Synthesis of Pyridazinones through the Copper(I)-Catalyzed Multicomponent Reaction of Aldehydes, Hydrazines, and Alkynylesters

Article abstract of DOI:10.1002/chem.201403873

The copper-catalyzed multicomponent cyclization reaction, which combined aldehydes, hydrazines, and alkynylesters, was applied in the synthesis of pyridazinones. The reaction was regioselective and gave only six-membered pyridazinones in the complete absence of five-membered pyrazoles or a regioisomeric mixture. During this investigation, the use of 2-halobenzaldehyde as the starting material, under identical reaction conditions, gave 6-(2-ethoxyphenyl)pyridazinones after sequential Michael addition/1,2-addition/Ullmann cross-coupling reactions.

Full text of DOI:10.1002/chem.201403873

DOI: 10.1002/chem.201403873
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Homogeneous Catalysis
Synthesis of Pyridazinones through the Copper(I)-Catalyzed
Multicomponent Reaction of Aldehydes, Hydrazines, and
Alkynylesters
Anderson C. Mantovani,[a] Tales A. C. Goulart,[a] Davi F. Back,[b] and Gilson Zeni*[a]
Abstract: The copper-catalyzed multicomponent cyclization
reaction, which combined aldehydes, hydrazines, and alkyny-
lesters, was applied in the synthesis of pyridazinones. The re-
action was regioselective and gave only six-membered pyri-
dazinones in the complete absence of five-membered pyra-
zoles or a regioisomeric mixture. During this investigation,
the use of 2-halobenzaldehyde as the starting material,
under identical reaction conditions, gave 6-(2-ethoxyphenyl)-
pyridazinones after sequential Michael addition/1,2-addition/
Ullmann cross-coupling reactions.
Introduction
The innovative features of this multicomponent reaction are
the preparation of six-membered pyridazinones instead of five-
membered azole derivatives.[6] We anticipated that this remark-
able selectivity was attributed to the carbon nucleophile addi-
tion to the Michael acceptor, promoted by the copper salt, in-
stead of nitrogen addition.
Five- and six-membered heterocycles, with two nitrogen atoms
in the structure, are a structural motif of particular interest in
synthetic and medicinal chemistry because they are present in
a large number of natural products, many of which have bio-
logical activity.[1] Among the various methods developed thus
far for the synthesis of five-membered heterocycles with two
nitrogen atoms, the most useful approaches are based on the
condensation of hydrazines with 1,3-dicarbonyl compounds
and the intermolecular 1,3-dipolar cycloaddition of nitrilimines
or diazo compounds to alkenes and alkynes (Scheme 1).[2] De-
spite the impressive progress achieved, the use of a 1,3-dipolar
cycloaddition approach to six-membered heterocycles with
two nitrogen atoms is relatively rare. The most common syn-
thetic route involves the cyclization reaction of hydrazines with
carbonyl compounds.[3] In addition to classical synthetic meth-
ods, multicomponent reactions, which combine three or more
substrates in a single operation, facilitate the cyclization of acy-
clic substrates to afford various functionalized N-heterocycles.[4]
However, this important tandem process has been efficiently
used to prepare five-membered N-heterocycles.[5] Herein, we
wish to extend the concept of multicomponent reactions and
report the synthesis of pyridazinones 4 by using a copper-cata-
lyzed multicomponent reaction, starting from aldehydes (1),
hydrazines (2), and alkynylesters (3; Scheme 1).
