Synthesis of functionalized pyridazin-3(2 H)-ones via nucleophilic substitution of hydrogen (SNH)

Article abstract of DOI:10.1021/ol102703w

Reaction of 2-benzyl-5-halopyridazin-3(2H)-ones (3) with Grignard reagents followed by quenching with electrophiles unexpectedly yielded 4,5-disubstituted pyridazin-3(2H)-ones instead of 5-substituted pyridazin-3(2H)-ones. These reactions represent the fi

Full text of DOI:10.1021/ol102703w

ORGANIC
LETTERS
2011
Vol. 13, No. 2
272-275
Synthesis of Functionalized
Pyridazin-3(2H)-ones via Nucleophilic
Substitution of Hydrogen (SNH)
Tom Verhelst, Stefan Verbeeck, Oxana Ryabtsova, Stefaan Depraetere, and
Bert U. W. Maes*
Organic Synthesis, Department of Chemistry, UniVersity of Antwerp,
Groenenborgerlaan 171, B-2020 Antwerp, Belgium
bert.maes@ua.ac.be
Received November 8, 2010
ABSTRACT
Reaction of 2-benzyl-5-halopyridazin-3(2H)-ones (3) with Grignard reagents followed by quenching with electrophiles unexpectedly yielded
4,5-disubstituted pyridazin-3(2H)-ones instead of 5-substituted pyridazin-3(2H)-ones. These reactions represent the first examples of cine
substitution in which the anionic σH-adduct is quenched by electrophiles (other than a proton) before elimination takes place. Insight into the
reaction mechanism led to the direct transformation of 2-benzylpyridazin-3(2H)-one (7) and 2-benzyl-6-chloropyridazin-3(2H)-one (9) into the
corresponding C-4 alkyl and aryl derivatives (when Br2 was used as the electrophile).
A pyridazin-3(2H)-one core can be considered as a privileged
scaffold in agrochemistry due to its presence in a remarkable
number of launched pesticides (e.g., herbicides: Chloridazon,
Norflurazon, Oxapyrazon, Flufenpyr, Dimidazon; fungicide:
Diclomezine; insecticides: Pyridaphenthion, Pyridaben).1
Remarkably, the number of available synthetic methods
involving C-functionalizations of the pyridazin-3(2H)-one
core is limited.2 In an attempt to fill this gap our research
group recently started to explore the reactivity of the
pyridazin-3(2H)-one core toward Grignard reagents. In 2009
we described a bromine-magnesium exchange on bromopy-
ridazin-3(2H)-ones followed by quenching with electro-
philes.3 While the intended functionalization was successfully
achieved on 2-benzyl-4-bromo-5-methoxypyridazin-3(2H)-
one, a different reactivity was observed with 2-benzyl-5-
bromo-4-methoxypyridazin-3(2H)-one. An unexpected tan-
dem reaction involving nucleophilic substitution via addition
elimination (SNAE) at C-4 and subsequent bromine-
magnesium exchange at C-5 occurred. Quenching with
electrophiles yielded 4,5-disubstituted pyridazin-3(2H)-ones
with the R group of the RMgX reagent built in at C-4, and
the electrophile at C-5.
To avoid the SNAE reaction, we decided to test 2-benzyl-
5-bromopyridazin-3(2H)-one (3a) as substrate since it does
not contain a leaving group at C-4. 3a can be synthesized in
a two-step procedure from commercially available 4,5-
dibromopyridazin-3(2H)-one.3 Surprisingly, reaction of 3a
with n-BuMgCl followed by quenching with D2O gave
2-benzyl-4-butyl-5-deuteropyridazin-3(2H)-one (4a) instead
of the expected 2-benzyl-5-deuteropyridazin-3(2H)-one (Table
1). This is exactly the same reaction product as obtained
when starting from 2-benzyl-5-bromo-4-methoxypyridazin-
(1) Unger, T. A. Pesticide Synthesis Handbook; Noyes: Park Ridge. NJ,
1996.
(2) For reviews dealing with the synthesis, functionalization, and
application of pyridazines and pyridazin-3(2H)-ones see: (a) Kolar, P.; Tisˇler,
M. AdV. Heterocycl. Chem. 1999, 75, 167. (b) Tapolcsa´nyi, P.; Ma´tyus, P.
In Targets in Heterocyclic Systems; Attanasi, O. A., Spinelli, D., Eds.;
Societa Chimica Italiana: Rome, Italy, 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) Maes, B. U. W.; Lemie`re, 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.
