Multicomponent condensation of 1,2-dihydropyrazol-3-one derivatives with carbonyl compounds and Meldrums acid

Article abstract of DOI:10.1007/s11172-015-0982-7

A convenient method for the synthesis of earlier unknown 3-aryl-3-(3-oxo-2,3-dihydro-1H-pyrazol-4-yl)propionic acid derivatives was developed based on the multicomponent condensation of 1,2-dihydropyrazol-3-ones, carbonyl compounds, and Meldrums acid.

Full text of DOI:10.1007/s11172-015-0982-7

Russian Chemical Bulletin, International Edition, Vol. 64, No. 5, pp. 1083—1088, May, 2015
1083
Multicomponent condensation of 1,2ꢀdihydropyrazolꢀ3ꢀone derivatives
with carbonyl compounds and Meldrum´s acid*
B. V. Lichitskii, A. O. Osipov, A. N. Komogortsev, A. A. Dudinov, and M. M. Krayushkin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky prosp., 119991 Moscow, Russian Federation.
Eꢀmail: mkray@ioc.ac.ru
A convenient method for the synthesis of earlier unknown 3ꢀarylꢀ3ꢀ(3ꢀoxoꢀ2,3ꢀdihydroꢀ
1
Hꢀpyrazolꢀ4ꢀyl)propionic acid derivatives was developed based on the multicomponent conꢀ
densation of 1,2ꢀdihydropyrazolꢀ3ꢀones, carbonyl compounds, and Meldrum´s acid.
Key words: multicomponent condensation, Meldrum´s acid, 1,2ꢀdihydropyrazolꢀ3ꢀones,
3
ꢀarylpropionic acids.
1
,2ꢀDihydropyrazolꢀ3ꢀone derivatives possess a wide
Scheme 1
range of biological activity. For example, the products
containing a 1,2ꢀdihydropyrazolꢀ3ꢀone fragment are sugꢀ
1
,2
gested as neuroprotectors and antiemetics. Therefore,
the development of new methods for the synthesis of these
products is an important direction of synthetic chemistry.
The use of multicomponent reactions as an efficient inꢀ
strument in the development and modification of various
3
,4
types of heterocyclic systems, in our opinion, is a conꢀ
venient approach to the preparation of a wide number of
products with certain substituents.
Earlier, we have suggested the methods for the syntheꢀ
sis of fused dihydropyranones 1 and substituted 3ꢀarylproꢀ
pionic acid esters 2 based on the multicomponent conꢀ
densation of hydroxypyridone 3 with aldehydes 4 and Melꢀ
5
drum´s acid (5). Note that the direction of the reaction
depends on the type of the solvent used: the process in
acetonitrile led to the formation of dihydropyranones 1,
whereas esters 2 were formed in alcohols (Scheme 1).
The purpose of the present work is the studies of the
multicomponent reaction of 1,2ꢀdihydropyrazolꢀ3ꢀone deꢀ
rivatives 6 with carbonyl compounds and Meldrum´s acid
(
5), as well as establishing structure and studies of properꢀ
Similarly to the multicomponent condensation for
hydroxypyridone 3 considered above, we studied the reꢀ
5
ties of the products formed. We have shown that the reacꢀ
tion of pyrazolones 6 with aldehydes 4 and Meldrum´s
acid (5) in methanol in the presence of triethylamine used
as a base led to methyl 3ꢀarylꢀ3ꢀ(3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀ
pyrazolꢀ4ꢀyl)propionates 7 in good yields (Scheme 2).
Most likely, unstable dihydropyranones 8 are initially
formed as a result of the multicomponent reaction, which
when treated with methanol undergo the pyran ring openꢀ
ing, leading to the target esters 7.
action of pyrazolones 6 with aldehydes 4 and Meldrum´s
acid (5) in acetonitrile in order to synthesize dihydropyrꢀ
anones 8. However, this the reaction did not lead to the
expected results because of the low stability of compound 8
under conditions of the process. We suggested that the
addition of an extra nucleophilic reagent to the reaction
mixture would lead to the formation of the corresponding
pyran ring opening product. In fact, the use of ammonium
acetate, serving as a source of ammonia, led to 3ꢀarylꢀ
3ꢀ(3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)propionic acid
amides 9 in good yields (Scheme 2).
