Methenamine as an efficient ligand for copper-catalyzed coupling of phenols with aryl halides

Article abstract of DOI:10.1002/cjoc.201100077

Employing methenamine as a new supporting ligand, the copper-catalyzed coupling reactions of aryl bromides or aryl iodides with various phenols successfully proceeded in good yields under mild conditions. A series of diaryl ethers were obtained with excellent yields in the presence of K ₃PO₄ and copper(I) salt. Copyright

Full text of DOI:10.1002/cjoc.201100077

NOTE
DOI: 10.1002/cjoc.201100077
Methenamine as an Efficient Ligand for Copper-catalyzed
Coupling of Phenols with Aryl Halides
Qian, Cunwei*,a(钱存卫)
Zong, Qianshoub(宗乾收)
Fang, Donga(方东)
a School of Chemistry and Chemical Engineering, Yancheng Teachers University, Yancheng,
Jiangsu 224051, China
b School of Biological and Chemical Engineering, Jiaxing University, Jiaxing, Zhejiang 314001, China
Employing methenamine as a new supporting ligand, the copper-catalyzed coupling reactions of aryl bromides
or aryl iodides with various phenols successfully proceeded in good yields under mild conditions. A series of diaryl
ethers were obtained with excellent yields in the presence of K3PO4 and copper(I) salt.
Keywords copper catalyst, methenamine, ullmann coupling, diaryl ethers
Introduction
tions of phenols with aryl halides is still an area of con-
siderable interest.
Carbon-oxygen bonds extensively exist in all kinds
of biologically active natural products, important phar-
maceutical compounds and polymers.[1,2] The palla-
dium-catalyzed formation of carbon-oxygen bonds is
one of the two major methods available for aryl ether
synthesis. However, palladium-based protocols, al-
though successful,[3] have some inherent limitations
such as moisture sensitivity, costly metal catalysts, and
environmental toxicity. The other one is the cop-
per-mediated Ullmann ether synthesis. The harsh clas-
sical conditions of the Ullmann ether synthesis also
have limitations in its application because of the high
temperatures (120—220 ℃) required and the use of
stoichiometric amounts of copper reagents.[4] In the past
years, significant advances have been achieved for the
copper-catalyzed synthesis of diaryl ethers by use of the
new ligands explored, such as 1-naphthoic acid,[5a]
8-hydroxyquinoline,[5b] 2,2,6,6-tetramethyl heptane-3,5-
dione,[5c] amino acids,[5d-5f] diimine ligands,[5g,5h]
PPAMP,[5i] phosphazene P4-t-Bu base,[5j] β-ketoester,[5k]
1,1'-binaphthyl-2,2'-diamine,[5l] tripod ligands,[5m] silica
supported Cu(II),[5n] aryl boronic acid,[5o] tetraethyl or-
thosilicate (as solvent),[5p] (2-pyridyl)acetone,[5q]
nBu4NBr (as phase transfer catalyst),[5r] picolinic acid[5s]
and some copper(I) complexes.[5t-5v] With the carefully
selected combinations of a catalytic amount of copper
sources, bases, and supporting ligands, aryl bromides
and aryl iodides had been reported to couple with phe-
nols with excellent yields under mild conditions.
Therefore, the further discovery of new facile ligand
structures for the copper-catalyzed cross-coupling reac-
Methenamine, as an inexpensive, commercially
available and ancillary material, has been used in the
synthesis of inorganic nanotubes[6] and nanorods.[7] To
our knowledge, there are very few examples available
involving it in copper-catalyzed arylation with phenols.
Here we report the efficient use of the methenamine (L1
in Figure 1) for the copper catalyzed O-arylation of phe-
nols with aryl halides.
Figure 1 Structures of ligands.
Results and Discussion
A variety of copper salts were examined using bro-
mobenzene and phenol as model substrates,
methenamine as a ligand, DMF as the solvent, and tri-
potassium phosphate as the base. The results are listed
in Table 1.
In preliminary studies with the CuI/K3PO4 system,
no desired coupling product was obtained (Table 1,
Entry 1). Upon addition of methenamine (as a ligand),
however, the remarkable increase in reactivity was ob-
served (Table 1, Entry 2). The catalytic activity of cu-
prous salts was compared and the choice of the copper
catalyst did not appear to be critical; CuCl, CuBr, CuI
and Cu2O gave similar results (Table 1, Entries 3—5).
Yet the use of CuCl2 led to slightly low conversions
(Table 1, Entry 6).
*
E-mail: qiancunwei@163.com; Tel.: 18962033519; Fax: 0086-0515-88233188
Received June 28, 2011; accepted August 23, 2011; published online December 23, 2011.
Chin. J. Chem. 2012, 30, 199—203
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199