Results and Discussion
In the first attempt, we examined the reaction of phenylhydra-
zone 5 (the isolated product of the reaction of aldehyde 1a
with aryl hydrazine 2a; 0.25 mmol), with ethyl 3-phenylpropio-
late (3a; 0.25 mmol), catalyzed by CuI (20 mol%) in CH2Cl2
(3 mL) at room temperature. These conditions gave a minor
amount of pyridazinone 4a (5% yield) together with a large
amount of inseparable regioisomer and aza-Michael addition
product. The screening of solvents, such as EtOH, CH2Cl2, DMF,
and MeCN, revealed that the use of MeCN gave pyridazinone
4a in 32% yield as a single isomer, which was separated from
unreacted starting materials by column chromatography. After
purification, the structural assignment of 4a was based on
NMR spectroscopy analysis and confirmed by X-ray diffraction,
which showed the exact position of the two nitrogen atoms
(Figure 1). Classical cyclocondensation of hydrazines with b-
keto esters gives a regioisomeric mixture of products.[7] Al-
[a] A. C. Mantovani, T. A. C. Goulart, Prof. Dr. G. Zeni
Departamento de Quꢀmica Orgꢁnica Laboratꢂrio de Sꢀntese
Reatividade, Avaliażo Farmacolꢂgica e Toxicolꢂgica
de OrganocalcogÞnios, Universidade Federal de Santa Maria
Santa Maria, Rio Grande do Sul, 97105-900 (Brazil)
E-mail: gzeni@pq.cnpq.br
[b] Prof. Dr. D. F. Back
Departamento de Quꢀmica Inorgꢁnica Laboratꢂrio
de Materiais Inorgꢁnicos, Universidade Federal de Santa Maria
Santa Maria, Rio Grande do Sul, 97105-900 (Brazil)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403873.
Scheme 1. General reaction scheme for the synthesis of five- and six-mem-
bered heterocycles with two nitrogen atoms.
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Table 1. Effect of different reaction parameters on the preparation of pyr-
idazinone 4a.[a]
Entry
Copper salt
([equiv])
Base
([equiv])
Yield[b]
[%]
1
2
3
4
5
6
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
–
–
49
72
30
15
0
K2CO3 (1)
Cs2CO3 (1)
KOH (1)
NaHCO3 (1)
Et3N (1)
7
8
9
CuI (1)
CuI (1.5)
CuI (1)
DBU (1)
19
15
53
42
38
27
0
60
59
57
9
49
13
9
11
0
Cs2CO3 (1)
Cs2CO3 (1.5)
Cs2CO3 (2)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
10
11
12
13
14
15
16
17[c]
18[d]
19[e]
20[f]
21[g]
22
CuI (1)
CuCl (1)
CuBr (1)
CuBr2 (1)
CuI (0.5)
CuI (0.2)
CuI (0.1)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
[AuCl(PPh3)]
Figure 1. ORTEP view of compound 4e. Ellipsoids are drawn at the 50%
probability level.
though under these conditions pyridazinone 4a was obtained
in low yield, neither a five-membered heterocyclic ring nor a re-
gioisomeric mixture was formed. After these results, we con-
centrated our study in investigating different reaction parame-
ters to improve the yield (Table 1). For instance, the use of
a stoichiometric amount of CuI failed to give pyridazinone 4a
(Table 1, entry 1).
[a] The reaction was performed in the presence of 5 (0.25 mmol), 3a
(0.25 mmol), CuI, and MeCN (3 mL), under an argon atmosphere at 808C
for 16 h. DBU=1,5-diazabicyclo[5.4.0]undec-5-ene. [b] Yields were deter-
mined by GC analysis. [c] An oxygen atmosphere (balloon) was used.
[d] nBu4NI (0.25 mmol) was used as an additive. [e] Silver triflate (AgOTf;
0.25 mmol) was used as an additive. [f] ZnCl2 (0.25 mmol) was used as an
additive. [g] KI (0.25 mmol) was used as an additive.