*
On the occasion of the 100th anniversary of the birth of Acadeꢀ
mician N. K. Kochetkov (1915—2005).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1083—1088, May, 2015.
066ꢀ5285/15/6405ꢀ1083 © 2015 Springer Science+Business Media, Inc.
1

1
084
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 5, May, 2015
Lichitskii et al.
Scheme 2
6
R1
H
Ph
7
a
b
с
d
e
R1
H
H
R2
2ꢀClꢀC H4
7
f
g
h
i
R1
Ph 2ꢀNO ꢀC H
6 4
R2
9
a
b
с
d
e
R1
H
H
H
H
R2
3ꢀPy
4ꢀMeOꢀC H4
9
f
g
h
i
R1
H
H
R2
Ph
a
b
с
6
2
2ꢀMeOꢀC H4
Ph 4ꢀMeOꢀC H4
4ꢀHOꢀ3ꢀMeOꢀC H3
6
6
6
6
EtO C
H
4ꢀMeOꢀC H4
Ph
Ph
Ph
4ꢀClꢀC H4
4ꢀPy
EtO C 3,4ꢀ(MeO) ꢀC H
2
6
2 2 6 3
H 2,5ꢀ(MeO) ꢀC H
H
2,4ꢀCl ꢀC H
EtO C
4ꢀMeOꢀC H4
6
4ꢀClꢀC H4
2
6
3
6
2
6
3
2
Ph
j
Ph 2,4ꢀCl ꢀC H
H
3,4,5ꢀ(MeO) ꢀC H
j
EtO C
2
6
3
3
6
2
2
6
k
Ph
4ꢀMeOꢀC H4
6
Such multicomponent reactions of 1,2ꢀdihydropyraꢀ
confirm the structure of the products suggested by us in
this work.
zolꢀ3ꢀones 6, aldehydes 4, and Meldrum´s acid (5) have
6
been studied earlier. When the reaction was carried out in
In the reactions considered above, various aldehydes
were used as the carbonyl component. It is obvious that
the involvement of ketones into the process under study
will make it possible to considerably broaden the possibilꢀ
ities of this method and vary the range of synthesized prodꢀ
ucts. As in the case of hydroxypyridone 3 (see Ref. 5), the
multicomponent condensation of pyrazolꢀ3ꢀone 6b, aceꢀ
tone, and Meldrum´s acid (5) in methanol in the presence
of triethylamine did not lead to the expected products.
Therefore, to accomplish the synthesis of the target prodꢀ
ucts we preliminary obtained 5ꢀisopropylideneꢀ2,2ꢀdiꢀ
methylꢀ[1,3]dioxaneꢀ4,6ꢀdione 11, the product of the
condensation of acetone and Meldrum´s acid. Its reacꢀ
tion with pyrazolꢀ3ꢀone 6b in methanol and triethylamine
as a base led to the synthesis of ester 12 in good yield
(Scheme 4). Note that for the increase in the yield of the
target product 12, we used a twoꢀfold excess of isopropylꢀ
an ionic liquid using ammonium acetate, the authors obꢀ
1
tained products 10 (Scheme 3). A comparison of the H
and 1 C NMR spectroscopy data, as well as melting points,
3
6
showed that products 10 obtained in the work are identiꢀ
cal to compounds 9 synthesized by us in this work. We
1
13
used 2D H— C HMBC NMR spectroscopy to unamꢀ
biguously confirm the structure 9.
1
13
Figure 1 shows a fragment of the 2D H— C HMBC
spectrum of compound 9d. The spectrum exhibits the
crossꢀpeaks between the signals for the amide protons
H(9), H(9´) ( 6.75 and 7.32) and carbon atom C(8)
(
 172.33), as well as a correlation of the signal for
the protons of the methylene fragment H(7) ( 2.78) with
the signal for carbon atom C(8) ( 172.33). These data
indicate the presence of the CH CONH fragment in
2
2
the structure of product 9d and, hence, unambiguously
Scheme 3

Multicomponent condensation
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 5, May, 2015
1085

1
1
1
1
65
70
75
80
7
6
5
4
3

1
13
Fig. 1. A fragment of the 2D H— C HMBC spectrum of compound 9d (600 MHz, DMSOꢀd ).
