Synthesis of (hetero)arylated pyridazin-3(2 H)-ones via Negishi reaction involving zincated pyridazin-3(2 H)-ones

Article abstract of DOI:10.1021/jo201587j

Zincated pyridazin-3(2H)-ones generated via bromine - magnesium exchange followed by transmetalation using ZnCl₂ or via lactam-directed ortho C4-H zincation with TMPZnCl·LiCl have been synthesized. These in situ created organometallics can be u

Full text of DOI:10.1021/jo201587j

Article
pubs.acs.org/joc
Synthesis of (Hetero)arylated Pyridazin-3(2H)-ones via Negishi
Reaction Involving Zincated Pyridazin-3(2H)-ones
Tom Verhelst, Zuming Liu, Jens Maes, and Bert U. W. Maes*
Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
S
* Supporting Information
ABSTRACT: Zincated pyridazin-3(2H)-ones generated via bro-
mine−magnesium exchange followed by transmetalation using ZnCl2
or via lactam-directed ortho C4-H zincation with TMPZnCl·LiCl have
been synthesized. These in situ created organometallics can be used in
Negishi reactions with iodo(hetero)arenes delivering a new approach
toward (hetero)arylpyridazin-3(2H)-ones.
exchange reagent allowing to perform double (C-4 and C-
5) functionalizations of the pyridazin-3(2H)-one core in one
step.3p,q As a continuation of this research program, we
report here the synthesis of zincated pyridazin-3(2H)-ones
which can be used as reagents to introduce (hetero)aryl
groups via a Pd-catalyzed cross-coupling protocol. Interest-
ingly, there are hitherto no reports in the literature on the
synthesis and use in Negishi reactions of zincated pyridazin-
3(2H)-ones.4,5 The more covalent character of a carbon zinc
in comparison with a carbon−magnesium bond is an
advantage as it will deliver synthetic protocols with a wider
functional group compatibility. Moreover, our previous
research on magnesiated pyridazin-3(2H)-ones revealed
that some representatives are unstable (even at lower
temperature), which might simply prevent to perform
cross-coupling reactions with these species.3q,r This was
confirmed in our group by a preliminary unsuccessful
Kumada type cross-coupling reaction of (2-benzyl-5-
methoxy-3-oxo-2,3-dihydropyridazin-4-yl)(halo)magnesium
halide (A) (Table 1) with 2-iodopyridine and iodobenzene
using iron, nickel, and palladium catalysis.6,7 The interest for
and importance of 4-, 5-, 4,5-di-, and 4,6-di(hetero)arylated
pyridazin-3(2H)-ones is highlighted by the substantial
number of publications and patents which appeared in the
last 5 years describing both pharmaceutical and agrochemical
applications [4-(hetero)arylpyridazin-3(2H)-ones: cathepsin
S inhibitors,8 herbicides,9 P2X7 receptor inhibitors (rheu-
matoid arthritis),10 serine protease inhibitors as treatment
INTRODUCTION
■
Pyridazin-3(2H)-ones are an important subclass of the
pyridazine family. The pyridazin-3(2H)-one core can be
found in a wide variety of launched pesticides (e.g., chloridazon,
norflurazon, oxapyrazon, flufenpyr, dimidazon, diclomezine,
pyridaphenthion, pyridaben) and drugs for human (e.g.,
azelastine, emorfazone) and veterinary use (e.g., pimobendan).1
Although there was historically less interest for this nucleus for
material science applications, this has changed in recent years.2
Remarkably the available synthetic methods to selectively C-
functionalize the pyridazin-3(2H)-one core are rather limit-
ed.1a,b,e,h Our group has a history of research on this privileged
core, primarily in generating synthetic tools to selectively
introduce substituents onto the 4 and 5 positions.3 Classically,
C-substituted pyridazin-3(2H)-ones have been constructed via
a ring buildup.1a,b,e,h Alternatively, in some specific cases a
regioselective nucleophilic substitution with carbon nucleo-
philes on halopyridazin-3(2H)-ones has been used.1b,h The
introduction of palladium-catalyzed reactions, however, has
transformed the reaction of carbon nucleophiles with
halopyridazin-3(2H)-ones into a main route for the synthesis
of C-functionalized pyridazin-3(2H)-ones (alkyl, alkenyl,
alkynyl, (hetero)aryl, alkoxycarbonyl).1g,h In order to extend
the arsenal of C-functionalization procedures, our group
investigated the synthesis of magnesiated pyridazin-3(2H)-
ones via reaction of Grignard reagents and magnesium
amides with halopyridazin-3(2H)-ones.3p−r Quenching of
these species with electrophiles allowed the direct
introduction of an even wider variety of functional groups.
In some substrates, the Grignard reagent interestingly acted
as a nucleophile rather than as a halogen-magnesium
Received: July 29, 2011
Published: October 21, 2011
© 2011 American Chemical Society
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Table 1. Bromine−Magnesium Exchange on 2-Benzyl-4-bromo-5-methoxypyridazin-3(2H)-one (1) Followed by
Transmetalation using ZnCl2 and Negishi Reaction
a
entry
ArX
2
yield (%)
1
2
p-EtOOCC6H4I
p-CH3OC6H4I
p-CH3OC6H4Br
o-ClC6H4I
2a
2b
2b
2c
2d
2e
2f
80
72
0
3
4
34
73
74
69
90
82
86
78
64
5
m-ClC6H4I
6
p-ClC6H4I
7
m-CF3C6H4I
p-CF3C6H4I
8
2g
2h
2i
9
2-iodopyridine
3-iodopyridine
2-iodopyrazine
2-iodothiophene
10
11
12
2j
2k
a
1 (1.0 mmol), 0.6 mL of 2 M n-BuMgCl solution in THF (1.2 equiv), THF (4.0 mL), −20 °C, 10 min; 2.86 mL of 0.7 M ZnCl2 solution in THF
(2.0 equiv), −20 °C, 15 min; ArX (4.0 equiv), Pd(dba)2 (5 mol %), P(o-furyl)3 (10 mol %), 50 °C, 30−120 min.
Table 2. Bromine−Magnesium Exchange on 2-Benzyl-5-bromo-4-methoxypyridazin-3(2H)-one (3) Followed by
Transmetalation Using ZnCl2 and Negishi Reaction
a
entry
ArX
4
yield (%)
1
2
p-EtOOCC6H4I
p-CH3OC6H4I
p-CH3OC6H4Br
o-ClC6H4I
4a
4b
4b
4c
4d
4e
4f
45
74
0
3
4
46
73
46
63
5
m-ClC6H4I
6
p-ClC6H4I
7
p-CF3C6H4I
b
8
2-iodopyridine
3-iodopyridine
2-iodopyrazine
2-iodothiophene
4g
4h
4i
10 (79)
b
9
0 (0)
10
11
63
78
4j
a
3 (1.0 mmol), 2.0 mL of 1 M MesMgBr solution in THF (2.0 equiv), THF (4.0 mL), −20 °C, 2 min; 4.29 mL of 0.7 M ZnCl2 solution in THF (3.0
b
equiv), −20 °C, 10 min; ArX (4.0 equiv), Pd(dba)2 (5 mol %), P(o-furyl)3 (10 mol %), 50 °C, 1−4 h. 3.00 mL of 2.24 M LiCl solution in DMF and
1.0 mL of DMF were added to the catalyst solution.
for hepatitis C infection,11 NS5B polymerase inhibitors,12
RESULTS AND DISCUSSION
■
histamine H3 inhibitors,13 α4 integrin receptor agonists,14
As a first approach we investigated the synthesis of zincated
pyridazin-3(2H)-ones via transmetalation on the corresponding
magnesium species. (2-Benzyl-5-methoxy-3-oxo-2,3-dihydro-
pyridazin-4-yl)(halo)magnesium (A) and (1-benzyl-5-me-
cholinesterase inhibitors;15 5-(hetero)arylpyridazin-3(2H)-
ones: human A1 adenosine receptor ligands,16 β-secretase
inhibitors,17 HCV NS5B polymerase inhibitors,18 mGluR5
modulators,19 MCH antagonists,20 inhibition of the
thoxy-6-oxo-1,6-dihydropyridazin-4-yl)(halo)magnesium (C)
production of PAI-1,21 histamine H3 inhibitors,13 CB1
were selected as test compounds (Table 1 and 2). We
antagonists22 and α2/α3 subtype selective GABA-A
previously reported the synthesis of these species starting from
agonists;23 4,5-di(hetero)arylpyridazin-3(2H)-ones: fungi-
2-benzyl-4-bromo-5-methoxypyridazin-3(2H)-one (1) and 2-
cides,24 antimicrobial agents,25 cannabinoid receptor modu-
benzyl-5-bromo-4-methoxypyridazin-3(2H)-one (3) via bro-
lators;26 4,6-di(hetero)arylpyridazin-3(2H)-ones: antimicro-
mine−magnesium exchange with n-BuMgCl and MesMgBr,
bial agents,27 serine protease inhibitors as treatment for
respectively. The use of MesMgBr for substrate 3 is essential as
with n-BuMgCl only nucleophilic substitution of the methoxy
group occurs. Transmetalation on A and C with ZnCl2 at −20 °C
hepatitis C infection,28,11a,b histamine H3 inhibitors,13 for
the treatment of pain,29 cholinesterase inhibitors15].
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Scheme 1. Lactam-Directed Ortho C−H Zincation of 2-Benzyl-5-methoxypyridazin-3(2H)-one (5) using TMPZnCl·LiCl
Followed by Negishi Reaction
generated the zinc halides (2-benzyl-5-methoxy-3-oxo-2,3-
dihydropyridazin-4-yl)(halo)zinc (B) and (1-benzyl-5-me-
thoxy-6-oxo-1,6-dihydropyridazin-4-yl)(halo)zinc (D) (Table 1
and 2).30 With the optimized protocol for the synthesis of the
zincated methoxypyridazin-3(2H)-ones B and D in hand,
attention was turned to developing the Negishi cross-coupling
methodology. A set of triphenylphosphine-based palladium
precatalysts were assessed (Pd(PPh3)4, PdCl2(PPh3)2), but a
combination of Pd(dba)2 and P(o-furyl)3 as a ligand was
identified as optimal.31 At room temperature, no cross-coupling
occurred so we increased the reaction temperature to 50 °C.
With this bromine−magnesium exchange/transmetalation/
Negishi reaction protocol in place it was possible to couple 1
and 3 with aryl iodides with both electron-releasing and
-withdrawing substituents (Tables 1 and 2). Substituents in the
meta and para positions on the aryl iodide were well tolerated,
while an ortho substituent seemed to work less as exemplified
by o-chloroiodobenzene (Table 1, entry 4; Table 2, entry 4).
