N-picolinamides as ligands for Ullmann-type homocoupling reactions

Article abstract of DOI:10.1016/j.tetlet.2013.11.111

The use of N-phenylpicolinamide (NPPA) as a ligand in Ullmann-type homocoupling reactions of aryl iodides and bromides in common solvents, such as DMF and MeCN has been successfully demonstrated at room temperature. In addition, this work provided the first example of the homocoupling of an aryl chloride at 82 °C, which is a relatively low temperature when compared to regular Ullmann reaction temperatures. Also, NPPA was successfully employed in base-and heat free Suzuki reactions, including electron rich and poor aryl halides with heteroarylboronic acids in moderate yields.

Full text of DOI:10.1016/j.tetlet.2013.11.111

Tetrahedron Letters 55 (2014) 690–693
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
N-picolinamides as ligands for Ullmann-type homocoupling
reactions
a
a
b
a
a
Fehmi Damkaci a, , Esra Altay , Matthew Waldron , Michael A. Knopp , David Snow , Nicholas Massaro
⇑
a Department of Chemistry, SUNY Oswego, Oswego, NY 13126, USA
b College of Arts and Sciences, University of Maine at Presque Isle, Presque Isle, ME 04769, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of N-phenylpicolinamide (NPPA) as a ligand in Ullmann-type homocoupling reactions of aryl
iodides and bromides in common solvents, such as DMF and MeCN has been successfully demonstrated
at room temperature. In addition, this work provided the first example of the homocoupling of an aryl
chloride at 82 °C, which is a relatively low temperature when compared to regular Ullmann reaction
temperatures. Also, NPPA was successfully employed in base—and heat free Suzuki reactions, including
electron rich and poor aryl halides with heteroarylboronic acids in moderate yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 8 November 2013
Accepted 29 November 2013
Available online 6 December 2013
Keywords:
Ullmann-type coupling
Homocoupling
Aryl–aryl coupling
Copper catalyzed
N-Picolinamides
Since its discovery, the Ullmann reaction has become one of the
general methods for C–C bond formation in aryl–aryl couplings, C–
N bond formation in diamines, and C–O bond formation in diaryl
ethers.1,2 It has been applied to the synthesis of natural products,
polyaromatics used as organic conductors or semiconductors pos-
sessing unique physical properties, and to the synthesis of efficient
and selective chiral biaryl ligands for asymmetric catalysis.3 The
use of the Ullmann coupling has undergone resurgence in the last
decade, because new application areas have emerged where the
Ullmann coupling showed an advantage over the other methods
and the various new modifications have increased its scope.
However, the Ullmann reaction has not been the preferred
method, compared to palladium catalyzed methods, because of
its main drawback: the necessity of high temperatures.4 This
requirement limits the scope of the Ullmann reaction, since most
organic molecules are sensitive to high temperatures.
Several modifications have been developed in order to run the
typical Ullmann reaction under milder temperatures, such as ultra-
sound, sonication, use of different copper sources (e.g. copper(I)
salts or copper nanoparticles), use of palladium colloids, and the
use of nickel complexes.1b,1c,2,3 Liebeskind et al. have shown that
copper(I)-thiophene carboxylate (CuTC) accomplishes the reduc-
tive Ullmann coupling to form C–C bonds at room temperature
in a highly polar coordinating solvent, N-methylpyrrolidone.5
Herein, we demonstrate the use of N-phenylpicolinamide
(NPPA) as a ligand in Ullmann-type homocoupling reactions of aryl
halides in acetonitrile at room temperature. We also present the
homo-coupling of the aryl chlorides in the presence of NPPA at
82 °C, which is a much lower temperature requirement than here-
tofore utilized. To our knowledge, this is the first example of the
use of picolinamides as ligands in Ullmann-type coupling reac-
tions. In addition, we also present some selected Suzuki-type
aryl–aryl heterocouplings using this methodology.
It has been shown that 2-picolinic acid serves as a ligand in the
Ullmann-type C–N bond formation in very low yields.6 We have
decided to prepare certain amides of 2-picolinic acid in order to in-
crease the efficiency of Ullmann-type couplings, because picolina-
mides potentially provide greater flexibility in tuning the ligand.
For our preliminary studies, N-phenylpicolinamide (NPPA) was se-
lected as the initial ligand for the Ullmann-type homocoupling
reactions in C–C bond formations (Table 1).
2-Iodonitrobenzene was well studied under typical Ullmann
reaction conditions and was known for its reactivity only at higher
temperatures.1c When 2-iodonitrobenzene was reacted with
copper in DMF at 120 °C in the absence of NPPA, homocoupled
product was obtained in 98% (Table 1, trial 1), which was similar
to the literature results. When the reaction was performed at room
temperature without NPPA (Table 1, trial 2), starting material was
recovered completely, as expected, since Ullmann-type couplings
do not generally proceed at room temperature. However, homo-
coupling in the presence of NPPA provided the product at room
temperature in 95% yield (Table 1, trial 3).
Homocoupling reaction in the presence of NPPA in acetonitrile
(MeCN) at room temperature gave similar results (98%), the
reaction in tetrahydrofuran (THF) provided reasonable yields
⇑
Corresponding author. Tel.: +1 315 312 2698; fax: +1 315 312 5424.
E-mail address: fehmi.damkaci@oswego.edu (F. Damkaci).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.111

