Novel heterocycles containing the pyrazole unit

Article abstract of DOI:10.1039/b201529n

New condensed pyrazolo[1,5-e][1,3,5]benzoxadiazocine and bridged 5,11-methano-[1,2,4]triazolo[1,2-c]-[1,3,4]benzoxadiazepine heterocyclic ring systems were prepared by cyclizations of 4,5-dihydro-3-methyl-5-(2-hydroxyphenyl)-1H-pyrazole-1-carboximidamide

Full text of DOI:10.1039/b201529n

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Novel heterocycles containing the pyrazole unit
Jan Sveˇtlík*a and Tibor Liptajb
a Department of Pharmaceutical Analysis and Nuclear Pharmacy, Faculty of Pharmacy,
Comenius University, Odbojarov 10, SK-832 32 Bratislava, Slovak Republic.
E-mail: svetlik@fpharm.uniba.sk
1
b NMR Laboratory, Slovak Technical University, Radlinskeho 9, SK-812 37 Bratislava,
Slovak Republic
Received (in Cambridge, UK) 11th February 2002, Accepted 25th March 2002
First published as an Advance Article on the web 15th April 2002
New condensed pyrazolo[1,5-e][1,3,5]benzoxadiazocine and bridged 5,11-methano-[1,2,4]triazolo[1,2-c]-
[1,3,4]benzoxadiazepine heterocyclic ring systems were prepared by cyclizations of 4,5-dihydro-3-methyl-
5-(2-hydroxyphenyl)-1H-pyrazole-1-carboximidamide with C1 reagents (triethylorthoformate and
1,1Ј-carbonyldiimidazole). In contrast, cyclocondensations with C2 and C3 reactants occur exclusively at
the amidine moiety yielding substituted pyrano[2,3-d]pyrimidine, pyrimidine, and imidazole derivatives.
Introduction
In a previous paper1 we reported an unprecedented ring closure
reaction of α,β-unsaturated ketones with aminoguanidine
leading to 5-aryl-4,5-dihydro-3-methyl-1H-pyrazole-1-carbox-
imidamides 1 and the corresponding carboxamides 2. Because
of our research interests in the chemistry of oxygen-bridged
heterocycles, we focused particularly on cyclisations of deriv-
ative 1a. Apparently, the presence of the phenolic hydroxy in
pyrazole 1a lends this compound another reactive centre that
could be subsequently coupled to an adjacent carboximidamide
moiety by a suitable linker. The aim of the present work is to
investigate cyclization reactions of compound 1a with C1–C3
reagents in an effort to explore the synthetic potential for the
preparation of fused heterocycles containing the pyrazole ring.
Such compounds are of interest because of their inhibiting
activity towards nitric oxide synthase, a significant pharmaco-
logical aspect addressed also in our previous work.1
The molecular formula of the higher-melting product 4,
C12H14N2O2, showed a loss of a [CH3N2] moiety and addition
of one acetyl group to the starting pyrazole 1a, C11H14N4O. The
presence of the original heterocyclic skeleton with both sub-
stituents in the 3 and 5 positions was proved by NMR spectro-
scopy. The loss of the afore-mentioned atoms suggested that an
amidine group was eliminated from the starting pyrazoline 1a.
This led to the structure of 1,3,5-trisubstituted pyrazole for 4,
which was unambiguously confirmed by independent synthesis
from 4-(2-hydroxyphenyl)but-3-en-2-one and hydrazine in
refluxing acetic acid adopting a literature method2 for similar
acetylated pyrazoles.
Results and discussion
We first attempted to connect both functionalities by using
acetic anhydride. However, refluxing amidine 1a in an excess
of acetic anhydride led to a rapid decomposition. When the
reaction was carried out at room temperature, the reactant sus-
pension became clear in 6 h and after 1 day we isolated two
products. Upon work-up of the reaction mixture, compound 3
(mp 148–150 ЊC) crystallized from ethyl acetate solution
whereas 4 (mp 176–177 ЊC) was isolated by column chrom-
atography of the mother liquor. The elemental composition of
the lower-melting product indicated that a triacetyl derivative
of 1a was produced. Of the three possible isomers, 3a, 3b and
3c, the acetylation product was identified as 3a by NMR spectra
which revealed three distinct 1H and 13C acetyl resonances.
Of particular interest was the reaction of hydroxyphenyl-
pyrazole 1a with triethyl orthoformate which is a widely used
single-carbon cyclizing reagent. Cyclocondensation was accom-
plished in refluxing orthoformate for 1 h. In another procedure
we employed DMF in which the starting material is relatively
soluble, but the purity and yield of the obtained product 5a
decreased in this solvent. Besides signals arising from the parent
1
molecule the H NMR spectrum of 5a exhibited an additional
sharp low-field singlet (δH 9.71) indicating an N–CH᎐N or
᎐
O–CH᎐N moiety. The corresponding tertiary sp2 carbon was
᎐
identified in the 13C NMR spectrum (APT technique) at
δC 165.7. Selective INEPT measurements revealed a long range
correlation between the above proton and the quaternary
1260
J. Chem. Soc., Perkin Trans. 1, 2002, 1260–1265
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b201529n

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aromatic carbon bearing the oxygen atom. Hence, a ᎐CH–O–
to be simple but it is not compatible with the fact that we have
᎐
Car connectivity is established which implies a cyclisation mode
involving both the phenolic oxygen and a nitrogen atom (“O–
N” mode) in the formation of 5a. Nevertheless, to be consistent
with the results from elemental analysis and HR MS, a CN2H2
fragment must be added to the expected tricyclic skeleton
formed by the condensation. Attachment of the C1 unit at the
exocyclic imine seems logically to lead to guanidine derivative
5a (Scheme 1). These findings are consistent with the low-field
not observed an analogous transfer of this fragment in the
other cyclocondensations. Hence, a different mechanism must
be operative. To envisage the formation of guanidine 5, we
postulate the following mechanism (Scheme 2). The reaction
is assumed to start with a re-esterification of triethyl ortho-
formate with phenolic hydroxys of two equivalents of pyrazol-
ine 1a. The resulting orthoester 9 then undergoes cyclisation
with the vicinal amidine moiety, thus producing an oxadiazoc-
ine skeleton (structure 10). Finally, a nucleophilic attack at the
carbon atom of the other amidine group by the adjacent exo-
cyclic imine nitrogen allows for C1-transfer which is followed by
elimination of the disubstituted pyrazoline unit to yield the
tricyclic derivative 5.