6
idene derivative 11, which decomposes to a considerable
degree in the process of the reaction. In contrast to the
reaction involving hydroxypyridone 3, for which the cyclic
dihydropyranone was exclusively obtained, only ester 12
was synthesized when pyrazole 6b was used.
3ꢀarylꢀ3ꢀ(3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)propionic
amides 9. Apparently the processes under study proceed
through the step of the formation of dihydropyranones 8,
which were not isolated in the free form in the case of 1,2ꢀdiꢀ
hydropyrazolꢀ3ꢀone derivatives because of their low stability.
5
Experimental
Scheme 4
1H, 13C, and Hꢀ C HMBC NMR spectra were recorded
1
13
on Bruker AMꢀ300 and Bruker AMꢀ600 spectrometers (300 and
6
00 MHz) in DMSOꢀd . Electrospray ionization (ESI) high resꢀ
6
olution mass spectra were recorded on a Bruker micrOTOF II
instrument. Melting points were measured on a Boetius heating
stage and were not corrected.
7
Compound 6a is commercially available, compounds 6c
8
and 11 were obtained according to the procedures described in
the literature.
5
ꢀBenzylꢀ1,2ꢀdihydropyrazolꢀ3ꢀone (6b). 4ꢀDimethylamiꢀ
nopyridine (4.88 g, 0.04 mol) and Meldrum´s acid (5) (5.76 g,
.04 mol) were dissolved in dichloromethane (40 mL). Phenylꢀ
0
acetic acid (5.44 g, 0.04 mol) was added to this solution with
stirring, then, a solution of DCC (10.30 g, 0.05 mol) in dichloꢀ
romethane (20 mL) was added dropwise. The mixture obtained
was stirred for 6 h and concentrated to a dry residue. Water
(100 mL) was added to this residue, stirred for 30 min, a precipiꢀ
tate of N,N´ꢀdicyclohexylurea was filtered off. The filtrate was
concentrated to a dry residue. A solution of hydrazine hydrate
(
6.00 g, 0.12 mol) in ethanol (10 mL) was added to this residue,
and the mixture was refluxed for 2 h. Then, acetic acid (12.00 g,
.2 mol) was added and concentrated. Water (40 mL) was added
In conclusion, we studied a multicomponent condenꢀ
sation of 1,2ꢀdihydropyrazolꢀ3ꢀones with carbonyl comꢀ
pounds and Meldrum´s acid and showed that the use of
methanol as the solvent leads to the formation of methyl
0
to the residue, and the product was filtered. The yield was 86%,
m.p. 183—185 C (cf. Ref. 9: m.p. 184 C). H NMR (DMSOꢀd ),

1
6
3
ꢀarylꢀ3ꢀ(3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)propionꢀ
: 3.79 (s, 2 H, CH ); 5.22 (s, 1 H, CH); 7.50 (m, 5 H, H );
2
A
r
13
ates 7. Carrying out the reaction in acetonitrile in the
10.51 (br.s, 2 H, NH). C NMR (DMSOꢀd ), : 32.01, 88.60,
6
presence of ammonium acetate allowed us to synthesize
126.10, 128.30, 139.19, 143.23, 160.67. MS (ESI), m/z: found:

1
086
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 5, May, 2015
Lichitskii et al.
+
2 H, NH). 13C NMR (DMSOꢀd ), : 10.18, 36.26, 38.34, 51.08,
1
75.0866 [M + H] . C H N O. Calculated: [M + H] =
1
0
10
2
6
=
175.0871.
Methyl 3ꢀ(5ꢀalkylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ3ꢀ
102.47, 126.47, 128.06, 128.29, 136.40, 144.50, 159.28, 172.00.
Found (%): C, 64.42; H, 6.15; N, 10.90. C H N O (260.30).
14
16
2
3
arylpropionates 7aꢀj (general procedure). A corresponding pyrꢀ
azole 6 (2 mol), Meldrum´s acid (5) (0.33 g, 2.3 mmol), a correꢀ
sponding aldehyde 4 (2.1 mmol), and triethylamine (0.23 g,
Calculated (%): C, 64.60; H, 6.20; N, 10.76.
