Reactions of arylpropynehydrazides with substituted malonyl chlorides: A route to pyrazolo-condensed 1,3-oxazines

Article abstract of DOI:10.1002/ejoc.201200267

Reaction of phenylpropynehydrazide with dimethylmalonyl chloride furnished the corresponding 4,4-dimethyl-1-(3-phenylprop-2-ynoyl)pyrazolidine-3,5-dione, which upon thermolysis underwent a 6-endo-dig cyclization to a pyrazolo[5,1-b][1,3]oxazine. The corresponding reaction of arylpropynehydrazides with monosubstituted malonyl chlorides furnished pyrazolo[5,1-b][1,3]oxazine-7- ones via intermediates that could not be isolated. Copyright

Full text of DOI:10.1002/ejoc.201200267

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200267
Reactions of Arylpropynehydrazides with Substituted Malonyl Chlorides:
A Route to Pyrazolo-Condensed 1,3-Oxazines
Olga A. Petina,*[a] Igor P. Yakovlev,[b] and Detlef Geffken[a]
Keywords: Hydrazides / Heterocycles / Cycloaddition / Cyclization / Pyrazoles
Reaction of phenylpropynehydrazide with dimethylmalonyl
chloride furnished the corresponding 4,4-dimethyl-1-(3-
phenylprop-2-ynoyl)pyrazolidine-3,5-dione, which upon
thermolysis underwent a 6-endo-dig cyclization to a pyr-
azolo[5,1-b][1,3]oxazine. The corresponding reaction of aryl-
propynehydrazides with monosubstituted malonyl chlorides
furnished pyrazolo[5,1-b][1,3]oxazine-7-ones via intermedi-
ates that could not be isolated.
Michael acceptors, as dienophiles in Diels–Alder reactions,
or as dipolarophiles in 1,3-dipolar cycloaddition reactions.
Although these reactions are well documented in the litera-
ture,[9] very few publications are dedicated to the corre-
sponding reactivity of α-alkynehydrazides.
Introduction
It is well known that hydrazines react with 1,3-dicarbonyl
compounds to yield a pyrazole ring with an NH–NH
group.[1] The pyrazole nucleus plays an important role in
medicinal chemistry.[2] Several pyrazolidinediones[3] are
used as nonsteroidal anti-inflammatory drugs, for example,
phenylbutazone, sulfinpyrazone, kebuzone, feprazone, and
mofebutazone (Figure 1).[4]
Results and Discussion
The reaction of 3-phenylprop-2-ynehydrazide (1a) with
dimethylmalonyl chloride led to the formation of expected
4,4-dimethyl-1-(3-phenylprop-2-ynoyl)pyrazolidine-3,5-di-
one (2, Scheme 1). Unambiguous structural assignment of
2, which crystallizes as the (NH)-tautomer, was achieved by
X-ray crystal structure analysis (see the Supporting Infor-
mation). Interestingly, when heated to its melting point
or when left in DMSO, pyrazolidinedione 2 undergoes 6-
endo-dig cyclization to 3,3-dimethyl-2,7-dioxo-5-phenyl-
3,7-dihydro-2H-pyrazolo[5,1-b][1,3]oxazin-8-ium-1-ide (3,
Scheme 1).
Figure 1. Pyrazolidinedione derivatives with anti-inflammatory ef-
fect.
In addition, pyrazole-condensed heterocycles obtainable
from the reaction of hydrazides with malonic esters have
been shown to be effective as anti-Alzheimer[5] and antitu-
mor[6] agents, analgesic and anti-inflammatory[7] agents, as
well as Farnesoid X receptor (FAX) antagonists.[8]
The aim of the present work was to investigate the reac-
tion of arylpropynehydrazides with malonyl chlorides,
which we expected to deliver novel fused pyrazolo[1,3]ox-
azines of type 3/5.
Alkynes with an activated triple bond have been proven
as valuable organic intermediates in heterocyclic chemistry.
