Synthesis of functionalized pyridazin-3(2H)-ones via bromine-magnesium exchange on bromopyridazin-3(2H)-ones

Article abstract of DOI:10.1021/jo9020985

(Chemical Equation Presented) The potential of halogen-magnesium exchange reactions, followed by quenching with electrophiles, for the functionalization of the pyridazin-3(2H)-one core was investigated. 2-Benzyl-4-bromo-5-methoxy- (1), 2-benzyl-5-bromo-4-

Full text of DOI:10.1021/jo9020985

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Synthesis of Functionalized Pyridazin-3(2H)-ones via
Bromine-Magnesium Exchange on Bromopyridazin-3(2H)-ones
Oxana Ryabtsova,† Tom Verhelst,† Mattijs Baeten,† Christophe M. L. Vande Velde,‡ and
Bert U. W. Maes*,†
†Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171,
B-2020 Antwerp, Belgium, and Karel de Grote University College, Department of Applied Engineering,
X-ray Crystallography Lab, Salesianenlaan 30, B-2660 Antwerp, Belgium
‡
bert.maes@ua.ac.be
Received September 29, 2009
The potential of halogen-magnesium exchange reactions, followed by quenching with electrophiles,
for the functionalization of the pyridazin-3(2H)-one core was investigated. 2-Benzyl-4-bromo-5-
methoxy- (1), 2-benzyl-5-bromo-4-methoxy- (4), and 2-benzyl-4,5-dibromopyridazin-3(2H)-one (10)
were selected as readily available model substrates. While 1 and 10 gave exclusively C-4 metalation, a
tandem reaction involving nucleophilic substitution via addition elimination and bromine-
magnesium exchange was observed with 4.
Introduction
halopyridazine derivatives with nucleophiles (O, N, S) via
SNAE (= nucleophilic substitution via addition elimination)
reactions is certainly the most documented reaction invol-
ving nucleophilic reagents.1 Because of the electron deficient
nature, halopyridazines (even chlorinated derivatives) can
also smoothly undergo carbon-carbon bond forming reac-
tion via Pd-catalyzed reactions.1c,d,3,4 This had a major
impact as alkyl, alkenyl, alkynyl, aryl, alkoxycarbonyl, and
aminocarbonyl moieties can be installed in an efficient way.
An even more attractive approach for functionalization
is the synthesis of metalated 1,2-diazines, which upon
Polyfunctionalized pyridazines are of considerable impor-
tance due to their application as drugs (e.g., Minaprine),
pesticides (e.g., Pyridaben), and advanced materials (e.g.,
polymers and oligomers with interesting optical and electro-
chemical properties).1 The number of synthetic methods
hitherto available to functionalize the 1,2-diazine skeleton
is rather limited due to the high π-deficient character of the
heterocycle.1 Pyridazine derivatives are therefore only suffi-
ciently reactive for electrophilic substitution when one or
more electron donating substituents are present. Conse-
quently, they are very susceptible for nucleophilic attack.
Minisci reactions involving nucleophilic radicals are well
explored and smooth alkylation, acylation, benzoylation,
and alkoxycarbonylation has been reported.1c,d,2 Mono-
functionalization and regioselectivity problems sometimes
hamper the efficiency of this process. Functionalization of
(3) For reviews dealing with Pd-catalyzed reactions on halopyridazines
ꢁ
and halopyridazin-3(2H)-ones see: (a) Maes, B. U. W.; Tapolcsanyi, P.;
ꢁ
Meyers, C.; Matyus, P. Curr. Org. Chem. 2006, 10, 377. (b) Maes, B. U. W. In
Palladium in Heterocyclic Chemistry; Tetrahedron Organic Chemistry Series;
Li, J. J., Gribble, G. W., Eds.; Elsevier: New York, 2006, Vol. 26, p 541.
(4) For selected examples of Pd-catalyzed reactions on halopyridazines
ꢁ
and halopyridazin-3(2H)-ones see: (a) Turck, A.; Ple, N.; Mojovic, L.;
Queguiner, G. Bull. Soc. Chim. Fr. 1993, 130, 488. (b) Trecourt, F.; Turck,
ꢁ
ꢁ
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ꢁ
A.; Ple, N.; Paris, A.; Queguiner, G. J. Heterocycl. Chem. 1995, 32, 1057. (c)
ꢁ
Draper, T. L.; Bailey, T. R. J. Org. Chem. 1995, 60, 748. (d) Turck, A.; Ple,
(1) For reviews dealing with the synthesis, functionalization and applica-
ꢀ
^
ꢂ
ꢁ
tions of pyridazines and pyridazin-3(2H)-ones see: (a) Kolar, P.; Tisler, M.
N.; Lepretre-Gaquere, A.; Queguiner, G. Heterocycles 1998, 49, 205. (e)
Parrot, I.; Rival, Y.; Wermuth, C. G. Synthesis 1999, 1163. (f) Maes, B. U.
