Expeditive synthesis of 4-substituted 3-aminopyridazines

Article abstract of DOI:10.1055/s-2003-40831

3-Aminopyridazines substituted at position 4 were prepared via palladium-catalysed cross-coupling reactions starting from 3-amino-4-bromopyridazines using Suzuki and Sonogashira experimental conditions.

Full text of DOI:10.1055/s-2003-40831

1482
LETTER
Expeditive Synthesis of 4-Substituted 3-Aminopyridazines
S
ynthesis of 4-Substitu
a
ted 3-Amin
r
opyrida
y
Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7081 CNRS/ULP, Université Louis Pasteur, Faculté de Pharmacie,
74, route du Rhin, 67401 Illkirch-Graffenstaden, France
Fax +33(3)90244310; E-mail: schmitt@pharma.u-strasbg.fr
Received 26 March 2003
We extended the scope of this approach to position 4, as
Abstract: 3-Aminopyridazines substituted at position 4 were pre-
unexpected results obtained in our laboratory allowed us
pared via palladium-catalysed cross-coupling reactions starting
to prepare the 4-bromo derivative II, the key intermediate
for palladium-catalysed cross-coupling reactions. This
latter compound was prepared from the 4-nitro precursor.
from 3-amino-4-bromopyridazines using Suzuki and Sonogashira
experimental conditions.
Key words: aminopyridazine, palladium, catalysis, arylations,
arylalkylations
4-Nitropyridazines 3a and 3b were prepared by nucleo-
philic displacement onto the 1,1-bis(thiomethyl)-2-nitro-
ethylene 1,2 first by benzylamine or 2,4-dimethoxy-
benzylamine (DMB), and then by hydrazine hydrate
(Scheme 2). Cyclocondensation of phenylglyoxal with
the enamine intermediate 2 yielded two regioisomers 3
and 4, which were separated by chromatography on silica
gel.11 The ratio of these regioisomers 3a/4a and 3b/4b was
similar, with the 6-phenyl derivative 3 as the major prod-
uct in both cases.
Substituted 3-aminopyridazines are known to possess a
wide range of pharmacological activities.1–4 Therefore,
new access to these derivatives still remains of great inter-
est for medicinal chemists.
Several methods exist for the synthesis of 3-amino-
pyridazines. As a typical example, the preparation of 3-
amino-6-phenylpyridazine substituted in position 4 (com-
pound I) involved a condensation of acetophenone with
an a-ketoester (Scheme 1). However, these a-ketoesters
have to be synthesised first, except for the commercially
available compounds (R = Me, Ph, Bn).4,5
Surprisingly, a first treatment of 4-nitropyridazine 3a with
aqueous HBr afforded the corresponding 4-bromo deriva-
tive 5b in poor yield (30%). Further optimisations of the
experimental conditions afforded the title compounds in
significantly improved yields (5a and 5b, 50% and 75%
respectively, reflux in a sealed tube in a 5.7 M HBr/AcOH
solution, Scheme 3).12 Under these conditions, the pro-
tecting group DMB was also removed, whereas neither
drastic acid conditions nor catalytic hydrogenation were
able to remove the benzyl group in compound 6.
As an alternative to this well-known five-step strategy
(Scheme 1),4 the use of palladium-catalysed cross-cou-
pling reactions appeared as the most suitable approach for
straightforward introduction of various substituents in
position 6, mainly aromatics, 6–8 or in position 59,10 of the
3-aminopyridazine nucleus.
Scheme 1
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1482,1484,ftx,en;G06203ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 4-Substituted 3-Aminopyridazines
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Scheme 2 i) RNH2, EtOH, reflux, 3.5 h, ii) H2NNH2, H2O, EtOH, reflux, 2 h, iii) PhCOCHO, EtOH, r.t., 5 h
Scheme 3 i) HBr, AcOH, sealed tube, 90 °C, 3 h, ii) ArB(OH)2, Pd(PPh3)4, Na2CO3 2 M, EtOH–toluene, iii) alkyne, PdCl2, CuI, PPh3, Et3N,
CH3CN
Earlier studies described efficient procedures using palla- In summary, the palladium-catalysed cross-coupling reac-
dium-catalysed cross-coupling reactions for introducing tion is a new route for functionalising the position 4 of the
aryl, heteroaryl, vinyl and alkynyl groups at positions 3-aminopyridazines without the need of any amino group
413,14 and 5 10 of pyridazinones and at position 6 of 3-ami- protection. Moreover, this method can be generalised to
6
nopyridazines, but to our knowledge, no report deals other 3-substituted aminopyridazines, as the benzylamine
with a similar functionalisation at position 4 of aminopy- used in Scheme 2 could be replaced by various other
ridazines. As an illustration of the scope of the expeditive alkylamines.2 These new compounds are under pharma-
method, Suzuki 15 and Sonogashira 16 reactions were per- cological evaluation as endogenous bioamine-interfering
formed with various reagents (Table 1) in good yields. CNS agents.
