Dimethylaminomethylphosphonic acid derivatives-promoted CuI-catalyzed synthesis of aryl ethers

Article abstract of DOI:10.1055/s-2006-941587

An inexpensive and efficient catalyst system for synthesis of aryl ethers has been developed by using 20 mol% CuI as the catalyst, 30 mol% dimethylaminomethylphosphonic acid derivatives as the new ligands, K ₂CO₃ as the base and toluene as the solvent. This is the first example using aminophosphonates as the ligands for Ullmann ether coupling reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-941587

1564
LETTER
Dimethylaminomethylphosphonic Acid Derivatives-Promoted CuI-Catalyzed
Synthesis of Aryl Ethers
Synthesis of
Aryl
E
thers ng Jin,a Jinyong Liu,a Yingwu Yin,a Hua Fu,*a Yuyang Jiang,a,b Yufen Zhaoa
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62781695; E-mail: fuhua@mail.tsinghua.edu.cn
b
Key Laboratory of Chemical Biology, Guangdong Province, College of Shenzhen, Tsinghua University,
Shenzhen 518057, P. R. of China
Received 23 March 2006
carried out according to the reported procedures
(Figure 1).6,7 We optimized the reaction conditions, in-
cluding the copper sources, bases, solvents, amount of
catalysts and the ligands in order to achieve the best
Abstract: An inexpensive and efficient catalyst system for synthe-
sis of aryl ethers has been developed by using 20 mol% CuI as the
catalyst, 30 mol% dimethylaminomethylphosphonic acid deriva-
tives as the new ligands, K2CO3 as the base and toluene as the
solvent. This is the first example using aminophosphonates as the results in the Ullmann coupling reactions.
ligands for Ullmann ether coupling reaction.
O
P
O
P
O
P
Key words: Ullmann reaction, aryl ether, copper-catalyzed, di-
methylaminomethylphosphonic acid derivative
OCH(CH3)2
OCH(CH3)2
OC2H5
OH
H3C
H3C
H3C
H3C
OH
OH
H3C
H3C
N
N
N
L1
L3
L2
Figure 1 Structure of ligands L1, L2 and L3
The aryl ether linkage is frequently encountered in de-
signed molecules and natural products, particularly in a
large number of biologically active compounds,1 so the
construction of such systems has attracted much attention.
The traditional Ullmann coupling reaction was extensive-
ly used for the formation of diaryl ethers.2 However, harsh
reaction conditions such as high temperature (125–
220 °C), the usual requirement of stoichiometric quanti-
ties of the copper catalysts, and the low to moderate yields
have greatly limited the utility of this reaction.3 Although
recent progress in palladium-catalyzed ether formation
Several copper salts, CuSO4, Cu(OAc)2, CuBr, CuCl2,
CuI were tested using 1-bromo-3-nitrobenzene and 1.5
equivalents of phenol as the model substrates for the
Ullmann coupling reaction. The reaction was performed
in toluene at 110 °C using 10 mol% copper salt as the cat-
alyst, 20 mol% L1 as the ligand, and 2 equivalents of
K2CO3 as the base. As shown in Table 1, the air-stable and
inexpensive CuI gave the highest yield (68%).
Table 1 Effect of Copper Catalyst on the Coupling of 1-Bromo-3-
reactions has been made in this area,4 the drawbacks of the nitrobenzene with Phenola
catalyst systems, such as air sensitivity, high cost and
Br
OH
NO2
10 mol% cat.
20 mol% L1
toxicity, limit their applications. During the past years, the
Ullmann ether formation reaction, in which an aryl
bromide or iodide reacts with a phenol under basic condi-
tions in the presence of copper salt catalysts, has been the
focus of recent studies because it provides a direct access
to diaryl ethers,5 which highly relied on the utilization of
some special additives as the copper ligands such as 1-
naphthoic acid,5a 2,2,6,6-tetramethylheptane-3,5-dione,5b
phosphazene P4-t-Bu base,5c N,N-dimethylglycine,5d 8-
hydroxyquinoline,5e neocuproine,5f salicylaldoxime
(Salox).5g Herein, we report three new ligands dimethyl-
aminomethylphosphonic acid derivatives that can pro-
mote copper-catalyzed formation of aryl ethers from the
reactions of aryl bromides or iodides with a variety of
phenols and alcohols.
+
O
K2CO3, 110 °C
toluene
NO2
Entry
Catalyst
Time (h)
Yield (%)b
1
2
3
4
5
6
CuSO4·5H2O
Cu(CH3COO)2·H2O
CuBr
36
36
36
36
36
36
40
45
43
35
68
CuCl2·2H2O
CuI
CuI
6c
a Reaction conditions: 1-bromo-3-nitrobenzene (1 mmol), phenol (1.5
mmol), catalyst (0.1 mmol), ligand (0.2 mmol), K2CO3 (2.0 mmol) in
toluene (3.0 mL) under N2.