The use of aryl iodides was found to be crucial as exemplified
by the use of 1-iodo-4-methoxybenzene in comparison with
1-bromo-4-methoxybenzene. While a good yield was obtained
with the former, no reaction product was formed with the latter
substrate (Table 1, entries 2 and 3; Table 2, entries 2 and 3).
Even with a very electron-deficient system like 4-bromobenzo-
nitrile no cross-coupled reaction product could be isolated
starting from 1. Iodoheteroarenes were subsequently screened
as substrates. Both representatives of six- (2-iodopyridine,
3-iodopyridine, iodopyrazine) and five-membered (2-iodothio-
phene) ring systems gave moderate to good yields (Table 1,
entries 9−12; Table 2, entries 10 and 11). An exception is the
coupling of 3 with 2-iodopyridine, which gave only 10% yield
(Table 2, entry 8). Based on a recent report of our research
group in which we described two new rate-accelerating halide
effects of LiCl in Stille reactions, we tried adding LiCl to the
reaction mixture. These halide effects proved especially useful
to speed up slow cross-coupling reactions with α-halogenated
azines and diazines.32 Gratifyingly, when dry LiCl in DMF was
added to the catalyst solution, the target compound 2-benzyl-4-
methoxy-5-pyridin-2-ylpyridazin-3(2H)-one (4g) was obtained
in 79% yield (Table 2, entry 8).32 Negishi reaction of 3-
iodopyridine with D, in the absence or presence of LiCl, gave
no reaction product (Table 2, entry 9). Generally, yields of the
bromine−magnesium exchange/transmetalation/cross-cou-
pling protocol are higher starting from 1 than those obtained
with regioisomer 3.
arylpyridazin-3(2H)-ones. 2-Benzyl-5-methoxypyridazin-
3(2H)-one (5) was selected as test substrate. With
(TMP)2Zn·2MgCl2·2LiCl4a (even at −78 °C) metalation
unfortunately did not proceed, but changing the base to
TMPZnCl·LiCl was successful.4,5 Metalation on 5 is complete
upon dropwise addition of the pyridazinone solution to the
TMPZnCl·LiCl complex solution over 1 min at room
temperature (Scheme 1). Upon completion of the zincation,
Negishi reaction with ethyl 4-iodobenzoate using the Pd-
(dba)2/P(o-furyl)3 catalyst system was tried which gave 2a in
86% yield. In this case, the reaction could be performed at room
temperature. Compound 2a is equal to the one obtained starting
from 2-benzyl-4-bromo-5-methoxypyridazin-3(2H)-one (1)
(Table 1, entry 1), and similar yields were obtained. This also
proves the regioselectivity of the direct zincation protocol.
A substituent at C5 which can be directly substituted by
SNAE- and Pd-catalyzed cross-coupling reactions, and which is
stable under the C4 zincation reaction conditions, would be
more interesting than a methoxy group since it allows a wide
range of further functionalization possibilities.3q 2-Benzyl-5-
chloropyridazin-3(2H)-one (6), which can be easily synthesized
via a two step synthesis from commercially available products,
was selected as a candidate for this purpose.33 Adding a
solution of pyridazinone 6 dropwise to a TMPZnCl·LiCl
solution over 1 min followed by a further 1 min stirring at room
temperature, was optimal for complete C4 zincation as
determined by quenching with D2O and MS analysis. We
wondered whether the same procedure could also be used on 2-
benzyl-6-chloropyridazin-3(2H)-one (8) allowing to access a
regioisomeric 6-chloro-4-(hetero) substitution pattern with the
same post functionalization possibilities. The decreased stability
of (2-benzyl-6-chloro-3-oxo-2,3-dihydropyridazin-4-yl)(di-μ-
chloro)lithium zinc (G) versus (2-benzyl-5-chloro-3-oxo-2,3-
dihydropyridazin-4-yl)(di-μ-chloro)lithium zinc (F) (vide
supra) required rapid addition of a solution of pyridazinone 8
to the TMPZnCl·LiCl solution, followed by stirring for 10 s at
room temperature. With the optimized direct zincation
protocols for 6 and 8 in hand we tested subsequent Negishi
reaction under the conditions used for E. Meta- and para-
substituted aryl iodides with both electron-donating and
-withdrawing groups could be successfully coupled in moderate
to good yields (Table 3, 4). As exemplified by 1-chloro-2-
iodobenzene, ortho substitution was again found to be
troublesome. Although we were able to produce 9c from 8 in
61% yield, no reaction product could be isolated in a coupling
reaction starting from regioisomer 6 (Table 3, entry 4, and
Table 4, entry 4). Similarly as observed for reactions involving
B and D no reaction occurred when coupling F and G with 1-
bromo-4-methoxybenzene, while Negishi reaction involving 1-
iodo-4-methoxybenzene worked smoothly (Table 3, entries 2
and 3, Table 4, entries 2 and 3). Also with a less electron-rich
bromoarene no cross-coupling took place (Table 3, entry 7,
Table 4, entry 7). It was possible to couple iodoheteroarenes
Recently, our group described the lactam directed ortho C4-
H magnesiation of pyridazin-3(2H)-ones with TMPMgCl·LiCl
as base.3r Via a subsequent reaction with electrophiles, a direct
functionalization was achieved. Based on this earlier research,
we wondered whether a similar approach could be used to
perform regioselective direct C4-H zincation utilizing zinc
amide bases. Subsequent Negishi reaction would deliver an
attractive alternative synthetic approach for 4-(hetero)-
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Article
(Table 3, entries 10 and 12). The cross-coupling with 2-
iodothiophene gave 7k in 40% yield (Table 3, entry 13). In
sharp contrast, all Negishi reactions of 8 with the same
heteraryl iodides gave very good yields (Table 4, entries 10−
13). Actually, this is a general trend as the yields of the
zincation/cross-coupling protocol with aryl iodides starting
from chloropyridazin-3(2H)-one 8 are generally higher than
those obtained with regioisomer 6.
Table 3. Lactam-Directed Ortho C−H Zincation of 2-Benzyl-
5-chloropyridazin-3(2H)-one (6) Using TMPZnCl·LiCl
Followed by Negishi Reaction
There seems to be a link between the stability of the zincated
pyridazin-3(2H)-ones and their successful use in Negishi
reactions, irrespective of the way they are synthesized. The
more stable zincated pyridazin-3(2H)-ones (D and F) are less
reactive in cross-coupling reactions than the less stable ones
(B and G) leading to lower yields and poorer performance,
especially with the more challenging heteroaromatic sub-
strates. The stability of the zincated pyridazin-3(2H)-ones was
evaluated by looking at the percentage remaining organozinc
compound in function of time (in the absence of substrate and
catalyst). Time point zero was chosen as the moment when
the (hetero)aryl iodide coupling partner and catalyst are
normally added. The percentage remaining zincated pyrida-
zin-3(2H)-one after a certain elapsed time can be determined
by quenching aliquots of the organozinc solution with D2O
and subsequently analyze the amount of D incorporation
versus H with MS (after 10 min at rt: B 24%, D 61%, F 64%,
G 10%).
The complete regioselectivity for C4 over C6 metalation in
6 and C4 over C5 metalation in 8 was determined by
hydrogenolysis (H2, Pd/C) of the reaction products of the
zincation/cross-coupling protocol (2-benzyl-5-chloro-4-(4-
methoxyphenyl)pyridazin-3(2H)-one (7b) and 2-benzyl-6-
chloro-4-(4-methoxyphenyl)pyridazin-3(2H)-one (9b)) yield-
ing the same reaction product 2-benzyl-4-(4-methoxyphenyl)-
pyridazin-3(2H)-one (10) (Scheme 2). Moreover, the coupling
constant of 4.3 Hz in 10 is very typical for a J5−6 (3−6 Hz) in
1H NMR.34
a
entry
ArX
7
yield (%)
1
2
p-EtOOCC6H4I
p-CH3OC6H4I
p-CH3OC6H4Br
o-ClC6H4I
7a
7b
7b
7c
7d
7e
7e
7f
80
65
0
3
4
0
5
m-ClC6H4I
44
74
0
6
p-ClC6H4I
7
p-ClC6H4Br
8
m-CF3C6H4I
p-CF3C6H4I
51
44
9
7g
7h
7i
b
10
11
12
13
2-iodopyridine
3-iodopyridine
2-iodopyrazine
2-iodothiophene
0 (0)
b
0 (30)
b
7j
0 (0)
7k
40
a
6 (1.0 mmol), 1.81 mL of 0.55 M TMPZnCl·LiCl solution in THF
(1.0 equiv), THF (4.0 mL), rt, 1 min; ArX (2.0 equiv), Pd(dba)2 (5
mol %), P(o-furyl)3 (10 mol %), rt, 15−30 min. 3.00 mL of 2.24 M
LiCl solution in DMF and 1.0 mL of DMF were added to the catalyst
solution.
b
Table 4. Lactam-Directed Ortho C−H Zincation of 2-Benzyl-
6-chloropyridazin-3(2H)-one (8) Using TMPZnCl·LiCl
Followed by Negishi Reaction
The methoxy group in the 4-(hetero)aryl (2) and 5-
(hetero)aryl (4) reaction products has been shown to be easily
transformable into a triflate group allowing subsequent
arylation via a Pd-catalyzed cross-coupling reaction.3c,m In this
way, 4,5-di(hetero)arylated pyridazin-3(2H)-ones with two
different (hetero)aryl groups can be obtained. Such compounds
have been synthesized from 4,5-dihalopyridazin-3(2H)-ones
with two different halogen atoms via two consecutive Pd-
catalyzed cross-coupling reactions (e.g., 5-chloro-4-iodo- and 4-
chloro-5-iodo-2-methylpyridazin-3(2H)-one).1h,35a,35b The se-
lectivity is based on the different reactivity of the two halogens
in an oxidative addition reaction. 4,5-Dihalopyridazin-3(2H)-
ones containing two chlorine atoms (e.g., 4,5-dichloro-2-
methylpyridazin-3(2H)-one) have shown to allow C-5
regioselective arylation. The selectivity is however very sensitive
to the applied cross-coupling conditions, requiring a thorough
optimization for each 2-substituted 4,5-dichloropyridazin-
3(2H)-one and arylboronic acid combination, which unfortu-
nately does not provide a generally applicable synthetic
protocol for library synthesis.35a 4,6-Di(hetero)arylated pyr-
idazin-3(2H)-ones have also been obtained via consecutive Pd-
catalyzed cross-reactions. In this case 1-substituted 5-bromo-6-
oxo-1,6-dihydropyridazin-3-yl tosylate was used as substrate in
consecutive Suzuki reactions.36 The oldest and classical route to
synthesize both 4,6- as well as 4,5-di(hetero)arylated pyridazin-
3(2H)-ones is via diazinone ring construction.1b,h Our new
synthetic protocol starting from a 5-chloropyridazin-3(2H)-one
a
entry
ArX
9
yield (%)
1
2
p-EtOOCC6H4I
p-CH3OC6H4I
p-CH3OC6H4Br
o-ClC6H4I
9a
9b
9b
9c
9d
9e
9e
9f
91
85
0
3
4
61
77
96
0
5
m-ClC6H4I
6
p-ClC6H4I
7
p-ClC6H4Br
8
m-CF3C6H4I
p-CF3C6H4I
97
95
87
71
86
78
9
9g
9h
9i
10
11
12
13
2-iodopyridine
3-iodopyridine
2-iodopyrazine
2-iodothiophene
9j
9k
a
8 (1.0 mmol), 1.81 mL of 0.55 M TMPZnCl·LiCl solution in THF
(1.0 equiv), THF (4.0 mL), rt, 10 s; ArX (2.0 equiv), Pd(dba)2 (5 mol
%), P(o-furyl)3 (10 mol %), rt, 15−30 min.
