Organophosphate-accelerated copper-catalyzed C(sp2)-C(sp) Sonogashira-type cross couplings

Article abstract of DOI:10.1002/aoc.3291

A dramatic acceleration in copper-catalyzed Sonogashira-type reactions was observed when an organophosphate was used as additive. The catalyst systems featuring low copper loading (0.5 mol% < Cu < 5 mol%) gave Sonogashira-type products with a broad scope

Full text of DOI:10.1002/aoc.3291

Full Paper
Received: 19 October 2014
Revised: 20 January 2015
Accepted: 20 January 2015
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.3291
Organophosphate-accelerated copper-
2
catalyzed C(sp )–C(sp) Sonogashira-type
cross couplings
Wei Xu, Bo Yu, Huaming Sun, Guofang Zhang, Weiqiang Zhang*
and Ziwei Gao*
A dramatic acceleration in copper-catalyzed Sonogashira-type reactions was observed when an organophosphate was used as
additive. The catalyst systems featuring low copper loading (0.5 mol% < Cu < 5 mol%) gave Sonogashira-type products with a
broad scope of aromatic and aliphatic terminal alkynes as well as aryl iodides in good to excellent yields. Among the
organophosphate/copper catalytic systems, thatof 4 mol%Cu(OTf)2/10 mol%(R)-(À)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate
exhibited the highest catalytic activity. Copyright © 2015 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Keywords: Sonogashira coupling; organophosphate; Cu(II) complexes
Introduction
Results and Discussion
Alkynes are efficient building blocks that can be used as a basic
We initially elucidated whether the CuI/L1 catalytic system is effec-
tive for Sonogashira coupling in DMF. The results are listed in
Table 1. The effect of solvents was investigated for the Sonogashira
coupling reaction of phenylacetylene with iodobenzene at 130 °C
under nitrogen (Scheme 1; Table 1, entries 1–7). Various solvents
such as dioxane, THF, toluene, DMF, ethanol, acetonitrile and DMSO
were tested under similar conditions, but less than 21% products
are obtained except when DMSO and DMF are employed as solvent
(Table 1, entries 4 and 5). Further screening experiments were con-
ducted using different bases and the best result is obtained when
Cs2CO3 is employed. Other commonly used inorganic bases such
as KOH, KF and K3PO4 show no marked effect on the cross-coupling
reactions (Table 1, entries 8–11). In addition, very low yields are
obtained when organic bases are used (Table 1, entries 12 and 13).
Encouraged by these preliminary results, a number of reaction
parameters (Table S1) were evaluated to determine the optimal re-
action conditions. It is found that the catalytic activity of CuI/L cat-
alytic system is sensitive to Cu loadings (Table S1, entries 1–8).
When 1, 2 and 3 mol% CuI are added, the yields of the products
are 43, 62 and 74%, respectively, in the presence of 10 mol% L1
(Table S1, entries 1–3). To our pleasure, when using 4 mol% CuI
the product yield can reach 94% (Table S1, entry 4). However, on
functional group in organic synthesis.[1–4] Nowadays, Pd/Cu–
phosphine-catalyzed Sonogashira cross coupling provides
a
straightforward access to C(sp)–C(sp2) bond formation and the
cross-coupling products are widely used as precursors for the
synthesis of pharmaceuticals, natural products and organic
materials.[5–8] One of the latest aspects of attention focuses on
the efficiency of catalyzed cross coupling of aryl halides with termi-
nal alkynes using copper catalysts,[9–15] for copper is less toxic and
far more economic than palladium. Since Miura and co-workers
reported that PPh3/CuI (10 mol%) catalyzed the Castro reactions
of aryl iodides and terminal alkynes in 1993,[16] there have been
reported huge innovations of copper-catalyzed C(sp2)–C(sp)
coupling reactions,[17–19] including those involving Cu(I)/
diamines,[20–22] Cu(I)/amino acid derivatives,[23–25] Cu(I)/1,4-
diazabicyclo[2.2.2]octane,[26] copper nanoparticles,[27–29] supported
copper complexes[30–32] and other copper catalytic systems.[33]
Although copper-based catalysts have been proposed as an alter-
native to palladium-based catalysts for Sonogashira couplings,
these catalyst systems generally require high copper loadings
(5–20 mol%) to maintain a catalytic cycle. Therefore, it is still highly
desirable to develop new copper-based catalytic systems with low
copper loadings.
Herein, we report a new copper-based catalyst system featuring
low copper loadings (0.5 mol% < Cu < 5 mol%) and organophos-
phate additives (Fig. 1), by which a number of Cu(I) and Cu(II)
compounds are activated for Songashira-type couplings. The com-
bination of an organophosphate and Cu(OTf)2 (4 mol%) is able to
catalyze the cross couplings of terminal alkynes and aryl iodides
with good to excellent yields. To the best of our knowledge, a
copper-based catalytic system promoting C(sp2)–C(sp) couplings
with copper loadings less than 5 mol% has been rarely reported
before.[11,14,35]
*
Correspondence to: Ziwei Gao, Key Laboratory of Applied Surface and Colloid
Chemistry, Ministry of Education, School of Chemistry and Chemical
Engineering, Shaanxi Normal University, 199 South Chang’an Road, Xi’an, China.
E-mail: zwgao@snnu.edu.cn
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education,
School of Chemistry and Chemical Engineering, Shaanxi Normal University, 199
South Chang’an Road, Xi’an, China
Appl. Organometal. Chem. (2015)
Copyright © 2015 John Wiley & Sons, Ltd.