For instance, acceptor-substituted alkynes can serve as
Scheme 1. Synthesis of 2 and its cyclization to 3.
[a] Institute of Pharmacy, University of Hamburg,
Bundesstrasse 45, 20146 Hamburg, Germany
The reaction of arylpropynehydrazides 1a and 1b with
monosubstituted malonyl chlorides or (chlorocarbonyl)eth-
ylketene[10] produced pyrazolo[1,3]oxazines 5a–g in 57–70%
yield (Table 1), presumably by 6-endo-dig cyclization of in-
termediates 4a–g, which cannot be isolated (Scheme 2).
E-mail: petina@chemie.uni-hamburg.de
[b] St Petersburg State Chemical Pharmaceutical Academy,
ul. Professora Popova 14, 197376 St. Petersburg, Russia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200267.
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O. A. Petina, I. P. Yakovlev, D. Geffken
SHORT COMMUNICATION
Scheme 2. Synthesis of pyrazolo[5,1-b][1,3]oxazine-7-ones (5).
Table 1. Synthesis of pyrazolo[5,1-b][1,3]oxazine-7-ones 5a–g.
Additional detailed NMR spectroscopic investigations of
5e in [D6]DMSO solution provided important information
about its structure and tautomerism. The NOESY spec-
trum (see the Supporting Information) unmistakably re-
vealed the structure of 5e as the reaction product isolated,
because its spectrum shows a clear positive NOE peak be-
tween H2Ј–H2ЈЈ and H2Ј–H6, which cannot occur in the
case of pyrazole 4e. The observation of an NOE peak be-
tween the H2Ј protons and the proton at δ = 11.42 ppm
provides evidence of the spatial proximity of these protons
and proof that 2-hydroxy-3,5-diphenyl-7H-pyrazolo[5,1-b]-
[1,3]oxazine-7-one (5e) mainly exists as the OH-tautomer
(Figure 2). In contrast, the corresponding phenyl protons
and the NH proton in the case of the NH-tautomer were
too far apart for an NOE to be detected.
Entry
Product
R
R1
Yield [%]
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
Ph
Ph
Ph
Ph
Ph
CH3
CH2CH3
CH(CH3)2
(CH2)3CH3
Ph
CH2Ph
Ph
65
61
70
59
68
64
57
Ph
5g
4-ClC6H4
Pyrazolo[5,1-b][1,3]oxazine-7-ones 5, which were found
to exist in a tautomeric equilibrium between 5A and 5B, are
of special interest to medicinal chemistry because of their
bioisosteric relationship to flavones, which are widely
spread bioactive natural compounds.[11]
Only a few related compounds with the same basic ring
structure but with other substituents, especially at the 2-
and 5-positions, have been reported.[12] For example, 2-alk-
ylpyrazolo[5,1-b][1,3]oxazines have been synthesized by
treating the corresponding substituted 2-pyrazolin-5-ones
with Fisher carbene analogues of the 3-phenylpropiolyl
group and further oxidative demetalation.[12d] Although
this synthetic pathway leads to a compound mixture in
which the pyrazolooxazines are present only as minor prod-
ucts (yield Ͻ 20%), we have successfully obtained pyr-
azolo[5,1-b][1,3]oxazine-7-ones 5 in a one-pot synthesis in
good yields. In contrast, antimicrobial 5-amino-2-methyl-
pyrazolo[5,1-b][1,3]oxazine-7-one
was
prepared
by
multistep synthesis and utilizes ethyl acetate and cyanoace-
tohydrazide as starting materials.[12c]
The structures of compounds 5a–g were determined by
mass spectrometry, IR, 1H NMR, and 13C NMR spec-
troscopy, and elemental analysis. The H NMR spectrum
Figure 2. Structure determination of 5e by NOE.