Alkynes 7g–7j were submitted to hydrogenation (H2, Pd/
C, 75 psi, 50–75% yields) and led to novel 3-aminopy-
ridazines bearing a functionalized aryl or alkyl chain in
References
(1) Franck, H.; Heinisch, G. Pharmacologically Active
Pyridazines, In Progress in Medicinal Chemistry, Vol. 27;
Ellis, G. P.; West, G. B., Eds.; Elsevier: Amsterdam, 1990,
1–49.
(2) Contreras, J. M.; Rival, Y. M.; Chayer, S.; Bourguignon, J.
J.; Wermuth, C. G. J. Med. Chem. 1999, 42, 730.
(3) Wermuth, C. G.; Bourguignon, J. J.; Schlewer, G.; Gies, J.
P.; Schoenfelder, A.; Melikian, A. J. J. Med. Chem. 1987,
30, 239.
(4) Wermuth, C. G.; Schlewer, G.; Bourguignon, J. J.;
Maghioros, G.; Bouchet, M.; Moire, C.; Kan, J. P.; Worms,
P.; Biziere, K. J. Med. Chem. 1989, 32, 528.
(5) Sitamze, J. M.; Schmitt, M.; Wermuth, C. G. J. Org. Chem.
1992, 57, 3257.
position 4.
Table 1 Palladium-catalysed Reactions on 5a,b
Com-
R1
Yield of 6
(%)
Yield of 7
(%)
pounds
7a
Ph
–
85
70
70
63
60
92
88
65
45
60
6b,7b
6c,7c
7d
4-MeOPh
4-ClPh
78
61
–
2-MeOPh
2-thiophenyl
2-BrPh
7e
–
(6) Guery, S.; Parrot, I.; Rival, Y.; Wermuth, C. G. Tetrahedron
Lett. 2001, 42, 2115.
7f
–
(7) Parrot, I.; Rival, Y.; Wermuth, C. G. Synthesis 1999, 1163.
(8) Maes, B. U. W.; Lemiere, G. L. F.; Dommisse, R.;
Augustyns, K.; Haemers, A. Tetrahedron 2000, 56, 1777.
(9) Estévez, I.; Coelho, A.; Ravina, E. Synthesis 1999, 1666.
(10) Coelho, A.; Ravina, E.; Sotelo, E. Synlett 2002, 2062.
(11) The structures of 3a,b and 4a,b were determined by 1H and
13C NMR. 3a: Yield 53%. 1H NMR (CDCl3, 300 MHz) d
5.11 (d, J = 5.6 Hz, 2 H, CH2Ph); 7.3–7.6 (m, 8 H, ArH); 7.99
(m, 1 H, NHBn exchange with D2O); 8.06 (m, 2 H, ArH);
8.40 (s, 1 H, H5). 13C NMR (CDCl3, 300 MHz) d 46.24
7g
–
6h,7h
6i,7i
7j
79
40
–
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M. Bourotte et al.
LETTER
(CH2); 118.29 (C5); 126.37 (2 CHAr); 128.27 (CHAr);
128.44 (2 CHAr); 129.29 (2 CHAr); 129.54 (2 CHAr);
129.95 (CHAr); 132.14 (C4); 135.39 (CAr); 138.00 (CAr);
149.57 (C3); 152.13 (C6). 4a: Yield 23%. 1H NMR (CDCl3,
200 MHz) d 4.98 (d, J = 5.4 Hz, 2 H, CH2Ph); 6.42 (m, 1 H,
NHBn exchange with D2O); 7.3–7.6 (m, 10 H, ArH); 8.79 (s,
1 H, H6). 13C NMR (CDCl3, 200 MHz) d 46.56 (CH2);
128.06 (2 CHAr); 128.25 (2 CHAr); 128.49 (2 CHAr);
129.26 (CHAr); 129.76 (2 CHAr); 130.55 (CHAr); 132.29
(C5); 133.06 (CAr); 133.34 (C4); 138.05 (CAr); 145.11
(C6); 149.46 (C3). Similar satisfactory spectral data were
obtained for 3b and 4b.
