N-Picolinamides as ligands for Ullmann-type C-N coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2016.04.017

The use of N-phenyl-2-pyridincarboxamide-1-oxide as a ligand with Cu₂O in Ullmann type C-N bond formations between aryl halides and N-heteroaryls in common solvents, such as MeCN, DMF, and DMSO at 82-120 °C has been successfully demonstrated. The ligand is effective when only 4% equiv is used relative to the substrate. The reaction provided the corresponding products in coupling of electron-rich, electron poor, and ortho-substituted aryl halides, including ortho aryl-chlorides, in good to very good yields. N-arylation is selectively preferred at the benzyl position when ortho-halide benzyl bromide is reacted with one equivalent of pyrazole. However, di-N-arylation is achieved in very high yields when 2.5 equiv of pyrazole is used, providing a stoichiometric control over the coupling reaction.

Full text of DOI:10.1016/j.tetlet.2016.04.017

Accepted Manuscript
N-Picolinamides as ligands for Ullmann-type C-N coupling reactions
Fehmi Damkaci, Abdulkhaliq Alawaed, Erik Vik
PII:
S0040-4039(16)30367-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.04.017
TETL 47517
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
24 March 2016
7 April 2016
Please cite this article as: Damkaci, F., Alawaed, A., Vik, E., N-Picolinamides as ligands for Ullmann-type C-N
coupling reactions, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.04.017
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Graphical Abstract
N-Picolinamides as ligands for Ullmann-type
C-N coupling reactions

Fehmi Damkaci, Abdulkhaliq Alawaed, and Erik Vik

1
Tetrahedron Letters
N-Picolinamides as ligands for Ullmann-type C-N coupling reactions

Fehmi Damkaci, Abdulkhaliq Alawaed, and Erik Vik
Department of Chemistry, SUNY Oswego, Oswego NY 13126, U.S.A.
ARTICLE INFO
ABSTRACT
The use of N-phenyl-2-pyridincarboxamide-1-oxide as a ligand with Cu2O in Ullmann type C-N
bond formations between aryl halides and N-heteroaryls in common solvents, such as MeCN,
DMF, and DMSO at 82-120 oC has been successfully demonstrated. The ligand is effective
when only 4% equiv is used relative to the substrate. The reaction provided the corresponding
products in coupling of electron-rich, electron poor, and ortho-substituted aryl halides, including
ortho aryl-chlorides, in good to very good yields. N-Arylation is selectively preferred at the
benzyl position when ortho-halide benzyl bromide is reacted with one equivalent of pyrazole.
However, di-N-arylation is achieved in very high yields when 2.5 equiv of pyrazole is used,
providing a stoichiometric control over the coupling reaction.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Ullmann-type coupling
C-N bond formation
Heterocoupling
Copper catalyzed
N-Picolinamides
2016 Elsevier Ltd. All rights reserved.
Since its discovery by Fritz Ullmann and Irma Goldberg in the
early 1900s,1 the Ullmann reaction has become one of the general
methods for C–C, C–N, and C–O bond formations in aryl
couplings.2 It has been applied in the synthesis of natural
products, compounds with medicinal importance, agrochemicals,
and materials with unique electronic and structural properties.3
However, the Ullmann reaction has not been the preferred
method until recently, because of its main drawbacks: the
necessity of high temperatures and need of high boiling polar
solvents. On the other hand, C-N cross couplings utilizing
palladium catalysts, developed by Buchwald-Hartwig, also have
limitations, which are mainly high reaction temperatures, long
reaction time, and high cost of palladium catalysts and their
severe toxicity.4
been also successfully employed as ligands in copper catalyzed
C-N coupling reactions.15 Picolinamide derived ligands have
also been successfully employed as ligands in group-directed C-
H bond activation16 and in asymmetric Mannich-type reactions.17
In our previous study, we successfully demonstrated the first
use of N-phenylpicolinamide (NPPA, L4) as an efficient ligand
to form aryl-aryl C-C bonds in Ullmann type homocoupling,
including aryl chlorides, and in base-free Suzuki-type heteroaryl
coupling.18 In continuation of our research on ligand
development for Ullmann-type copper catalyzed couplings, we
herein
successfully
demonstrate
the
use
of
N-
phenylpicolinamide-1-oxide (NPPA-N-Oxide) as a ligand for
Ullmann-type C-N coupling reactions of aryl iodide, aryl
bromide as well as aryl chloride with various N-arylheterocycles
in acetonitrile or DMSO at moderate temperatures.