ꢁ
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Adv. Heterocycl. Chem. 1999, 75, 167. (b) Tapolcsanyi, P.; Matyus, P. In
Targets in Heterocyclic Systems; Attanasi, O. A., Spinelli, D., Eds.; Societa
Chimica Italiana: Rome, 2002, Vol. 6, p 369. (c) Haider, N., Holzer, W. In Science
of Synthesis; Yamamoto, Y., Ed.; Thieme: New York, 2004, Vol. 16, p 125. (d)
ꢀ
W.; R’kyek, O.; Kosmrlj, J.; Lemiere, G. L. F.; Esmans, E.; Rozenski, J.;
Dommisse, R. A.; Haemers, A. Tetrahedron 2001, 57, 1323. (g) R’Kyek, O.;
ꢂ
ꢂ
Maes, B. U. W.; Jonckers, T. H. M.; Lemiere, G. L. F.; Dommisse, R. A.
Tetrahedron 2001, 57, 10009. (h) Parrot, I.; Ritter, G.; Wermuth, C. G.;
ꢂ
Maes, B. U. W., Lemiere, G. L. F. In Comprehensive Heterocyclic Chemistry III;
~
Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Aitken, A.,
Eds; Elsevier: New York, 2008, Vol. 8, p 1.
(2) (a) Heinisch, G.; Matuszczak, B.; Mereiter, K.; Soder, J. Heterocycles
Hibert, M. Synlett 2002, 1123. (i) Sotelo, E.; Coelho, A.; Ravina, E.
Tetrahedron Lett. 2003, 44, 4459. (j) Stevenson, T. M.; Crouse, B. A.; Thieu,
T. V.; Gebreysus, C.; Finkelstein, B. L.; Sethuraman, M. R.; Dubas-Cordery,
C. M.; Piotrowski, D. L. J. Heterocycl. Chem. 2005, 42, 427.
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1995, 41, 1461. (b) Haider, N.; Kaferbock, J. Heterocycles 2000, 53, 2527.
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9440 J. Org. Chem. 2009, 74, 9440–9445
Published on Web 11/20/2009
DOI: 10.1021/jo9020985
r
2009 American Chemical Society

Ryabtsova et al.
JOCArticle
quenching with electrophiles (with or without the aid of a
transition metal catalyst or prior transmetalation with a
metal salt) allow the direct introduction of an even wider
variety of functional groups. Investigation of the metalation
(Li) and metal (Li, Mg)-halogen (I, Br) exchange on (halo)-
pyridazines has been reported.5-7 Surprisingly, for the im-
portant pyridazin-3(2H)-one subclass, only Li-halogen
exchange (I, Br) has been hitherto investigated.4j 4-Iodo-5-
methoxy-2-methyl-, 2-substituted (Me, Et,t-Bu, Ph) 4-bromo-
5-methoxy-, and 5-chloro-4-iodo-2-methylpyridazin-3(2H)-
one were used as substrates with n-BuLi as exchange reagent
at -70 °C in THF. Benzaldehydes, Me3SnCl, MeI, D2O, and
CO2 proved to be suitable electrophiles, but DMF for
instance not. The more covalent character of a carbon-
magnesium bond allowing a wider functional group compat-
ibility, the possibility to work at higher temperatures and the
absence of literature data on halogen-magnesium exchange
reactions involving halopyridazin-3(2H)-ones inspired us to
perform such a study. 2-Benzyl-4-bromo-5-methoxy- (1),
2-benzyl-5-bromo-4-methoxy- (4), and 2-benzyl-4,5-dibro-
mopyridazin-3(2H)-one (10) were selected as test substrates.
The choice for an N-benzyl protective group is based on its
potential removal after functionalization.8
TABLE 1. Functionalization of Pyridazin-3(2H)-ones via Bromine-
Magnesium Exchange on 2-Benzyl-4-bromo-5-methoxypyridazin-3(2H)-
one (1)a
entry RMgCl
electrophile
n-BuMgCl D2O
i-PrMgCl D2O
PhMgCl D2O
E
2
yield (%)
1
2
3
D
D
D
2a
2a
2a
2c
2d
2d
2d
95
83
71b
43
4
5
6
n-BuMgCl PhCHO
n-BuMgCl Ph2CO
i-PrMgCl Ph2CO
PhCH(OH)
Ph2C(OH)
Ph2C(OH)
Ph2C(OH)
62
48
7
PhMgCl
Ph2CO
66b
43
8
n-BuMgCl PhCOCOOMe PhC(OH)COOMe 2e
9
n-BuMgCl DMF
n-BuMgCl HCON(CH2)5 HCO
HCO
2f
2f
2g
2h
2i
66
52
10
11
12
13
n-BuMgCl TsCN
n-BuMgCl MeSSMe
n-BuMgCl I2
CN
SMe
I
46
57c
79
a1 (1 mmol), 0.5 mL 2M RMgCl (1 equiv), THF (4 mL), -20 °C,
10 min; electrophile (1 equiv); aq NH4Cl. b1 mL 2M PhMgCl (2 equiv)
and a bromine-magnesium exchange reaction time of 90 min were used.
c2-Benzyl-4,5-bis(methylthio)pyrdiazin-3(2H)-one (2o) (18%) was also
isolated.
