Screening of ligands for the Ullmann synthesis of electron-rich diaryl ethers

Article abstract of DOI:10.3762/bjoc.8.122

In the search for new ligands for the Ullmann diaryl ether synthesis, permitting the coupling of electron-rich aryl bromides at relatively low temperatures, 56 structurally diverse multidentate ligands were screened in a model system that uses copper iodide in acetonitrile with potassium phosphate as the base. The ligands differed largely in their performance, but no privileged structural class could be identified.

Full text of DOI:10.3762/bjoc.8.122

Screening of ligands for the Ullmann synthesis of
electron-rich diaryl ethers
Nicola Otto and Till Opatz*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1105–1111.
Institute of Organic Chemistry, University of Mainz,
Duesbergweg 10–14, 55128 Mainz, Germany
doi:10.3762/bjoc.8.122
Received: 27 April 2012
Accepted: 04 July 2012
Published: 17 July 2012
Email:
Till Opatz* - opatz@uni-mainz.de
* Corresponding author
Associate Editor: M. Rueping
Keywords:
© 2012 Otto and Opatz; licensee Beilstein-Institut.
License and terms: see end of document.
catalysis; C–O bond formation; diaryl ethers; nucleophilic aromatic
substitution; Ullmann-type coupling
Abstract
In the search for new ligands for the Ullmann diaryl ether synthesis, permitting the coupling of electron-rich aryl bromides at rela-
tively low temperatures, 56 structurally diverse multidentate ligands were screened in a model system that uses copper iodide in
acetonitrile with potassium phosphate as the base. The ligands differed largely in their performance, but no privileged structural
class could be identified.
Introduction
The diaryl ether linkage is a common structural motif encoun- protocol suffers from considerable limitations due to the use of
tered in numerous classes of natural products. Moreover, stoichiometric or superstoichiometric amounts of copper
various diaryl ethers have been shown to possess antibacterial, powder and typically requires high reaction temperatures
anti-inflammatory, antifungal and herbicidal activity, rendering (≈200 °C), thus tolerating only a limited number of functional
this compound class attractive for pharmaceutical and agro- groups. Alternatively, C–O bond formation can be accom-
chemical research [1,2]. Prominent examples of bioactive plished by efficient Pd-catalyzed arylations of phenols devel-
natural representatives include the glycopeptide antibiotic oped by Buchwald [10,11] and Hartwig [12,13] in the 1990s.
vancomycin [3,4], the bisbenzylisoquinolines tubocurarine [5] Nevertheless, the use of this expensive metal in combination
and tetramethylmagnolamine [6], and the antifungal diamine with sensitive and costly phosphine ligands limits the use of
piperazinomycin [7] (Figure 1).
palladium catalysis for industrial-scale applications and
economic aspects have led to a renaissance of the Cu-catalyzed
A straightforward method for the formation of diaryl ethers is reaction in recent years [14]. It is known that certain additives,
the Cu-catalyzed coupling of aryl halides with phenols, first such as N,N- and N,O-chelating ligands, accelerate the Ullmann
reported by Fritz Ullmann in 1903 [8,9]. However, the classical diaryl ether synthesis and permit a considerable reduction of the
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Beilstein J. Org. Chem. 2012, 8, 1105–1111.
Results and Discussion
A set of 56 multidentate ligands with different chelating func-
tionalities and bite angles, belonging to the structural classes of
amino acids, acetic acid derivatives, phosphinites, phospho-
nates, imines, diimines, oximes, oxime ethers and diketones
were selected for the screening (Figure 2). Several of these
compounds have been employed in diaryl ether syntheses
before [22-24].
As a starting point, N,N-dimethylglycine (L1) introduced by
Ma et al. [22,25] in combination with copper iodide as the
Cu-source was chosen, as this ligand has been successfully
applied by us in a synthesis of two dimeric benzylisoquinoline
alkaloids [26]. This model system was optimized with respect to
the influence of different bases, molecular sieves, solvents, and
temperatures (Table 1).