In contrast, the transformation of hydroxyphenylpyrazole
1a with 1,1Ј-carbonyldiimidazole,8 proceeded in a more con-
ventional fashion, as upon treatment in DMF (100 ЊC, 1 h) the
reaction afforded an oxygen-bridged pyrazolotriazole deriv-
ative 11 (Scheme 3). The structure of 11 was easily inferred
from the 13C NMR spectrum which lacked the C-3 resonance
from the educt 1a. Instead, a new signal occurred at δC 88.5
from the hemiaminal C(O)N atom9 which indicated a change in
the pyrazoline ring 3-position. In addition, the CH3–C(O)N–
CH2CH–C6H4 connectivity pattern was deduced from the
INEPT measurements. The presence of the ureido C᎐O and
᎐
imine C᎐N double bonds from the triazoline substructure was
᎐
confirmed by both IR (ν 1707 and 1668 cmϪ1, respectively) and
the 13C NMR spectra (δC 166.1 and 163.8). It is noteworthy
that, to the best of our knowledge, 5,11-methano-3H,11H-
[1,2,4]triazolo[1,2-c][1,3,4] benzoxadiazepine 11 represents a
new tetracyclic bridged system.
Scheme 1
The formation of this novel compound can be rationalized in
terms of a [4 ϩ 1] cyclization, involving the formation of two
nitrogen–carbonyl bonds, and a subsequent O-bridging process.
Presumably, an iminium intermediate 13 is formed from the
imidazolide precursor 12 that might play a crucial role in this
transformation (Scheme 3). Note that 13 is reminiscent of
highly reactive N-acyliminium ions.10 Accordingly, an increased
electrophilicity of the iminium carbon in 13 facilitates the
intramolecular addition of the phenolic hydroxy. The absence
of a direct hydroxy reaction with 1,1Ј-carbonyldiimidazole is
somewhat unexpected, although it is well known that some
substituted phenols are inert toward this reagent.11
quaternary 13C signal whose chemical shift value, δC 166.3,
closely resembles the published data for amidinohydrazones3
and substituted guanidines.4 Furthermore, the spectral pattern
of exchangeable amine protons of the ᎐N–C(᎐NH)NH
᎐
᎐
2
appendage pointed to the presence of three distinct NH signals
that indicated a chemical non-equivalence of primary amine
hydrogens; this could be attributed to an intramolecular hydro-
gen bonding. Accordingly, the terminal NH2 group may be
oriented so as to interact with the near N-6 ring atom whereby
an E configuration at the exocyclic C᎐N double bond is
᎐
expected (see 5). In this context we deduced that of the three
observed NH resonances the relatively narrow, lowest-field
peak (δH 7.96) corresponds to the signal of the H-bridge
proton.
The results of the cyclocondensation studied were further
verified by a reaction of 1a with diethoxymethyl acetate which
proves to be a reactive formate equivalent.5 Under milder con-
ditions (10 min, 80 ЊC, DMF) compound 5a was produced but
in a low yield (Scheme 1). Moreover, a 7-methyl homologue (5b)
was prepared similarly from triethyl orthoacetate (Scheme 1).
Finally, 1,12b-dihydro-5H-pyrazolo[1,5-e][1,3,5]benzoxadiazo-
cine derivatives obtained here represent a hitherto unknown
ring system in the literature.
In order to avoid heterocyclization by the phenolic hydroxy
group, 5-tolylpyrazole 1b was allowed to react with triethyl
orthoformate. Surprisingly, an unusual transformation occur-
red again. Taking into account formation of the lateral guan-
idine function in compound 5, structure of resulted product 6
was readily established as 2-amino-4-(pyrazol-1-yl)-1,3,5-
triazine derivative (Scheme 1). Formation of the product 6 is
analogous to the condensations of amidines with carboxylic
acid derivatives forming unsymmetrical 1,3,5-triazines,6,7
although in our case disubstituted pyrazoline is eliminated
instead of ammonia (Scheme 2). One could presume that a
similar pathway may lead to the compound 5. Nevertheless, this
does not appear to be the case. Formally, tricycle 5 can be
derived from an “O–N” ring closure and a transfer of a
HNCNH moiety onto the imine function. Such a route seems
Heterocyclization with diethyl oxalate afforded an expected
product. When refluxed with an excess of diethyl oxalate,
hydroxyphenylpyrazole 1a gave rise to imidazoledione deriv-
ative 14 as a result of an “N–N” ring closure (Scheme 4) instead
of the “O–N” path which would yield a nine-membered oxa-
diazonine skeleton. Elemental analysis, also indicates a form-
ation of a solvate with 1 mol of dioxane, and absence of any
ethoxy signals in the 1H NMR spectrum confirmed a 1 : 1 con-
densation stoichiometry. Two additional resonances of quater-
nary sp2 carbons between 160–170 ppm were observed by 13C
NMR which are attributable to the amide and ester groups.12
Convincing evidence for structure 14 came from the IR spec-
trum. In the carbonyl region three absorptions were observed:
a medium intense band at 1787 cmϪ1 accompanied by a weaker
one at 1740 cmϪ1, and another strong, broad band at 1618 cmϪ1
.