F. Damkaci et al. / Tetrahedron Letters 55 (2014) 690–693
691
Table 1
Table 2
The effect of NPPA and solvent on homocouplinga
Screening of N-picolinamide derivativesa
NO2
NO2
X
NO2
NO2
O2N
Cu(0)
Cu(0), L
2
2
I
20 hrs
MeCN, RT
O
O2N
R
N
N
Trial
NPPA
Solvent
Temp
Yield (%)
H
1
2
3
4
5
6
À
À
+
+
+
DMF
DMF
DMF
MeCN
THF
120 °C
RT
RT
RT
RT
98
NR
95
98
75
45
N-Picolinamides
L
R
X = Ia
X = Bra
X = Ib
X = Brb
L1
L2
L3
L4
L5
L6
L7
OMe
Me
H
Cl
CN
F
85
95
98
95
95
95
65
30
75
89
+
Dioxane
RT
98
65
46
24
a
In trials 1 and 2, the reactions were run in the absence of NPPA ligand. NPPA
was used in 2 equiv and copper was used in 8 equiv.
87
30
NR
60
NO2
(Table 1, trial 5), while the reaction in dioxane at room tempera-
ture gave low yields (trial 6). The results with NPPA as a ligand al-
lowed the use of two common solvents (MeCN and DMF) for the
Ullmann-type homocouplings at room temperature. MeCN was
chosen in the following optimization reactions because of its low
boiling point and consequent ease of removal.
It has been known that picolinamide or its N-substituted deriv-
atives coordinate copper ions by acting as N,O-coordinating ligands
under neutral conditions, which may also explain the results ob-
served in our coupling reactions by the addition of NPPA.7 Presum-
ably, copper(I) ion, generated in situ, was coordinated by both the
nitrogen of the pyridine and the oxygen of the carbonyl moiety of
NPPA8.
a
The reactions were run for 20 h.
The reactions were run for 4 h.
b
Table 3
Time and ligand/starting material ratio effecta
NO2
O2N
NO2
Cu(0), NPPA
2
I
MeCN, Time, RT
Trial
NPPA:SM
Cu
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
2:1
2:1
1:1
0.5:1
0.5:1
1:1
8
8
8
8
8
2
2
1
20
2
8
4
2
20
4
4
>98
>98
>98
>98
54
>98
>98
45b
In order to understand the structure–activity relationship of
picolinamides in Ullmann type homocouplings, structurally related
ligands as shown in Figure 1 have been tested under general
coupling conditions9 (Table 3, Trial 1). The results showed that
picolinic acid is better as a ligand compared to picolinamide. How-
ever, an N-phenyl group on amide nitrogen, as in NPPA, signifi-
cantly increases the reactivity of the ligand. These results show
the importance of the aryl amide moiety, which may have both
electronic and steric effects on ligand activity. When 2-pyridinethi-
oamide was used as ligand, starting material was recovered com-
pletely showing the importance of the carbonyl oxygen in
coordinating to copper.
1:1
1:1
a
49% of the starting material is recovered.
It was observed that even 2 h was sufficient time to complete
Several N-picolinamide derivatives have been tested in order to
further our understanding of the effect of N-phenylamide on the
activity of the ligand (Table 2). The ligand has been modified on
the N-phenyl group at the para-position with different electron
donating and withdrawing groups. However, the survey results
demonstrated that the original ligand (NPPA) serves as the best li-
gand for the homocoupling. When enough time is given for the
homocoupling of a highly reactive aryl iodide, almost all ligand
derivatives performed well at room temperature. However, when
a less reactive aryl bromide was used as substrate, the reaction
yields dropped as the N-phenyl moiety became more electron rich
(Table 2, L2 and L3). When the reaction is limited to 4 h for either
aryl iodides or bromides, the reaction yields also dropped with the
electron-poor N-phenyl group. The results demonstrate that NPPA
is the best ligand under these conditions.
the homocoupling of 2-iodonitrobenzene when the ligand to start-
ing material ratio was 2:1 (Table 3, trial 2). When the reaction was
run in less than 2 h, it did not go to completion. In addition, the
homocoupling reaction provided a quantitative yield even with
0.5:1 ratio of NPPA to 2-iodonitrobenzene in 4 h (Trial 4). However,
when the ratio was decreased to 0.5:1 NPPA:starting material and
the time is reduced to 2 h, only 54% of the product was afforded,
with the recovery of starting material (Trial 5). More than 2 h is
needed to complete the reaction when less than one equivalent
of the ligand is used (Trials 6 and 7). The reaction can be accom-
plished using lower than 0.5 equiv of NPPA at longer reaction
times.
It was known that at least 2 equiv of copper was required for
coupling of aryl halides in Ullmann-type couplings.1c The reaction
with NPPA worked well when 2 equivalents of copper was used,
and provided the product in a quantitative yield (Table 3, trial 6).
When one equivalent of copper was used, almost half of the start-
ing material was recovered, as expected.
O
O
O
S
N
N
N
N
Different aryl halides were tested to determine the scope of the
reaction using NPPA as the ligand (Table 4). Generally, aryl
bromides have low reactivity in Ullmann-type couplings. The best
result reported in the literature was obtained by Liebeskind and
co-workers with using CuTC ligand.4 In their study, 2-bromonitro-
benzene was homocoupled at 70 °C in NMP as solvent in 86% yield.
NHPh
NH2
OH
NH2
98%
NPPA
42%
58%
NR
Figure 1. The yields of NPPA derivatives under general conditions to show the
structure–activity relationship of the ligand.