A minor increase in yield was observed when CuI (1 equiv)
was used in association with K2CO3 as a base and increasing
the reaction temperature to 808C (Table 1, entry 2). In contrast,
the yield significantly increased to 72% when Cs2CO3 was used
as base (Table 1, entry 3). Other bases proved to be less effi-
cient than Cs2CO3 or no reaction occurred with Et3N (Table 1,
entries 4–7). Increasing the amount of either CuI or Cs2CO3 led
to a lower yield of 4a (Table 1, entries 8–10). The use of other
copper salts, such as CuCl and CuBr, did not further improve
the yield of 4a, and no reaction occurred when CuBr2 was
used (Table 1, entries 11–13).
an argon atmosphere at 808C, pyridazinone 4a was obtained
in 64% yield.
In a similar way, this optimized procedure was then applied
to different aldehydes 1, hydrazines 2, and alkynylesters 3; the
results are listed in Table 2. The results show that pyridazi-
nones 4a–e were obtained in good yield, regardless of the
substituents (electron-withdrawing or -donating groups) pres-
ent on the aromatic ring of the aldehydes. When this cycliza-
tion was carried out with 4-nitro-benzaldehyde, product 4g
was not stable enough to be purified and characterized. The
reactivity of aryl alkynylester 3 under the previously optimized
reaction conditions was also investigated. Because aryl alkyny-
lesters 3 substituted with both electron-withdrawing and -do-
nating groups allowed the formation of pyridazinones 4h–r in
variable yields (from 40 to 85%), the relationship between
these two variables, substituents and yields, indicates a weak
correlation. When we tried to extend the optimized conditions
to an alkynylester, with an alkyl chain directly bonded to the
triple bond, product 4s was not detected at all. Next, the mul-
ticomponent reaction, with two different hydrazines, was ex-
amined for the preparation of pyridazinones 4s–v. The opti-
To make the present cyclization more economical and envi-
ronmentally attractive, we examined the catalytic activity of
CuI. Variation in the catalyst amount from 50 to 10 mol% did
not show any improvement in the yields of 4a, even when
using additives or changing the catalyst (Table 1, entries 14–
22). In copper-catalyzed reactions, the use of chelating ligands
has a substantial effect and often leads to improved reactivi-
ty.[8] From this point of view, the reaction of 5 (0.25 mmol), 3a
(0.25 mmol), CuI (0.05 mmol), Cs2CO3 (0.25 mmol), and MeCN
(3 mL) was examined with in presence of ligands L1–L7
(0.1 mmol), which are shown in Figure 2. Of these ligands,
1,10-phenanthroline (L4) was the most effective, and gave
product 4a in 94% yield. Finally, we turned our attention to
applying these conditions to a multicomponent reaction. Thus,
when aldehyde 1a (0.25 mmol), hydrazine 2a (0.25 mmol), and
alkynylester 3a (0.25 mmol) were treated with CuI (0.05 mmol),
L4 (0.1 mmol), and Cs2CO3 (0.25 mmol) in MeCN (3 mL) under
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Table 2. Synthesis of pyridazinone 4.[a,b]
Figure 2. Studies of the effect of ligands L1–L7 on the reaction.
mized conditions were efficient for hydrazines with a methyl
group and chloro atom, which gave the corresponding pyrida-
zinones in moderate to good yields. However, the use of un-
substituted or aliphatic hydrazines did not give the product,
even when subjected to harsh reaction conditions. In this case,
the absence of p bonds in the alkyl chain could result in a de-
creased reactivity for nucleophilic attack on the carbon–carbon
triple bond.
When we investigated the formation of pyridazinone 4a, we
observed that the ethoxyl group, from alkynylester 3, was not
incorporated into the structure; this indicated that it could be
released into the reaction medium. Thus, we speculate that
this ethoxyl group should be a suitable internal nucleophile to
promote the in situ Ullmann coupling. It has been well docu-
mented that copper(I) iodide, L4, and cesium carbonate are
good reaction partners to promote the coupling of aryl halides
and aliphatic alcohols.[9]
Therefore, we applied exactly the same reaction conditions
as those used in the preparation of pyridazinone 4 (Table 1) to
the reaction of hydrazines, alkynylesters, and 2-halobenzalde-
hydes. The sequential Michael addition/1,2-cyclization addi-
tion/Ullmann cross-coupling reactions proceeded smoothly to
give pyridazinones 6a–c in good yields (Scheme 2). After these
experimental results, we assumed that, when 2-halobenzalde-
hydes are used, the oxidative addition of copper iodide to the
carbon–halogen bond occurs after pyridazinone ring formation
supported by the interaction of copper with the nitrogen
atom from the pyridazinone ring. This assumption can be fur-
ther supported by the fact that the Ullmann coupling did not
occur with 4-halobenzaldehyde derivatives.
