all the examples, we used 0.1 equiv of TMHD. As a general
procedure, the aryl halide (11.3 mmol), the phenol (22.6
mmol), TMHD (1.1 mmol), and cesium carbonate (22.6
mmol) were added to 19 mL of anhydrous NMP. The
mixture was degassed and filled with nitrogen. To this
mixture was added CuCl (5.6 mmol), and the mixture was
degassed and filled with nitrogen three times. This mixture
was then heated to 120 °C under nitrogen and followed by
HPLC until completion of the reaction. The reaction was
diluted with MTBE and filtered. The filtrate was washed
with 2 M HCl and then 0.6 M HCl, 2 M NaOH, and 10%
NaCl. The desired product was isolated by flash column
chromatography or direct crystallization from hexanes. The
product purity was at least 98% by HPLC or GC in all
examples, and the assay yields were relative to the isolated
products as the standards.5 The major advantages of the
process reported here are the low cost and the simplicity of
operation.
From Table 1, it can be observed that the Ullmann
coupling reactions under these conditions follow the general
trend that electron-donating groups on the phenol and
electron-withdrawing groups on the halide make the reaction
favorable and fast, as indicated by the higher yields and
shorter reaction times for entries 2, 3, and 8 compared to 1
and 4. This has been a well-established trend in copper- and
palladium-catalyzed ether formation reactions. Under the
current conditions, 4-methoxylphenyl bromide and 4-N,N-
dimethylaminophenyl bromide reacted with 4-fluorophenol
within a reasonable time frame (10-15 h) at 120 °C, giving
the desired products in good yields (entries 1 and 4). This
represents a significant improvement over the classical
conditions, which generally do not work with aryl halides
with strong electron-donating groups and phenols with
electron-withdrawing groups.3 In fact, the palladium-
catalyzed reactions suffer the same drawback.4 The electron-
neutral phenols and aryl halides worked well under the
current conditions, as indicated in entries 5, 6, and 10. Some
tolerance of electron-withdrawing groups on the phenols was
observed, as the reactions with 4-fluorophenol and isopropyl
4-hydroxybenzoate (entries 1-7 and 11) gave reasonable to
good yields. The major side reaction in these Ullmann ether
formations is the reduction of the aryl halides to the arene
(Ar-Br to Ar-H). Phenols with extremely strong electron-
withdrawing groups do not undergo the desired ether
formation, and in those cases, the reduction of the aryl halide
to the corresponding arene (Ar-Br to Ar-H) becomes the
dominating reaction. For example, the reaction of 4-hydroxy-
benzaldehyde with 4-bromotoluene gave very little desired
products and toluene was formed. Similar results were
observed for the reaction between 4-methoxyphenyl bromide
and 4-hydroxybenzonitrile. Neighboring groups on the phe-
nols and the aryl bromide had various effects in the reaction.
A methyl group had little effect, as indicated in entry 10.
However, an ortho methoxy group slows the reaction and
ortho acetyl even more (entries 7 and 9), perhaps due to
chelating effects on the copper catalyst. The reaction is mildly
basic, so it tolerates a variety of functional groups such as
ketone, aldehyde, nitrile, amino, and hindered ester groups.
Finally, the reaction of an aryl iodide is faster and higher
yielding than the corresponding bromide, as indicated by
entries 13 and 1.
(5) All products gave satisfactory mass spectrometry data (molecular ions
were observed). All new compounds are characterized by satisfactory proton
and 13C NMR, elemental analysis (within 0.4% of theory), and HPLC or
1
GC (g98%). (a) oil; H NMR (CDCl3, 100 MHz) δ 7.04-6.85 (m, 8H),
3.81 (s, 3H); 13C NMR (CDCl3, 400 MHz) δ 158.4 (d, J ) 240.4 Hz),
155.9, 154.3, 150.7, 120.3, 119.2 (d, J ) 8.2 Hz), 116.2 (d, J ) 23.3 Hz),
115.0, 55.7. (b) Tanaka, A.; Terasawa, T.; Hagihara, H.; Ishibe, N.; Sawada,
M.; Sakuma, Y.; Hashimoto, M.; Takasugi, H.; Tanaka, H. J. Med. Chem.