The preparation of diisopropyl dimethylaminomethyl-
phosphonate (L1), ethyl dimethylaminomethylphospho-
nate (L2), dimethylaminomethylphosphonic acid (L3) was
b Isolated yields.
c No ligand.
SYNLETT 2006, No. 10, pp 1564–1568
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-941587; Art ID: W06006ST
© Georg Thieme Verlag Stuttgart · New York
2
1
.0
6
.2
0
0
6
The coupling reaction of 1-bromo-3-nitrobenzene with
phenol was tested in different bases, K2CO3, Na2CO3,
Cs2CO3 and K3PO4. As shown in Table 2, the Ullmann

LETTER
Synthesis of Aryl Ethers
1565
The scope of the copper-catalyzed Ullmann ether cou-
pling reaction was explored under our standard coupling
conditions, 20 mol% CuI as the catalyst, 30 mol% L1, L2
or L3 as the ligand, 2 or 2.5 equivalents of K2CO3 as the
base, toluene as the solvent. The coupling reactions of aryl
bromides and iodides with various phenols and alcohols
were carried out, and the desired O-arylation products
were obtained in moderate to good yields. As shown in
Table 3, the data suggested that three ligands performed
quite well for most of the substrates examined, and ligand
L2 was the most effective for arylation of phenols. Aryl io-
dides reacted faster (compare entries 1 and 14), and pro-
vided higher reaction yields (see entries 10–12, 14 and 15)
than aryl bromides in the coupling reactions. Aryl bro-
mides and iodides containing an electron-withdrawing
group (see entries 5–12) and phenols containing an elec-
tron-donating group (compare entries 1, 2 and 3) are good
substrates. The steric hindrance of phenols is slightly dis-
favored for this reaction, for example, 3-methylphenol
(entry 3) gave higher yield than 2-methylphenol (entry 2).
2-Bromopyridine is a good substrate, its reaction with 4-
methoxyphenol provided excellent yields for the three
ligands (entry 19). Additionally, arylation reaction of al-
cohols also gave moderate to good yields in the presence
of the three catalyst systems, and surprisingly, ligand L3
showed better catalytic activity than ligands L1 and L2
(entries 20 and 21).
Table 2 Effect of Base and Solvent on the Coupling of 1-Bromo-3-
nitrobenzene with Phenola
Br
OH
NO2
10 mol% cat.
20 mol% L1
+
O
base, 110 °C
solvent
NO2
Entry Base
Time (h)
Solvent
Toluene
Toluene
Toluene
Toluene
DMF
Yield (%)b
1
2
3
4
5
6
K2CO3
30
30
30
30
30
30
65
45
63
60
55
46
Na2CO3
Cs2CO3
K3PO4
K2CO3
K2CO3
1,4-Dioxane
a Reaction conditions: 1-bromo-3-nitrobenzene (1 mmol), phenol (1.5
mmol), catalyst (0.1 mmol), ligand (0.2 mmol), base (2.0 mmol) in
different solvent (3.0 mL) under N2.
b Isolated yields.
ether coupling reaction using K2CO3 as the base gave the
highest yield (65%). We also investigated the coupling re-
actions in different solvents, DMF, 1,4-dioxane and tolu-
ene. Toluene was found to be the most effective solvent
compared with DMF or 1,4-dioxane (entry 1 in Table 2).
The cross-coupling of 1-bromo-3-nitrobenzene with phe-
nol in toluene using 30 mol% of the standard ligand, N,N-
dimethylglycine,5d was tested under the same coupling
conditions above (20 mol% CuI and 2 equiv of K2CO3),
and we found that the conversion ratio was 89%, which
was almost equal to the result using L2 as the ligand (entry
5 in Table 3).
In the process of optimization, the effect of the amount of
CuI and the ligand was also investigated. Only 10% diaryl
ethers (entry 13 in Table 3) was obtained in the absence of
ligand, which showed that the ligand could enhance the
Ullmann coupling rate of diaryl ethers, and the further ex-
periments showed that the catalyst system containing 20
mol% CuI and 30 mol% ligand, relative to aryl halide, was
the optimal choice.