It turned out that caesium carbonate as a base without addition
of molecular sieves did not result in any diaryl ether formation,
presumably due to the formation of water inactivating the base.
With chemical drying agents such as magnesium sulfate, only
trace amounts of the product were obtained. In contrast, potas-
sium phosphate proved to be a more suitable base for diaryl
ether formation and did not require the addition of molecular
sieves. After screening of different solvents, the combination of
copper(I) iodide (10 mol %), N,N-dimethylglycine L1
(10 mol %) as the ligand, potassium phosphate (2.0 equiv) as
the base and acetonitrile as solvent (80 °C) was identified as an
efficient system for the coupling of the above-mentioned
starting materials (1.0 mmol each in 0.6 mL). Although the sub-
strate conversion in acetonitrile at 80 °C was lower than in
toluene at 110 °C (Table 1, entries 5 and 7), acetonitrile was
selected as the solvent for the ligand screening in order to be
able to compare ligands that give higher conversions than L1
and to get a better impression of the respective reaction rates.
The substrate conversion of the screening reactions was moni-
Figure 1: Selected examples of bioactive natural diaryl ethers.
reaction temperature [15-17]. Successful approaches towards a tored and determined by 1H NMR spectroscopy at specific time
mild coupling were, e.g., developed by Taillefer and Buchwald intervals (2 h 15 min and 24 h).
in 2003 and 2004 who used multidentate ligands and a
5–10 mol % catalyst loading at 90–110 °C [18-20]. However, In the short-term screening, promising results were obtained
the majority of ligands reported in the literature to date exhibit a with N,P-chelating phosphinite ligands such as L19 and L20,
limited substrate scope, and application of the methodology to amino acid-derived N,O-ligands such as L2 and L3 and N,O-
more complex molecules is still challenging.
and N,N-ligands with a rigid backbone such as 8-aminoquino-
line (L44) and 8-hydroxyquinoline (L47) (Table 2 and
For the synthesis of alkaloids containing the diaryl ether Figure 3). These ligands have been reported to be effective in
linkage, we searched for efficient ligands for the Ullmann the Cu-catalyzed diaryl ether synthesis before [21,27-29].
coupling of electron-rich aryl bromides as the substrates and
performed a ligand screening using the model system A disadvantage of ligands with free amino or hydroxy groups,
4-bromoanisole/4-methoxyphenol. To the best of our knowl- such as L44, is that they themselves can act as substrates in the
edge, this represents the most diverse ligand set investigated for Ullmann-type coupling, which may result in the formation of
a similar purpose so far [21].
undesired side products and a loss in catalyst performance. To
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Beilstein J. Org. Chem. 2012, 8, 1105–1111.
Figure 2: Ligands that were subjected to the ligand screening.
avoid this complication, the N,N-dimethylated derivative L43 tested, but even these minor modifications of the ligand struc-
was synthesized and turned out to exhibit an improved catalytic ture led to a drastically decreased catalytic activity.
activity compared to L44. Since L1 showed high catalytic
activity, its 2,2-dimethylated analogue L5 and the structurally Interestingly, not only the N,P-chelating phosphinite ligands
related pyrrolidino- and piperidinoacetic acids L9 and L15 were L19 and L20 but also the N,O-chelating phosphonate ligand
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Beilstein J. Org. Chem. 2012, 8, 1105–1111.
Table 1: Effect of base, molecular sieves and solvent on the coupling of 4-bromoanisole and 4-methoxyphenol with L1.a
ratio of
4-bromoanisole/product
entry
base
drying agent
CuI (mol %)
solvent
1
2
3
4
5
6
7
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
–
10
5
tolueneb
tolueneb
tolueneb
tolueneb
MeCNd
no conversionc
conversionc
conversionc
tracesc
MS 4 Å
MS 4 Å
10
10
10
10
10
MgSO4
–
–
–
8:1e
K3PO4
1,4-dioxanef
tolueneb
9:1e
K3PO4
2:1e
aReaction conditions: base (2.0 equiv), CuI (10 mol %), L1 (10 mol %), 4-methoxyphenol (1.00 mmol, 1.0 equiv), 4-bromoanisole (1.00 mmol,
1.0 equiv), solvent (0.6 mL), argon atmosphere; b110 °C; cjudged by TLC; d80 °C; edetermined by 1H NMR; f100 °C.