Development of ligands for Ullmann type copper catalyzed
coupling reactions by Buchwald,5 Nicolaou,6 Liebeskind,7 and
Ma8 resulted in improved reaction conditions with wider
substrate scope. Therefore, extensive research efforts have been
devoted to promote alternative ligands to overcome of the
limitations of copper catalyzed reactions in Ullmann type
couplings in order to reduce the catalyst loadings and increase the
yields using moderate reaction conditions.2, 9 The use of ligands
with copper salts in catalytic amounts have been shown to be
highly economical and versatile method compared to palladium
catalyzed systems. They are less expensive, environmentally
friendly, and easy to purify and scale up.
For our preliminary studies, the coupling reaction of pyrazole
and 4-bromonitrobenzene was investigated to optimize reaction
conditions including ligand, solvent, base, and the copper source
by following our general coupling procedure (Table 1).19
First, to explore the role of ligands on catalytic activity,
several ligands L1-L5 were screened for N-arylation of pyrazole
with 4-Bromonitrobenzene using 10 mol % of activated copper
and Cs2CO3 in acetonitrile (MeCN) at reflux temperature (Table
1, entries 1-5). When picolinic acid (L1) and picolinic acid N-
oxide (L2) were used as the ligands, the coupled product was
obtained in only 41% and 52% yields, respectively (Table 1,
entries 1 and 2), which were similar to the literature results.14a,b
When picolinamides L3 and L4 were used as ligands, the
reaction provided yields in 70 and 77%, respectively (Table 1,
Several class of ligands have been developed for Ullmann
type C-N bond formations, including phenanthrolines,10 amino
alcohols,11 diamines,F12 diols,F13 β-diketones and β-keto
esters,14 and others.9 Recently, various pyridine N-oxides have
———

Corresponding author. Tel.: +1-315-312-2698; fax: +1-315-312-5424; e-mail: fehmi.damkaci@oswego.edu

2
Tetrahedron
entries 3 and 4). However, N-oxide on the pyridine moiety of
either no or very low yield, respectively (Table 1, entries 7 and
8). The results with NPPA-O as a ligand allowed the use of three
common solvents (MeCN, DMF and DMSO) for the Ullmann-
type C-N bond formations at 82 oC.
picolinamide L5 (NPPA-O) significantly increases the reactivity
of the ligand by providing the coupled product in 92% yield in
MeCN at 82 oC (Table 1, entry 5).
When K2CO3 or K3PO4 was used as a base, the starting
materials were recovered completely, which made Cs2CO3 as the
base choice for the C-N bond formations (Table 1, entries 5, 11-
12). Finally, in addition to activated copper, several other copper
sources such as activate copper CuI, CuBr, CuBr2 and Cu2O
were also evaluated by using NPPA-O as ligand. The reactions
with CuI, CuBr, CuBr2 produced the coupled products in modest
to good yields (52-77%, Table 1, entries 13, 14 and 15), but
lower than the reaction which is used activated copper (92%). To
our delight, Cu2O was selected as the best copper salt to promote
the highest yield of C-N coupling (95%, Table 1, entry 16), even
better than activate copper. In the absence of any copper metal
source in the reaction, only a 9% yield was realized.
Figure 1. Structures of ligands which were surveyed in Table 1.