3ꢀ(5ꢀBenzylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ3ꢀ(2ꢀnitroꢀ
phenyl)propionic acid methyl ester (7f). The yield was 75%, m.p.
1
2
.3 mmol) were mixed in methanol (5 mL). The reaction mixꢀ
211—213 C. H NMR (DMSOꢀd ), : 2.96 (dd, 1 H, H—C—H,
6
ture was refluxed 2 h and concentrated dry, the residue was
recrystallized from aqueous methanol. A precipitate formed was
filtered and washed with aqueous methanol on the filter.
J = 15.8 Hz, J = 7.1 Hz); 3.09 (dd, 1 H, H—C—H, J = 15.8 Hz,
J = 7.8 Hz); 3.45 (s, 3 H, OCH ); 3.77 (m, 2 H, CH ); 4.81
3
2
(t, 1 H, CH, J = 7.2 Hz); 6.76—7.80 (m, 9 H, H ); 10.79 (br.s,
Ar
13
3
ꢀ(2ꢀChlorophenyl)ꢀ3ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀ
2 H, NH). C NMR (DMSOꢀd ), : 30.08, 30.79, 38.49, 51.25,
6
pyrazolꢀ4ꢀyl)propionic acid methyl ester (7a). The yield was 69%,
100.90, 123.72, 126.01, 127.36, 127.83, 128.17, 129.93, 132.81,
138.11, 138.25, 139.62, 148.57, 159.46, 171.25. Found (%):
C, 63.20; H, 4.91; N, 11.17. C H N O (381.39). Calculated (%):
1
m.p. 207—209 C. H NMR (DMSOꢀd ), : 2.06 (s, 3 H, CH );
6
3
2
.92 (dd, 1 H, H—C—H, J = 15.7 Hz, J = 9.3 Hz); 3.12 (dd, 1 H,
20
19
3 5
H—C—H, J = 15.7 Hz, J = 6.5 Hz); 3.51 (s, 3 H, OCH ); 4.60
C, 62.99; H, 5.02; N, 11.02.
3
(
t, 1 H, CH, J = 6.9 Hz); 7.16—7.61 (m, 4 H, HAr); 10.43 (br.s,
3ꢀ(5ꢀBenzylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ3ꢀ(4ꢀmethꢀ
oxyphenyl)propionic acid methyl ester (7g). The yield was 52%,
1
3
2
5
1
H, NH). C NMR (DMSOꢀd ), : 10.09, 32.55, 37.62,
6
1
1.17, 100.75, 126.99, 127.63, 129.05, 129.23, 132.05, 136.78,
41.05, 159.52, 171.60. Found (%): C, 57.24; H, 5.20; N, 9.36.
m.p. 193—195 C. H NMR (DMSOꢀd ), : 2.92 (dd, 1 H,
6
H—C—H, J = 15.6 Hz, J = 7.2 Hz); 3.09 (dd, 1 H, H—C—H,
C H ClN O (294.74). Calculated (%): C, 57.05; H, 5.13;
J = 15.6 Hz, J = 7.9 Hz); 3.45 (s, 3 H, OCH ); 3.68 (s, 3 H,
14
15
2
3
3
N, 9.50.
ꢀ(2ꢀMethoxyphenyl)ꢀ3ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀ
OCH ); 3.79 (m, 2 H, CH ); 4.14 (t, 1 H, CH, J = 7.3 Hz);
3
2
13
3
6.71—7.10 (m, 9 H, H ); 11.30 (br.s, 2 H, NH). C NMR
Ar
pyrazolꢀ4ꢀyl)propionic acid methyl ester (7b). The yield was 54%,
(DMSOꢀd ), : 30.26, 35.35, 38.82, 51.02, 54.87, 102.93, 113.29,
126.03, 128.16, 128.19, 128.21, 136.39, 138.80, 138.85, 157.30,
6
1
m.p. 199—201 C. H NMR (DMSOꢀd ), : 2.06 (s, 3 H, CH );
6
3
2
1
3
.84 (dd, 1 H, H—C—H, J = 15.2 Hz, J = 9.7 Hz); 3.08 (dd,
159.14, 171.94. Found (%): C, 69.04; H, 6.17; N, 7.82. C H N O
(366.42). Calculated (%): C, 68.84; H, 6.05; N, 7.65.
