Sequential regio and chemoselective cross-coupling reactions by means of O6-tri-isopropylsulfonate of 4-bromo-pyridazine 3,6-dione

Article abstract of DOI:10.1016/j.tetlet.2006.06.056

Regioselective desymmetrization of 4-substituted pyridazin-3,6-diones using sterically hindered 2,4,6-triisopropylphenyl-sulfonylchloride allowed efficient sequential palladium cross-coupling reactions.

Full text of DOI:10.1016/j.tetlet.2006.06.056

Tetrahedron Letters 47 (2006) 6125–6128
Sequential regio and chemoselective cross-coupling
reactions by means of O6-tri-isopropylsulfonate
of 4-bromo-pyridazine 3,6-dione
Joao X. de Arau´jo-Ju´nior,a,b Martine Schmitt,a,*
˜
Pascal Benderittera and Jean-Jacques Bourguignona
aInstitut Gilbert Laustriat, UMR 7175, Faculte´ de Pharmacie, 74 route du Rhin, BP 60024, 67401 Illkirch, France
bEscola de Enfermagem e Farmacia, Deptode Quı´mica, Universidade Federalde Alagoas, cidade Universitaria, 57.072-970,
Maceio´-AL, Brazil
Received 16 May 2006; revised 8 June 2006; accepted 12 June 2006
Available online 7 July 2006
Abstract—Regioselective desymmetrization of 4-substituted pyridazin-3,6-diones using sterically hindered 2,4,6-triisopropylphenyl-
sulfonylchloride allowed efficient sequential palladium cross-coupling reactions.
Ó 2006 Elsevier Ltd. All rights reserved.
The increasing interest for pharmacologically active
6-aryl 3-aminopyridazines 31–7 formally emphasizes the
two critical steps allowing introduction of both the
aromatic ring and the amino functions. The historical
approach first involves a condensation of various aryl-
methylketones with commercially available a-ketoacids
leading to the corresponding 6-aryl pyridazinones 1
(method a). Thus an additional activation of the result-
ing amide by means of POCl3 afforded the correspond-
ing chloropyridazine 2, which was finally submitted to
amination reactions.3–7 However, the reaction did not
allow rapid structural optimization of both the aryl
substituents (or heteroaryl or aralkyl) and the amino
substituents (NR1R2). As the result of the dramatic in-
crease of palladium cross-coupling reactions (PCCR)
applied to various heterocycles, that is, pyridazines,
the starting 3,6-dichloropyridazines 4 constitute valu-
able intermediates for combining in a sequential manner
both the Suzuki and amination reactions.8–14
available 4-methyl and 4-phenyl 3,6-dichloropyridazines
(compounds 4b and 4c, respectively, method b) (see
Scheme 1).
However the first step leading to substitution of 4b and
4c (amination or Suzuki reaction) was not regioselective,
as it afforded a mixture of both regioisomers depending
on the selected route (amination/Suzuki).14 The pres-
ence of a major regioisomer (about 70% of the mixture)
resulted from a clear steric hindrance effect of the substi-
tuent R. This effect was enhanced, when the nucleophile
presented also some steric hindrance. Thus amination
with a secondary amine (morpholine) took place on
the less hindered iminochloride, and afforded a single
isomer, which was further submitted to a Suzuki reac-
tion, yielding the pure regioisomer 5.14
The aim of this work was to investigate other opportu-
nities of using the pyridazine 3,6-dione precursor 6, but
with a preliminary step of desymmetrization of amide
functions, thus allowing a sequential activation of both
the 3 and 6 positions of the pyridazine ring. We focused
our attention on the pyridazine 3,6-diones 6, and
selected O-aryl sulfonates 8 as valuable leaving groups
for both aminations and Suzuki reactions. Whereas
the known reactivity of O-triflates was applied with
success in PCCR involving various amide heterocycles
including pyridazines,15,16 the use of other pyridazine
O-sulfonates may offer more versatility, and might help
The commercially available 3,6-dichloropyridazine 4a
(R = H) has been already used for that purpose.8–13
A
similar strategy was applied by our group with the easily
Keywords: 4-Bromo-pyridazine-3,6-dione; 3,6-Dichloropyridazines;
Amination; Palladium cross-coupling reaction; Microwave heating;
Suzuki reaction.
*
Corresponding author. Tel.: +33 390 244231; fax: +33 390 244310;
e-mail: schmitt@pharma.u-strasbg.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.056

