Effect of microwave heating on Ullmann-type heterocycle-aryl ether synthesis using chloro-heterocycles

Article abstract of DOI:10.1016/j.tetlet.2006.05.103

Ullmann ether synthesis was conducted on a variety of chloro-heterocycles with different phenols using optimized conditions involving copper powder and cesium carbonate. On many substrates, microwave heating afforded higher yields in significantly shorter reaction times compared to conventional heating conditions. These findings provide a facile method for aryl ether synthesis from chloropyridines, chloroquinolines, and chlorobenzothiazoles.

Full text of DOI:10.1016/j.tetlet.2006.05.103

Tetrahedron Letters 47 (2006) 5045–5048
Effect of microwave heating on Ullmann-type heterocycle-aryl
ether synthesis using chloro-heterocycles
Noel D. D’Angelo,a Joseph J. Peterson,b Shon K. Booker,a Ingrid Fellows,c
Celia Dominguez,a Randall Hungate,a Paul J. Reidera and Tae-Seong Kima,*
aDepartment of Chemistry Research and Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799,
United States
bDepartment of Chemistry, Rochester Institute of Technology, 85 Lomb Memorial Drive, Rochester, NY 14623-5603, United States
cChemistry Department, California State University Fresno, 2555 E. San Ramon Ave, Fresno, CA 93740, United States
Received 14 January 2006; revised 12 May 2006; accepted 17 May 2006
Abstract—Ullmann ether synthesis was conducted on a variety of chloro-heterocycles with different phenols using optimized con-
ditions involving copper powder and cesium carbonate. On many substrates, microwave heating afforded higher yields in signifi-
cantly shorter reaction times compared to conventional heating conditions. These findings provide a facile method for aryl ether
synthesis from chloropyridines, chloroquinolines, and chlorobenzothiazoles.
Ó 2006 Elsevier Ltd. All rights reserved.
The Ullmann ether synthesis has been widely employed
in organic chemistry since its discovery in the early 20th
century.1 In particular, the copper-mediated coupling of
aryl halides and phenols has proven to be one of the pri-
mary methods for aryl ether synthesis.2 Initially, this
reaction required high temperatures (>200 °C) and toxic
solvents and often afforded low yields. Consequently, its
scope was rather limited.3–6 However, recent modifica-
tions have allowed for this reaction to be run under
milder conditions (90–110 °C) on chemically diverse
substrates, often furnishing products in high yields.7
These improvements have been achieved mainly by the
introduction of palladium8 and copper catalysis.9 With
these improvements, the scope of the Ullmann ether
synthesis has been extended to heterocycle-alkyl ether
synthesis.10 To our knowledge, however, there has been
no report on its application to heterocycle-aryl ether
synthesis to date.
the Ullmann ether synthesis by Wu and later by Wang
for synthesis of aryl ethers and N-aryl heterocycles.12
Cherng reported microwave-assisted nucleophilic substi-
tution of halo-heterocycles with sodium phenoxide on
pyridine, quinoline, isoquinoline, pyrazine, and pyrimi-
dine systems.13 However, with inactivated heterocycles
such as halopyridines, the coupling reaction is still diffi-
cult and requires a large excess of the phenoxide and
toxic solvents such as HMPA for best yields even for
iodopyridines.13c
Here we report a facile method with microwave irradia-
tion for Ullmann ether synthesis between electronically
diverse phenols and nitrogen containing chloro-hetero-
cycles such as chloropyridines, chloroquinolines, and
chlorobenzothiazoles. Chloro-heterocycles are stable
and easy to make relative to bromo- and iodo-hetero-
cycles, but, as a consequence, they are also less reactive.
Thus, the primary objective was to determine how effec-
tive microwave heating would be in improving the yields
of Ullmann ether synthesis between different phenols
and chloro-heterocycles.
The advent of microwave technology has provided an-
other means of improving the efficiency of many organic
reactions.11 This technology has also been explored for
Our first approach was to identify the optimized reaction
conditions using 4-chloropyridinium hydrochloride (1)
and phenol (2, R = H). This was performed by systemat-
ically varying the solvent, copper source, and base under
Keywords: Ullmann ether synthesis; Microwave.
*
Corresponding author. Tel.: +1 805 447 8895; fax: +1 805 480
3016; e-mail: tkim@amgen.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.103