692
F. Damkaci et al. / Tetrahedron Letters 55 (2014) 690–693
Table 4
I
B(OH)2
S
Survey of different substrates and halides
S
Pd(Ph3P)4, Cu(0), NPPA
THF, 48 hrs, RT
R
R
Cu(0), NPPA
MeCN, Time, Temp
R
2
X
R
R = NO2, 56%
R = OMe, 53%
R
Trial
R
X
Temp (°C)
Time (h)
Yield (%)
Figure 2. Base-free Suzuki type coupling with NPPA at RT.
1
2
3
4
5
6
7
8
9
NO2
NO2
NO2
NO2
Br
Br
Br
Cl
Cl
I
I
I
Br
I
I
RT
RT
RT
82
RT
RT
RT
RT
82
RT
82
82
20
20
7
20
20
20
7
NRa
89
25
>98
NR
>98
96
62
NR
85
NR
NR
yields using various solvents (Table 5). The reaction can be run at
room temperature as long as 48–74 h or at reflux temperature of
DMF for 30 min. to achieve yields around 50–62%. Its base-free
and heat-free Suzuki coupling conditions might offer an alternative
for complex substrates where base and heat can be destructive.
The reaction was tested using 2-thiopheneboronic acid (Fig. 2)
in order to see the reactivity with hetero aromatic substrates.
The reaction did perform similarly at RT with yields ranging 53–
56%. The nature of the aryl halide (electron poor vs rich) appeared
to have had negligible effect on the outcome of the results which
make it useful in general substrate class.
NO2
C(O)Me
C(O)Me
C(O)Me
C(O)Me
CO2Et
OMe
2
20
20
20
20
10
11
12
Me
I
a
The reaction was run in the absence of NPPA.
Table 5
The use of N-phenylpicolinamide as a ligand in Ullmann-type
homocoupling reactions of aryl iodides and bromides in common
solvents, such as DMF and MeCN at room temperature has been
successfully demonstrated. In addition, this work provided the first
example of the homocoupling of an aryl chloride at 82 °C, which is
a relatively low temperature when compared to regular Ullmann
reaction temperatures. Also, the ligand was successfully employed
in base—and heat free Suzuki reactions, including electron rich and
poor aryl halides with heteroarylboronic acids in moderate yields.
It has been demonstrated that the NPPA is effective when
0.5 equiv is used relative to the substrate without any yield loss.
Attempts at coupling of electron-rich and electron-neutral aryl ha-
lides were unsuccessful. Also, substrates lacking ortho-ligating
groups did not couple under Ullmann conditions even with the
addition of NPPA. These substrates were known not to couple un-
der Ullmann conditions and our methodology has not made any
progress in this instance.
Solvent survey for base-free Suzuki type coupling with NPPA
I
Ph
PhB(OH)2
Pd(Ph3P)4, Cu(0), NPPA
O2N
Solvent
Solvent, Time, Temp
O2N
Trial
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
5
DMF
DMF
DMF
MeCN
THF
60
42
17
0.5
74
48
59
62
50
46
52
100
153
RT
RT
a
5% Pd(Ph3P)4 was used.
But to our knowledge, there is no example in the literature show-
ing the homocoupling of 2-bromonitrobenzene at room tempera-
ture. In our hands, homocoupling of 2-bromonitrobenzene using
NPPA as the ligand afforded the product in 88% yield and gave no
product in the absence of ligand at room temperature (Table 4, trial
1 and 2).
Exploitation of the NPPA and its derivatives in Ullmann type C–
N bond formation has provided promising results for further inves-
tigation, which will be published in the near future..
Acknowledgment
Furthermore, we were successful in the homocoupling of 2-
chloronitrobenzene, which has not been achieved before, using