6126
J. X. de Arau´jo-Ju´nior et al. / Tetrahedron Letters 47 (2006) 6125–6128
Method a
O
R
R
R
1) RCOCO2H
2) NH2NH2
POCl3
R1
Ar
O
R
Ar
Cl
Ar
N
HNR1R2
(excess)
Ar
R2
N
N
H
N
N
N
R
N
2
3
1
Method b
R
R
R1
R1
amination/ Suzuki
Ar
N
Ar
N
Cl
Cl
O
O
+
or Suzuki/ amination
R2
R2
N
N
N
N
N
N
N
H
N
H
R = H, 4a
R = Me, 4b
R = Ph, 4c
3
5
6
4
Scheme 1. Access to 4 (or 5) substituted 3-amino-6aryl pyridazine 3 (or 5).
to better control regioselectivity, when the arylsulfonyl-
chloride presents some steric hindrance. Thus a first
study describes the reaction of various arylsulfonylchlo-
rides 7 with the 4-substituted pyridazine 3,6-diones 6
(Table 1). In major cases a mixture of both regioisomers
8 and 9 were obtained. Ratio of regioisomers has been
determined by 1H NMR analysis (integration of HA
and HB signals) of the pyridazine ring in the crude reac-
tion mixture.
tematically the O-sulfonyl pyridazinone 8 as the major
isomer.
In the O-tosyl series a more pronounced effect was ob-
served with R = Ph. In all cases the major isomer could
be easily recovered as a pure compound by recrystalliza-
tion in ethyl acetate (entries 2–4) or cyclohexane (entries
9 and 10).18 Structures 8b and 9b were assigned by NMR
analysis (HMBC and NOE techniques) of the com-
pound 10b which was obtained from 8b by a Suzuki
reaction under l-wave irradiation.18
The position of the O-sulfonyl group in C-6 causes a sig-
nificant downfield shift for the adjacent aromatic proton
HA in structure 8. As found in our previous papers,
significant steric effect of the R substituent yielded sys-
In order to avoid any formation of the minor isomer 9,
when starting from 6, the influence of the steric hin-
Table 1. Reaction of pyridazine 3,6-diones with various arylsulfonylchlorides
HA
R
HB
R
R
O
O
S
Ar-SO2-Cl
7
Ar
S
O
O
Ar
O
O
O
O
+
Pyridine
0 ˚C to RT, 2h
72-90%
N
N
H
N
N
H
N
H
N
H
O
O
R = H, 6a
R = Me, 6b
R = Ph, 6c
R = Br, 6d
9
6
8
Entry
Cpds
R
Ar
Global yield (%)
8/9 Ratio (%)
1
2
3
4
5
6
8a
H
4Me–Ph
4Me–Ph
4Me–Ph
4Me–Ph
b-Naphthyl
a-Naphthyl
90
72
90
88
76
73
8b/9b
8c/9c
8d/9d
8e/9e
8f/9f
Me
Ph
Br
Br
Br
80
P90
70
80
85
20
nd
30
20
15
7
8g/9g
Br
70
85
80
15
MeO
8
8h/9h
Br
73
20
O
9
8i/9i
8j/9j
Br
83
90
P95
P95
65
65
10
Me

