Diversity-oriented Multicomponent Heterocyclizations Involving Derivatives of 3(5)-Aminoisoxazole, Aldehydes and Meldrum's or N,N′-Dimethylbarbituric Acid

Article abstract of DOI:10.1002/jhet.2656

5-Amino-3-methylisoxazole and 3-amino-5-methylisoxazole were studied in details in the multicomponent heterocyclizations with aromatic aldehydes and Meldrum's or N,N′-dimethylbarbituric acid with help of classical and non-classical (microwave and ultrasonic irradiation) activation methods.

Full text of DOI:10.1002/jhet.2656

Month 2016
Diversity-oriented Multicomponent Heterocyclizations Involving
Derivatives of 3(5)-Aminoisoxazole, Aldehydes and Meldrum’s or
N,N′-Dimethylbarbituric Acid
Alisa D. Morozova,a Elena A. Muravyova,a Svitlana V. Shishkina,a,b Elena V. Vashchenko,a Yulia V. Sen’ko,a and
Valentin A. Chebanova,b
*
aState Scientific Institution “Institute for Single Crystals” of National Academy of Sciences of Ukraine, Nauky Ave.
60, 61072 Kharkiv, Ukraine
bChemistry Faculty, Karazin Kharkiv National University, Svobody sq. 4, 61022 Kharkiv, Ukraine
*
E-mail: chebanov@isc.kharkov.com
Received December 12, 2015
DOI 10.1002/jhet.2656
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
5-Amino-3-methylisoxazole and 3-amino-5-methylisoxazole were studied in details in the multicompo-
nent heterocyclizations with aromatic aldehydes and Meldrum’s or N,N′-dimethylbarbituric acid with help
of classical and non-classical (microwave and ultrasonic irradiation) activation methods.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
Multicomponent reactions of aminoazoles and carbonyl
compounds with Meldrum’s acid are of interest because
of the possibility of their proceeding in several alternative
directions as well [8,9]. For example, in case of 5-amino-
3-methylisoxazole under microwave irradiation the forma-
tion of two heterocyclic systems IX [14] and X [10] was
observed (Fig. 2). However, it should be noted that the
reason of change in the direction of the treatment from
spiro-compounds towards isoxazolodihydropyridone under
the very similar conditions is not clear. Indeed, our
attempts to reproduce the described procedures [10,14]
led either to the mixture of compounds IX and X or to sole
spiro-heterocycle IX in lower yields in comparison with
the literature data.
N,N′-Dimethylbarbituric acid likewise Meldrum’s acid
may also acts as C1 synthon in the formation of
spiroisoxazolopyridines under microwave irradiation [15].
On the other hand, multicomponent reactions involving
isomeric 3-amino-5-methylisoxazole, to the best of our
knowledge, are not adequately explored. Its reactivity has
been only described in synthesis of pyrrolones [17], in
Hantzsch [18] and Betti [19] reactions, and in four-component
reactions for construction of imidazole moiety [20].
Isoxazole scaffold plays an important role in drug devel-
oping for search of substances having high biological ac-
tivity, for example, antiproliferative [1], analgesic [2],
and antipsychotic actions [3]. Molecular drug targets in-
clude muscarinic receptors M1 and M2 [4], dopamine D2,
serotonin 5-HT2A and 5-HT2C [3], β-adrenergic receptors
of all subtypes [5], and voltage-gated sodium channels
[6]. The role of isoxazole moiety is various: from the de-
veloping of conformational rigid systems [3] to the en-
hancement of affinity of a drug for a receptor [4]. The
wide variety of molecular drug targets for isoxazole deriv-
atives, as well as diversity of problems solved with the help
of such compounds, determines the high interest to them.
Multicomponent reactions are proved as fast and efficient
method for the formation of azoloazine systems [7–9]. The
application of multicomponent approach allows obtaining
arrays of compounds with high diversity because of the var-
iation of substituents, skeleton and stereochemistry. Similar
to other aminoazoles, 5-amino-3-methylisoxazole in most
cases reacts as 1,3-binucleophile in such reactions: the ac-
tive sites of the molecule are exocyclic amino group and
methine carbon atom. For instance, there are literature data
on the formation of different structures like I–VIII based on
the treatment of 5-amino-3-methylisoxazole, aromatic alde-
hydes, and non-cyclic or cyclic active methylene com-
pounds under different conditions (Fig. 1) [10–16].
Therefore, the main goal of the present work was to study
in details the multicomponent reactions of 5-amino-
3-methylisoxazole and 3-amino-5-methylisoxazole with aro-
matic aldehydes and Meldrum’s or N,N′-dimethylbarbituric
acid, to develop simple and reproducible synthetic
© 2016 Wiley Periodicals, Inc.

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A. D. Morozova, E. A. Muravyova, S. V. Shishkina, E. V. Vashchenko,
Y. V. Sen'ko, and V. A. Chebanov
Figure 1. Several examples of multicomponent reactions involving 5-amino-3-methylisoxazole.
procedures for obtaining the target heterocyclic compounds
with help of classical and non-classical activation methods.
Additional task was to compare the reactivity of both
aminoisoxazoles under identical conditions.
[21], the treatment of the starting compounds using both ultra-
sonic bath and ultrasonic horn was studied as well. As a result
of flask immersion in ultrasonic bath the reaction’s time re-
duced in three times (24h), while application of the ultrasonic
horn allowed to obtain the target heterocycles 4 in 15–120 min
depending on aldehyde 2. Compound 4 contains two moieties
of the aldehyde component; therefore, an appropriate excess
of this reagent was used allowing yields within 54–76%.
Spiro-compound 4 may be also synthesized by conver-
gent scheme: two-component reaction between preliminary
obtained arylidene derivative of Meldrum’s acid 9a and
azomethine 10 resulted in the formation of heterocycle 4c
in 79% yield (Scheme 2). Furthermore, substance 4c was
obtained by ultrasonication in EtOH the mixtures of
azomethine 10 and Meldrum’s acid 3 or 5-amino-3-
methynisoxazole 1 and arylidene derivative 9a in 28%
and 20% yields, respectively.
RESULTS AND DISCUSSION
It was found that the multicomponent reaction between
5-amino-3-methylisoxazole 1, aromatic aldehyde 2, and
Meldrum’s acid 3 (Scheme 1) in ethanol under stirring
for a long time (72 h) at 25°C resulted in the formation of
4,6-diaryl-2′,2′,3-trimethyl-6,7-dihydro-4H-spiro
[isoxazolo[5,4-b]pyridine-5,5′-[1,3]dioxane]-4′,6′-dione 4
in 34–46% yields.
Because ultrasonic-promoted procedure may considerably
increase efficiency of the reaction and reduce reaction’s time
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Multicomponent Heterocyclizations Involving Derivatives of 3(5)-Aminoisoxazole
Figure 2. Switching the multicomponent reaction involving 5-amino-3-methylisoxazole, aldehyde, and Meldrum’s acid.
Scheme 1. Switching the three-component reaction involving 5-amino-3-methylisoxazole, aromatic aldehydes and Meldrum’s acid.