In summary, the optimal conditions for this cross-coupling
The comparison of ligands L2, L4, and L5 shows the
importance of the both phenyl amide and N-pyridyl oxide
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 study in
homocoupled C-C bond formations.18 On the other hand, the
reaction provided almost no product without any ligand, showing
its necessity for activity (Table 1, entry 6).
consisted of the combination of Cu2O (10 mol %), L5 (4 mol %),
O
Cs2CO3 (2 equiv.) in acetonitrile or DMSO at 82 OC or 120 C,
respectively for 20h under nitrogen atmosphere by following the
general coupling procedure.19
With the best conditions in hand, we subsequently tested the
scope of pyrazole 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. First, we observed that iodobenzene as
substrate with no substituent reacted with 1H-pyrazole and gave
83% yield (Table 2, entry, 1). We also noted that both electron-
donating and electron-withdrawing substituents, such as nitro,
acetyl, methyl, and methoxy were tolerated smoothly on the aryl
iodide component in C-N coupling reactions under our reaction
conditions. Electron-poor para disubstituted aryl iodides
including, 4-iodonitrobenzene and 4-iodoacetophenone coupled
with pyrazole in very high yields (98-99%, Table 2, entries 2 and
11), while aryl iodides with electron rich substituent groups
including, 4-iodotoluene and 4-iodomethoxy also provided
Table 1. Survey of ligand, base, copper source, and solvent.
Entry
1
Ligand
L1
L2
L3
L4
L5
-
Base
Copper source
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Dioxane
THF
Yield (%)a
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
Cu
Cu
41
52
70
77
92
3
2
3
Cu
4
Cu
o
desired products in 45% and 32% yields in MeCN at 82 C,
5
Cu
respectively (Table 2, entries 12 and 16). However, when the
o
reaction was run in DMSO as solvent at 120 C, similar to other
6
Cu
literature couplings using N-pyridine oxides as ligands,[F14a]
electron rich aryl iodides resulted in much higher yields (Table 2,
entries 13 and 17). Furthermore, the sterically hindered aryl
halides have a very small impact (3-6% reduction yields) on the
outcome of the reaction which was evidenced in using ortho
substituted aryl iodides, bromides and chlorides compared to
their para substituted counterparts (Table 2, entries 6-9 and 19-
20). Generally, aryl bromides have lower reactivities than aryl
iodides in Ullmann-type couplings, which was the case under our
reaction conditions as well, providing C-N bond formation in 50-
95% yield, depending on the electronic nature of the aryl halide
(Table 2, entries 3, 7, 18 and 19).
7
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
Cu
NR
5
8
Cu
9
Cu
DMF
91
91
NR
NR
52
74
77
95
9 b
10
11
12
13
14
15
16
17
Cu
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Cu
Cu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CuI
CuBr
CuBr2
Cu2O
-
Usually, aryl chlorides have not appeared as coupling partners
in C-N 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, when a few aryl
chlorides with strong electron withdrawing groups were
examined using our ligand, they provided coupled products in
moderate to good yields (60-78%, Tale 2, entries 4, 5, 8, and 9).
To our surprise, even sterically hindered ortho-chloro substrates
were able to couple under these reaction conditions.
a Isolated yield. b The reaction was carried out at 120 oC
It has been shown that the coordination properties of N-oxide
and the carboxyl group of picolinic acid N-oxide or its substituted
derivatives would be capable of participating in the formation of
six-membered-ring coordinates with a copper center.15a
N-arylation of pyrazole in the presence of NPPA-O in both
DMF and DMSO gave similar results (91%) to MeCN (Table 1,
entries 9 and 10), while the reaction in dioxane or THF provided

3
Table 2. Survey of different substrates and halides with pyrazole.
Table 4. Survey of different substrates and halides with pyrrole.
