N-Picolinamides as ligands in Ullman type C–O coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2017.07.099

Copper-catalyzed modified Ullmann coupling reactions creating C–O bonds, including diaryl ethers or phenols, are vital to organic synthesis. Synthesized N-phenyl-2-pyridinecarboxamide and its derivatives were used as ligands in conjunction with catalytic copper sources in the formation of various diaryl ethers and phenols. Various aryl and heteroaryl halides with electron donating and withdrawing groups were reacted with various phenols under mild reaction conditions providing moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2017.07.099

Accepted Manuscript
N-Picolinicamides as ligands in Ullman type C-O coupling reactions
Fehmi Damkaci, Cihad Sigindere, Thomas Sobiech, Erik Vik, Joshua Malone
PII:
S0040-4039(17)30969-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.099
TETL 49181
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 July 2017
25 July 2017
28 July 2017
Please cite this article as: Damkaci, F., Sigindere, C., Sobiech, T., Vik, E., Malone, J., N-Picolinicamides as ligands
in Ullman type C-O coupling reactions, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.07.099
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N-Picolinicamide Derivatives as Ligands in
Ullman Type C-O Coupling Reaction
∗
Fehmi Damkaci, Cihad Sigindere, Thomas Sobiech, Erik Vik, and Joshua Malone
Department of Chemistry, SUNY Oswego, Oswego NY 13126, USA
NPPA (20%),
Cu (20%)
NPPA (5%),
Cu2O (5%)
X
YH
X
Z
Y
Z
OH
R
R1
R2
R1
R2
+
R
Cs2CO3, MeCN
82oC, 24 hr.
2mL DMSO,
2 mL 3M NaOH
MW, 160oC, 10 min
W
W
X = I, Br, Cl
W = C or N
Y = O or S
Z = C or N
11-95%
51-98%

1
Tetrahedron Letters
journal homepage: www.els evier.com
N-Picolinicamides as ligands in Ullman type C-O coupling reactions
∗
Fehmi Damkaci, Cihad Sigindere, Thomas Sobiech, Erik Vik, and Joshua Malone
Department of Chemistry, SUNY Oswego, Oswego NY 13126, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Copper-catalyzed modified Ullmann coupling reactions creating C-O bonds, including diaryl
ethers or phenols, are vital to organic synthesis. Synthesized N-phenyl-2-pyridinecarboxamide
and its derivatives were used as ligands in conjunction with catalytic copper sources in the
formation of various diaryl ethers and phenols. Various aryl and heteroaryl halides with electron
donating and withdrawing groups were reacted with various phenols under mild reaction
conditions providing moderate to excellent yields.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
Ullmann-type coupling
Diaryl ether synthesis
Copper catalyzed
N-Picolinamides
Phenols
1. Introduction
phenanthroline,21e l-sodium ascorbate,21f imidazole-4-carboxylic
acid,21g and others.21h,i Various pyridine N-oxides have been
successfully employed as ligands in copper - catalyzed coupling
reactions.22 Picolinamide - derived ligands have also been
utilized as ligands in group-directed C-H bond activation23 and in
asymmetric Mannich-type reactions.24
The importance of diaryl ethers and phenols arise from their
frequent incorporation in several biologically active molecules,1
including several natural products such as Verbanachalone,2
Fenoprofe,3 Sorafenib,4 XK469,5 Tafenoquine,6 AMG900,7 and
many polymers.8
In our previous studies, we successfully demonstrated the first
use of N-phenylpicolinamide (NPPA, L4 in Figure 1) as an
efficient ligand to form aryl-aryl C-C bonds in Ullmann type
homocoupling reactions, utilizing aryl chlorides, and in base-free
Suzuki-type heteroaryl coupling.25 Recently, we also showed the
use of N-phenylpicolinamide-1-oxide (NPPA-O, L5 in Figure 1)
as a ligand for Ullmann-type C-N coupling reactions of aryl
halides, again using aryl chlorides, with various N-
arylheterocycles in acetonitrile or DMSO at moderate
temperatures.26
Since its discovery by Fritz Ullmann and Irma Goldberg in the
early 1900s,9 the Ullmann reaction has become one of the
general methods for C–C, C–N, and C–O bond formation in aryl
couplings.10 However, the Ullmann reaction has not been the
preferred method until recently, because of its main drawbacks:
the necessity of high temperatures, high boiling polar solvents,
and the large amount of copper required.