21
22
2
4
H, H—C—H, J = 15.2 Hz, J = 5.5 Hz); 3.49 (s, 3 H, OCH );
3
.76 (s, 3 H, OCH ); 4.51 (t, 1 H, CH, J = 6.5 Hz); 6.82—7.31
3ꢀ(5ꢀBenzylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ3ꢀphenylꢀ
propionic acid methyl ester (7h). The yield was 51%, m.p.
3
13
(
m, 4 H, H ); 10.30 (br.s, 2 H, NH). C NMR (DMSOꢀd ),
Ar 6
1

: 9.89, 28.63, 37.29, 51.01, 55.27, 101.54, 110.47, 119.97, 126.91,
27.66, 131.83, 136.68, 155.90, 159.70, 172.12. Found (%):
C, 61.85; H, 6.30; N, 9.46. C H N O (290.32). Calculated (%):
175—177 C. H NMR (DMSOꢀd ), : 2.95 (dd, 1 H, H—C—H,
6
1
J = 15.7 Hz, J = 7.2 Hz); 3.05 (dd, 1 H, H—C—H, J = 15.7 Hz,
J = 7.8 Hz); 3.46 (s, 3 H, OCH ); 3.80 (m, 2 H, CH ); 4.19
15
18
2
4
3
2
C, 62.06; H, 6.25; N, 9.65.
ꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀ
(t, 1 H, CH, J = 7.2 Hz); 7.05—7.26 (m, 10 H, HAr); 11.54 (br.s,
13
3
2 H, NH). C NMR (DMSOꢀd ), : 30.28, 36.16, 38.52, 51.05,
6
pyrazolꢀ4ꢀyl)propionic acid methyl ester (7c). The yield was 57%,
102.61, 125.76, 126.05, 127.21, 127.92, 128.21, 138.75, 139.07,
144.34, 159.22, 171.90. Found (%): C, 71.22; H, 6.08; N, 8.45.
C H N O (336.39). Calculated (%): C, 71.41; H, 5.99; N, 8.33.
1
m.p. 197—199 C. H NMR (DMSOꢀd ), : 2.02 (s, 3 H, CH );
6
3
3
.01 (dd, 1 H, H—C—H, J = 15.5 Hz, J = 9.5 Hz); 3.18 (dd, 1 H,
20
20
2
3
H—C—H, J = 15.5 Hz, J = 6.5 Hz); 3.49 (s, 3 H, OCH ); 3.69
3ꢀ(5ꢀBenzylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ3ꢀ(4ꢀchloroꢀ
3
(
s, 3 H, OCH ); 4.11 (t, 1 H, CH, J = 6.5 Hz); 7.21 (d, 2 H, H ,
phenyl)propionic acid methyl ester (7i). The yield was 53%, m.p.
3
Ar
1
J = 7.8 Hz); 7.71 (d, 2 H, HAr, J = 7.8 Hz); 10.36 (br.s, 2 H,
NH). C NMR (DMSOꢀd ), : 9.97, 35.51, 51.03, 54.87, 102.78,
163—165 C. H NMR (DMSOꢀd ), : 2.98 (dd, 1 H, H—C—H,
6
13
J = 15.5 Hz, J = 7.2 Hz); 3.00 (dd, 1 H, H—C—H, J = 15.5 Hz,
6
1
13.46, 113.62, 128.09, 136.27, 136.53, 157.37, 159.25, 172.03.
J = 7.9 Hz); 3.46 (s, 3 H, OCH ); 3.82 (m, 2 H, CH ); 4.18
3
2
Found (%): C, 62.35; H, 6.37; N, 9.48. C H N O (290.32).
(t, 1 H, CH, J = 7.9 Hz); 7.05—7.25 (m, 9 H, H ); 10.55 (br.s,
15
18
2
4
Ar
13
Calculated (%): C, 62.06; H, 6.25; N, 9.65.
