Betti base as an efficient ligand for copper-catalyzed ullmann coupling of phenol with aryl halides

Article abstract of DOI:10.1080/00397911.2014.903421

GRAPHICAL ABSTRACT A simple, general, and highly efficient Betti base ligand has been developed for copper-catalyzed Ullmann coupling of phenol with aryl halides without the protection of an inert atmosphere. The reaction proceeds smoothly in the presence of K2CO3 as the base and dimethylsulfoxide as the solvent. The catalyst was reused several times with no evident loss of catalytic activity and is environmentally friendly.

Full text of DOI:10.1080/00397911.2014.903421

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Betti Base as an Efficient Ligand for
Copper-Catalyzed Ullmann Coupling of
Phenol with Aryl Halides
Li Yang a , Qichao Yang b , Jianxin Shi a , Yufang Wang a & Mingjie
Zhang a
a Chemistry Department, School of Science , Tianjin University ,
Tianjin , China
b Chemistry and Pharmaceutical Engineering College , Nanyang
Normal University , Nanyang , China
Accepted author version posted online: 06 May 2014.Published
online: 01 Jul 2014.
To cite this article: Li Yang , Qichao Yang , Jianxin Shi , Yufang Wang & Mingjie Zhang (2014) Betti
Base as an Efficient Ligand for Copper-Catalyzed Ullmann Coupling of Phenol with Aryl Halides,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:17, 2468-2477, DOI: 10.1080/00397911.2014.903421
To link to this article: http://dx.doi.org/10.1080/00397911.2014.903421
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Synthetic Communications1, 44: 2468–2477, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.903421
BETTI BASE AS AN EFFICIENT LIGAND FOR
COPPER-CATALYZED ULLMANN COUPLING OF
PHENOL WITH ARYL HALIDES
Li Yang,1 Qichao Yang,2 Jianxin Shi,1 Yufang Wang,1 and
Mingjie Zhang1
1Chemistry Department, School of Science, Tianjin University,
Tianjin, China
2Chemistry and Pharmaceutical Engineering College,
Nanyang Normal University, Nanyang, China
GRAPHICAL ABSTRACT
Abstract A simple, general, and highly efficient Betti base ligand has been developed for
copper-catalyzed Ullmann coupling of phenol with aryl halides without the protection of
an inert atmosphere. The reaction proceeds smoothly in the presence of K2CO3 as the base
and dimethylsulfoxide as the solvent. The catalyst was reused several times with no evident
loss of catalytic activity and is environmentally friendly.
Keywords Aryl halides; Betti base; copper; phenol; Ullmann coupling
INTRODUCTION
Diaryl ethers play an important part in many biologically active compounds
and polymers and has applications in industrial and life sciences.[1–14] The traditional
formation of C-O bond is the Ullmann reaction, which used aryl halide and
phenol as substrates.[15] Subsequently, aryl acetate,[16–18] aryl boronic acid,[19–22] aryl
siloxane,[23,24] and arylstannane[25] were introduced to react with phenol. However,
these methods often suffered harsh reaction conditions, such as high temperature
and the stoichiometric unrecyclable catalyst. Therefore, much effort has been
devoted to developing more convenient methods of Ullmann-type O-arylation.
Because of the low cost, copper[26–30] was investigated as an alternative catalyst
to palladium.[31–36] 1-Naphthoic acid,[37] 2,2,6,6-tetramethylheptane-3,5-dione,[38]
Received December 4, 2013.
Address correspondence to Mingjie Zhang, Chemistry Department, School of Science, Tianjin
University, Tianjin 300072, China. E-mail: mjzhangtju@163.com
2468

BETTI BASE AS AN EFFICIENT LIGAND
2469
1,10-phenanthroline,[39] neocuproine,[40] triphenylphosphine,[41] N,N-dimethylgly-
cine,[42] 8-hydroxyquinoline,[43] pyrrolidine-2-phosphonic acid phenyl monoester,[44]
1,10-binaphthyl-2,20-diamineand,[45] and (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)
prop-2-en-1-one[46] have been used in these reaction as ligands. However, these
ligands have major drawbacks of limited recyclability and difficult preparation.
Herein, we report a simple and high-efficiency Betti ligand for copper-catalyzed
Ullmann-type O-arylation to obtain these diaryl ethers. This catalyst system could
be reused.
RESULTS AND DISCUSSION
The ligands were prepared by classical Mannich reaction[47,48] (Fig. 1). The
reaction could occur smoothly at room temperature. We tested the catalytic ability
of these Betti bases in the O-arylation reaction catalyzed by CuI, and the results
are presented in Table 1. The result showed that the ligand formed by pyridine alde-
hyde is more efficient than benzaldehyde (Table 1, entries 1–4 and 5–8). The reason
may be that the pyridyl ligands has the capability to coordinate with metal centers to
form a six-member stable cycle chelate and could coordinate with the metal center
via the pyridyl nitrogen. We choose 1-(dimethylamino-1-yl-pyridin-2-yl-methyl)-
naphthalen-2-ol (L1) as the best ligand for the reaction.
Then, we further optimized the reaction conditions, and the results are listed in
Table 2. The results showed that dimethylsulfoxide (DMSO) was the best solvent
(Table 2, entry 1), and dimethylformamide (DMF) and toluene (Table 2, entries 2
and 7) provided lower yields when using H2O, N-methyl pyrrolidone (NMP), and
1,4-dioxane (Table 2, entries 3–5) as the solvents, no product was obtained. Interest-
ingly, we also obtained desired product at the solvent-free condition (Table 2,
Figure 1. List of ligands.

2470
L. YANG ET AL.
Table 1. Ligands in Ullmann-type O-arylation reaction
Entry
L
Yield (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
88
75
42
53
3
18
21
5
entry 9). Among the various copper sources, the CuI was found to be the best
catalyst (Table 2, entries 10–19), and Cuþ catalytic effect is better than the Cu2þ salt.
There is no product without catalyst (Table 2, entry 19).
The influence of base was also screened: K2CO3 showed more improvement
than Cs2CO3, K3PO4, and KOH to give product 3a in 88% yield. Some organic bases
such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine, and diethylamine
showed no reactivity in this reaction (Table 2, entries 20–25). In addition, the yield
was significantly decreased when the reaction was performed at the lower tempera-
ture (Table 2, entry 28). When changing the reaction time (Table 2, entries 26 and 27)
the yield of the product was also reduced. Furthermore, no product was obtained
without the participation of L1.
Under the optimized reaction conditions (Table 2, entry 1), we continued
extended the scope of the substituted phenols (2) with iodobenzene (1a), and the
results are summarized in Table 3. An electron-donating group of phenols reacted
with iodobenzene in the presence of 0.1 mmol CuI, 0.2 mmol L1, and 2.0 equiv
K2CO3 in DMSO to give the corresponding diarylethers in excellent yields
(Table 3, entries 1–7). Under the same reaction conditions, electron-withdrawing
groups gave no yields (Table 3, entries 14–16). Notablely, phenol with group of
–OCH3, no matter ortho- or para-, display an effective effect with the yields 100%
(Table 3, entries 4 and 5). Entries 11–13 performed moderate in this reaction only
with a yield of about 30%, probably due to the steric hindrance.
To further reveal the scope of this catalyst system in the O-arylation reaction,
various substituted aryl halides were coupled with phenol, and the results are
summarized in Table 4. Generally, the reaction activities of chlorobenzene and bro-
mobenzene are less (Table 4, entry 1), When substituted with electron-withdrawing
groups, particularly nitro group, the reaction reacted smoothly with m-cresol to give
a satisfactory product in a 99% yield (Table 4, entries 2–6). Aldehyde and carbonyl
substituted chlorobenzene and bromobenzene also afforded the corresponding diaryl
ethers in excellent yields (Table 4, entries 7–9). However, a strong electron-donating
group of aryl halides evidently restrained the coupling reaction (Table 4, entries 11

