Conversion of γ-bicyclic lactams to 4,5-dihydro-2H-pyridazin-3-ones

Article abstract of DOI:10.1016/j.tetlet.2003.08.071

Bicyclic lactams are uniquely suited as precursors for the synthesis of chiral substituted 4,5-dihydro-2H-pyridazinones. This paper describes the development of a method for the direct conversion of unsubstituted and 4-substituted γ-bicyclic lactams to 4,5-dihydro-2H-pyridazin-3-ones and 2-phenyl-4,5-dihydro-2H-pyridazin-3-ones.

Full text of DOI:10.1016/j.tetlet.2003.08.071

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7799–7801
Conversion of g-bicyclic lactams to
4,5-dihydro-2H-pyridazin-3-ones
Yu Jin Lim, Mia Angela and Paul T. Buonora*
Department of Chemistry & Biochemistry, California State University, 1250 Bellflower Blvd. Long Beach, CA 90840-3903, USA
Received 1 August 2003; revised 18 August 2003; accepted 19 August 2003
Abstract—Bicyclic lactams are uniquely suited as precursors for the synthesis of chiral substituted 4,5-dihydro-2H-pyridazinones.
This paper describes the development of a method for the direct conversion of unsubstituted and 4-substituted g-bicyclic lactams
to 4,5-dihydro-2H-pyridazin-3-ones and 2-phenyl-4,5-dihydro-2H-pyridazin-3-ones.
© 2003 Elsevier Ltd. All rights reserved.
Pyridazines show a diverse range of agrochemical and
pharmacological activities, including bronchodilatory,
cardiotonic, anti-inflammatory and platelet aggregation
activity, inspiring a variety of synthetic approaches.1
Chiral substituted 4,5-dihydro-2H-pyridazinones, such
as KF 15232, are of particular interest owing to the
influence of chirality on general efficacy2 and isozyme
selectivity.3 Synthetically, such chirality has been
derived through the resolution of precursor racemic
g-ketoacids4 or the lipase-catalyzed hydrolysis5 of the
racemic dihydro-2H-pyridazin-3-one.
Pyridazin-3-ones are masked g-dicarbonyl compounds.
Any generally applicable synthetic scheme requires the
ability to generate chiral centers, including cyclic sys-
tems, at the 4- and 5-positions of the pyridazin-3-one.
Bicyclic lactams (Scheme 1), as amply demonstrated by
Meyers et al., provide access to chiral g-dicarbonyl
frameworks needed.6 The lacking component for the
synthesis of chiral substituted 4,5-dihydro-2H-pyri-
dazin-3-ones is the conversion of the g-bicyclic lactams
to the desired products.
Initially we considered the conversion of the 4-substi-
tuted g-bicyclic lactams to the corresponding g-
ketoacids with subsequent conversion to the
4,5-dihydro-2H-pyridazin-3-one. The synthesis of chiral
a,a-disubstituted-g-ketoacids from bicyclic lactams has
been demonstrated, but has not been widely utilized.7
This may be due in part to the loss of stereochemistry
on the conversion of monoalkylated bicyclic lactams,
Scheme 1.
* Corresponding author. Tel.: +1-562-985-4946; fax: +1-562-985-8557; e-mail: pbuonora@csulb.edu
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.071

7800
Y. J. Lim et al. / Tetrahedron Letters 44 (2003) 7799–7801
Table 1. Conversion of bicyclic lactam to 6-phenyl-4,5-dihydropyridazin-3-one
Entry
R1
R2
R3
R4
Time
5
6a
1
2
3
4
5
6
7
8
H
H
H
Ph
H
H
Ph
H
H
H
H
H
H
Me
Me
Me
Me
H
H
H
H
H
H
H
Me
12
12
12
12
24
24
24
96
5
5
5
5
0
0
0
0
95
95
95
95
99 (95)
99 (94)
92 (68)
34
i-Pr
Ph
H
i-Pr
Ph
H
i-Pr
a Values in parentheses represent yields at 12 h based on gas chromatographic analysis.
owing to the strongly acidic conditions required for the
transformation. Meyers et al. demonstrated that the
racemization occurs on the bicyclic lactam prior to the
solvolysis reaction (Eq. (1)).
While the focus of this study is on the transformation
of bicyclic lactam to pyridazinone, the retention of
stereochemical configuration is critically important to
the utility of the method. Our initial analysis by optical
rotation shows that we have retained some level of
enantiopurity in the conversion of 4 to the 4-methyl-
4,5-dihydro-2H-pyridazin-3-one (Table 1: entry 5).
Investigation of the extent of retention and the general-
ity of this observation are underway and will be
reported in the future.
(1)
Recognizing the inherent nucleophilicity of hydrazine,
we reasoned that direct addition of hydrazine might
allow direct conversion to the 4,5-dihydropyridazin-3-
one under mild acid conditions. In our initial effort we
utilized hydrazine dihydrochloride in a 1:1 etha-
nol:water mixture. Under these conditions the a-unsub-
Substitution at the amide nitrogen of the pyridazin-3-
one is important to the efficacy of the target com-
pounds. While substitution may be accomplished after
synthesis of the pyridazin-3-one ring system, it would
be useful to accomplish this substitution in the ring-
forming step. We attempted the conversion to 2-phenyl
substituted system by reaction with 10 equiv. of phenyl
hydrazine hydrochloride (Table 2). The reactivity of
this system is reduced, requiring 4 days to reach syn-
thetically useful yields in the monomethylated case
(entries 5–7).
stituted
bicyclic
lactams
are
converted
to
6-phenyl-4,5-dihydro-2H-pyridazin-3-one in a 12 h
reflux (Eq. (2)). Monoalkylated bicyclic lactams such as
4 showed lower reactivity and poor solubility in the
ethanol:water solution. Bisalkylated bicyclic lactams
show extremely poor solubility in this solvent system.
Table 2. Conversion of bicyclic lactam to 2,6-diphenyl-4,5-
dihydropyridazin-3-one
(2)
The use of a mixed dioxane:water solvent enabled us to
solubilize both the hydrazine dihydrochloride and the
bicyclic lactam. Under these conditions the reaction
with 10 equiv. of hydrazine dihydrochloride and
bicyclic lactam produced the desired 4,5-dihydro-pyri-
dazin-3-ones (Table 1). In this solvent system low levels
of 3-benzoylpropionic acid 5 were produced when a-
unsubstituted bicyclic lactams (entries 1–4) were investi-
gated. Analysis by GC of the reaction of methylated
systems (entries 5–8) showed no acid formation at any
point during the reactions. The bismethylated bicyclic
lactam (entry 8) showed low reactivity requiring 4 days
to reach 34% completion.
Entry
R1
R2
R3
R4
Time
7
1
2
3
4
5
6
7
8
H
H
H
Ph
H
H
Ph
H
H
H
H
H
H
Me
Me
Me
Me
H
H
H
H
H
H
H
Me
12
12
12
12
96
96
96
96
82
89
85
75
84
65
65
9
i-Pr
Ph
H
i-Pr
Ph
H
i-Pr