Table 3 Coupling of Aryl Halides with Various Phenols and Alcoholsa
X
OH
20 mol% CuI
30 mol% L
O
+
R
R'
K2CO3
toluene
R
R'
2
1
3
X = Br, I
Entry
Aryl halide
Product
Time (h)
32
Yield (%)b
L1
L2
L3
O
1
2
64
66
68
58
Br
Br
3a
3b
3c
Me
32
70
88
60
66
O
O
Me
3
30
85
Br
Synlett 2006, No. 10, 1564–1568 © Thieme Stuttgart · New York

1566
Y. Jin et al.
LETTER
Table 3 Coupling of Aryl Halides with Various Phenols and Alcoholsa (continued)
X
OH
20 mol% CuI
30 mol% L
O
+
R
R'
K2CO3
toluene
R
R'
2
1
3
X = Br, I
Entry
Aryl halide
Product
Time (h)
30
Yield (%)b
L1
L2
L3
O
OMe
4
76
85
82
56
Br
3d
O2N
O2N
5
6
28
28
92
95
56
82
O
O
Br
Br
3e
O2N
O2N
91
Me
3f
O2N
O2N
O2N
O2N
7
8
20
28
85
70
88
84
78
65
O
OMe
Br
Br
Br
3g
O2N
O
3h
O2N
9
10
11
30
18
18
72
84
88
80
95
91
64
80
73
O
Cl
3i
O2N
3j
O
O2N
O2N
I
I
Me
O2N
O
3k
O2N
12
18
92
94
84
O2N
I
O
3l
O
13
14
15
24
28
28
10 (no ligand)
I
I
I
3a
3a
3d
O
O
65
73
86
93
70
82
OMe
Me
16
28
56
69
52
I
O
3b
Synlett 2006, No. 10, 1564–1568 © Thieme Stuttgart · New York

LETTER
Synthesis of Aryl Ethers
1567
Table 3 Coupling of Aryl Halides with Various Phenols and Alcoholsa (continued)
X
OH
20 mol% CuI
30 mol% L
O
+
R
R'
K2CO3
toluene
R
R'
2
1
3
X = Br, I
Entry
Aryl halide
H3CO
Product
Time (h)
30
Yield (%)b
L1
L2
L3
MeO
O
O
17
80
84
76
Br
Br
3d
MeO
OMe
18
19
30
18
58
92
89
94
46
81
H3CO
3m
O
OMe
N
N
Br
3n
Me
O
20
18
60
86
90
H3C
I
I
3o
Me
O
(H2C)2
21
22
23
18
30
28
58
68
76
60
70
88
66
60
52
H3C
3p
Me
O
Br
Ac
O
Ac
Br
3q
a Reaction conditions: CuI (0.4 mmol), ligand (0.6 mmol), K2CO3 (4 mmol for ligand L1; 5 mmol for hydrochloride salts of ligands L2 and L3)
in toluene (4 mL) under N2. Temperature: 110 °C for entries 1–7, 9–12, 16–19, 22 and 23; 85 °C for entry 8; 90 °C for entry 13; 100 °C for
entries 14, 15 and 21; 80 °C for entry 20. Aryl halide (2 mmol), phenol (3 mmol).
b Isolated yields.
mixture was stirred at the indicated temperature in the correspond-
ing reaction time (see Table 3). The reaction mixture was then
allowed to cool to r.t., diluted with 10 mL of Et2O and washed
sequentially with 5% aq NaOH, H2O and brine. The organic phase
was dried over Mg2SO4 and concentrated under vacuum to give the
crude product. Purification by column chromatography on silica gel
(hexane–EtOAc 30:1 to 100% hexane) afforded the desired pure
product.8
In summary, we have developed an efficient protocol for
coupling of aryl halides with various phenols and alcohols
using dimethylaminomethylphosphonic acid derivatives
as the new ligands of CuI in the Ullmann ether reactions.
The CuI-catalyzed coupling reactions were promoted by
the new bidentate ligands, which were simple, inexpen-
sive and readily available, and this is the first aminophos-
phonate-type example for copper-catalyzed formation of
aryl ethers. Hence, the catalyst system for the construction
of aryl ethers will be attractive.
Acknowledgment
This work was supported by the Excellent Dissertation Foundation
of the Chinese Ministry of Education (No. 200222), Program for
New Century Excellent Talents in University (NCET) in China, the
Excellent Young Teacher Program of MOE, P. R. of China, the
National Natural Science Foundation of China (Grant No.
20472042) and the Key Subject Foundation from Beijing Depart-
ment of Education (XK100030514).