[a] The reaction was performed in the presence of aldehyde
1 (0.25 mmol), hydrazine 2 (0.25 mmol), alkynylester 3 (0.25 mmol), CuI
(0.05 mmol), L4 (0.1 mmol), Cs2CO3 (0.25 mmol), and MeCN (3 mL), under
an argon atmosphere at 808C for 16 h. [b] Yield of product isolated after
column chromatography. [c] The product of Ullmann coupling was ob-
tained in 39% yield. [d] The reaction was carried out by using 0.5 mmol
of Cs2CO3.
To investigate the role of the CuI catalyst, we carried out the
reaction of aldehyde 1a, hydrazine 2a, and alkynylester 3a
under the optimized conditions in the absence of CuI. This re-
action gave the aza-Michael addition adduct 7 as the sole
product (Scheme 3).[10] In addition, when the reaction was per-
formed with phenylhydrazone 5 (Table 1), pyridazinones 4
were obtained in good yields. It seems clear that phenylhydra-
zone 5 is a possible intermediate in the multicomponent pro-
cess. Based on these results, we propose that the cyclization
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Conclusion
We have described a one-pot, three-component intermolecular
cyclization involving aldehydes, hydrazines, and alkynylesters.
This process provided efficient access to substituted pyridazi-
nones in good to excellent yields. Application of the present
methodology in the preparation of the Ullmann product was
also investigated. The optimization reactions showed that the
yields of the cyclization reaction were highly dependent on
the presence and nature of the base and ligand; the best re-
sults were obtained when Cs2CO3 was used as the base and L4
was used as the ligand. The use of L4 in association with CuI
avoided the use of equimolar amounts of copper salt and the
use of a multicomponent reaction became the method with
good atom economy. Carbon nucleophile addition to a Michael
acceptor, promoted by the copper salt, instead of nitrogen ad-
dition was the main factor to prevent the formation of unde-
sired azole derivatives, giving exclusively pyridazinones.
Scheme 2. Preparation of pyridazinones 6a–c.
involves the initial formation of hydrazone 5 from the reaction
of aldehydes 1 and hydrazines 2 (Scheme 3). Deprotonation of
NH from hydrazones 5 gives, after resonance, intermediate
a.[11] Intermediate a reacts with CuI to form cuprate b. The Mi-
chael addition of b into the carbon–carbon triple bond of the
alkynylester[10] gives adduct c’, which after isomerization gives
c.[12] Michael addition via a trans-copper adduct is in accord-
ance with the known ability of organocopper reagents to un-
dergo p complexation with a carbon–carbon triple bond and
with a carbonyl group. The intramolecular 1,2-addition of nitro-
gen to the ester carbonyl functionality gives d, which delivers
pyridazinone 4 (Scheme 3). Although intermediates c/c’ pro-
posed in the mechanism could not be isolated, we tried to
trap these intermediates with electrophiles. However, the addi-
tion of primary alkyl halides, a,b-unsaturated carbonyl com-
pounds, and allyl bromide, or quenched with proton sources,
did not allow any trapping products and gave only pyridazi-
none 4 as the product.