1998, 41, 4408. (c) Hogenkamp, D. J.; Nguyen, P.; Shao, B. Patent WO
2001/68612. Mp 68-71 °C; 1H NMR (CDCl3, 400 MHz) δ 7.97-7.90 (m,
2H), 7.13-7.01 (m, 4H), 6.99-6.93 (m, 2H), 2.53 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 196.7, 162.2, 159.6 (d, J ) 243.5 Hz), 151.3, 132.0,
130.7, 121.8 (d, J ) 8.5 Hz), 116.9, 116.8 (d, J ) 23.5 Hz), 26.5. (d)
Baliah, V.; Kanagasabapathy, V. M. Indian J. Chem., Sect. B 1978, 16B,
The mechanism of Ullmann ether formation reactions has
not been well established.6 While it is not clear how the
diketone accelerates the Ullmann coupling reaction under
these conditions, the Cu(II) bis(2,2,6,6-tetramethylheptane-
3,5-dionate) is a commercially available, stable solid and,
to the best of our knowledge, has not been shown to be a
superb catalyst for the Ullmann reaction. In fact, when we
used it for the Ullmann coupling reaction between 4-meth-
oxyphenyl bromide and 4-fluorophenol, it showed lower
reactivity than the CuCl/TMHD combination, and it is also
more expensive (note, however, that the reduction of the aryl
halide as the side reaction was suppressed, though not
eliminated). It was also observed that CuCl was soluble under
the reaction conditions even without added ligands, so the
role of the ligands was not simply to dissolve the copper
salt. It was also observed that reducing the amount of the
diketone from 0.25 to 0.1 equiv slowed the reaction. NMR
studies of the reaction mixture indicated that when 4-fluo-
rophenol and TMHD were dissolved in deuterated NMP in
the presence of cesium carbonate, the phenol is partially
deprotonated as indicated by the upfield shift of the aromatic
proton chemical shifts. The diketone exists primarily as the
ketone (as opposed to the enol) form. Upon addition of CuCl,
a slight downfield shift of the phenol aromatic proton signals
1
810. Mp 58-61 °C; H NMR (CDCl3, 400 MHz) δ 7.03-6.87 (m, 6H),
6.79-6.72 (m, 2H), 2.95 (s, 6H); 13C (CDCl3, 100 MHz) δ 158.13 (d, J )
240.1), 154.9, 147.9, 147.7, 120.5, 118.7 (d, J ) 8.10), 116.0 (d, J ) 23.2),
1
114.0, 41.2. (e) oil; H NMR (CDCl3, 400 MHz) δ 7.14 (d, 2H, J ) 8.1
Hz), 7.07-6.92 (m, 4H), 6.89 (d, 2H, J ) 8.2 Hz), 2.35 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 158.6 (d, J ) 241.0 Hz), 155.3, 153.5, 132.9, 130.3,
120.0 (d, J ) 8.2 Hz), 118.6, 116.2 (d, J ) 23.3 Hz), 20.7. (f) oil; 1H
NMR (CDCl3, 400 MHz) δ 7.30-7.24 (m, 1H), 7.21-7.14 (m, 1H), 7.11-
6.97 (m, 3H), 6.93-6.84 (m, 3H) 2.27 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 158.4 (d, J ) 240.3 Hz), 155.0, 153.7, 131.6, 129.7, 127.2, 123.9,
119.1, 118.9 (d, J ) 8.3 Hz), 116.2 (d, J ) 23.3 Hz), 16.2. (g) oil; 1H
NMR (CDCl3, 100 MHz) δ 7.88-7.80 (m, 1H), 7.48-7.39 (m, 1H), 7.22-
7.13 (m, 1H), 7.13-7.04 (m, 2H), 7.04-6.96 (m, 2H), 6.86 (d, 1H, J )
8.3 Hz), 2.66 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 198.9, 159.2 (d, J )
242.5 Hz), 156.7, 152.2, 133.7, 130.6, 130.3, 123.5, 120.5 (d, J ) 8.3 Hz),
118.6, 116.7 (d, J ) 23.5 Hz), 31.6. (h) Wang, L.; Xi, H.; Sun, X.; Shen,
Y.; Yang, Y.; Pan, Y.; Hu, H. Synth. Comm. 2000, 30, 227. (i) Mp 77-87
°C; 1H NMR (CDCl3, 400 MHz) δ 7.11-7.04 (m, 1H), 7.03-6.98 (m,
1H), 6.98-6.92 (m, 2H), 6.92-6.83 (m, 4H), 3.89 (s, 3H), 3.80 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ 155.5, 151.1, 150.9, 146.8, 123.8, 121.0,
119.4, 119.3, 114.8, 112.7, 56.1, 55.7. (j) Mp 52-55 °C; 1H NMR (CDCl3,
400 MHz) δ 8.04-7.86 (m, 2H), 7.24-7.15 (m, 2H), 7.02-6.95 (m, 4H),
5.25 (sept, 1H, J ) 6.2 Hz), 2.37 (s, 3H), 1.37 (d, 6H, J ) 6.3 Hz); 13C
NMR (CDCl3, 100 MHz) δ 165.7, 162.1, 153.4, 134.2, 131.6, 130.5, 125.0,
120.1, 117.0, 68.2, 22.0, 20.8.
(6) For kinetic and mechanistic work, see: (a) Litvak, V. V.; Shein, S.
M. Zh. Organ. Khim. 1975, 11, 92. (b) Paine, A. J. J. Am. Chem. Soc.
1987, 109, 1496.
Org. Lett., Vol. 4, No. 9, 2002
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