The foregoing multicomponent method allowed to ob-
tain spirofused compounds with the same substituents in
positions 4 and 6 of isoxazolopyridine ring. However, an
introduction of two different fragments of aldehyde in such
way is impossible. To solve this matter the modified version
of the abovementioned three-component reactions were ap-
plied. It was established that the treatment of unsaturated
carbonyl compounds 9a,b with 5-amino-3-methylisoxazole
1 and aldehydes 2b,c led selectively to compounds 4g,h as
the mixture of two diastereomers (Scheme 2). In contrast,
the cyclization between azomethine 10, aldehyde 2b,c,
and Meldrum’s acid 3 under ultrasonication at r.t. in EtOH
resulted in decomposition of azomethine into the initial
compounds and in the formation of the mixture of several
spiro-compounds with random presence of aldehyde
substituents.
the mixture of substances 4 and 5. Similar results were
observed when the starting reagents were fused in few
drops of DMF [9,22] (Entry 3). Therefore, this multicom-
ponent heterocyclization was studied in details in order to
direct it towards selective obtaining compounds 5.
Entries 4, 5 (Table 1) show the synthesis of the target
isoxazolopyridinones 5 under refluxing in DMF or
n-butanol in 28–29% yields. The disadvantage of DMF
medium was the fast blackening of the mixture, while
using of n-butanol allowed to isolate pure substance after
recrystallization of solid residue from EtOH. Analysis of
NMR spectra of dry rest of mother liquor indicated the
presence of substance 5 as the main reaction product; no
any individual compound in amount more than 5% was
additionally observed.
The application of microwave (MW) irradiation often
allows to optimize the reaction conditions and to obtain
target compounds in higher yields [12,23–30]. Frequently
water and ethanol [31] serve as solvents in the
microwave-assisted synthesis because of their usability
On the other hand, the application of thermal heating
caused changing the multicomponent process’ behavior:
refluxing the starting materials 1, 2, and 3 in methanol
(Scheme 2, Table 1, Entry 1) or ethanol (Entry 2) yielded
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A. D. Morozova, E. A. Muravyova, S. V. Shishkina, E. V. Vashchenko,
Y. V. Sen'ko, and V. A. Chebanov
Scheme 2. Other pathways for synthesis of the compound 4.
and ecological compatibility. These media allow a quick
heating of the initial compounds to a predetermined tem-
peratures, which enables to avoid by-reactions. Proceeding
the reaction studied in aqua medium under MW-irradiation
at different temperatures (Entries 6–9) yielded the mixtures
of heterocycles 4 and 5 or 5 and unusual compound 6
(Scheme 2). Substance 6 was isolated with the help of sil-
ica column chromatography eluted with CH2Cl2. It is inter-
esting that melting point and 1H NMR spectra for the
compound 6 were very different from the data published
earlier in the literature [32,33].
MW-irradiation under higher temperature led to the lower-
ing yield of compound 5c (Entry 13).
Low yields of isoxazolodihydropyridone 5 may be con-
nected with thermal decay of either starting substances or
intermediates; therefore, multicomponent schemes with
excess of one reagent (1 or 3) and convergent pathways
were tried out. However, carrying out the reaction with
the double excess of aminoisoxazole 1 in BuOH led to
the mixture of compounds 5c, 7, and 8 (Entry 14). The
presence of the substances 7, 8 was established without
1
their isolation by the analysis of H NMR data. Mean-
Our attempts to synthesize compound 6 in individual state
were unsuccessful: the reaction between 5-amino-
3-methylisoxazole and aldehyde 2c in water under
MW-irradiation for 10min at 150°C gave azomethine 9 in
trace amounts with no admixture of compound 6. The same
results were observed when the reaction was carried out in
the presence of catalytic amounts of HCl or Meldrum’s acid.
Replacement of aqua medium with EtOH gave single
compound 5 under 120°C or 150°C in low yields (Entries
11, 12), while proceeding the reaction under 100°C led
again to the mixture of compounds 4 and 5 (Entry 10).
Despite the fact that this reaction in boiled BuOH allowed
to form substances 5 in moderate outcome, application the
while, proceeding the reaction with the twofold excess
of the Meldrum’s acid 3 increased the yields of 5 to
53–66% (Entries 15–20).
Supplementary research of microwave irradiation’s in-
fluence on the reaction with twofold excess of Meldrum’s
acid in water gave the mixture of substances 4c and 5c
(Entry 21) or 5c and 6 with trace amounts of 4c (Entry
22) depending on the reaction’s temperature. Application
of the MW-irradiation in BuOH under different tempera-
tures resulted in mixture of 4c and 5c under 80°C (Entry
23) and pure compound 5c under higher temperatures
(Entries 24–26). The best yield was observed at 100°C
and 15min of irradiation (Entries 27, 28). However, the
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Multicomponent Heterocyclizations Involving Derivatives of 3(5)-Aminoisoxazole
Table 1
Optimization of the conditions for obtaining 4-aryl-3-methyl-4,7-dihydroisoxazolo[5,4-b]pyridin-6(5H)-one 5.
Yielda, %
Entry
Aldehyde and R
Ratio 1:2:3
Conditions
Solvent
Time, min
4
5
1
2
3
4
5
6
7
8
2c OCH3
2c OCH3
2c OCH3
2c OCH3
2c OCH3
2d Cl
2c OCH3
2c OCH3
2c OCH3
2c OCH3
2c OCH3
2c OCH3
2c OCH3
2c OCH3
2a H
2b CH3
2c OCH3
2d Cl
2e COOCH3
2f NO2
2c OCH3
2c OCH3
2c OCH3
2c OCH3
2c OCH3
2c OCH3
2c OCH3
2c OCH3
2a H
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
2:1:1
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
Δ, ~65°C
Δ, ~78°C
Fusion
MeOH
EtOH
DMF
DMF
BuOH
H2O
H2O
H2O
H2O
EtOH
EtOH
EtOH
BuOH
BuOH
BuOH
BuOH
BuOH
BuOH
BuOH
BuOH
H2O
45
45
3
Trace
10
Trace
—
—
39
19
—
—
11
—
—
—
—
—
—
—
—
—
—
29
Trace
4
65
32
38
29
28
4
14
15b
7c
Δ, ~153°C
Δ, ~118°C
MW, 100°C
MW, 120°C
MW, 150°C
MW, 170°C
MW, 100°C
MW, 120°C
MW, 150°C
MW, 150°C
Δ, ~118°C
Δ, ~118°C
Δ, ~118°C
Δ, ~118°C
Δ, ~118°C
Δ, ~118°C
Δ, ~118°C
MW, 100°C
MW, 120°C
MW, 80°C
MW, 100°C
MW, 120°C
MW, 150°C
MW, 100°C
MW, 100°C
MW, 100°C
MW, 100°C
MW, 100°C
MW, 100°C
MW, 100°C
7
45
12
9
7
2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
10
10
10
10
45
45
45
45
45
45
45
10
10
10
10
10
10
15
20
15
15
15
15
15
17
12
8
16
50d
53
62
59
66
62
59
21
39e
47
53
46
33
61
48
51
53
63
59
61
H2O
BuOH
BuOH
BuOH
BuOH
BuOH
BuOH
BuOH
BuOH
BuOH
BuOH
BuOH
—
—
—
—
—
—
—
—
6
2b CH3
2d Cl
2e COOCH3
2f NO2
—
aYields for mixtures are calculated by 1H NMR data.
bYield of by-product 6–9%.
cYield of by-product 6–11%.
dYield of by-products: 7–6%, 8–3%.
eYield of by-product 6–21%.
application of such procedure for obtaining substances 5a,
b,d–f (Entries 29–33) showed its general inefficiency.