but only with limited success for Negishi reactions involving F
(Table 3, entries 11 and 13). For the cross-coupling of F with
3-iodopyridine it was necessary to add LiCl in DMF, as was
used in the synthesis of 4g, but even in this case the yield was
only 30%.32 Unfortunately, for the coupling of F with 2-
iodopyridine and 2-iodopyrazine this did not improve the yield
as still no 4-(hetero)arylpyridazin-3(2H)-ones were formed
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Article
Scheme 2. Hydrogenolysis (H2, Pd/C) of the Reaction Products 2-Benzyl-5-chloro-4-(4-methoxyphenyl)pyridazin-3(2H)-one
(7b) and 2-Benzyl-6-chloro-4-(4-methoxyphenyl)pyridazin-3(2H)-one (9b)
and a 6-chloropyridazin-3(2H)-one provides a new approach
for 5-chloro- and 6-chloro-4-(hetero)arylpyridazin-3(2H)-ones,
respectively. Via a subsequent Pd-catalyzed cross-coupling an
alternative synthetic route for 4,5-di- and 4,6-di(hetero)-
arylpyridazin-3(2H)-ones with two different (hetero)aryl
groups is achieved. The 5-chloro- and 6-chloro-4-(hetero)-
arylpyridazin-3(2H)-one compound classes are very interesting
on themselves as the chlorine allows further decoration of the
pyridazinone core via SNAE and other Pd-catalyzed cross-
coupling reactions than arylations, hereby also giving access to
a new protocol for a variety of 5- and 6-substituted 4-
(hetero)arylpyridazin-3(2H)-ones. The main advantage of our
new approach to introduce a (hetero)aryl substituent in C4 of
the pyridazinone nucleus is that it is based on a metalated
pyridazinone and a halogenated (hetero)arene rather than on
a halopyridazinone and a metalated (hetero)arene as coupling
partners. After all, the (commercial) availability of metalated
(hetero)arenes, especially the heteroarenes, is still rather
limited and often there are stability issues. In addition,
protodemetalation of these species in transition metal
catalyzed cross-coupling reactions is a well-known com-
petitive process.
As it has previously been shown that pyridazin-3(2H)-ones
with two different halogens can be used in selective Pd-
catalyzed cross-coupling reactions and these are not always so
easily accessible (vide supra), we wondered whether quenching
of the zincated chloropyridazin-3(2H)-ones with iodine and
bromine would allow a simpler access to such compounds.
Interestingly this worked smoothly and 2-benzyl-4-bromo-5-
chloro- (11a),37 2-benzyl-5-chloro-4-iodo- (11b),38 2-benzyl-4-
bromo-6-chloro- (12a),39 and 2-benzyl-6-chloro-4-iodopyrida-
zin-3(2H)-one (12b) were obtained in high yields (Tables 5
Table 6. Lactam-Directed Ortho C−H Zincation of 2-Benzyl-
6-chloropyridazin-3(2H)-one (8) Using TMPZnCl·LiCl
Followed by Reaction with Halogens
a
entry
X2
X
12
yield (%)
1
2
Br2
I2
Br
I
12a
12b
91
91
a
8 (1.0 mmol), 1.81 mL of 0.55 M TMPZnCl·LiCl solution in THF
(1.0 equiv), THF (4.0 mL), rt, 10 s; X2 (2.0 equiv), rt, 15 min.
CONCLUSION
■
In this paper, the synthesis of hitherto unknown zincated
pyridazin-3(2H)-ones is presented. Both transmetalation with
ZnCl2 on C4 and C5 magnesiated pyridazin-3(2H)-ones,
previously synthesized in our group, and lactam-directed C4
deprotonation with a Zn amide base can be used to prepare
these zincated pyridazin-3(2H)-ones. We showed that these
compounds can be used in Negishi reactions with iodo-
(hetero)arenes providing a new way to access C4 and C5
(hetero)arylated pyridazin-3(2H)-ones in moderate to good
yields. The directed C4 zincation of 2-benzyl-5-chloro- and 2-
benzyl-6-chloropyridazin-3(2H)-one is especially interesting as
the chlorine present in the substrate provides a tool for post
functionalization via SNAE and Pd-catalyzed cross-coupling
reactions. The (2-benzyl-chloro-3-oxo-2,3-dihydropyridazin-4-
yl)(di-μ-chloro)lithiumzinc compounds can also be used in a
reaction with iodine and bromine providing a smooth access to
4,5- and 4,6-dihalogenated pyridazin-3(2H)-ones. These can be
used as substrates for selective SNAE and palladium catalyzed
reactions. The presented synthetic protocols further expand the
limited functionalization procedures of the pyridazin-3(2H)-
one scaffold hitherto available.
Table 5. Lactam-Directed Ortho C−H Zincation of 2-Benzyl-
5-chloropyridazin-3(2H)-one (6) Using TMPZnCl·LiCl
Followed by Reaction with Halogens
EXPERIMENTAL SECTION
■
General Methods. All melting points reported are determined on
a melting point apparatus and are uncorrected. The H NMR and 13
C
1
NMR spectra were recorded on a 400 MHz spectrometer in the
solvent indicated with TMS as the internal standard. J values are given
in Hz, and the chemical shifts are given in ppm. For high-resolution
mass-spectrometric analysis, samples were dissolved in CH3OH/
CH3CN 50/50 containing 0.1% formic acid and diluted to a
concentration of approximately 10−5 mol/L. A 2 μL portion was
injected using a CapLC system and electrosprayed through the
nanoelectrospray source. The nanoelectrospray source was operated in
positive ion mode at an electrospray potential of 1.7 kV. The eluent
used was 30% A (H2O 0.1% formic acid) and 70% B (ACN/H2O 95/5
0.1% formic acid) at a flow rate of 6 μL/min. Samples were injected
with an interval of 3 min. Before analysis and after each seventh sample
a 2 μL volume of a 0.025% H3PO4 solution (50/50 MeOH/H2O) was
a
entry
X2
X
11
yield (%)
1
2
Br2
I2
Br
I
11a
11b
76
73
a
6 (1.0 mmol), 1.81 mL of 0.55 M TMPZnCl·LiCl solution in THF
(1.0 equiv), THF (4.0 mL), rt, 1 min; X2 (2.0 equiv), rt, 15 min.
and 6). Scale-up of these reactions to 10.0 mmol were tried
without any drop-off in yield. Interestingly, no 6-chloro-4-
iodopyridazin-3(2H)-ones have hitherto been described in
literature.
9652
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The Journal of Organic Chemistry
Article
injected that could be used as lock mass. The MS was calibrated prior
to use with a 0.015% H3PO4 solution. The spectra were lock mass
corrected using the known mass of the nearest H3PO4 cluster. Flash
column chromatography was performed on Kieselgel 60 or using an
automated chromatography system with Silica Flash Cartridges. Dry
THF on molecular sieves was bought from a commercial source. The
Grignard reagents n-BuMgCl and mesitylmagnesium bromide were
bought from a commercial source as solutions in THF.
122.4, 121.2, 113.3, 57.1, 55.5, 55.2; HRMS (ESI) for C19H18N2O3 [M
+ H]+ calcd 323.1390, found 323.1388.
2-Benzyl-4-(2-chlorophenyl)-5-methoxypyridazin-3(2H)-one
(2c). The general procedure 1 was followed using 1-chloro-2-
iodobenzene (0.489 mL, 4.00 mmol). The reaction time was 90 min.
1
Compound 2c was obtained in 34% (0.111 g) yield: yellow oil; H
NMR (CDCl3) δ 7.86 (s, 1H), 7.47−7.41 (m, 3H), 7.32−7.23 (m,
6H), 5.38 (d, 1H, J = 13.65 Hz), 5.32 (d, 1H, J = 13.65), 3.81 (s, 3H);
13C NMR (CDCl3) δ 160.4, 155.7, 136.5, 134.1, 131.9, 130.2, 129.7,
General Procedure 1 for the Functionalization of 2-Benzyl-
4-bromo-5-methoxypyridazin-3(2H)-one (1). 2-Benzyl-4-bromo-
5-methoxypyridazin-3(2H)-one (1) (0.295 g, 1.0 mmol)3p was
brought in a dry 25 mL double-necked flask and was placed under
argon atmosphere using a Schlenck apparatus. Subsequently, THF (4
mL) was added, and the solution was cooled to −20 °C (ice−salt
bath). n-BuMgCl (0.6 mL, 2 M solution) was quickly added via a
syringe. The mixture was stirred for 10 min, after which time ZnCl2
(2.86 mL, 0.7 M solution) was added via a syringe and the mixture
stirred for 15 min at −20 °C. In another 10 mL dry flask Pd(dba)2
(0.029 g, 0.05 mmol) and tri(2-furyl)phosphine (0.023 g, 0.10 mmol)
were weighed out, and 1 mL of THF was added under an argon flow.
This solution was stirred for 5 min. The catalyst solution and
(hetero)aryl iodide (4.00 mmol) were added simultaneously to the
reaction mixture, which was placed in an oil bath at 50 °C and stirred
until the reaction was completed. The resulting mixture was quenched
with aq. NH4Cl and extracted with EtOAc (3 × 50 mL) and
subsequently dried over MgSO4. The organic phase was evaporated to
dryness under reduced pressure and the residue separated with an
automated chromatography system using a silica flash cartridge
applying a heptane−ethyl acetate gradient (from 100% heptane to
100% ethyl acetate in 25 min, 25 mL/min).
129.5, 129.0, 128.9, 128.6, 128.6, 127.9, 126.6, 57.2, 55.3; HRMS
(ESI) for C18H15ClN2O2 [M + H]+ calcd 327.0895, found 327.0891.
2-Benzyl-4-(3-chlorophenyl)-5-methoxypyridazin-3(2H)-one
(2d). The general procedure 1 was followed using 1-chloro-3-
iodobenzene (0.496 mL, 4.00 mmol). The reaction time was 1 h.