(3) Ryabtsova, O.; Verhelst, T.; Baeten, M.; Maes, B. U. W. J. Org.
Chem. 2009, 74, 9440.
10.1021/ol102703w  2011 American Chemical Society
Published on Web 12/07/2010

Table 1. Cine Substitution on 5-Halopyridazin-3(2H)-ones (3) Involving Electrophiles
entry
R
electrophile
E
4
yield (3a, X ) Br) (%)a
yield (3b, X ) Cl) (%)b
1
n-Bu
n-Bu
i-Pr
Ph
n-Bu
i-Pr
Ph
n-Bu
i-Pr
Ph
n-Bu
n-Bu
n-Bu
Ph
D2O
D
4a
4b
4c
4d
4e
4f
43
47
46
35c
14
25
38c
62
60
38c
0
66
67
82
79d
69
42
75d
67
76
61d
0
2
PhCHO
PhCHO
PhCHO
PhCOCOOMe
PhCOCOOMe
PhCOCOOMe
Furfural
Furfural
Furfural
DMF
PhCH(OH)
PhCH(OH)
PhCH(OH)
PhC(OH)COOMe
PhC(OH)COOMe
PhC(OH)COOMe
(C4H3O)CHOH
(C4H3O)CHOH
(C4H3O)CHOH
HCO
3
4
5
6
7
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
18
4j
4k
4l
MeSSMe
MeSO2SMe
MeSO2SMe
I2
SMe
0
0
SMe
4l
83
93d
0
40
58
22d
SMe
4m
4n
4n
4n
4o
n-Bu
n-Bu
n-Bu
Ph
Cl
0
0
ICl
Cl
Br2
Cl
Br2
Cl
a 3a (1 mmol), 0.5 mL of 2 M RMgCl (1 equiv), THF (4 mL), -20 °C, 1 min; electrophile (1.2 equiv); aq NH4Cl. b 3b (1 mmol), 0.65 mL of 2 M
RMgCl (1.3 equiv), THF (4 mL), -20 °C, 1 min; electrophile (1.6 equiv); aq NH4Cl. c 3a (1 mmol), 1 mL of 2 M RMgCl (2 equiv), THF (4 mL), -20 °C,
1 min; electrophile (2.1 equiv); aq NH4Cl. d 3b (1 mmol), 1.30 mL of 2 M RMgCl (2.6 equiv), THF (4 mL), -20 °C, 1 min; electrophile (2.86 equiv); aq
NH4Cl.
3(2H)-one.3 RMgX apparently still acts as a nucleophile even
though no leaving group is present in C-4 and the electrophile
is built in the C-5 position. MS analysis of the crude reaction
mixture revealed that besides 4a, also 2-benzyl-4-butylpy-
ridazin-3(2H)-one and a product of which the molecular mass
is consistent with 1′,2-dibenzyl-5′-butyl-4,4′-bipyridazine-
3,6′(1′H,2H)-dione (5) were formed. To suppress the forma-
tion of these side products the reaction conditions were
optimized. Using just 1 equiv of n-BuMgCl and a maximum
reaction time of 1 min, before quenching with D2O,
maximized the yield of 4a (Table 1, entry 1). Longer reaction
times consistently led to the formation of undesired 2-benzyl-
4-butylpyridazin-3(2H)-one and 5. A variety of electrophiles
were tested under the optimized conditions: benzaldehyde,
methyl oxo(phenyl)acetate, and furfural gave the correspond-
ing products (4b, 4e, and 4h) in moderate to good yields
(Table 1, entries 2, 5, and 8). Interestingly, when DMF,
Me2S2, and I2 were used, no reaction product was formed
(Table 1, entries 11, 12, and 15). Besides n-BuMgCl, two
other organomagnesium reagents (i-PrMgCl and PhMgCl)
were tested in combination with the same set of electrophiles.
For i-PrMgCl the same reaction conditions were applied,
which resulted in similar yields (Table 1, entries 3, 6, and
9). The less nucleophilic PhMgCl, however, required 2 equiv
(Table 1, entries 4, 7, and 10).
available furfural.4 To suppress the formation of 5 a larger
amount of RMgCl was required for 3b in comparison with
analogous reactions on 3a. Gratifyingly, significantly higher
yields were indeed obtained (Table 1).