W. Xu et al.
Table 2. Effect of copper salts on the Sonogashira cross-coupling
reactiona
Entry
Copper salt
Ligand
Yield (%)b
1
2
3
4
5
6
7
8
9
10
CuI
L1
L2
L3
L1
L1
L1
L1
L1
L1
L1
91
58
43
42
51
63
96
40
46
81
CuI
CuI
CuCl
CuBr
Cu2O
Cu(OTf)2
Cu(OAc)2
CuO
Cu(acac)2
aReaction conditions: Cu (4 mol%), Cs2CO3 (99.995%, 1.0 mmol,
0.3259 g), (10 mol%), 4-iodoanisole (1 mmol, 0.2410 g),
L
phenylacetylene (1 mmol, 109.8 μl), DMSO (3.0 mL), 130 °C, 12 h.
1H NMR yields.
b
Figure 1. Structures of organophosphate ligands: L1
binaphthyl-2,2′-diyl hydrogenphosphate; L2 = 2-ethylhexyl-2-ethylpentyl
=
(R)-(À)-1,1′-
hydrogenphosphate; L3 = 1,2,3-propanetriol-1-(dihydrogenphosphate).
Table 1. CuI/L1-catalyzed Sonogashira cross couplinga
Entry
Cu
Solvent
Base
Yield (%)b
Scheme 3. Cu(OTf)2-catalyzed cross coupling of aryl iodides and alkynes.
1
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Toluene
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
KF
18
0
2
3
1,4-Dioxane
DMF
12
69
74
11
21
40
10
13
78
12
16
show that with less than 10 mol% L1, the product yields are no
more than 60% (Table S1, entries 9–13). When L1 is increased to
10 mol%, the yield increases markedly to 94%. However, higher
concentration (15–30 mol%) of L1 does not promote the cross-
coupling reaction further.
4
5
DMSO
6
Acetonitrile
Ethanol
DMSO
7
8
We next investigated the effects of the ligands and copper salts
in order to further optimize reaction conditions. The cross coupling
of phenylacetylene and 1-iodo-4-methoxybenzene in DMSO
(Scheme 2) was conducted as a model reaction. The product yield
using CuI/L1 catalytic system is 91%, much higher than that using
L2 and L3 (Table 2, entries 1–3). The high efficiency of L1 indicates
that this aromatic phosphate ligand preferentially stabilizes the cat-
alytically active Cu(I) species compared to its aliphatic analogue L2,
whilst L3 is a multi-dentate hard donor ligand that inhibits the for-
mation of Cu(I) by chelating Cu(II) pre-catalyst. Furthermore, seven
commercial Cu(I) and Cu(II) salts were assessed in the coupling reac-
tions. Other commonly used Cu(II) salts such as CuO, Cu(OAc)2 and
Cu(acac)2 also accelerate the cross-coupling reaction (Table 2, en-
tries 7–10). Among them, Cu(OTf)2 gives the highest yield of 96%
(Table 2, entry 7).
The cross coupling of arylacetylenes with aryl iodides (Scheme 3)
containing electron-donating groups (p-OMe or m-CH3) gives iso-
lated yields of 76 to 96% (Table 3, entries 1, 2, 9, 10, 13, 14, 22).
When aryl iodides with electron-withdrawn groups (o-CF3, m-NO2
or p-NO2) are used, the product yields decrease dramatically and
even no cross-coupling product is isolated in the case of
p-nitroiodobenzene as substrate (Table 3, entries 3, 7, 19–21,
23, 24). When 1-octyne is employed instead of phenylacetylene,
lower yields (0À60%) are obtained (Table 3, entries 5À8). When
phenylacetylene and p-ethylphenylacetylene are involved in the
coupling reaction, good to excellent yields are obtained (Table 3,
entries 10, 13, 17). However, for aliphatic alkynes coupled with
iodobenzenes, only p-OMe- and m-CH3-substituted iodobenzes
give moderate yields (50–78%; Table 3, entries 5, 6, 11, 12, 16),
and o-CF3-substituted iodobenzene gives almost no coupling
9
DMSO
10
11
12
13
DMSO
KOH
DMSO
Cs2CO3
Pyridine
Et3N
DMSO
DMSO
aReaction conditions: CuI (99.995%, 2.0 mol%), L1 (10 mol%), solvent
(3.0 mL), base (1 mmol), aryl iodide (1 mmol, 112 μl), alkyne (1
mmol, 109.8 μl), 130 °C, stirred in nitrogen, 12 h.
bGC yield based on alkyne.
increasing CuI to 10, 20 and 30 mol% the product yields fall to 45,
44 and 42%, respectively (Table S1, entries 6–8). According to the
literature, the ligand concentration has a major impact on copper-
catalyzed cross-coupling reactions.[35] Therefore, we further investi-
gated the concentration effect of L1 in the coupling reaction. CuI
(4 mol% Cu)-catalyzed cross-coupling reaction was conducted
using 1–30 mol% L1 (Table S1, entries 9–16). The screening results
Scheme 1. CuI-catalyzed cross coupling of aryl iodide and alkyne.
Scheme 2. Copper salt-catalyzed cross coupling of aryl iodide and alkyne.
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Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2015)