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N. D. D’Angelo et al. / Tetrahedron Letters 47 (2006) 5045–5048
microwave (CEM, DiscoverÒ) conditions of 100 °C and
60 W for 10 min. The first conditions examined used
copper powder, DMF, and potassium hydroxide and
afforded 4-phenoxypyridine (3) in 20% yield. Changing
the copper source to copper(I) salts such as CuI and
CuCl resulted in yields ranging from 8% to 11%. Like-
wise, with other solvents such as NMP, toluene, and a
1:1 DMF/pyridine mixture, the yields were still below
10%. The base had the greatest influence on the reaction,
and while K3PO4, K2CO3, and KOH also afforded yields
under 10%, the use of Cs2CO3 in the presence of copper
powder in DMF afforded 3 in 69% isolated yield.14 Once
these optimized conditions had been identified, they
were used in all subsequent conventional heating and
microwave reactions.15
in the microwave and on the bench top were obtained
and are summarized in Table 2. For the first three aryl
chlorides, the yields on the bench top and in the micro-
wave were similar, with the microwave yields being
about 10% higher. The similar yields could be the
result of these chloro-heterocycles being more reactive
than 4-chloropyridine.
Different halopyridines were also explored, where the
halide substituent and its position were varied. For
these experiments, 2-chloropyridine, 2-bromopyridine,
and 2-iodopyridine were studied, as well as their 4-halo-
pyridine counterparts. The chloropyridine substrates
showed low reactivity under conventional heating con-
ditions, regardless of 2-, 3-, or 4-positioning. The yields
under conventional heating clearly improved when bro-
mine and iodine were used. The microwave conditions
afforded moderate to good yields for all three haloge-
nated substrates, however the improvement in yield
relative to the conventional heating conditions was
most dramatic for the chloropyridine species. Finally,
under microwave conditions, 2-chloropyridine and
4-chloropyridine afforded the desired product in moder-
ate to good yield, while 3-chloropyridine hardly gave
any product. From these results, one can conclude that
microwave heating is most advantageous for chloro-
heterocycle substrates, in terms of shortening reaction
times and, most significantly, improving reaction
yields.
Using these conditions, the Ullmann ether synthesis of 1
with different phenols was conducted in order to investi-
gate the sensitivity of this reaction to electronics. For
this series, the phenol was varied from electron donating
to electron withdrawing, and the Ullmann ether synthe-
sis was then conducted on the bench top and in the
microwave using the optimized conditions. The isolated
yields were then compared and are summarized below in
Table 1.
Two noteworthy trends are apparent. First, the yields
in most cases were higher in the microwave than on
the bench top, demonstrating the advantage of using
the microwave for these substrates. This is important
from a practical point of view, as the reactions under
conventional heating were run under nitrogen for
18 h in a 100 °C oil bath, while the microwave reac-
tions took 10 min. Second, under microwave condi-
tions, the yields observed increased with more
electron deficient phenols. No such trend was observed
on the reactions under conventional heating, suggesting
that microwave heating is especially beneficial for elec-
tron-deficient phenols.
In summary, microwave heating can be quite effective in
improving the yields and decreasing the reaction times
of Ullmann ether synthesis, especially for couplings that
are otherwise sluggish and low yielding. Primarily,
microwave heating enables the use of less reactive
chloro-heterocycles for these couplings, thereby expan-
ding their synthetic utility. Even for reactive substrates
such as iodopyridines, microwave heating affords the
advantage of dramatically decreased reaction times
(10 min vs 18 h) with similar, if not better, yields. These
conditions should facilitate the synthesis of aryl ethers
and thereby aid in the discovery of new drug candidates.
Further efforts toward this end will be reported in due
course.
For the next series, different chloro-heterocycles and
halopyridines were explored using phenol (2) as the
nucleophile. For this series, the reactions were run un-
der the same conditions as before, and again the yields
Table 1. Effect of microwave on Ullmann ether synthesis yields with different phenols
O
HO
Cl
copper powder (0.1 eq.), Cs2CO3 (3 eq.),
DMF, 100 oC, 60 Watts (microwave only)
+
R
R
N
N
*HCl
1 (1 eq.)
2 (1.5 eq.)
3-8
Entry
R
Product
Conventional heating yielda (%)
Microwave heating yielda (%)
1
2
3
4
5
6
H
(3)
(4)
(5)
(6)
(7)
(8)
17
36
31
26
29
23
69
34
38
76
72
79
4-Methoxy
4-Methyl
4-Fluoro
3-Fluoro
2-Fluoro
a Isolated yield.