We believe that the carbonyl of the lactam function 3
coordinates the RMgX reagent (A) (Scheme 1). Hereby the
Scheme 1
.
Proposed Reaction Mechanism for Cine Substitution
on 5-Halopyridazin-3(2H)-ones (3)
nucleophilicity of the Grignard reagent is increased as well as
the electrophilicity of C-4, both favoring nucleophilic addition
As nucleophilicity of the RMgCl reagent seemed to play
an important role we reasoned that a more electrophilic
substrate such as 2-benzyl-5-chloropyridazin-3(2H)-one (3b)
should give better yields. Chloropyridazinone 3b can be
obtained in a two-step synthesis starting from commercially
(4) Hachihama, Y.; Shono, T.; Ikeda, S. J. Org. Chem. 1964, 29, 1371.
(5) The lactam function acts as a directing group for the nucleophilic
addition reaction, which resembles a Directed Metallation Group (DMG)
in Directed ortho Metallations (DoMs) with organometallic species. For a
review dealing with directed metallation of diazines, see: Turck, A.; Ple´,
N.; Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4489.
Org. Lett., Vol. 13, No. 2, 2011
273

at C-4 of the pyridazin-3(2H)-one.3,5 Moreover, the coordina-
tion creates a proximity effect of R- toward C-4 (intramo-
lecular reaction). Nucleophilic addition is expected to occur
easier on more electrophilic substrates, presumably explain-
ing the differences observed between substrates 3a and 3b.
Nucleophilic addition at C-4 yields the anionic σH-adduct
B, which is inductively stabilized by the halogen atom at
C-5 and resonance stabilized at N-1 (Scheme 1). Upon
addition of electrophile a 5-substituted 4-alkyl (or 4-aryl)-
2-benzyl-5-halo-4,5-dihydropyridazin-3(2H)-one (C) is formed,
which subsequently eliminates HX yielding 4 (Scheme 1).6
Remarkably, when benzoyl chloride was used as the elec-
trophile no elimination occurs and 5-benzoyl-2-benzyl-4-
alkyl-5-chloro-4,5-dihydropyridazin-3(2H)-ones (6) were
isolated (Table 2). This supports our mechanistic hypothesis.
explain why weaker electrophiles such as DMF, Me2S2, and
I2 cannot be used in our functionalization process (Table 1,
entries 11, 12, and 15). This was further supported by an
experiment in which MeSSMe was replaced by the more
electrophilic MeSSO2Me, smoothly yielding the desired
pyridazin-3(2H)-one 4l in 83% yield (Table 1, entry 13). A
similar reaction involving PhMgCl as the nucleophile gave
2-benzyl-4-phenyl-5-methylthiopyridazin-3(2H)-one (4m) in
a good yield (Table 1, entry 14). Analogously, when I2 was
replaced by ICl as reagent in a reaction with n-BuMgCl,
2-benzyl-4-butyl-5-chloropyridazin-3(2H)-one (4n) could be
obtained (Table 1, entry 16). The use of more electrophilic
Br2 gave a higher yield of 4n (Table 1, entry 17). Interest-
ingly, no trace of 2-benzyl-4-butyl-5-iodopyridazin-3(2H)-
one or 5-bromopyridazin-3(2H)-one was detected when using
ICl or Br2, respectively, as the electrophile. This can be
rationalized in terms of better leaving group properties of
iodine and bromine. Reaction of 3b with PhMgCl and
quenching with Br2 gave 2-benzyl-5-chloro-4-phenylpy-
ridazin-3(2H)-one (4o) (Table 1, entry 18). The 5-chloro-4-
(alkyl or aryl)pyridazin-3(2H)-one compound class is very
interesting as the C-5 chlorine allows further decoration of
the pyridazinone core via SNAE and Pd-catalyzed cross-
coupling reactions.2,9,10 When alcohols are used as nucleo-
philes on 5-chloro-4-arylpyridazin-3(2H)-one substrates for
instance, 5-alkoxy-4-arylpyridazin-3(2H)-ones are obtained.