General Procedure for the Preparation of Compounds 3a–q
Aryl halide (2 mmol), phenol (3 mmol), ligand L1, L2 or L3 (0.6
mmol) were added to a flask with K2CO3 (552 mg, 4 mmol for
ligand L1; 690 mg, 5 mmol for hydrochloride salts of ligands L2 and
L3) and toluene (4 mL), the mixture was stirred for 30 min at r.t. un-
der nitrogen atmosphere, and CuI (76 mg, 0.4 mmol) was added to
the flask. The flask was immersed in an oil bath, and the reaction
Synlett 2006, No. 10, 1564–1568 © Thieme Stuttgart · New York

1568
Y. Jin et al.
LETTER
Synthesis of Ethyl Dimethylaminomethylphosphonate
(L2).
References and Notes
(1) (a) Evans, D. A.; DeVries, K. M. In Glycopeptide
Antibiotics, Drugs and the Pharmaceutical Sciences, Vol.
63; Nagarajan, R., Ed.; Marcel Decker, Inc.: New York,
1994, 63–104. (b) Theil, F. Angew. Chem. Int. Ed. 1999, 38,
2345. (c) Itokama, H.; Takeya, K. Heterocycles 1993, 35,
1467. (d) Kase, H.; Masami, K.; Yamada, K. J. Antibiot.
1987, 40, 450. (e) Williams, D. H. Acc. Chem. Res. 1984,
17, 364. (f) Pearson, A. J.; Bignan, G.; Zhang, P.; Chelliah,
M. J. Org. Chem. 1996, 61, 3940. (g) Janetka, J. W.;
Raman, P.; Satyshur, K.; Flentke, G. R.; Rich, D. H. J. Am.
Chem. Soc. 1997, 119, 441. (h) Nicolaou, K. C.; Boddy, C.
N. C.; Natarajan, S.; Yue, T.-Y.; Li, H.; Bräse, S.;
Ramanjulu, J. M. J. Am. Chem. Soc. 1997, 119, 3421.
(i) Boger, D. L.; Patane, M. A.; Zhou, J. J. Am. Chem. Soc.
1994, 116, 8544.
The mixed solution of diethyl phosphite (22 mmol, 3.0 g),
dimethylamine hydrochloride (22 mmol, 1.79 g) in EtOH
(30 mL) was added dropwise to 37% aq formaldehyde (1.8
mL), and the resulting solution was refluxed for 6 h. The
solvent was removed by rotary evaporation, the residue was
dissolved in 5 mL of H2O and 10 mL of EtOH. Then, LiOH
(22 mmol, 0.53 g) was added, and the solution was stirred at
60 °C for 3 h. The solution was extracted with CH2Cl2, the
aqueous phase was acidified with 3 M HCl to pH 3, and
evaporated to dryness to provide a solid mixture. MeOH was
added to the remaining solid, and the insoluble solid was
filtrated. The filtrate was concentrated and dried over P2O5
in vacuo, and the desired product ethyl dimethylamino-
methylphosphonate hydrochloride salt (L2) was obtained in
the form of a white solid. Yield 3.81 g, 85%. 31P NMR
(121.5 MHz, CDCl3): d = 6.8 ppm. 1H NMR (300 MHz,
CDCl3): d = 8.98 (s, 1 H), 3.71–3.61 (m, 2 H), 2.80 (d,
J = 20.4 Hz, 2 H), 2.59 (s, 6 H), 0.95 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 60.5, 55.2, 55.3, 45.3, 16.7.
ESI-HRMS: m/z calcd for C5H15NO3P [M + H]+: 168.0790;
found: 168.0783.
(2) Ullmann, F. Ber. Dtsch. Chem. Ges. 1904, 37, 853.
(3) Lindley, J. Tetrahedron 1984, 40, 1433.
(4) For palladium-mediated ether synthesis, see: (a)Torraca, K.
E.; Huang, X.; Parrish, C. A.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 123, 10770. (b) Aranyos, A.; Old, D. W.;
Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J.
Am. Chem. Soc. 1999, 121, 4369. (c) Mann, G.; Hartwig, J.
F. Tetrahedron Lett. 1997, 38, 8005. (d) Mann, G.;
Incarvito, C.; Rheigold, A. L.; Hartwig, J. F. J. Am. Chem.
Soc. 1999, 121, 3224. (e) Shelby, Q.; Kataoka, N.; Mann,
G.; Hartwig, J. J. Am. Chem. Soc. 2000, 122, 10718.
(5) For some recent reports, see: (a) Marcoux, J.-F.; Doye, S.;
Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 10539.
(b) Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.;
Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623.
(c) Palomo, C.; Oiarbide, M.; Lopez, R.; Gomez-Bengoa, E.
Chem. Commun. 1998, 2091. (d) Ma, D.; Cai, Q. Org. Lett.
2003, 5, 3799. (e) Fagan, P. J.; Hauptman, E.; Shapiro, R.;
Casalnuovo, A. J. Am. Chem. Soc. 2000, 122, 5043.