ꢀ(2,5ꢀDimethoxyphenyl)ꢀ3ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ
2 H, NH). C NMR (DMSOꢀd ), : 30.27, 35.54, 38.35, 51.04,
6
3
102.11, 126.06, 127.78, 128.10, 128.40, 129.07, 130.33, 138.71,
1
Hꢀpyrazolꢀ4ꢀyl)propionic acid methyl ester (7d). The yield was
139.14, 143,28, 159.12, 171.73. MS (ESI), m/z: found: 371.1157
1
+
6
0%, m.p. 182—184 C. H NMR (DMSOꢀd ), : 2.06 (s, 3 H,
[M + H] . C H ClN O . Calculated: [M + H] = 371.1162.
6
20 19
2
3
CH ); 2.84 (dd, 1 H, H—C—H, J = 15.4 Hz, J = 9.6 Hz); 3.06
3ꢀ(5ꢀBenzylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ3ꢀ(2,4ꢀ
dichlorophenyl)propionic acid methyl ester (7j). The yield was
3
(
dd, 1 H, H—C—H, J = 15.4 Hz, J = 6.5 Hz); 3.50 (s, 3 H,
1
OCH ); 3.65 (s, 3 H, OCH ); 3.73 (s, 3 H, OCH ); 4.53 (t, 1 H,
61%, m.p. 213—215 C. H NMR (DMSOꢀd ), : 2.90 (dd, 1 H,
3
3
3
6
CH, J = 6.5 Hz); 6.67—6.94 (m, 3 H, H ); 10.54 (br.s, 2 H,
H—C—H, J = 15.8 Hz, J = 8.5 Hz); 3.00 (dd, 1 H, H—C—H,
Ar
13
NH). C NMR (DMSOꢀd ), : 9.83, 28.74, 37.35, 51.01, 55.07,
J = 15.8 Hz, J = 8.5 Hz); 3.46 (s, 3 H, OCH ); 3.81 (m, 2 H,
6
3
5
1
5.82, 101.49, 110.44, 111.35, 114.79, 133.20, 136.72, 150.10,
52.87, 159.61, 172.03. Found (%): C, 60.23; H, 6.39; N, 8.89.
CH ); 4.61 (t, 1 H, CH, J = 7.9 Hz); 7.02—7.53 (m, 8 H, HAr);
2
13
10.50 (br.s, 2 H, NH). C NMR (DMSOꢀd ), : 30.36, 32.48,
6
C16H20N O (320.35). Calculated (%): C, 59.99; H, 6.29;
37.57, 51.20, 100.46, 125.98, 127.16, 127.93, 128.11, 128.30,
2
5
N, 8.74.
ꢀ(5ꢀMethylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ3ꢀphenylꢀ
propionic acid methyl ester (7e). The yield was 61%, m.p.
130.48, 131.25, 132.85, 138.31, 139.44, 140.26, 159.49, 171.28.
+
3
MS (ESI), m/z: found: 405.0767 [M + H] . C H Cl N O .
2
0
18
2
2
3
Calculated: [M + H] = 405.0773.
1
1
88—190 C. H NMR (DMSOꢀd ), : 2.03 (s, 3 H, CH ); 3.03
3ꢀArylꢀ3ꢀ(5ꢀalkylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)propꢀ
ionic acid amides 9a—k (general procedure). A corresponding
pyrazole 6 (2 mmol), Meldrum´s acid (5) (0.33 g, 2.3 mmol),
a corresponding aldehyde 4 (2.1 mmol), ammonium acetate
6
3
(
dd, 1 H, H—C—H, J = 15.3 Hz, J = 9.5 Hz); 3.11 (dd, 1 H,
H—C—H, J = 15.3 Hz, J = 7.2 Hz); 3.49 (s, 3 H, OCH ); 4.16
3
(
t, 1 H, CH, J = 7.7 Hz); 7.13—7.32 (m, 5 H, H ); 10.35 (br.s,
Ar

Multicomponent condensation
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 5, May, 2015
1087
(
0.46 g, 6 mmol), and triethylamine (0.23 g, 2.3 mmol) were
H—C—H, J = 14.6 Hz, J = 7.3 Hz); 2.86 (dd, 1 H, H—C—H,
J = 14.6 Hz, J = 8.2 Hz); 4.21 (t, 1 H, CH, J = 7.60 Hz); 6.66
mixed in acetonitrile (5 mL). The reaction mixture was refluxed
for 1 h and cooled. A precipitate formed was filtered and washed
aqueous ethanol on the filter.