Disadvantageous aspects of the copper catalyzed cross-
coupling reactions have been addressed by using the ligands
developed by Buchwald,11 Ma,12 and Libenskind.13 These
advances have increased the scope of Ullman - based cross-
coupling reactions. Therefore, during the last decade extensive
research efforts have been devoted to develop alternative ligands
to overcome the limitations of copper - catalyzed reactions in
Ullmann type couplings in order to increase the yields using
moderate reaction conditions.10,14,15 The use of ligands with
copper salts in catalytic amounts affords reactions which are less
expensive, environmentally friendly, with easily purified
products more amenable to scale-up; thus more versatile
methodology relative to palladium-catalyzed systems.16 Other
metal catalyzed methods using Cu nanoparticles,17 FeCl3,18
NiLn,19 and Rh(OAc)420 have been also reported for the synthesis
of phenols and ethers.
In continuation of our efforts on ligand development for
Ullmann-type copper catalyzed couplings, we herein successfully
demonstrate the use of NPPA and NPPA-O as ligands for
Ullmann-type C-O bond formations from aryl iodides and
bromides as well as aryl chlorides to synthesize diaryl ethers,
diaryl thiothers, and phenols.
2. Results and Discussion
For our preliminary studies, the coupling reaction of 3,5-
dimethylphenol and iodobenzene was investigated to optimize
the reaction conditions including ligand, solvent and base by
following our general coupling procedure (Table 1).27
First, to explore the role of ligands on catalytic activity,
several ligands L1-L5 were screened for O-arylation of
iodobenzene with 3,5-dimethylphenol using 20 mol % of
activated copper and Cs2CO3 in acetonitrile (MeCN) at reflux
temperature (Table 1, entries 1–5). When picolinic acid (L1,
Several classes of ligands have been developed for Ullmann
type C-O bond formations, including 4-pyrrolidinopyridine,21a 1-
naphthonic acid,21b 8-hydroxyquinoline,21c β-keto ester,21d 1,10-

2
Tetrahedron
Figure 1) and picolinic acid N-oxide (L2, Figure 1) were used
O-arylation of iodobenzene in the presence of L4 (NPPA) in
both dioxane and DMF gave similar but slightly lower yields
(73–79%) to MeCN (Table 1, entries 8 and 10), while the
reaction in pyridine provided a much lower yield, respectively
(Table 1, entries 7). The outcomes with L5 (NPPA-O) as a ligand
using solvents such as pyridine, dioxane, DMF, DMSO, and THF
did not improve upon the results with L4 (Table 1, entries 11–
15). Since the yield was increased only slightly with increased
as the ligands, the coupled diaryl ether product was obtained in
only 59% and 14% yields, respectively (Table 1, entries 1 and 2),
which were similar to the literature results.21g When
picolinamides L3 and L5 were used as ligands, the reaction
provided yields in 62% and 63%, respectively (Table 1, entries 3
and 5). However, N-phenylpicolinamide L4 (NPPA) showed a
significant increase in reactivity by providing the coupled
product in 83% yield in MeCN at 82 oC (Table 1, entry 4).
O
temperature by using dioxane at 100 C as the solvent compared
to reaction at 82 oC (Table, 1 entries 4, 8, and 9), acetonitrile was
preferred as a solvent to achieve good results at lower
temperatures.
O
O
O
N
O
N
N
OH
OH
OH
L3
When K2CO3 or K3PO4 were used as bases, the starting
materials were mostly recovered, which made Cs2CO3 the base of
choice for the C-O bond formations (Table 1, entries 5, 16–17).
Finally, in addition to activated copper, CuI was also evaluated
along with using L4 as the ligand. The reaction with CuI
produced the coupled products in somewhat lower yield (77%,
Table 1, entry 18) when compared to reactions in which activated
copper (83%) was used. In the absence of any copper metal
source in the reaction, the starting materials were recovered
completely.
L2
L1
O
O
N
O
N
N
H
N
H
L5
L4
Figure 1. Picolinicamide derivatives as ligands
The comparison of ligands, L3 (62%), L4 (83%), L5 (63%),
shows the importance of both N-phenyl amide and pyridyl
nitrogen moieties for increased activity. The importance of the N-
phenyl amide moiety, which may have both electronic and steric
effects on ligand activity, was also shown in our previous studies
of C-C and C-N bond formation.25,26 On the other hand, the
reaction provided almost no product without any ligand, showing
its necessity for activity (Table 1, entry 6).