1
Compound 2d was obtained in 73% (0.239 g) yield: orange oil; H
NMR (CDCl3) δ 7.89 (s, 1H), 7.50 (s, 1H), 7.47−7.23 (m, 8H), 5.34
(s, 2H), 3.87 (s, 3H); 13C NMR (CDCl3) δ 160.5, 154.9, 136.3, 133.6,
132.0, 130.4, 129.0, 128.9, 128.7, 128.6, 128.4, 127.9, 127.6, 120.0,
57.2, 55.6; HRMS (ESI) for C18H15ClN2O2 [M + H]+ calcd 327.0895,
found 327.0892.
2-Benzyl-4-(4-chlorophenyl)-5-methoxypyridazin-3(2H)-one
(2e).40 The general procedure 1 was followed using 1-chloro-4-
iodobenzene (0.954 g, 4.00 mmol). The reaction time was 2 h.
1
Compound 2e was obtained in 74% (0.242 g) yield: orange oil; H
NMR (CDCl3) δ 7.87 (s, 1H), 7.49−7.41 (m, 4H), 7.36−7.21 (m,
5H), 5.33 (s, 2H), 3.81 (s, 3H); 13C NMR (CDCl3) δ 160.6, 154.8,
136.4, 134.1, 131.9, 128.9, 128.8, 128.6, 128.0, 128.0, 127.8, 120.2,
57.2, 55.6; HRMS (ESI) for C18H15ClN2O2 [M + H]+ calcd 327.0895,
found 327.0889.
2-Benzyl-5-methoxy-4-[3-(trifluoromethyl)phenyl]-
pyridazin-3(2H)-one (2f). The general procedure 1 was followed
using 1-iodo-3-(trifluoromethyl)benzene (0.588 mL, 4.00 mmol). The
reaction time was 40 min. Compound 2f was obtained in 69% (0.249
Ethyl 4-(2-Benzyl-5-methoxy-3-oxo-2,3-dihydropyridazin-4-
yl)benzoate (2a). The general procedure 1 was followed using ethyl
4-iodobenzoate (0.670 mL, 4.00 mmol). The reaction time was
30 min. Compound 2a was obtained in 80% (0.292 g) yield.
1
g) yield: yellow oil; H NMR (CDCl3) δ 7.92 (s, 1H), 7.79 (s, 1H),
7.71 (d, 1H, J = 7.81 Hz), 7.57 (d, 1H, J = 7.84 Hz), 7.50 (d, 1H, J =
7.79 Hz), 7.45 (m, 2H), 7.29 (m, 3H), 5.36 (s, 2H), 3.87 (s, 3H); 13C
NMR (CDCl3) δ 160.5, 155.0, 136.3, 133.9, 131.1, 130.2 (q, J = 32.3
Hz), 128.9, 128.6, 128.2, 128.0, 127.6, 127.4 (q, J = 3.8 Hz),125.0 (q,
J = 3.6 Hz), 124.0 (q, J = 273.4), 119.8, 57.2, 55.6; HRMS (ESI) for
C19H15F3N2O2 [M + H]+ calcd 361.1158, found 361.1158.
A dry 50 mL double-necked flask placed under argon atmosphere
using a Schlenck apparatus was charged with TMPZnCl·LiCl4 (1.818
mL, 0.55 M solution in THF). 2-Benzyl-5-methoxypyridazin-3(2H)-
one (5) (0.216 g, 1.0 mmol)3p was brought in a second dry 25 mL
double-necked flask and placed under argon atmosphere using a
Schlenck apparatus. Subsequently, THF (2 mL) was added. In a third
dry 25 mL double-necked flask Pd(dba)2 (0.029 g, 0.05 mmol) and
tri(2-furyl)phosphine (0.023 g, 0.10 mmol) were weighed out, and
1 mL of THF was added under an argon flow. Ethyl 4-iodobenzoate
(0.335 mL, 2.00 mmol) was added to this solution after which it was
stirred for 5 min. The pyridazin-3(2H)-one solution was added
dropwise to the TMP solution (1 min) after which it was stirred for
10 s; subsequently, the catalyst solution was immediately added to this
solution. The reaction mixture was stirred at room temperature for
60 min. The resulting mixture was quenched with aq NH4Cl and
extracted with EtOAc (3 × 50 mL) and subsequently dried over
MgSO4. The organic phase was evaporated to dryness under reduced
pressure, and the residue separated with an automated chromatog-
raphy system using a silica flash cartridge applying a heptane−ethyl
acetate gradient (from 100% heptane to 100% ethyl acetate in 25 min,
25 mL/min). Compound 2a was obtained in 86% (0.315 g) yield:
orange solid; mp 87−88 °C; 1H NMR (CDCl3) δ 8.06 (d, 2H, J = 8.61
Hz), 7.91 (s, 1H), 7.59 (d, 2H, J = 8.66 Hz), 7.45 (m, 2H), 7.33−7.25
(m, 3H), 5.35 (s, 2H), 4.37 (q, 2H, J = 7.19 Hz), 3.87 (s, 3H), 1.38 (t,
3H, J = 7.17 Hz); 13C NMR (CDCl3) δ 166.3, 160.5, 155.0, 136.3,
135.1, 130.5, 129.0, 128.9, 128.6, 128.6, 127.9, 127.7, 120.4, 60.9, 57.2,
55.6, 14.3; HRMS (ESI) for C21H20N2O4 [M + H]+ calcd 365.1496,
found 365.1461.
2-Benzyl-5-methoxy-4-[4-(trifluoromethyl)phenyl]-
pyridazin-3(2H)-one (2g). The general procedure 1 was followed
using 1-iodo-4-(trifluoromethyl)benzene (0.588 mL, 4.00 mmol). The
reaction time was 90 min. Compound 2g was obtained in 90% (0.324
1
g) yield: orange oil; H NMR (CDCl3) δ 7.91 (s, 1H), 7.63 (m, 4H),
7.45 (m, 2H), 7.28 (m, 3H), 5.34 (s, 2H), 3.84 (s, 3H); 13C NMR
(CDCl3) δ 160.5, 155.0, 136.6, 134.3, 130.9, 130.0 (q, J = 33.0 Hz),
128.9, 128.6, 128.0, 127.6, 124.7 (q, J = 3.7 Hz), 124.2 (q, J = 271.9
Hz), 119.8, 57.2, 55.7; HRMS (ESI) for C19H15F3N2O2 [M + H]+
calcd 361.1158, found 361.1158.
2-Benzyl-5-methoxy-4-(pyridin-2-yl)pyridazin-3(2H)-one
(2h). The general procedure 1 was followed using 2-iodopyridine
(0.425 mL, 4.00 mmol). The reaction time was 60 min. Compound 2h
1
was obtained in 82% (0.241 g) yield: yellow oil; H NMR (CDCl3) δ
8.73 (d, 1H, J = 4.96 Hz), 7.96 (s, 1H), 7.77 (td, 1H, J = 7.81, 1.78
Hz), 7.53 (d, 1H, J = 8.03 Hz), 7.45 (m, 2H), 7.30 (m, 4H), 5.36 (s,
2H), 3.87 (s, 3H); 13C NMR (CDCl3) δ 161.0, 156.3, 150.4, 149.4,
136.6, 136.1, 128.8, 128.6, 128.5, 128.0, 126.6, 123.2, 119.6, 57.6, 55.6;
HRMS (ESI) for C17H15N3O2 [M + H]+ calcd 294.1237, found
294.1235.
2-Benzyl-5-methoxy-4-(pyridin-3-yl)pyridazin-3(2H)-one
(2i). The general procedure 1 was followed using 3-iodopyridine
(0.820 g, 4.00 mmol). The reaction time was 60 min. Compound 2i
was obtained in 86% (0.252 g) yield: orange solid; mp 201−202 °C;
1H NMR (CDCl3) δ 9.03 (s, 1H), 8.70 (d, 1H, J = 4.72 Hz), 8.29 (d,
1H, J = 8.10 Hz), 7.96 (s, 1H), 7.54 (m, 1H), 7.40 (m, 2H), 7.30 (m,
3H), 5.34 (s, 2H), 3.95 (s, 3H); 13C NMR (CDCl3) δ 160.1, 155.6,
150.5, 147.4, 141.9, 135.9, 128.8, 128.7, 128.7, 128.1, 127.4, 124.5,
115.4, 57.5, 55.9; HRMS (ESI) for C17H15N3O2 [M + H]+ calcd
294.1237, found 294.1237.
2-Benzyl-5-methoxy-4-(4-methoxyphenyl)pyridazin-3(2H)-
one (2b). The general procedure 1 was followed using 4-iodoanisole
(0.936 g, 4.00 mmol). The reaction time was 30 min. Compound 2b
1
was obtained in 72% (0.232 g) yield: orange oil; H NMR (CDCl3) δ
7.87 (s, 1H), 7.50 (m, 2H), 7.46 (m, 2H), 7.30 (m, 3H), 6.93 (d, 2H,
J = 9.02 Hz), 5.35 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H); 13C NMR
(CDCl3) δ 161.0, 159.5, 154.4, 136.6, 131.8, 128.9, 128.5, 128.1, 127.8,
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The Journal of Organic Chemistry
Article
2-Benzyl-5-methoxy-4-(pyrazin-2-yl)pyridazin-3(2H)-one
(2j). The general procedure 1 was followed using 2-iodopyrazine
(0.395 mL, 4.00 mmol). The reaction time was 90 min. Compound 2j
2-Benzyl-5-(3-chlorophenyl)-4-methoxypyridazin-3(2H)-one
(4d). The general procedure 2 was followed using 1-chloro-3-
iodobenzene (0.497 mL, 4.00 mmol). The reaction time was
90 min. Compound 4d was obtained in 73% (0.239 g) yield: yellow
solid; mp 54−55 °C; 1H NMR (CDCl3) δ 7.74 (s, 1H), 7.47 (m, 2H),
7.45−7.38 (m, 4H), 7.36−7.24 (m, 3H), 5.34 (s, 2H), 4.09 (s, 3H);
13C NMR (CDCl3) δ 157.9, 151.6, 137.9, 136.2, 134.6, 134.0, 129.9,
1
was obtained in 78% (0.230 g) yield: yellow oil; H NMR (CDCl3) δ
8.75 (d, 1H, J = 1.51 Hz), 8.66 (dd, 1H, J = 2.56, 1.51 Hz), 8.49 (d,
1H, J = 2.56 Hz), 7.95 (s, 1H), 7.44 (m, 2H), 7.34−7.26 (m, 3H),
5.35 (s, 2H), 3.89 (s, 3H); 13C NMR (CDCl3) δ 160.2, 156.6, 147.1,
147.0, 144.1, 143.4, 136.0, 128.9, 128.6, 128.0, 127.6, 117.3, 57.5, 55.5;
HRMS (ESI) for C16H14N4O2 [M + H]+ calcd 295.1190, found
295.1179.