Thus, the best method for synthesis of 4,6-diaryl-
2′,2′,3-trimethyl-6,7-dihydro-4H-spiro[isoxazolo[5,4-b]pyr-
idine-5,5′-[1,3]dioxane]-4′,6′-dione 4 is the usage of the
ultrasonic promoted multicomponent procedure in ethanol
with twofold excess of carbonyl compound 2, while for
4-aryl-3-methyl-4,7-dihydroisoxazolo[5,4-b]pyridin-6(5H)-
one 5—refluxing the mixture containing aminoazole 1,
aldehyde 2 and double excess of Meldrum’s acid 3 in
n-butanol.
The formation of compounds 4 and 5 may be the result
of kinetic and thermodynamic controlled pathways of the
reaction, as it was described in our earlier publications
for similar treatments [34,35]. In this case heating the
spiro-compound 4 should lead to its rearrangement into
isoxazolodihydropyridone 5. Indeed, it was found that
compound 4b in EtOH/H2O (1:1) under MW-irradiation
at 150°C for 15min transformed into heterocycle 5b in
31% yield. However, experiment’s results allow no unam-
biguous conclusion in favor of kinetic and thermodynamic
control of the processes.
The plausible mechanisms for the formation of the com-
pounds 4 and 5 are depictured in Scheme 3. It is assumed
the both the sequences begin from the formation of the
arylidene derivatives of Meldrum’s acid 9, but then there
are two alternative pathways for the treatment. Pathway
A occurring under heating of the reaction mixture supposes
the nucleophilic addition of the CH-center of 5-amino-
3-methylisoxazole 1 to the double bond of compound 9
[36]. Further elimination of acetone and CO2 results in
unstable ketene which cyclizes in the pyridone 5. In con-
trast, the formation of the spiro-substance 4 observing at
room temperature presumably proceeds as hetero-Diels–
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A. D. Morozova, E. A. Muravyova, S. V. Shishkina, E. V. Vashchenko,
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Scheme 3. Plausible mechanisms of the formation of the compounds 4 and 5.
Alder reaction between arylidene 9 and azomethine 10
forming in situ (Pathway B) [7].
pyridine-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione 12 in
61–74% yields (Scheme 4). The same reaction in boiled
DMF resulted in the tarring of the reacting compounds, al-
though the fusion of the initial reagents with few drops of
DMF allowed to obtain substance 12 in good yields
(49–78%). It is worth noting that thermolabile compound
12f was not obtained in such way.
Because the substance 13 had not been formed by the
methods described in [37] for pyrazolopyridines, other
known approaches were tested as well. However, the reac-
tion of equimolar mixture of 5-amino-3-methylisoxazole 1,
aromatic aldehyde 2, N,N′-dimethylbarbituric acid 11 in
the presence of t-BuOK [35] under MW irradiation in
tert-butanol gave only potassium salt of N,N′-
dimethylbarbituric acid (70% yield).
N,N′-Dimethylbarbituric acid as a stable cyclic active
methylene compound was also studied in this reaction.
Earlier, it had been shown by Jiang et al., that multicompo-
nent treatment between 5-amino-3-methylisoxazole, N,N′-
dimethylbarbituric acid and aromatic aldehydes under
MW-irradiation had given spiro-fused substances 12 [15].
On the other hand, the similar reaction involving
5-aminopyrazoles had shown bidirectionality [37]: two
types of pyrazolopyridines depending on the reaction con-
ditions had been isolated.
In our case it was established that the reaction between
aminoisoxazole 1, double excess of aromatic aldehyde
2a–f and N,N′-dimethylbarbituric acid 11 in EtOH under
ultrasonication at r.t. gave also 4,6-diaryl-1′,3,3′-
trimethyl-6,7-dihydro-2′H,4H-spiro[isoxazolo[5,4-b]
The efficiency of trimethylsilyl chloride (TMSCl) as
heterocyclization promoter [17,38] was sampled for the
Scheme 4. Multicomponent reaction of 5-amino-3-methylisoxazole, aromatic aldehydes and N,N′-dimethylbarbituric acid.
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Multicomponent Heterocyclizations Involving Derivatives of 3(5)-Aminoisoxazole
condition studied. Nevertheless, boiling the reaction mix-
ture in dry DMF containing TMSCl under 100°C or
ultrasonication at room temperature yielded contaminated
compound 12 with no trace of substance 13.
Determination of the structures. Identification of all the
compounds synthesized was made with the help of
elemental analysis, 1D and 2D NMR spectroscopy, mass
spectrometry, and X-ray analysis. The NMR spectra of
compounds 4 and 12 are in good correlation with the data
published in the literature [14,15]. In case of containing
the same aldehydes residues at the positions 4 and 6 the
spectra show the formation of only one diastereoisomeric
pair despite the presence of two stereogenic centers while
in the presence of the different aldehyde’s moieties
(compounds 4g,h) the formation of two diastereoisomeric
pair is observed.
The realization of linear pathways via preliminary synthe-
sis of arylidene derivatives of dimethylbarbituric acid and
its treatment with 5-amino-3-methylisoxazole 1 in boiled
EtOH, DMF, or by fusion with a few drops of DMF yielded
compound 12 containing a lot of impurities. Another way
consisted in prior reaction between aminoazole 1 and
barbituric acid 11 with consequent treatment with aldehyde
allowed to reisolate only the unchanged acid. The application
of higher temperatures with help of MW-irradiation in
N-methyl-2-pyrrolidone at 150°C resulted in the tarring of
the reacting compounds in 2min.
Spiro-compounds 12 were stable in boiled EtOH; how-
ever, their refluxing in DMF led to the decay of the reaction
mixture but gave no trace of isoxazolopyridopyrimidines
13. Hence, compound 13 was not obtained under the condi-
tions studied.
When 5-amino-3-methylisoxazole was replaced by iso-
meric 3-amino-5-methylisoxazole 14, its multicomponent
reaction with aromatic aldehydes 2 and Meldrum’s acid 3
or N,N′-dimethylbarbituric acid 9 did not lead to the for-
mation of new heterocyclic rings (Scheme 5). Proceeding
the reaction between the reagents 2c,d, 11, and 14 under
ultrasonication at room temperature or in boiled DMF
allowed arylidenebarbituric acids 15a,b to be obtained.
Similar results were observed when the reaction mixture
containing compounds 2c,d, 3, and 14 was ultrasonicated
in EtOH at room temperature—compounds 9a,c were only
isolated. The same treatment in refluxed EtOH or DMF had
different direction and proceeded as acylation reaction giv-
ing compound 16. Its structure was additionally proven by
direct acylation of isoxazole in refluxed acetic anhydride.
Hence, 3-amino-5-methylisoxazole 14, in contrast to
5-amimo-3-methylisoxazole 1, possesses no property of
1,3-binucleophile in the reactions studied, and such differ-
ence in their behavior requests further complementary
study, including the methods of quantum chemistry.
1
The H NMR spectra of compounds 4, 12 contain sin-
glets for two nonequivalent CH3-groups of Meldrum’s acid
rest at 0.42–0.62ppm or N,N′-dimethylbarbituric acid moi-
ety at 2.67–2.85 ppm. The singlet for CH3-group of
isoxazole ring is located near 1.51–1.57ppm, the signals
for two methine protons are found in the range of
4.79–5.33ppm, NH-group at 8.04–8.62ppm. Signals for
protons for aromatic rings and for other terminal substitu-
ents are presented at the appropriate areas of the spectra.