Entry
1
R
X
I
Product
Yield (%)a
90
Entry
R
X
I
Product
15
Yield (%)a
H
4
3
1
2
3
4
5
6
7
8
9
H
90
97
94
92
80
75
71
89
75
2
4-NO2
4-NO2
4-NO2
4-NO2
2-NO2
2-NO2
2-NO2
2-NO2
3-NO2
4-COMe
4-Me
I
98
4-NO2
4-NO2
4-NO2
2-NO2
2-NO2
2-NO2
4-Me
4-OMe
I
16
3
Br
Cl
Cl
I
3
95
Br
Cl
I
16
4
3
65
16
5
3
78b
17
6
5
89
Br
Cl
I
17
7
Br
Cl
Cl
I
5
86
17
8
5
60
18
9
5
73b
I
19
10
11
12
13
14
15
16
17
18
19
20
6
88
a Isolated yields
I
7
99
I
8
45
Next, the chemistry of Cu2O/ L5 in C–N cross-coupling with
various N-heterocyclic compounds such as pyrrole, indazole, and
indole with a variety of aryl halides was explored by following
the general coupling procedure. In these studies, DMSO was
chosen as solvent instead of MeCN for increased solubility of
heteroaryls and the ability to increase the reaction temperature up
4-Me
I
8
70b
NR
41b
32
4-Me
Br
Br
I
8
4-Me
8
4-OMe
4-OMe
4-CN
2-CN
2-CN
9
o
to 120 C. The results of N-arylation of pyrrole are summarized
I
9
51b
in Table 4. The reaction of pyrrole with electronically neutral or
poor aryl halides, including iodide, bromide, and chloride
afforded yields higher than 90% (Table 4, entries 1-4). Indeed,
sterically hindered ortho-nitro substituted halobenzenes,
including chlorides, gave relatively lower yields as compared to
the para-isomer, but still in very good yields (7180%, Table 4,
entries 5-7). The reaction of aryl iodides with electron-donating
substituents groups such as methyl and methoxy substituents
proceeded with no reduction in yields (75-89%, Table 4, entries 8
and 9). Overall, coupling of electron rich, poor, or ortho-
substituted aryl halides, including chlorides, with pyrrole under
our reaction conditions works well to furnish the desired C-N
couple products in good to high yields, showing a wide reaction
scope.
Br
Br
Br
10
11
11
82
51
70b
a Isolated yield. b The reaction was carried out at 120 oC in DMSO
We have also studied the effect of varying the stoichiometry
of pyrzole substrates with various ortho-halide benzyl bromides.
When benzyl bromide reacted with pyrazole, the reaction
afforded the coupled product 13a in 87% yield (Table 3, entry 1),
while 2-chloro benzyl bromide as a substrate provided the
coupled product 13c in 92%, coupling only at the benzyl bromide
side (Table 3, entry 3). However, when 2-iodo benzyl bromide
was used, either mono (13b) or di-coupled (14) was obtained by
simply varying the stoichiometry of pyrazole (1.1 or 2.5 equiv.,
respectively) used in the reaction (Table 3, entry 2). Both
products were isolated in very high yields (92-95%). This
method is superior to the only example in the literature, showing
diamination of ortho halide of benzyl bromide with pyrazole
providing product 14 in 73% yield over two steps.20
Table 5. Survey of different substrates and halides with indazole.
Entry
R
X
I
Product
20
Yield (%)a
Table 3. Survey of ortho-halide benzyl bromide with pyrazole.
1
2
3
4
5
6
7
8
9
H
81
86
84
79
80
70
68
89
70
4-NO2
4-NO2
4-NO2
2-NO2
2-NO2
2-NO2
4-Me
4-OMe
I
21
Br
Cl
I
21
21
22
Entry
X
13,Yield (%)a
87 (13a)
14, Yield (%)a
Br
Cl
I
22
1
2
3
H
22
I
92 (13b)
95b
23
Cl
92 (13c)
I
24
a Isolated yield. b 2.5 equiv. of pyrazole was used.
a Isolated yields

4
Tetrahedron
Similar to pyrrole couplings, indazole also afforded good to
Acknowledgments
high yields, ranging between 68 and 89% yields, in coupling with
various aryl halides, including electron rich, poor, and ortho-
substituted iodides, bromides, and chlorides as shown in Table 5.