129.0, 128.9, 128.8, 128.6, 128.0, 127.2, 127.0, 60.3, 55.3; HRMS
(ESI) for C18H15ClN2O2 [M + H]+ calcd 327.0895, found 327.0891.
2-Benzyl-5-(4-chlorophenyl)-4-methoxypyridazin-3(2H)-one
(4e). The general procedure 2 was followed using 1-chloro-4-
iodobenzene (0.954 g, 4.00 mmol). The reaction time was 60 min.
2-Benzyl-5-methoxy-4-(2-thienyl)pyridazin-3(2H)-one (2k). The
general procedure 1 was followed using 2-iodothiophene (0.422 mL,
4.00 mmol). The reaction time was 90 min. Compound 2k was
1
Compound 4e was obtained in 46% (0.151 g) yield: yellow oil; H
1
NMR (CDCl3) δ 7.74 (s, 1H), 7.49−7.44 (m, 3H), 7.39−7.24 (m,
6H), 5.34 (s, 2H), 4.11 (s, 3H); 13C NMR (CDCl3) δ 158.0, 151.4,
138.0, 136.2, 135.1, 130.6, 130.2, 128.9, 128.8, 128.6, 128.0, 127.5,
60.2, 55.3; HRMS (ESI) for C18H15ClN2O2 [M + H]+ calcd 327.0895,
found 327.0884.
2-Benzyl-4-methoxy-5-(4-(trifluoromethyl)phenyl)-
pyridazin-3(2H)-one (4f). The general procedure 2 was followed
using 1-iodo-4-(trifluoromethyl)benzene (0.588 mL, 4.00 mmol). The
reaction time was 90 min. Compound 4f was obtained in 63% (0.227
g) yield: white solid; mp 87−88 °C; 1H NMR (CDCl3) δ 7.76 (s, 1H),
7.70 (d, 2H, J = 8.22 Hz), 7.60 (d, 2H, J = 8.09 Hz), 7.48 (m, 2H),
7.36−7.26 (m, 3H), 5.35 (s, 2H), 4.13 (s, 3H); 13C NMR (CDCl3) δ
157.9, 151.8, 137.8, 136.2, 136.0, 131.0 (q, J = 32.7 Hz), 129.3, 128.9,
128.7, 128.1, 127.2, 125.6 (q, J = 3.6 Hz), 124.0 (q, J = 272.7 Hz),
60.4, 55.4; HRMS (ESI) for C19H15F3N2O2 [M + H]+ calcd 361.1158,
found 361.1157.
2-Benzyl-4-methoxy-5-(pyridin-2-yl)pyridazin-3(2H)-one
(4g). 2-Benzyl-5-bromo-4-methoxypyridazin-3(2H)-one (3) (0.295 g,
1.0 mmol)3p was brought in a dry 25 mL double-necked flask and
placed under argon atmosphere using a Schlenck apparatus.
Subsequently, THF (4 mL) was added, and the solution was cooled
to −20 °C (ice−salt bath). MesMgBr (2.00 mL, 1 M solution) was
quickly added via a syringe. The mixture was stirred for 2 min, after
which ZnCl2 (4.29 mL, 1 M solution) was added and the resulting
mixture stirred for 10 min at −20 °C. In another 10 mL dry flask
Pd(dba)2 (0.029 g, 0.05 mmol), tri(2-furyl)phosphine (0.023 g, 0.10
mmol) and lithium chloride (3.00 mL, 2.24 M solution in DMF) were
weighed out, and 1 mL of DMF was added under an argon flow. 2-
Iodopyridine (0.820 g, 4.00 mmol) was added, and this solution was
stirred for 5 min. The catalyst/2-iodopyridine solution was added to
the reaction mixture which was placed in an oil bath at 50 °C and
stirred for 90 min until the reaction was completed. The resulting
mixture was quenched with aq NH4Cl, extracted with EtOAc (3 × 50
mL), and subsequently dried over MgSO4. The organic phase was
evaporated to dryness under reduced pressure and the residue
separated with an automated chromatography system using a silica
flash cartridge applying a heptane−ethyl acetate gradient (from 100%
heptane to 100% ethyl acetate in 25 min, 25 mL/min). Compound 4g
was obtained in 79% (0.23 g) yield: white solid; mp 100−101 °C; 1H
NMR (CDCl3) δ 8.70 (m, 1H), 8.39 (s, 1H), 7.94 (dt, 1H, J = 8.0, 1.0
Hz), 7.74 (td, 1H, J = 7.8, 1.8 Hz), 7.48−7.43 (m, 2H), 7.35−7.24 (m,
4H), 5.35 (s, 2H), 4.18 (s, 3H); 13C NMR (CDCl3) δ 158.2, 152.2,
150.6, 149.6, 138.3, 136.4, 136.3, 128.6, 128.6, 127.9, 126.6, 125.9,
123.4, 60.2, 55.3; HRMS (ESI) for C17H15N3O2 [M + H]+ calcd
294.1237, found 294.1228.
obtained in 64% (0.191 g) yield: orange solid; mp 129−130 °C; H
NMR (CDCl3) δ 8.25 (dd, 1H, J = 3.97, 1.08 Hz), 7.87 (s, 1H), 7.48
(dd, 1H, J = 5.24, 1.04 Hz), 7.43 (m, 2H), 7.32−7.23 (m, 3H), 7.12
(m, 1H), 5.41 (s, 2H), 4.03 (s, 3H); 13C NMR (CDCl3) δ 159.7,
152.6, 136.4, 131.8, 131.0, 129.0, 128.7, 128.6, 127.9, 127.1, 126.3,
115.3, 57.0, 55.6; HRMS (ESI) for C16H14N2O2S [M + H]+ calcd
299.0849, found 299.0856.
General Procedure 2 for the Functionalization of 2-Benzyl-
5-bromo-4-methoxypyridazin-3(2H)-one (3). 2-Benzyl-5-bromo-
4-methoxypyridazin-3(2H)-one (3) (0.295 g, 1.0 mmol)3p was
brought in a dry 25 mL double-necked flask and placed under argon
atmosphere using a Schlenck apparatus. Subsequently THF (4 mL)
was added and the solution was cooled to −20 °C (ice-salt bath).
MesMgBr (2.00 mL, 1 M solution) was quickly added via a syringe.
The mixture was stirred for 2 min after which ZnCl2 (4.29 mL, 0.7 M
solution) was added and the resulting mixture stirred for 10 min at
−20 °C. In another 10 mL dry flask Pd(dba)2 (0.029 g, 0.05 mmol)
and tri(2-furyl)phosphine (0.023 g, 0.10 mmol) were weighed out, and
1 mL of THF was added under an argon flow. This solution was
stirred for 5 min. The catalyst solution and (hetero)aryl iodide (4.00
mmol) were added simultaneously to the reaction mixture which was
placed in an oil bath at 50 °C and stirred until the reaction was
completed. The resulting mixture was quenched with aq NH4Cl and
extracted with EtOAc (3 × 50 mL) and subsequently dried over
MgSO4. The organic phase was evaporated to dryness under reduced
pressure and the residue separated with an automated chromatography
system using a Silica Flash Cartridge applying a heptane−ethyl acetate
gradient (from 100% heptane to 100% ethyl acetate in 25 min, 25 mL/
min).
Ethyl 4-(1-Benzyl-5-methoxy-6-oxo-1,6-dihydropyridazin-4-
yl)benzoate (4a). The general procedure 2 was followed using ethyl
4-iodobenzoate (0.670 mL, 4.00 mmol). The reaction time was
60 min. Compound 4a was obtained in 45% (0.164 g) yield: orange
oil; 1H NMR (CDCl3) δ 8.11 (d, 2H, J = 8.38 Hz), 7.78 (s, 1H), 7.56
(d, 2H, J = 8.52 Hz), 7.48 (m, 2H), 7.30 (m, 3H), 5.35 (s, 2H), 4.40
(q, 2H, J = 7.21 Hz), 4.11 (s, 3H), 1.40 (t, 3H, J = 7.21 Hz); 13C
NMR (CDCl3) δ 166.0, 158.0, 151.7, 137.9, 136.6, 136.2, 130.8, 129.7,
128.9, 128.8, 128.6, 128.0, 127.6, 61.2, 60.3, 55.3, 14.3; HRMS (ESI)
for C21H20N2O4 [M + H]+ calcd 365.1496, found 365.1485.
2-Benzyl-4-methoxy-5-(4-methoxyphenyl)pyridazin-3(2H)-
one (4b).41 The general procedure 2 was followed using 4-
iodoanisole (0.936 g, 4.00 mmol). The reaction time was 40 min.
1
Compound 4b was obtained in 74% (0.238 g) yield: orange oil; H
NMR (CDCl3) δ 7.79 (s, 1H), 7.47 (m, 4H), 7.36−7.24 (m, 3H), 6.97
(m, 2H), 5.34 (s, 2H), 4.06 (s, 3H), 3.83 (s, 3H); 13C NMR (CDCl3)
δ 160.2, 158.3, 151.0, 138.6, 136.4, 130.2, 128.8, 128.6, 128.6, 127.9,
124.4, 114.1, 60.0, 55.3, 55.1; HRMS (ESI) for C19H18N2O3 [M + H]+
calcd 323.1390, found 323.1381.
2-Benzyl-5-(2-chlorophenyl)-4-methoxypyridazin-3(2H)-one
(4c). The general procedure 2 was followed using 1-chloro-2-
iodobenzene (0.489 mL, 4.00 mmol). The reaction time was
60 min. Compound 4c was obtained in 46% (0.151 g) yield: yellow
oil; 1H NMR (CDCl3) δ 7.63 (s, 1H), 7.55−7.49 (m, 2H), 7.41−7.32
(m, 5H), 7.29−7.25 (m, 1H), 5.39 (s, 2H), 4.06 (s, 3H); 13C NMR
(CDCl3) δ 158.0, 152.3, 138.3, 136.2, 133.2, 131.6, 131.1, 130.2, 129.9,
128.9, 128.7, 128.0, 126.9, 126.0, 60.2, 55,4; HRMS (ESI) for
C18H15ClN2O2 [M + H]+ calcd 327.0895, found 327.0899.