(13) Maes, B. U. W.; R’kyek, O.; Kosmrlj, J.; Lemiere, G. L. F.;
Esmans, E.; Rozenski, J.; Dommisse, R.; Haemers, A.
Tetrahedron 2001, 57, 1323.
(14) Maes, B. U. W.; Monsieurs, K.; Loones, K. T. J.; Lemiere,
G. L. F.; Dommisse, R.; Matyus, P.; Riedl, Z.; Hajos, G.
Tetrahedron 2002, 58, 9713.
(15) Representative procedure for Suzuki arylations. A
suspension of 5a or 5b (0.60 mmol, 1 equiv), phenylboronic
acid (0.69 mmol, 1.15 equiv), sodium carbonate 2 M (0.64
mL, 1.27 mmol, 2.12 equiv) in toluene (1.8 mL) and ethanol
(0.2 mL) was stirred under an atmosphere of argon for 30
min. Pd(PPh3)4 (0.027 mmol, 0.045 equiv) was then added
and the mixture was heated at 110 °C for 20 h. The toluene
was removed in vacuo, the residue was diluted with H2O and
extracted with EtOAc (3 × 5 mL). The organic layers were
dried over sodium sulfate, concentrated in vacuo and then
purified by flash chromatography on silica gel (for
compounds 6: EtOAc–hexane 1:2; for compounds 7:
EtOAc–hexane 1:1, TEA 2%). Satisfactory spectral data
were obtained for all new compounds. As an example 7b:
mp 167–169 °C; 1H NMR (CDCl3, 200 MHz) d 3.93 (s, 3 H,
OCH3); 5.02 (br s, 2 H, NH2 exchange with D2O); 7.10 (d,
J = 8.3 Hz, 2 H, ArH); 7.4–7.5 (m, 5 H, ArH); 7.55 (s, 1 H,
H5); 8.04 (d, J = 8.2 Hz, 2 H, ArH).
(12) Structures of compounds 3a and 4a have been
unambiguously assigned by hsqc experiments: strong
correlations have been observed between C3 and CH2Ph and
between C3 and C5H for compound 3a, whereas no
correlation could be observed between C3 and C6-H for
compound 4a (Figure 1).
(16) Representative procedure for Sonogashira couplings. A
mixture of 5a or 5b (0.76 mmol, 1 equiv), alkyne (1.14
mmol, 1.5 equiv), Pd(PPh3)2Cl2 (0.076 mmol, 0.1 equiv),
CuI (0.076 mmol, 0.1 equiv) and dry triethylamine
(0.158mL, 1.14 mmol, 1.5 equiv) in dry acetonitrile (5 mL)
was flushed with argon for 5 min. The reaction mixture was
heated at 70 °C for 12 h. The solution was concentrated to
dryness under reduced pressure. The residue was purified by
flash chromatography on silica gel (for compounds 6:
EtOAc–hexane 1:3; for compounds 7: EtOAc–hexane 1:1,
Et3N 2%). Satisfactory spectral data were obtained for all
new compounds. As an example 6i: 1H NMR (CDCl3, 200
MHz) d 1.93 (m, 2 H, CH2); 2.64 (t, J = 6.9 Hz, 2 H, CH2);
3.59 (t, J = 6.8 Hz, 2 H, CH2); 4.49 (s, 2 H, OCH2Ph); 4.90
(d, J = 5.6 Hz, 2 H, NHCH2Ph); 5.50 (t, J = 5.6 Hz, 1 H, NH
exchange with D2O); 7.3–7.5 (m, 13 H, ArH); 7.59 (s, 1 H,
H5); 8.00 (m, 2 H, ArH).
Figure 1
Representative procedure for the preparation of 5a,b
from 3a,b. To a solution of 3-substituted amino-4-nitro-6-
phenylpyridazine 3a,b (1.36 mmol) in acetic acid (8 mL)
was added 720 mL of a 5.7 M solution of HBr–AcOH (4.10
mmol, 3 equiv). The mixture was then heated at 90 °C in a
sealed tube during 3 h. The solvent was evaporated and the
crude oil was purified by flash chromatography (EtOAc–
hexane, 1:2). 5b: Yield 75%. 1H NMR (CDCl3, 200 MHz) d
5.61 (br s, 2 H, NH2 exchange with D2O); 7.3–7.5 (m, 3 H,
ArH); 7.80 (s, 1 H, H5); 7.8–7.9 (m, 2 H, ArH). ESMS m/z:
250 (M+, 79Br), 252 (M+, 81Br). Similar satisfactory spectral
data were obtained for 5a.
Synlett 2003, No. 10, 1482–1484 © Thieme Stuttgart · New York