The former two higher wavenumbers belonging to the lactam
vibrations are in very good agreement with the data reported
by Goerdeler for analogous imidazole-4,5-diones prepared
from N-substituted benzamidines and oxalyl chloride.13
It was also of interest to examine the behaviour of 1a
towards a higher diester homologue, such as diisopropyl
malonate. This heterocyclization proved to be a complex
process leading to compound 15 with an empirical formula
C17H14N4O5. It followed that two malonate acyls were present
in the resulting molecule. This was supported by an EI MS
spectrum that displayed a consecutive loss of two ketene mole-
cules from Mϩ. Although there are a number of theoretical
J. Chem. Soc., Perkin Trans. 1, 2002, 1260–1265
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Scheme 2
Evidently, compound 15 has to originate from precursor 16A
(Scheme 5). This 1 : 1 condensation product may exist in two
tautomeric enol forms 16B and 16C (when we omit a lactam–
lactim tautomerism); either is theoretically capable of a further
reaction with the second equivalent of malonate. Such a process
which forms the pyranone ring can be visualized as a Claisen
type condensation followed by lactonization and proton shift.
It should be stressed that our experimental procedure (DMF,
reflux) contrasts with the basic conditions generally employed
in Claisen condensations.17 Apparently, the “N–N” ring closure
is the decisive factor determining the course of the reaction.
Heterocyclizations of 1a with pentane-2,4-dione, ethoxy-
methylenemalononitrile and diethyl ethoxymethylenemalonate
were also carried out and the products were identified as sub-
stituted pyrazol-2-ylpyrimidines 17, 18 and 19, respectively.
Consistently, reactions of 1a with C3 reagents proceeded
exclusively as “N–N” ring closures forming thus functional-
ized pyrimidine rings. The structures were routinely established
from spectral data. The presence of the pyrimidine skeleton in
molecules 17 and 18 was also proved by comparison of the
one-bond 13C,1H coupling constants with literature values18
reported for ring positions 4 and 5. In the case of product 19,
we propose the formation of a 6-oxopyrimidine-5-carboxylate
rather than a heteroaromatic compound. Indeed, the observed
chemical shifts were compatible with structure 19. Moreover,
NMR spectra predicted by the ACD software19 confirmed this
conclusion.
Scheme 3
Scheme 4
possibilities for the product 15, we have postulated two isomeric
structures 15 and 15Ј that are compatible with the spectral
data and the proposed reaction mechanism (Scheme 5). The
pyranone methine was easily recognized in the NMR spectra at
δH 5.10 and δC 84.0. These chemical shifts closely resemble those
reported for the corresponding 3-position in 4-methoxy-6-
methyl-2H-pyran-2-one (δH 5.44 and δC 87.3).14,15 Moreover, the
1
one-bond 13C, H-coupling constant of 169.7 Hz parallels the
1
published value15 JCH = 172 Hz. A careful comparison of
the observed absorption bands in the range of 1500–1750 cmϪ1
with the detailed IR data reported for similar 2-substituted
5-hydroxy-4,5-dihydro-4H-pyrano[2,3-d]pyrimidine-4,7(3H )-
diones 16 allowed us to establish tautomer 15 as the most prob-
able reaction product.
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Scheme 5
(33), 202 (13), 186 (11), 175 (40), 145 (43), 135 (23), 125 (13), 83
(59), 43 (100) and 42 (13).
Experimental
The melting points (uncorrected) were determined with a
Kofler hot stage microscope. The IR spectra were recorded on a
Nicolet Impact 400 D spectrophotometer. The EI mass spectra
were obtained on a JEOL JMS D-100 (operating at 75 eV)
for 3a, 4, 15, VG 7070E (70 eV) for 5a, 5b, 6, 11, 17–19. The
FAB mass spectrum of 14 was measured on a Finnigan
MAT 95 instrument (Xe, 6 keV, 2 mA). Peak matching with
perfluoro-kerosene as the reference was utilized for accurate
mass measurements by HRMS. Ion elemental compositions are
reported in parentheses with the mass spectra. The NMR spec-
tra were measured on a Bruker AC-400 spectrometer with a
dual 1H/13C probe (400.136 MHz for 1H and 100.614 MHz for
13C) for 5a, Bruker Avance-400 for 5b, 11, 14, 15, 18 and 19 and
Varian VXR-300 (299.943/75.429 MHz) for 3a, 4, 6 and 17.
J values are given in Hz.
1-Acetyl-4,5-dihydro-3-methyl-5-(2-hydroxyphenyl)-1H-pyrazole
4
This compound was obtained as a colourless solid (0.15 g,
46%), mp 176–177 ЊC (from toluene) (Found: C, 65.7; H, 6.3; N,
12.6. C12H14N2O2 requires C, 66.0; H, 6.5; N, 12.8%); νmax(KBr)/
cmϪ1 1643 (CO amide) and 1629 (C᎐N); δH (CDCl3) 2.17 (3 H,
᎐
s, Me), 2.29 (3 H, s, Me amide), 3.00 (1 H, dd, J 18.3 and 3.0,
4-Ha), 3.35 (1 H, dd, J 18.3 and 11.1, 4-Hb), 5.69 (1 H, dd, J 11.1
and 3.0, 5-H), 6.83–6.93 (3 H, m, Har), 7.10–7.26 (1 H, m, Har)
and 9.35 (1 H, br s, OH); δC (CDCl3) 16.1 (Me), 21.4 (Me
amide), 43.9 (CH2-4), 53.3 (CH-5), 118.8 (CHar-3Ј), 120.7
(CHar-5Ј), 125.5 (CHar-6Ј), 127.1 (Car-1Ј), 129.6 (CHar-4Ј), 155.1
(Car-2Ј), 158.6 (C-3) and 169.4 (CON); m/z 218 (C12H14N2O2,
Mϩ, 24%), 175 (C10H11N2O, 56), 145 (C10H9O, 41), 94 (11),
91 (16), 83 (C4H7N2, 100), 77 (23), 51 (22), 43 (52), 42 (28) and
39 (29).