(s, 1 H, H—N—H); 7.06—7.31 (m, 6 H, H + H—N—H); 10.38
Ar
13
(br.s, 2 H, NH). C NMR (DMSOꢀd ), : 10.18, 35.91, 39.86,
6
3
ꢀ(5ꢀMethylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ3ꢀ(pyriꢀ
103.41, 125.48, 127.31, 127.89, 136.34, 145.26, 159.37, 173.00.
dinꢀ3ꢀyl)ꢀpropionic acid amide (9a). The yield was 71%, m.p.
Found (%): C, 63.85; H, 6.25; N, 17.00. C H N O (245.28).
Calculated (%): C, 63.66; H, 6.16; N, 17.13.
13
15
3
2
1
2
01—203 C. H NMR (DMSOꢀd ), : 2.07 (s, 3 H, CH ); 2.69
6
3
(
dd, 1 H, H—C—H, J = 14.8 Hz, J = 8.0 Hz); 2.93 (dd, 1 H,
3ꢀ(4ꢀHydroxyꢀ3ꢀmethoxyphenyl)ꢀ3ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2,3ꢀdiꢀ
H—C—H, J = 14.8 Hz, J = 6.0 Hz); 4.24 (t, 1 H, CH, J = 7.9 Hz);
hydroꢀ1Hꢀpyrazolꢀ4ꢀyl)propionic acid amide (9g). The yield was
1
6
1
3
1
.67 (s, 1 H, H—N—H); 7.23—8.50 (m, 5 H, H + H—N—H);
63%, m.p. 235—237 C. H NMR (DMSOꢀd ), : 2.07 (s, 3 H,
Ar
6
0.44 (br.s, 2 H, NH). 13C NMR (DMSOꢀd ), : 10.06,
CH ); 2.56 (dd, 1 H, H—C—H, J = 14.5 Hz, J = 7.3 Hz); 2.66
6
3
3.65, 39.22, 102.61, 123.14, 134.74, 136.74, 140.39, 146.80,
48.82, 159.33, 172.63. Found (%): C, 58.74; H, 5.66; N, 22.62.
(dd, 1 H, H—C—H, J = 14.5 Hz, J = 7.7 Hz); 3.68 (s, 3 H, O
CH ); 4.06 (t, 1 H, CH, J = 7.7 Hz); 6.76 (s, 1 H, H—N—H);
3
C12H14N O (246.27). Calculated (%): C, 58.53; H, 5.73;
6.81—7.38 (m, 4 H, H + H—N—H); 8.61 (br.s, 1 H, OH);
4
2
Ar
1
3
N, 22.75.
ꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀ
pyrazolꢀ4ꢀyl)propionic acid amide (9b). The yield was 56%, m.p.
10.53 (br.s, 2 H, NH). C NMR (DMSOꢀd ), : 10.21, 35.55,
6
3
40.38, 55.46, 103.84, 111.81, 114.87, 119.47, 136.29, 136.32,
144.33, 147.01, 159.33, 173.27. MS (ESI), m/z: found: 292.1292
1
+
2
17—219 C. H NMR (DMSOꢀd ), : 2.02 (s, 3 H, CH ); 2.63
[M + H] . C H N O . Calculated: [M + H] = 292.1297.
