A new approach to the synthesis of 4-(N-aryl)carbamoylmethyl-4,5- dihydropyridazin-3(2H)-ones

Article abstract of DOI:10.1016/j.tetlet.2011.04.038

Reaction of N-aryl substituted maleimides with aliphatic ketazines leads to the formation of 4,5-dihydropyridazin-3(2H)-ones in moderate yields. The reaction proceeds through 1,4-addition of an azine to the maleimide double bond, as confirmed by separatio

Full text of DOI:10.1016/j.tetlet.2011.04.038

Tetrahedron Letters 52 (2011) 3146–3149
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Tetrahedron Letters
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A new approach to the synthesis of
4-(N-aryl)carbamoylmethyl-4,5-dihydropyridazin-3(2H)-ones
Alexander V. Stepakov a, , Michail A. Kinzhalov a, Vitaly M. Boitsov b, Liubov V. Stepakova a,
⇑
Galina L. Starova a, Sergey Yu. Vyazmin c, Elena V. Grinenko c
a Chemistry Department, Saint-Petersburg State University, Universitetsky prosp. 26, St.-Petersburg 198504, Russian Federation
b Saint-Petersburg Academic University—Nanotechnology Research and Education Centre RAS, Khlopin str. 8/3, St.-Petersburg 195220, Russian Federation
c Saint-Petersburg State Forest Technical Academy, Institutsky per. 5, St.-Petersburg 194021, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of N-aryl substituted maleimides with aliphatic ketazines leads to the formation of 4,5-dihyd-
ropyridazin-3(2H)-ones in moderate yields. The reaction proceeds through 1,4-addition of an azine to
the maleimide double bond, as confirmed by separation of the corresponding adducts in some cases,
which are then converted into 4,5-dihydropyridazin-3(2H)-ones. In addition, the solid-state synthesis
of 4,5-dihydropyridazin-3(2H)-ones is demonstrated for the first time.
Received 15 December 2010
Revised 25 March 2011
Accepted 8 April 2011
Available online 15 April 2011
Ó 2011 Published by Elsevier Ltd.
Keywords:
N-Arylmaleimides
Aliphatic ketazines
4,5-Dihydropyridazin-3(2H)-ones
Solvent-free conditions
Microwave irradiation
Michael addition product
The 4,5-dihydropyridazin-3(2H)-one subunit appears in com-
pounds displaying a considerable range of biological activity: in
phosphodiesterase 3/4 (PDE3/PDE4) inhibitors,1 inhibitors of
cyclooxygenase-2 (COX-2),2 subtype-4 receptor (MC4R) agonists,3
platelet aggregation inhibitors,4 inhibitors of adenosine 3’,5’-cyclic
phosphate phosphodiesterase III (CAMP PDE III),5 p38 MAP kinase
inhibitors,6 b-adrenoreceptor antagonists,7 and in compounds with
antihypertensive,8 positive inotropic,9 cardiotonic,10 antithrom-
botic, antiinflammatory and antiulcer activites.11 4,5-Dihydropyri-
dazin-3(2H)-ones are readily obtained by treating 4-oxocarboxylic
acids or their derivatives (esters, thioesters, amides and lactams)
with hydrazine or monosubstituted hydrazines.12 In the present
work, we show for the first time that (N-aryl)carbamoylmethyl-
4,5-dihydropyridazin-3(2H)-ones can be produced in moderate
yields by reaction of N-arylmaleimides with aliphatic ketazines.
The [3+2]-cycloaddition reaction of N-phenylmaleimide to acetone
azine was previously described in the literature, but the spectral
properties of the products were not provided.13,14 The reaction of
cyclohexanone azine with N-phenylmaleimide, leading to Michael
addition products as mixtures of stereoisomers in low yields (ca.
16%), is described in a review dedicated to reactions of azines with
dienophiles.15
Heating N-arylmaleimides 1a–h and acetone azine (2) in xylene
(140 °C, 8 h) led to the formation of 4,5-dihydropyridazin-3(2H)-
ones 3a–h (the best results were achieved using an imide/azine
ratio of 1:4). The product yields are given in Table 1.16–18 The
compositions and structures of products 3a–h were established
by elemental and spectral analysis.19 The structure of compound
3g was confirmed additionally by X-ray diffraction analysis
(Fig. 1).20
Despite the fact that the reaction mixtures decompose partially
during this process, it was possible to isolate most of the products
by crystallization from ethanol. Alternatively, the products were
isolated by preparative thin layer chromatography. In some cases
the corresponding aminobenzenes were observed in the reaction
mixtures and these could also be isolated.