Reaction of 4,5-dihydro-3-methyl-5-(2-hydroxyphenyl)-1H-
pyrazole-1-carboximidamide 1a with acetic anhydride
A suspension of pyrazole 1a (0.33 g, 1.5 mmol) in acetic
anhydride (15 cm3) was stirred for 24 h at room temperature.
The solution was concentrated on a vacuum rotary evaporator,
the syrupy residue was dissolved in ethyl acetate (8 cm3) and
allowed to crystallize. The crystalline material was filtered off
to obtain triacetate 3a. The filtrate was chromatographed on
silica gel using ethyl acetate as an eluent giving pyrazole 4.
Preparation of pyrazole derivative 4 – alternative method
To a solution of 4-(2-hydroxyphenyl)but-3-en-2-one (0.81 g,
5 mmol) in acetic acid (10 cm3) was added hydrazine mono-
hydrate (1.25 cm3, 25 mmol) and the reaction mixture was
refluxed for 1 h. The solvent was evaporated and to the oily
residue cold water was added (30 cm3). The resultant precipitate
was filtered, washed with water and dried. Yield (0.70 g, 64%),
mp 175–177 ЊC. This product was identical in all respects with
acetylpyrazole 4.
2-[1-(N,NЈ-Diacetylcarbamimidoyl)-4,5-dihydro-3-methyl-1H-
pyrazol-5-yl]phenyl acetate 3a
This compound was obtained as colourless needles (0.20 g,
39%), mp 148–150 ЊC (from toluene) (Found: C, 59.5; H, 6.1;
N, 16.1. C17H20N4O4 requires C, 59.3; H, 5.85; N, 16.3%);
N-[(5E )-1,12b-Dihydro-2-methyl-5H-pyrazolo[1,5-e][1,3,5 ]-
benzoxadiazocin-5-ylidene]guanidine 5a
νmax(KBr)/cmϪ1 1751 (COO), 1711 (HN–C᎐O) and 1587
A suspension of pyrazole 1a (0.33 g, 1.5 mmol) in triethyl
orthoformate (30 cm3) was refluxed under stirring for 1 h. After
cooling the reaction mixture was diluted with diethyl ether
(20 cm3) and kept standing overnight. The precipitated product
was filtered, washed with ether and dried. The title compound
was obtained as a white powder (0.15 g, 74%), mp 280–282 ЊC
(from methanol) (Found: C, 57.5; H, 5.0; N, 30.8. C13H14N6O
requires C, 57.8; H, 5.2; N, 31.1%); νmax(KBr)/cmϪ1 3328 and
᎐
(᎐NCO/C᎐N); δ [(CD ) SO] 1.77 (3 H, s, Me amide), 1.97 (3 H,
᎐
᎐
H
3 2
s, Me amide), 2.02 (3 H, s, Me), 2.32 (3 H, s, Me ester), 2.56
(1 H, dd, J 18.5 and 5.9, 4-Ha), 3.49 (1 H, dd, J 18.5 and 12.2,
4-Hb), 5.48 (1 H, dd, J 12.2 and 5.9, 5-H), 7.11–7.35 (4 H, m,
Har) and 10.27 (1 H, s, NH); δC [(CD3)2SO] 15.5 (Me), 20.7
(Me ester), 23.6 (Me–CONH), 26.3 (Me–CON᎐), 45.1 (CH -4),
᎐
2
55.7 (CH-5), 122.9 (CHar-3Ј), 126.1, 126.2 (CHar-4Ј/CHar-5Ј),
128.2 (CHar-6Ј), 133.8 (Car-1Ј), 141.5, 147.4, 157.2
3178 (NH , NH), 1662 and 1568 (C᎐N), 1485 and 1459;
᎐
2
(C-3/C -2Ј/N–C᎐N), 168.3 (CONH), 169.0 (CO ester) and
δH [(CD3)2SO] 1.98 (3 H, s, Me), 2.51 (1 H, dd, J 18.0 and 3.4,
1-Ha), 3.44 (1 H, ddd, J 18.0, 11.4 and 1.1, 1-Hb), 5.61 (1 H, dd,
J 11.4 and 3.4, 12b-H), 6.70 (2 H, m, 11-H ϩ 12-H), 6.82 (1 H,
᎐
ar
180.0 (CON᎐); m/z 344 (Mϩ, 0.5%), 329 (C H N O , 5), 303
᎐
16 17
4
4
(C15H17N3O4, 12), 287 (14), 261 (12), 260 (C13H14N3O3, 12), 218
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d, J 7.9, 9-H), 6.84 (1 H, br s, NH), 7.03 (1 H, ddd, J 8.0, 5.7
and 3.2, 10-H), 7.04 (1 H, br s, NH), 7.96 (1 H, br s, NH) and
10-H); δC [(CD3)2SO] 21.1 (Me), 40.4 (CH2), 54.8 (CH), 88.4
(C-5), 114.9 (CH-7), 119.6 (CH-9), 120.6 (C-10a), 127.6, 129.40
9.71 (1 H, s, 7-HC᎐); δ [(CD ) SO] 15.8 (Me), 44.7 (CH ), 56.0
(CH-8/CH-10), 152.3 (C-6a), 163.8 and 166.1 (C᎐N/C᎐O);
᎐
᎐ ᎐
C
3
2
2
(CH), 115.5 (CH-9), 118.8 (CH-1), 124.8 (CH-10), 124.9 (CH-
12), 128.4 (C-12a), 153.8 (C-8a), 156.7 (C-2), 161.2 (C-5), 165.7
(O–CH᎐N) and 166.3 (HN᎐C–NH ); m/z 271 (Mϩ ϩ 1, 7%),
m/z 244 (Mϩ, 5%), 201 (9), 175 (5), 160 (6), 146 (20), 145 (100),
144 (50), 131 (35), 115 (62), 100 (46), 91 (17), 73 (18), 63 (22),
57 (25), 51 (28) and 43 (67).