Table 2: Short-term screening.a
entry
ligand
ratio 4-bromoanisole/productb
entry
ligand
ratio 4-bromoanisole/productb
1
L1
8:1
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
L29
L30
L31
L32
L33
L34e
L35
L36
L37
L38
L39
L40f
L41
L42
L43
L44
L45
L46
L47
L48
L49
L50
L51g
L52g
20:1
2
L2
12:1
31:1
3
L3
15:1
no conversion
no conversion
no conversion
15:1
4
L4
18:1
5
L5
19:1
6
L6
20:1
7
L7
20:1
18:1
8
L8
20:1
20:1
9
L9
21:1
20:1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
L10
L11
L12
L13
L14
L15
L16c
L17d
L18
L19
L20
L21
L22
L23
L24
21:1
20:1
26:1
24:1
27:1
28:1
29:1
traces
traces
13:1
30:1
32:1
40:1
15:1
traces
no conversion
12:1
24:1
24:1
15:1
12:1
12:1
15:1
traces
23:1
25:1
40:1
15:1
traces
15:1
1108

Beilstein J. Org. Chem. 2012, 8, 1105–1111.
Table 2: Short-term screening.a (continued)
25
26
27
28
L25
L26
L27
L28
traces
53
54
55
56
L53
L54
L55
L56
21:1
traces
27:1
no conversion
17:1
traces
no conversion
areaction conditions: K3PO4 (2.0 equiv), CuI (10 mol %), ligand (10 mol %), 4-methoxyphenol (1.00 mmol, 1.0 equiv), 4-bromoanisole (1.00 mmol,
1.0 equiv), MeCN (3 mL), 80 °C, argon atmosphere; bdetermined by 1H NMR; ctime: 2 h; dtime: 2 h 35 min; etime: 3 h; ftime: 2 h 40 min;
gtime: 2 h 25 min.
L21 showed a significant catalytic activity. From the group of tested ligands showed a higher substrate conversion than L1
diimine ligands, L28 [30] gave the best results. It should be did.
noted that also in this class, structurally related ligands showed
drastically different catalytic activities in the screening, as can The most promising ligands of the short-term screening were
be seen by comparison of L28, L32, and L33. Furthermore, subsequently subjected to a long-term screening (24 h) to
oxime ethers, which, to the best of our knowledge, represent a examine their thermal and chemical stability (Table 3,
new class of ligands for Ullmann-type couplings, were also Figure 3).
screened in the model reaction. All tested oxime ethers and
oximes showed catalytic activity, although the substrate conver- In the long-term screening the ligands L2, L43 and L48 showed
sion was lower compared to the amino acid-derived ligands. promising results since their substrate conversions were only
The catalytic activities of the oximes did not, however, differ slightly lower than that of L1, which again was unsurpassed.
from those of the oxime ethers. On the other hand, the salicyl The phosphinite ligands L19 and L20, which showed compa-
aldehyde-derived oxime ether and oxime ligands [31] showed rable catalytic activities to L2, L43 and L48 in the short-term
only poor substrate conversions in comparison to other classes screening, in comparison gave lower substrate conversions in
of multidentate ligands. L48 also proved to possess a high the long-term screening. This decrease of catalytic activity may
catalytic activity, which is consistent with the results reported be due to oxidation and subsequent hydrolysis of the air- and
by Beller et al. [32] who used the ligand for the synthesis of water-sensitive phosphinites to their corresponding phosphinic
various diaryl ethers. In the short-term screening, none of the acids and 8-hydroxyquinoline (L47), which showed a compa-
Figure 3: Conversions of the model reaction versus the ligand numbers. For structures of the ligands refer to Figure 2.