Some of the reactions were performed under solvent-free con-
ditions (on SiO2) under microwave irradiation (Table 1, entries 5
and 11),21 or under conventional heating (Table 1, entries 6 and
12).22 Optimal times for microwave (1 h) and conventional (3 h)
heating were determined on the basis of several experiments.
Reaction of azine 2 and N-(4-methoxyphenyl)maleimide (1i) in
xylene at first led to formation of the Michael addition product 4 as
an inseparable mixture of stereoisomers. Further heating of adduct
4 in xylene did not afford the corresponding dihydropyridazinone.
However, dihydropyridazinone 3i was obtained in 28% overall
yield by heating adduct 4 under solvent-free conditions (on SiO2)
using microwave irradiation (Scheme 1).
⇑
Corresponding author. Fax: +7 812 4286939.
E-mail address: alstepakov@yandex.ru (A.V. Stepakov).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.04.038

A. V. Stepakov et al. / Tetrahedron Letters 52 (2011) 3146–3149
3147
Reaction of azine 5 with imides 1d,h proceeds with formation of
O
O
H
N
Me
O
a mixture of Michael addition products 6a,b and diastereomeric
a
b
N
O
dihydropyridazinones 7a,b (Table 2, entries 1–4).23 The products
N
Ar
N Ar
N
Ar
N
Me
N
H
O
O
Table 1
Me
Me
Ar = 4-MeOC6H4
Synthesis of 4,5-dihydropyridazin-3(2H)-ones 3a–h from imides 1a–h and azine 2a
1i
4
3i
O
Me
Me
N
H
N
Scheme 1. Reagents, conditions and yields: (a) azine 2 (4 equiv), p-xylene, 140 °C,
8 h, 69%; (b) MW (180 W), solvent-free conditions (SiO2), 1 h, 41%.
O
N
+
N
Ar
N
O
Ar
Me
N
H
O
Me
Me
1a-h
2
3a-h
Me
Me
O
H
N
Yieldb (%)
O
Entry
Imide
Ar
Product
a
N
O
N
Ar
1
2
3
4
1a
1b
1c
1d
1d
1d
1e
1f
1g
1h
1h
1h
C6H5
4-ClC6H4
4-FC6H4
4-IC6H4
4-IC6H4
4-IC6H4
4-O2NC6H4
3,4-Cl2C6H3
3,5-Cl2C6H3
3-Cl,4-MeC6H3
3-Cl,4-MeC6H3
3-Cl,4-MeC6H3
3a
3b
3c
3d
3d
3d
3e
3f
3g
3h
3h
3h
44
41
39
39
41
57
49
45
43
51
38
52
N
Ar
N
H
N
Me
O
Me Me
Ar = 4-IC6H4 (a), 3-Cl,4-MeC6H3 (b)
cis-7a,b
5c
6d
7
Me
6a,b
8
9
10
11c
12d
Scheme 2. Reagents, conditions and yields: MW (180 W), solvent-free conditions
(SiO2), 1 h, 85% (cis-7a), 74% (cis-7b).
of the reactions were isolated by preparative thin layer chromatog-
raphy on silica. Crystallization of the mixture of cis/trans-7 from
methanol resulted in pure cis-7a,b; trans-7a,b were not isolated
in pure form. The compositions and structures of the products 6
and 7 were established by elemental and spectral analysis.24
Spin–spin coupling constants between protons H–C4 and H–C5
were 7 Hz for cis-7 and 3 Hz for trans-7.25 Further confirmation
of the cis stereochemical assignment came from NOE experiments
carried out on cis-7b. Thus, irradiation of H-5 (d = 2.60, q) gave rise
to a 6% NOE enhancement of H-4 (d = 2.71, q).26
a
The reactions were performed using imide (2 mmol) and azine (8 mmol) in p-
xylene (10 mL) at 140 °C for 8 h.
b
Isolated yield.
c
The reactions were performed using imide (1 mmol) and azine (4 mmol) via a
solvent-free procedure (on SiO2) under microwave irradiation (180 W) for 30 min.
d
The reactions were performed using imide (1 mmol) and azine (4 mmol) under
solvent-free conditions (on SiO2) and conventional heating at 140 °C for 3 h.
Adducts 6a,b, obtained under conventional heating in p-xylene,
were transformed under solvent-free conditions (on SiO2) using
microwave irradiation into cis-7a,b in high yields (Scheme 2).