1
The same tautomeric form was detected for 2-hydroxy-3-
of 5a in DMSO shows the presence of methyl protons (s, δ methyl-5-phenyl-7H-pyrazolo[5,1-b][1,3]oxazine-7-one (5a)
= 1.97 ppm, 3 H), aromatic protons (m, δ = 8.05 ppm, 2 H; by X-ray crystal structure analysis (Figure 3).
m, δ = 7.58 ppm, 3 H; s, δ = 6.82 ppm, 1 H) and mobile
The acetylation of 5a and 5e by using acetyl chloride
protons of the NH- or OH group (br. s., δ = 11.42 ppm, 1 furnished exclusively O-acylated products 6a and 6b
1
H). In accordance with the H NMR spectrum, the corre- (Scheme 3), characterized by three sharp IR absorption
sponding 13C NMR spectrum shows the presence of 10 C bands at 1780–1785 (C=O, ester), 1700–1710 (C=O, oxazin-
1
atoms. The H NMR and 13C NMR spectra of 5b–g are one), and 1640–1650 cm–1 (C=N).
similar to those of 5a. Unfortunately, the 1H NMR and 13
C
When 5a was treated with diazomethane no reaction
NMR spectroscopic data do not give unambiguous infor- took place. However, reaction of 5a with iodomethane in
mation about the structure of the obtained compounds, as boiling DMSO in the presence of potassium carbonate fur-
they could match structure 4 or 5. However, the absence nished a mixture of compounds 7 (27%) and 8 (43%,
of a characteristic triple bond absorption band in the IR Scheme 4), which could be separated easily by column
spectrum allowed structure 4 to be excluded.
chromatography on silica gel.
2
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A Route to Pyrazolo-Condensed 1,3-Oxazines
was placed into the freezer for additional crystallization. Yield:
0.64 g (83%); colorless crystals; m.p. 223–225 °C (acetonitrile). IR
(KBr): ν = 2217 (CϵC), 1785 (C=O), 1710 (C=O), 1664 (C=O)
˜
1
cm–1. H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 12.22 (br. s, 1
H, OH), 7.69 (m, 2 H, 2,6-Ph), 7.68 (m, 1 H, 4-Ph), 7.53 (m, 2 H,
3,5-Ph), 1.32 (s, 6 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO,
25 °C): δ = 171.4 and 170.6 (C-3 and C-5), 143.0 (C-1Ј), 132.9 (2,6-
Ph), 131.6 (4-Ph), 129.3 (3,5-Ph), 119.1 (1-Ph), 92.2 (C-3Ј), 81.7 (C-
2Ј), 45.1 (C-4), 21.0 (CH3) ppm. MS: m/z (%) = 256 (5) [M]+, 130/
129 (13/100) [PhCϵCCO]+, no other peaks Ͼ10%. C14H12N2O3
(256.26): calcd. C 65.62, H 4.72, N 10.93; found C 65.62, H 4.84,
N 11.02.
Figure 3. Molecular structure of compound 5a.
3,3-Dimethyl-2,7-dioxo-5-phenyl-3,7-dihydro-2H-pyrazolo[5,1-b]-
[1,3]oxazin-8-ium-1-ide (3): 4,4-Dimethyl-1-(3-phenylprop-2-ynoyl)-
pyrazolidin-3,5-dione (2; 0.26 g, 1 mmol) was heated to its melting
point for 5 min. After cooling, the resulting product was recrys-
tallized from toluene.
General Procedure for the Preparation of 5-Aryl-2-hydroxy-7H-pyr-
azolo[5,1-b][1,3]oxazine-7-ones 5a–g: The corresponding malonyl
dichloride [(chlorocarbonyl)ethylketene] (3.1 mmol) was added to a
stirred solution of 4a,b (3 mmol) in absolute dichloroethane or
THF (30 mL) at room temperature. The reaction mixture was
heated at reflux for 12–14 h. During this time, a white solid de-
posited. The solid separated upon cooling and was filtered off and
recrystallized from either dimethylformamide (for 5a–d and 5g) or
DMSO (for 5e and 5f) to give analytically pure products.