᎐
᎐
2
270 (C13H14N6O, Mϩ, 41), 269 (4), 229 (8), 228 (C11H10N5O, 24),
212 (7), 177 (C7H9N6, 64), 146 (9), 145 (C10H9O, 100), 126 (9),
118 (6), 111 (17), 109 (11), 96 (10), 91 (11), 83 (14), 77 (9), 68
(16), 65 (7), 63 (6), 51 (7), 43 (32), 42 (16) and 41 (8).
2-[4,5-Dihydro-5-(2-hydroxyphenyl)-3-methyl-1H-pyrazol-1-yl]-
1H-imidazole-4,5-dione 14
A suspension of pyrazole 1a (0.33 g, 1.5 mmol) in diethyl
oxalate (50 cm3) was refluxed under stirring for 1 h. Volatile
components were removed on the vacuum rotary evaporator
and the oily rest was triturated with dioxane. The crystalline
solid was filtered and washed with ether (0.21 g, 39%), mp 170–
171 ЊC (from dioxane) (Found: C, 56.9; H, 5.3; N, 15.8.
C13H12N4O3ؒdioxane requires C, 56.6; H, 5.6; N, 15.55%);
νmax(KBr)/cmϪ1 3433 (NH), 1787 (COO), 1740 (CO), 1618
(CON) and 1444; δH [(CD3)2CO] 2.28 (3 H, s, Me), 3.25 (1 H,
dd, J 18.6 and 3.7, 4-Ha), 3.59 (8 H, br s, dioxane), 3.78 (1 H,
ddd, J 18.6, 11.0 and 1.0, 4-Hb), 5.85 (1 H, dd, J 11.0 and 3.7,
5-H), 6.86 (1 H, ddd, J 7.8, 7.2 and 1.2, 5Ј-H), 6.98 (1 H, dd,
J 8.1 and 1.2, 3Ј-H), 7.13 (1 H, dd, J 7.8 and 1.6, 6Ј-H), 7.17
(1 H, ddd, J 8.1, 7.2 and 1.6, 4Ј-H), 9.82 (1 H, br s, OH/NH)
and 10.93 (1 H, br s, NH/OH); δC [(CD3)2CO] 16.1 (Me), 45.7
(CH2), 57.8 (CH), 67.7 (CH2 dioxane), 119.1 (CH-3Ј), 121.3
(CH-5Ј), 127.3 (C-1Ј), 127.8 (CH-6Ј), 130.6 (CH-4Ј), 155.9
N-[(5E )-1,12b-Dihydro-2,7-dimethyl-5H-pyrazolo[1,5-e][1,3,5]-
benzoxadiazocin-5-ylidene]guanidine 5b
This compound was prepared analogously from 1a and triethyl
orthoacetate, as a colourless solid (0.11 g, 52%), mp 312–313 ЊC
(from DMF) (Found: C, 59.4; H, 5.8; N, 29.5. C14H16N6O
requires C, 59.1; H, 5.7; N, 29.6%); νmax(KBr)/cmϪ1 3490 and
3299 (NH , NH), 1642 and 1568 (C᎐N), 1537 and 1458;
᎐
2
δH [(CD3)2SO] 1.99 (3 H, s, Me-2), 2.07 (3 H, s, Me-7), 2.57 (1 H,
dd, J 17.8 and 3.4, 1-Ha), 3.42 (1 H, dd, J 17.8 and 11.2, 1-Hb),
5.62 (1 H, dd, J 11.2 and 3.4, 12b-H), 6.68 (1 H, dd, J 7.4 and
7.2, 11-H), 6.74 (1 H, d, J 7.4, 12-H), 6.83 (1 H, d, J 8.0, 9-H),
6.85 (2 H, br s, NH2), 7.04 (1 H, dd, J 8.0 and 7.2, 10-H) and
9.85 (1 H, s, NH); δC [(CD3)2SO] 15.7 (Me-2), 24.8 (Me-7), 44.5
(CH2), 55.8 (CH), 115.8 (CH-9), 118.9 (CH-11), 125.4 (CH-12),
127.9 (CH-10), 128.4 (C-12a), 154.0 (C-8a), 156.3 (C-2), 161.8
(C-5), 166.6 (HN–C᎐NH ) and 174.3 (C-7); accurate mass:
284.1389, C14H16N6O requires 284.1385.
(C-2Ј), 162.1, 163.8, 167.8 and 168.6 (C᎐N/C᎐N/CO/CO);
᎐ ᎐
᎐
2
m/z(FAB) 273 (M ϩ H)ϩ.