Next, the reactions of N-arylmaleimides with azines of cyclic
ketones 8 and 9 were investigated. Reactions of ketazines 8 and
9 with N-arylmaleimides 1d,h in p-xylene at 140 °C led to the for-
mation of Michael addition products 10a,b and 11a,b as mixtures
of isomers. Formation of dihydropyridazinones under these condi-
tions was not observed (Table 3). Carrying out this reaction under
solvent-free conditions (on SiO2) using microwave irradiation led
to the formation of the corresponding dihydropyridazinones
Figure 1. ORTEP drawing of 3g.
Table 2
Synthesis of 4,5-dihydropyridazin-3(2H)-ones 7a,b from imides 1d,h and azine 5
Me
Me
O
H
N
H
N
Me
O
Me
O
1d,h
N
O
N
O
N
Ar
+
N
+
N
N
Ar
Ar
N
N
H
N
H
Me
Me
O
Me
Me Me
Me Me
Me
5
6
trans-7
cis-7
Entry
Ar (imide)
Conditions
Products
Yielda (%)
6
7b (cis:trans)
1
2
3
4
4-IC6H4 (1d)
4-IC6H4 (1d)
3-Cl,4-MeC6H3 (1h)
3-Cl,4-MeC6H3 (1h)
p-Xylene, 140 °C, 4 h
p-Xylene, 140 °C, 14 h
p-Xylene, 140 °C, 4 h
p-Xylene, 140 °C, 14 h
6a, 7a
6a, 7a
6b, 7b
6b, 7b
51
7
41
9
5 (n.d.)c
42 (4:1)
6 (n.d.)c
37 (5:1)
a
b
c
Isolated yield.
Determined from the crude reaction mixtures by 1H NMR spectroscopy.
No data.

3148
A. V. Stepakov et al. / Tetrahedron Letters 52 (2011) 3146–3149
Table 3
O
Reactions of imides 1d,h with azines 8 and 9
H
N
N
Ar
O
O
N
O
Ar
O
N
Ar
n
a
N
H
N
N
n
1d,h
n
O
n
N
N
o
N
N
p-xylene, 140 C, 8 h
n = 1, Ar = 4-IC H
n = 1, Ar = 3-Cl,4-MeC H 12b (47%)
12a (52%)
6
4
n
n
6
3
n = 2, Ar = 4-IC H
13a (67%)
6
4
10a,b,11a,b
n = 1
n = 2
8
9
n
n = 2 Ar = 3-Cl,4-MeC H 13b (54%)
,
6
3
n = 1 10a,b
n = 2 11a,b
Scheme 3. Reagents and conditions: MW (180 W), solvent-free conditions (SiO2),
1 h.
Entry
Ar
4-IC6H4
3-Cl,4-MeC6H3
4-IC6H4
n
Product
Yielda (%)
1
2
3
4
1
10a
10b
11a
11b
31
35
42
48
1
2
2
Cl
Cl
3-Cl,4-MeC6H3
H
N
H
N
Cl
Cl
O
a
O
Isolated yield.
a
N
O
N
O
Me
N
H
Me
N
H
Table 4
3f
14
The reaction of imides 1d,h with azines 8 and 9 under solvent-free conditions (on
SiO2) using microwave irradiation
Scheme 5. Reagents, conditions and yields: CuCl2, acetonitrile, 82 °C, 30 min, 61%.
H
N
O
n
N
O
1d,h
N
N
Although the mechanism of this reaction is still under investiga-
tion, a plausible route would involve a 1,4-addition step of azine
tautomeric form (A) to maleimide (B) which leads to Michael addi-
tion product (C) (this was confirmed by isolation in some cases).27
Next, adduct (C) can transform into 4,5-dihydropyridazin-3(2H)-
one (E) via N-substituted dihydropyridazinone (D). Formation of
dihydropyridazinone (D) occurs through intramolecular nucleo-
philic substitution on the carbonyl group (Scheme 4).28
4,5-Dihydropyridazin-3(2H)-one 3f can be transformed into the
corresponding pyridazinone 14 in 61% yield by reaction with CuCl2
in acetonitrile (Scheme 5).
Ar
MW (180 W), SiO , 1h
2
N
H
n
n
n = 1
n = 2
8
n = 1 12a,b
n = 2 13a,b
9
Entry
Ar
n
Product
Yielda (%)
1
2
3
4
4-IC6H4
3-Cl,4-MeC6H3
4-IC6H4
1
1
2
2
12a
12b
13a
13b
9
11
23
28
3-Cl,4-MeC6H3
a
Isolated yield.
In summary, we have developed a new method for the synthesis
of (N-aryl)carbamoylmethyl-4,5-dihydropyridazin-3(2H)-ones by
reaction of N-aryl substituted maleimides with aliphatic ketazines.