Experimental Section
General procedure for copper-catalyzed tandem three-com-
ponent reaction of aldehyde, arylhydrazine, and alkynyles-
ter
Aldehyde (0.25 mmol), arylhydrazine (0.25 mmol), alkynylester
(0.25 mmol), CuI (0.05 mmol), and L4 (0.1 mmol) in MeCN (3 mL)
were added to a two-necked round-bottomed flask equipped with
a reflux condenser, under an argon atmosphere. The reaction mix-
ture was stirred for the indicated time at 808C. The mixture was fil-
tered through silica gel with ethyl acetate and concentrated under
vacuum. The residue was purified by flash chromatography
(hexane/ethyl acetate=20:1).
2,5,6-Triphenylpyridazin-3(2H)-one (4a)
Pale-white solid; yield: 0.049 g, 61%; m.p. 250–2528C; 1H NMR
(CDCl3, 400 MHz): d=7.74 (d, J=7.3 Hz, 2H), 7.48 (t, J=7.6 Hz, 2H),
7.40–7.22 (m, 9H), 7.17–7.14 (m, 2H), 7.07 ppm (s, 1H); 13C NMR
(CDCl3, 100 MHz): d=159.6, 146.5, 145.5, 141.4, 135.7, 135.2, 130.0,
129.2, 129.0, 128.7, 128.6, 128.4, 128.1, 128.0, 125.3 ppm; MS (EI,
70 eV): m/z (%): 324 (100), 296 (31), 191 (92), 189 (44), 165 (39), 105
(20), 77 (86); HRMS (ESI): m/z calcd for C22H16N2O+H: 325.1341
[M+H]+; found: 325.1345.
2,5-Diphenyl-6-(p-tolyl)pyridazin-3(2H)-one (4b)
1
Yellow oil; yield: 0.056 g, 66%; H NMR (CDCl3, 200 MHz): d=7.74
(d, J=7.0 Hz, 2H), 7.52–7.24 (m, 6H), 7.24–7.01 (m, 7H), 2.30 ppm
(s, 3H); 13C NMR (CDCl3, 100 MHz): d=159.6, 146.5, 145.5, 141.4,
138.6, 135.8, 132.2, 130.0, 129.1, 128.9, 128.7, 128.6, 128.4, 128.0,
125.3, 21.1 ppm; MS (EI, 70 eV): m/z (%): 338 (100), 323 (14), 205
(85), 164 (12), 77 (45); HRMS (ESI): m/z calcd for C22H16N2O+H:
339.1497 [M+H]+; found: 339.1497.
6-(2-Chlorophenyl)-5-(2,5-dimethoxyphenyl)-2-phenylpyrida-
zin-3(2H)-one (4l)
1
Orange oil; yield: 0.042 g, 40%; H NMR (CDCl3, 400 MHz): d=7.75–
7.72 (m, 2H), 7.48 (t, J=7.5 Hz, 2H), 7.38 48 (t, J=7.3 Hz, 1H), 7.17
(s, 4H), 7.03 (s, 1H), 6.91 (dd, J=3.1 Hz, J=5.8 Hz, 1H), 6.85 (d, J=
Scheme 3. Proposed mechanism for the preparation of 4 through the multi-
component reaction.
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2.1 Hz, 1H), 6.65 (d, J=9.0 Hz, 1H), 3.78 (s, 3H), 3.25 ppm (s, 3H);
13C NMR (CDCl3, 100 MHz): d=159.5, 153.8, 149.7, 146.2, 143.1,
141.4, 134.8, 134.3, 130.8, 129.2, 128.6, 128.0, 127.8, 125.2, 115.8,
115.6, 112.3, 55.7, 55.2 ppm; MS (EI, 70 eV): m/z (%): 418 (100), 387
(50), 375 (15), 285 (35), 162 (14), 147 (10), 77 (57); HRMS (ESI): m/z
calcd for C24H19ClN2O3 +H: 419.1162 [M+H]+; found: 419.1168.