2-Benzyl-4-methoxy-5-(pyrazin-2-yl)pyridazin-3(2H)-one
(4i). The general procedure 2 was followed using 2-iodopyrazine
(0.395 mL, 4.00 mmol). The reaction time was 60 min. Compound 4i
was obtained in 63% (0.186 g) yield: yellow solid; mp 106−107 °C;
1H NMR (CDCl3) δ 9.25 (s, 1H), 8.66 (s, 1H), 8.54 (d, 1H, J = 2.4
Hz), 8.38 (s, 1H), 7.48−7.43 (m, 2H), 7.36−7.25 (m, 3H), 5.35 (s,
2H), 4.30 (s, 3H); 13C NMR (CDCl3) δ 157.7, 152.5, 146.9, 146.9,
144.2, 143.9, 137.4, 136.1, 128.7, 128.6, 128.0, 123.3, 60.6, 55.4;
HRMS (ESI) for C16H14N4O2 [M + H]+ calcd 295.1190, found
295.1203.
2-Benzyl-4-methoxy-5-(2-thienyl)pyridazin-3(2H)-one (4j). The
general procedure 2 was followed using 2-iodothiophene (0.442 mL,
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4.00 mmol). The reaction time was 60 min. Compound 4j was
obtained in 78% (0.232 g) yield: white solid; mp 92−94 °C; 1H NMR
(CDCl3) δ 8.09 (s, 1H), 7.55 (dd, 1H, J = 3.9, 1.0 Hz), 7.46 (dd, 1H,
J = 5.1, 1.0 Hz), 7.45−7.41 (m, 2H), 7.35−7.23 (m, 3H), 7.10 (dd,
1H, J = 5.1, 3.9 Hz), 5.31 (s, 2H), 4.24 (s, 3H); 13C NMR (CDCl3) δ
157.8, 148.3, 136.3, 135.7, 133.1, 129.4, 128.7, 128.6, 127.9, 127.4,
127.1, 122.6, 59.6, 55.0; HRMS (ESI) for C16H14N2O2S [M + H]+
calcd 299.0849, found 299.0842.
2-Benzyl-5-chloro-4-(3-(trifluoromethyl)phenyl)pyridazin-
3(2H)-one (7f). The general procedure 3 was followed using 1-iodo-
3-(trifluoromethyl)benzene (0.288 mL, 2.00 mmol). The reaction time
was 20 min. Compound 7f was obtained in 51% (0.186 g) yield:
1
yellow oil; H NMR (CDCl3) δ 7.92 (s, 1H), 7.79 (s, 1H), 7.71 (d,
1H, J = 7.81 Hz), 7.57 (d, 1H, J = 7.84 Hz), 7.50 (d, 1H, J = 7.79 Hz),
7.45 (m, 2H), 7.29 (m, 3H), 5.36 (s, 2H), 3.87 (s, 3H); 13C NMR
(CDCl3) δ 160.5, 155.0, 136.3, 133.9, 131.1, 130.2 (q, J = 32.3 Hz),
128.9, 128.6, 128.2, 128.0, 127.6, 127.4 (q, J = 3.8 Hz),125.0 (q, J = 3.6
Hz), 124.0 (q, J = 273.4), 119.8, 57.2, 55.6; HRMS (ESI) for
C19H15F3N2O2 [M + H]+ calcd 361.1158, found 361.1158.
General Procedure 3 for the Functionalization of 2-Benzyl-
5-chloropyridazin-3(2H)-one (6). A dry 50 mL double-necked
flask placed under argon atmosphere using a Schlenck apparatus was
charged with TMPZnCl·LiCl4 (1.818 mL, 0.55 M solution in THF). 2-
Benzyl-5-chloropyridazin-3(2H)-one (6) (0.221 g, 1.0 mmol)3q was
brought in a second dry 25 mL double-necked flask and was placed
under argon atmosphere using a Schlenck apparatus. Subsequently,
THF (2 mL) was added. In a third dry 25 mL double-necked flask
Pd(dba)2 (0.029 g, 0.05 mmol) and tri(2-furyl)phosphine (0.023 g,
0.10 mmol) were weighed out, and 1 mL THF was added under an
argon flow. (Hetero)aryl iodide (2.00 mmol) was added to this
solution after which it was stirred for 5 min. The pyridazin-3(2H)-one
solution was added dropwise to the TMP solution (1 min) after which
it was stirred for an additional 1 min; subsequently, the catalyst/
(hetero)aryl iodide solution was immediately added to this solution
and stirred until the reaction was completed. The resulting mixture
was quenched with aq NH4Cl, extracted with EtOAc (3 × 50 mL), and
subsequently dried over MgSO4. The organic phase was evaporated to
dryness under reduced pressure, and the residue separated with an
automated chromatography system using a silica flash cartridge
applying a heptane−ethyl acetate gradient (from 100% heptane to
100% ethyl acetate in 25 min, 25 mL/min).
Ethyl 4-(2-Benzyl-5-chloro-3-oxo-2,3-dihydropyridazin-4-
yl)benzoate (7a). The general procedure 3 was followed using
ethyl 4-iodobenzoate (0.335 mL, 2.00 mmol). The reaction time was
15 min. Compound 7a was obtained in 80% (0.295 g) yield: yellow
oil; 1H NMR (CDCl3) δ 8.12 (d, 2H, J = 8.46 Hz), 7.86 (s, 1H), 7.52
(d, 2H, J = 8.44 Hz), 7.47 (m, 2H), 7.36−7.27 (m, 3H), 5.32 (s, 2H),
4.39 (q, 2H, J = 7.17 Hz), 1.40 (t, 3H, J = 7.17 Hz); 13C NMR
(CDCl3) δ 166.0, 158.6, 137.3, 137.1, 135.9, 135.7, 135.5, 131.2, 129.8,
129.3, 129.1, 128.7, 128.2, 61.1, 56.0, 14.3; HRMS (ESI) for
C20H17ClN2O3 [M + H]+ calcd 369.1000, found 369.0996.
2-Benzyl-5-chloro-4-(4-(trifluoromethyl)phenyl)pyridazin-
3(2H)-one (7g). The general procedure 3 was followed using 1-iodo-
4-(trifluoromethyl)benzene (0.288 mL, 2.00 mmol). The reaction time
was 30 min. Compound 7g was obtained in 44% (0.160 g) yield:
1
yellow solid; mp 75−76 °C; H NMR (CDCl3) δ 7.90 (s, 1H), 7.74
(d, 2H, J = 7.7 Hz), 7.60 (d, 2H, J = 7.7 Hz), 7.52−7.47 (m, 2H),
7.39−7.31 (m, 3H), 5.35 (s, 2H); 13C NMR (CDCl3) δ 158.7, 137.2,
136.9, 136.2, 135.6, 134.7, 131.4 (q, J = 32.7 Hz), 130.3, 129.2, 128.8,
128.4, 125.3 (q, J = 3.8 Hz), 123.9 (q, J = 272.5 Hz), 56.2; HRMS
(ESI) for C18H12F3ClN2O [M + H]+ calcd 365.0663, found 365.0655;
HRMS (ESI) for C18H12F3ClN2O [M + H]+ calcd 365.0663, found
365.0661.
2-Benzyl-5-chloro-4-(pyridin-3-yl)pyridazin-3(2H)-one (7i). A
dry 50 mL double-necked flask placed under argon atmosphere
using a Schlenck apparatus was charged with TMPZnCl·LiCl4 (1.818
mL, 0.55 M solution in THF). 2-Benzyl-5-chloropyridazin-3(2H)-one
(6) (0.221 g, 1.0 mmol)3q was brought in a second dry 25 mL double-
necked flask and placed under argon atmosphere using a Schlenck
apparatus. Subsequently, THF (2 mL) was added. In a third dry 25 mL
double-necked flask Pd(dba)2 (0.029 g, 0.05 mmol), tri(2-furyl)-
phosphine (0.023 g, 0.10 mmol), lithium chloride (3.00 mL, 2.24 M
solution in DMF), and 3-iodopyridine (0.410 g, 2.00 mmol) were
weighed out, and 1 mL of DMF was added under an argon flow; this
solution was stirred for 5 min. The pyridazin-3(2H)-one solution was
added dropwise to the TMP solution (1 min), after which it was
stirred for an additional 1 min; subsequently, the catalyst/3-
iodopyridine solution was immediately added to this solution and
stirred for 20 min. The resulting mixture was quenched with aq
NH4Cl, extracted with EtOAc (3 × 50 mL), and subsequently dried
over MgSO4. The organic phase was evaporated to dryness under
reduced pressure and the residue separated with an automated
chromatography system using a silica flash cartridge applying a
heptane−ethyl acetate gradient (from 100% heptane to 100% ethyl
acetate in 25 min, 25 mL/min). Compound 7i was obtained in 30%
2-Benzyl-5-chloro-4-(4-methoxyphenyl)pyridazin-3(2H)-one
(7b). The general procedure 3 was followed using 4-iodoanisole
(0.468 g, 2.00 mmol). The reaction time was 15 min. Compound 7b
1
was obtained in 65% (0.212 g) yield: yellow solid; mp 88−89 °C; H
1
NMR (CDCl3) δ 7.78 (s, 1H), 7.48−7.41 (m, 3H), 7.31−7.20 (m,
4H), 6.93 (m, 2H), 5.28 (s, 2H), 3.76 (s, 3H); 13C NMR (CDCl3) δ
160.4, 159.3, 137.7, 136.0, 134.9, 131.4, 129.1, 128.1, 127.6, 126.6,
123.1, 113.6, 55.9, 55.1; HRMS (ESI) for C18H15ClN2O2 [M + H]+
calcd 327.0895, found 327.0892. The structure was unambiguously
confirmed by single-crystal XRD analysis; see the Supporting
Information and CCDC 848578.
(0.089 g) yield: orange solid; mp 114−116 °C; H NMR (CDCl3) δ
8.73 (d, 1H, J = 1.4 Hz), 8.66 (dd, 1H, J = 4.7, 1.2 Hz), 7.90 (s, 1H),
7.85 (dt, 1H, J = 8.0, 1.9 Hz), 7.50−7.46 (m, 2H), 7.42−7.30 (m, 4H),
5.35 (s, 2H); 13C NMR (CDCl3) δ 158.7, 150.2, 150.3, 137.5, 137.1,
136.3, 135.5, 135.0, 129.1, 128.7, 128.3, 127.3, 122.9, 56.1; HRMS
(ESI) for C16H12ClN3O [M + H]+ calcd 298.0742, found 298.0743.
2-Benzyl-5-chloro-4-(2-thienyl)pyridazin-3(2H)-one (7k). The
general procedure 3 was followed using 2-iodothiophene (0.221 mL,
2.00 mmol). The reaction time was 15 min. Compound 7k was
obtained in 40% (0.121 g) yield: yellow solid; mp 75−77 °C; 1H NMR
(CDCl3) δ 8.24 (dd, 1H, J = 3.99, 1.07 Hz), 7.83 (s, 1H), 7.69−7.65
(m, 1H), 7.45 (dd, 2H, J = 8.20, 1.60 Hz), 7.35−7.23 (m, 3H), 7.17
(m, 1H), 5.36 (s, 2H); 13C NMR (CDCl3) δ 158.1, 137.9, 135.7,
132.6, 131.6, 131.5, 131.3, 130.2, 128.9, 128.7, 128.1, 126.4, 56.1;
HRMS (ESI) for C15H11ClN2OS [M + H]+ calcd 303.0353, found
303.0353.
