Synthesis of regiospecifically polysubstituted pyridazinones

Article abstract of DOI:10.1016/j.tetlet.2007.09.013

Desymmetrization of pyridazine-3,6-diones by the use of N-benzyl protective groups leads to useful starting materials for building polysubstituted pyridazine libraries in a regioselective manner.

Full text of DOI:10.1016/j.tetlet.2007.09.013

Tetrahedron Letters 48 (2007) 7817–7820
Synthesis of regiospecifically polysubstituted pyridazinones
Joao X. de Arau´jo-Ju´nior,a,c Martine Schmitt,a,* Cyril Antheaumea,b
˜
and Jean-Jacques Bourguignona
aInstitut Gilbert Laustriat, UMR 7175, 74 route du Rhin, BP 60024, 67401 Illkirch, France
bService Commun de RMN, Faculte´ de Pharmacie, 74 route du Rhin, BP 60024, 67401 Illkirch, France
cEscola de Enfermagem e Farmacia, Instituto de Quı´mica e Biotecnologia, Universidade Federal de Alagoas,
cidade Universitaria, 57.072-970 Maceio´-AL, Brazil
Received 11 June 2007; revised 3 August 2007; accepted 4 September 2007
Available online 6 September 2007
Abstract—Desymmetrization of pyridazine-3,6-diones by the use of N-benzyl protective groups leads to useful starting materials for
building polysubstituted pyridazine libraries in a regioselective manner.
Ó 2007 Elsevier Ltd. All rights reserved.
Pyridazine derivatives, in particular pyridazinones, pres-
R1
R1
R1
ent various pharmacological properties.1–7 In most
cases, the compounds bear an aryl group in position 6.
Some of them are also substituted in position 42 or
5.1,3b They are prepared by means of classical methodol-
ogies,1,3,4 generally offering fair structural diversity.
More recent approaches involving palladium cross-
coupling reactions were developed starting from 3,6-di-
chloropyridazines,8–12 4-bromopyridazines,13–16 or O-tosyl
pyridazines.17,18 However, they still presented limited
structural variations.
i)
+
O
O
O
O
O
O
O
N
H
N
N
N
85-94%
H
Bn
Bn
3
1
2
2%b(%)c
50 (45)
68 (62)
55 (53)
3%b(%)c
50 (40)
32 (28)
45 (41)
Entry
R1
Me
Ph
Br
Total yield (%)
a
b
c
85
90
94
a) total recovery of 2 and 3 after purification by recrystallization, b) 2/3
ratio characterized by 1HNMR in the reaction mixture, c) recovery after
recrystallisation
To control the regioselectivity of the substitution, we re-
port an original method using desymmetrization of pyr-
idazine-3,6-diones by
a
N-benzyl group. These
Scheme 1. Preparation of substituted N-benzyl-pyridazine-diones 2
and 3 as pure regioisomers. Reagents and conditions: (i) BnNHNH2,
HCl, H2O, reflux, 12 h.
dissymmetric intermediates permit regioselective control
of chemical variations on different positions 3, 4, 5 and 6
of the pyridazine backbone.
Thus, the treatment of substituted maleic anhydrides 1
with N-benzyl hydrazine in acidic medium (Scheme 1)
gave a mixture of the expected N-benzyl pyridazine
3,6-diones 2 and 3.
simple trituration of the crude material containing 2c
and 3c (R1=Br) with a mixture of ethyl acetate and ethyl
ether (1/4) gave an insoluble residue, which was recov-
ered and recrystallized from ethanol, giving a pure regio-
isomer 2c.
Due to their close Rf values, the regioisomers could not
be separated by column chromatography. However, a
The structure of isomer 2c was established as the Sono-
gashira-type reaction product using phenylacetylene or
aliphatic acetylene spontaneously cyclized yielding
furo-pyridazones 4 (Scheme 2).17,20
Keywords: N-Benzyl 4 (5)-substituted pyridazine 3,6-diones amination;
Palladium cross coupling reaction; Microwave heating; Suzuki;
Sonogashira.
*
The filtrate was recrystallized from isopropyl ether
Corresponding author. Tel.: +33 390 244231; fax: +33 390 244310;
e-mail: schmitt@pharma.u-strasbg.fr
affording the other isomer 3c. Similar treatments could
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.013

