An efficient copper-catalyzed N-arylation of pyridazinones with a structurally well-defined copper complex

Article abstract of DOI:10.1016/j.tetlet.2005.10.164

N-Arylation of pridazinone derivatives 1 with an aryl or heteroaryl bromide or iodide 2 has been achieved in 70-94% isolated yield using catalytic amounts of the stable and structurally well defined copper catalyst 4b under standard Ullmann-Goldberg reaction conditions. The structure of copper catalyst 4b was characterized by ESI-MS, DSC and the single crystal X-ray.

Full text of DOI:10.1016/j.tetlet.2005.10.164

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 149–153
An efficient copper-catalyzed N-arylation of pyridazinones with
a structurally well-defined copper complex
*
Yu-Ming Pu, Yi-Yin Ku, Tim Grieme, Rodger Henry and Ashok V. Bhatia
Process Research and Development, Global Pharmaceuticals Research and Development, Abbott Laboratories,
1
401 Sheridan Road, North Chicago, IL 60064, USA
Received 18 October 2005; accepted 31 October 2005
Available online 17 November 2005
Abstract—N-Arylation of pridazinone derivatives 1 with an aryl or heteroaryl bromide or iodide 2 has been achieved in 70–94%
isolated yield using catalytic amounts of the stable and structurally well defined copper catalyst 4b under standard Ullmann–Gold-
berg reaction conditions. The structure of copper catalyst 4b was characterized by ESI-MS, DSC and the single crystal X-ray.
ꢀ
2005 Elsevier Ltd. All rights reserved.
The pyridazine and its derivatives, although known for
almost a century, received little attention until the recent
discovery of medicinally useful natural products.
X
N
N
R1
R2
Y
1
+
R2
R O
R1
O
Today, the pyridazine nucleus and its 3-oxo derivative
NHNH2
O
(
2H-pyridazin-3-one) moieties have been recognized as
3
versatile pharmacophores. This key subunit is consti-
tuted in many biologically active substances with a
broad range of biological and pharmaceutical activities
Scheme 1. Synthesis of 3 via classic cyclocondensation of arylhydr-
azine with 1,4-difunctionalized compound.
2
including inhibitors of PED III and IV, a1- and
3
a -adrenoceptors, anti-bacterial and anti-fungal activi-
2
8
halide and a protected hydrazine. On the other hand,
4
5
ties, 5-lipoxygenase inhibitors, and inhibitors of inter-
leukin-1b production.
the transition-metal catalyzed N-arylation of pyrida-
zin-3-one with an aryl halide could offer a greater poten-
tial for access to a wide range of 2-aryl or 2-heteroaryl
substituted pyridazin-3-ones 3 (Scheme 2).
6
Recently, during the course of our investigation into the
7
synthesis of potent and selective COX II inhibitors, it
was necessary to prepare a series of 2-aryl or heteroaryl
substituted pyridazin-3-one derivatives 3 for SAR stud-
ies. A survey of the literature revealed the lack of a gen-
eral, and efficient method for their preparation. Thus,
we became interested in developing an efficient proce-
dure for their synthesis. Traditionally, these compounds
were obtained by base-catalyzed cyclocondensation
reaction of N-arylhydrazine with various 1,4-difunction-
alized compounds (Scheme 1). However, only a limited
number of arylhydrazines are commercially available,
and their preparation often involved either a diazotiza-
tion-reduction protocol starting from more readily
available anilines or a cross-coupling reaction of an aryl
Palladium-catalyzed N-arylation of a variety of nitro-
gen-base nucleophiles has recently emerged as an impor-
tant synthetic tool in the preparation of arylamine
9
derivatives. However, N-arylation of pyridazin-3-one
1a with aryl bromides did not succeed under the typical
palladium-catalyzed amination or amidation conditions,
presumably due to the poor nucleophilicity of this sub-
strate. This prompted us to consider a copper-mediated
cross-coupling reaction as an alternative method. Cop-
per-catalyzed N-arylation reactions typically call for
the use of a stoichiometric amount of copper catalyst
at high reaction temperatures in polar solvents.1 How-
ever, significant progress has been made in the past
few years to address these concerns with the judicious
choice of efficient ligands, suitable copper sources,
0
*
Corresponding author. Tel.: +1 847 935 2984; fax: +1 847 938
932; e-mail: yuming.pu@abbott.com
1
1
5
appropriate bases and solvents. As results, a number
1
2–15
Structural Chemistry.
of novel applications have been reported.
Herein,
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.164