N. D. D’Angelo et al. / Tetrahedron Letters 47 (2006) 5045–5048
5047
Table 2. Effect of microwave on Ullmann ether synthesis yields with different heterocycles
HO
copper powder (0.1 eq.), Cs2CO3 (3 eq.),
DMF, 100 oC, 60 Watts (microwave only)
O
Het
+
Het-X (1.0 eq.)
9-13
(R=H)
2
Entry
1
Het–X
Product
Conventional heating
yielda (%)
Microwave heating
yielda (%)
4-Chloroquinoline
72
80
O
N
(9)
N
O
2
3
2-Chloropyrimidine
85
76
97
87
N
(10)
S
N
O
2-Chlorobenzothiazole
(11)
4
5
6
7
8
9
4-Bromopyridine
4-Iodopyridine
3-Chloropyridine
2-Chloropyridine
2-Bromopyridine
2-Iodopyridine
4-Phenoxypyridine (3)
4-Phenoxypyridine (3)
3-Phenoxypyridine (12)
2-Phenoxypyridine (13)
2-Phenoxypyridine (13)
2-Phenoxypyridine (13)
32
82
Trace
11
64
83
75
4
49
83
86
91
a Isolated yield.
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Acknowledgements
We thank Professors Stephen Buchwald and Eric Jacob-
sen and Dr. Michael Martinelli for helpful discussion
and encouragement.
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14. Microwave irradiation of just the copper powder in DMF,
followed by coupling using conventional heating at 100 °C
for 18 h afforded only a modest increase in the yield of 3,
from 17% to 25%.
15. General microwave reaction procedure: 4-chloropyridine
hydrochloride (224 mg, 1.5 mmol) and phenol (221 mg,
2.24 mmol) were suspended in DMF (3.3 ml) in a micro-
wave vial and copper powder (9.5 mg, 0.15 mmol, Aldrich
99%, 1–5 lm), and cesium carbonate (1.45 g, 4.45 mmol)

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N. D. D’Angelo et al. / Tetrahedron Letters 47 (2006) 5045–5048
were added. The vial was sealed, shaken for 10 s, and then
crude material was purified via flash chromatography
(50:1 CH2Cl2/MeOH) to afford 4-phenoxypyridine (3,
175 mg, 69%) as a white solid: 1H NMR (400 MHz,
CDCl3) d 8.48 (d, J = 4.0 Hz, 2H), 7.44 (t, J = 8.0 Hz,
2H), 7.29–7.25 (m, 1H), 7.11 (d, J = 8.0 Hz, 2H), 6.85 (d,
J = 8.0 Hz, 2H); MS (API-ES) calcd for C11H10NO
(MH)+: 172.1, found 172.0 m/z; Elemental analysis calcd
for C11H9NO: C, 77.17; H, 5.30; N, 8.18. Found: C, 77.02;
H, 5.25; N, 8.06.
placed in the microwave (CEM, DiscoverÒ). The reaction
was run by ramping the temperature setting to 100 °C over
5 min and then maintaining this temperature setting for
10 min. For the entire experiment, the power setting was
held at 60 W. The reaction was then cooled to room
temperature and diluted with CH2Cl2 (25 ml). The organic
phase was washed with 1 N NaOH (60 ml) and water,
dried over sodium sulfate, filtered, and concentrated. The