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Beilstein J. Org. Chem. 2012, 8, 1105–1111.
Table 3: Long-term screening.a
entry
ligand
L1
time
ratiob
entry
ligand
L20
time
ratiob
1
2
2 h 15 min
24 h
8:1
3:1
5
6
2 h 15 min
24 h
12:1
6.5:1
L2
2 h 15 min
24 h
12:1
3.5:1
L28
2 h 15 min
3 h 15 min
24 h
17:1
9:1
5:1
3
4
L3
2 h 15 min
24 h
15:1
5:1
7
8
9
L43
L47
L48
2 h 15 min
24 h
13:1
3.5:1
L19
2 h 15 min
24 h
12:1
4.5:1
2 h 15 min
24 h
15:1
5:1
2 h 15 min
24 h
12:1
3.5:1
aReaction conditions: K3PO4 (2.0 equiv), CuI (10 mol %), ligand (10 mol %), 4-methoxyphenol (1.00 mmol, 1.0 equiv), 4-bromoanisole (1.00 mmol,
1.0 equiv), MeCN (3 mL), 80 °C; bratio of 4-bromoanisole to product, determined by 1H NMR.
rable catalytic activity. It was found that the conversion within a published ligands used for other C-heteroatom bond-formation
specific time interval decreased over time stronger than antici- reactions showed unexpected low activity in our system.
pated, and finally the reaction ceased. The stagnation may be
Experimental
due to the formation of traces of water in the reaction mixture or
General procedure for model reactions of the
ligand screening
formation of a catalytically less active copper(I)–bromide com-
plex from liberated bromide ions. Another alternative may be
the decomposition of the ligands.
A dried reaction tube (diameter 1.5 cm) equipped with a stir-
ring bar (length 0.6 cm) is charged with anhydrous K3PO4
(430 mg, 2.00 mmol, 2.0 equiv) under an argon atmosphere in
counterflow. CuI (14 mg, 0.10 mmol, 10 mol %), ligand
(0.10 mmol, 10 mol %), 4-methoxyphenol (124 mg, 1.00 mmol,
1.0 equiv), 4-bromoanisole (130 μL, 187 mg, 1.00 mmol,
1.0 equiv) and 1 mL of anhydrous acetonitrile is subsequently
added, and the tube is sealed with a septum and equipped with
an argon balloon. The reaction mixture is stirred for 30 min at
room temperature and is then placed in a heating bath at 80 °C.
Samples of 500 μL of the reaction mixture are taken after
2 h 15 min and 24 h. The samples are filtered over Celite and
washed with dichloromethane, and the filtrate is evaporated in
vacuo. The conversion of starting material is determined by
1H NMR spectroscopy.
Conclusion
A collection of 56 multidentate ligands were screened in a
model system for the Ullmann diaryl ether synthesis of elec-
tron-rich phenols and aryl bromides. Structurally diverse
ligands showed a catalytic activity in the coupling, but none of
the ligands showed a higher catalytic activity than N,N-
dimethylglycine (L1). In the long-term screening, the ligands
L2, L43 and L48 were found to exhibit only slightly lower
catalytic activity than L1 in the model reaction. In conclusion,
N-methylated amino acid-derived N,O-ligands, N,N-ligands
with small bite angles, and N-butylimidazole proved to be the
most efficient ligands for Ullmann diaryl ether formation under
the tested conditions. The synthesized phosphinite-type P,N-
ligands derived from 8-hydroxyquinoline performed well in the
short-term screening but lost catalytic activity over time. While
active ligands were found in various structural classes, even
relatively small variations of the efficient ligands can lead to a
dramatic loss of catalytic activity, which complicates their
rational optimization. In general, strongly chelating ligands with
four coordinating atoms should be avoided. Coordination of the
copper atom by one N- and one N- or O-atom may be a desir-
able structural motif for the design of new ligands. Remarkably,
Supporting Information
Supporting Information File 1
Experimental procedures and characterization data of
ligands and starting materials.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-122-S1.pdf]
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