(m, 1H), 4.09 (q, J=7.2 Hz, 2H), 1.14 ppm (t, J=7.0 Hz, 3H);
13C NMR (CDCl3, 100 MHz): d=166.0, 148.0, 145.1, 140.2, 139.6,
137.7, 129.4, 129.1, 128.4, 127.9, 127.1, 126.9, 124.0, 123.1, 122.1,
121.8, 118.1, 110.6, 59.9, 13.9 ppm; MS (EI, 70 eV): m/z (%): 368 (88),
323 (33), 296 (100), 293 (11), 165 (11), 77 (12); MS (EI, 70 eV): m/z
(%): 414 (100), 383 (65), 308 (56), 281 (46), 251 (46), 163 (10), 132
(22), 121 (21), 77 (38); HRMS (ESI): m/z calcd for C24H20N2O2 +H:
369.1603 [M+H]+; found: 369.1609.
5-(2,5-Dimethoxyphenyl)-2-phenyl-6-p-tolylpyridazin-3(2H)-
one (4o)
6-(2-Ethoxyphenyl)-5-(4-methoxyphenyl)-2-phenylpyridazin-
3(2H)-one (6c)
1
Yellow solid; yield: 0.062 g, 62%; m.p. 164–1668C; H NMR (CDCl3,
400 MHz): d=7.75 (d, J=7.6 Hz, 2H), 7.46 (t, J=7.8, 2H), 7.36 (t,
J=7.3, 1H), 7.12 (d, J=8.1 Hz, 2H), 7.03 (s, 1H), 6.99 (d, J=7.8 Hz,
2H), 6.87 (dd, J=9.0 Hz, 1H), 6.83 (d, J=2.9 Hz, 1H), 6.65 (d, J=
9.0 Hz, 1H), 3.76 (s, 1H), 3.23 (s, 1H), 2.27 ppm (s, 1H); 13C NMR
(CDCl3, 100 MHz): d=159.6, 153.7, 150.0, 147.4, 143.5, 141.6, 138.1,
133.4, 130.7, 128.6, 128.2, 127.8, 125.9, 125.3, 115.6, 115.5, 112.3,
55.7, 55.3, 21.0 ppm; MS (EI, 70 eV): m/z (%): 398 (100), 367 (50),
265 (33), 206 (22); HRMS (ESI): m/z calcd for C25H22N2O3 +H:
399.1709 [M+H]+; found: 369.1719.
1
Dark-orange oil; yield: 0.054 g, 54%; H NMR (CDCl3, 200 MHz): d=
7.71 (t, J=7.2 Hz, 3H), 7.52 (t, J=7.8 Hz, 2H), 7.39–7.23 (m, 4H),
7.06–6.8 (m, 4H), 4.12 (q, J=7.0 Hz, 2H), 3.85 (s, 3H), 1.19 ppm (t,
J=7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): d=166.0, 159.9, 147.6,
145.7, 140.2, 139.6, 130.8, 129.7, 129.3, 127.0, 126.9, 124.1, 123.0,
122.0, 121.9, 117.7, 113.3, 110.5, 59.9, 55.1, 14.0 ppm; MS (EI, 70 eV):
m/z (%): 398 (65), 353 (28), 326 (100), 282 (21), 192 (13), 135 (26),
77 (33); HRMS (ESI): m/z calcd for C25H22N2O3 +H: 399.1709 [M+
H]+; found: 399.1700.