NPPA as ligand Table 4, trial 4). The reaction does not work at room
temperature, but provides high yields (98%) when run in MeCN un-
der reflux. The homocoupling of 2-iodoacetophenone at room tem-
perature was successful even when the reaction was run for 7 h
instead of 20 h (Trials 6–8). However, neither 2-bromo- or 2-chlo-
roacetophenone coupled even at higher temperatures (Trial 9). In
addition, the homocoupling of 2-iodobenzoic acid ethyl ester using
NPPA at room temperature provided the homocoupled product in
85% (Trial 10).
Substrates with ortho electron donating groups, did not react
even with NPPA; the starting aryl halide was recovered unreacted
completely after refluxing for 20 h. This result was not a surprise
since it was also the case with CuTC. In addition, substrates with
strong electron withdrawing group at the para position did not
couple either. Based on the results obtained during these studies,
it was demonstrated that Ullmann homocoupling reactions can
be accomplished with NPPA addition only with the substrates con-
taining electron-withdrawing at the ortho position.
The authors gratefully acknowledge SUNY at Oswego for
providing a Student Scholarly Creativity and Activity Grant for sup-
porting undergraduate students David Snow and Nicholas Massaro,
and Dr. Joe LeFevre, Mr. Fred Scoles, Mrs. Kristin Gublo, for their
support services, feedback, and time.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
11.111.
References and notes
1. For reviews on Ullmann coupling, see: (a) Hassan, J.; Svignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359–1469; (b) Evano, G.;
Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054–3131; (c) Crouch, R. D. In
Organic Reactions; Overman, L. E., Ed.; John and Wiley: New York, 2004; pp 265–
555; (d) Fanta, P. E. Chem. Rev. 1964, 64, 613–632.
2. (a) Lu, X.; Guo, Y.; Chen, Q. Synlett 2011, 1, 77–80; (b) Monopoli, A.; Calo, V.;
Ciminale, F.; Cotugno, P.; Angelici, C.; Cioffi, N.; Nacci, A. J. Org. Chem. 2010, 75,
3908–3911; (c) Karimi, B.; Esfahani, F. K. Chem. Comm. 2011, 47, 10452–10454.
3. Musolino, B.; Quinn, M.; Hall, K.; Coltuclu, V.; Kabalka, G. W. Tetrahedron Lett.
2013, 54, 4080–4082.
When NPPA is subject to base-free Suzuki type coupling using
phenyl boronic acid and 5% Pd(0) catalyst with activated copper
bronze, we were successful to obtain coupled product in moderate

F. Damkaci et al. / Tetrahedron Letters 55 (2014) 690–693
693
4. (a) Wang, J.; Gao, Y.; Hlil, A. R.; Hay, A. S. Macromolecules 2008, 41, 298–300; (b)
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9. General homocoupling procedure: To an oven dried 100 mL round bottom flask
with
a stir bar, the starting material (1.00 equiv), ligand (2.00 equiv), and
activated copper (8.00 equiv) were charged. The flask was vacuumed and
purged with nitrogen no less than three times. 15 mL dry acetonitrile was added
through a septum via syringe. After stirring the mixture at stated temperature
for 20 h (or for the stated duration in the paper), the reaction was immediately
vacuum filtered and washed three times with 10 mL of 1M copper acetate
solution. The organic layer was washed with 30 mL of H2O, and dried over
MgSO4, filtered, and was kept under vacuo to yield the product.