Results and Discussion
We started our study by comparing three commercially
available RMgCl (2M in THF) reagents (n-BuMgCl,
i-PrMgCl, and PhMgCl) in the bromine-magnesium ex-
change reaction on 2-benzyl-4-bromo-5-methoxypyridazin-
3(2H)-one (1). The efficiency of these reagents was evaluated
by quenching the reaction mixture with D2O as electrophile
and comparing the isolated yields of 2-benzyl-4-deutero-5-
methoxypyridazin-3(2H)-one (2a). When n-BuMgCl and
i-PrMgCl were used, no substrate remained when perfor-
ming bromine-magnesium exchange for 10 min at -20 °C
followed by hydrolysis with D2O. The yield of 2a was 95%
for the reaction with n-BuMgCl and 83% with i-PrMgCl
(Table 1, entries 1 and 2), pointing at the former as the most
efficient reagent. PhMgCl was also tested but, as expected,
found to be much slower in the halogen-metal exchange
process. Two equiv of PhMgCl as well as an increase of the
reaction time to 90 min were required to achieve complete
conversion of 1. In addition, the isolated yield of 2a (71%)
was substantially lower than that obtained with the alkyl-
magnesium chlorides (Table 1, entry 3). Attempts to use
t-BuMgCl as reagent and D2O as quenching agent com-
pletely failed. Even when 2 equiv of t-BuMgCl were used,
some starting material (1) always remained. Moreover, the
main reaction product was 2-benzyl-5-methoxypyridazin-
3(2H)-one (2b), presumably formed via dehydrohalogenation
of the in situ created t-butyl halide by (2-benzyl-5-methoxy-
3-oxo-2,3-dihydropyridazin-4-yl)magnesium halide.
Next, we investigated the optimal time for bromine-
magnesium exchange by taking samples after 1, 5, 10, 30,
and 60 min reaction time and quenching these with D2O.
Qualitative MS-analysis of these samples (relative intensity
of signals from 2a and 2b) revealed that the amount of
incorporated deuterium versus hydrogen gradually reduced
as a function of time. This is probably due to a reaction of (2-
benzyl-5-methoxy-3-oxo-2,3-dihydropyridazin-4-yl)magne-
sium halide with the alkyl halide formed in the halogen-
metal exchange reaction. With n-BuMgCl at -20 °C a 1:1
ratio 2a/2b was observed after 60 min. No deuterium in-
corporation could be detected after 2 h. For reaction with i-
PrMgCl, the point of no deuterium incorporation was
already obtained after 1 h. The presence of β-hydrogens in
the alkyl halide formed, which allows elimination, seems to
be crucial for the stability of (2-benzyl-5-methoxy-3-oxo-2,3-
dihydropyridazin-4-yl)magnesium halide. This was con-
firmed by reacting 1 with PhMgCl at -20 °C, as after stirring
overnight no hydrogen incorporation was detected. Our
quenching experiments with D2O revealed that the exchange
reaction with n-BuMgCl and i-PrMgCl is fast. The subse-
quent reaction with electrophiles will therefore require its
rapid addition. An exchange time of around 10 min proved
to be optimal.
ꢁ
ꢁ
(5) (a) Turck, A.; Ple, N.; Tallon, V.; Queguiner, G. Tetrahedron 1995, 51,
13045. (b) Turck, A.; Ple, N.; Mojovic, L.; Ndezi, B.; Queguiner, G.; Haider,
ꢁ
ꢁ
N.; Schuller, H.; Heinisch, G. J. Heterocycl. Chem. 1995, 32, 841. (c) Turck,
ꢁ
A.; Ple, N.; Pollet, P.; Mojovic, L.; Duflos, J.; Queguiner, G. J. Heterocycl.
Chem. 1997, 34, 621. (d) Turck, A.; Ple, N.; Pollet, P.; Queguiner, G. J.
ꢁ
ꢁ
ꢁ
ꢁ
Heterocycl. Chem. 1998, 35, 429. (e) Pollet, P.; Turck, A.; Ple, N.; Queguiner,
G. J. Org. Chem. 1999, 64, 4512. (f) Lepretre, A.; Turck, A.; Ple, N.; Knochel,
ꢁ
^
ꢁ
ꢁ
P.; Queguiner, G. Tetrahedron 2000, 56, 265. (g) Chapoulaud, V. G.; Ple, N.;
Turck, A.; Queguiner, G. Tetrahedron 2000, 56, 5499. (h) Le Fur, N.;
ꢁ
ꢁ
ꢁ
Mojovic, L.; Ple, N.; Turck, A.; Marsais, F. Tetrahedron 2005, 61, 8924. (i)
Berghian, C.; Darabantu, M.; Turck, A.; Ple, N. Tetrahedron 2005, 61, 9637.
ꢁ
ꢁ
(j) Decrane, L.; Ple, N.; Turck, A. J. Heterocycl. Chem. 2005, 42, 509.
(6) For recent reviews dealing (partly) with halogen-magnesium ex-
change see: (a) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.;
Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003,
42, 4302. (b) Ila, H.; Baron, O.; Wagner, A. J.; Knochel, P. Chem. Commun.
2006, 583. (c) The Chemistry of Organomagnesium Compounds, Parts 1-2:
R-Mg; Rappoport, Z. Marek, I., Eds.; Wiley-VCH: New York, 2008. (d) Seyferth,
D. Organometallics 2009, 28, 1598.
(7) The scope of the process is unfortunately usually limited to electron
rich pyridazines avoiding competitive addition reactions. For the addition
reaction of s-BuLi on pyridazines and pyridazin-3(2H)-ones see Dal Piaz, V.;
Capperucci, A. Synlett 1998, 762.
With optimal bromine-magnesium exchange reaction
conditions in hand (1 equiv n-BuMgCl, THF, -20 °C, 10 min),
ꢂ
(8) Riedl, Z.; Maes, B. U. W.; Monsieurs, K.; Lemiere, G. L. F.; Matyus,
ꢁ
ꢁ
P.; Hajos, G. Tetrahedron 2002, 58, 5645.
J. Org. Chem. Vol. 74, No. 24, 2009 9441

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SCHEME 1. Attempted Syntheses of 4-Benzoyl-2-benzyl-5-methoxypyridazin-3(2H)-one (2k) via Bromine-Magnesium Exchange on
2-Benzyl-4-bromo-5-methoxypyridazin-3(2H)-one (1)
we tested a variety of electrophiles. Benzaldehyde, benzophe-
none, methyl oxo(phenyl)acetate, DMF, N-formylpiperidine,
TsCN, Me2S2, and I2 gave the corresponding 4-[hydroxy-
(phenyl)methyl] (2c), 4-[hydroxy(diphenyl)methyl] (2d),
4-(2-methoxy-1-hydroxy-2-oxo-1-phenylethyl) (2e), 4-for-
myl (2f), 4-cyano (2g), 4-methylthio- (2h), and 4-iodo- (2i)
substituted pyridazin-3(2H)-ones in good to excellent yields
(Table 1, entries 4, 5, 8-13). For benzophenone as electro-
phile, the three RMgCl exchange reagents were again com-
pared, confirming that n-BuMgCl gives a better result than
i-PrMgCl as observed for D2O (Table 1, entries 5 and 6). In
this case, an equal yield could be obtained with PhMgCl
(Table 1, entry 7). The reaction with benzoyl chloride pro-
vided 4,40-[hydroxy(phenyl)methylene]bis(2-benzyl-5-meth-
oxypyridazin-3(2H)-one) (2j), even with a 10-fold excess of
benzoyl chloride (Scheme 1). 4-Benzoyl-2-benzyl-5-methoxy-
pyridazin-3(2H)-one (2k) could be obtained via prior trans-
metalation of (2-benzyl-5-methoxy-3-oxo-2,3-dihydropyrida-
zin-4-yl)magnesium halide to the corresponding organocop-
per reagent via reaction withCuCN, followed byreactionwith
benzoyl chloride (Scheme 1).9 Alternatively, the 4-benzoyl
derivative 2k was obtained by oxidation of alcohol 2c with
MnO2.4j Interestingly, homo coupled product 2,20-dibenzyl-
5,50-dimethoxy-4,40-bipyridazine-3,30(2H,20H)-dione (3) was
the main reaction product when a transmetalation with
MnBr2 instead of Cu(I)CN was attempted (Scheme 1).10
These homocoupled pyridazinones represent to the best of
our knowledge a new class of compounds.
2-benzyl-5-(dimethylamino)-3-oxo-2,3-dihydropyridazine-
4-carbaldehyde (2l) and 2-benzyl-3-oxo-5-piperidin-1-yl-2,3-
dihydropyridazine-4-carbaldehyde (2m) are obtained as the
reaction products resulting from respectively the use of
DMF and N-formylpiperidine as electrophile.11 This can
be rationalized by considering how the intermediate depro-
tonated hemiaminal A is decomposed upon adding a proton
source (Scheme 3). When saturated aq NH4Cl is used, A gets
immediately O- and N-protonated in the low pH medium
forming B, followed by extrusion of dimethylamine or
piperidine, which will be immediately protonated, hereby
losing its nucleophilic properties. Upon using MeOH as
proton source, the deprotonated heminal A can only be O-
protonated due to the much higher pH of the mixture.
Collapse of the hemiaminal C therefore in this case will
deliver dimethylamine or piperidine, which subsequently
reacts in C-5 of the formed pyridazin-3(2H)-one 2f. This
mechanism is supported by an independent reaction of 2f
with dimethylamine in MeOH at room temperature, giving a
smooth conversion to 2l (99% yield). Interestingly, when
MeSNa was added after the addition of DMF electrophile
workup of the reaction mixture with aq NH4Cl revealed
the presence of 2-benzyl-5-(methylthio)-3-oxo-2,3-dihydropyri-
dazine-4-carbaldehyde (2n), indicating that even C-5 of A is
susceptible for intermolecular nucleophilic attack (Scheme 2).
The susceptibility of the C-5 methoxy group in pyridazin-3(2H)-
ones for nucleophilic substitution is independently shown by the
reaction of (2-benzyl-5-methoxy-3-oxo-2,3-dihydropyridazin-4-
yl)magnesium halide with dimethyldisulfide, as besides 57% of
expected 2-benzyl-5-methoxy-4-(methylthio)pyridazin-3(2H)-
one (2h), also 18% of 2-benzyl-4,5-bis(methylthio)pyridazin-
3(2H)-one (2o) was isolated (Table 1, entry 12). The latter can
be rationalized by nucleophilic attack of in situ formed
methylthiolate on the reaction product 2h.12
The reaction of (2-benzyl-5-methoxy-3-oxo-2,3-dihydro-
pyridazin-4-yl)magnesium halide with DMF or N-formylpi-
peridine as electrophiles proved to be very interesting, as a
different reaction product was obtained depending on the
workup procedure applied (Scheme 2). When the reaction is
worked up by pouring it quickly into a big amount of a
saturated aq NH4Cl solution, the main reaction product is
the expected 2-benzyl-5-methoxy-3-oxo-2,3-dihydropyrida-
zine-4-carbaldehyde (2f). If the reaction mixture is, however,
treated with dry MeOH, prior to adding aq NH4Cl solution,
Subsequently, we investigated 2-benzyl-5-bromo-4-meth-
oxypyridazin-3(2H)-one (4), an isomer of 1, as substrate.
(11) A similar reaction involving the additional substitution of a C-4
halogen by a dimethylamino group was observed when using 3,6-dimethoxy-
4,5-diodo- and 3,6-dimethoxy-4,5-dibromopyridazine as substrates, i-
PrMgCl as halogen-magnesium exchange reagent and DMF as the electro-
phile: see ref 5f.
(9) Dieter, R. K.; Topping, C. M.; Nice, L. E. J. Org. Chem. 2001, 66,
2302.
(10) Cahiez, G.; Rivas-Enterrios, J.; Clery, P. Tetrahedron Lett. 1988, 29,
3659.
(12) For ipso substitutions in (η6-arene)tricarbonylchromium, see: Rose-
Munch, F.; Rose, E. Eur. J. Inorg. Chem. 2002, 6, 1269.
9442 J. Org. Chem. Vol. 74, No. 24, 2009

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SCHEME 2. Dependence of the Reaction Product Formation on the Workup Procedure after Quenching of (2-Benzyl-5-methoxy-3-oxo-
2,3-dihydropyridazin-4-yl)magnesium halide with DMF or N-Formylpiperidine
SCHEME 3. Plausible Mechanism Explaining the Different Reaction Products Obtained when a Workup with MeOH or aq NH4Cl was
Performed
When applying the optimal reaction conditions identified for
bromine-magnesium exchange on 1 (1 equiv n-BuMgCl,
THF, -20 °C, 10 min) on 4, a remarkable observation was
made. Quenching with D2O as electrophile revealed the
formation of 2-benzyl-4-butyl-5-deuteropyridazin-3(2H)-
one (5a). Apparently, an SNAE reaction in C-4 as well as a
bromine-magnesium exchange in C-5 occurred in a single
reaction step. As this process requires at least 2 equiv of n-
BuMgCl to achieve complete conversion, we subsequently
performed the reaction with 3 equiv of exchange reagent and
applied an extended reaction time of 20 min before the
addition of the electrophile. This resulted in a complete
conversion of 4 and an isolated yield of 22% of 5a
(Table 2, entry 1). A similar reaction protocol with i-PrMgCl
gave 61% of 2-benzyl-5-deutero-4-isopropylpyridazin-
3(2H)-one (6a) (Table 2, entry 2). With PhMgCl, which is
less nucleophilic and slower in bromine-magnesium ex-
change reactions, 4 equiv of organomagnesium reagent and
a reaction time of 90 min were used before the electrophile
was added. This gave 2-benzyl-5-deutero-4-phenylpyrida-
zin-3(2H)-one (7a) in 18% yield (Table 2, entry 3). Next,
the generality of the tandem protocol was tested with a
variety of electrophiles using n-BuMgCl and i-PrMgCl as
well as PhMgCl as Grignard reagents. Benzaldehyde, methyl
oxo(phenyl)acetate, and Me2S2 gave the corresponding
5-[hydroxy(phenyl)methyl] (5b, 6b, 7b), 5-(2-methoxy-1-hy-
droxy-2-oxo-1-phenylethyl) (5c, 6c, 7c), and 5-(methylthio)-
(5d, 6d, 7d) substituted 4-alkyl or 4-phenyl-2-benzylpyrida-
zin-3(2H)-ones in good to excellent yields by taking into
account that two reactions occurred in one synthetic step
(Table 2, entries 4-12). We believe that the carbonyl of the
lactam function of the substrate coordinates the RMgX
compound. Hereby the nucleophilicity of the Grignard
reagent is increased (ionic character) as well as the electro-
philicity of C-4 (inductive effect), both favoring nucleophilic
addition reaction at C-4 of the pyridazin-3(2H)-one. More-
over, the coordination creates a proximity effect of the R
group toward C-4. Interestingly, the bromine-magnesium
exchange reaction at C-5 could be completely suppressed
when a lower reaction temperature was selected pointing at
SNAE as the fastest step of the tandem protocol. This is
exemplified by a reaction of n-BuMgCl with 4 at -78 °C.
Even with a 3-fold excess of n-BuMgCl, only 2-benzyl-
5-bromo-4-butylpyridazin-3(2H)-one (8) was obtained in
an excellent yield (83%). With less nucleophilic PhMgCl,
bromine-magnesium exchange and SNAE become more
J. Org. Chem. Vol. 74, No. 24, 2009 9443

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TABLE 2. Tandem Functionalization of Pyridazin-3(2H)-ones via SNAE
and Bromine-Magnesium Exchange on 2-Benzyl-5-bromo-4-methox-
ypyridazin-3(2H)-one (4)a
TABLE 3. Functionalization of Pyridazin-3(2H)-ones via Regioselec-
tive Bromine-Magnesium Exchange on 2-Benzyl-4,5-dibromopyridazin-
3(2H)-one (10)a
entry
electrophile
E
11
yield (%)
yield
(%)
entry
RMgCl
electrophile
D2O
D2O
E
5, 6, 7
1
2
3
4
5
6
D2O
H2O
PhCHO
DMF
Ph2CO
MeSSMe
D
H
11a
11b
11c
11d
11e
11f
44
55
49
78
80
0b
1
n-BuMgCl
i-PrMgCl
PhMgCl
D
D
D
5a
6a
7a
5b
6b
7b
5c
6c
7c
5d
6d
7d
22
61
18b
CH(OH)Ph
CHO
Ph2C(OH)
SMe
2
3
D2O
4
n-BuMgCl
i-PrMgCl
PhMgCl
PhCHO
PhCHO
PhCHO
PhCH(OH)
PhCH(OH)
PhCH(OH)
43
76
73b
5
a1 (1 mmol), 0.5 mL 2M RMgCl (1 equiv), THF (4 mL), -20 °C, 3
min; electrophile (2 equiv); aq NH4Cl. bOnly 2-benzyl-4,5-dimethylthio-
pyridazin-3(2H)-one (2o) was isolated (58%).
6
7
n-BuMgCl
i-PrMgCl
PhMgCl
PhCOCOOMe PhC(OH)COOMe
PhCOCOOMe PhC(OH)COOMe
PhCOCOOMe PhC(OH)COOMe
56
72
31b
8
9
10
11
12
n-BuMgCl
i-PrMgCl
PhMgCl
MeSSMe
MeSSMe
MeSSMe
SMe
SMe
SMe
54
70
78b
electrophiles were subsequently tested. Benzaldehyde, DMF,
and benzophenone gave the corresponding 4-[hydroxy-
(phenyl)methyl] (11c), 4-formyl (11d), and 4-[hydroxy-
(diphenyl)methyl] (11e) substituted pyridazin-3(2H)-ones in
good to excellent yields (Table 3, entries 3-5). When using
DMF as the electrophile treatment of the reaction mixture
with dry MeOH, prior to adding aq NH4Cl solution, gave
47% 2-benzyl-5-(dimethylamino)-3-oxo-2,3-dihydropyrida-
zine-4-carbaldehyde (2l) instead of 2-benzyl-5-bromo-3-
oxo-2,3-dihydropyridazine-4-carbaldehyde (11d). The same
behavior was observed with substrate 1 when dry MeOH was
used as the proton source (Scheme 2). The use of dimethyldi-
sulfide as electrophile gave exclusively 2-benzyl-4,5-bis-
(methylthio)pyridazin-3(2H)-one (2o) and no 2-benzyl-5-
bromo-4-(methylthio)pyridazin-3(2H)-one (11f) was formed
(Table 3, entry 6). On the basis of the reaction of substrate 1
with n-BuMgCl, using the same electrophile as quencher, this
result is not surprising as in that case a methoxy group could be
smoothly substituted by the in situ formed methylthiolate
nucleophile (Table 1, entry 12).
a4 (1 mmol), 1.5 mL 2M RMgCl (3 equiv), THF (4 mL), -20 °C,
20 min; electrophile (2,5-11 equiv); aq NH4Cl. b2 mL 2M PhMgCl
(4 equiv) and a bromine-magnesium exchange reaction time of 90 min
were used.
similar in reaction rate at the same temperature, the latter
being still favored. This is supported by the reaction
of 4 with PhMgCl at -78 °C using benzaldehyde as the
quenching electrophile because besides 67% of 2-benzyl-
5-[hydroxy(phenyl)methyl]-4-phenylpyridazin-3(2H)-one
(7b) also 23% of 2-benzyl-5-[hydroxy(phenyl)methyl]-
4-methoxypyridazin-3(2H)-one (9) was obtained after
workup.
Finally, wewonderedwhether C-4regioselectivebromine-
magnesium exchange in 2-benzyl-4,5-dibromopyridazin-
3(2H)-one (10) would be a feasible process. On the basis of
the presumed anchoring of the RMgX reagent via coordina-
tion with the lactam function of the substrate, a C-4 pre-
ference was theoretically expected.13 As for substrate 1, the
optimal time for bromine-magnesium exchange was deter-
mined by taking samples which were subsequently quenched
with D2O. Analysis of these samples with mass spectroscopy
revealed that a reaction time of only 3 min is optimal for the
removal of one bromine atom in 10 (Table 3, entry 1).
Bromine-magnesium exchange of 10 with 1 equiv n-
BuMgCl in THF followed by quenching with H2O
gave 55% of 2-benzyl-5-bromopyridazin-3(2H)-one (11b)
(Table 3, entry 2). Exclusive formation of 11b revealed that
C-4 regioselective exchange can indeed be achieved on 10.
11b could easily be distinguished from its regioisomer 2-
benzyl-4-bromopyridazin-3(2H)-one based on its specific
4J coupling constant between H-4 and H-6.1 An X-ray
confirmed the structure. Interestingly, as in substrate 1,
SNAE is no competitive reaction, as only traces of 4-butyl
substituted pyridazin-3(2H)-ones could be observed in the
crude reaction mixture. With optimal reaction conditions in
hand (1 equiv n-BuMgCl, THF, -20 °C, 3 min), a variety of
Conclusion
Our results show that bromine-magnesium exchange on
bromopyridazin-3(2H)-ones is a new and interesting way to
achieve efficient functionalization of the pyridazin-3(2H)-
one core. Regioselective exchange as well as tandem functio-
nalizations could be achieved as exemplified on substrate 10
and 4, respectively. As a diverse set of groups can be easily
introduced using this methodology, the identified protocols
will allow to synthesize a wide variety of new substituted
pyridazin-3(2H)-ones (involving functionalities hitherto lar-
gely unexplored) with potential applications in pharmaceu-
tical chemistry, agrochemistry, and material science.14
Experimental Section
General Procedure 1 for the Functionalization of Pyridazin-
3(2H)-ones via Bromine-Magnesium Exchange with RMgCl on
2-Benzyl-4-bromo-5-methoxypyridazin-3(2H)-one (1). Bromo-
pyridazin-3(H)-one 1 (0.295 g, 1 mmol) was brought in a
(13) For regioselective bromine-magnesium exchange in dibromopyr-
ꢁ
idines, see: Trecourt, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.;
ꢁ
(14) A Scifinder database search revealed that 70% of the molecules
synthesized in this manuscript (with the specific substituents on C-4 and C-5
shown in the tables, schemes and figures, leaving the N-2 and C-6 substituents
undefined) were hitherto unknown.
Queguiner, G. Tetrahedron 2000, 56, 1349. For regioselective bromine-
magnesium exchange in 4,5-dibromo-2,6-dimethoxypyrimidine see: Boudet,
N.; Knochel, P. Org. Lett. 2006, 8, 3737.
9444 J. Org. Chem. Vol. 74, No. 24, 2009

Ryabtsova et al.
JOCArticle
50 mL two-necked round-bottomed flask and put under argon
atmosphere making use of a Schlenk apparatus. Subsequently,
4 mL of THF was added and the solution was cooled to -20 °C
(ice-salt bath). n-BuMgCl or i-PrMgCl (0.5 mL, 2M solution) or
PhMgCl (1 mL, 2M solution) was added via a syringe in one
portion. The mixture was stirred at -20 °C for 10 min when
n-BuMgCl or i-PrMgCl was used and 90 min with PhMgCl.
Then the solution was quenched at -20 °C by the addition of
electrophile via a syringe. Finally, the reaction mixture was
poured into a saturated aq NH4Cl solution (10 mL). The
resulting mixture was extracted with CH2Cl2 (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% ethylacetate in 25 min,
25 mL/min).
J = 6.9 Hz). HRMS (ESI) for C21H22N2O2 [M þ H]þ, calcd
335.1760, found 335.1758. 13C NMR (CDCl3) δ: 159.5, 143.2,
141.4, 141.4, 136.5, 135.9, 128.9, 128.7, 128.5, 128.3, 127.7,
126.5, 70.2, 55.1, 28.5, 19.3, 18.5.
General Procedure 3 for the Functionalization of Pyridazin-
3(2H)-ones via Regioselective Bromine-Magnesium Exchange
with RMgCl on 2-Benzyl-4,5-dibromopyridazin-3(2H)-one (10).
Bromopyridazin-3(2H)-one 10 (0.344 g, 1 mmol) was brought in
a 50 mL two-necked round-bottomed flask and put under argon
atmosphere making use of a Schlenk apparatus. Subsequently,
4 mL of THF was added and the solution was cooled down to
-20 °C (ice-salt bath). n-BuMgCl (0.5 mL, 2M solution) was
added via a syringe in one portion. The mixture was stirred at
-20 °C for 3 min. Then the solution was quenched at -20 °C by
the addition of electrophile via a syringe. Finally, the reaction
mixture is poured into a saturated solution of aq NH4Cl
(10 mL). The resulting mixture was extracted with CH2Cl2
(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 Cartridges applying a heptane-ethyl acetate
gradient (from 100% heptane to 100% ethylacetate in 25 min,
25 mL/min).
As an example, the following compound was prepared ac-
cording to this general procedure:
2-Benzyl-4-deutero-5-methoxypyridazin-3(2H)-one (2a). n-
BuMgCl (1.8 mL, 3.60 mmol) and D2O (0.2 mL, 11.6 mmol).
The yield of 2a is 95% (0.206 g); light-yellow needles. 1H NMR
(CDCl3) δ: 7.79 (s, 1H), 7.41-7.36 (m, 2H), 7.34-7.27 (m, 3H),
5.27 (s, 2H), 4.26 (s, 3H). MP 93 °C. HRMS (ESI) for
As an example, the following compound was prepared ac-
cording to this general procedure:
C12H11DN2O2 [M þ H]þ, calcd 218.1040, found 218.1044. 13
C
NMR (CDCl3) δ: 161.8, 160.4, 136.6, 132.7, 128.6, 127.8, 103.2
(t, C-D, J = 25.52 Hz), 55.7, 54.3.
2-Benzyl-5-bromo-3-oxo-2,3-dihydropyridazine-4-carbalde-
hyde (11d). DMF (0.23 mL, 3 mmol). The reaction mixture was
stirred for 45 min, after which it was quenched with aq NH4Cl.
Compound 11d was obtained in 78% (0.229 g) yield; yellow oil.
1H NMR (CDCl3) δ: 10.28 (s, 1H), 7.97 (s, 1H), 7.46-7.41 (m,
2H), 7.37-7.29 (m, 3H), 5.31 (s, 2H). HRMS (ESI) for
General Procedure 2 for the Tandem Functionalization of
Pyridazin-3(2H)-ones via SNAE and Bromine-Magnesium Ex-
change with RMgCl on 2-Benzyl-5-bromo-4-methoxypyridazin-
3(2H)-one (4). Bromopyridazin-3(2H)-one 4 (0.295 g, 1 mmol)
was brought in a 50 mL two-necked round-bottomed flask and
put under argon atmosphere making use of a Schlenk apparatus.
Subsequently 4 mL of THF was added and the solution was
cooled to -20 °C (ice-salt bath). n-BuMgCl or i-PrMgCl
(1,5 mL, 2M solution) or PhMgCl (2 mL, 2M solution) was
added via a syringe in one portion. The mixture was stirred at
-20 °C for 20 min when n-BuMgCl or i-PrMgCl was used and
90 min with PhMgCl. Then, the solution was quenched at
-20 °C by the addition of electrophile via a syringe and stirred
overnight (to ambient temperature). Finally, the reaction mix-
ture was poured into a saturated aq NH4Cl solution (10 mL).
The resulting mixture was extracted with CH2Cl2 (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 Cartridges applying a heptane-ethyl acetate gra-
dient (from 100% heptane to 100% ethylacetate in 25 min,
25 mL/min).
C12H9BrN2O2 [M þ H]þ, calcd 292.9926, found 292.9937. 13
C
NMR (CDCl3) δ: 158.6, 139.9, 143.8, 129.6, 129.0, 128.9, 128.6,
128.7, 128.5, 55.6.
Acknowledgment. This work was supported by the
Fund for Scientific Research-Flanders (FWO-Vlaanderen)
(postdoctoral fellowship for Dr. Oxana Ryabtsova and
project 1.5.162.08), the Institute for the Promotion of
Innovation by Science and Technology in Flanders
(IWT-Vlaanderen) (Ph.D. scholarship for T. Verhelst), the
Flemish Government (Impulsfinanciering van de Vlaamse
Overheid voor Strategisch Basisonderzoek PFEU 2003), the
Hercules Foundation, and E.I. Dupont de Nemours and
Company. We thank Dr. Sergey Sergeyev for valuable
discussions and Prof. Matthias Zeller of Youngstown State
University for the collection of X-ray datasets. The diffracto-
meter was funded by NSF grant 0087210, Ohio Board of
Regents grant CAP-491, and YSU.
As an example, the following compound was prepared ac-
cording to this general procedure:
2-Benzyl-5-[hydroxy(phenyl)methyl]-4-isopropylpyridazin-
3(2H)-one (6b). Benzaldehyde (0.3 mL, 2.96 mmol). Compound
6b was obtained in 76% (0.255 g) yield; yellow oil. H NMR
(CDCl3) δ: 7.99 (s, 1H), 7.40-7.21 (m, 10H), 5.98 (d, 1H, J =
4.2 Hz), 5.28 (d, 1H, J = 14.1 Hz), 5.17 (d, 1H, J = 14.1 Hz),
3.14 (m, 2H, J = 6.9 Hz), 1.29 (d, 3H, J = 6.9 Hz), 1.11 (d, 3H,
Supporting Information Available: Instrumentation and
chemicals, experimental procedures and characterization data
for all compounds, crystallographic information (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
J. Org. Chem. Vol. 74, No. 24, 2009 9445