N,N-Dimethyl Glycine-Promoted Ullmann Coupling Reaction of Phenols and Aryl Halides

Article abstract of DOI:10.1021/ol0350947

(Matrix presented) Ullmann-type diaryl ether synthesis can be performed at 90°C using either aryl iodides or aryl bromides as the substrates under the assistance of N,N-dimethylglycine.

Full text of DOI:10.1021/ol0350947

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3799-3802
N,N-Dimethyl Glycine-Promoted Ullmann
Coupling Reaction of Phenols and Aryl
Halides
Dawei Ma* and Qian Cai
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
madw@pub.sioc.ac.cn
Received June 16, 2003 (Revised Manuscript Received August 26, 2003)
ABSTRACT
Ullmann-type diaryl ether synthesis can be performed at 90 °C using either aryl iodides or aryl bromides as the substrates under the assistance
of N,N-dimethylglycine.
Numerous synthetically challenging and biologically impor-
tant chemicals contain diaryl ethers as structural elements.
Traditionally, copper-catalyzed Ullmann coupling between
an aryl iodide or bromide and a phenol has been extensively
used for the formation of diaryl ether. However, harsh
reaction conditions such as high temperatures (125-220 °C),
the usual requirement of stoichiometric quantities of the
copper catalyst, and the low to moderate yields have greatly
limited the utility of this reaction.1 Thus, development of
new methods for assembling diaryl ethers under relatively
mild reaction conditions is receiving increasing interest.2-4
By using 1-naphthoic acid,3d 2,2,6,6-tetramethylheptane-3,5-
dione,3a or phosphazene P4-t-Bu base3c as the additive,
Ullmann diaryl ether synthesis at 110-120 °C was achieved.
A similar result was observed when soluble copper catalyst
was employed.3b However, in these cases, less conveniently
available catalysts3b,d or additives,3a,c as well as higher
reaction temperatures, are required.
Table 1. Coupling Reaction of 4-Iodoanisole with Phenol
under the Catalysis of Copper Salts and Amino Acidsa
entry
copper salt
amino acid
yieldb (%)
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuBr
MeNHCH2CO2H
L-proline
37c
35
85
83
71
73
80
74
Me2NCH2CO2H‚HCl
Me2NCH2CO2H‚HCl
Me2NCH2CO2H‚HCl
Me2NCH2CO2H‚HCl
Me2NCH2CO2H‚HCl
Me2NCH2CO2H‚HCl
(1) For reviews, see: (a) Lindley, J. Tetrahedron 1984, 40, 1433-1456.
(b) Sawyer, J. S. Tetrahedron 2000, 56, 5045-5065.
(2) For palladium-catalyzed diaryl ether formation, see: (a) Mann, G.;
Hartwig, J. F. Tetrahedron Lett. 1997, 46, 8005-8008. (b) Aranyos, A.;
Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J.
Am. Chem. Soc. 1999, 121, 4369-4378 and references therein.
(3) For recent copper-catalyzed direct coupling reaction of aryl halides
and phenols, see: (a) Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.;
Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623-1626. (b) Gujadhur,
R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001, 3, 4315-4317. (c)
Palomo, C.; Oiarbide, M.; Lopez, R.; Gomez-Bengoa, E. Chem. Commun.
1998, 2091-2092. (d) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 10539-10540.
CuCl
Cu(OAc)2
CuSO4
CuCl2‚2H2O
a Reaction conditions: [Cu] (0.04 mmol), amino acid (0.15 mmol),
4-iodoanisole (2 mmol), phenol (3 mmol), Cs2CO3 (4 mmol), dioxane (4
mL), 90 °C. b Isolated yield. c N-(4-methoxyphenyl)-N-methylglycine was
isolated in 2% yield.
10.1021/ol0350947 CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/26/2003