6-(4-Chlorophenyl)-2-(2,5-dimethylphenyl)-5-(4-methoxyphe-
nyl)pyridazin-3(2H)-one (4t)
X-ray crystallography
1
White solid; yield: 0.056 g, 54%; m.p. 218–2198C; H NMR (CDCl3,
CCDC-974780 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
400 MHz): d=7.24–7.15 (m, 7H), 7.08 (d, J=8.8 Hz, 2H), 7.03 (s,
1H), 6.84 (d, J=8.8 Hz, 2H), 3.81 (s, 3H), 2.35 (s, 3H), 2.21 ppm (s,
3H); 13C NMR (CDCl3, 100 MHz): d=160.4, 159.6, 145.3, 145.2,
140.2, 136.6, 134.7, 133.9, 131.5, 130.8, 130.6, 130.1, 130.0, 129.0,
128.2, 127.6, 127.5, 114.1, 55.2, 20.7, 17.2 ppm; MS (EI, 70 eV): m/z
(%): 416 (44), 399 (100), 305 (13), 255 (25), 212 (33), 176 (80), 151
(29), 105 (72), 77 (73); HRMS (ESI): m/z calcd for C25H21ClN2O2 +H:
417.1370 [M+H]+; found: 417.1375.
Acknowledgements
We are grateful to FAPERGS, CAPES, and CNPq (CNPq/INCT-cat-
alise) for financial support. CNPq is also acknowledged for fel-
lowships (G.Z., A.C.M., and T.A.C.G.). We thank the LMI-UFSM
for support of X-ray crystallography results.
General procedure for copper-catalyzed tandem three-com-
ponent reaction of aldehyde, arylhydrazine, and alkynyles-
ter and consecutive Ullmann coupling
Aldehyde (0.25 mmol), arylhydrazine (0.25 mmol), alkynylester
(0.25 mmol), CuI (0.05 mmol), and L4 (0.1 mmol) in MeCN (3 mL)
were added to a two-necked round-bottomed flask equipped with
a reflux condenser, under an argon atmosphere. The reaction mix-
ture was stirred for the desired time at 808C. The mixture was fil-
tered through silica gel with ethyl acetate and concentrated under
vacuum. The residue was purified by flash chromatography
(hexane/ethyl acetate=20:1).
Keywords: copper · cyclization · heterocycles · homogeneous
catalysis · multicomponent reactions
[1] T. D. Heightman, A. T. Vasella, Angew. Chem. 1999, 111, 794; Angew.
Chem. Int. Ed. 1999, 38, 750.
[2] a) Y. L. Janin, Chem. Rev. 2012, 112, 3924; b) S. Fustero, M. Sꢁnchez-Rose-
llꢂ, P. Barrio, A. Simꢂn-Fuentes, Chem. Rev. 2011, 111, 6984; c) O. A. Atta-
nasi, P. Filippone, Synlett 1997, 1128.
[3] a) S. G. Lee, J. J. Kim, D. H. Kweon, Y. J. Kang, S. D. Cho, S. K. Kim, Y. J.
Yoon, Curr. Med. Chem. 2004, 11, 1461; b) P. J. Mꢁatyus, Het. Chem.
1998, 35, 1075.
5-(2,5-Dimethoxyphenyl)-6-(2-ethoxyphenyl)-2-phenylpyri-
dazin-3(2H)-one (6a)
[4] a) P. Wipf, Z. Fang, L. Ferrie, M. Ueda, M. A. A. Walczak, Y. Yan, Pure Appl.
Chem. 2013, 85, 1079; b) G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112,
6104; c) R. Dalpozzo, G. Bartolib, G. Bencivennib, Chem. Soc. Rev. 2012,
41, 7247; d) S. Werner, S. D. Nielsen, P. Wipf, D. M. Turner, P. G. Cham-
bers, S. J. Geib, D. P. Curran, W. J. Zhang, J. Comb. Chem. 2009, 11, 452;
e) P. Wipf, C. R. J. Stephenson, Org. Lett. 2005, 7, 1137.
[5] P. Liu, Y. Pan, Y. Xu, H. Wang, Org. Biomol. Chem. 2012, 10, 4696.
[6] a) S. Safaei, I. Mohammadpoor-Baltork, A. R. Khosropour, M. Moghadam,
S. Tangestaninejad, V. Mirkhani, New J. Chem. 2013, 37, 2037; b) X.-C. Tu,
H. Feng, M.-S. Tu, B. Jiang, S.-L. Wang, S.-J. Tu, Tetrahedron Lett. 2012,
53, 3169; c) S. Safaei, I. Mohammadpoor-Baltork, A. R. Khosropour, M.