2-Amino-4-[4,5-dihydro-3-methyl-5-(4-methylphenyl)-1H-
pyrazol-1-yl]-1,3,5-triazine 6
5-Hydroxy-2-[4,5-dihydro-5-(2-hydroxyphenyl)-3-methyl-1H-
pyrazol-1-yl]-4H-pyrano[2,3-d]pyrimidine-4,7(3H)-dione 15
A suspension of 4,5-dihydro-3-methyl-5-(4-methylphenyl)-1H-
pyrazole-1-carboximidamide acetate 1b (0.44 g, 1.6 mmol) in
triethyl orthoformate (20 cm3) was refluxed under stirring for
1 h. Evaporation of the solvent gave an oily residue which was
triturated with ether. The solid obtained was collected and
recrystallized from ethanol. This compound was obtained as
colourless crystals (0.14 g, 65%), mp 241–243 ЊC (from
EtOH) (Found: C, 62.5; H, 6.1; N, 31.2. C14H16N6 requires C,
62.7; H, 6.0; N, 31.3%); νmax(KBr)/cmϪ1 3365 and 3311 (NH2,
A suspension of pyrazole 1a (0.33 g, 1.5 mmol) and diisopropyl
malonate (4 cm3) in DMF (20 cm3) was refluxed under stirring
for 1 h. The solution was concentrated under reduced pressure
to give a semisolid. After trituration with ethanol the resultant
precipitate was filtered and thoroughly washed with ethanol
and then with ether. The title compound was obtained as a
colourless powder (0.15 g, 28%), mp 340–341 ЊC (decomp.)
(from DMF) (Found: C, 57.9; H, 4.0; N, 16.0. C17H14N4O5
requires C, 57.6; H, 4.0; N, 15.8%); νmax(KBr)/cmϪ1 3273 (OH),
NH), 1644, 1631 and 1587 (C᎐N), 1558, 1536 and 1463;
3104 (NH), 1717 (COO), 1667 (CON), 1626 (C᎐N), 1592 (C᎐C)
᎐
᎐ ᎐
δH [(CD3)2SO] 2.01 (3 H, s, Me), 2.24 (3 H, s, Me–Tol), 2.59
(1 H, dd, J 18.3 and 3.6, 4-Ha), 3.47 (1 H, dd, J 18.3 and 11.4,
4-Hb), 5.47 (1 H, dd, J 11.4 and 3.6, 5-H), 6.91 (2 H, br s, NH2),
7.00 (2 H, AAЈ part of AAЈBBЈ, J 8.1, 3Ј-H ϩ 5Ј-H), 7.09 (2 H,
BBЈ part, J 8.1, 2Ј-H ϩ 6Ј-H) and 7.94 (1 H, s, triazine 6-H);
δC [(CD3)2SO] 15.8 (Me), 20.6 (Me–Tol), 45.8 (CH2), 59.9 (CH),
125.3 (CH-2Ј ϩ CH-6Ј), 129.1 (CH-3Ј ϩ CH-5Ј), 136.0 (C-4Ј),
140.1 (C-1Ј), 155.9 (C-3), 161.3 (triazine C-4), 165.7 (triazine
CH-6) and 166.2 (triazine C-2); m/z 268 (Mϩ, 11%), 228 (11),
227 (74), 226 (100), 186 (12), 177 (6), 158 (7), 136 (5), 129 (5),
118 (17), 117 (11), 110 (7), 96 (13), 83 (11), 77 (6), 68 (10), 65 (6),
54 (4), 43 (18), 42 (8) and 39 (6).
and 1556; δH [(CD3)2SO] 2.12 (3 H, s, Me), 2.76 (1 H, dd, J 18.6
and 4.2, pyrazole 4-Ha), 3.60 (1 H, dd, J 18.6 and 11.3, pyrazole
4-Hb), 5.10 (1 H, s, 6-H), 5.65 (1 H, dd, J 11.3 and 4.2, pyrazole
5-H), 6.73 (1 H, t, J 7.1, 5Ј-H), 6.84–6.87 (2 H, m, 3Ј-H ϩ 6Ј-H),
7.09 (1 H, t, J 8.3, 4Ј-H), 9.78, 11.93 and 12.33 (3 × 1 H, s,
NH/NH/OH); δC [(CD3)2SO] 15.6 (Me), 45.4 (pyrazole CH2),
1
57.5 (pyrazole CH), 84.0 (᎐CH-6, JCH 169.7), 87.4 (C-4a),
᎐
115.5 (CH-3Ј), 118.9 (CH-5Ј), 126.0 (CH-4Ј), 126.5 (C-1Ј),
128.4 (CH-6), 153.9 (C-2Ј), 149.4, 160.7, 162.5, 164.2, 166.2
and 169.5 (pyrazole C᎐N/C-4/C-5/C-7/C-8a/C-2); m/z 354
᎐
(C17H14N4O5, Mϩ, 33%), 312 (8, C15H12N4O4), 271 (6), 270
(6, C13H10N4O3), 261 (4), 254 (3), 229 (6), 219 (5), 193 (4), 145
(C10H9O, 100), 118 (14), 94 (4), 91 (13) and 69 (25).