The formation of diastereoisomers is indicated by the pres-
ence in 1H and 13C NMR spectra of identical minor signals
for CH3-groups of Meldrum’s acid, CH3- and OCH3-
groups of aldehyde’s residues and other protons. The appli-
cation of TLC confirms the presence of two individual
compounds in the solid mixture as well.
The structure of compound 4c was also confirmed by 2D
NMR spectral data. In COSY spectrum (Fig. 3A) there are
signals of spin–spin correlation between one of the methine
protons (δH 5.00) and NH hydrogen (δH 8.16) and the ab-
sence of cross-peaks between the methine protons at
4.79 ppm and 5.00 ppm. Selected cross-peaks of HMBC
spectrum (Fig. 3B) represent long-range heteronuclear cor-
relations H-4 (δH 4.79) – C-3,5,6,7 (δC 89.32, 58.79, 64.33,
161.00) and H-6 (δH 5.00) – C-2,4,5,7 (δC 166.36, 46.35,
58.79, 161.00) which unambiguously prove the structure
of compounds 4.
Identification of the position of two different aryl substi-
tutes in compound 4g was carried out with help of NOE
Scheme 5. Reactivity of 3-amino-5-methylisoxazole in the multicomponent interactions studied.
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A. D. Morozova, E. A. Muravyova, S. V. Shishkina, E. V. Vashchenko,
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Figure 3. Selected data of COSY (A) and HMBC (B) experiments for compound 4c; selected data of NOE experiments for compound 4g (C).
experiments: irradiation of methyl group of toluene frag-
ment and proton at the position 6 of pyridine ring on the
corresponding resonance frequencies causes an increase
in the integrated intensity of signals of the same aromatic
system (Fig. 3C).
ring with the C12, C4, and O2 atoms from one side and ar-
omatic ring with the methoxy-substituent from other side)
are turned relatively each other on 12.1°. It is the result
of reciprocal influence of two factors: a) the C6―H…O2
intramolecular hydrogen bond formation (H…O 2.22 Å
C―H…O 147°) that stabilizes the planar position of these
fragments; b) the presence of the H4…H10 2.27 Å and
H4…C12 2.70Å intramolecular shortened contacts (van
der Waals radii sum [39] are 2.34 Å and 2.87Å, respec-
tively) that causes their non-planarity. The disturbance of
conjugation results also in the elongation of the C2–C4
double bond (1.355(4) Å as compared to its mean value
[40] 1.326Å) and its twisting (the C3–C2–C4–C5 torsion
angle is ꢀ8.1(6)°).
The 1H NMR spectra of compounds 5a–f showed singlet
for methyl-group at 1.79–1.81ppm, ABX system of sig-
nals consists two doublet of doublets for methylene pro-
tons at 2.58–2.64 and 2.95–3.07ppm and doublet of
doublets for methine proton at 4.09–4.38 ppm, as well as
broad singlet for NH-group at 11.52–11.71ppm. Signals
for protons of aromatic rings and for other terminal substit-
uents are presented at the appropriate areas of the spectra.
However, two positional isomers A and B (Fig. 4) corre-
spond to the spectral data obtained; therefore, the NOE
experiments were carried out which proved the formation
of the structure of type A.
NMR spectral data for all other compounds obtained corre-
spond well to the structures assigned (see Experimental part).
1H NMR spectra of compound 6 contains singlet for
methyl-group of isoxazole moiety at 2.25ppm, sharp
singlet for ¼CH proton at 7.87ppm, multiplets for protons
of aryl ring at 7.15 – 8.52ppm, as well as signals for other
terminal substituents. Mass-spectrum contains peak
217m/z, which corresponds to M (Fig. 5)
Finally, X-ray diffraction study of single crystals shows
that the compound 6 is not quite planar as could be
expected taking into account the presence of conjugated
system. Two planar within 0.01 Å fragments (the isoxazole
CONCLUSIONS
Thus, the multicomponent reactions between 5-amino-3-
methylisoxazole, aromatic aldehydes, and Meldrum’s acid
depending on the conditions led to the compounds with dif-
ferent skeleton: ultrasonication of the starting materials in
EtOH resulted in the formation of 4,6-diaryl-2′,2′,3-
trimethyl-6,7-dihydro-4H-spiro[isoxazolo[5,4-b]pyridine-
5,5′-[1,3]dioxane]-4′,6′-diones, while the refluxing of the
reaction mixture in n-BuOH gave 4-aryl-3-methyl-4,7-
dihydroisoxazolo[5,4-b]pyridin-6(5H)-ones. The treatment
of 5-amino-3-methylisoxazole, aromatic aldehydes and N,
N′-dimethylbarbituric acid regardless of the reaction con-
ditions gave 4,6-diphenyl-1′,3,3′-trimethyl-6,7-dihydro-2′H,
4H-spiro[isoxazolo[5,4-b]pyridine-5,5′-pyrimidine]-2′,4′,6′
(1′H,3′H)-triones. In contrast, isomeric 3-amino-5-
methylisoxazole showed no property of 1,3-binucleophile-
aromatic aldehydes and both Meldrum’s and N,N′-
dimethylbarbituric acids did not react with 3-amino-5-
methylisoxazole forming new heterocycles.
Figure 4. Application of NOE correlations for determination of the struc-
ture of compounds 5.
EXPERIMENTAL
General methods. The melting points of all compounds
synthesized were determined with a Kofler apparatus. The
1H NMR spectra were recorded in DMSO-d6 at 200 MHz
with a Varian Mercury VX-200 spectrometer, 13C NMR
Figure 5. The molecular structure of compound 6 according to X-ray analysis.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Multicomponent Heterocyclizations Involving Derivatives of 3(5)-Aminoisoxazole
and two-dimensional spectra were recorded in DMSO-d6 at
150MHz with a Bruker Avance DRX 600 and at 100MHz
with a Varian MR 400 spectrometers. The MS spectra were
measured on a GC-MS Varian 1200L instrument (ionizing
voltage 70 eV, direct input of the sample). Elemental
analysis was realized on EuroVector EA-3000. Samples
for elemental analysis were previously dried at 50°C in
vacuum for 2days.
Ultrasonication was carried out with an ultrasonic horn
UZDN (Sumy, Ukraine) at 44.2kHz, 60% of the nominal
power and with a standard ultrasonic bath (44.2 kHz). Mi-
crowave experiments were performed using the reactors
Emrys Creator EXP from Biotage AB and Monowave
300 from Anton Paar possessing single-mode microwave
cavities producing controlled irradiation at 2.45GHz.
The compounds 9a,b and 10 were obtained according
the known methods [41].
4,6-Bis(4-methoxyphenyl)-2′,2′,3-trimethyl-6,7-dihydro-
4H-spiro[isoxazolo[5,4-b]pyridine-5,5′-[1,3]dioxane]-
4′,6′-dione (4c). Yield 76% of colorless solid, mp 182–183°C.
1H NMR (200MHz, DMSO-d6) δ 0.53 (s, 3H, CH3), 0.62 (s,
3H, CH3), 1.54 (s, 3H, CH3), 3.72 (s, 3H, OCH3),3.74 (s, 3H,
OCH3), 4.79 (s, 1H CH), 5.00 (s, 1H CH), 6.76 – 7.32 (m,
8H, 2Ar), 8.16 (s, 1H, NH). 13C NMR (151MHz, DMSO-
d6) δ 11.67, 28.02, 28.71, 46.35, 55.64, 55.78, 58.79,
64.33, 89.32, 105.89, 114.43, 114.56, 114.98, 126.87,
127.31, 129.73, 129.83,132.04, 157.65, 159.87, 160.54,
161.00, 166.36, 167.75. Mass spectrum, m/z: 478 (7) [M],
215 (45). Anal. Calcd. for C26H26N2O7: C 65.26, H 5.48,
N 5.85. Found: C 65.10, H 5.58, N 5.71%.
