Features of 3-amino-5-methylisoxazole in heterocyclizations involving pyruvic acids

Article abstract of DOI:10.1007/s10593-019-02422-8

[Figure not available: see fulltext.] The chemical properties of 3-amino-5-methylisoxazole in the reactions involving pyruvic acid derivatives are reported. The multicomponent condensation of 3-amino-5-methylisoxazole, aromatic aldehyde, and pyruvic acid was not effective while the treatment of the starting amine with pyruvic acid derivatives led to suitable synthetic procedures for selective synthesis of furanones and pyrrolones. It was established that only NH₂-nucleophilic center of 3-amino-5-methylisoxazole takes part in the heterocyclizations with pyruvic acid derivatives.

Full text of DOI:10.1007/s10593-019-02422-8

DOI 10.1007/s10593-019-02422-8
Chemistry of Heterocyclic Compounds 2019, 55(1), 78–89
Features of 3-amino-5-methylisoxazole
in heterocyclizations involving pyruvic acids
Alisa D. Morozova1, Elena A. Muravyova1, Svitlana V. Shishkina1,2,
Dmytro Sysoiev3, Toma Glasnov4, Vladimir I. Musatov1,
Sergey M. Desenko1,2, Valentyn A. Chebanov1,2*
1 Division of Chemistry of Functional Materials,
State Scientific Institution ''Institute for Single Crystals''
of National Academy of Sciences of Ukraine,
60 Nauky Ave., Kharkiv 61072, Ukraine; e-mail: chebanov@isc.kh.ua
2 Faculty of Chemistry, V. N. Karazin Kharkiv National University,
4 Svobody Sq., Kharkiv 61077, Ukraine
3 Department of Chemistry, University of Konstanz,
10 Universitaetsstrasse, Konstanz 78467, Germany; e-mail: dmytro.sysoiev@uni-konstanz.de
4 Institute of Chemistry, University of Graz,
1/4 Schubertstraße, Graz 8010, Austria; e-mail: toma.glasnov@uni-graz.at
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(1), 78–89
Submitted November 11, 2018
Accepted December 10, 2018
H2N
Ar
N
Me
O
Ar1
HO
Me
O
N
O
O
O
N
Ar
Me
O
N
N
H
Me
O
O
N
N
O
N
Ar
Me
N
H
The chemical properties of 3-amino-5-methylisoxazole in the reactions involving pyruvic acid derivatives are reported. The multi-
component condensation of 3-amino-5-methylisoxazole, aromatic aldehyde, and pyruvic acid was not effective while the treatment of the
starting amine with pyruvic acid derivatives led to suitable synthetic procedures for selective synthesis of furanones and pyrrolones.
It was established that only NH2-nucleophilic center of 3-amino-5-methylisoxazole takes part in the heterocyclizations with pyruvic acid
derivatives.
Keywords: 3-amino-5-methylisoxazole, furanones, pyrrolones, pyruvic acids, heterocyclization.
The cascade hetorocyclizations involving α-aminoazoles
and carbonyl compounds is a simple and efficient way for
the construction of different five- and six-membered
heterocycles. Among them, there are aza-Diels–Alder,1–4
Biginelli,4,5 Doebner, Povarov reactions,6,7 etc.4 The most
well-studied amines in such heterocyclizations are different
3(5)-aminopyrazoles, 2-aminobenzimidazoles, 3-amino-
1,2,4-triazoles, and 5-aminotetrazoles.8–13 However, the
α-aminoazoles based on isoxazole moiety had not been
well studied in such reactions before our research:14–18
there are significantly fewer publications devoted to the
treatments of 5-amino-3-methylisoxazole1,19–27 and 3-amino-
5-methylisoxazole6,28–33 in one-pot reactions.
Concerning 5-amino-3-methylisoxazole, it was shown
that its two- and multicomponent heterocyclizations in the
most cases led to isoxazolopyridines (Fig. 1). It was found
by our group that 5-amino-3-methylisoxazole was not
stable in two- and multicomponent reactions with pyruvic
acid and its arylidene derivatives while two-component
condensations with ethyl 4-aryl-2-oxobut-3-enoate in the
presence of Sc(OTf)3 gave not only isoxazolo[5,4-b]-
pyridines I, but also both di- and tetrahydropyridines II
and III.18
Thus, 5-amino-3-methylisoxazole usually reacts as 1,3-bi-
nucleophile involving exocyclic amino group and position
C-4 in the isoxazole moiety as reaction centers. It is also
0009-3122/19/55(1)-0078©2019 Springer Science+Business Media, LLC
78

Chemistry of Heterocyclic Compounds 2019, 55(1), 78–89
Figure 1. Some products of heterocyclization involving 5-amino-
3-methylisoxazole.
worth noting that two-component reactions between 5-amino-
isoxazole and carbonyl compounds where 5-amino-
isoxazole exhibits properties of C-mononucleophile are
described,26,34–40 as well as its condensations with the
formation of imides.20
On the other hand, the literature data on the behavior of
3-amino-5-methylisoxazole in such heterocyclizations are
ambiguous. For instance, its reaction with mercaptoacetic
acid and aromatic aldehydes was described as a step-by-
step process leading to the formation of thiazolidinones
IV32 (Fig. 2), while similar condensation with isatin as
carbonyl component gave isoxazolo[2,3-c][1,3,5]thiadi-
azepinones V.33 Among the treatments affecting only
amino group there are not only the reactions leading to
thiazolidinone formation: the condensation of 3-amino-
5-methylisoxazole, aromatic aldehyde, and pyruvates in
TMSCl/DMF gave 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones
VI;41 the product of the reaction of aryl isothiocyanate and
3-amino-5-methylisoxazole undergoes Boulton–Katritzky
rearrangement with the opening of the isoxazole ring and
formation of 1,2,4-thiadiazole moiety (compounds VII).39,40
The reactions of 3-amino-5-methylisoxazole involving
both nitrogen atoms (exo- and endocyclic) without
isoxazole ring opening are also described.28–31 However, of
greatest interest for our studies is the article published by
Llona-Minguez et al.6 reporting an aza-Diels–Alder
cycloaddition leading to isoxazolo[2,3-a]pyrimidines VIII,
structure of which was proved by X-ray studies. On the
other hand, our attempts to synthesize isoxazolo[2,3-a]-
pyrimidines by multicomponent condensation of 3-amino-
5-methylisoxazole, aromatic aldehyde, and Meldrum's acid
resulted in the acylation of the starting amine by the
Figure 3. Reactions of α-aminoazoles, aromatic aldehydes, and
pyruvic acids.
Meldrum's acid under reflux and the formation of the
ylidene derivatives of aromatic aldehyde and Meldrum's /
N,N-dimethylbarbituric acids at room temperature, while
similar treatment of 5-amino-3-methylisoxazole gave
isoxazolo[5,4-b]pyridines.17 Rahmati et al.24 described the
multicomponent reaction of isatin, barbituric acid deriva-
tive, and 5-amino-3-methylisoxazole to yield isoxazolo[5,4-b]-
dihydropyridine moiety, however the product of the same
condensation involving 3-amino-5-methylisoxazole was
not isolated.
The interest in the 3-amino-5-methylisoxazole as a
reactant for condensations involving pyruvic acids and
carbonyl compounds is connected with a variety of target
compounds that have been obtained in similar experiments:
the formation of several types of azoloazines XIII, XIV,
furanones XVI, and pyrrolones XV has been described
(Fig. 3). On the other hand, the behavior of 3-amino-5-methyl-
isoxazole in such reactions is unclear, since it is known that
some aminoisoxazoles may be unstable in acidic medium,42
however the condensation of the selected amines with/in
the presence of acids has been described.
Herein we present our recent results of the study of two-
and three-component heterocyclizations of 3-amino-
5-methylisoxazole with aromatic aldehydes, pyruvic acid,
and its derivatives, as well as of the comparison of the
chemical behavior of 3-amino-5-methyl- and 5-amino-
3-methylisoxazole in such reactions.
The multicomponent reaction of 3-amino-5-methyl-
isoxazole (1), pyruvic acid (3), and aromatic aldehyde 2
under ultrasonication in acetic acid for 48 h (the procedure
used for the similar reaction earlier4) resulted in the
formation of furanones 4 (R = OMe) or their mixtures with
pyrrolones 5 (R = Cl, COOMe) (Scheme 1). The precipitate
was usually contaminated by pyruvic acid which was
difficult to separate from the mixture. This result in the
Figure 2. Some products of heterocyclization involving 3-amino-
5-methylisoxazole.