In some cases Michael addition intermediates were isolated, which
were then converted into the corresponding 4,5-dihydropyridazin-
3(2H)-ones. The solid-state synthesis of 4,5-dihydropyridazin-
3(2H)-ones has been described for the first time. The reactions
are operationally simple and do not require temperature manipu-
lations or inert atmospheres. Further extension of this study is
ongoing.
12a,b and 13a,b in low yields (Table 4). The obtained Michael addi-
tion products 10a,b and 11a,b were transformed under solvent-
free conditions (on SiO2) using microwave irradiation into the cor-
responding dihydropyridazinones 12a,b and 13a,b in moderate
yields (Scheme 3). Due to the generation of two stereogenic
centres, the products 12 and 13 were obtained as mixtures of
diastereoisomers which could not be separated by column
chromatography.
O
N
Ar
N
N
N
N
H
O
B
A
O
O
H
N
O
H2O
N
N
Ar
N
Ar
N
O
N
O
O
_
Ar
N
N
O
O
N
H
N
Ar
HN
O
N
H
C
E
D
Scheme 4. A plausible reaction mechanism.

A. V. Stepakov et al. / Tetrahedron Letters 52 (2011) 3146–3149
3149
34, 1732–1739; (e) Singh, P. R.; Surpur, M. P.; Patil, S. B. Tetrahedron Lett. 2008,
49, 3335–3340; (f) Brulé, C.; Bouillon, J.-P.; Nicolaï, E.; Portella, C. Synthesis
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Acknowledgement
We sincerely thank LumexÒ Ltd (St.-Petersburg) for access to
the focused microwave reactor (MinotavrÒ).
13. Sammour, A.; Fahmy, A. F. M.; Sayed, G. H. Egypt J. Chem. 1975, 18, 445–458.
14. In our work we could not reproduce the results listed in Ref. 13.
15. Wagner-Jauregg, T. Synthesis 1976, 349–359.
16. The use of an inert atmosphere did not influence the product yields.
17. General procedure for the synthesis of 4,5-dihydropyridazin-3(2H)-ones 3a–h:
Supplementary data
A
mixture of the corresponding imide 1 (2 mmol) and acetone azine 2
(8 mmol) in p-xylene (10 ml) was stirred under reflux for 8 h. The solvent was
evaporated under reduced pressure and the residue was purified either by
crystallization from MeOH or by preparative thin layer chromatography
eluting with CH2Cl2–MeOH (40:1).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.038.
18. The use of additives such as Et3N, Cs2CO3 or L-proline did not affect either the
References and notes
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greatest yields of products were reached using an azine/imide ratio of 4:1.
Using a reagent ratio of 2:1 the reaction only proceeded in trace amount.
However, further increasing the azine quantity led to an increased amount of
polymeric products.
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19. 1H NMR data for 3a: dH (300 MHz, DMSO-d6) 1.94 (s, 3H, Me), 2.30–2.40 (m,
2H, CH2CO), 2.53–2.59 (m, 1H, CH), 2.73–2.82 (m, 2H, (C@N)CH2CH), 7.02 (t,
1H, Ph, J = 8.0 Hz), 7.28 (d, 2H, Ph, J = 8.0 Hz), 7.58 (d, 2H, Ph, J = 8.0 Hz), 10.00
(s, 1H, NH), 10.50 (s, 1H, NH). 13C NMR data for 3a: dc (75 MHz, DMSO-d6) 23.5
(Me), 31.7 (CH2), 33.0 (CH), 36.8 (CH2), 119.9 (CArH), 123.9 (CArH), 129.5 (CArH),
140.0 (CAr), 153.0 (C@N), 169.3 (C@O), 170.0 (C@O).
20. Crystallographic data for the structure 3g have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication number
CCDC 801739. Copies of these data can be obtained on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (email: deposit@ccdc.cam.ac.uk).
21. General procedure for the synthesis of 4,5-dihydropyridazin-3(2H)-ones 3d,h
using solvent-free conditions under microwave irradiation: A mixture of imide
1 (1 mmol), acetone azine 2 (4 mmol) and silica (1.5 g, Chemapol 35/70) was
irradiated in a focused microwave reactor (MinotavrÒ) at 180 W for 60 min. In
all reactions the compounds were isolated by adding acetone to the mixture
and separating the silica by filtration. The solvent was removed under reduced
pressure, and the residue was purified either by crystallization from EtOH or by
preparative thin layer chromatography eluting with CH2Cl2–MeOH (40:1).