7818
J. X. de Arau´jo-Ju´nior et al. / Tetrahedron Letters 48 (2007) 7817–7820
Br
erature.19 Coupling this mono acid 5 with N-benzyl-
R
hydrazine yielded hydrazide as an intermediate, which
easily cyclized to afford the pure regioisomer 2c bearing
the bromine atom in position 4.
i)
O
O
O
O
N
H
N
N
N
R=Ph, 65%
R=(CH2)3-CO2Et, 85%
Bn
Bn
Pyridazine-3,6-diones 2 and 3 are suitable intermediates
for the preparation of 6-aryl-pyridazinones by means of
Suzuki-type reactions (Scheme 4).20 However, the classi-
cal activation step using POCl3 at 80 °C gave a complex
reaction mixture, probably as a result of partial removal
of the benzyl group. Thus the O-tosyl derivatives (6 and
7) were prepared in nearly quantitative yield, and reacted
in the presence of different aryl boronic acids and
Pd(PPh3)4 to yield the corresponding pyridazinones 8
and 9 in satisfactory yields.20 Deprotection of the benzyl
group was performed using AlCl3 as Lewis catalyst and
under microwave conditions (5 min) leading to the free
pyridazine-3-ones 10 and 11. The yields were satisfactory.
However, as a limitation for generalization of the meth-
od, a quantitative O-demethylation was also observed,
when the aromatics were bearing methoxy groups.
2c
4
Scheme 2. Formation of furopyridazinones 4. Reagents and condi-
tions: (i) R-„, CuI, PdCl2(PPh3)2 (3.5 mol%), NEt3, l-waves, 80 °C,
5 min.
be efficiently applied to other mixtures of regioisomers
(2a/3a and 2b/3b). When applying such simple treat-
ments on larger scales, several grams of each pure regio-
isomer could be prepared and submitted to further
reactions.
Regioisomer 2c could also be selectively prepared start-
ing from bromo-maleic anhydride 1c, as shown in
Scheme 3. The first methanolysis of anhydride in acid
medium led to monoacid 5, as reported in the recent lit-
Br
Br
Br
The 4 (or 5)-bromo-1-N-benzyl pyridazine-3,6-diones
(2c and 3c) are more interesting key intermediates, as
the halide constitutes an additional anchor to introduce
diversity, mainly through Pd(0) coupling reactions
(Schemes 5 and 6).
ii, iii)
70%
i)
MeO
O
O
O
O
O
O
O HO
N
N
85%
H
Bn
5
1c
2c
Scheme 3. Non-ambiguous preparation of 2c as a single regioisomer.
Reagents and conditions: (i) MeOH, rt; (ii) ClCO2iBu, DCM, ꢀ25 °C
to rt; (iii) BnNHNH2, HCl, TEA, DCM, ꢀ25 °C to rt.
The bromo compound 2c could be first reacted in Suzu-
ki-type reactions yielding intermediates 2b (Ar1 = Ph) or
12 (Ar1 5 Ph), which could be further reacted in differ-
R4
R5
R4
R5
R4
R5
i)
O
O
TsO
O
Cl
O
N
H
N
N
6,7
N
N
N
85-95%
Bn
Bn
Bn
2,3
ii)
75-85%
R4
R5
R4
R5
X
X
iii)
65-85%
O
O
N
N
N
N
H
8,9
10,11
Bn
X= H, Cl, OMe
X= H, Cl, OH
2,6,8,10: R4=Me, Ph, R5=H
3,7,9,11: R4=H, R5= Me, Ph
Starting
material
2a
X
H
4-Cl
4-OMe
H
4-OMe
4-OMe
4-OMe
6,7
yield(%)
6a(88)
8,9
10,11
yield(%)
8a(75)
8b(80)
8c(85)
9a(78)
9b(82)
8d(70)
9d(82)
yield(%)
10a(85)
10b(73)
10c(65)a
11a(79)
7a(85)
3a
6b(90)
7b(95)
2b
3b
a OMe→OH
Scheme 4. Access to 4 (or 5) substituted 6-aryl-pyridazinones. Reagents and conditions: (i) TsCl, pyridine, rt; (ii) ArB(OH)2, Pd(PPh3)4 (7%), lw,
DME, 30 min, 110 °C; (iii) AlCl3 (2 equiv), lw, toluene, 5 min, 140 °C.