Ortho-substitution results in only 10-12% loss in yields compared
to couplings with para-substituted substrates.
The authors greatly acknowledge SUNY at Oswego for
providing a Student Scholarly Creativity and Activity Grant for
supporting undergraduate student Erik Vik and graduate student
Abdulkhaliq Alawaed, and Dr. Mike Knopp, Mr. Fred Scoles,
and Mrs Kristin Gublo for their support service, feedback, and
time.
Indoles are an important class of heterocycles not only
because they are among the most ubiquitous compounds in
nature, by being incorporated into the amino acid tryptophan and
hormones serotonin and melatonin, but also because they have a
wide range of biological activities, including antihypertensive,
antiviral, analgesic, antitumor, anti-inflammatory, antimicrobial,
and antifungal.21 Hence, it is not surprising that creating new
compounds with indole as the building block is highly important.
When indole was used as a nitrogen containing heterocycle in our
reaction, indole derivatives were successfully obtained in good to
high yields by using a range of aryl halides as shown in Table 6.
Following the previous trends of pyrazole, pyrrole, and indazole,
indoles also worked well with various aryl halides using
Cu2O/L5 as catalysts system, since the nature of the aryl halide
(electron poor vs rich) appeared to have a negligible effect on the
outcome of the results. This makes the indoles useful in general
substrate class. These results suggested that, five membered ring
N-heterocycles such as pyrazole and pyrrole can be efficiently
coupled to aryl halides derivatives with higher yields than those
of indazole and indole substrates, It can be concluded that, due to
steric interactions arising from the peri-like 7-proton of both
indazole and indole.9d
Supplementary Data
Supplementary material associated with this article can be
found, in the online version, at
References and notes
1. (a) Ullmann, F.; Sponagel, P. Ber. Dtsch. Chem. Ges. 1905, 38, 2211 –
2212. (b) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691–1692.
2. 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)
Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954–6971.
(d) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–
5449. (e) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (f)
Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428–2439. (g)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337–
2364. (h) D. Ma, Q. Cai, Acc. Chem. Res. 2008, 41, 1450– 1460.
3. (a) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2008, 47, 3096–
3099. (b) Reis, L.A.; Ligiéro, C. B. P.; Andrade, A. A.; Taylor, J. G.;
Miranda, P. C. M. L. Materials 2012, 5, 2176–2189. (c) De Hoz, A.;
Diaz-Ortiz, A.; Elguero, J.; Martinez, L. J.; Moreno, A.; Sanchez-
Migallon, A. Tetrahedron, 2001, 57, 4397–4403. (d) Musolino, B.;
Quinn, M.; Hall, K.; Coltuclu, V.; Kabalka, G.W. Tetrahedron Lett.
2013, 54, 4080–4082.
Table 6. Survey of different substrates and halides with indole.
4. For recent reviews palladium catalyzed C-N bond formation, see: (a)
Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth. Catal.
2006, 348, 23–39; (b) Kienle, M.; Dubbaka, S. R.; Brade, K.; Knochel, P.
Eur. J. Org. Chem. 2007, 4166–4176; (c) Hartwig, J. F. Acc. Chem. Res.
2008, 41, 1534–1544; (d) Surry, D. S.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2008, 47, 6338–6361.
5. (a) J.-F. Marcoux, S. Doye, S. L. Buchwald, J. Am. Chem. Soc. 1997,
119, 10539 –10540. (b) A. Kiyomori, J.- J.-F. Marcoux, S. L. Buchwald,
Tetrahedron Lett. 1999, 40, 2657 –2660.
6. K. C. Nicolaou, C. N. C. Boddy, S. Natarajan, T. Y. Yue, H. Li, S. Brase,
J. M. Ramanjulu, J. Am. Chem. Soc. 1997, 119, 3421–3422.
7. S. Zhang, D. Zhang, L. S. Liebeskind, J. Org. Chem. 1997, 62, 2312–
2313.