22. General procedure for the synthesis of 4,5-dihydropyridazin-3(2H)-ones 3d,h
using solvent-free conditions under conventional heating: A mixture of imide 1
(1 mmol), acetone azine 2 (4 mmol) and silica (2 g, Chemapol 35/70) was
stirred at 140 °C for 3 h. Acetone was added to the mixture and the silica was
separated by filtration. The solvent was removed under reduced pressure, and
the pure product was obtained either by crystallization from EtOH or by
preparative thin layer chromatography (CH2Cl2–MeOH, 40:1).
23. Maleimides 1d,h were chosen for further investigations because they form well
crystallizing products in excellent yields.
24. 1H NMR data for (cis-7a): dH (300 MHz, DMSO-d6) 0.88 (d, 3H, Me, J = 7.1 Hz),
1.04 (t, 3H, Me, J = 7.3 Hz), 2.25–2.35 (m, 3H, CH2CH3, H-C5), 2.55–2.60 (m, 1H,
CH2–C4, overlapped with the solvent signal), 2.80 (dd, 1H, CH2–C4, J = 15.9 and
7.2 Hz), 3.00 (q, 1H, H–C4, J = 7.0 Hz), 7.44 (d, 2H, Aryl, J = 8.7 Hz), 7.62 (d, 2H,
Aryl, J = 8.7 Hz), 10.14 (s, 1H, NH), 10.55 (s, 1H, NH). 13C NMR data for (cis-7a):
dc (75 MHz, DMSO-d6) 10.3 (Me), 11.2 (Me), 28.4 (CH2), 33.8 (CH2), 33.9 (CH),
37.5 (CH), 87.1 (CAr-I), 122.0 (2CArH), 138.1 (2CArH), 139.9 (CAr), 161.2 (C@N),
169.2 (C@O), 170.6 (C@O). 1H NMR data for (cis-7b): dH (300 MHz, CDCl3) 1.07
(t, 3H, Me, J = 7.1 Hz), 1.15 (d, 3H, Me, J = 7.0 Hz), 2.23 (s, 3H, Me), 2.26 (dd, 1H,
CH2CH3, J = 16.1 and 7.4 Hz), 2.32 (dd, 1H, CH2CH3, J = 16.1 and 7.4 Hz), 2.41
(dd, 1H, CH2–C4, J = 14.7 and 7.0 Hz), 2.57 (dd, 1H, CH2–C4, J = 14.7 and 5.6 Hz),
2.60 (q, 1H, H–C5, J = 7.0 Hz), 2.71 (q, 1H, H–C4, J = 6.9 Hz), 7.03 (d, 1H, Aryl,
J = 8.4 Hz), 7.19 (d, 1H, Aryl, J = 7.7 Hz), 7.64 (s, 1H, Aryl), 8.66 (s, 1H, NH), 8.93
(s, 1H, NH). 13C NMR data for (cis-7b): dc (75 MHz, DMSO-d6) 11.1 (Me), 11.2
(Me), 19.8 (Me), 28.6 (CH2), 33.5 (CH2), 33.9 (CH), 37.5 (CH), 118.6 (CArH), 120.0
(CArH), 130.7 (CAr), 132.0 (CArH), 133.8 (CAr), 139.0 (CAr), 158.9 (C@N), 168.6
(C@O), 169.4 (C@O).
25. Alvarez-Ibarra, C.; Csáky, A. G.; Oliva, C. J. Org. Chem. 2002, 67, 2789–
2797.
26. No NOE enhancement of H-4 was observed on irradiation of H-5 in trans-7a.
27. On the tautomerization of acetone azine, see: Kobychev, V. B.; Vitkovskaya, N.
M.; Pavlova, N. V.; Schmidt, E. Yu.; Trofimov, B. A. J. Struct. Chem. 2004, 45, 748–
755.
28. The choice of substituents on the aromatic ring of the imide was to ensure that
during the cyclization stage, nucleophilic substitution at the carbonyl would be
facilitated by electron-withdrawing groups. Harsher conditions are necessary
for the synthesis of pyridazinone from N-(4-methoxyphenyl)maleimide.
12. (a) Grundmann, C. Chem. Ber. 1948, 81, 1–11; (b) Gregory, H.; Wiggins, L. F. J.
Chem. Soc. 1949, 2546–2549; (c) Wan, W.; Hou, J.; Jiang, H.; Wang, Y.; Zhu, S.;
Deng, H.; Hao, J. Tetrahedron 2009, 65, 4212–4219; (d) Jungheim, N. L.; Boyd, D.
B.; Indelicato, J. M.; Pasini, C. E.; Preston, D. A.; Alborn, W. E. J. Med. Chem. 1991,