First synthesis of 4,5-dihydro-3(2H)-pyridazinones via Zn-mediated hydrohydrazination

Article abstract of DOI:10.1016/j.tetlet.2008.05.084

The hydrohydrazination of 4-pentynoic acid with different arylhydrazines proceeds smoothly in the presence of zinc chloride. The domino amination-amidation sequence leads to aryl-substituted 4,5-dihydro-3(2H)-pyridazinones.

Full text of DOI:10.1016/j.tetlet.2008.05.084

Tetrahedron Letters 49 (2008) 4607–4609
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Tetrahedron Letters
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First synthesis of 4,5-dihydro-3(2H)-pyridazinones via Zn-mediated
hydrohydrazination
*
Karolin Alex, Annegret Tillack, Nicolle Schwarz, Matthias Beller
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The hydrohydrazination of 4-pentynoic acid with different arylhydrazines proceeds smoothly in the pres-
ence of zinc chloride. The domino amination–amidation sequence leads to aryl-substituted 4,5-dihydro-
3(2H)-pyridazinones.
Received 8 April 2008
Revised 18 May 2008
Accepted 19 May 2008
Available online 23 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Hydrazine
Hydroamination
Intermolecular
Pentynoic acid
Pyridazinone
Zinc
Pyridazines represent an important class of biologically active
compounds.1 Especially pyridazinone derivatives are well known
for their treatment in cardiovascular and heart diseases because
of their blood pressure reduction properties as well as platelet-
aggregation-inhibition and cardiotonic effects.2 Besides, aryl-
substituted 4,5-dihydro-3(2H)-pyridazinones such as imazodan
are reported to show ionotropic properties comparable to milri-
none and amrinone (Scheme 1).3
R
O
N
R1
O
NH
N
R2
N
H
N
N
Amrinone (R1= NH2, R2= H)
Milrinone (R1= CN, R2= CH3)
Imazodan (R = H)
CI-930 (R = CH3)
Scheme 1. Selected examples of biologically active pyridazinones.
In general, the synthesis of 4,5-dihydro-3(2H)-pyridazinones
proceeds via reaction of
c-ketoacids and their derivatives with
alkylhydrazines or phenylhydrazines to give the corresponding
hydrazones.4 The resulting hydrazones are known to be converted
by a simple condensation reaction to pyridazinones.5 Other syn-
theses of pyridazinones are based for example on condensation
With respect to the analogy of alkynes and carbonyl
compounds, we thought that 4-pentynoic acid derivatives should
behave similar to c-ketoacid derivatives (Scheme 2).
Based on this idea, herein we describe for the first time the
synthesis of different aryl-substituted 4,5-dihydro-3(2H)-pyridaz-
inones from alkynes.
To our delight, the reaction of phenylhydrazine (1a) with 4-
pentynoic acid (2) in the presence of 1 equiv ZnCl2 resulted in
the formation of the corresponding pyridazinone 3a (Scheme 3).
In agreement with previous work the hydrohydrazination reaction
proceeds with complete regioselectivity toward the Markovnikov
product.13
of Wittig reagents with arylhydrazones or condensation of
a-keto-
esters with hydrazinocarbonyl-acetic acid esters.6
For some time, we have been involved in catalytic intermole-
cular hydroamination reactions of alkynes with amines7,8 and
arylhydrazines (hydrohydrazination).9 Notably, in these domino
reactions alkynes behave somewhat similar to carbonyl com-
pounds. Indeed, imines as well as interesting heterocycles such
as indoles9,10 and pyrazolines11 are directly available from alkynes.
Most recently, we demonstrated that zinc chloride and zinc triflate
are especially well-suited as catalysts for such reactions of termi-
nal alkynes.12
COOR
COOR
O
* Corresponding author. Tel.: +49 (0)381 1281113; fax: +49 (0)381 128151113.
E-mail address: matthias.beller@catalysis.de (M. Beller).
Scheme 2. Analogy of c-ketoacids and 4-pentynoic acid.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.084