J. X. de Arau´jo-Ju´nior et al. / Tetrahedron Letters 47 (2006) 6125–6128
6127
Table 2. Sequential PCCR reactions with 8j
Entry Starting 8
8j ! 10; Ar2 (yield %)
When considering the bromo intermediate 8i, a first
PCCR (Suzuki) took place regioselectively at position
4 (4-bromo more reactive than O6-TiPS). Satisfactory
yields were obtained when using microwave technolo-
gies (150 °C, 15 min).14 A second Suzuki reaction could
be performed with the resulting intermediate 1117 using
same experimental conditions, but with a longer reac-
tion time (155 °C, 40 min) leading to 4,6-diaryl pyridaz-
inone 12 in satisfactory yields (Table 2, entries 3–6).
1
8j
3OMe–Ph (63)
2
8j
4Cl–Ph (72)
8i ! 11; Ar1
11 ! 12; Ar2
(yield %)
(yield %)
3
4
5
6
8i
8i
8i
8i
Ph (76)
Ph (76)
4-Cl–Ph (76)
3,4-DiOMe–Ph (ꢀ48a)
4-OMe–Ph (90)
H2C@CHPh (92) 3-MeO–Ph (72)
Ph (68)
Finally the difunctionalized pyridazinone 8i is very effi-
cient in producing rapidly various 4,6-disubstituted
pyridazinones by means of different Pd(0) coupling reac-
tions using various catalysts, experimental conditions,
and substrates (Suzuki, Sonogashira, Stille, Heck, Buch-
wald). However, when a Sonogashira reaction was first
performed with the 4-bromo pyridazinones 8d and 9d,
different chemical behaviours were observed.
a Low yield due to product low solubility.
drance of the starting arylsulfonylchloride was checked.
No significant modification of the ratio of regioisomers
8 and 9 was observed (Table 1, entries 4–8). However,
when using the 2,4,6-triisopropyl-sulfonylchloride, the
corresponding regioisomer 8 was recovered nearly pure
(P95%, entries 9 and 10) and in good yield (83–90%).
In particular, recrystallization in cyclohexane afforded
the pure O6-(2,4,6-triisopropylphenylsulfonyl) (O6-
TiPS) 4-bromo-pyridazine 3-one 8i. This compound of-
fers an additional anchor point for further chemical
transformations (see Table 2). O6-TiPS derivatives could
be used as valuable intermediates in Suzuki reactions
(entries 1 and 2 as examples) (see Scheme 2).
The minor isomer 9d gave the corresponding alkyne 13,
whereas the major isomer 8d afforded an intermediate,
which spontaneously cyclized to give the furo[2,3-c]pyr-
idazine in good yield.18 It is interesting to notice that the
bi-cyclic compound 14 is ready to be further substituted,
as it still contains a tosyl function (compound 15,
Scheme 3).
Ar1
Ar1
8i, R=Br
TiPSO
O
Ar2
O
Ar1-B(OH)2, Pd(PPh3)4
Ar2-B(OH)2, Pd(PPh3)4
N
N
H
N
N
H
mW, 150 ºC, 15min
mW, 155 ºC, 40min
76-92%
R
45-76%
11
12
TiPSO
O
Me
N
N
H
8j, R=Me
Ar2
O
10
8
Ar2-B(OH)2, Pd(PPh3)4
N
N
H
mW, 155 ºC, 40min
60-72%
Scheme 2. Use of O6-TiPS-pyridazinones in PCCR.
R
Br
R(CH2)2
R
1) Hydrogenation
2) Suzuki reaction
TsO
O
TsO
O
Ar2
O
PdCl2(PPh3)2
7mn, mw, 65%
N
N
H
N
N
H
N
N
H
9d (30 %)
13
6a
+
R
R
R
Br
R
PCCR
O
R1
O
TsO
TsO
O
N
N
PdCl2(PPh3)2
7mn, mw, 60%
N
N
N
N
H
TsO
O
N
N
15
14
8d (70 %)
H
R=(CH2)3COOEt
Scheme 3. Easy access to furo[2,3-c]pyridazines.

6128
J. X. de Arau´jo-Ju´nior et al. / Tetrahedron Letters 47 (2006) 6125–6128
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ing from the 4-bromo pyridazine derivatives 8i, the
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some cases, the Sonogashira reaction performed on the
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