4,6-Bis(4-chlorophenyl)-2′,2′,3-trimethyl-6,7-dihydro-
4H-spiro[isoxazolo[5,4-b]pyridine-5,5′-[1,3]dioxane]-
4′,6′-dione (4d). Yield 71% of colorless solid, mp 185–
1
186°C. H NMR (200MHz, DMSO-d6) δ 0.53 (s, 3H,
4,6-Diaryl-2′,2′,3-trimethyl-6,7-dihydro-4H-spiro[isoxazolo
[5,4-b]pyridine-5,5′-[1,3]dioxane]-4′,6′-dione (4). The mixture
of 5-amino-3methylisoxazole (1.02 mmol), aromatic alde-
hydes (2.04 mmol), and Meldrum’s acid (1.02 mmol) was
ultrasonicated with ultrasonic horn in EtOH (5 ml) (for
compound 4e MeOH should be used because of solvate
with EtOH) until the formation of the thick-flowing suspen-
sion (~2h). The reaction mixture was set aside for a day.
The precipitate formed was filtered out to give the solid
compound, which was washed with ethanol and air-dried.
2′,2′,3-Trimethyl-4,6-diphenyl-6,7-dihydro-4H-spiro
[isoxazolo[5,4-b]pyridine-5,5′-[1,3]dioxane]-4′,6′-dione
CH3), 0.61 (s, 3H, CH3), 1.53 (s, 3H, CH3), 4.89 (s, 1H,
CH), 5.08 (s, 1H, CH), 6.87 – 7.27 (m, 8H, 2Ar), 8.36
(br. s, 1H, NH). 13C NMR (100MHz, DMSO-d6) δ 16.41,
32.62, 33.44, 50.97, 63.11, 68.87, 93.61, 110.84, 134.04,
134.18, 134.21, 135.22, 135.27, 137.46, 138.53, 138.61,
139.30, 139.49, 162.28, 165.32, 170.99, 171.95. Mass
spectrum, m/z: 486 (12), 488 (7) [M], 219 (78). Anal. Calcd.
for C24H20Cl2N2O5: C 59.15, H 4.14, Cl 14.55, N 5.75.
Found: C 59.24, H 4.10, Cl 14.44, N 5.59%.
Dimethyl 4,4′-(2′,2′,3-trimethyl-4′,6′-dioxo-6,7-dihydro-
4H-spiro[isoxazolo[5,4-b]pyridine-5,5′-[1,3]dioxane]-
4,6-diyl)dibenzoate) (4e). Yield 88% of colorless solid, mp
154–155°C. 1H NMR (200MHz, DMSO-d6) δ 0.43 (s, 3H,
CH3) 0.50 (s, 3H, CH3), 1.51 (s, 3H, CH3), 3.82 (s, 3H,
COOCH3), 3.84 (s, 3H, COOCH3), 5.01 (s, 1H, CH), 5.20
(d, 3JAB = 2.2 Hz, 1H, CH), 7.05 – 8.11 (m, 8H, 2Ar), 8.47
(d, 1H, NH). 13C NMR (100MHz, DMSO-d6) δ 11.60,
27.84, 28.67, 31.07, 46.77,52.66, 52.76, 58.13, 64.49,
88.82, 106.12, 129.17, 129.25, 130.01, 130.10, 130.30,
130.44, 131.20, 131.45, 139.88, 141.00, 157.55, 160.40,
166.02, 166.09, 166.26, 167.04. Mass spectrum, m/z: 534
(8) [M], 286 (80), 164 (56), 133 (100). Anal. Calcd. for
C28H26N2O9: C 62.92, H 4.90, N 5.24. Found: C 62.80, H
5.01, N 5.32 %.
2′,2′,3-Trimethyl-4,6-bis(4-nitrophenyl)-6,7-dihydro-
4H-spiro[isoxazolo[5,4-b]pyridine-5,5′-[1,3]dioxane]-
4′,6′-dione (4f). Yield 73% of colorless solid, mp 178–179°C.
1H NMR (200 MHz, DMSO-d6) δ 0.48 (s, 3H, CH3), 0.56 (s,
3H, CH3), 1.54 (s, 3H, CH3), 5.14 (s, 1H, CH), 5.33 (s, 1H,
CH), 7.19– 8.43 (m, 8H, 2Ar), 8.62 (br. s, 1H, NH). 13C
NMR (100MHz, DMSO-d6) δ 11.69, 27.94, 28.93, 46.36,
58.09, 64.15, 88.72, 106.41, 124.40, 124.50, 124.63,
130.29, 130.34, 132.50, 141.76, 143.18, 148.13, 148.73,
157.55, 160.31, 166.16, 166.77. Mass spectrum, m/z: 273
(43), 231 (53), 214 (55), 166 (46), 151(71), 150 (100). Anal.
Calcd. for C24H20N4O9: C 56.70, H 3.97, N 11.02. Found:
C 56.92, H 3.91, N 10.95%.
1
(4a). Yield 54% of colorless solid, mp 155–156°C. H
NMR (200 MHz, DMSO-d6) δ 0.42 (s, 3H, CH3), 0.50
(s, 3H, CH3), 1.52 (s, 3H, CH3), 4.86 (s, 1H, CH), 5.06
3
(d, JAB = 2.1 Hz, 1H, CH), 6.92–7.51 (m, 10H, 2Ar),
8.26 (d, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ
11.63, 27.79, 28.50, 47.04, 58.47, 64.75, 89.04, 105.91,
128.57, 129.23, 129.26, 129.44, 129.98, 130.90, 134.95,
135.58, 157.58, 160.68, 166.36, 167.43. Mass spectrum,
m/z: 418 (60) [M], 239 (47), 185 (83), 132 (73). Anal.
Calcd. for C24H22N2O5: C 68.89, H 5.30, N 6.69. Found:
C 68.72, H 5.25, N 6.81%.
2′,2′,3-Trimethyl-4,6-di-p-tolyl-6,7-dihydro-4H-spiro
[isoxazolo[5,4-b]pyridine-5,5′-[1,3]dioxane]-4′,6′-dione
1
(4b). Yield 56% of colorless solid, mp 184–185°C. H
NMR (200 MHz, DMSO-d6) δ 0.45 (s, 3H, CH3) 0.53 (s,
3H, CH3), 1.51 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.27 (s,
3
3H, CH3), 4.79 (s, 1H, CH), 4.98 (d, JAB = 2.3 Hz, 1H,
CH), 6.85 – 7.27 (m, 8H, Ar), 8.16 (d, 1H, NH). 13C
NMR (100 MHz, DMSO-d6) δ 11.66, 21.07, 21.11,
27.85, 28.55, 46.68, 58.49, 64.58, 89.14, 105.85, 128.43,
129.62, 129.78, 129.81, 130.75, 131.98, 132.52, 138.47,
139.47, 157.58, 160.77, 166.36, 167.56, 167.56. Mass
spectrum, m/z: 446(42) [M], 199 (100). Anal. Calcd. for
C26H26N2O5: C 69.94, H 5.87, N 6.27. Found: C 70.05,
H 5.89, N 6.21%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Vol 000
A. D. Morozova, E. A. Muravyova, S. V. Shishkina, E. V. Vashchenko,
Y. V. Sen'ko, and V. A. Chebanov
6-(4-Methoxyphenyl)-2′,2′,3-trimethyl-4-(p-tolyl)-6,7-
dihydro-4H-spiro[isoxazolo[5,4-b]pyridine-5,5′-[1,3]
dioxane]-4′,6′-dione (4g). Yield 76% of colorless solid.