79

Chemistry of Heterocyclic Compounds 2019, 55(1), 78–89
Scheme 1
combination with the rather poor yields (<35%) forced us
to look for more efficient procedures to synthesize com-
pounds 4 and 5.
methanol instead of the acetic acid can improve yields due
to increasing the stability of the starting material. Indeed,
using MeOH in the combination with an ultrasonic horn
instead of the ultrasonic bath (to improve grinding of the
reagents) reduced the reaction time from 48 to 3 h without
raising the temperature (Scheme 2, Table 1, entries 12–15).
This procedure showed good results for acids 7a,c–e,
however, acid 7b was completely insoluble in MeOH,
therefore the corresponding product was obtained only in
acetic acid.
Our attempts to carry out the reaction of 3-amino-5-methyl-
isoxazole (1) with unsaturated acid 7h (R = COOMe) in
acetic acid medium led to a mixture of compounds 4 and 5,
that could not be separated by recrystallization or column
chromatography (Scheme 2, Table 1, entries 5, 9). The
reaction in MeOH under ultrasonication by the horn gave
the mixtures of compounds 4 and 7; an excess of amine 1
Firstly, the scheme of the reaction was changed from
multicomponent to sequential via preliminary synthesis of
arylidene derivatives of pyruvic acid 7.43 Further conden-
sation of amine 1 with unsaturated acid 7a–c under ultra-
sonication (an ultrasonic bath) in acetic acid gave pure
furanone 4a–c in 37–55% yields (Scheme 2, Table 1,
entries 1–3). To optimize the reaction conditions, variation
of activation methods and solvents was used. We found
that refluxing of the reaction mixture resulted in its tarring,
however, heating in AcOH at 50–70°C for 1 h led to
isolation of the same products in slightly better yields
(Table 1, entries 6–8).
At the same time, 3-amino-5-methylisoxazole (1) is
unstable in acidic medium,42 therefore the application of
Scheme 2
O
HCl
O
R
EtOH–H2O
42–73%
O
OH
O
R
R
7a–i
O
KOH
OH
+
Me
EtOH, rt, 12 h
60–85%
OK
O
O
R
6a–i
3
O
AcCl
O
2a–i
EtOH, , 6 h
30–68%
OEt
8a–c
O
O
i
O
N
N
R
Me
Me
N
H
4a–g
O
H2N
O
+
Me
4 + 5
N
Me
OR1
O
O
R
N
1
6a–i, 7a–i, 8a–c
ii, iii
O
N
O
R
N
H
5a–c,e
i: 6a–g
ii: 8a–c
iii: 7h
4a–g; AcOH, 25°C, 3 h, 46–66%
5a–c; Sc(OTf)3 (20 mol %), MeCN, –15°C, 7 days, 23–51%
5e; MeOH, , 45 min, 36%
2, 4 a R = H, b R = Me, c R = OMe, d R = OEt, e R = F, f R = Cl, g R = Br, h R = COOMe, i R = CN
5 a R = H, b R = Me, c R = Cl, d R = Br, e R = COOMe
6 R1 = K; a R = H, b R = Me, c R = OMe, d R = OEt, e R = F, f R = Cl, g R = Br, h R = COOMe, i R = CN
7 R1 = H; a R = H, b R = Me, c R = OMe, d R = OEt, e R = F, f R = Cl, g R = Br, h R = COOMe, i R = CN
8 R1 = Et; a R = H, b R = Me, c R = Cl
80

Chemistry of Heterocyclic Compounds 2019, 55(1), 78–89
Table 1. Reaction between 3-amino-5-methylisoxazole (1) and pyruvic acid derivatives 6–8 under different conditions
Yield, %
Molar ratio
Entry
Compound
R
R1
Conditions
1:6(7, 8)
4
37
5
–
1
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
K
K
K
K
K
K
K
K
K
Et
Et
Et
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
2:1
1:1
1:1
1:1
2:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
2:1
2:1
2:1
2:1
2:1
US (bath), AcOH, rt, 48 h
US (bath), AcOH, rt, 48 h
US (bath), AcOH, rt, 48 h
US (bath), AcOH, rt, 48 h
US (bath), AcOH, rt, 48 h
AcOH, 50–70°C, 1 h
7a
7b
7c
7f
2
48
–
3
OMe
Cl
55
–
4
53
6
5
COOMe
H
Traces
46
Traces
–
7h
7a
7b
7c
7h
7f
6
7
Me
AcOH, 50–70°C, 1 h
57
–
8
OMe
COOMe
Cl
AcOH, 50–70°C, 1 h
64
–
9
AcOH, 50–70°C, 1 h
25
10
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
AcOH, 50–70°C, 1 h
45
Br
AcOH, 50–70°C, 1 h
36
9
7g
7a
7c
7d
7e
7h
7i
H
US (horn), MeOH, rt, 3 h
US (horn), MeOH, rt, 3 h
US (horn), MeOH, rt, 3 h
US (horn), MeOH, rt, 3 h
US (horn), MeOH, rt, 3 h
US (horn), MeOH, rt, 3 h
US (horn), MeOH, rt, 3 h
US (horn), MeOH, rt, 3 h
MeOH, , 45 min
51
–
OMe
OEt
F
64
–
61
–
56
–
COOMe
CN
24*
Traces**
55
–
–
Cl
6
7f
Br
40
18
3
7g
7h
7h
6a
6b
6c
6d
6e
6f
COOMe
COOMe
H
18
–
36
–
MeOH, , 45 min
AcOH, 25°C, 3 h
53
Me
AcOH, 25°C, 3 h
46
–
OMe
OEt
F
AcOH, 25°C, 3 h
66
–
AcOH, 25°C, 3 h
61
–
AcOH, 25°C, 3 h
50
–
Cl
AcOH, 25°C, 3 h
63
–
Br
AcOH, 25°C, 3 h
57
–
6g
6h
6i
COOMe
CN
AcOH, 25°C, 3 h
5
22
3
AcOH, 25°C, 3 h
Traces
H
Sc(OTf)3 (20 mol %), MeCN, –15°C, 7 days
Sc(OTf)3 (20 mol %), MeCN, –15°C, 7 days
Sc(OTf)3 (20 mol %), MeCN, –15°C, 7 days
23
29
51
8a
8b
8c
–-
–
Me
Cl
–
* The product was contaminated with equal amount of compound 7h.
** The precipitate was contaminated with traces of compound 7i.
did not affect the product ratio (Scheme 2, Table 1, entries
16, 17). Therefore, we firstly tried to dissolve the starting
acids 7h,i in boiling MeOH, then added amine 1 and
refluxed the mixture for 45 min.
When the ratio of the reagents was 1:1 the mixture of
compounds 4 and 5 was isolated (Scheme 2, Table 1, entry 20),
while the twofold excess of aminoazole 1 allowed to isolate
pure pyrrolone 5e (R = COOMe, Table 1, entry 21).
However, compound 5f (R = CN) was not synthesized
selectively by this procedure due to the very low solubility
of acid 7i. Carrying out the reaction in refluxing DMF,
meant to increase the solubility of the reagents, resulted in
the tarring of the reaction mixture, therefore, it could not be
applied as a synthetic procedure. The reactions of amine 1
and acids 7f,g (R = Cl, Br) under different conditions
(Table 1, entries 4, 10, 11, 18, 19) always gave furanones
4f,g, contaminated with sufficient amounts of pyrrolones
5c,d. It is interesting that pure compounds 4f,g were
obtained when the starting unsaturated acids 7f,g were
replaced with their potassium salts 6f,g (R1 = K): the
reaction of 3-amino-5-methylisoxazole 1 and the solution
of these salts in acetic acid at 25°C yielded furanones 4f,g
(Scheme 2, Table 1, entries 27, 28). The same results were
obtained in the case of compounds 6a–e (Scheme 2, Table 1,
81

Chemistry of Heterocyclic Compounds 2019, 55(1), 78–89
Scheme 3
entries 22–26). Unfortunately, the reactions of salts 6h,i
gave mixtures of furanones 4 and pyrrolones 5 in very low
yields (Scheme 2, Table 1, entries 29, 30) even after
preliminary dissolving the starting materials.
arylpyruvic acids 10 gave pyrrolones 11 (Scheme 4)
formation of which was observed under a wide range of
conditions (Table 2, entries 1, 2). However, the best results
were obtained when the reaction was carried out in boiling
i-PrOH (Table 2, entry 3). The only drawback was the
formation of a thick mixture that inhibited the reaction. Our
attempts to increase the amount of the solvent to avoid this
effect led to the decreasing of the yields (Table 2, entry 4)
while application of the ultrasonication instead of refluxing
led to the formation of the mixtures containing azomethine
12, acid 10, and product 11 (ratio 1:1:0.3, Scheme 5, Table 2,
entry 5). At the same time, surprisingly, dissolving of all
starting compounds decreased the yield due to the side
reactions (Table 2, entry 6).
There are several possible known side reactions:
decomposition of 3-amino-5-methylisoxazole (1) and aryl-
pyruvic acid 10, two-component reaction between amine 1
and aldehyde 2 with the formation of azomethine 12, or
condensation of amine with arylpyruvic acid (Scheme 5),
while the product of the reaction between aromatic
aldehyde and arylpyruvic acid could not be isolated. Thus,
we tried to increase the yields of target pyrrolone 11 by
variation of starting material ratio. The application of the
excess of amine 1 and/or aldehyde 2 did not affect the
yields while a twofold excess of arylpyruvic acid 10
significantly improved them (Table 2, entry 9). Analysis of
the mother liquor showed that it contained acid 10, target
compound 11 with traces of starting aldehyde 2, however,
the mass of the solid residue was smaller than calculated
value, which indirectly indicated the decomposition of both
amine 1 and acid 10. The replacement of the second
equivalent of acid 11 with trifluoroacetic acid did not
increase the yield, that points to the influence of the
arylpyruvic acid but not additional acidity (Table 2, entry 10)
When the potassium salt of arylpyruvic acid was used
instead of acid the formation of pyrrolones was not observed.
Carrying out the reaction with twofold excess of acid 10
at 70°C still gave the target compound in comparable
yields (Table 2, entries 11, 15–25), however, further
In the next stage, we used ethyl esters of unsaturated
acids 8a–c due to their higher solubility in a wide range of
solvents in comparison with compounds 6 and 7. The
treatment of amine 1 with esters 8 in the EtOH, PhMe,
MeCN, or CH2Cl2 under refluxing or heating at lower
temperatures or under ultrasonication at the room tempe-
rature did not allow to isolate any reaction product. On the
other hand, carrying out the reaction between amine 1 and
ester 8c in acetic acid under reflux gave compound 5с; the
same result was observed in the EtOH–HCl medium.
However, the yields of compound 5 were unreproducible
(20–40%) due to the partial decomposition of 3-amino-
5-methylisoxazole. Therefore, we applied Sc(OTf)3 catalysis
which could increase electrophilicity of the C=O group,
and thus facilitate the reaction.44–46 Indeed, the treatment of
reagents 1 and 8a–c in MeCN in the presence of Sc(OTf)3
gave the single product of the reaction – furanones 5a–c.
The best yields were observed at –15°C with 20 mol %
Sc(OTf)3, but they were below 51% (Scheme 2, Table 1,
entries 31–33). Additionally, it was established that keeping
ester 8c with Sc(OTf)3 in the presence of piperidine
(instead of aminoazole 1 to create basic conditions) in
MeCN for 7 days gave a yellow precipitate which accord-
1
ing to H NMR and X-ray fluorescence data was scandium
salt 9 (Scheme 3). Such coordination with unsaturated acid
instead of triflate anion apparently affects the catalytic
activity of catalyst that may be the reason of lower yields.
Although esters 8 could be replaced by the synthetic pre-
cursors – aromatic aldehydes and ethyl pyruvate, their multi-
component reaction with 3-amino-5-methylisoxazole (1)
did not yield any reaction product and only tarring of the
reaction mixtures was observed in the case of heating them
in HOAc, 1,4-dioxane, or acetonitrile with Sc(OTf)3 catalyst.
The multicomponent reaction between 3-amino-
5-methylisoxazole (1), aromatic aldehydes 2, and
Scheme 4
82

Chemistry of Heterocyclic Compounds 2019, 55(1), 78–89
Table 2. Reaction condition optimization for the synthesis
of 4,5-diaryl-3-hydroxy-1-(5-methylisoxazol-3-yl)-1,5-dihydro-2H-pyrrol-2-ones 11a–l
Entry
Compound
R
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
Compound
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10b
10b
10c
R1
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
Ratio 1:2:10
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
2:1:1
2:2:1
1:1:2
1:1:1
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
Conditions
AcOH (1.5 ml), Δ, 3 h
EtOAc (1.5 ml), Δ, 3 h
i-PrOH (1.5 ml), Δ, 3 h
i-PrOH (5 ml), Δ, 3 h
US (horn), i-PrOH (3 ml), rt, 3 h
i-PrOH (1.5 ml), Δ, 3 h
i-PrOH (1.5 ml), Δ, 3 h
i-PrOH (1.5 ml), Δ, 3 h
i-PrOH (1.5 ml), Δ, 3 h
TFA (1 equiv), i-PrOH (1.5 ml), Δ, 3 h
i-PrOH, 70°C, 3 h
Product Yield, %
1
28
30
2c
11c
11c
11c
11c
11c
11c
11c
11c
11c
11c
11c
11c
11c
11c
11a
11b
11d
11e
11f
11g
11h
11i
2
2c
3
33
2c
4
8
2c
5
Traces*
20**
23
2c
6
2c
7
2c
8
30
2c
9
56
2c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
36
2c
56
2c
i-PrOH, 70°C, 0.5 h
i-PrOH, 70°C, 1 h
30
2c
44
2c
i-PrOH, 70°C, 2 h
50
2c
i-PrOH, 70°C, 3 h
72
2a
2b
2f
Me
i-PrOH, 70°C, 3 h
64
Cl
i-PrOH, 70°C, 3 h
65
COOMe
CN
i-PrOH, 70°C, 3 h
81
2h
2i
i-PrOH, 70°C, 3 h
91
H
i-PrOH, 70°C, 3 h
93
2a
2c
OMe
Cl
H
i-PrOH, 70°C, 3 h
87
Me
H
i-PrOH, 70°C, 3 h
70
2f
COOMe
OMe
COOMe
i-PrOH, 70°C, 3 h
92
2h
2c
10b
10c
11j
11k
11l
Me
Me
i-PrOH, 70°C, 3 h
83
i-PrOH, 70°C, 3 h
84
2h
10c
* A mixture containing aryl pyruvic acid 10a, product 11a, and azomethine 12 was obtained.
** All reactants were separately dissolved in i-PrOH prior to the reaction.
decreasing of the temperature did not allow to isolate the
target heterocycles. Our attempts to decrease the reaction
time resulted in declining yields (Table 2, entries 12–14)
while its increasing results in the formation of a thick
mixture with poor mass transfer.
Thus, we developed synthetic procedures to obtain com-
pounds 4, 5, and 11: the optimal conditions for the
synthesis of furanones 4a–g are stirring of 3-amino-5-methyl-
isoxazole 1 and potassium 4-aryl-2-oxobut-3-enoate 6 at
25°C in AcOH for 3 h, however the suitable procedure for
selective synthesis of compounds 4h,i was not developed;
pyrrolones 5a–c could be synthesized via Sc(OTf)3-cata-
lyzed heterocyclization of 3-amino-5-methylisoxazole (1)
and ethyl 4-aryl-2-oxobut-3-enoate 8a–c in MeCN at 5°C;
pyrrolone 5e could be obtained by the reaction of
4-(4-(methoxycarbonyl)phenyl)-2-oxobut-3-enoic acid 7h
Scheme 5
83

Chemistry of Heterocyclic Compounds 2019, 55(1), 78–89
and twofold excess of 3-amino-5-methylisoxazole (1) in
methanol under refluxing, on the other hand, these condi-
tions aren't suitable for the synthesis of compounds 5d,f
and corresponding methods weren't developed; the optimal
procedure for the synthesis of pyrrolones 11a–l is the
heating of 3-amino-5-methylisoxazole (1), aromatic aldehyde
2, and twofold excess of arylpyruvic acid 10a–c at 70°C in
i-PrOH for 3 h.
The results of our study concerning the two- and three-
component heterocyclization reactions involving 3-amino-
5-methylisoxazole and pyruvic acid derivatives show that
the chemical behavior of 3-amino-5-methylisoxazole (1)
sufficiently differs from the chemical behavior of 5-amino-
3-methylisoxazole that has been described earlier.18 It is
clear that in the most cases, the nucleophilic sites of the
latter in such reactions are NH2 group and 4-CH center of
isoxazole ring while in the analogous reactions of the
former, 4-CH center is never involved in the formation of
final heterocycles.
The reason for such contrast most likely is due to
difference in the electronic structure of these two amino-
isoxazoles that may influence both the center for primary
attack by electrophilic reagent and on the further cascade of
the reactions including energy of possible transition states
and stability of intermediates. This hypothesis calls for the
further detailed studies by means of quantum chemistry,
but even in crystalline state X-ray diffraction analysis
allowed to find significant differences in the structures of
these aminoazoles (Fig. 4).
The analysis of the bond lengths for two isomeric
aminomethylisoxazoles has shown the essential influence
of the amino group position on the electron density
distribution within the cycle in the crystal phase (Fig. 4).
The conjugation between the nitrogen lone pair and the
endocyclic double bond is stronger in 5-amino-3-methyl-
isoxazole: its C–N exocyclic bond is shorter and the degree
of the amino group pyramidalization is smaller as com-
pared to 3-amino-5-methylisoxazole (the sum of bond
angles centered at the nitrogen atom of the amino group is
346° in 3-amino-5-methylisoxazole (1) and 357° in 5-amino-
3-methylisoxazole). It may be caused also by the parti-
cipation of the high electronegative oxygen atom in the
conjugation with the same endocyclic double bond in
5-amino-3-methylisoxazole. It is confirmed additionally by
the elongation of C=C double bond and shortening of the
C–O bond as compared to 3-amino-5-methylisoxazole (1).
The differences in electronic structure between the two
isomers are also observed in solutions according to 13C and
15N NMR data. Thus, the analysis of the 13C NMR data
obtained for 3-amino-5-methylisoxazole (1) and 5-amino-
3-methylisoxazole showed that electronic density on the
C-4 atom of isoxazole ring is higher in the case of 5-amino-
3-methylisoxazole which is manifested the upfield shift of
the signal by 16.57 ppm. Reverse situation is observed with
the signals of the NH2 groups: the 15N NMR experiments
showed that exocyclic nitrogen atom of 3-amino-5-methyl-
isoxazole (1) is more shielded by the electrons in
comparison with the same atom of 5-amino-3-methyl-
isoxazole (difference in 12.4 ppm).42
Figure 4. The molecular structure of a) 3-amino-5-methyl-
isoxazole (1) and b) 5-amino-3-methylisoxazole with atoms repre-
sented by thermal vibration ellipsoids of 50% probability.
The structures of the all compounds synthesized were
1
established via H, 13C NMR studies, mass spectroscopy,
and elemental analysis.
The structure of compounds 4 was also confirmed by 2D
NMR analysis of its representative 4c. Compound 4c can
exist as 4 different structures A–D (Fig. 5). However, the
IR spectrometry data showed the absence of any carboxyl
group, therefore, the structures C and D should be
excluded.
The choice in favor of structure A was made on the basis
of a set of two-dimensional NMR spectra. The most
1
important data was acquired by H–13C HMBC, COSY,
and NOESY experiments (Fig. 6). COSY and NOESY
spectra show that position 4'-CH of the isoxazole moiety is
unsubstituted: COSY spectra contain spin-spin coupling
between 4'-CH proton and CH3 group protons in the
position C-3 with 4J = 1.0 Hz. The 1H–13C HMBC
spectrum confirms the existence of the furanone ring
without correlations between the signals of the furanone
and isoxazole moieties; on the other hand, the NH group
has cross peaks with both rings. The IR spectroscopy data
confirms the presence of furan-2(5H)-one fragment (C=O
1743 cm–1) and NH group (N–H 3336 cm–1). The
1
comparison of H and 13C NMR spectra of compounds 4
with literature data47 for similar furanones confirms the
structure A as well.
Figure 5. Feasible structures of compound 4c.
84

Chemistry of Heterocyclic Compounds 2019, 55(1), 78–89
OMe
OMe
Experimental
1H and 13C NMR spectra were recorded on Bruker
Avance III 300 MHz (300 and 75 MHz, respectively;
1H NMR – compounds 4b–f, 5a–c,e, 11a–c,h,k,l, 13C NMR –
compounds 4a–g, 5a–c,e, 11a–c,e,f,h,j–l) and Varian
H
H
H
H
O
O
N
H
N
H
O
O
1
N
O
N
O
400-MR (400 MHz; H NMR – compounds 4a,g, 11e,f,j)
H
H
H
H
spectrometers. COSY, NOESY, 1H–13C HSQC, and
1H–13C HMBC spectra of compound 4с (400 and 100 MHz
for 1H and 13C NMR spectra, respectively; 1H and
13C NMR – compounds 11d,g,i) were acquired on a Bruker
Avance III 400 MHz spectrometer. DMSO-d6 was used as
solvent and chemical shifts were reported relative to the
residual solvent protons as internal standard (DMSO-d6:
1H NMR – 2.50 ppm, 13C NMR – 39.52 ppm). Mass
spectra were registered on an Advion ExpressionL CMS
mass spectrometer (direct input of sample) applying ESI
(negative ion mode) for compounds 11a–c,e,f,l and APCI
(N2, positive mode) for compounds 4a–g, 5a–c,e, 11d,g–k.
Elemental analyses were conducted on a EuroVector
EA3000 instrument. Melting points were determined on a
Kofler melting point apparatus. Ultrasonication was
performed using standard ultrasonic bath (SELDI, Ukraine)
with working frequency of 44.2 kHz or ultrasonic horn
UZDN (Sumy, Ukraine) at 44.2 kHz (60% of the nominal
power).
H
H
H
H
NOESY
COSY
MeO
H
5
O1
4
2'
2
N
3
1'O
3'
N
H
O
Me5'
4'
1H–13C HMBC
Figure 6. Some important 2D NMR correlations of compound 4c.
The structures of compounds 5 and 11 were proved by
IR and H, 13C NMR spectra together with their compa-
1
rison with literature data. Thus, the NMR data for com-
pounds 5 look very similar to data for compounds 4
excepting the presence of signals for the second isoxazole
The starting α,β-unsaturated acids 7, salts 6, esters 8
were synthesized according to known literature methods.43,49
3-Amino-5-methylisoxazole (1), aldehydes 2, pyruvic acid
(3) are commercially available. Arylpyruvic acids 10 were
obtained according to the known procedure.50
1
ring. The shifts in H NMR spectra for the OH group
(10.74–11.21 ppm) and the 5-CH group of pyrrolone ring
(6.10–6.36 ppm) are in good accordance with chemical
shifts described in the literature for similar compounds.48
The IR data for heterocycles 5b and 11g contains peaks of
lactone moiety C=O at 1693 cm–1 and NH at 3320 cm–1 and
C=O at 1698 cm–1 and enol OH at 3240 cm–1, respectively.
As it was expected, the chemical behavior of 3-amino-
5-methylisoxazole in heterocyclizations with pyruvic acids
significantly differs from chemical behavior of 5-amino-
3-methylisoxazole: only one nucleophilic center of 3-amino-
5-methylisoxazole (NH2 group) takes part in the trans-
formations while in the analogous reactions of 5-amino-
3-methylisoxazole, two nucleophilic centers (NH2 group
and 4-CH center of isoxazole ring) are involved in the
heterocyclizations in most cases. The multicomponent
reactions of 3-amino-5-methylisoxazole with aromatic
aldehyde and pyruvic acids under any studied conditions
gave insufficient results from the viewpoint of purity and
yields of the target compounds, therefore sequential
procedures including preliminary synthesis of arylidene
derivatives of pyruvic acid should be used instead. By the
means of modification of starting pyruvic acids and reaction
conditions several preparative procedures were developed
that allowed synthesis of pure 5-aryl-3-[(5-methylisoxazol-
3-yl)amino]-2(5H)-ones, 5-aryl-1-(5-methylisoxazol-3-yl)-
3-[(5-methylisoxazol-3-yl)amino]-1,5-dihydro-2H-pyrrol-
2-ones, and 4,5-diaryl-3-hydroxy-1-(5-methylisoxazol-
3-yl)-1,5-dihydro-2H-pyrrol-2-ones. The differences in
electronic structure of the above-mentioned aminoazoles
were discussed both in crystalline state (X-ray analysis)
and in solutions (13C, 15N NMR).
Synthesis of 5-aryl-3-[(5-methylisoxazol-3-yl)amino]-
furan-2(5H)-ones 4a–i (General method). Potassium
4-aryl-2-oxobut-3-enoate 6 (1 mmol) was completely dis-
solved in minimum amount of acetic acid at 25°C, and after
that 3-amino-5-methylisoxazole (1) (0.098 g, 1 mmol) was
added. The mixture was stirred at 25°C for 3 h. The preci-
pitate was filtered off, washed with EtOH, and dried on air.
3-[(5-Methylisoxazol-3-yl)amino]-5-phenylfuran-2(5H)-
one (4a). Yield 140 mg (53%), white solid, mp 189–191°C
1
(HOAc). H NMR spectrum, δ, ppm (J, Hz): 2.32 (3H, d,
4J = 1.1, 3-CH3 isoxazole); 6.03 (1H, d, 4J = 1.1,
H-4 isoxazole); 6.22 (1H, d, 3J = 2.2, 5-CH furanone); 6.98
(1H, d, 3J = 2.2, 4-CH furanone); 7.20–7.57 (5H, m, H Ph);
9.47 (1H, s, NH). 13C NMR spectrum, δ, ppm: 12.4; 81.8;
95.3; 123.4; 127.1 (2С); 127.6; 129.3 (2С); 129.4; 137.0;
160.6; 168.8; 169.8. Mass spectrum (APCI), m/z (Irel, %):
257 [M+H]+ (100). Found, %: C 65.46; H 4.75; N 11.01.
C14H12N2O3. Calculated, %: C 65.62; H 4.72; N 10.93.
3-[(5-Methylisoxazol-3-yl)amino]-5-(p-tolyl)furan-2(5H)-
one (4b). Yield 125 mg (46%), white solid, mp 184°C
1
(HOAc). H NMR spectrum, δ, ppm (J, Hz): 2.30 (3H, s,
4
4-CH3C64H4); 2.31 (3H, d, J = 1.1, 3-CH3 isoxazole); 6.03
3
(1H, d, J = 1.1, H-4 isoxazole); 6.17 (1H, d, J = 2.2,
3
5-CH furanone); 6.95 (1H, d, J = 2.2, 4-CH furanone);
7.22 (4H, s, H Ar); 9.45 (1H, s, NH). 13C NMR spectrum,
δ, ppm: 12.3; 21.2; 81.8; 95.3; 123.4; 127.2 (2С); 127.6;
129.8 (2С); 133.9; 138.8; 160.7; 168.8; 169.9. Mass
spectrum (APCI), m/z (Irel, %): 271 [M+H]+ (100). Found, %:
85

Chemistry of Heterocyclic Compounds 2019, 55(1), 78–89
C 66.59; H 5.21; N 10.48. C15H14N2O3. Calculated, %:
(1H, d, 3J = 2.2, 4-CH furanone); 7.22–7.71 (4H, m, H Ar);
9.50 (1H, s, NH). 13C NMR spectrum, δ, ppm: 12.4; 81.0;
95.3; 122.5; 122.9; 127.7; 129.4 (2C); 132.2 (2C); 136.5;
160.6; 168.8; 169.7. Mass spectrum (APCI), m/z (Irel, %):
336 [M+H]+ (100). Found, %: C 50.32; H 3.29; Br 23.70;
N 8.45. C14H11BrN2O3. Calculated, %: C 50.17; H 3.31;
Br 23.84; N 8.36.
C 66.66; H 5.22; N 10.36.
5-(4-Methoxyphenyl)-3-[(5-methylisoxazol-3-yl)amino]-
furan-2(5H)-one (4c). Yield 186 mg (66%), white solid,
mp 192–194°C (HOAc). 1H NMR spectrum, δ, ppm
4
(J, Hz): 2.32 (3H, d, J = 1.1, 3-CH3 isoxazole); 3.76 (3H,
s, 4-CH33OC6H4); 6.03 (1H, d, 4J = 1.1, H-4 isoxazole); 6.16
3
(1H, d, J = 2.2, 5-CH furanone); 6.93 (1H, d, J = 2.2,
5-Aryl-1-(5-methylisoxazol-3-yl)-3-[(5-methylisoxazol-
4-CH furanone); 6.94–7.32 (4H, m, H Ar); 9.45 (1H, s,
NH). 13C NMR spectrum, δ, ppm: 12.4 (3-CH3); 55.6
(4-CH3OC6H4); 81.7 (C-5 furanone); 95.3 (C-4 isoxazole);
114.6 (2C Ar); 123.2 (C-4 furanone); 127.7 (C-3 furanone);
128.6 (C Ar); 128.9 (2C Ar); 160.2 (C Ar); 160.7 (C-1
isoxazole); 168.8 (C-3 isoxazole); 169.9 (C=O). Mass
spectrum (APCI), m/z (Irel, %): 287 [M+H]+ (100). Found, %:
C 63.07; H 4.95; N 9.73. C15H14N2O4. Calculated, %:
C 62.93; H 4.93; N 9.79.
3-yl)amino]-1,5-dihydro-2H-pyrrol-2-ones
5a–c,e.
Method A (for compounds 5a–c). A mixture of ethyl 4-aryl-
2-oxobut-3-enoate 8a–c (0.5 mmol), 3-amino-5-methyl-
isoxazole (1) (0.098 g, 1 mmol), and acetonitrile (0.5 ml)
was cooled to –15°C. After that, Sc(OTf)3 (0.050 g, 0.1 mmol,
20 mol %) was added. The mixture was stirred at –15°C
until all ester was dissolved. After that, the reacting
mixture was left for 7 days at –15°C. The precipitate was
filtered off, washed with acetonitrile, and dried on air.
Method B (for compound 5e). 4-[4-(Methoxycarbonyl)-
phenyl]-2-oxobut-3-enoic acid (7h) (0.234 g, 1 mmol) was
dissolved in minimum amount of refluxing methanol, and
3-amino-5-methylisoxazole (1) (0.196 g, 2 mmol, 2 equiv)
was added. The mixture was heated under reflux for 45 min.
After cooling of the reaction mixture, the solid precipitate
was filtered off and dried on air.
5-(4-Ethoxyphenyl)-3-[(5-methylisoxazol-3-yl)amino]-
furan-2(5H)-one (4d). Yield 183 mg (61%), white solid,
mp 158–159°C (HOAc). 1H NMR spectrum, δ, ppm
3
(J, Hz): 1.31 (3H, t, J = 7.0, 4-CH3CH2OC6H4); 2.32 (3H, s,
3-CH3 isoxazole); 4.02 (2H, q, 3J = 7.0, 4-CH3CH2OC6H4);
6.03 (1H, s, H-4 isoxazole); 6.16 (1H, s, 5-CH furanone);
6.87–7.33 (5H, m, H Ar, 4-CH furanone); 9.44 (1H, s,
NH). 13C NMR spectrum, δ, ppm: 12.4; 15.0; 63.6; 81.7;
95.3; 115.1 (2C); 123.2; 127.7; 128.5; 128.9 (2C); 159.5;
160.7; 168.8; 169.9. Mass spectrum (APCI), m/z (Irel, %):
301 [M+H]+ (100). Found, %: C 64.10; H 5.31; N 9.31.
C16H16N2O4. Calculated, %: C 63.99; H 5.37; N 9.33.
1-(5-Methylisoxazol-3-yl)-3-[(5-methylisoxazol-3-yl)-
amino]-5-phenyl-1,5-dihydro-2H-pyrrol-2-one (5a). Yield
39 mg (23%), white solid, mp 243–245°C (MeCN).
4
1H NMR spectrum, δ, ppm (J, Hz): 2.30 (3H, d, J = 1.1,
4
3-CH3 isoxazole); 2.36 (3H, d, J = 1.1, 3-CH3 isoxazole);
3
5-(4-Fluorophenyl)-3-[(5-methylisoxazol-3-yl)amino]-
furan-2(5H)-one (4e). Yield 136 mg (50%), white solid,
5.79 (1H, d, J = 2.6, 5-CH pyrrolone); 6.05 (1H, d,
3
4J = 1.1, H-4 isoxazole); 6.65 (1H, d, J = 2.6, 4-CH
1
mp 181°C (HOAc). H NMR spectrum, δ, ppm (J, Hz):
pyrrolone); 6.83 (1H, d, 4J = 1.1, H-4 isoxazole); 7.15–7.41
(5H, m, H Ar); 9.38 (1H, s, NH). 13C NMR spectrum,
δ, ppm: 12.3; 12.6; 62.4; 95.3; 95.6; 119.4; 126.9 (2C);
128.3; 129.1 (2C); 130.3; 137.6; 156.5; 160.7; 166.1;
168.5; 170.6. Mass spectrum (APCI), m/z (Irel, %): 337
[M+H]+ (100). Found, %: C 64.33; H 4.83; N 16.54.
C18H16N4O3. Calculated, %: C 64.28; H 4.79; N 16.66.