Y. J. Lim et al. / Tetrahedron Letters 44 (2003) 7799–7801
7801
In both the hydrazine and phenyl hydrazine reactions
little, if any, decomposition or byproduct formation is
observed. Although steric issues may play a role, one
rationale for the lower yields in the phenyl hydrazine case
is that the concentration of acid is half that in the
hydrazine dihydrochloride. We are currently investigat-
ing the influence of acid concentration on the reaction
to determine if the addition of acid will improve the yields
in these reactions.
Centeno, N. B.; Rodrigo, J.; Ravina, E. Tetrahedron
2002, 58, 2389; (c) Rohr, M.; Toussaint, D.; Chayer, S.;
Manna; Suffer, J.; Wermuth, C. G.; Enguehard, A.;
Hervet, M.; Allouchi, H.; dBouzy, J. C.; Gueiffier, A.
Synthesis 2001, 4, 595.
2. Owings, F. F.; Fox, M.; Kowalski, C. J.; Baine, N. H.
J. Org. Chem. 1991, 56, 1963.
3. (a) Westfall, M. V.; Wahler, G. M.; Solaro, R. J. Bio-
chemistry 1993, 32, 10464; (b) Lues, I.; Beier, N.; Jonas,
R.; Klockow, M.; Haeusler, G. J. Card. Pharm. 1993,
21, 883.
4. Nomoto, Y.; Takai, H.; Ohno, T.; Nadashima, K.; Yao,
K.; Yamada, K.; Kazuhiro, K.; Ichimura, M.; Mihara,
A.; Kase, H. J. Med. Chem. 1996, 39, 297.
5. Yoshida, N.; Aono, M.; Tsubuki, T.; Awano, K.;
Kobayashi, T. Tetrahedron: Asymmetry 2003, 14, 529.
6. (a) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503;
(b) Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997,
1; (c) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000,
56, 9843.
The reactions described here demonstrate the feasibility
of using g-bicyclic lactams as precursors to substituted
4,5-dihydropyridazin-3-ones.8 While this study has been
limited to the 4-substituted-4,5-dihydro-2H-pyridazin-3-
one, in bioactive pyridazin-3-ones, substitution at the 5-
position is common. Our preliminary studies on these
systems are promising and will be reported in the near
future.
Acknowledgements
7. Meyers, A. I.; Harre, M.; Garland, R. J. Am. Chem.
Soc. 1984, 106, 1146.
The authors wish to acknowledge the College of Natural
Sciences and Mathematics and the Department of Chem-
istry and Biochemistry of the California State University,
Long Beach for financial support for this project.
8. Experimental: To a 25 mL flask was added 1 mmol of
5-isopropyl-2-methyl-7a-phenylhexahydropyrrolizin-3-one,
10 mmol of hydrazine dihydrochloride and 15 mL of 1:1
dioxane:water. The mixture was heated with stirring to
85°C for 12 h. The volatiles were removed in vacuo and
the residue taken up in dichloromethane, and extracted
with water. The organic phase was dried over magne-
sium sulfate and the solvent evaporated to yield the
desired 4-methyl-4,5-dihydropyridazin-3-one as a white
solid.
References
1. (a) Van der Mey, M.; Bommele, K. M.; Boss, H.;
Hatzelmann, A.; Slingerland, M. V.; Sterk, G.; Timmer-
man, H. J. Med. Chem. 2003, 46, 2008; (b) Sotelo, E;