(5R*,11R*)-1-Amino-5-methyl-5,11-methano-3H,11H- [1,2,4]-
triazolo[1,2-c][1,3,4]benzoxadiazepin-3-one 11
4,6-Dimethyl-2-[4,5-dihydro-5-(2-hydroxyphenyl)-3-methyl-1H-
pyrazol-1-yl]pyrimidine 17
A solution of pyrazole 1a (0.66 g, 3.0 mmol) and 1,1Ј-
carbonyldiimidazole (0.56 g, 3.4 mmol) in DMF (40 cm3) was
heated at 100 ЊC for 1 h with stirring. On cooling precipitated
product was filtered and washed with ether. The title compound
was obtained as a colourless solid (0.55 g, 75%), mp 259–260 ЊC
(from DMF) (Found: C, 59.3; H, 5.2; N, 23.2. C12H12N4O2
requires C, 59.0; H, 4.95; N, 22.9%); νmax(KBr)/cmϪ1 3246
A suspension of pyrazole 1a (0.33 g, 1.5 mmol) and pentane-
2,4-dione (2 cm3) in DMF (20 cm3) was refluxed under stirring
for 1 h. After removal of the solvent the oily residue was tritur-
ated with ethanol. Crystalline product was filtered off and
washed with ether. This compound was obtained as colourless
crystals (0.31 g, 73%), mp 281–283 ЊC (from DMF) (Found:
C, 67.9; H, 6.6; N, 20.0. C16H18N4O requires C, 68.1; H, 6.4;
(NH), 1707 (C᎐O), 1668 (C᎐N) and 1560; δ [(CD3)2SO] 1.90
᎐
᎐
H
(3 H, s, Me), 2.50 (1 H, d, J 12.0, 13-Ha), 2.86 (1 H, dd, J 12.0
and 4.7, 13-Hb), 5.04 (1 H, d, J 4.7 Hz, 11-H), 6.78 (1 H, d,
J 8.2, 7-H), 6.86 (1 H, dd, J 7.3 and 7.2, 9-H), 7.19 (1 H, dd,
J 8.2 and 7.2, 8-H), 7.26 (2 H, br s, NH2) and 7.28 (1 H, d, J 7.3,
N, 19.8%); νmax(KBr)/cmϪ1 3245 (OH), 1583 and 1560 (C᎐N,
᎐
C᎐C), 1482, 1458 and 1377; δH (CDCl3) 2.28 (3 H, s, Me), 2.40
᎐
(6 H, s, Me-2 ϩ Me-4), 3.13 (1 H, dd, J 18.5 and 3.7, pyrazole
4-Ha), 3.48 (1 H, ddd, J 18.5, 11.7 and 1.3, pyrazole 4-Hb), 5.75
1264
J. Chem. Soc., Perkin Trans. 1, 2002, 1260–1265

View Article Online
(1 H, dd, J 11.7 and 3.7, pyrazole 5-H), 6.39 (1 H, s, pyrimidine
5-H), 6.88 (1 H, ddd, J 7.8, 7.1 and 1.4, 5Ј-H), 6.97 (1 H, dd,
J 8.2 and 1.3, 3Ј-H), 7.10 (1 H, dd, J 7.8 and 1.7, 6Ј-H), 7.19
(1 H, ddd, J 8.2, 7.1 and 1.7, 4Ј-H) and 9.95 (1 H, br s, OH);
δC (CDCl3) 16.3 (Me), 23.7 (Me-4 ϩ Me-6), 44.9 (pyrazole
δH [(CD3)2SO] 1.19 (3 H, t, Me ester), 2.08 (3 H, s, Me), 2.71
(1 H, dd, J 18.4 and 4.2, pyrazole 4-Ha), 3.58 (1 H, dd, J 18.4
and 11.3, pyrazole 4-Hb), 4.11 (2 H, q, CH2 ester), 5.66 (1 H, dd,
J 11.3 and 4.2, pyrazole 5-H), 6.71 (1 H, dd, J 7.6 and 7.3,
5Ј-H), 6.79 (1 H, dd, J 7.6 and 1.6, 6Ј-H), 6.84 (1 H, d, J 7.9,
3Ј-H), 7.07 (1 H, ddd, J 7.9, 7.3 and 1.6, 4Ј-H), 8.23 (1 H, s,
pyrimidine 4-H), 9.74 (1 H, s, OH) and 10.98 (1 H, s, NH);
δC [(CD3)2SO] 14.2 (Me ester), 15.7 (Me), 45.5 (pyrazole CH2),
56.8 (pyrazole CH), 59.2 (CH2 ester), 104.9 (pyrimidine C-5),
115.5 (CH-3Ј), 118.9 (CH-5Ј), 125.5 (CH-6Ј), 127.1 (C-1Ј),
128.2 (CH-4Ј), 153.8 (C-2Ј), 152.1, 158.2 (pyrimidine C-2/C-6),
161.3 (pyrazole C-3), 161.8 (pyrimidine CH-4) and 163.8
(COO); accurate mass: 342.1324, C17H18N4O4 requires 342.1328.
1
CH2), 54.3 (pyrazole CH), 110.9 (pyrimidine CH-5, J 163.2),
119.0 (CH-3Ј), 121.2 (CH-5Ј), 127.1 (CH-6Ј), 128.8 (C-1Ј),
129.6 (CH-4Ј), 155.2 (C-2Ј), 155.7 (pyrazole C-3), 156.8
(pyrimidine C-2) and 168.0 (pyrimidine C-4 ϩ C-6); m/z 283
(Mϩ ϩ 1, 8%), 282 (Mϩ, 44), 281 (11), 265 (6), 241 (11), 240
(62), 190 (13), 189 (100), 163 (8), 146 (12), 145 (85), 123 (19),
107 (15), 91 (9), 67 (25), 42 (17) and 39 (12).
4-Amino-2-[4,5-dihydro-5-(2-hydroxyphenyl)-3-methyl-1H-
pyrazol-1-yl]pyrimidine-5-carbonitrile 18
Acknowledgements
A
suspension of pyrazole 1a (0.33 g, 1.5 mmol) and
This work was supported by the Grant Agency of the Slovak
Republic (# 1/8215/01). The authors wish to thank Dr V. Hanus
of the Heyrovsky Institute of Physical Chemistry, Prague, for
measuring the mass spectra.
ethoxymethylenemalononitrile (0.21 g, 1.7 mmol) in DMF
(20 cm3), was refluxed under stirring for 1 h. After evaporation
of the solvent the oily residue was dissolved in ethanol (5 cm3)
and allowed to crystallize at room temperature. The resultant
precipitate was filtered and washed with ethyl acetate. This
compound was obtained as colourless crystals (0.21 g, 40%),
mp 314–316 ЊC (from MeOH) (Found: C, 61.2; H, 4.7; N, 28.3.