Moghadam, S. Tangestaninejad, V. Mirkhani, Adv. Synth. Catal. 2012,
354, 3095; d) S. A. Raw, A. T. Turner, Tetrahedron Lett. 2009, 50, 696.
[7] B. C. Hamper, M. L. Kurtzweil, J. P. Beck, J. Org. Chem. 1992, 57, 5680.
[8] a) D. S. Surry, S. L. Buchwald, Chem. Sci. 2010, 1, 13; b) A. Klapars, J. C.
Antilla, X. Huang, S. L. Buchwald, J. Am. Chem. Soc. 2001, 123, 7727.
1
Dark-orange oil; yield: 0.042 g, 39%; H NMR (CDCl3, 400 MHz): d=
7.72 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.5 Hz, 1H), 7.51 (t, J=7.5 Hz,
2H), 7.39–7.29 (m, 2H), 7.12 (s, 1H), 7.03–6.84 (m, 5H), 4.09 (q, J=
7.9 Hz, 2H), 3.74 (s, 3H), 3.65 (s, 3H), 1.14 ppm (t, J=7.2 Hz, 3H);
13C NMR (CDCl3, 100 MHz): d=165.8, 153.5, 151.4, 144.6, 144.1,
140.3, 139.8, 129.4, 128.2, 127.0, 126.8, 123.9, 123.1, 122.1, 121.6,
119.2, 116.0, 114.6, 112.5, 110.6, 59.8, 56.6, 55.7, 14.0 ppm; HRMS
(ESI): m/z calcd for C26H24N2O4 +H: 429.1814 [M+H]+; found:
429.1819.
6-(2-Ethoxyphenyl)-2,5-diphenylpyridazin-3(2H)-one (6b)
1
Dark-orange oil; yield: 0.069 g, 75%; H NMR (CDCl3, 200 MHz): d=
7.72 (t, J=7.7 Hz, 3H), 7.57–7.24 (m, 9H), 7.04–6.97 (m, 2H), 6.76
Chem. Eur. J. 2014, 20, 1 – 7
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[9] a) G. E. Job, S. L. Buchwald, Org. Lett. 2002, 4, 3703; b) M. Wolter, G.
Nordmann, G. E. Job, S. L. Buchwald, Org. Lett. 2002, 4, 973.
Tetrahedron Lett. 1995, 36, 3059; c) T. Saegusa, I. Murase, Y. Ito, Tetrahe-
dron 1971, 27, 3795.
[10] Z. Yuan, Y. Wei, M. Shi, Eur. J. Org. Chem. 2010, 4088.
[11] X. Deng, N. S. Mani, Org. Lett. 2008, 10, 1307.
Received: June 8, 2014
[12] a) A. Alexakis, K. Croset, Org. Lett. 2002, 4, 4147; b) M. van Klaveren,
E. S. M. Persson, A. Del Villar, D. M. Grove, J.-E. Bꢃckvall, G. van Koten,
Published online on && &&, 0000
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FULL PAPER
&
Homogeneous Catalysis
A. C. Mantovani, T. A. C. Goulart,
D. F. Back, G. Zeni*
&& – &&
Synthesis of Pyridazinones through
the Copper(I)-Catalyzed
Multicomponent Reaction of
Aldehydes, Hydrazines, and
Alkynylesters
All in! A copper-catalyzed multicompo-
nent cyclization reaction, which com-
bined aldehydes, hydrazines, and alky-
nylesters, was applied to the synthesis
of pyridazinones (see scheme). The reac-
tion was regioselective to give only six-
membered pyridazinones in the com-
plete absence of five-membered pyra-
zoles or a regioisomeric mixture.
Chem. Eur. J. 2014, 20, 1 – 7
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