This pyridazin-3(2H)-one subclass possesses interesting
biological properties such as the recently disclosed insecti-
cidal activity against Myzus Persicae.11 An example of a
Pd-catalyzed cross-coupling reaction on 4-aryl-5-chloropy-
ridazin-3(2H)-ones is a Suzuki reaction with arylboronic
Table 2. Attempted Cine Substitution on
5-Chloropyridazin-3(2H)-one (3b) with Benzoyl Chloride as
Electrophilea
entry
R
electrophile
6
yield (%)
1
2
n-Bu
i-Pr
PhCOCl
PhCOCl
6a
6b
37
60
a 3b (1 mmol), 0.5 mL of 2 M RMgCl (1 equiv), THF (4 mL), -20 °C,
1 min; electrophile (1.5 equiv); aq NH4Cl.
Mechanistically, the reaction is a cine-type substitution in
which the anionic σH-adduct formed upon nucleophilic
addition is quenched by electrophiles (other than a proton)
before elimination takes place.7,8 To the best of our
knowledge no such cine nucleophilic substitutions of hy-
drogen have hitherto appeared in the literature. The resonance
and inductive stabilization effects of the anionic species B
(9) For reviews dealing with Pd-catalyzed reactions on halopyridazines
and halopyridazin-3(2H)-ones, see: (a) Maes, B. U. W.; Kosˇmrlj, J.; Lemie`re,
G. L. F. J. Heterocycl. Chem. 2002, 39, 535. (b) Maes, B. U. W.;
Tapolcsa´nyi, P.; Meyers, C.; Ma´tyus, P. Curr. Org. Chem. 2006, 10, 377.
(c) 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
.
(10) For selected examples of Pd-catalyzed reactions on halopyridazines
and halopyridazin-3(2H)-ones, see: (a) Turck, A.; Ple´, N.; Mojovic, L.;
Que´guiner, G. Bull. Soc. Chim. Fr. 1993, 130, 488. (b) Tre´court, F.; Turck,
A.; Ple´, N.; Paris, A.; Que´guiner, G. J. Heterocycl. Chem. 1995, 32, 1057.
(c) Draper, T. L.; Bailey, T. R. J. Org. Chem. 1995, 60, 748. (d) Turck, A.;
Ple´, N.; Lepreˆtre-Gaque`re, A.; Que´guiner, G. Heterocycles 1998, 49, 205.
(e) Parrot, I.; Rival, Y.; Wermuth, C. G. Synthesis 1999, 1163. (f) Maes,
B. U. W.; R’kyek, O.; Kosˇmrlj, J.; Lemie`re, G. L. F.; Esmans, E.; Rozenski,
J.; Dommisse, R. A.; Haemers, A. Tetrahedron 2001, 57, 1323. (g) R’Kyek,
O.; Maes, B. U. W.; Jonckers, T. H. M.; Lemie`re, G. L. F.; Dommisse,
R. A. Tetrahedron 2001, 57, 10009. (h) Tapolcsa´nyi, P.; Krajsovszky, G.;
Ando´, R.; Lipcsey, P.; Horva´th, G.; Ma´tyus, P.; Riedl, Z.; Hajo´s, G.; Maes,
B. U. W.; Lemie`re, G. L. F. Tetrahedron 2002, 58, 10137. (i) Parrot, I.;
Ritter, G.; Wermuth, C. G.; Hibert, M. Synlett 2002, 1123. (j) Sotelo, E.;
Coelho, A.; Ravin˜a, E. Tetrahedron Lett. 2003, 44, 4459. (k) 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. (l) Johnston, K. A.; Allcock, R. W.; Jiang, Z.; Collier,
I. D.; Blakli, H.; Rosair, G. M.; Bailey, P. D.; Morgan, K. M.; Kohno, Y.;
Adams, D. R. Org. Biomol. Chem. 2008, 6, 175. (m) Clapham, K. M.;
Batsanov, A. S.; Greenwood, R. D. R.; Bryce, M. R.; Smith, A. E.; Tarbit,
(6) The elimination of HX from 5-substituted 4-alkyl (or 4-aryl)-2-
benzyl-5-halo-4,5-dihydropyridazin-3(2H)-one (C) can occur before or after
the addition of NH4Cl.
