullmann-type reactions for the formation of
C-O and C-C bonds. (c) Taillefer, M.; Xia, N.; Ouali, A. US 2006. 60/
818,334 and PCT 001836, 2007. (d) Xia, N.; Taillefer, M. US patent
60996830, 2007. (e) Taillefer, M.; Xia,N. Chem. Eur. J. 2008,DOI: 10/
1002/chem.200800436.
(8) (a) Streiter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 127, 4120. (b) Zhang, S.-L.; Liu, L.; Fu, Y.; Guo, Q.-X.
Organometallics 2007, 26, 4546. (c) Altman, R. A.; Koval, E. D.; Buchwald,
S. L. J. Org. Chem. 2007, 72, 6190.
Org. Lett., Vol. 10, No. 15, 2008
3205

cross-coupling of terminal alkynes with aryl iodides and
may be able to displace the original Sonogashira method
entirely.
Supporting Information Available: A general synthetic
procedure and complete characterization and NMR spectra
for products 3-14. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. Authors gratefully acknowledge the
CNRS for financial support.
OL801025U
3206
Org. Lett., Vol. 10, No. 15, 2008