J. X. de Arau´jo-Ju´nior et al. / Tetrahedron Letters 48 (2007) 7817–7820
7819
Ar1
Method A
Ar1
N
Br
Ar1
N
R2
R3
vi)
i)
iv)
N
O
TfO
O
O
O
O
O
N
N
60-90%
70-88%
N
60-78%
N
H
N
H
N
Bn
20, 21
Bn
Bn
Bn
2b, 3b: Ar1=Ph
18, 19
2c, 3c
12, 13: Ar Ph
=
1
ii)
ii)
iii)
70-85%
85-90%
65-90%
Ar1
Method B
Ar1
N
Br
v)
iii)
4-substituted compounds: 2c, 2b, 6, 8, 12, 14, 16, 18, 20, 22
5-substituted compounds: 3c, 3b, 7, 9, 13, 15, 17, 19, 21, 23
TsO
O
Ar2
O
TsO
O
80-88%
75-95%
N
N
N
N
N
Bn
Bn
8, 9: Ar1=Ph
Bn
6b, 7b: Ar1=Ph
14, 15: Ar1=Ph
16, 17: Ar1=Ph
22, 23
Starting
material
2c
18a
2c
12a
3c
19a
3c
3c
22
23
23
Method
Ar1
Cpd
Cpd
Yield(%)
18a (85)
Ar2
Cpd
Yield(%)
8d (81)
8e (79)
16a (75)
16a (80)
9d (84)
9e (81)
17a (82)
-
Yield(%)
2b (70)
-
12a (70)
-
3b (92)
-
13a (60)
13b (75)
6b (90)
7b (75)
15a (68)
A
-
A
-
A
-
A
A
B
B
B
Ph
-
4-OMe Ph
4-OMe Ph
3-OMe-Ph
Ph
-
18b (90)
14a (78)
19a (65)
-
Ph
-
Ph
4-OMe Ph
3,4-OMePh
Ph
-
4-OMe Ph
3-OMe-Ph
Ph
Ph
4-OMe Ph
19b (88)
19c (90)
-
4-OMe Ph
4-OMe Ph
Ph
8d (70)
9d (80)
17a (88)
-
-
-
Scheme 5. Introduction of chemical diversity on the pyridazine ring by Suzuki/amination reactions. Reagents and conditions: (i) R1B(OH)2,
Pd(PPh3)4 (7%), lw, DME, 20 min, 160 °C; (ii) TsCl, pyridine; (iii) ArB(OH)2, Pd(PPh3)4 (7%), lw, DME, 20 min, 100 °C; (iv) Tf2O, pyridine, 0 °C;
(v) Ar2B(OH)2, Pd(PPh3)4 (7%), lw, DME, 30 min, 110 °C; (vi) see Scheme 6.
reactive toward amination reactions. The replacement
of the OTs by an OTf group (derivatives 18) dramatically
increased the reactivity in particular towards amination
reactions, (Scheme 6), and afforded the corresponding
amino-compounds 20 in good yields (5 equiv of amine,
40 min, lw, 180 °C, 12 bar, 70–95% yield).20,21
Ar1
Ar1
i)
X
N
O
RO2SO
O
N
N
N
N
Bn
Bn
20, 21
18, 19
Similar results were obtained with the other regioisomer
3c. Finally, the difunctionalized pyridazinones 22 and 23
could be prepared, and presented the same order of
reactivity toward PCCR (4-Br > 6-OTs, Schemes 5 and
7). The sequence combining Suzuki (3c!13)/activation
(13!19)/Suzuki (19!17) reactions could be compared
with an alternative pathway combining activation
(3c!23) and two successive Suzuki-type reactions
(23!15!17, Scheme 5).
Starting
material
7b
19a
19a
19a
19c
18a
R
X
n
Time
(min)
60*
15
40
40
40
40
40
20, 21
(%)
4-MePh
CF3
CF3
CF3
CF3
O
O
O
N-Ph
N-Ph
O
5
3
5
4
4
5
5
21a(traces)
21a(30)
21a(78)
21b(68)
21c (62)
20a(60)
20b(65)
CF3
CF3
O
18b
* at 200˚C; n: number of equiv. of amine
Finally, the most efficient pathway will be selected
depending on the nature of the involved reactions (nature
of activating group or type of PCCR). As an example of
the importance of the pathway selection compound 28
could be prepared from 2c following a sequence involving
the activation of the unprotected amide leading to tosyl-
ate 22, which was reacted in a Sonogashira-type reaction
giving the acetylenic derivative 24. Hydrogenation of the
alkyne led to the saturated side chain (compound 26).
Finally, a Suzuki-type reaction permitted to substitute
Scheme 6. Preparation of amino-pyridazinones. Reagents and condi-
tions: (i) lw, 180 °C, 12 bar, 70–95% yield.
ent ways (Scheme 5). The corresponding OTs derivatives
6 or 14 could be submitted to a second palladium cross-
coupling reaction (PCCR). In particular, the Suzuki-type
reaction using various aryl boronic acids allowed intro-
duction in a very straightforward manner of various
substituted aryl groups in position 6 (compounds 8 and
16, respectively). However, the OTs derivative was not