(7) For reviews and a book dealing with nucleophilic aromatic substitu-
tion of hydrogen see: (a) Chupakhin, O. N.; Charushin, V. N.; van der Plas,
H. C. Nucleophilic Aromatic Substitution of Hydrogen; Academic Press:
San Diego, CA, 1994. (b) Suwin˜ski, J.; Œwierczek, K. Tetrahedron 2001,
57, 1639. (c) van der Plas, H. C. AdV. Heterocycl. Chem. 2004, 86, 1. (d)
Ma´kosza, M.; Wojciechowski, K. Chem. ReV. 2004, 104, 2631. (e)
Gulevskaya, A. V.; Pozharskii, A. F. Russ. Chem. Bull. 2008, 57, 913. (f)
Ma´kosza, M. Chem. Soc. ReV. 2010, 39, 2855
.
(8) For cine substitutions in 5-bromo- and 5-chloropyridazine-3,6(1H,2H)-
diones with O, S, and N nucleophiles yielding the corresponding 4-substi-
tuted pyridazine-3,6(1H,2H)-diones see: (a) Stam, C.; Zwinselman, J. J.;
van der Plas, H. C.; Bałoniak, S. J. Heterocycl. Chem. 1979, 16, 855. (b)
Bałoniak, S.; Ostrowicz, A. Pol. J. Chem. 1991, 65, 1085. (c) Bałoniak, S.;
Ostrowicz, A. Pol. J. Chem. 1992, 66, 935. Cine substitutions in halopy-
ridazin-3(2H)-ones have not been reported. Addition of Grignard reagents
to pyridazine derivatives yielding substituted dihydropyridazines have been
described. A separate reaction step is normally required for a full reoxidation
to the pyridazine. For examples, see: (d) Tisˇler, M.; Stanovnik, B. In
ComprehensiVe Heterocyclic Chemistry I; Katritzky, A. R., Rees, C. W.,
Boulton, A. J., McKillop, A., Eds.; Elsevier: New York, 1984; Vol. 3, p 1.
(e) Coates, W. J. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Boulton, A. J., Eds.; Elsevier: New
B. J. Org. Chem. 2008, 73, 2176
.
(11) Lehr, S.; Schenke, T.; Rosinger, C. H.; Fischer, R.; Haeuser-Hahn,
I.; Feucht, D.; Dittgen, J.; Cristau, P.; Gaertzen, O.; Hermann, S.; Malsam,
O.; Franken, E.-M. WO 2010078912 A1, 2010.
(12) (a) Li, C. S.; Brideau, C.; Chan, C. C.; Savoie, C.; Claveau, D.;
Charleson, S.; Gordon, R.; Greig, G.; Gauthier, J. Y.; Lau, C. K.; Riendeau,
D.; The´rien, M.; Wong, E.; Prasit, B. Bioorg. Med. Chem. Lett. 2003, 13,
597. (b) Li, C. S.; Prasit, P.; Gauthier, J. Y.; Lau, C. K.; Therien, M. WO
Patent 9841511 A1, 1998; Chem. Abstr. 1998, 129, 275920.
York, 1996; Vol. 6, p 1
.
274
Org. Lett., Vol. 13, No. 2, 2011

acids yielding 4,5-diarylpyridazin-3(2H)-ones which are
known as potent, selective, and orally active cyclooxyge-
nase-2 inhibitors.12
Table 4. Functionalization of Pyridazin-3(2H)-one 9 via
Oxidative Nucleophilic Substitution of Hydrogena
In view of the reactivity of 3 with RMgX reagents we
wondered whether 2-benzylpyridazin-3(2H)-one (7) would also
undergo nucleophilic addition. When an electrophile, which can
act as a leaving group (e.g., Br2), would be used to quench the
σH-adduct, elimination can still occur.8 In this way C-unsub-
stituted pyridazin-3(2H)-one 7 could be directly transformed
into 4-alkyl- and 4-aryl-2-benzylpyridazin-3(2H)-ones (8) with-
out prior introduction of a leaving group in the pyridazin-3(2H)-
one substrate. Mechanistically this is an oxidative nucleophilic
substitution of hydrogen.7 Gratifyingly, a test experiment with
n-BuMgCl revealed that this approach indeed works when Br2
is used as electrophile (Table 3, entry 1). 3 (R ) alkyl) to 4 (R
entry
R
10
yield (%)
1
2
3
4
5
6
7
n-Bu
10a
10b
10c
10d
10e
10f
62
60
20
57
40
36
83
i-Pr
Ph
4-MePh
4-MeOPh
2-MeOPh
3,5-Cl2Ph
10g
a 9 (1 mmol), 2 M RMgCl (3-4 equiv), THF (4 mL), -20 °C, 5-10
min; Br2 (4-5 equiv); aq NH4Cl.