1-(5-Methylisoxazol-3-yl)-3-[(5-methylisoxazol-3-yl)-
4
2.32 (3H, d, J = 1.1, 3-CH3 isoxazole); 6.03 (1H, d,
4J = 1.1, H-4 isoxazole); 6.23 (1H, d, 3J = 2.2, 5-CH furanone);
3
6.98 (1H, d, J = 2.2, 4-CH furanone); 7.19–7.46 (4H, m,
H Ar); 9.48 (1H, s, NH). 13C NMR spectrum, δ, ppm
(J, Hz): 12.3; 81.1; 95.3; 116.1 (2C, d, JCF = 21.7); 123.1;
127.7; 129.5 (2C, d, JCF = 8.6); 133.2; 160.6; 162.7; 168.8;
169.7. Mass spectrum (APCI), m/z (Irel, %): 275 [M+H]+
(100). Found, %: C 61.24; H 3.98; F 7.02; N 10.09.
C14H11FN2O3. Calculated, %: C 61.31; H 4.04; F 6.93;
N 10.21.
amino]-5-(p-tolyl)-1,5-dihydro-2H-pyrrol-2-one
(5b).
Yield 50 mg (29%), white solid, mp 253–255°C (MeCN).
1H NMR spectrum, δ, ppm (J, Hz): 2.25 (3H, s, 4-CH3C6H4);
4
5-(4-Chlorophenyl)-3-[(5-methylisoxazol-3-yl)amino]-
furan-2(5H)-one (4f). Yield 183 mg (63%), white solid,
2.30 (3H, d, J = 1.0, 3-CH3 isoxazole); 2.35 (3H, d,
3
4J = 1.0, 3-CH3 isoxazole); 5.74 (1H, d, J = 2.6, 5-CH
1
mp 194–196°C (HOAc). H NMR spectrum, δ, ppm (J, Hz):
pyrrolone); 6.05 (1H, d, 4J = 1.0, H-4 isoxazole); 6.63 (1H,
4
3
4
2.32 (3H, d, 4J = 1.0, 3-CH3 isoxazole); 6.02 (1H d, J = 1.0,
d, J = 2.6, 4-CH pyrrolone); 6.81 (1H, d, J = 1.0,
H-4 isoxazole); 7.11 (4H, s, H Ar), 9.36 (1H, s, NH).
13C NMR spectrum, δ, ppm: 12.3; 12.5; 21.1; 62.2; 95.3;
95.6; 119.5; 126.9 (2C); 129.7 (2C); 130.3; 134.5; 137.6;
156.5; 160.7; 166.1; 168.5; 170.6. Mass spectrum (APCI),
m/z (Irel, %): 351 [M+H]+ (100). Found, %: C 65.19;
H 5.14; N 16.04. C19H18N4O3. Calculated, %: C 65.13;
H 5.18; N 15.99.
H-4 isoxazole); 6.24 (1H, d, 3J = 2.2, 5-CH furanone); 6.97
(1H, d, 3J = 2.2, 4-CH furanone); 7.23–7.60 (4H, m, H Ar);
9.49 (1H, s, NH). 13C NMR spectrum, δ, ppm: 12.4; 80.9;
95.3; 123.0; 127.7; 129.1 (2С); 129.3 (2С); 133.9; 136.0;
160.6; 168.8; 169.7. Mass spectrum (APCI), m/z (Irel, %):
291 [M+H]+ (100). Found, %: C 57.90; H 3.75; Cl 12.11;
N 9.77. C14H11ClN2O3. Calculated, %: C 57.84; H 3.81;
Cl 12.19; N 9.64.
5-(4-Chlorophenyl)-1-(5-methylisoxazol-3-yl)-3-[(5-methyl-
isoxazol-3-yl)amino]-1,5-dihydro-2H-pyrrol-2-one (5c).
Yield 94 mg (51%), white solid, mp 250–251°C (MeCN).
5-(4-Bromophenyl)-3-[(5-methylisoxazol-3-yl)amino]-
furan-2(5H)-one (4g). Yield 195 mg (57%), white solid,
1
4
mp 198–200°C (HOAc). H NMR spectrum, δ, ppm (J, Hz):
1H NMR spectrum, δ, ppm (J, Hz): 2.30 (3H, d, J = 1.1,
2.32 (3H, d, 4J = 1.1, 3-CH3 isoxazole); 6.02 (1H, d, 4J = 1.1,
H-4 isoxazole); 6.22 (1H, d, 3J = 2.2, 5-CH furanone); 6.97
3-CH3 isoxazole); 2.36 (3H, d, J = 1.1, 3-CH3 isoxazole);
4
5.80 (1H, d, 3J = 2.6, 5-CH pyrrolone); 6.05 (1H, d, 4J = 1.1,
86

Chemistry of Heterocyclic Compounds 2019, 55(1), 78–89
3
H-4 isoxazole); 6.64 (1H, d, J = 2.6, 4-CH pyrrolone);
6.83 (1H, d, 4J = 1.1, H-4 isoxazole); 7.15–7.52 (4H, m, H Ar);
9.41 (1H, s, NH). 13C NMR spectrum, δ, ppm: 12.3; 12.6;
61.7; 95.3; 95.5; 118.8; 129.0 (2C); 129.1 (2C); 130.6; 132.8;
136.7; 156.5; 160.7; 166.0; 168.5; 170.7. Mass spectrum
(APCI), m/z (Irel, %): 371 [M+H]+ (100). Found, %:
C 58.41; H 4.05; Cl 9.63; N 15.03. C18H15ClN4O3.
Calculated, %: C 58.31; H 4.08; Cl 9.56; N 15.11.
4-(4-Chlorophenyl)-3-hydroxy-5-(4-methoxyphenyl)-
1-(5-methylisoxazol-3-yl)-1,5-dihydro-2H-pyrrol-2-one (11c).
Yield 170 mg (56%), brick-red solid, mp 241–243°C
1
(i-PrOH). H NMR spectrum, δ, ppm (J, Hz): 2.33 (3H, d,
4J = 1.1, 3-CH3 isoxazole); 3.66 (3H, s, 4-CH3OC6H4); 6.15
4
(1H, s, 5-CH pyrrolone); 6.75 (1H, d, J = 1.1, H-4
isoxazole); 6.76–7.33 (4H, m, H Ar); 7.33–7.83 (4H, m,
H Ar); 11.05 (1H, s, 3-OH pyrrolone). 13C NMR spectrum,
δ, ppm: 12.5; 55.4; 60.2; 95.8; 114.2; 123.6; 128.8 (2C); 128.9
(2C); 129.7 (4C); 130.6; 132.5; 143.1; 156.3; 159.4; 165.4;
170.4. Mass spectrum (ESI), m/z (Irel, %): 395 [M(35Cl)–H]–
(100), 397 [M(37Cl)–H]– (31). Found, %: C 63.64; H 4.27;
Cl 8.82; N 7.08. C21H17ClN2O4. Calculated, %: C 63.56;
H 4.32; Cl 8.93; N 7.06.
Methyl 4-{1-(5-methylisoxazol-3-yl)-4-[(5-methylisoxazol-
3-yl)amino]-5-oxo-2,5-dihydro-1H-pyrrol-2-yl}benzoate
(5e). Yield 140 mg (36%), white solid, mp 232–234°C
1
(MeOH). H NMR spectrum, δ, ppm (J, Hz): 2.30 (3H, d,
4J = 1.1, 3-CH3 isoxazole); 2.36 (3H, d, J = 1.0, 3-CH3
4
isoxazole); 3.83 (3H, s, 4-CH3OOCC6H4); 5.88 (1H, d,
3J = 2.6, 5-CH pyrrolone), 6.05 (1H, d, J = 1.1, H-4
4,5-Bis(4-chlorophenyl)-3-hydroxy-1-(5-methylisoxazol-
3-yl)-1,5-dihydro-2H-pyrrol-2-one (11d). Yield 200 mg
4
3
isoxazole); 6.65 (1H, d, J = 2.6, 4-CH pyrrolone); 6.85
4
1
(1H, d, J = 1.0, H-4 isoxazole); 7.35–7.95 (4H, m, H Ar);
(65%), brick-red solid, mp 242–244°C (i-PrOH). H NMR
9.45 (1H, s, NH). 13C NMR spectrum, δ, ppm: 12.3; 12.6;
52.6; 62.0; 95.3; 95.4; 118.5; 127.3 (2C); 129.6; 130.1
(2C); 130.7; 143.3; 156.5; 160.7; 166.0; 166.3; 168.6;
170.8. Mass spectrum (APCI), m/z (Irel, %): 395 [M+H]+
(100). Found, %: C 60.84; H 4.68; N 14.11. C20H18N4O5.
Calculated, %: C 60.91; H 4.60; N 14.21.
spectrum, δ, ppm (J, Hz): 2.34 (3H, s, 3-CH3 isoxazole);
6.25 (1H, s, 5-CH pyrrolone); 6.78 (1H, s, H-4 isoxazole);
7.19–7.79 (8H, m, H 2Ar); 11.14 (1H, s, 3-OH pyrrolone).
13C NMR spectrum, δ, ppm: 12.5; 59.9; 95.7; 123.5; 128.9
(4C); 129.6; 130.3 (2C); 130.4 (2C); 132.8; 133.2; 136.5;
143.4; 156.3; 165.4; 170.6. Mass spectrum (APCI), m/z
(Irel, %): 400 [M(35Cl, 35Cl)]+ (100), 401 [M(35Cl, 37Cl)]+
(22). Found, %: C 60.02; H 3.56; Cl 17.51; N 7.04.
C20H14Cl2N2O3. Calculated, %: C 59.87; H 3.52; Cl 17.67;
N 6.98.
Synthesis of 4,5-diaryl-3-hydroxy-1-(5-methylisoxazol-
3-yl)-1,5-dihydro-2H-pyrrol-2-ones 11a–l (General method).
3-Amino-5-methylisoxazole (1) (0.068 g, 0.75 mmol) and
arylpyruvic acid 10a–c (1.5 mmol) were added to a
solution of aldehyde 2 (0.75 mmol) in i-PrOH (1.5 ml). The
mixture was stirred on the water bath at 70°C for 3 h. After
that, the mixture was filtered and washed with i-PrOH. The
precipitate was heated in i-PrOH (5 ml) for 10 min, filtered
off, washed with i-PrOH, hexane, and dried.
Methyl 4-[3-(4-chlorophenyl)-4-hydroxy-1-(5-methyl-
isoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl]benzoate
(11e). Yield 263 mg (81%), brick-red solid, mp 225°C
1
(MeOH). H NMR spectrum, δ, ppm (J, Hz): 2.33 (3H, d,
4J = 1.1, 3-CH3 isoxazole); 3.78 (3H, s, 4-CH3OOCC6H4);
4
4-(4-Chlorophenyl)-3-hydroxy-1-(5-methylisoxazol-
3-yl)-5-phenyl-1,5-dihydro-2H-pyrrol-2-one (11a). Yield
202 mg (72%), brick-red solid, mp 238–240°C (i-PrOH).
6.33 (1H, s, 5-CH pyrrolone); 6.78 (1H, d, J = 1.1, H-4
isoxazole); 7.27–7.95 (8H, m, H 2Ar); 11.21 (1H, s, 3-OH
pyrrolone). 13C NMR spectrum, δ, ppm: 12.5; 52.6; 60.2;
95.6; 123.5; 128.8 (2C); 128.9 (2C); 129.6 (2C); 129.7
(2C); 129.9; 130.2; 132.8; 142.9; 143.4; 156.2; 165.4;
166.2; 170.6. Mass spectrum (ESI), m/z (Irel, %): 423
[M(35Cl)–H]– (100), 424 [M]– (23), 425 [M(37Cl)–H]– (48).
Found, %: C 62.22; H 4.08; Cl 8.40; N 6.57. C22H17ClN2O5.
Calculated, %: C 62.20; H 4.03; Cl 8.34; N 6.59.
1H NMR spectrum, δ, ppm (J, Hz): 2.33 (3H, d, J = 1.1,
4
3-CH3 isoxazole); 6.21 (1H, s, 5-CH pyrrolone); 6.76 (1H,
4
d, J = 1.1, H-4 isoxazole); 7.10–7.80 (9H, m, H 2Ar);
11.09 (1H, s, 3-OH pyrrolone). 13C NMR spectrum, δ, ppm: 12.5;
60.7; 95.7; 123.8; 128.4 (2C); 128.6; 128.8 (2C); 128.8
(2C); 129.7 (2C); 130.4; 132.6; 137.3; 143.2; 156.3; 165.5;
170.5. Mass spectrum (ESI), m/z (Irel, %): 367 [M(37Cl)–H]–
(48), 366 [M]– (20), 365 [M(35Cl)–H]– (100). Found, %:
C 65.60; H 4.18; Cl 9.54; N 7.75. C20H15ClN2O3. Calculated, %:
C 65.49; H 4.12; Cl 9.66; N 7.64.
4-[3-(4-Chlorophenyl)-4-hydroxy-1-(5-methylisoxazol-
3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl]benzonitrile (11f).
Yield 272 mg (91%), brick-red solid, mp 226°C (MeOH).
4
1H NMR spectrum, δ, ppm (J, Hz): 2.34 (3H, d, J = 1.1,
4-(4-Chlorophenyl)-3-hydroxy-1-(5-methylisoxazol-
3-yl)-5-(p-tolyl)-1,5-dihydro-2H-pyrrol-2-one (11b). Yield
185 mg (64%), brick-red solid, mp 244°C (i-PrOH). 1H NMR
spectrum, δ, ppm (J, Hz): 2.17 (3H, s, 4-CH3C6H4); 2.33 (3H,
d, 4J = 1.1, 3-CH3 isoxazole); 6.16 (1H, s, 5-CH pyrrolone);
3-CH3 isoxazole); 6.36 (1H, s, 5-CH pyrrolone); 6.79 (1H,
4
d, J = 1.1, H-4 isoxazole); 7.23–7.88 (8H, m, H Ar);
11.25 (1H, s, 3-OH pyrrolone). 13C NMR spectrum, δ, ppm:
12.5; 60.0; 95.5; 111.5; 118.8; 123.2; 128.9 (2C); 129.5
(2C); 129.6 (2C); 130.0; 132.8 (3C); 143.3; 143.6; 156.2;
165.4; 170.8. Mass spectrum (ESI), m/z (Irel, %): 390
[M(35Cl)–H]– (100), 391 [M]– (24), 392 [M(37Cl)–H]– (33).
Found, %: C 64.43; H 3.58; Cl 8.92; N 10.67.
C21H14ClN3O3. Calculated, %: C 64.38; H 3.60; Cl 9.05;
N 10.72.
4
6.75 (1H, d, J = 1.1, H-4 isoxazole); 6.99–7.29 (4H, m,
H Ar); 7.31–7.75 (4H, m, H Ar); 11.06 (1H, s, 3-OH
pyrrolone). 13C NMR spectrum, δ, ppm: 12.5; 21.1; 60.4;
95.8; 123.8; 128.3 (2C); 128.8 (2C); 129.4 (2C); 129.7
(2C); 130.5; 132.6; 134.2; 137.9; 143.1; 156.2; 165.5;
170.4. Mass spectrum (ESI), m/z (Irel, %): 379 [M(35Cl)–H]–
(100), 380 [M]– (22), 381 [M(37Cl)–H]– (38). Found, %:
C 66.18; H 4.52; Cl 9.41; N 7.44. C21H17ClN2O3.
Calculated, %: C 66.23; H 4.50; Cl 9.31; N 7.36.
3-Hydroxy-1-(5-methylisoxazol-3-yl)-4,5-diphenyl-1,5-
dihydro-2H-pyrrol-2-one (11g). Yield 235 mg (93%),
white solid, mp 258°C (i-PrOH). 1H NMR spectrum,
δ, ppm (J, Hz): 2.34 (3H, s, 3-CH3 isoxazole); 6.20 (1H, s,
87

Chemistry of Heterocyclic Compounds 2019, 55(1), 78–89
5-CH pyrrolone); 6.77 (1H, s, H-4 isoxazole); 7.08–7.81
Methyl 4-[4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-
3-(p-tolyl)-2,5-dihydro-1H-pyrrol-2-yl]benzoate (11l).
Yield 260 mg (84%), white solid, mp 240–242°C (i-PrOH).
1H NMR spectrum, δ, ppm (J, Hz): 2.21 (3H, s,
(10H, m, H Ph); 10.82 (1H, s, 3-OH pyrrolone). 13C NMR
spectrum, δ, ppm: 12.5; 60.8; 95.8; 125.2; 128.1 (2C);
128.2; 128.4 (2C); 128.5; 128.7 (2C); 128.8 (2C); 137.6;
131.6; 142.7; 156.4; 165.7; 170.4. Mass spectrum (APCI), m/z
(Irel, %): 333 [M+H]+ (100). Found, %: C 72.33; H 4.77;
N 8.50. C20H16N2O3. Calculated, %: C 72.28; H 4.85; N 8.43.