1H NMR (200 MHz, DMSO) δ 0.46 (s, 3H, CH3), 0.58
(s, 3H, CH3), 1.51 (s, 3H, CH3), 2.24 (s, 3H, CH3), 3.72
(3.70) (s, 3H, OCH3), 4.78 (s, 1H, CH), 4.97 (d,
3JAB = 2.4Hz, 1H, CH), 6.80– 7.25 (m, 8H, 2Ar), 8.17 (d,
1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 11.65,
21.07, 28.00, 28.54, 38.21, 41.83, 46.69, 55.74, 58.63,
63.04, 64.29, 89.11, 105.84, 114.52, 126.82, 128.42,
129.77, 129.83, 130.74, 132.56, 138.46, 157.58, 160.52,
160.85, 166.39, 167.65. Mass spectrum, m/z: 462 (100)
[M], 131 (47). Anal. Calcd. for С26H26N2O6: C 67.52, H
5.67, N 6.06. Found: C 67.68, H 5.64, N 6.10%.
21.00, 32.71, 40.41, 94.45, 127.09, 129.82, 136.60,
139.78, 158.39, 162.62, 169.84. Mass spectrum, m/z: 242
(100) [M], 131 (35), 130 (41), 129 (47), 115 (61). Anal.
Calcd. for C14H14N2O2: C 69.41, H 5.82, N 11.56. Found:
C 69.58, H 5.88, N 11.49%.
4-(4-Methoxyphenyl)-3-methyl-4,7-dihydroisoxazolo
[5,4-b]pyridin-6(5H)-one (5c). Yield 59% of colorless
1
solid, mp 143–144°C. H NMR (200 MHz, DMSO-d6) δ
2
3
1.79 (s, 3H, CH3), 2.58 (dd, JAB = 16.4Hz, JAX =5.9 Hz,
3
1H, CH2), 2.95 (dd, JBX = 7.5 Hz,1H, CH2), 3.70 (s, 3H,
OCH3), 4.09 (dd, 1H, CH), 7.16– 6.75 (m, 4H, Ar),
11.52 (br. s, 1H). 13C NMR (100MHz, DMSO-d6) δ
15.02, 37.09, 45.31, 60.19, 99.41, 119.37, 133.04,
139.36, 163.16, 163.41, 167.30, 174.64. Mass spectrum,
m/z: 258 (100) [M], 215 (45), 147 (46). Anal. Calcd. for
C14H14N2O3: C 65.11, H 5.46, N 10.85. Found: C 64.98,
H 5.51, N 10.99%.
4-(4-methoxyphenyl)-2′,2′,3-trimethyl-6-(p-tolyl)-6,7-
dihydro-4H-spiro[isoxazolo[5,4-b]pyridine-5,5′-[1,3]
dioxane]-4′,6′-dione (4h). Yield 73% of colorless solid. 1H
NMR (200MHz, DMSO) δ 0.50 (0.46) (s, 3H, CH3), 0.55
(0.60) (s, 3H, CH3), 1.51 (s, 3H, CH3), 2.27 (2.25) (s, 3H,
CH3), 3.70 (3.72) (s, 3H, OCH3), 4.79 (s, 1H, CH), 4.98
4-(4-Chlorophenyl)-3-methyl-4,7-dihydroisoxazolo
[5,4-b]pyridin-6(5H)-one (5d). Yield 66% of colorless
1
solid, mp 150–151°C. H NMR (200 MHz, DMSO-d6) δ
3
2
3
(d, JAB =1.8 Hz, 1H, CH), 6.86– 7.26 (m, 8H, 2Ar), 8.17
1.80 (s, 3H, CH3), 2.60 (dd, JAB = 16.4Hz, JAX =5.8 Hz,
(d, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 11.62,
21.11, 27.85, (27.98), 28.69, 40.63, (40.87), 46.34, 55.60,
55.75, 58.63, (58.75), (64.29), 64.60, (89.28), 89.34,
105.84, 114.39, (114.52), 114.94, 127.24, 128.41, 129.62,
129.72, (129.79), 132.01, 139.45, 157.60, 159.84,
(160.51), 160.88, 166.31, 167.62, 167.62.Mass spectrum,
m/z: 462 (2) [M], 117 (100). Anal. Calcd. for
С26H26N2O6: C 67.52, H 5.67, N 6.06. Found: C 67.45, H
5.63, N 5.99%.
3
1H, CH2), 3.00 (dd, JBX = 7.8 Hz, 1H, CH2), 4,19 (dd,
1H, CH), 7.15– 7.43 (m, 4H, Ar), 11.57 (br. s, 1H, NH).
13C NMR (100MHz, DMSO-d6) δ 15.06, 37.28, 44.86,
98.67, 133.97, 136.84, 146.52, 163.09, 167.52, 174.36.
Mass spectrum, m/z: 264 (4), 262 (8), [M], 140 (43), 115
(100). Anal. Calcd. for C13H11ClN2O2: C 59.44, H 4.22,
Cl 13.49, N 10.66. Found: C 59.32, H 4.19, Cl 13.38, N
10.80%.
Methyl 4-(3-methyl-6-oxo-4,5,6,7-tetrahydroisoxazolo
[5,4-b]pyridin-4-yl)benzoate (5e). Yield 62% of colorless
4-Aryl-3-methyl-4,7-dihydroisoxazolo[5,4-b]pyridin-
6(5H)-one (5). The mixture of 5-amino-3-methylisoxazole
(1.02mmol), aromatic aldehydes (1.02mmol), and Meldrum’s
acid (2.04 mmol) was heated to reflux in 0.5ml n-BuOH for
45 min in a round-bottom flask equipped with a condenser.
The solvent was evaporated, a residual solid was filtered out,
and recrystallized from EtOH.
1
solid, mp 170–171°C. H NMR (200 MHz, DMSO) δ 1.79
2
3
(s, 3H, CH3), 2.64 (dd, JAB =16.4Hz, JAX =5.9Hz, 1H,
CH2), 3.04 (dd, 3JBX = 8.2Hz, 1H, CH2), 4.28 (dd, 1H, CH),
7.02– 8.17 (m, 4H, Ar), 11.66 (s, 1H, NH). 13C NMR
(100MHz, DMSO-d6) δ 10.31, 33.13, 39.81, 52.51, 93.64,
127.79, 128.92, 130.24, 148.27, 158.35, 162.85, 166.34,
169.52. Mass spectrum, m/z: 286 (100) [M], 285 (49), 243
(47), 154 (50), 143 (46). Anal. Calcd. for C15H14N2O4: C
62.93, H 4.93, N 9.79. Found: C 62.84, H 4.96, N 9.87%.