Table 3. Functionalization of Pyridazin-3(2H)-one 7 via
Diphenylpyridazin-3(2H)-one, for instance, is a precursor for
the synthesis of Minozac (4,6-diphenyl-3-(4-(pyrimidin-2-
yl)piperazin-1-yl)pyridazine), which is a drug candidate for the
treatment of Alzheimer disease.14 The classical approach to
prepare 4,6-disubstituted (alkyl, aryl) pyridazin-3(2H)-ones
involves ring synthesis via condensation of an appropriately
substituted 4-oxoalkanoic acid or ester with hydrazine deriv-
atives.8e
In conclusion, our results show that regioselective nucleo-
philic addition at C-4 of pyridazin-3(2H)-ones followed by
quenching with electrophiles is an interesting and versatile new
way to C-functionalize the pyridazin-3(2H)-one scaffold. When
a leaving group is present at C-5, a double functionalization
(C-4 and C-5) can be achieved in a single synthetic step. The
absence of such a leaving group in combination with quenching
with Br2 as electrophile in situ places a leaving group at C-5,
allowing C-4 mono functionalization. As a diverse set of groups
can be easily introduced by using this SNH synthetic methodol-
ogy, the identified protocols will allow the synthesis of a wide
variety of new substituted pyridazin-3(2H)-ones (involving
functional groups hitherto largely unexplored) with potential
applications in agrochemistry as well as in pharmaceutical
chemistry and material science.
Oxidative Nucleophilic Substitution of Hydrogena
entry
R
8
yield (%)
1
2
3
n-Bu
i-Pr
4-MePh
8a
8b
8c
40
53
27
a 7 (1 mmol), 2 M RMgCl (3-4 equiv), THF (4 mL), -20 °C, 1-10
min; Br2 (4-5 equiv); aq NH4Cl.
) aryl) equiv of RMgCl and 4 to 5 equiv of Br2 were required.
The use of I2 instead of Br2 gave very poor results, which is in
agreement with the results obtained for 3b (Table 1, compare
entries 15 and 17). Besides butyl other alkyl groups, exemplified
by isopropyl, could similarly be introduced when the corre-
sponding RMgCl reagent was used (Table 3, entry 2). Interest-
ingly, extension to C-4 arylation via reaction with ArMgCl
nucleophiles is also possible (Table 3, entry 3). Subsequently,
we decided to test the suitability of 2-benzyl-6-chloropyridazin-
3(2H)-one (9) as substrate. This pyridazin-3(2H)-one is defi-
nitely more challenging as a competitive SNAE reaction at C-6
could occur. 9 can be easily synthesized in two steps starting
from commercially available 3,6-dichloropyridazine.10l Interest-
ingly, the alkylation and arylation procedure developed for 7
could be directly applied on 9 without any sign of SNAE at
C-6 (Table 4).13 The yields obtained starting from 9 were
slightly higher than those with substrate 7, presumably due to
its increased electrophilic character. Reaction products 10 are
very interesting synthetic intermediates as these compounds
allow subsequent C-6 functionalization via SNAE or Pd-
catalyzed cross-coupling reactions with organometallic reagents
accessing 4,6-disubstituted pyridazin-3(2H)-ones, which are
well-known for their interesting biological activities. 4,6-
Acknowledgment. This work was supported by the Fund
for Scientific Research-Flanders (FWO-Vlaanderen) (postdoc-
toral fellowship for 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), and the Hercules foundation).
Supporting Information Available: Characterization data
for all compounds and experimental procedures. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
OL102703W
(13) The coordination of the RMgX reagent to the carbonyl of the
substrate presumably favors σH- over σCl-adduct formation. For a discussion
on the preferential formation of σH- over σX-adducts in electron deficient
arenes, see ref 7f.
(14) Ranaivo, H. R.; Craft, J. M.; Hu, W.; Guo, L.; Wing, L. K.; Van
Eldik, L. J.; Watterson, D. M. J. Neurosci. 2006, 26, 662.
Org. Lett., Vol. 13, No. 2, 2011
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