3-Hydroxy-5-(4-methoxyphenyl)-1-(5-methylisoxazol-
3-yl)-4-phenyl-1,5-dihydro-2H-pyrrol-2-one (11h). Yield
4
4-CH3C6H4); 2.32 (3H, d, J = 1.1, 3-CH3 isoxazole); 3.77
(3H, s, 4-CH3OOCC6H4); 6.28 (1H, s, 5-CH pyrrolone);
4
6.78 (1H, d, J = 1.1, H-4 isoxazole); 7.05–7.88 (8H, m,
H Ar); 10.84 (1H, s, 3-OH pyrrolone). 13C NMR spectrum,
δ, ppm: 12.5; 21.3; 52.5; 60.3; 95.6; 125.2; 127.9 (2C);
128.4; 128.8 (2C); 129.4 (2C); 129.6 (2C); 137.9; 129.8;
142.3; 143.4; 156.3; 165.7; 166.2; 170.5. Mass spectrum
(ESI), m/z (Irel, %): 403 [M–H]– (100), 404 [M]– (44).
Found, %: C 68.24; H 5.04; N 6.98. C23H20N2O5.
Calculated, %: C 68.31; H 4.98; N 6.93.
1
240 mg (87%), white solid, mp 248°C (i-PrOH). H NMR
4
spectrum, δ, ppm (J, Hz): 2.33 (3H, d, J = 1.1, 3-CH3
isoxazole); 3.65 (3H, s, 4-CH3OC6H4); 6.15 (1H, s, 5-CH
pyrrolone); 6.75 (1H, d, 4J = 1.1, H-4 isoxazole); 6.76–7.79
(9H, m, H Ar); 10.80 (1H, s, 3-OH pyrrolone). 13C NMR
spectrum, δ, ppm: 12.5; 55.4; 60.3; 95.8; 114.1 (2C);
125.0; 128.1 (2C); 128.1; 128.7 (2C); 129.1; 129.7 (2C);
131.7; 142.6; 156.3; 159.3; 165.6; 170.3. Mass spectrum
(APCI), m/z (Irel, %): 363 [M+H]+ (100). Found, %:
C 69.68; H 5.08; N 7.71. C21H18N2O4. Calculated, %:
C 69.60; H 5.01; N 7.73.
X-ray structural investigation of 3-amino-5-methyl-
isoxazole (1) and 5-amino-3-methylisoxazole. The crystals of
3-amino-5-methylisoxazole (C4H6N2O) are triclinic. At 293 K:
a 5.3016(8), b 7.257(1), c 7.4066(9) Å; α 68.56(1), β 83.83(1),
γ 71.19(1)°; V 251.04(6) Å3, Mr 98.11, Z 2, space group P1¯,
dcalc 1.298 g/cm3, µ(MoKα) 0.097 mm–1, F(000) 104.
Intensities of 1594 reflections (876 independent, Rint 0.009)
were measured on a Xcalibur-3 diffractometer (graphite
monochromated MoKα radiation, CCD detector, ω-scaning,
2Θmax 50°).
The crystals of 5-amino-3-methylisoxazole (C4H6N2O)
are orthorhombic. At 293 K: a 7.4663(6), b 8.8879(7),
c 7.8373(7) Å; V 520.08(7) Å3; Mr 98.11; Z 4; space group
Pna21; dcalc 1.253 g/cm3, μ(MoKα) 0.093 mm–1; F(000) 208.
Intensities of 4663 reflections (1179 independent,
Rint 0.030) were measured on a Xcalibur-3 diffractometer
(graphite monochromated MoKα radiation, CCD detector,
ω-scaning, 2Θmax 60°).
The structures were solved by direct method using the
SHELXTL package.51 Position of the hydrogen atoms were
located from electron density difference maps and refined
by ''riding'' model with Uiso = nUeq of the carrier atom (n = 1.5
for methyl group and n = 1.2 for other hydrogen atoms).
The hydrogen atoms of amino groups were refined using
isotropic approximation. Full-matrix least-squares refine-
ment of the structures against F2 in anisotropic approxi-
mation for non-hydrogen atoms using 876 (3-amino-
5-methylisoxazole (1)), 1078 (5-amino-3-methylisoxazole)
reflections was converged to: wR2 0.097 (R1 0.035 for 789
reflections with F > 4σ(F), S 1.100) for structure of 3-amino-
5-methylisoxazole (1) and wR2 0.056 (R1 0.027 for
700 reflections with F > 4σ(F), S 0.891) for structure of
5-amino-3-methylisoxazole. The final atomic coordinates
and crystallographic data for molecules of 3-amino-
5-methylisoxazole (1) and 5-amino-3-methylisoxazole have
been deposited at the Cambridge Crystallographic Data
Center (deposits CCDC 1865795 for 3-amino-
5-methylisoxazole (1) and CCDC 1865794 for 5-amino-
3-methylisoxazole).
5-(4-Chlorophenyl)-3-hydroxy-1-(5-methylisoxazol-
3-yl)-4-(p-tolyl)-1,5-dihydro-2H-pyrrol-2-one (11i). Yield
200 mg (70%), brick-red solid, mp 254–256°C (i-PrOH).
1H NMR spectrum, δ, ppm (J, Hz): 2.23 (3H, s,
4-CH3C6H4); 2.34 (3H, s, 3-CH3 isoxazole); 6.20 (1H, s,
5-CH pyrrolone); 6.78 (1H, s, H-4 isoxazole); 7.03–7.71
(8H, m, H Ar); 10.76 (1H, s, 3-OH pyrrolone). 13C NMR
spectrum, δ, ppm: 12.5; 21.3; 60.0; 95.6; 125.1; 128.0
(2C); 128.5; 128.8 (2C); 129.4 (2C); 130.3 (2C); 133.0;
136.9; 137.9; 142.2; 156.3; 165.7; 170.5. Mass spectrum
(APCI), m/z (Irel, %): 381 [M+H]+ (100). Found, %:
C 66.18; H 4.52; Cl 9.22; N 7.40. C21H17ClN2O3. Calcu-
lated, %: C 66.23; H 4.50; Cl 9.31; N 7.36.
Methyl 4-[4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-
3-phenyl-2,5-dihydro-1H-pyrrol-2-yl]benzoate
(11j).
Yield 274 mg (92%), white solid, mp 260–262°C (i-PrOH).
1H NMR spectrum, δ, ppm (J, Hz): 2.33 (3H, d, J = 1.0,
4
3-CH3 isoxazole); 3.77 (3H, s, 4-CH3OOCC6H4); 6.32 (1H,
4
s, 5-CH pyrrolone); 6.79 (1H, d, J = 1.0, H-4 isoxazole);
7.17–7.86 (9H, m, H Ar); 10.99 (1H, br. s, 3-OH pyrrolone).
13C NMR spectrum, δ, ppm: 12.5; 52.6; 60.3; 95.6; 124.9;
128.0 (2C); 128.3; 128.8 (4C); 129.7 (2C); 129.8; 131.3;
142.9; 143.2; 156.3; 165.7; 166.2; 170.6. Mass spectrum
(APCI), m/z (Irel, %): 391 [M+H]+ (100). Found, %:
C 67.74; H 4.71; N 7.12. C22H18N2O5. Calculated, %:
C 67.69; H 4.65; N 7.18.
3-Hydroxy-5-(4-methoxyphenyl)-1-(5-methylisoxazol-
3-yl)-4-(p-tolyl)-1,5-dihydro-2H-pyrrol-2-one (11k). Yield
240 mg (83%), white solid, mp 225–226°C (i-PrOH).
1H NMR spectrum, δ, ppm (J, Hz): 2.22 (3H, s, 4-CH3C6H4);
4
2.33 (3H, d, J = 1.1, 3-CH3 isoxazole); 3.65 (3H, s,
4-CH3OC6H4); 6.10 (1H, s, 5-CH pyrrolone); 6.75 (1H d,
4J = 1.1, H-4 isoxazole); 6.75–7.67 (8H, m, H Ar); 10.74
(1H, br. s, 3-OH pyrrolone). 13C NMR spectrum, δ, ppm:
12.5; 21.3; 55.4; 60.3; 95.8; 114.1 (2C); 125.3; 128.0 (2C);
128.8; 129.3; 129.3 (2C); 129.7 (2C); 137.7; 141.9; 156.3;
159.3; 165.7; 170.3. Mass spectrum (APCI), m/z (Irel, %):
377 [M+H]+ (100). Found, %: C 70.22; H 5.32; N 7.37.
C22H20N2O4. Calculated, %: C 70.20; H 5.36; N 7.44.
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