In summary, the optimal conditions for this cross-coupling
consisted of the combination of activated Cu (20 mol %), L4 (20
mol %), Cs2CO3 (1.5 equiv.) in acetonitrile at 82 oC or dioxane at
100 OC, for 24h under nitrogen atmosphere by following the
general coupling procedure.27
Once the conditions were optimized, we subsequently tested
the scope of the reaction with various aryl halides carrying
different substituents to furnish the corresponding products in
moderate to excellent yields under the standard reaction
conditions, as detailed in Table 2.
Table 1.The effect of ligand, solvent and base type on aryl ether formation
OH
I
O
Cu, Ligand
+
Base, Solvent
82oC, 24 hr.
Solvent
MeCN
Table 2. 3,5-dimethylphenol reacting with various aryl halides
Entry
1
Ligand
L1
Base
Yield (%)a
59
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
OH X
+
O
Cu, NPPA
2
L2
MeCN
24
R
R
3
L3
MeCN
62
Cs2CO3, MeCN
82oC, 24 hr.
4
L4
MeCN
83
Yield (%)a
83
5
L5
MeCN
63
Entry
1
X
I
R
6
None
L4
MeCN
9
H
7
Pyridine
Dioxane
Dioxane
DMF
55
2
I
4-COCH3
2-OCH3
4-OCH3
2-CH3
4-CH3
2-NO2
3-NO2
4-NO2
4-CH3
2-NO2
4-NO2
2-NO2
4-OCH3
65
8
L4
79
88b
3
I
30
9
L4
4
I
58
10
11
12
13
14
15
16
17
18
L4
73
5
I
45
L5
Pyridine
Dioxane
DMF
48
6
I
81
L5
33
60b
7
I
76
L5
8
I
78
L5
DMSO
THF
40
3c
9
I
93
L5
10
11
12
13
14
Br
Br
Br
Cl
Cl
25
L5
MeCN
29
70
L5
MeCN
K3PO4
18
77d
83
L4
MeCN
Cs2CO3
80b
NRb
a Isolated yield. Cu and ligand were used at 20% ratio. b at 100 °C. c at 66 °C,
starting material is recovered. d CuI used as instead of Cu.
a
Isolated yields. b Solvent is dioxane reacting at 100 °C.
It has been known that picolinamide or its N-substituted
derivatives coordinate copper ions by acting as N,O-
coordinating ligands under neutral conditions,22a which may also
explain the results observed in our coupling reactions by the
addition of NPPA.13 Presumably, copper (I) ion, generated in-
situ, was coordinated by both the nitrogen of the pyridine and
the oxygen of the carbonyl moiety of L4 (NPPA) by the
formation of five-membered-ring coordinates with a copper
center, whereas L5 (NPPA-O) was shown to form six-membered
ring coordinates with a copper center.22a
First, we observed that both electron-donating and electron-
withdrawing substituents, such as nitro, acetyl, methyl, and
methoxy at the para-position were tolerated on the aryl iodide
component in C-O coupling reactions under our reaction
conditions. Electron-poor para-disubstituted aryl iodides
including, 4-iodonitrobenzene and 4-iodoacetophenone coupled
with 3,5-dimethylphenol in high yields (65–93%, Table 2, entries
2 and 9), while aryl iodides with electron - rich substituent
groups including, 4-iodomethoxybenzene and 4-iodotoluene also

3
provided desired products in 59% and 81% yields in MeCN at 82
oC, respectively (Table 2, entries 4 and 6). Furthermore, the
sterically hindered aryl halides had an impact (20-30% reduction
in yields) on the outcome of the reaction, which was indicated by
using ortho substituted aryl iodides and bromides in comparison
to their para - substituted counterparts (Table 2, entries 2–9 and
11–12). Generally, aryl bromides have a lower reactivity than
aryl iodides in Ullmann-type couplings, which was shown to be
the case under our reaction conditions as well, providing C-O
bond formation in 25-83% yield, depending on the electronic
nature of the aryl halide (Table 2, entries 10–12).
despite its sterically hindered nature compared to phenol, with
electron - poor or rich aryl iodides and bromides proceeded with
slightly higher yields (Table 3, entries 6–9). Indeed, electron -
rich 4-methoxy phenol provided coupled products with electron -
rich or poor aryl iodides and bromides in very good yields (82–
92%, Table 4, entries 10–13). Overall, coupling of electron - rich,
neutral, or ortho-substituted phenols, with electron - poor or rich
aryl iodides and bromides under our reaction conditions works
well to furnish the desired C-O couple products in good to high
yields, showing a wide reaction scope.
Table 4. Heterocyclic diaryl ether and thioether synthesisa
Usually, aryl chlorides have not appeared as coupling partners
in C-O bond formations in the recent literature; either they do not
work or they were not tested, since they are well known for their
low reactivity in coupling reactions. However, to our surprise,
when a sterically hindered ortho-subsituted aryl chloride with a
strong electron withdrawing group was examined using our
ligand, it provided coupled product in good yields (80%, Table 2,
entry 13) at 100 oC. On the other hand, electron rich aryl
chlorides did not react even at elevated temperatures (Table 2,
entry 14).
Entry
R1
3,5-CH3
3,5-CH3
3,5-CH3
H
W
CH
CH
CH
N
Y
O
O
O
O
O
X
Br
Cl
Cl
I
Z
N
R2
H
Yield (%) a
1
2
3
4
5
53
60b
57b
95
N
H
N
6-Cl
4-NO2
4-NO2
CH
CH
H
N
Br
89
6
7
4-CH3
4-CH3
CH
CH
S
S
I
CH
CH
4-NO2
4-NO2
93
88
Br
a Isolated yields. b Solvent is dioxane reacting at 100 °C.
Diaryl ethers containing heteroaryl ring systems28 and thio
aryl ethers have significant importance as intermediates in
organic synthesis as well in pharmaceuticals.29 Hence, it is not
surprising that synthesis of novel compounds of heteroaryl diaryl
ethers and thioaryl ethers as the building blocks looms as an area
of active research endeavor. The coupling reactions with
heterophenols and heteroaryls, including chlorides, proceeded
with good yields (Table 4). The reaction of 3,5-dimethylphenol
with 2-bromo pyridine gave the coupled heterocyclic products in
moderate yields (53%, Table 4, entry 1). When 2-chloro pyridine
was used, the reaction afforded similar yields in dioxane at 100
oC (60%, entry 2). The reaction of 2,6-dichloropyridine gave only
Figure 2. Selectivity with benzyl halides vs aryl halides.
We have also studied the effect of varying the stoichiometry
of 3,5-dimethylphenol with various ortho-halide benzyl bromides
(Figure 2). When 2-iodo benzylbromide reacted with 3,5-
dimethylphenol, the reaction afforded the benzyl site - coupled
product in 85% yield, while 2-chloro benzyl bromide as a
substrate provided the analogous product in 74% yield. However,
varying the stoichiometry of 3,5-dimethylphenol (1.1 or 2.5
equiv.) used in the reaction did not provide the di-coupled
product as it did in our previous studies in C-N coupling using
the same ligand.26 This result shows that C-O coupling is much
more sensitive to steric hindrance than C-N coupling under
similar reaction conditions.
mono etherification with no loss of yields (57%, entry 3).
A
heteroaryl phenol, such as 3-pyridyl phenol, reacted similarly
under our reaction conditions with aryl iodides and bromides
(95%, 89%, respectively, entries 4 and 5). Thiols did not differ in
terms of reactivity toward coupling with aryl halides and
provided high yields (entries 6 and 7).
Table 3. The effect of steric and electronic changes on phenol
OH X
+
O
Cu, NPPA
When ligands L4 and L5 were tested in converting aryl
halides into phenols using microwave irradiation, we were
successful in obtaining corresponding phenols in very good
yields after 10 minutes. Catalytic amounts of activated copper
also generated phenols similarly, however due to the use of the
microwave as the heating source, it was avoided. Therefore, our
focus shifted towards the use of copper (I) salts in converting aryl
halides into phenols under microwave irradiation.
R1
R2
R1
R2
Cs2CO3, MeCN
82oC, 24 hr.
X
Entry
1
R1
H
R2
Yield (%)a
71
I
I
4-OCH3
4-CH3
4-NO2
4-CH3
4-NO2
4-CH3
4-NO2
4-CH3
4-NO2
4-CH3
4-NO2
H
2
H
H
H
H
76
84
39
81
79
88
41
79
83
92
82
89
3
I
4
Br
Br
I
5
For our preliminary studies, the reaction of 1-iodo-4-
nitrobenzene and 4-iodoanisole in aqueous sodium hydroxide
were investigated to optimize the reaction conditions including
ligand, solvent, solvent/base solution ratio, and temperature by
following our general coupling procedure for the synthesis of
phenols using Cu2O as the copper source (Table 5).30
6
2-CH3
2-CH3
7
I
8
2-CH3
Br
Br
I
9
2-CH3
10
4-OCH3
4-OCH3
4-OCH3
4-OCH3
11
I
12
I
Both ligands L4 (NPPA) and L5 (NPPA-O) ligands were
successful in converting electron - rich and poor aryl halides into
phenols under our reaction conditions by using Cu2O and ligand
in 5% amount (Table 5). Cu2O was selected as the copper source
due to its air stability and high performance in initial testing
under our conditions when compared to copper (I) iodide and
bromide. L4 was selected as the ligand in further studies, since
its synthesis is simpler than that of N-oxide derivative L5.
13
a Isolated yields.
Br
4-NO2
Next, the chemistry of Cu/ L5 in C-O cross-coupling of
various phenols with a variety of aryl halides was explored in an
attempt to probe the effect of steric and electronic changes on the
phenolic component in these reactions by following the general
coupling procedure (Table 3). The reaction of 2-methyl phenol,

4
Tetrahedron
o
When the temperature was lowered to 125 C, the reaction
Next, we have studied the effect of electron density and steric
hindrance around aryl halides in their conversion into phenol
under our conditions (Table 6). Meta substitution by a nitro
group (44% yield, entry 3) or a sterically hindered ortho-methoxy
group reduced the reactivity in half (53% yield, entry 5) and
afforded the desired phenols in moderate yields.
slowed significantly and resulted in lower yields during a 10
minute reaction time (39%, Table 5, entry 5). It should be noted
o
that the reaction went to completion at 125 C if allowed to run
for 30 minutes (97%, entry 6). In order to complete the reaction
o
within 10 minutes, we set the microwave temperature at 160 C
(98% yield, entries 6 and 7).
When aryl dihalides, such as iodo-bromo or iodo-chloro
systems were employed, the reaction provided only mono-
substitutions at the iodo position, even with increased
concentrations of NaOH, generating 4-bromo phenols or 4-chloro
phenols in moderate to good yields (72% and 51% yields,
respectively, entries 6 and 7).
Table 5. The effect of ligand, solvent and base type on phenol formation
X
HO
Cu2O (5%), Ligand (5%)
R
R
3 M NaOH, Solvent,
MW, 10 min, Temp.
Both aryl bromides and chlorides were shown to be reactive
under our conditions providing corresponding phenols with little
loss in yield compared to aryl iodides (entries 10-11). 1-
iodonaphthalene was converted into 1-naphtol in 10 minutes with
97% yield using the Cu2O/NPPA catalyst system under our
reaction conditions.
Entry
R
X
Br
Br
Br
Br
Br
Br
Br
I
3M NaOH DMSO Ligand T,oC Yield (%)a
1
2
4-NO2
4-NO2
3 mL
-
1 mL
4 mL
1 mL
1 mL
1 mL
1 mL
2 mL
2 mL
2 mL
2 mL
2 mL
2 mL
L5
L5
L4
L4
L4
L4
L4
L4
-
170
170
170
150
125
125
160
160
160
160
160
160
98
0
3
4-NO2
3 mL
3 mL
3 mL
3 mL
2 mL
2 mL
2 mL
2 mL
2 mL
2 mL
98
94
39
97b
98
98
42
0c
4
4-NO2
5
4-NO2
3. Conclusion
6
4-NO2
7
4-NO2
In summary, the use of a catalytic amount of N-phenyl-2-
pyridincarboxamide (L4) as a ligand with activated copper in
Ullmann - type diaryl syntheses between aryl bromides and
iodides and heterophenols in MeCN at 82oC has been
successfully demonstrated. In addition, this work provided
diarylether synthesis in good to high yields using aryl chlorides
in dioxane as solvent at 100 oC, which is a relatively low
temperature when compared to regular Ullmann reaction
temperatures with aryl chorides.The reaction provided the
corresponding products in the coupling of electron-rich, electron
- poor, and ortho-substituted aryl halides, including ortho –
substituted arylchlorides, in good to very good yields. O-
Arylation is selectively preferred at the benzyl position when
ortho-halide benzyl bromide is reacted.
8
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
9
I
10
11
I
-
I
L1
L4
84
98d
12
I
a
b
c
d
Isolated yields. Run for 30 min. Without Cu2O. Solvent is ethylene
glycol.