Table 2. Coupling Reaction of Aryl Iodides with Phenols under the Catalysis of CuI and N,N-Dimethylglycinea
a Reaction conditions: CuI (0.04 mmol), N,N-dimethylglycine HCl salt (0.15 mmol), aryl iodide (2 mmol), phenol (3 mmol), Cs2CO3 (4 mmol), dioxane
(4 mL), 90 °C. b Isolated yield. c Performed with 0.2 mmol of CuI and 0.6 mmol of N,N-dimethylglycine HCl salt. d Performed with 2 mol of CuI and 2
mmol of N,N-dimethylglycine HCl salt. e Performed with 4 mmol of phenol.
On the basis of our observation that the structures of R-
and â-amino acids could induce acceleration of Ullmann-
type aryl amination of aryl halides and amino acids,6 we
recently reported that CuI/L-proline (or N-methylglycine) is
an efficient catalytic system to make Ullmann-type aryl
(5) For other recent examples, see: (a) Li, F.; Wang, Q.; Ding, Z.; Tao,
F. Org. Lett. 2003, 5, 2169-2171. (b) Wipf, P.; Lynch, S. M. Org. Lett.
2003, 5, 1155-1158. (c) Krenitsky, P. J.; Boger, D. L. Tetrahedron Lett.
2002, 43, 407-410. (d) Kalinin, A. V.; Bower, J. F.; Riebel, P.; Snieckus,
V. J. Org. Chem. 1999, 64, 2986-2987. (e) Sawyer, J. S.; Schmittling, E.
A.; Palkowitz, J. A.; Smith, W. J. J. Org. Chem. 1998, 63, 6338-6343. (f)
Zhu, J. Synlett 1997, 133-144 and references therein. (g) Nicolaou, K. C.;
Boddy, C. N. C.; Natarajan, S.; Yue, T.-Y.; Brase, S.; Ramanjulu, J. M. J.
Am. Chem. Soc. 1997, 119, 3421-3422. (h) Zhu, J. P.; Beugelmans, R.;
Bourdet, S.; Chastanet, J.; Roussi, G. J. Org. Chem. 1995, 60, 6389-6396.
(4) For recent copper-catalyzed coupling reaction of arylboronic acids
or arylboronates with phenols, see: (a) Evans, D. A.; Katz, J. L.; West, T.
R. Tetrahedron Lett. 1998, 39, 2937-2940. (b) Chen, D. M. T.; Monaco,
K. L.; Wang, R.-P.; Winters, M. Tetrahedron Lett. 1998, 39, 2933-2936.
(c) Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1999, 64, 2976-2977. (d)
Dicicco, C. P.; Song, Y.; Evans, D. A. Org. Lett. 2001, 3, 1029-1032. (e)
Petrassi, H. M.; Sharpless, K. B.; Kelly, J. W. Org. Lett. 2001, 3, 139-
142. (f) Chen, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.; Clark, C. G.;
Lam, P. Y. S. Tetrahedron Lett. 2003, 44, 3863-3865.
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Org. Lett., Vol. 5, No. 21, 2003