8. D. Ma, Y. Zhang, J. Yao, S. Wu, F. Tao, J. Am. Chem. Soc. 1998, 120,
12459–12467.
Entry
R
X
I
Product
25
Yield(%)a
1
2
3
4
5
6
H
95
89
84
81
80
72
4-NO2
4-NO2
4-NO2
4-Me
4-OMe
I
26
Br
Cl
I
26
26
27
I
28
9. For other copper catalyzed N-arylations, see: (a) Rizwan, K.; Karakaya,
I.; Heitz, D.; Zubair, M.; Rasool, N.; Molander, G. A. Tetrahedron Lett.,
2015, 56, 6839–6842. (b) Talukdar, D.; Das, G.; Thakur, S.; Karak, N.;
Thakur, A. J. Catal. Commun. 2015, 59, 238–243. (c) Zhang, C.; Zhan,
Z.; Lei, M.; Hu, L. Tetrahedron, 2014, 70, 8817–8821. (d) Farahat, A.
A.; Boykin, D.W.; Tetrahedron Lett., 2014, 55, 3049–3051. (e) Yang, Q.;
Wang, Y.; Yang, L.; Zhang, M. Tetrahedron, 2013, 69, 6230–6233. (f)
Liu, Y.; Liu, W.; Zhang, Q.; Liu, P.; Xie, J.-W.; Dai, B. J. Chem. Res.,
2013 37, 636–637. (g) Zhang, H.; Cai, Q.; Ma, D.; Zhang, H.; Cai, Q.;
Ma, D. J. Org. Chem. 2005, 70, 5164–5173. (h) Rampazzi, V.; Massard,
A.; Richard, P.; Picquet, M.; Le Gendre, P. ChemCatChem, 2012, 4,
1828–1835. (i) D. Zhu, R.; Wang, J.; Mao, L.; Xu, F.; Wu, B.; Wan, J.
Mol. Catal. A Chem., 2006, 256, 256–260. (j) Teo, Y.-C.; Yong, F.-F.;
Lim, G.S. Tetrahedron Lett., 2011, 52, 7171–7174. (k) Liu, Y.; Liu, Y.;
Ma, X.; Liu, P.; Xie, J.; Dai, B.; Chinese Chem. Lett., 2014, 25, 1–4. (l)
Singh, R.; Allam, B.K.; Raghuvanshi, D.S.; Singh, K.N. Tetrahedron,
2013, 69, 1038–1042. (m) Liu, Y.-H.; Chen, C.; Yang, L.-M.
Tetrahedron Lett. 2006, 47, 9275–9278. (n) Nandurkar, N.S.;
Bhanushali, M.J.; Bhor, M.D.; Bhanage, B.M.Tetrahedron Lett. 2007,
48, 6573–6576.
aIsolated yields
In summary, the use of N-phenyl-2-pyridincarboxamide-1-oxide
(L5) as a ligand with Cu2O in Ullmann type C-N bond
formations between aryl halides and N-heteroaryls in common
o
solvents, such as MeCN, DMF, and DMSO at 82-120 C has
been successfully illustrated. The ligand is effective when only
4% equiv is used relative to the substrate. The reaction provided
the corresponding products in coupling of electron-rich, electron
poor, and ortho-substituted aryl halides, including ortho aryl-
chlorides, in good to very good yields. N-Arylation is selectively
preferred at benzyl position when ortho-halide benzyl bromide is
reacted with one equivalent of pyrazole. However, di-N-arylation
is achieved in very high yields when 2.5 equiv. of pyrazole is
used, providing a stoichiometric control over the coupling
reaction.
10. Altman, R. A.; Kowal, E. D.; Buchwald, S. L. J. Org. Chem. 2007, 72,
6190–6199.
11. (a) Lu, Z.; Twieg, R. J.; Huang, S. D. Tetrahedron Lett. 2003, 44, 6289–
6291. (b) Lu, Z.; Twieg, R. J. Tetrahedron 2005, 61, 903–907.