7820
J. X. de Arau´jo-Ju´nior et al. / Tetrahedron Letters 48 (2007) 7817–7820
R
(CH2)2-R
(CH2)2-R
Br
iii)
ii)
i)
iv)
TsO
O
Ar2
O
N
TsO
O
TsO
O
2c, 3c
N
N
N
N
N
N
N
90-95%
Bn
Bn
Bn
Bn
28, 29
22, 23
24, 25
26, 27
Ar2 = 3,4-(OMe)2-Ph
Yields %
4-substituted compounds: 2c, 22, 24, 26, 28
5-substituted compounds: 3c, 23, 25, 27, 29
R
24 25
91 72
89 95
79 77
26
90
88
99
27
82
88
82
28
91
70
67
29
85
71
85
a
b
c
(CH2)3NHBOC
(CH2)3OBn *
(CH2)3CO2Et
* after hydrogenation OBn→OH
Scheme 7. Introduction of chemical diversity on the pyridazine ring by means of Sonogashira/Suzuki sequential reactions. Reagents and conditions:
(i) CuI, TEA, CH3CN, PdCl2(PPh3)2, (3.5%), Ph-„, lw, 5 min, 80 °C; (ii) TsCL, pyridine; (iii) H2, Pd/C, MeOH; (iv) Ar2B(OH)2, Pd(PPh3)4 (7%),
lw, 30 min, 120 °C.
3. (a) Wermuth, C. G.; Bourguignon, J. J.; Hoffmann, R.;
the tosylate giving the expected pyridazinone 28 (Scheme
7),20 whereas direct Sonogashira-type reaction in the
vicinity of a free NH-amide group gave quantitatively
the furo-pyridazinone 4 (Scheme 2).
´
Boigegrain, R.; Brodin, R.; Kan, J. P.; Soubrie, P. Bioorg.
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After removal of the protective benzyl group as de-
scribed above, the second amide function opened the
ways to supplementary structural variations around
the pyridazine backbone.
In conclusion the reported methodologies based on the
desymmetrization of pyridazin-3,6-dione by means of
N-benzyl-hydrazine and maleic anhydrides led to valu-
able intermediates possessing up to three different
anchors able to introduce large diversity for the synthe-
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Acknowledgement
11. Chekmarev, D. S.; Stepanov, A. E.; Kasatkin, A. N.
Tetrahedron Lett. 2005, 46, 1303–1305.
12. Schmitt, M.; de Arau´jo-Ju´nior, J. X.; Bourguignon, J. J.
Mol. Divers. 2006, 10, 429–434.
13. Bourotte, M.; Pellegrini, N.; Schmitt, M.; Bourguignon, J.
J. Synlett 2003, 1482–1484.
Financial supports (Proc No. 0085057) of CAPES/Bra-
zil to J.X.A.-J. and Cofecub are acknowledged. The
authors thank Dr. Gilbert Schlewer for helpful discus-
sions and encouragement.
14. Coelho, A.; Novoa, H.; Peeters, H.; Blaton, N.; Sotelo, E.
Tetrahedron 2003, 61, 4785–4791.
15. Coelho, A.; Sotelo, E.; Ravina, E. Tetrahedron 2003, 59,
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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.2007.
09.013.
´
16. Crespo, A.; Meyers, C.; Coelho, A.; Yanez, M.; fraiz, N.;
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19. Batchelor, M. J.; Mellor, J. M. J. Chem. Soc., Perkin
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20. Supporting information available: Experimental proce-
dures and spectral data. This material is available free of
charge.
21. Microwave irradiation has been performed using biotage
Initiator EXP (http://www.biotage.com).
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