Qian, Zong & Fang
NOTE
Table 1 Influence of various copper salts on copper-catalyzed
O-arylation of phenol with aryl bromidesa
tries 1, 2 and 3). In this study, to compare the effect of
different tertiary amines as ligands in the C—O cou-
pling reaction, methenamine (L1), TMEDA (L2) and
tributylamine (L3) (Figure 1) were selected as the
multi-, bi-, and monodentate ligand, respectively.
Among the ligands L1, L2 and L3 tested, L1 was more
efficient than L2, L3 only gave trace amounts of product
(Table 2, Entries 2, 4 and 5). Moreover, the results
showed that the optimal ratio of Cu(I) (5 mmol%) to
methenamine (L1) used in this study was equal to 1∶
1.5 (Table 2, Entries 2, 6 and 7). After screening a series
of bases, 2 equiv. of K3PO4 was determined to be the
most effective base and gave diphenyl ether in 75%
yield (Table 2, Entries 2, 9 and 10). While replacing
K3PO4 with K2CO3 gave no reaction (Table 2, Entry 8).
A slight excess of the phenol was employed (0.2 and 0.5
equiv. excess) since the use of 1.0 equiv. resulted in very
slow conversion as the reaction neared completion (Ta-
ble 2, Entries 6 and 12). Finally, on turning our attention
to examining solvent effects, we found that DMF as a
solvent gave the best result, furnishing diphenyl ether in
75% yield (Table 2, Entries 2 and 11). Therefore, the
optimized conditions employed 5 mol% of CuI, 7.5
mol% of methenamine, and 2 equiv. of K3PO4 relative
to aryl halide in DMF under argon. Under the optimum
condition, O-arylation of phenol with iodobenzene gave
excellent yields (94%) (Table 2, Entry 13).
Entry Copper salt, mol%
Ligand/mol%
Yieldb/%
1
2
3
4
5
CuI, 10
CuI, 5
0
5
5
5
5
5
0
85
81
84
80
74
CuCl, 5
CuBr, 5
Cu2O, 2.5
CuCl2, 5
6
a
General reaction conditions: 1.2 mmol of phenol, 1.0 mmol of
b
ArX, 2.0 mmol of K3PO4, 0.5 mL of anhydrous DMF. Isolated
yield.
Rationalizing that phenol could be resistant to de-
protonation, we conducted optimization studies with
phenols and aryl halide as the model substrates. The
results are summarized in Table 2.
Table 2 Copper-catalyzed O-arylation of phenol with aryl hal-
ide: optimization of the reaction conditionsa
The scope of the copper-catalyzed C—O bond for-
mation was explored by using a variety of aryl iodides
with substituted phenols under the optimized conditions.
As shown in Table 3, O-arylation of aryl iodides with
phenol bearing either electron-withdrawing or elec-
tron-donating substituents was shown to give the corr-
sponding products in excellent yields of 81%—91%
(Table 3, Entries 1—5) with the exception of 4'-hydro-
xyacetophenone, which led to a low yield (15%) for the
coupling reaction (Table 3, Entry 9). This might be due
to the decreased nucleophilicity of phenols induced by
the keto group. No spectacular electronic effects were
observed when various phenols were submitted to cou-
pling with para-methyl aryl iodides, and only slight de-
creases in the reaction yields were noted (Table 3, En-
tries 10—17 vs. 1—7). Whereas the O-arylation of
various substituted phenols and 2-iodotoluene gave only
moderate to good product yields (51%—72%) (Table 3,
Entries 18—22), which might be attributable to the in-
fluence of steric hindrance. As above mentioned, the
results clearly indicated that steric hindrance had a huge
influence on the coupling reaction (Table 3, Entry 8 vs.
1—4). For instance, only 48% yield was obtained after
24 h under our standard reaction conditions when 2,6-
dimethylphenol coupled with phenyl iodides (Table 3,
Entry 8). When their reaction times were prolonged, the
better yields were obtained (Table 3, Entry 8), which
was consistent with previous studies.[5h,5r-5t, 8] It was also
found that the reaction of ortho-substituted aryl iodides
was, in some cases, slightly more demanding than that
for ortho-substituted phenols; for example, the coupling
Entry
1
X
Br
I
Copper salt, mol% Ligand, mol%
Yieldb/%
51
CuCl, 5
CuCl, 5
CuCl, 5
CuCl, 5
CuCl, 5
CuCl, 5
CuCl, 5
CuCl, 5
CuCl, 5
CuCl, 5
CuCl, 5
CuCl, 5
CuI, 5
L1, 5
L1, 5
2
75
3
Cl
I
L1, 5
0
4
L2, 5
31
5
I
L3, 5
Trace
84
6
I
L1, 7.5
L1, 10
L1, 5
7
I
63
8c
9d
10e
11f
12g
I
Trace
74
I
L1, 5
I
L1, 5
40
I
L1, 5
Trace
91
I
L1, 7.5
L1, 7.5
13g
I
94
a
General reaction conditions: 1.2 mmol of phenol, 1.0 mmol of
b
ArX, 2.0 mmol of K3PO4, 0.5 mL of anhydrous DMF. Isolated
yield. c K2CO3 was used in place of K3PO4. d Reaction carried out
e
with 3.0 mmol of K3PO4 as base. Reaction carried out with 1.0
mmol of K3PO4 as base. f In toluene. g 1.5 mmol phenol was used
instead of 1.2 mmol phenol.
As previously reported,[5] aryl iodides displayed
higher reactivity than aryl bromides, and aryl chlorides
were unreactive in the coupling reactions (Table 2, En-
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Chin. J. Chem. 2012, 30, 199—203