Exploitation of the NPPA, NPPA-N-oxide, and their
derivatives in Ullmann type C–O bond formation has been
underway, which will be published in the near future.

5
12. (a) Antila, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org.
Chem. 2004, 69, 5578–5587. (b) Klapars, A.; Antila, J. C.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727–7729. (c) Antila, J.
C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684–
11688. (d) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 7421–7428. (e) Larsson, P.-F.; Correa, A.; Carril, M.; Norrby,
P.-O.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48, 5691–5693; (f) Antilla,
J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004,
69, 5578–5587.
13. (a) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581–
584. (b) Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 3703–3706.
14. (a) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742–8743.
(b) de Lange, B.; Lambers-Verstappen, M. H.; Schmieder-van de
Vondervoort, L.; Sereinig, N.; de Rijk, R.; de Vries, A. H. M.; de Vries,
J. G. Synlett 2006, 3105–3109. (c) Shafir, A.; Lichtor, P. A.; Buchwald,
S. L. J. Am. Chem. Soc. 2007, 129, 3490–3491. (d) Lv, X.; Bao, W. J.
Org. Chem. 2007, 72, 3863–3867. (e) Xia, N.; Taillefer, M. Angew.
Chem., Int. Ed. 2009, 48, 337–339.
15. (a) Yang, K.; Qiu, Y.; Li, Z.; Wang, Z.; Jiang, S. J. Org. Chem., 2011,
76, 3151–3159. (b) Wu, F.-T.; Yan, N.-N.; Liu, P.; Xie, J.-W.; Liu, Y.;
Dai, B. Tetrahedron Lett., 2014, 55, 3249–3251. (c) Liang, L.; Li, Z.;
Zhou, X. Org. Lett., 2009, 11, 3294–3297.
16. (a) Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726 –
11743. (b) Nadres, E. T.; Santos, G. I. F.; Shabashov, D.; Daugulis, O. J.
Org. Chem. 2013, 78, 9689–9714. (c) Nadres, E. T.; Daugulis, O. J. Am.
Chem. Soc. 2012, 134, 7–10.
17. Hayashi, M.; Iwanaga, M.; Shiomi, N.; Nakane, D.; Masuda, H.;
Nakamura, S. Angew. Chem. Int. Ed. 2014, 53, 8411– 8415.
18. Damkaci, F.; Altay, E.; Waldron, M.; Knopp, M. A.; Snow, D.; Massaro,
N. Tetrahedron Lett. 2014, 55, 690–693.
19. General coupling procedure: In 50 mL round bottom flask, aryl halide
(1.0 mmol), pyrazole (1.2 mmol), ligand (0.04 mmol), Cu2O (0.10
mmol), cesium carbonate (2.0 mmol), and dry solvent (20 mL) were
placed under nitrogen atmosphere. The reaction mixture was heated in oil
bath up to specified temperature under constant stirring for 20 h and then
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. If DMSO is used as solvent, it is extracted by washing the filtrate
with 25 mL water for three times. The organic phase was dried over
anhydrous MgSO4 and was removed under reduced pressure to provide
the crude product which was purified by column chromatography on
silica gel, using hexane and ethyl acetate in 3:1 ratio, respectively, as an
eluent.
20. Liddle, B. J.; Hall, D.; Lindeman, S. V. ; Smith, M.D.; Gardinier, J.R.
Inorg. Chem. 2009, 48, 8404–8414.
21. Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.; Verma,
K. V.; Choi, E. H. Molecules 2013, 18, 6620–6662.
Highlights
.
.
.
.
.
N-phenyl-2-pyridincarboxamide-1-oxide as a ligand with Cu2O
in C-N bond formations
The ligand is effective when only 4% equiv is used relative to
the substrate.
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
di-N-arylation occurs when ortho-halide benzyl bromide is
reacted with excess pyrazole