(f) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org.
Lett. 2001, 3, 4135. (g) Cristau, H. J.; Cellier, P. P.;
Hamada, S.; Spindler, J. F.; Tailefer, M. Org. Lett. 2004, 6,
913.
Synthesis of Dimethylaminomethylphosphonic Acid (L3).
This compound was synthesized according to the known
method.2 Dimethylamine hydrochloride (50 mmol, 4.2 g),
H3PO4 (50 mmol, 4.1 g) and 20 mL of HCl (6.5 M in H2O)
were added to a round-bottom flask fitted with a reflux
condenser, and the solution was heated for 5 min. Then, 52
mmol (3.87 mL) of formaldehyde (36% aq solution) was
added, and the solution was refluxed for 90 min. After
removal of H2O in vacuo, the residue was heated in 60 mL
of EtOH to lead to the formation of a white solid. This solid
was collected after filtration, and dried in vacuo to obtain
dimethylaminomethyl phosphonic acid hydrochloride salt
(L3, 8.42 g, 96%). 31P NMR (121.5 MHz, DMSO-d6,): d =
9.3 ppm. 1H NMR (300 MHz, DMSO-d6): d = 5.86 (s, 2 H),
3.30 (d, J = 12.7 Hz, 2 H), 2.83 (s, 6 H). 13C NMR (75 MHz,
DMSO-d6): d = 54.7, 52.8, 44.8. ESI-HRMS: m/z calcd for
C3H11NO3P [M + H]+: 140.0477; found: 140.0481.
(8) Characterization data of two representative compounds are
shown as follows:
(6) (a) Hardy, T. A. US Patent 4083897, 1978. (b) Diel, P. J.;
Maier, L. Phosphorus Sulfur Relat. Elem. 1984, 20, 13.
(7) Synthesis of Diisopropyl Dimethylaminomethyl-
phosphonate (L1).
4-Nitrophenyl Phenyl Ether (3j)9
Yellow solid; mp 58–60 °C (Lit.7 60 °C). 1H NMR (300
MHz, CDCl3): d = 8.17 (d, J = 9.27 Hz, 2 H), 7.42 (t,
J = 7.89 Hz, 2 H), 7.25 (t, J = 7.56 Hz, 1 H), 7.08 (d, J = 7.82
Hz, 2 H), 7.00 (d, J = 8.85 Hz, 2 H). 13C NMR (75 MHz,
CDCl3): d = 163.5, 154.8, 142.7, 130.4, 126.0, 125.5, 120.6,
117.2. HRMS (EI): m/z calcd for C12H9NO3 [M+]: 215.0582;
found: 215.0574.
The mixed solution of diisopropyl phosphite (22 mmol, 3.7
g), dimethylamine hydrochloride (22 mmol, 1.79 g) and
Et3N (22 mmol, 3.2 mL) in EtOH (30 mL) was added
dropwise to 37% aq formaldehyde (1.8 mL), and the
resulting solution was refluxed for 8 h. The 31P NMR
spectroscopy showed that the starting material diisopropyl
phosphite was almost quantitatively transferred into ligand
L1 (d = 26.9 ppm). The solvent was removed by rotary
evaporation, the residue was isolated by silica gel column
chromatography using CHCl3–MeOH (10:1) as eluent, and
the pure L1 was obtained as a colorless liquid. Yield 4.50 g,
92%. 31P NMR (121.5 MHz, CDCl3): d = 26.9 ppm. 1H NMR
(300 MHz, CDCl3): d = 4.78–4.71 (m, 2 H), 2.75 (d, J = 20.4
Hz, 2 H), 1.33 (s, 6 H), 2.41–2.38 (m, 12 H). 13C NMR (75
MHz, CDCl3): d = 70.2, 56.9, 47.4, 24.0. ESI-HRMS: m/z
calcd for C9H23NO3P [M + H]+: 224.1416; found: 224.1411.
Bis(4-methoxyphenenyl)ether (3m)5b
White solid; mp 101–103 °C (Lit.5b 102–103 °C). 1H NMR
(300 MHz, CDCl3): d = 6.92 (d, J = 9.27 Hz, 4 H), 6.85 (d,
J = 9.27 Hz, 4 H), 3.79 (s, 3 H). 13C NMR (75 MHz, CDCl3):
d = 155.4, 151.7, 119.6, 114.8, 55.8. HRMS (EI): m/z calcd
for C14H14O3 [M+]: 230.0943; found: 230.0949.
(9) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 11684.
Synlett 2006, No. 10, 1564–1568 © Thieme Stuttgart · New York