Table 3. Coupling Reaction of Aryl Bromides with Phenols under the Catalysis of CuI and N,N-Dimethylglycinea
a Reaction conditions: CuI (0.2 mmol), N,N-dimethylglycine HCl salt (0.6 mmol), aryl bromide (2 mmol), phenol (3 mmol), Cs2CO3 (4 mmol), dioxane
(4 mL), 90 °C. b Isolated yield. c Reaction was carried out at 105 °C.
amination work at the lowest temperature reported to date.7
As an extension of this work, we have found that under the
action of N,N-dimethylglycine, CuI-catalyzed coupling reac-
tion of aryl halides and phenols could be carried out at 90
°C to give the corresponding diaryl ethers in good to
excellent yields. Herein we wish to detail this result.
As summarized in Table 1, we chose the coupling of
4-iodoanisole with phenol mediated with cesium carbonate
as a model for exploring the suitable catalytic system.
Because of their excellent activity in CuI-catalyzed aryl
amination, N-methylglycine and L-proline were initially
checked as the additives for the present reaction. It was found
that the reaction worked at 90 °C in dioxane under the action
of 2 mol % CuI and 7.5 mol % N-methylglycine to give
4-methoxyphenyl phenyl ether (entry 1). However, the yield
was low due to poor conversion and N-(4-methoxyphenyl)-
N-methylglycine was isolated as a side product, which
indicated that the activity of this catalytic system was
eliminated by the coupling of the additive with the substrate.
After L-proline was observed to give the similar result (entry
2), we moved our attention to employing N,N-dimethylgly-
cine as the additive because this compound is unable to
process the N-aryl amination. As we expected, when 7.5 mol
% commercially available N,N-dimethylglycine hydrochlo-
ride salt was used, the reaction provided 4-methoxyphenyl
phenyl ether in 85% yield (entry 3). Under the assistance of
N,N-dimethylglycine hydrochloride salt, other Cu(I) and Cu-
(II) salts also worked under the above reaction conditions,
giving the coupling product in 71-83% yields (entries 4-8).
These results demonstrated that the choice of copper salts
appeared not to be very critical for the present reaction.
On the basis of the above results, the coupling reaction
catalyzed by CuI (2 mol %)/N,N-dimethylglycine (7.5 mol
%) was tested with several different aryl iodides and phenols,
and the results are summarized in Table 2. Both electron-
rich (entries 3-7) and electron-deficient (entries 8-11) aryl
iodides are suitable substrates for this reaction to provide
the corresponding diaryl ethers in good to excellent yields.
A variety of functional groups of aryl iodides are known to
tolerate this reaction condition, which include alkoxyl, amino,
fluoro, nitro, carbonyl, and cyano groups. The steric hin-
(6) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc.
1998, 120, 12459. (b) Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583-2586.
(7) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453-2455.
Org. Lett., Vol. 5, No. 21, 2003
3801

drance of phenols is slightly disfavored for this reaction. For
example, when 2-methoxyphenol was used as the substrate,
the reaction gave considerably lower yield in comparison
with that of less hindered phenol (compare entries 3 and 12).
In this case, increasing the amount of the catalyst and additive
gave improved results (entries 12 and 13). However, the
steric hindrance of aryl iodides is highly disfavored for this
reaction because the coupling reaction of 2-iodoanisole with
phenol required 1 equiv of catalyst for completion (entry
14). Under the action of 10 mol % CuI and 30 mol % N,N-
dimethylglycine, the coupling reaction of 1,4-diiodobenzene
with phenol gave the double-coupling product. In addition,
higher catalyst and additive loading were observed to
accelerate the reaction (compare entries 1 and 16).
As shown in Table 3, the present catalytic system is also
extremely effective for coupling reaction of aryl bromides
and phenols. In all cases, 10 mol % CuI and 30 mol % N,N-
dimethylglycine hydrochloride salt were used to promote the
reaction. High yields were obtained even for those aryl
bromides with an electron-donating group (entries 2 and 3)
and sterically hindered phenols (entries 8 and 9). Noteworthy
is the fact that the reaction of 4-methoxyphenyl bromide with
4-chlorophenol, which should be a difficult case for classical
Ullmann coupling method,1,3a gave the coupling product in
75% yield (entry 4). The excellent yield observed in the
reaction of 4-chlorophenyl bromide and 3-methylphenol
implies that good selectivity is desirable between aryl
bromides and aryl chlorides (entry 7). Additionally, the
relatively lower yield for reaction of 2-methylphenyl bromide
with 4-methoxyphenol implies that the steric hindrance of
aryl bromides is still disfavored for coupling reaction (entry
10). A similar result was observed in the coupling reaction
of an ortho-substituted bromide and an ortho-substituted
phenol (entry 11). The poor yields resulted from low
conversion in both cases because good yields were obtained
by raising the reaction temperature to 105 °C (entries 10
and 11).
In summary, we have developed a cheap and simple way
to carry out the Ullmann diaryl ether synthesis at the lowest
temperature reported to date, which is applicable to a wide
variety of substrates with different functional groups. The
application of this method to the synthesis of more complex
diaryl ethers, as well as mechanism studies, is in progress.
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foundation
of China (Grant 20132030), and the Qiu Shi Science &
Technologies Foundation for their financial support.
Supporting Information Available: Experimental pro-
cedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0350947
3802
Org. Lett., Vol. 5, No. 21, 2003