The efficiency of the reaction dropped by half when no ligand
was added into the reaction mixture (42% yield, Table 5, entry 9)
and the reaction did not proceed at all when both ligand and
copper source was omitted (entry 10), showing the importance of
ligand and copper (I) oxide for reaction completion under our
conditions. Picolinic acid (L1), which lacks the N-phenylamide
moiety in comparison to ligands L4 and L5, afforded the phenol
with a moderate reduction in yield. This result demonstrates the
importance of electron density around the carbonyl oxygen as
evidenced in our C-O coupling studies (Table 1) and earlier
studies.25,26
The coupling of electron-rich and electron-neutral aryl halides
with various phenols provided good yields of C-O coupled
products, except when they are ortho - substituted. However, the
coupling of ortho - substituted electron-poor aryl halides
(including aryl chlorides) with phenols were very successful in
providing high yields of corresponding C-O coupled products.
Also, the ligand L4 was successfully employed in the synthesis
of diaryl thioethers and heterocyclic diaryl ethers in good yields.
Ethylene glycol was also shown to be a good solvent for this
transformation, since it provided similar results compared to
DMSO (Table 5, entry 12).
In addition, L4 and its derivative L5 were successfully
employed in phenol synthesis from their corresponding aryl
halides, including chlorides with the use of only 5% Cu2O/NPPA
at 160 oC under microwave irradiation.
Table 6. Synthesis of phenols from electron rich, poor, or neutral aryl halides.
X
HO
Cu2O (5%), NPPA (5%)
R
R
2:2 mL (3 M NaOH: DMSO),
MW, 10 min, 160 oC
Exploitation of the NPPA ligand and its derivatives in
Ullmann type C–H activations has provided promising results for
further investigation, which will be published in the near future.
Entry
X
I
R
H
Yield (%)a
1
96
98
44
98
53
72
51
55
42
98
94
97
2
I
4-NO2
3-NO2
4-OCH3
2-OCH3
4-Br
3
I
Acknowledgments
4
I
The authors gratefully acknowledge SUNY at Oswego for
providing a Student Scholarly Creativity and Activity Grant for
supporting undergraduate and graduate students, and Fred Scoles,
Dr. Michael Knopp, and Mrs. Kristin Gublo, for their support
services, feedback, and time.
5
I
6
I
7
I
4-Cl
8
I
4- CH3
4- CH3
4-NO2
4-NO2
1-nahpthyl
9
Br
Br
Cl
I
10
11
12
Supplementary data
a
Isolated yields.
Supplementary data associated with this article can be found,
in the online version, at …...

5
Soc. 1999, 121, 4369–4372. (c) Shelby, Q.; Kataoka, N.; Mann, G.;
Hartwig, J. J. Am. Chem. Soc. 2000, 122, 10718–10721. (d) Mann, G.;
References and notes
1.
For selected reviews dealing with diaryl ethers of biological relevance,
see: (a) Nicolaou, K. C.; Boddy, C. N. C.; Brase, S.; Winssinger, N.
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and 20 mL of acetonitrile were added. The mixture was stirred at 82 °C
for 24h. The reaction mixture was diluted with ethyl acetate and filtered
through Celite in a fritted filter funnel to remove any inorganic salts.
The solvent was then removed with the help of a rotary evaporator. The
residue was purified by flash chromatography using hexane and ethyl
acetate as an eluent to yield the product.
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30. General coupling procedure for the synthesis of phenols: To a 10 mL
pressure vessel, aryl halide (1.00 mmol), copper (I) oxide (0.05 mol),
ligand (0.05 mol), 3M sodium hydroxide (2 mL), and organic solvent (2
mL) were added. The reaction mixture was irradiated at 160°C for 10
min with strong stirring. The reaction mixture was allowed to cool to
room temperature. The reaction mixture was filtered through a plug of
celite in a fritted filter funnel and washed with ethyl acetate. The
product was extracted using 30 mL of ethyl acetate for three times. The
organic extract is washed three times with 10 mL water and two times
with 10 mL of brine. The combined organic phase was dried over
anhydrous MgSO4 and the solvent was removed under reduced pressure
to provide the product.
16. For selected examples of palladium catalyzed diaryl ether synthesis,
see: (a) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am.
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Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem.

6
Tetrahedron
N-Picolinicamides as ligands in Ullman type C-O
coupling reactions
∗
Fehmi Damkaci, Cihad Sigindere, Thomas
Sobiech, Erik Vik, and Joshua Malone
Highlights
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
N-phenyl-2-pyridincarboxamide as a ligand with Cu in diaryl
ether synthesis
The reaction provided diarylthio ethers and hetero diarylethers
in good yields.
Electron-rich and poor including ortho aryl-chlorides gave
good to very good yields.
Preferred at the benzyl position when ortho-halide benzyl
bromide is reacted
N-phenyl-2-pyridincarboxamide as a ligand with Cu2O in
phenol synthesis