3-Methyl-4-(4-nitrophenyl)-4,7-dihydroisoxazolo[5,4-
b]pyridin-6(5H)-one (5f). Yield 59% of colorless solid, mp
172–173°C. 1H NMR (200MHz, DMSO-d6) δ 1.81 (s, 3H,
3-Methyl-4-phenyl-4,7-dihydroisoxazolo[5,4-b]pyridin-
6(5H)-one (5a). Yield 53% of colorless solid, mp 133–134°C.
1H NMR (200 MHz, DMSO) δ 1.79 (s, 3H, CH3), 2.62 (dd,
2JAB =16.4Hz, 3JAX = 5.5 Hz, 1H, CH2), 3.00 (dd, 3JBX =7.7Hz,
1H, CH2), 4.16 (dd, 1H, CH), 7.03 – 7.43 (m, 5H, Ar), 11.60 (s,
1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 10.28, 33.11,
40.28, 94.33, 127.24, 127.49, 129.28, 142.81, 158.39,
162.67, 169.80. Mass spectrum, m/z: 228 (68) [M], 117 (32),
116 (65), 115 (100). Anal. Calcd. for C13H12N2O2: C 68.41,
H 5.30, N 12.27. Found: C 68.49, H 5.37, N 12.40%.
3-Methyl-4-(p-tolyl)-4,7-dihydroisoxazolo[5,4-b]
pyridin-6(5H)-one (5b). Yield 62% of colorless solid, mp
2
3
CH3), 2.66 (dd, JAB = 16.4Hz, JAX = 5.8 Hz, 1H, CH2),
3
3.07 (dd, JBX = 7.9 Hz,1H, CH2), 4.38 (dd, 1H, CH),
7.24– 8.35 (m, 4H, Ar), 11.71 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) δ 10.34, 32.98, 39.61, 93.26,
124.51, 128.80, 147.05, 150.57, 158.32, 162.99, 169.32.
Mass spectrum, m/z: 273 (94) [M], 162 (47), 161 (57),
140 (47), 130 (55). Anal. Calcd. for C13H11N3O4: C
57.14, H 4.06, N 15.38. Found: C 57.22, H 4.01, N 15.27%.
(Z)-4-(4-methoxybenzylidene)-3-methylisoxazol-5
(4H)-one (6). Yield 21% of yellow solid, mp 143–144°C.
1H NMR (200MHz, DMSO-d6) δ 2.25 (s, 3H, CH3),
1
148–149°C. H NMR (200 MHz, DMSO) δ 1.80 (s, 3H,
2
CH3), 2.25 (s, 3H, CH3), 2.60 (dd, JAB = 16.3Hz,
3
3JAX = 5.7Hz, 1H, CH2), 2.98 (dd, JBX = 7.8 Hz, 1H,
CH2), 4.11 (dd, 1H, CH), 6.86– 7.25 (m, 4H, Ar), 11.57
(s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 10.29,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Multicomponent Heterocyclizations Involving Derivatives of 3(5)-Aminoisoxazole
3.88 (s, 3H, OCH3),7.87 (s, 1H, CH), 7.05–8.60 (m, 4H,
Ar). 13C NMR (100 MHz, DMSO-d6) δ 11.71, 56.28,
115.11, 115.66, 126.22, 137.32, 151.68, 162.70, 164.68,
169.03. Mass spectrum, m/z: 217 (100) [M], 218 (15) [M
+ 1], 216 (8) [M 1]. Anal. Calcd. for C12H11NO3: C
66.35, H 5.10, N 6.45. Found: C 66.46, H 5.14, N 6.52%.
4,6-Diaryl-1′,3,3′-trimethyl-6,7-dihydro-2′H,4H-spiro
[isoxazolo[5,4-b]pyridine-5,5′-pyrimidine]-2′,4′,6′(1′H,3′
H)-trione (12). The mixture of 5-amino-3methylisoxazole
(1.02mmol), aromatic aldehydes (2.04mmol), N,N′-
dimethylbarbituric acid (1.02mmol) was ultrasonicated with
ultrasonic horn in EtOH (5ml) with 2 drops of DMF until the
formation of the thick-flowing suspension (~2h). The reac-
tion mixture was set aside for a day. The precipitate was fil-
tered out to give the solid compound, which was washed
with ethanol and air-dried.
354 (45), 136 (100). Anal. Calcd. for C26H26N4O6: C 63.66,
H 5.34, N 11.42. Found: C 63.52, H 5.42, N 11.53.
4,6-Bis(4-chlorophenyl)-1′,3,3′-trimethyl-6,7-dihydro-
2′H,4H-spiro[isoxazolo[5,4-b]pyridine-5,5′-pyrimidine]-
2′,4′,6′(1′H,3′H)-trione (12d). Yield 58% of colorless solid,
1
mp 214–215°C. H NMR (200MHz, DMSO-d6) δ 1.55 (s,
3H, CH3), 2.72 (s, 3H, CH3), 2.87 (s, 3H, CH3), 4.91 (s,
3
1H, CH), 5.02 (d, JAB =2.4Hz, 1H, CH), 6.92 – 7.48 (m,
8H, 2Ar), 8.25 (d, 1H, NH). 13C NMR (100MHz, DMSO-
d6) δ 11.66, 27.92, 28.73, 46.28, 58.83, 64.27, 89.03,
128.98, 129.03, 129.66, 130.85, 133.35, 133.79, 134.40,
134.45, 149.43, 157.56, 164.05, 166.35, 169.39. Mass spec-
trum, m/z: 500 (1), 498 (4) [M], 219 (100), 151 (65). Anal.
Calcd. for C24H20Cl2N4O4: C 57.73, H 4.04, Cl 14.20, N
11.22. Found: C 57.59, H 4.07, Cl 14.13, N 11.16%.
Dimethyl 4,4′-(1′,3,3′-trimethyl-2′,4′,6′-trioxo-1′,3′,4′,
6,6′,7-hexahydro-2′H,4H-spiro[isoxazolo[5,4-b]pyridine-
5,5′-pyrimidine]-4,6-diyl)dibenzoate (12e). Yield 69% of
colorless solid, mp 194–195°C. 1H NMR (200MHz,
DMSO-d6) δ 1.55 (s, 3H, CH3), 2.67 (s, 3H, CH3), 2.85 (s,
3H, CH3), 3.79 (s, 3H, CH3), 3.82 (s, 3H, CH3), 5.02 (s,
1′,3,3′-Trimethyl-4,6-diphenyl-6,7-dihydro-2′H,4H-
spiro[isoxazolo[5,4-b]pyridine-5,5′-pyrimidine]-2′,4′,6′
(1′H,3′H)-trione (12a). Yield 74% of colorless solid, mp
1
177–178°C. H NMR (200 MHz, DMSO-d6) δ 1.54 (s,
3H, CH3), 2.67 (s, 3H, CH3), 2.83 (s, 3H, CH3), 4.88 (s,
3
3
1H, CH), 5.00 (d, JAB = 2.4 Hz, 1H, CH), 6.86– 7.44 (m,
1H, CH), 5.13 (d, JAB =2.1Hz, 1H, CH), 7.01 – 8.02 (m,
10H, 2Ar), 8.18 (d, 1H, NH). 13C NMR (100MHz,
DMSO-d6) δ 11.66, 27.78, 28.58, 47.07, 59.11, 64.99,
89.21, 127.70, 128.81, 128.89, 128.95, 129.84, 134.90,
135.46, 149.50, 157.65, 164.27, 166.48, 169.78. Mass
spectrum, m/z: 430 (26) [M], 324 (71), 199 (47), 185
(100), 156 (52). Anal. Calcd. for C24H22N4O4: C 66.97, H
5.15, N 13.02. Found: C 67.07, H 5.10, N 13.09%.