BETTI BASE AS AN EFFICIENT LIGAND
2471
Table 2. Optimization of the typical reaction conditionsa
Entry
Solvent
Base
Catalyst
Time (h)
Yield (%)b
1
2
DMSO
DMF
NMP
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOH
CuI
CuI
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
36
20
24
24
88
36
0
3
CuI
CuI
4
H2O
1,4-Dioxane
THF
0
5
CuI
CuI
0
6
11
32
20
36
62
50
41
39
25
26
11
35
58
0
7
Toluene
CH3CN
—
CuI
CuI
8
9
CuI
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Cu power
CuBr
CuCl
CuO
CuBr2
CuCl2 ꢀ 2H2O
CuSO4
Cu(OAC)2 ꢀ H2O
Cu2O
——
CuI
72
55
35
10
0
K3PO4
Cs2CO3
DBU
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Triethylamine
Diethylamine
K2CO3
K2CO3
K2CO3
K2CO3
0
62
60
2c
0d
aReaction conditions: iodobenzene (1.0 mmol), m-cresol (1.0 mmol), CuX (0.1 mmol), L (0.2 mmol), 2.0
equiv base, solvent (3 mL), 120 ꢁC.
bGC yield determined by using methoxybenzene as internal standard.
cReaction temperature is 80 ꢁC.
dWithout L.
and 12). When using dichlorobenzene we observed no desired product in the reaction
(Table 4, entry 10).
Finally, the reusability of the catalyst system was tested: The catalyst can be
recovered and reused for five runs without any significant loss of catalytic activity
for coupling reaction of iodobenzene with m-cresol (Table 5).
EXPERIMENTAL
General Procedure for the Synthesis of Ligands
A solution of b-naphthol (1.0 g, 6.93 mmol) and aldehyde (0.74 g, 6.93 mol) in
absolute alcohol (2 mL) was prepared. Amine (0.61 g, 6.93 mmol) was slowly added
to this solution, and the mixture was stirred for 48 h at room temperature. Subsequ-
ently, the solid was filtered off and washed twice with cold ethyl alcohol (2–3 mL). It

2472
L. YANG ET AL.
Table 3. Copper-catalyzed O-arylation of phenols with iodobenzenea
Entry
Phenol
Product
Yield (%)b
1
88
2
3
4
5
87
88
>99
>99
6
7
90
91
8
9
65
35
10
58
(Continued )

BETTI BASE AS AN EFFICIENT LIGAND
2473
Table 3. Continued
Entry
11
Phenol
Product
Yield (%)b
35
12
35
13
14
32
0
15
16
0
0
aReaction conditions: iodobenzene (1.0 mmol), phenol (1.0 mmol), CuI (0.1 mmol), L1 (0.2 mmol),
2.0 equiv K2CO3, DMSO (3 mL), 120 ꢁC.
bIsolated yield.
was recrystallized from a mixture of petroleum ether and ethyl acetate to get
colorless crystals of L ligands.
General Procedure for the Synthesis of Coupling Products
All reactions were carried out under air. Aryl halides (1.0 mmol) were treated
with phenol (1.0 mmol) in the presence of 0.1 mmol CuI, 0.2 mmol 1-(a-
aminobenzyl)-2-naphthols and 2.0 equiv K2CO3 in 3 mL DMSO at 120 ꢁC for
24 h. The progress of the reaction was monitored by gas chromatography (GC).
After completion of the reaction, the catalyst was filtered easily and the product
was extracted with EtOAc, The combined organic layers were dried over MgSO4

2474
L. YANG ET AL.
Table 4. Copper-catalyzed O-arylation of m-cresol with aryl halidesa
Entry
1
Ar-X
Product
Yield (%)b
I: 88
Br: 0
Cl: 0
2
3
>99
>99
4
>99
5
6
>99
>99
7
8
70
69
9
71
(Continued )

BETTI BASE AS AN EFFICIENT LIGAND
2475
Table 4. Continued
Entry
10
Ar-X
Product
Yield (%)b
0
11
12
0
0
aReaction conditions: aryl halides (1.0 mmol), m-cresol (1.0 mmol), CuI (0.1 mmol), L1 (0.2 mmol), 2.0
equiv K2CO3, DMSO (3 mL), 120 ꢁC.
bIsolated yield.
Table 5. Recyclability studies of CuI for O-arylation
Run
1
2
3
4
5
Yield (%)
93
91
89
88
85
for 12 h. The solvent was evaporated under reduced pressure and the desired product
was purified by flash chromatography on a silica-gel column using petroleum ether=
ethyl acetate (10:1).
In summary, we have developed a practical CuI-Betti base ligand for
copper-catalyzed coupling of a variety of phenol and aryl halides. The ligands are
easy to synthesize and the reaction can proceed smoothly without the protection
of an inert atmosphere. The catalytic system can be recycled and is environmentally
friendly.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
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