C15H14N6O requires C, 61.2; H, 4.8; N, 28.55%); νmax(KBr)/cmϪ1
References
1 J. Svetlik, J. Heterocycl. Chem., in the press.
3456, 3350, 3238 (OH, NH ), 2208 (CN), 1631 (C᎐N), 1587
2 S. G. Beech, J. H. Turnbull and W. Wilson, J. Chem. Soc., 1952, 4686.
3 Z. Gyorgydeak, W. Holzer and K. Mereiter, Monatsh. Chem., 1999,
130, 899.
᎐
2
(C᎐N, C᎐C), 1537, 1522 and 1460; δ [(CD3)2SO] 1.99 (3 H, s,
᎐
᎐
H
Me), 2.54 (1 H, dd, J 18.0 and 3.1, pyrazole 4-Ha), 3.46 (1 H,
dd, J 18.0 and 11.2, pyrazole 4-Hb), 5.68 (1 H, dd, J 11.2 and
3.1, pyrazole 5-H), 6.60–6.70 (2 H, m, 5Ј-H ϩ 6Ј-H), 6.82 (1 H,
d, J 8.0, 3Ј-H), 7.02 (1 H, ddd, J 8.0, 6.6 and 1.5, 4Ј-H), 7.37
(2 H, s, NH2), 8.18 (1 H, s, pyrimidine 6-H) and 9.64 (1 H,
s, OH); δC [(CD3)2SO] 15.7 (Me), 44.8 (pyrazole CH2), 56.6
(pyrazole CH), 79.6 (pyrimidine C-5), 115.4 (CH-3Ј), 117.0
(CN), 118.7 (CH-5Ј), 125.0 (CH-6Ј), 127.7 (CH-4Ј), 128.4
(C-1Ј), 153.8 (C-2Ј), 157.2 (pyrazole C-3), 157.7 (pyrimidine
C-2), 162.9 (pyrimidine C-4, 3J 5.3) and 161.8 (pyrimidine
4 H.-O. Kalinowski, S. Berger and S. Braun, 13C-NMR-Spektroskopie,
Thieme Verlag, Stuttgart, 1983, p. 223.
5 E. C. Taylor, S. R. Fletcher, C. McCarthy, V. Cody and R. J.
Kempton, J. Org. Chem., 1988, 53, 6118.
6 J. M. E. Quirke, in Comprehensive Heterocyclic Chemistry, ed.
A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford, 1985,
vol. 3, p. 512.
7 H. Bredereck, F. Effenberger and A. Hofmann, Chem. Ber., 1963,
96, 3265.
8 L. A. Paquette, Encyclopedia of Reagents for Organic Synthesis,
Wiley, Chichester, 1995, p. 1006.
9 J. Svetlik, T. Liptaj and F. Turecek, J. Heterocycl. Chem., 1999, 36,
209.
10 W. N. Speckamp and H. Hiemstra, Tetrahedron, 1985, 41, 4367.
11 M. Ogata, H. Matsumoto, S. Kida and S. Shimizu, Tetrahedron
Lett., 1979, 5011.
1
CH-6, J 182.5); accurate mass: 294.1232, C15H14N6O requires
294.1229.
Ethyl 1,6-dihydro-2-[4,5-dihydro-5-(2-hydroxyphenyl)-3-methyl-
1H-pyrazol-1-yl]-6-oxopyrimidine-5-carboxylate 19
12 H.-O. Kalinowski, S. Berger and S. Braun, 13C-NMR-Spektroskopie,
Thieme Verlag, Stuttgart, 1983, p. 183 and 189.
13 J. Goerdeler and R. Sappelt, Chem. Ber., 1967, 100, 2064.
14 P. Beak and H. Abelson, J. Org. Chem., 1962, 27, 3715.
15 W. V. Turner and W. H. Pirkle, J. Org. Chem., 1974, 39, 1935.
16 N. S. Habib and T. Kappe, Monatsh. Chem., 1984, 115, 1459.
17 J. March, Advanced Organic Chemistry, Wiley, New York, 4th edn.,
1992, p. 491.
A suspension of pyrazole 1a (0.33 g, 1.5 mmol) and 3 cm3
diethyl ethoxymethylenemalonate in DMF (20 cm3) was
refluxed under stirring for 1 h. After evaporation of the solvent
the syrupy residue was dissolved in ethyl acetate (6 cm3) and the
solution was refrigerated. The precipitate was filtered off and
washed with cold ethyl acetate. This compound was obtained as
colourless crystals (0.30 g, 58%), mp 240–242 ЊC (from
MeCN) (Found: C, 59.65; H, 5.3; N, 16.2. C17H18N4O4 requires
C, 59.6; H, 5.3; N, 16.4%); νmax(KBr)/cmϪ1 3248 (OH, NH),
1736 (COO), 1678, 1662 (CON) and 1589 (C᎐N, C᎐C);
18 H.-O. Kalinowski, S. Berger and S. Braun, 13C-NMR-Spektroskopie,
Thieme Verlag, Stuttgart, 1983, p. 455.
19 ACD/HNMR, ACD/CNMR Predictor, Vers. 4.6, Advanced
Chemistry Development, Toronto, 2000. All details are available
on: http://www.acdlabs.com
᎐
᎐
J. Chem. Soc., Perkin Trans. 1, 2002, 1260–1265
1265