Methenamine as an Efficient Ligand for Copper-catalyzed Coupling of Phenols with Aryl Halides
of 2-iodotoluene with phenol carried out gave 67% yield
Continued
Yieldb/%
of the desired product under our optimal conditions, but
the coupling of 2-methylphenol proceeded more readily
(Table 3, Entry 4 vs. 22). The results also revealed that
an electron-withdrawing group in the aryl iodides fa-
vored the coupling reactions. For example, 1-iodo-4-
chlorobenzene successfully coupled with ortho-
substituted phenols with higher yields than that for io-
dobenzene without electron-withdrawing group (Table 3,
Entry 23 vs. 4, 11). In addition, the coupling reaction
of benzyl alcohol with 1-iodo-4-chlorobenzene af-
forded the expected ethers in 82% yield (Table 3, Entry
24). It was noteworthy that the coupling reaction of
4-acetylphenyl bromide with varied substituted phenols
obtained good yields (73%—90%) at 130 ℃, albeit aryl
bromides are less reactive than aryl iodides for arylation
(Table 3, Entries 25—29). Similarly, the coupling of 1-
or 2-naphthol and aryl iodides (or 4-iodotoluene) was
found to proceed in good yields (Table 3, Entries 6, 7,
15 and 16).
Aryl
Phenol
Entry
10
Product
halide (Alcohol)
61
85
11
12
78
13
14
15
88
75
67
Table 3 Cu-Catalyzed coupling reaction of aryl iodides (bro-
mide) with phenols (or benzyl alcohol)a
16
17
68
82
Aryl
Phenol
Entry
1
Product
Yieldb/%
85
halide (Alcohol)
18
19
66
72
2
3
87
91
20
21
22
72
51
67
4
5
6
7
8
9
81
86
64
85
23
91
82
48 (78c)
15
24d
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www.cjc.wiley-vch.de
201

Qian, Zong & Fang
NOTE
Continued
Yieldb/%
temperature (110 ℃) for 24 h. The reaction mixture was
allowed to reach room temperature and then diluted
with dichloromethane (10 mL). The slurry was filtered,
and filter cake was washed with 10 mL of dichloro-
methane. The solvent was removed in vacuo, and the
residue was purified by column chromatography on sil-
ica gel to afford the desired product (2-naphthyl phe-
nylether). 2-Naphthyl phenylether: 1H NMR (400 MHz,
CDCl3) δ: 7.17—7.25 (m, 3H), 7.35—7.38 (m, 1H),
7.43—7.55 (m, 5H), 7.78 (d, J＝8 Hz, 1H), 7.90—7.91
(m, 2H); 13C NMR (100 MHz, CDCl3) δ: 109.4, 114.5,
115.3, 118.8, 120, 121.9, 122.5, 123.1, 125.1, 125.2,
125.5, 129.7, 150.4, 152.5.[9]
Aryl
Phenol
Entry
Product
halide (Alcohol)
25e
26e
80
90
27e
28e
88
73
85
Acknowledgement
29e
We are grateful to Yancheng Teachers University for
the financial support (Nos. 6106053058, 620610C448).
a
Unless otherwise stated, general reaction conditions: 1.5 mmol
of phenol, 1.0 mmol of ArX, 2.0 mmol of K3PO4, 0.5 mL of an-
hydrous DMF under Ar atmosphere for 24 h. Isolated yield.
c Reaction time of 48 h. d 1 mL benzyl alcohol as solvent instead
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Methenamine (7.5 mol%), CuI (5 mol%), 2-naphthol
(1.5 mmol, 216 mg) and K3PO4 (425 mg, 2.0 mmol)
were added to a screw-capped Schlenk tube under argon.
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