4608
K. Alex et al. / Tetrahedron Letters 49 (2008) 4607–4609
Table 2
COOH
Reaction of arylhydrazines 1 with 4-pentynoic acid (2) to various aryl-substituted
pyridazinones 3a
NH2
N
H
1a
2
Entry
Pyridazinone 3
Yieldb (%)
ZnX2, THF
N
N
1
2
3
4
5
6
7
72
3a
O
OH
O
N
N
N
O
N
N
NH
61
47
64
53
67
71
57
-H2O
3b
O
3a
pyridazinone
Scheme 3. Synthesis of pyridazinone 3a.
arylhydrazone
N
N
3c
O
In order to study this novel pyridazinone formation in more
detail, we examined the influence of different reaction conditions
(variation of Lewis acids, solvents, temperature), and changes in
reaction time on the reaction of phenylhydrazine (1a) with
4-pentynoic acid (2). Selected results are presented in Table 1.
Initially, we investigated the effects of different Zn salts as well
as Yb(OTf)3 or FeCl3 as Lewis acids. All the Zn salts showed full
conversion and the best yield (81%) is obtained applying Zn(OTf)2
(Table 1, entries 1–5). Increasing the amount of Zn(OTf)2 from
1 equiv to 3 equiv the yield dropped down (Table 1, entries 1 and
8). Advantageously, using 3 equiv of ZnCl2 the desired product is
observed in 90% yield (Table 1, entry 7). It is important to note that
applying catalytic amounts of zinc salts gave significantly lower
yields. The necessity to apply stoichiometric amounts of the Zn salt
is explained due to deactivation by the product similar to Friedel–
Crafts acylation reactions.14 As solvents, dioxane and toluene gave
a much lower yield compared to tetrahydrofuran (Table 1, entries 9
and 10). In general, the alkyne is consumed relatively fast, but the
best yields are obtained after 24 h (Table 1, entries 11 and 12).
Apparently, the intramolecular amidation reaction seems to be
the rate-determining step. By comparing the stoichiometric ratio
of the starting materials the highest product yield is obtained with
a slight excess of phenylhydrazine (Table 1, entries 7, 13, and 14).
Next, we studied reactions of 4-pentynoic acid (2) with substi-
tuted arylhydrazines 1 under optimized conditions in the presence
of the cheap and easily available ZnCl2. After Zn-mediated hydro-
hydrazination and subsequent condensation reactions, it is possi-
N
N
3d
O
N
MeO2S
NC
N
O
3e
N
N
3f
O
N
Br
N
O
3g
N
N
Cl
Cl
8
3h
O
a
Reaction conditions: 4-pentynoic acid (1.5 mmol), arylhydrazine (1.95 mmol),
3 equiv ZnCl2, THF (3 mL), 24 h, 100°C.
b
Isolated yield.
Table 1
Reaction of phenylhydrazine (1a) with 4-pentynoic acid (2) under different conditionsa
Entry
Lewis acid
Equiv
Solvent
Time (h)
Ratio (alkyne:hydrazine)
Conversionb (%)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Zn(OTf)2
Zn(OAc)2
Yb(OTf)3
FeCl3
ZnCl2
ZnCl2
ZnCl2
Zn(OTf)2
ZnCl2
ZnCl2
ZnCl2
1
1
1
1
1
2
3
3
3
3
3
3
3
3
THF
THF
THF
THF
THF
THF
THF
THF
Dioxane
Toluene
THF
THF
THF
24
24
24
24
24
24
24
24
24
24
9
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1
100
100
89
81
69
14
0
32
100
100
100
100
100
100
100
100
100
100
56
74
90
57
45
35
59
71
74
56
ZnCl2
ZnCl2
ZnCl2
16
24
24
THF
1:2
a
Reaction conditions: phenylhydrazine, 4-pentynoic acid, solvent (2 mL), 100 °C.
Yield and conversion were determined by GC analysis with dodecane as internal standard.
b

K. Alex et al. / Tetrahedron Letters 49 (2008) 4607–4609
4609
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In conclusion, we have developed a novel method for the syn-
thesis of aryl-substituted 4,5-dihydro-3(2H)-pyridazinones based
on domino hydrohydrazination and condensation reactions. Eight
substituted arylhydrazines react with 4-pentynoic acid in the pres-
ence of ZnCl2 to give the corresponding pyridazinone derivatives in
a one-pot process in moderate to good yields. Notably, this conve-
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This work has been funded by the State of Mecklenburg-Wes-
tern Pomerania, the BMBF (Bundesministerium für Bildung und
Forschung), the Deutsche Forschungsgemeinschaft (Graduierten-
kolleg 1213, and Leibniz-price), and the Fonds der Chemischen
Industrie (FCI). We thank Dr. W. Baumann, Dr. C. Fischer, S. Buch-
holz, S. Schareina, and K. Mevius for their excellent technical and
analytical support.
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Holenz, J.; Diaz, J. L.; Beller, M. Org. Biomol. Chem. 2008, 6, 1802–1807; (b)
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.084.
10. (a) Banerjee, S.; Barnea, E.; Odom, A. L. Organometallics 2008, 27, 1005–1014;
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