150
Y.-M. Pu et al. / Tetrahedron Letters 47 (2006) 149–153
N
R2
X
N
metal-catalyst
N
R2
+
R1
HN
R1
O
O
2
(2a, X=Br, R1=p-OMe) 1 (1a, R2=H)
3 (3a, R1=p-OMe, R2=H)
Scheme 2. Synthesis of 3 via transition-metal catalyzed cross-coupling reaction.
we describe our results in developing an efficient N-aryl-
ation protocol for pyridazinones and its derivatives.
R
O
Cu(I)Cl
N
R
Cu
Our initial investigation for the suitable reaction condi-
tions started by studying cross-coupling of 2H-pyrida-
zin-3-one (1a) with 4-bromoanisole (2a) as a model
reaction. In the first stage, the source of copper catalyst
in a ligandless system was investigated. A number of
copper catalysts using DMF as the solvent, and
K CO as the base were examined. Preliminary results
2
N
R
N
K
2
CO
3
, DMF
O
OH
4
a, R= H, 99%
4b, R= CH2CH2CH3, 95%
Scheme 3. Preparation of copper complex 4a and 4b.
2
3
showed that Cu(I) salts such as CuCl, CuI, and CuBr
were more effective catalysts than Cu(II) salts such as
Cu(OAc) , CuBr , and CuSO . CuCl was found to be
the most efficient among the Cu(I) salts investigated.
For this reason, CuCl was used to further study the cat-
alytic system (Table 1). As shown in Table 1, dramatic
differences in yield were observed in reactions using che-
lating ligands such as TMEDA, cis-1,2-diaminocyclo-
(Scheme 3). When catalyst 4a was used in the subse-
quent cross-coupling reaction, there was no erosion in
catalytic activity for the reaction. However, attempts
to elucidate the structure of this precatalyst either by
NMR or X-ray were not successful, as it is very insolu-
ble in most organic solvents at ambient temperature. To
circumvent this difficulty, we envisioned that the solubil-
ity of a copper-catalyst should be increased if an alkyl
substituted 8-hydroxyquinoline ligand was employed.
In fact, when commercially available 7-n-propyl-8-
hydroxyquinoline was used, copper catalyst 4b was
obtained in 95% yield. Having sufficient solubility and
stability, the structure of 4b was readily characterized
by ESI-MS, and later confirmed unambiguously by the
2
2
4
hexane, 1,10-phenanthroline, 8-hydroxyquinoline and
0
2
,2 -dipyridyl. 8-Hydroxyquinoline appears to be the
most effective (Table 1, entry 6); presumably acting as
O- and N-donor ligands forming a copper complex (vide
infra). Our attention then turned to the effect of base
and solvent, using the CuCl and 8-hydroxyquinoline as
the catalyst system in the reaction. Among the inorganic
bases (Na CO , K CO , Cs CO , KOH, K PO ) and
2
3
2
3
2
3
3
4
2
0,21
t-butoxides (KOtBu, NaOtBu) examined, K CO and
single crystal X-ray (Fig. 1).
2
3
KOtBu proved very effective in DMF, and much less
effective in DMA, NMP, toluene, and dioxane.
The X-ray of 4b clearly indicated that one copper ion is
bound to two 7-n-propyl-8-hydroxyquinolinate anions
through the ring nitrogen atoms and the O groups in
ꢀ
To better understand the nature of copper catalyst, com-
plex 4a was prepared from the reaction of CuCl with
a transplanar configuration. The bond lengths for two
Cu–O bonds are identical (1.920(4) A) and comparable
˚
8
-hydroxyquinoline in the presence of K CO in DMF
2
3
a
Table 1. Copper-catalyzed coupling reaction of pyridazin-3-one with 4-bromoanisole
N
N
Br
+
N
5
mole% CuCl, 10 mole% Ligand
HN
o
K
2
CO
3
, DMF, ~140 C
O
MeO
MeO
O
2a
1a
3a
b
Entry
Ligand
Yield (%)
1
2
3
4
5
6
7
—
DMAP
TMEDA
cis-1,2-Diaminocyclohexane
1,10-Phenanthroline
30
31
28
30
46
94
31
8-Hydroxyquinoline
2,2 -Dipyridyl
0
a
Reaction conditions: 1.0 mmol of 4-bromoanisole, 1.5 mmol of pyridazin-3-one, 0.05 mmol copper(I) chloride, 1.5 mmol of K
3.0 mL) under nitrogen for 20 h.
The yields are the average of two runs, and are assayed by HPLC against a pure and characterized standard.
2 3
CO in DMF
(
b

Y.-M. Pu et al. / Tetrahedron Letters 47 (2006) 149–153
151
with average Cu–O of 1.95(3) seen in other cop-
per(II)hydroxyquinolinate complexes. These data sug-
gested that copper(II) ion is in the complex, similar to
1
6
those of 4a.
The complex is flat with the n-propyl groups curled out
of the plane. Although a copper(I) species was initially
used in the preparation of 4b, it is likely that the cop-
per(I) species is oxidized to copper(II) species prior to,
or during complex formation. Moreover, this explana-
tion was supported by the fact when either a Cu(I) or
Cu(II) salt was used, 4b was always obtained. Although
4
a has been utilized as the anti-fungal, anti-bacterial and
1
7
anti-microbial agents, its application as precatalyst in
Figure 1. ORTEP plot of copper catalyst 4b.
Table 2. Cu-catalyzed N-arylation of pyridazinone core
N
X
+
N
R2
5
mole% of 4b
N
R2
R1
HN
K CO , DMF
R1
2
3
O
O
2
1
3
a
b
Entry
1
Aryl halide
Pyridazinones
Product
Isolated yield (assayed )
Br
Br
N
N
N
85 (93)
HN
MeO
MeO
0
c
1
75 (82)
O
O
O
3
a
N
N
N
2
3
80 (90)
80 (89)
MeO
NC
HN
MeO
NC
O
3b
N
I
N
N
HN
O
O
3
c
N
N
N
4
HN
80 (90)
94 (98)
O
I
O
3
d
N
N
N
5
6
NC
I
HN
O
O
NC
3
e
N
N
N
Br
HN
90 (98)
70 (80)
O
N
N
O
3
f
N
I
N
N
7
HN
O
Br
Br
O
3
g
a
b
c
Not optimized.
The yields are the average of two runs, and are assayed by HPLC against a pure and characterized standard.
Performed under air.

152
Y.-M. Pu et al. / Tetrahedron Letters 47 (2006) 149–153
organic reactions is rare.18 Given consideration with the
better solubilities of 4b in many organic solvents than
5. Brooks, D. W.; Basha, A.; Kerdesky, F. A. J.; Holms, J.
A.; Ratajcyk, J. D.; Bhatia, P.; Moore, J. L.; Martin, J. G.;
Schmidt, S. P.; Albert, D. H.; Dyer, R. D.; Young, P.;
Carter, G. W. Bioorg. Med. Chem. Lett. 1992, 2, 1357–
4
4
a, 4b was the catalyst of choice for our purposes. When
b was subjected to the model reaction, we were pleased
1
360.
to find that 3a was produced in excellent yield (Table 2,
entry 1).
6
7
. Matsuda, T.; Aoki, T.; Koshi, T.; Ohkuchi, M.; Shigyo,
H. Biorg. Med. Chem. Lett. 2001, 11, 2373–2375.
. (a) Harris, R. R.; Black, L.; Surapaneni, S.; Kolasa, T.;
Majest, S.; Namovic, M. T.; Grayson, G.; Komater, V.;
Wilcox, D.; King, L.; Marsh, K.; Jarvis, M. F.; Nuss, M.;
Nellans, H.; Prusser, L.; Reinhart, G. A.; Cox, B.;
Jacobson, P.; Stewart, A.; Coghlan, M.; Carter, G.; Bell,
R. L. J. Pharmacol. Exp. Ther. 2004, 311, 904–912; (b) Li,
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Charleson, S.; Gordon, R.; Greig, G.; Gauthier, J. Y.;
Lau, C. K.; Riendeau, D.; Therien, M.; Wong, E.; Prasit,
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With the optimal reaction conditions and the catalyst in
hand, we began to examine C–N bond forming reactions
involving functionalized aryl bromides or iodides and
1
9
pyridazinone derivatives (Table 2). There was no sig-
nificant difference in yield in all reactions surveyed under
the reaction conditions. A variety of functional groups
including cyano, methoxy, bromo, and hydroxyl on
the aryl halide component are well tolerated. Also, no
significant electronic or steric effects were observed for
para- and meta-substituted aryl halides. It should be
noted that this Cu-catalyzed reaction is sensitive to the
presence of exogenous oxygen to some extent. The yield
was found to be ꢁ10% lower when the reaction was per-
formed under air rather than under nitrogen (Table 2,
8
. Wolter, M.; Klapars, A.; Buchwald, S. Org. Lett. 2001, 3,
3
803–3805.
9
. (a) Huang, X.; Anderson, K. M.; Zim, D.; Jiang, L.;
Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
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Acc. Chem. Res. 1998, 31, 805–818.
0
entry 1 ).
In conclusion, we have developed an effective cross-cou-
pling protocol using the structurally well-defined copper
(
II) catalyst 4b for the N-arylation of pyridazinones,
complimentary to Pd-catalyzed C–N bond forming reac-
tions. The reaction proceeds at ꢁ100 ꢁC for aryl iodides
and ꢁ140 ꢁC for aryl bromides. Many functional groups
in aryl halide are well tolerated. Extension of this proto-
col to include other nitrogen nucleophiles is in progress.
1
0. For the recent review, (a) Ley, S. V.; Thomas, A. W.
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1
1
7
Acknowledgement
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2. Yamada, K.; Kurokawa, T.; Tokuyama, H.; Fukuyama,
T. J. Am. Chem. Soc. 2003, 125, 6630–6631.
We are grateful to Dr. Zhe Wang, safety evaluation lab.
for DSC data of 4a and 4b.
13. Han, C.; Shen, R.; Su, S.; Porco, J. A. Org. Lett. 2004, 6,
7–30.
2
1
4. Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.
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Supplementary data
1
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Electronic supplementary data: a complete description
of experimental details and product characterization.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
1
1
6. Bevan, J. A.; Graddon, D. P.; McConnell, J. F. Nature
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963, 199, 373.
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19. A typical experimental procedure: To a resealable pressure
tube were charged copper catalyst 4b (87.1 mg, 0.20
mmol), K CO powder (828 mg, 6.0 mmol), aryl halide
2 3
1
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Gueudet, C.; Biziere, K. Life Sci. 1986, 39, 2199–2208.
. Nomoto, Y.; Takai, H.; Ohno, T.; Nagashima, K.; Yao,
K.; Yamada, K.; Kubo, K.; Ichimura, M.; Mihara, A.;
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(4.0 mmol), pyridazinone derivative (6.0 mmol), and
DMF (5.0 mL). The tube was evacuated, and back-
filled with nitrogen. The reaction mixture was heated to
100 ꢁC (aryl iodide) or 140 ꢁC (aryl bromide), and stirred
for 20 h. The resulting mixture was cooled to room
2
3
4
temperature, diluted with CH
2 2
Cl , washed with concd
NH OH solution, and 25% brine. The organic was
4
filtered through a pad of Celite, and the filtrate concen-
trated to dryness. Purification of the crude product by
flash chromatography on silica gel gave the desired
. Sayed, G. H.; Hamed, A. A.; Meligi, G. A.; Boraie, W. E.;
Shafik, M. Molecules 2003, 8, 322–332.

Y.-M. Pu et al. / Tetrahedron Letters 47 (2006) 149–153
153
product (see Supplementary data for MS, NMR spectral
data).
a Bruker SMART system using MoKa radiation (k =
0.71073 A). Refinement of the structure using full matrix
˚
2
0. Crystal data for 4b: MW = 436.006, C H CuN O ,
least squares refinement of 135 parameters on 1456
observed reflections with I > 2.0r(I) gave R = 0.0937,
Rw = 0.2072 and GOF = 1.063.
2
4
24
2
2
crystal dimensions 1.0 · 0.2 · 0.02 mm, monoclinic, P2
1
/c,
˚
˚
˚
a = 5.112(2) A, b = 18.974(8) A, c = 10.324(4) A, b =
˚
3
3
9
8.532(8)ꢁ, V = 990.3(7) A , Z = 2, Dcalcd = 1.462 g/cm ,
21. Johnson, C. K. ORTEPII Report ORNL-5138; Oak Ridge
National Laboratory: Tennessee, USA, 1976.
2
hmax = 56.62ꢁ, crystallographic data were collected with