Scheme 3. Acetylation of pyrazolo[5,1-b][1,3]oxazine-7-ones 5a and
5e.
2-Hydroxy-3-methyl-5-phenyl-7H-pyrazolo[5,1-b][1,3]oxazin-7-one
(5a): Yield: 0.47 g (48%); colorless solid; m.p. Ͼ300 °C (dimethyl-
formamide). IR (KBr): ν = 1715 (C=O), 1664 (C=N) cm–1. 1H
˜
NMR (400 MHz, [D6]DMSO, 25 °C): δ = 11.42 (br. s, 1 H, OH),
8.05 (m, 2 H, 2,6-Ph), 7.58 (m, 3 H, 4-Ph and 3,5-Ph), 6.82 (s, 1
H, 6-H), 1.97 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO,
25 °C): δ = 163.3 (C-2), 160.0 (C-5), 152.8 (C-7), 137.7 (C-3a), 132.0
(4-Ph), 129.5 (1-Ph), 129.1 (3,5-Ph), 126.1 (2,6-Ph), 96.8 (C-6), 84.9
(C-3), 4.5 (CH3) ppm. MS: m/z (%) = 243/242 (13/85) [M]+, 146
(10), 130/129 (11/100) [PhCϵCHCO]+, 105 (39), 102 (37)
[PhCϵCH]+, 83 (57), 77 (32) [Ph]+, 76 (11), 69 (12), 56 (11), 51
(19) [C4H3]+, 44 (13), 40 (41), no other peaks Ͼ10%. C13H10N2O3
(242.23): calcd. C 64.46, H 4.16, N 11.56; found C 64.40, H 4.16,
N 11.48.
Scheme 4. Methylation of compound 5a.
CCDC-867859 (for 2) and -867860 (for 5a) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Conclusions
In conclusion, we have developed a simple and efficient
one-pot synthesis of 2-hydroxypyrazolo[5,1-b][1,3]oxazine-
7-ones (5). Furthermore, thermolysis of 4,4-dimethyl-1-(3-
phenylprop-2-inoyl)pyrazolidine-3,5-dione (2), obtained
from the reaction of phenylpropynehydrazide with dimeth-
ylmalonyl chloride, produced mesoionic pyrazolo[5,1-b]-
[1,3]oxazine 3.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data for all compounds, copies of the 1H
NMR and 13C NMR spectra, and selected crystallographic data.
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Experimental Section
4,4-Dimethyl-1-(3-phenylprop-2-ynoyl)pyrazolidine-3,5-dione
(2):
Dimethylmalonyl dichloride (3.1 mmol, 0.36 mL) was added to a
stirred solution of 1a (3 mmol, 0.44 g) in absolute dichloroethane
(30 mL) at room temperature. The reaction mixture was heated at
reflux for 8 h and then allowed to cool to room temperature. The
solid product formed was filtered and recrystallized from acetoni-
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O. A. Petina, I. P. Yakovlev, D. Geffken
SHORT COMMUNICATION
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Received: March 5, 2012
Published Online: ᭿
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A Route to Pyrazolo-Condensed 1,3-Oxazines
Cyclization
O. A. Petina,* I. P. Yakovlev,
D. Geffken ........................................ 1–5
Reactions of Arylpropynehydrazides with
Substituted Malonyl Chlorides: A Route to
Pyrazolo-Condensed 1,3-Oxazines
Keywords: Hydrazides
/
Heterocycles
/
Cycloaddition / Cyclization / Pyrazoles
The reaction of arylpropynehydrazides
with monosubstituted malonyl chlorides
leading to pyrazolo[5,1-b][1,3]oxazines is
reported. This method can also be ex-
tended to the synthesis of pyrazolidine-3,5-
dione, which subsequently can be con-
verted by thermolysis into a pyrazolo[5,1-
b][1,3]oxazine.
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