2-Benzyl-5-chloro-4-(3-chlorophenyl)pyridazin-3(2H)-one
(7d). The general procedure 3 was followed using 1-chloro-3-
iodobenzene (0.477 g, 2.00 mmol). The reaction time was 20 min.
1
Compound 7d was obtained in 44% (0.146 g) yield: yellow oil; H
NMR (CDCl3) δ 7.84 (s, 1H), 7.46 (m, 2H), 7.38 (m, 3H), 7.35−7.30
(m, 4H), 5.31 (s, 2H); 13C NMR (CDCl3) δ 158.7, 137.1, 136.9,
136.0, 135.6, 134.2, 132.7, 129.7, 129.5, 129.5, 129.1, 128.7, 128.2,
127.9, 56.0; HRMS (ESI) for C17H12Cl2N2O [M + H]+ calcd
331.0399, found 331.0396.
2-Benzyl-5-chloro-4-(4-chlorophenyl)pyridazin-3(2H)-one
(7e).42 The general procedure 3 was followed using 1-chloro-4-
iodobenzene (0.477 g, 2.00 mmol). The reaction time was 15 min.
Compound 7e was obtained in 74% (0.245 g) yield: orange solid; MP
122−123 °C; 1H NMR (CDCl3) δ 7.83 (s, 1H), 7.46 (m, 2H), 7.41−
7.38 (m, 4H), 7.34−7.27 (m, 3H), 5.30 (s, 2H); 13C NMR (CDCl3) δ
158.8, 143.3, 137.2, 135.7, 131.2, 129.4, 129.1, 129.0, 128.7, 128.5,
128.2, 125.5, 56.0; HRMS (ESI) for C17H12Cl2N2O [M + H]+ calcd
331.0399, found 331.0396.
General Procedure 4 for the Functionalization of 2-Benzyl-
6-chloropyridazin-3(2H)-one (8). A dry 50 mL double-necked
flask placed under argon atmosphere using a Schlenck apparatus was
charged with TMPZnCl·LiCl4 (1.818 mL, 0.55 M solution in THF). 2-
Benzyl-6-chloropyridazin-3(2H)-one (8) (0.221 g, 1.0 mmol)3q was
brought in a second dry 25 mL double-necked flask and was placed
under argon atmosphere using a Schlenck apparatus. Subsequently,
THF (2 mL) was added. In a third dry 25 mL double-necked flask
Pd(dba)2 (0.029 g, 0.05 mmol) and tri(2-furyl)phosphine (0.023 g,
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0.10 mmol) were weighed out, and 1 mL of THF was added under an
argon flow. (Hetero)aryl iodide (2.00 mmol) was added to this
solution after which it was stirred for 5 min. The pyridazin-3(2H)-one
solution was immediately added to the TMP solution (1 s) after which
it was stirred for 10 s; subsequently, the catalyst/(hetero)aryl iodide
solution was immediately added (1 s) to this solution. The reaction
mixture was stirred at room temperature until the reaction was
completed. The resulting mixture was quenched with aq NH4Cl,
extracted with EtOAc (3 × 50 mL), and subsequently dried over
MgSO4. The organic phase was evaporated to dryness under reduced
pressure and the residue separated with an automated chromatography
system using a silica flash cartridge applying a heptane−ethyl acetate
gradient (from 100% heptane to 100% ethyl acetate in 25 min, 25 mL/
min).
129.0, 128.7, 128.3, 126.8 (q, J = 3.7 Hz), 125.6 (q, J = 4.0 Hz), 123.8
(q, J = 273.4 Hz), 56.2; HRMS (ESI) for C18H12F3ClN2O [M + H]+
calcd 365.0663, found 365.0661.
2-Benzyl-6-chloro-4-(4-(trifluoromethyl)phenyl)pyridazin-
3(2H)-one (9g). The general procedure 4 was followed using 1-iodo-
4-(trifluoromethyl)benzene (0.294 mL, 2.00 mmol). The reaction time
was 30 min. Compound 9g was obtained in 95% (0.346 g) yield:
yellow oil; 1H NMR (CDCl3) δ 7.84 (d, 2H, J = 8.27 Hz), 7.65 (d, 2H,
J = 8.31 Hz), 7.48 (m, 2H), 7.34−7.24 (m, 4H), 5.30 (s, 2H); 13C
NMR (CDCl3) δ 158.1, 140.5, 137.6, 136.4, 135.5, 131.9 (q, J = 32.6
Hz), 130.3, 129.2, 129.1, 128.7, 128.3, 125.4 (q, J = 3.8 Hz), 123.9 (q,
J = 273.1 Hz), 56.2; HRMS (ESI) for C18H12F3ClN2O [M + H]+ calcd
365.0663, found 365.0652. The structure was unambiguously
confirmed by single-crystal XRD analysis; see the Supporting
Information and CCDC 848580.
Ethyl 4-(2-Benzyl-6-chloro-3-oxo-2,3-dihydropyridazin-4-
yl)benzoate (9a). The general procedure 4 was followed using
ethyl 4-iodobenzoate (0.335 mL, 2.00 mmol). The reaction time was
20 min. Compound 9a was obtained in 91% (0.226 g) yield: white
2-Benzyl-6-chloro-4-(pyridin-2-yl)pyridazin-3(2H)-one (9h). The
general procedure 4 was followed using 2-iodopyridine (0.213 mL,
2.00 mmol). The reaction time was 30 min. Compound 9h was
1
1
obtained in 87% (0.259 g) yield: white solid; mp 131−132 °C; H
solid; mp 102−103 °C; H NMR (CDCl3) δ 8.09 (d, 2H, J = 8.51
NMR (CDCl3) δ 8.68 (m, 1H), 8.64 (m, 1H), 8.19 (s, 1H), 7.74 (td,
1H, J = 7.80, 1.81 Hz), 7.47 (m, 2H), 7.35−7.26 (m, 4H), 5.35 (s,
2H); 13C NMR (CDCl3) δ 158.5, 149.7, 149.6, 138.4, 138.3, 136.6,
135.7, 131.2, 128.8, 128.7, 128.2, 125.4, 124.8, 56.1; HRMS (ESI) for
C16H12ClN3O [M + H]+ calcd 298.0742, found 298.0739.
Hz), 7.83 (d, 2H, J = 8.64 Hz), 7.50 (m, 2H), 7.37−7.27 (m, 4H), 5.33
(s, 2H), 4.40 (q, 2H, J = 7.13 Hz), 1.40 (t, 3H, J = 7.13 Hz); 13C
NMR (CDCl3) δ 165.9, 158.2, 141.0, 137.6, 137.0, 135.5, 131.9, 130.2,
129.6, 129.1, 128.7, 128.7, 128.2, 61.3, 56.2, 14.3; HRMS (ESI) for
C20H17ClN2O3 [M + H]+ calcd 369.1000, found 369.0997.
2-Benzyl-6-chloro-4-(pyridin-3-yl)pyridazin-3(2H)-one (9i). The
general procedure 4 was followed using 3-iodopyridine (0.410 g, 2.00
mmol). The reaction time was 15 min. Compound 9i was obtained in
71% (0.211 g) yield: orange solid; mp 115−116 °C; 1H NMR
(CDCl3) δ 8.88 (d, 1H, J = 2.10 Hz), 8.66 (dd, 1H, J = 4.89, 1.54 Hz),
8.21 (td, 1H, J = 8.03, 1.98 Hz), 7.49 (m, 2H), 7.40−7.28 (m, 5H),
5.33 (s, 2H); 13C NMR (CDCl3) δ 158.2, 151.0, 149.0, 139.0, 137.6,
136.4, 135.4, 129.8, 129.0, 128.7, 128.3, 123.1, 56.2 (only 13 of 14
carbons resolved); HRMS (ESI) for C16H12ClN3O [M + H]+ calcd
298.0742, found 298.0742.
2-Benzyl-6-chloro-4-(4-methoxyphenyl)pyridazin-3(2H)-one
(9b).3q The general procedure 4 was followed using 4-iodoanisole
(0.468 g, 2.00 mmol). The reaction time was 15 min. Compound 9b
was obtained in 85% (0.278 g) yield: yellow solid; mp 101−102 °C;
1H NMR (CDCl3) δ 7.78 (m, 2H), 7.48 (m, 2H), 7.35−7.25 (m, 3H),
7.21 (s, 1H), 6.92 (m, 2H), 6.31 (s, 2H), 3.81 (s, 3H); 13C NMR
(CDCl3) δ 161.4, 158.7, 141.3, 137.8, 135.9, 130.4, 129.0, 128.6, 128.1,
127.9, 125.3, 114.0, 56.1, 55.4; HRMS (ESI) for C18H15ClN2O2 [M +
H]+ calcd 327.0895, found 327.0888.
2-Benzyl-6-chloro-4-(2-chlorophenyl)pyridazin-3(2H)-one
(9c). The general procedure 4 was followed using 1-chloro-2-
iodobenzene (0.245 mL, 2.00 mmol). The reaction time was 20 min.
Compound 9c was obtained in 61% (0.202 g) yield: orange solid; mp
2-Benzyl-6-chloro-4-(pyrazin-2-yl)pyridazin-3(2H)-one (9j). The
general procedure 4 was followed using 2-iodopyrazine (0.197 mL,
2.00 mmol). The reaction time was 15 min. Compound 9j was
1
1
obtained in 86% (0.284 g) yield: white solid; mp 125−126 °C; H
108−109 °C; H NMR (CDCl3) δ 7.51−7.44 (m, 3H), 7.37−7.27
(m, 6H), 7.22 (s, 1H), 5.32 (s, 2H); 13C NMR (CDCl3) δ 157.9,
141.7, 137.0, 135.7, 133.0, 132.7, 132.1, 130.9, 130.7, 130.0, 129.1,
128.7, 128.2, 126.8, 56.1; HRMS (ESI) for C17H12Cl2N2O [M + H]+
calcd 331.0399, found 331.0392.
NMR (CDCl3) δ 9.92 (s, 1H), 8.62 (s, 2H), 8.19 (s, 1H), 7.49 (m,
2H), 7.37−7.27 (m, 3H), 5.38 (s, 2H); 13C NMR (CDCl3) δ 158.0,
146.2, 145.7, 145.6, 144.2, 138.1, 136.6, 135.4, 131.9, 128.9, 128.7,
128.3, 56.2; HRMS (ESI) for C15H11ClN4O [M + H]+ calcd 299.0694,
found 299.0694.