Organophosphate-accelerated Cu-catalyzed Sonogashira cross coupling
Table 3. Cu(OTf)2-catalyzed Sonogashira cross-coupling reaction of aryl iodides with terminal alkynesa
Entry
R1
R2
Yield (%)b
Entry
R1
R2
Yield (%)b
1
p-OMe
m-CH3
o-CF3
C6H5
96
83
74
90
60
52
—
—
85
90
73
68
13
14
15
16
17
18
19
20
21
22
23
24
m-CH3
m-CH3
m-CH3
m-CH3
o-CF3
p-C2H5C6H5
n-C5H13C6H5
n-C4H9
80
76
—
50
82
74
—
—
83
78
60
54
2
C6H5
3
C6H5
4
H
C6H5
n-C5H11
5
p-OMe
m-CH3
o-CF3
n-C6H13
n-C6H13
n-C6H13
n-C6H13
C6H5
p-C2H5C6H5
p-CH3C6H5
n-C4H9
6
o-CF3
7
o-CF3
8
p-NO2
p-OMe
p-OMe
p-OMe
p-OMe
o-CF3
n-C5H11
9
o-CF3
n-C5H13C6H5
n-C5H13C6H5
n-C5H13
10
11
12
p-CH3C6H5
n-C4H9
n-C5H11
m-CH3
m-NO2
p-NO2
p-CH3C6H5
aReaction conditions: Cu(OTf)2 (99.995%, 4 mol%), Cs2CO3 (1 mmol, 0.3259 g), aryl iodide (1 mmol), alkyne (1 mmol), 130 °C, 16 h. L1 (10 mol%), DMSO (2.5 mL).
bIsolated yields.
reaction in this case (Table 3, Entries 19, 20). Therefore, it can be
concluded that in the presence of Cu(OTf)2/L1, iodobenzenes with
electron-donating groups and arylalkynes are beneficial to the cou-
pling reaction, but iodobenzenes containing an electron-
withdrawing group and aliphatic alkynes decrease the coupling
product yield.
(20120202120005), Natural Science Basic Research Plan in Shaanxi
Province of China (2012JM2006) and Shaanxi Innovative Team of
Key Science and Technology (2013KCT-17).
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Acknowledgments
This work was supported by the 111 Project (B14041), National Nat-
ural Science Foundation of China (21171112, 21271124, 21371112),
Fundamental Doctoral Fund of Ministry of Education of China
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Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2015)