8H, 2Ar), 8.37 (d, 1H, NH). 13C NMR (100MHz, DMSO-
d6) δ 11.66, 27.90, 28.73, 46.78, 52.55, 52.69, 58.68,
64.56, 88.86, 128.30, 129.80, 129.98, 130.89, 139.91,
140.93, 149.32, 157.60, 163.83, 166.00, 166.14, 166.37,
169.23. Mass spectrum, m/z: 546 (19) [M], 243 (60), 229
(40), 164 (100). Anal. Calcd. for C28H26N4O8: C 61.53, H
4.80, N 10.25. Found: C 61.43, H 4.76, N 10.39%.
1′,3,3′-Trimethyl-4,6-di-p-tolyl-6,7-dihydro-2′H,4H-
spiro[isoxazolo[5,4-b]pyridine-5,5′-pyrimidine]-2′,4′,6′
(1′H,3′H)-trione (12b). Yield 56% of colorless solid, mp
1′,3,3′-Trimethyl-4,6-bis(4-nitrophenyl)-6,7-dihydro-
2′H,4H-spiro[isoxazolo[5,4-b]pyridine-5,5′-pyrimidine]-
2′,4′,6′(1′H,3′H)-trione (12f). Yield 68% of colorless
1
1
175–176°C. H NMR (200 MHz, DMSO-d6) δ 1.53 (s,
solid, mp 185–186°C. H NMR (200 MHz, DMSO-d6) δ
3H, CH3), 2.21 (s, 3H, CH3), 2.23 (s, 3H, CH3), 2.68 (s,
3H, CH3), 2.83 (s, 3H, CH3), 4.82 (s, 1H, CH),4.93 (s,
1H, CH), 6.79– 7.20 (m, 8H, 2Ar), 8.07 (s, 1H, NH),.
13C NMR (100 MHz, DMSO-d6) δ 11.67, 21.06, 21.12,
27.83, 28.60, 46.80, 59.04, 64.80, 89.33, 127.60, 129.43,
131.96, 132.41, 137.92, 139.12, 149.62, 157.64, 164.38,
166.44, 169.88. Mass spectrum, m/z: 458 (35) [M], 338
(43), 200 (47), 199 (100), 156 (52). Anal. Calcd. for
C26H26N4O4: C 68.11, H 5.72, N 12.22. Found: C 68.01,
H 5.79, N 12.29%.
1.57 (s, 3H, CH3), 2.71 (s, 3H, CH3), 2.88 (s, 3H, CH3),
5.13 (s, 1H, CH), 5.24 (s, 1H, CH), 7.15– 8.33 (m, 8H,
2Ar), 8.51 (s, 1H, NH). 13C NMR (100MHz, DMSO-d6)
δ 16.46, 32.77, 33.62, 51.12, 63.28, 68.98, 93.58, 128.84,
134.23, 135.37, 146.64, 147.96, 152.54, 153.19, 153.94,
162.35, 168.37, 171.03, 173.56. Mass spectrum, m/z: 520
(4) [M], 289 (82), 288 (100), 230 (52). Anal. Calcd. for
C24H20N6O8: C 55.39, H 3.87, N 16.15. Found: C 55.47,
H 3.80, N 15.99%.
X-ray experimental part.
The colorless crystals of 6
4,6-Bis(4-methoxyphenyl)-1′,3,3′-trimethyl-6,7-dihydro-
2′H,4H-spiro[isoxazolo[5,4-b]pyridine-5,5′-pyrimidine]-
2′,4′,6′(1′H,3′H)-trione (12c). Yield 60% of colorless solid,
(C12H11NO3) are monoclinic. At 293K a =12.8478(9),
b =6.9287(5), c =12.816(1) Å, β =112.484(7)°, V=1054.2
(1) Ǻ3, Mr =217.22, Z = 4, space group P21/c, dcalc =1.369g/
сm3, (MoK)= 0.099mmꢀ1, F(000)=456. Intensities of 9706
reflections (3066 independent, Rint = 0.091) were measured
on the«Xcalibur-3» diffractometer (graphite monochromated
MoKα radiation, CCD detector, ω-scanning, 2Θmax = 60°).
The structure was solved by direct method using SHELXTL
package [42]. Positions of the hydrogen atoms were located
from electron density difference maps and refined by
“riding” model with Uiso =nUeq (n =1.5 for methyl groups
1
mp 233–234°C. H NMR (200MHz, DMSO-d6) δ 1.53 (s,
3H, CH3), 2.71 (s, 3H, CH3), 2.85 (s, 3H, CH3), 3.67 (s, 3H,
OCH3), 3.69 (s, 3H, OCH3), 4.79 (s, 1H, CH), 4.91 (d,
3JAB = 2.4 Hz, 1H, CH), 6.76– 7.10 (m, 8H, 2Ar), 8.04 (d,
1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 16.37, 32.61,
33.36, 51.16, 60.14, 60.32, 64.08, 69.25, 94.23, 118.97,
131.52, 131.89, 133.73, 154.44, 162.40, 164.14, 164.91,
169.29, 171.15, 174.75. Mass spectrum, m/z: 490 (12) [M],
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Vol 000
A. D. Morozova, E. A. Muravyova, S. V. Shishkina, E. V. Vashchenko,
Y. V. Sen'ko, and V. A. Chebanov
[16] Tkachenko, V. V; Muravyova, E. A.; Desenko, S. M.Shishkin,
O. V; Shishkina, S. V; Sysoiev, D. O.; Müller, T. J. J.; Chebanov, V. A.
Beilstein J. Org Chem 2014, 10, 3019.
[17] Ryabukhin, S. V.; Panov, D. M.; Plaskon, A. S.; Grygorenko,
O. O. ACS Comb Sci 2012, 14, 631.
[18] Rajanarendar, E.; Nagi, R. M.; Raju, S. Indian J Chem 2011,
50B, 751.
[19] Shafiee, M.; Khosropour, A. R.; Mohammadpoor-Baltork, I.;
Moghadam, M.; Tangestaninejad, S.; Mirkhani, V. Tetrahedron Lett
2012, 53, 3086.
[20] Rajanarendar, E.; Murthy, K. R.; Reddy, M. N. Indian J Chem
2011, 50B, 926.
[21] Muravyova, E. A.; Desenko, S. M.; Musatov, V. I.; Knyazeva,
I. V.; Shishkina, S. V.; Shishkin, O. V.; Chebanov, V. A. J. Comb Chem
2007, 9, 797.
and n =1.2 for other hydrogen atoms) of the carrier atom. Full-
matrix least-squares refinement against F2 in anisotropic
approximation for non-hydrogen atoms using 2996
reflections was converged to wR2 =0.165 (R1 =0.070 for
943 reflections with F > 4σ(F), S =0.820). The final atomic
coordinates, and crystallographic data for molecule 6 have
been deposited to with the Cambridge Crystallographic Data
Centre, 12 Union Road, CB2 1EZ, UK (fax: +44-1223-
336033; e-mail: deposit@ccdc.cam.ac.uk) and are available
on request quoting the deposition numbers CCDC 1423242).
[22] Chebanov, V.; Desenko, S. Multicomponent heterocyclizations
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containing Mono-, Bi- and Polynucleophiles; LAP LAMBERT Academic
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet