Highly selective mono-substitution in Pd-catalyzed cross-coupling reactions of 3,6-dichloropyridazine with organozinc compounds

Article abstract of DOI:10.1016/j.tetlet.2004.12.124

Pd-catalyzed cross-coupling reactions of 3,6-dichloropyridazine (1) with benzyl, aryl, and alkyl organozinc compounds led to selective mono-substitution of one of the chlorine atoms. The subsequent cross-coupling of the resulting monochlorides with RZnCl afforded unsymmetrical 3,6-carbon-disubstituted pyridazines.

Full text of DOI:10.1016/j.tetlet.2004.12.124

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1303–1305
Highly selective mono-substitution in Pd-catalyzed
cross-coupling reactions of 3,6-dichloropyridazine with
organozinc compounds
Dmitriy S. Chekmarev,a,b Alexander E. Stepanova and Alexander N. Kasatkinb,*
aM.V. Lomonosov Moscow State Academy of Fine Chemical Technology, Malaya Pirogovskaya 1, 119435 Moscow, Russia
bChemBridge Corporation, Malaya Pirogovskaya 1, 119435 Moscow, Russia
Received 7 October 2004; revised 14 December 2004; accepted 22 December 2004
Abstract—Pd-catalyzed cross-coupling reactions of 3,6-dichloropyridazine (1) with benzyl, aryl, and alkyl organozinc compounds
led to selective mono-substitution of one of the chlorine atoms. The subsequent cross-coupling of the resulting monochlorides with
RZnCl afforded unsymmetrical 3,6-carbon-disubstituted pyridazines.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Pyridazine derivatives continue to attract considerable
attention due to the wide range of their biological
activity.1,2 Most of the bioactive compounds are
3,6-disubstituted pyridazines. The readily available 3,6-
dichloropyridazine (1) seems to be an appropriate start-
ing material for these compounds. It is well known that
selective mono-substitution of a single chlorine atom in
1 can be achieved when 1 is allowed to react with
oxygen,3–9 sulfur,10 nitrogen3,6,11–13 or halogen nucleo-
philes.14 To our knowledge, selectivity (mono- vs disub-
stitution) in carbon–carbon bond formation reactions
of 1 has been studied to a much lesser extent. The treat-
ment of 1 with a-lithiated nitriles afforded Ôone to oneÕ
alkylation products exclusively.1,15–19 Pd-catalyzed Stille
reactions of 1 with (a-alkoxyvinyl)stannanes also led
to the mono-substitution products in high yield.20,21
On the other hand, Suzuki cross-coupling with
phenylboronic acid22 and Sonogashira reactions with
terminal acetylenes23 suffered from a lack of selectivity.
To our knowledge, there are no effective and general
protocols in the literature for highly selective mono-sub-
stitutions of a single chlorine atom in 1 with an alkyl,
aryl, benzyl or allyl fragment.24 However, for combina-
torial chemistry applications one needs facile and rapid
access to a library of various 3,6-carbon-disubstituted
pyridazines.
Here we report our results on the palladium catalyzed
cross-coupling reactions of commercially available 3,6-
dichloropyridazine (1) with a range of organozinc com-
pounds prepared in situ by the treatment of ZnCl2 with
the corresponding organolithiums or organomagne-
siums.25–27 We chose zinc derivatives because they are
non-toxic, readily available, tolerant to functional
groups (ester-, nitrile-, etc.)26,28, and have proved to be
effective partners in cross-couplings with various hetero-
aryl halides.29,30 All reactions were carried out in THF
in the presence of Pd(PPh3)4 (Scheme 1 and Table 1).
As represented by the results shown in Table 1, the reac-
tions of 1 with 1.05 equiv of benzyl and phenylzinc bro-
mides afforded the corresponding mono-substitution
R
R
Cl
N
N
RZnX
N
N
N
N
+
5 mol.% Pd(PPh )
3 4
o
THF, 20
C
R
Cl
Cl
Keywords: 3,6-Dichloropyridazine; Organozinc compounds; Palla-
dium; Cross-coupling reactions.
3
1
2
R = benzyl, aryl, alkyl
*
Corresponding author. Tel.: +7 095 775 0654; fax: +7 095 956
4948; e-mail: kasatkin@chembridge.ru
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.124

1304
D. S. Chekmarev et al. / Tetrahedron Letters 46 (2005) 1303–1305
Table 1. Reactions of 3,6-dichloropyridazine (1) with organozinc
compoundsa
and 6). The reactions of 1 with 1.6 or 1.05 equiv of the
other benzyl and aryl organozinc compounds afforded
the mono-substitution products 2 in high yields and
more than 92% selectivity (entries 4, 7, 8, and 9). To
our delight, the primary alkylzinc compounds proved
to be excellent reaction partners giving almost exclu-
sively the corresponding monochlorides 2 in good yields
(entries 10 and 11). However, with cyclohexylzinc bro-
mide the yield of 2 decreased to 27% due to formation
of a complex mixture of unidentified side-products
(entry 12). In comparison with benzyl, aryl, and alkyl
organozinc compounds, the reaction of 1 with (phenyl-
ethynyl)ZnCl proceeded more slowly (42% of 1 was
recovered from the reaction mixture even when
3.2 equiv of RZnX was used) and with less selectivity
(entry 13).
Entry
1
RZnX
RZnX/1
2+3, %b
2/3c
1.05
65e
>98:2
2
3
1.05d
1.6
71
86
86:14
88:12
ZnBr
ZnCl
Cl
4
1.6
64
>98:2
5
6
1.05
1.6
37e
72
>98:2
92:8
ZnBr
7
1.6
92
96:4
MeO
ZnCl
8
1.6
86
61
87
92:8
>98:2
>98:2
Cl
ZnCl
The possibility of a subsequent cross-coupling of the
monochlorides 2 with another equivalent of an organo-
zinc reagent was demonstrated by the reactions repre-
sented in Scheme 2. In all cases the unsymmetrical
3,6-carbon-disubstituted pyridazines 431 were obtained
in good yields when the reaction temperature was
increased from 20 to 60 ꢁC.
9
1.05f
1.6
EtO2C
ZnI
10
ZnBr
11
1.6
63
>98:2
ZnBr
ZnBr
In conclusion, in this letter we have shown that palla-
dium catalyzed cross-coupling reactions of 3,6-dichloro-
pyridazine (1) with benzyl, aryl, and alkyl organozinc
compounds represents an effective and practical method
for the synthesis of various 3,6-disubstituted pyridazines
where both the substituents can be varied
independently.à
12
13
2
27
>98:2
80:20
3.2
49e
ZnCl
a All reactions were carried out in THF at 20 ꢁC for 24 h under Ar
unless stated otherwise.
b Total yields of 2+3 isolated by column chromatography.
c According to GC-MS and 1H NMR data.
d At 50 ꢁC.
References and notes
e 25%, 51%, and 42% of 1 (for entries 1, 5, and 13 respectively)
remained in the crude reaction mixtures according to GC-MS data.
f Commercial (Aldrichꢂ) 0.5 M solution of RZnI in THF was used.
1. Yamada, T.; Nobuhara, Y.; Shimamura, H.; Yoshihara,
K.; Yamaguchi, A.; Ohki, M. Chem. Pharm. Bull. 1981,
29, 3433–3439.
1
1
R
R
In the absence of Pd-catalyst only the starting dichloride (>90%) was
isolated from the reaction of 1 with 1.6 equiv of PhZnCl (THF,
20 ꢁC). However, treatment of 1 with 1.6 equiv of PhMgBr led to a
complex mixture of products (where the desired product of mono-
substitution was completely absent).
R2ZnX
N
N
N
N
5 mol.% Pd(PPh3)4
THF, 60 o
C
2
R
Cl
à Typical experimental procedure (Table 1, entry 6): to a stirred solution
of bromobenzene (252 mg, 1.60 mmol) in THF (6.0 mL), n-BuLi
(1.00 mL, 1.6 M in hexanes) was added dropwise at À78 ꢁC. The
resulting solution was stirred for 30 min at À78 ꢁC, then a solution of
ZnCl2 (218 mg, 1.60 mmol) in THF (2.0 mL) was added, the cooling
bath was removed, and the reaction mixture was stirred for 30 min at
room temperature. A solution of 1 (149 mg, 1.00 mmol) and
Pd(PPh3)4 (58 mg, 0.05 mmol) in THF (2.0 mL) was added via
syringe. After stirring for 24 h at 20 ꢁC the reaction mixture was
quenched by addition of saturated aq NaHCO3 (5 mL) and filtered
through Celite. The organic layer was separated and the aqueous
layer was extracted with chloroform (2 · 5 mL). The combined
organic layers were dried over Na2SO4 and concentrated under
reduced pressure. Small amounts of unreacted 1 were removed by
sublimation in vacuo (0.1 mmHg, 50 ꢁC, 2 h). The residue was
purified by column chromatography on silica gel (hexane–ethyl
acetate, 30:1) to give 3-chloro-6-phenylpyridazine (140 mg, 72%
yield), as a white solid, mp 157 ꢁC. Spectral data were in exact
agreement with those reported.14
4, 70-80% yield
= n-Bu
2
1
2
2
2
R
R
R
= 4-EtO CC H ,
R
R
R
2
6 4
1
1
= Ph,
= 4-MeOC H ,
= PhCH
= Ph
2
6
4
Scheme 2.
products 2 in moderate yields and with more than 98%
selectivity (entries 1 and 5). According to NMR analysis
of the crude reaction mixtures, significant amounts of 1
remained in both cases. Note that prolonged reaction
times or additional amounts of the Pd-catalyst did not
increase the conversion of 1. Increasing the temperature
or the use of 1.6 equiv of RZnBr in the reactions of 1
with PhCH2ZnBr and PhZnBr, although improving
conversion, led to formation of detectable (8–14%)
amounts of the di-substitution products 3 (entries 2, 3,

D. S. Chekmarev et al. / Tetrahedron Letters 46 (2005) 1303–1305
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1
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