2-Benzyl-6-chloro-4-(3-chlorophenyl)pyridazin-3(2H)-one
(9d). The general procedure 4 was followed using 1-chloro-3-
iodobenzene (0.477 g, 2.00 mmol). The reaction time was 20 min.
Compound 9d was obtained in 77% (0.255 g) yield: white solid; mp
2-Benzyl-6-chloro-4-(2-thienyl)pyridazin-3(2H)-one (9k). The
general procedure 4 was followed using 2-iodothiophene (0.221 mL,
2.00 mmol). The reaction time was 15 min. Compound 9k was
1
1
78−79 °C; H NMR (CDCl3) δ 7.76 (d, 1H, J = 1.84 Hz), 7.61 (m,
obtained in 78% (0.288 g) yield: yellow solid; mp 182−183 °C; H
1H), 7.48 (m, 2H), 7.40−7.27 (m, 5H), 7.23 (s, 1H), 5.30 (s, 2H);
NMR (CDCl3) δ 7.83 (dd, 1H, J = 3.86, 1.09 Hz), 7.57 (dd, 1H, J =
5.11, 1.04 Hz), 7.50−7.46 (m, 2H), 7.45 (s, 1H), 7.35−7.27 (m, 3H),
7.12 (m, 1H), 5.35 (s, 2H); 13C NMR (CDCl3) δ 157.3, 137.9, 135.6,
134.9, 133.6, 132.3, 129.0, 128.9, 128.6, 128.2, 127.4, 123.8, 56.1;
HRMS (ESI) for C15H11ClN2OS [M + H]+ calcd 303.0353, found
303.0346.
13C NMR (CDCl3) δ 158.1, 140.4, 137.6, 135.6, 134.6, 134.5, 130.3,
129.9, 129.8, 129.0, 128.8, 128.7, 128.3, 126.9, 56.2; HRMS (ESI) for
C17H12Cl2N2O [M + H]+ calcd 331.0399, found 331.0393.
2-Benzyl-6-chloro-4-(4-chlorophenyl)pyridazin-3(2H)-one
(9e). The general procedure 4 was followed using 1-chloro-4-
iodobenzene (0.477 g, 2.00 mmol). The reaction time was 15 min.
Compound 9e was obtained in 96% (0.318 g) yield: orange solid; mp
126−127 °C; 1H NMR (CDCl3) δ 7.70 (m, 2H), 7.48 (m, 2H), 7.42−
7.27 (m, 5H), 7.23 (s, 1H), 5.30 (s, 2H); 13C NMR (CDCl3) δ 158.2,
140.5, 137.6, 136.4, 135.5, 131.2, 130.0, 129.3, 129.0, 128.7, 128.6,
128.2, 56.1; HRMS (ESI) for C17H12Cl2N2O [M + H]+, calcd
331.0399, found 331.0394. The structure was unambiguously
confirmed by single-crystal XRD analysis; see the Supporting
Information and CCDC 848579.
2-Benzyl-4-(4-methoxyphenyl)pyridazin-3(2H)-one (10). In
a Pyrex Parr flask 2-benzyl-5-chloro-4-(4-methoxyphenyl)pyridazin-
3(2H)-one (7b) (0.163 g, 0.5 mmol) was weighed out and dissolved in
6 mL of EtOAc. Palladium on carbon (0.053 g, 10%) and potassium
carbonate (0.138 g, 1.0 mmol) were added to the pyridazin-3(2H)-
one-solution under an argon flow. The reaction mixture was placed
under 40 psi of hydrogen gas and stirred overnight. The resulting
mixture was filtered through a path of Celite and concentrated under
vacuum. The residue was separated with an automated chromatog-
raphy system using a silica flash cartridge applying a heptane−ethyl
acetate gradient (from 100% heptane to 100% ethyl acetate in 25 min,
25 mL/min). Compound 10 was obtained in 64% (0.094 g) yield.
In a Pyrex Parr flask 2-benzyl-6-chloro-4-(4-methoxyphenyl)-
pyridazin-3(2H)-one (9b) (0.163 g, 0.5 mmol) was weighed out and
dissolved in 6 mL of EtOAc. Palladium on carbon (0.053 g, 10%) and
potassium carbonate (0.138 g, 1.0 mmol) were added to the pyridazin-
3(2H)-one solution under an argon flow. The reaction mixture was
2-Benzyl-6-chloro-4-(3-(trifluoromethyl)phenyl)pyridazin-
3(2H)-one (9f). The general procedure 4 was followed using 1-iodo-
3-(trifluoromethyl)benzene (0.288 mL, 2.00 mmol). The reaction time
was 20 min. Compound 9f was obtained in 97% (0.354 g) yield:
1
yellow oil; H NMR (CDCl3) δ 8.01 (s, 1H), 7.93 (d, 1H, J = 8.07
Hz), 7.67 (d, 1H, J = 7.75 Hz), 7.52 (t, 1H, J = 7.80 Hz), 7.48 (m,
2H), 7.34−7.27 (m, 4H), 5.32 (s, 2H); 13C NMR (CDCl3) δ 158.1,
140.4, 137.6, 135.5, 133.6, 132.1, 131.0 (q, J = 32.8 Hz), 130.1, 129.0,
9656
dx.doi.org/10.1021/jo201587j|J. Org. Chem. 2011, 76, 9648−9659

The Journal of Organic Chemistry
Article
placed under 35 psi of hydrogen gas for 4 h. The resulting mixture was
filtered through a path of Celite and concentrated under vacuum. The
residue was separated with an automated chromatography system
using a silica flash cartridge applying a heptane−ethyl acetate gradient
(from 100% heptane to 100% ethyl acetate in 25 min, 25 mL/min).
Compound 10 was obtained in 77% (0.113 g) yield: white solid; mp
119−121 °C; 1H NMR (CDCl3) δ 7.85−7.80 (m, 3H), 7.54−7.48 (m,
2H), 7.38−7.27 (m, 3H), 7.24 (d, 1H, J = 4.3 Hz), 6.99−6.94 (m,
2H), 5.42 (s, 2H), 3.86 (s, 3H); 13C NMR (CDCl3) δ 160.8, 160.2,
139.5, 136.5, 136.5, 130.2, 128.9, 128.6, 127.9, 126.3, 126.2, 113.9,
55.9, 55.4; HRMS (ESI) for C18H16N2O2 [M + H]+ calcd 293.1285,
found 293.1278.
General Procedure 5 for the Functionalization of 2-Benzyl-
5-chloropyridazin-3(2H)-one (6). A dry 50 mL double-necked
flask placed under argon atmosphere using a Schlenck apparatus was
charged with TMPZnCl·LiCl4 (1.818 mL, 0.55 M solution in THF). 2-
Benzyl-5-chloropyridazin-3(2H)-one (6) (0.221 g, 1.0 mmol)3q was
brought in a second dry 25 mL double-necked flask and placed under
argon atmosphere using a Schlenck apparatus. Subsequently, THF (4
mL) was added. The pyridazin-3(2H)-one solution was added
dropwise to the TMP solution (1 min) after which it was stirred for
1 min; subsequently, the electrophile (2 mmol) was immediately
added to this solution and stirred until the reaction was completed.
The resulting mixture was quenched with aq NH4Cl, and aq NaHSO3
was added. The aqueous phase was extracted with EtOAc (3 × 50 mL)
and subsequently dried over MgSO4. The organic phase was
evaporated to dryness under reduced pressure and the residue
separated with an automated chromatography system using a silica
flash cartridge applying a heptane−ethyl acetate gradient (from 100%
heptane to 100% ethyl acetate in 25 min, 25 mL/min).
in 91% (0.273 g) yield: yellow solid; mp 118−119 °C; 1H NMR
(CDCl3) δ 7.55 (s, 1H), 7.46 (m, 2H), 7.37−7.28 (m, 3H), 5.27 (s,
2H). 13C NMR (CDCl3) δ 156.2, 136.3, 135.0, 135.0, 130.6, 129.2,
128.7, 128.5, 57.0; HRMS (ESI) for C11H8BrClN2O [M + H]+ calcd
298.9581, found 298.9576.
2-Benzyl-6-chloro-4-iodopyridazin-3(2H)-one (12b). The
general procedure 6 was followed using iodine (0.381 g, 2.00 mmol)
dissolved in 1 mL of THF. The reaction time was 15 min. Compound
12b was obtained in 91% (0.315 g) yield: yellow solid; mp 127−128
1
°C; H NMR (CDCl3) δ 7.79 (s, 1H), 7.45 (m, 2H), 7.35−7.25 (m,
3H), 5.27 (s, 2H); 13C NMR (CDCl3) δ 157.0, 142.1, 136.6, 135.0,
129.1, 128.7, 128.4, 109.3, 57.2; HRMS (ESI) for C11H8ClIN2O [M +
H]+ calcd 346.9443, found 346.9434. The structure was unambigu-
ously confirmed by single-crystal XRD analysis; see the Supporting
Information and CCDC 848582.
ASSOCIATED CONTENT
* Supporting Information
■
S
Copies of NMR spectra of all compounds. X-ray structural data
of compounds 7b, 9e,g, 11b, and 12b. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: bert.maes@ua.ac.be.
■
ACKNOWLEDGMENTS
■
This work was supported by the Fund for Scientific Research
Flanders (FWO-Vlaanderen), the Agency for Innovation by
Science and Technology in Flanders (IWT-Vlaanderen) (Ph.D.
scholarship for T.V.), the Hercules foundation, and E.I. Dupont
de Nemours and Company. We thank Prof. Matthias Zeller of
Youngstown State University (Youngstown, OH), Dr.
Christophe Vande Velde of Karel de Grote University College
(Antwerp, Belgium), and the STaRBURSTT Cyberdiffraction
consortium for collecting the X-ray diffraction data sets.
2-Benzyl-4-bromo-5-chloropyridazin-3(2H)-one (11a). The
general procedure 5 was followed using bromine (0.077 mL, 2.00
mmol). The reaction time was 15 min. Compound 11a was obtained
in 76% (0.219 g) yield: yellow solid; mp 118−119 °C; 1H NMR
(CDCl3) δ 7.70 (s, 1H), 7.43 (m, 2H), 7.36−7.28 (m, 3H), 5.32 (s,
2H); 13C NMR (CDCl3) δ 156.8, 139.5, 135.5, 135.1, 129.1, 128.7,
128.4, 127.5, 56.6; HRMS (ESI) for C11H8BrClN2O [M + H]+ calcd
298.9581, found 298.9575.
2-Benzyl-5-chloro-4-iodopyridazin-3(2H)-one (11b). The
general procedure 5 was followed using iodine (0.381 g, 2.00 mmol)
dissolved in 1 mL of THF. The reaction time was 15 min. Compound
11b was obtained in 73% (0.263 g) yield: yellow solid; mp 127−129
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(38) 4-Iodo-5-chloropyridazin-3(2H)-one can be synthesized by
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9659
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