6
3
14 17
3
4
(
dd, 1 H, H—C—H, J = 14.4 Hz, J = 7.3 Hz); 2.81 (dd, 1 H,
{4ꢀ[2ꢀCarbamoylꢀ1ꢀ(3,4ꢀdimethoxyphenyl)ethyl]ꢀ5ꢀoxoꢀ2,5ꢀ
H—C—H, J = 14.4 Hz, J = 8.3 Hz); 3.69 (s, 3 H, OCH ); 4.15
dihydroꢀ1Hꢀpyrazolꢀ3ꢀyl}acetic acid ethyl ester (9h). The yield
3
1
(
t, 1 H, CH, J = 7.9 Hz); 6.63 (s, 1 H, H—N—H); 6.74 (d, 2 H,
was 49%, m.p. 164—166 C. H NMR (DMSOꢀd ), : 1.12 (t, 3 H,
6
H , J = 8.2 Hz); 7.20 (d, 2 H, H , J = 8.2 Hz); 7.25 (s, 1 H,
CH , J = 7.0 Hz); 2.66 (dd, 1 H, H—C—H, J = 15.2 Hz,
J = 7.4 Hz); 2.80 (dd, 1 H, H—C—H, J = 15.2 Hz, J = 7.9 Hz);
Ar
Ar
3
13
H—N—H); 10.36 (br.s, 2 H, NH). C NMR (DMSOꢀd ),
6

: 10.16, 35.10, 40.19, 54.87, 103.71, 113.27, 128.23, 136.18,
3.51 (m, 2 H, CH ); 3.71 (s, 6 H, 2 OCH ); 3.98 (q, 2 H, CH ,
2
3
2
1
37.31, 157.14, 159.30, 173.07. MS (ESI), m/z: found: 276.1343
J = 6.6 Hz); 4.14 (t, 1 H, CH, J = 7.0 Hz); 6.65 (s, 1 H, H—N—H),
+
[
M + H] . C H N O . Calculated: [M + H] = 276.1348.
6.77—6.94 (m, 3 H, H ); 7.25 (s, 1 H, H—N—H); 11.12 (br.s,
14
17
3
3
Ar
13
3
ꢀ(5ꢀMethylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ4ꢀ(pyriꢀ
2 H, NH). C NMR (DMSOꢀd ), : 13.85, 30.73, 35.27, 39.52,
6
dinꢀ3ꢀyl)ꢀpropionic acid amide (9c). The yield was 60%, m.p.
55.26, 55.47, 60.41, 104.71, 111.41, 111.92, 119.29, 133.31,
137.07, 146.80, 148, 15, 158.72, 169.34, 173.05. Found (%):
C, 57.50; H, 6.05; N, 10.98. C H N O (377.40). Calculated (%):
1
2
57—259 C. H NMR (DMSOꢀd ), : 2.07 (s, 3 H, CH ); 2.74
6 3
(
dd, 1 H, H—C—H, J = 14.8 Hz, J =7.0 Hz); 2.92 (dd, 1 H,
H—C—H, J = 14.8 Hz, J = 8.6 Hz); 4.25 (t, 1 H, CH, J = 7.5 Hz);
.73 (s, 1 H, H—N—H); 7.23 (s, 1 H, H—N—H); 7.30 (d, 2 H,
HAr, J = 5.2 Hz); 8.40 (d, 2 H, HAr, J = 5.2 Hz); 10.55 (br.s, 2 H,
18
23
3 6
C, 57.29; H, 6.14; N, 11.13.
6
{4ꢀ[2ꢀCarbamoylꢀ1ꢀ(4ꢀmethoxyphenyl)ethyl]ꢀ5ꢀoxoꢀ2,5ꢀdiꢀ
hydroꢀ1Hꢀpyrazolꢀ3ꢀyl}acetic acid ethyl ester (9i). The yield was
13
1
NH). C NMR (DMSOꢀd ), : 10.09, 35.26, 38.79, 101.97,
64%, m.p. 193—195 C. H NMR (DMSOꢀd ), : 1.12 (t, 3 H,
6
6
1
22.81, 136.61, 149.16, 153.71, 159.33, 172.53. Found (%):
CH , J = 7.1 Hz); 2.65 (dd, 1 H, H—C—H, J = 14.8 Hz, J = 7.0 Hz);
3
C, 58.74; H, 5.62; N, 22.90. C H N O (246.27). Calculated (%):
2.80 (dd, 1 H, H—C—H, J = 14.8 Hz, J = 8.4 Hz); 3.49 (m, 2 H,
CH ); 3.68 (s, 3 H, OCH ); 3.99 (q, 2 H, CH , J = 7.1 Hz); 4.15
12
14
4 2
C, 58.53; H, 5.73; N, 22.75.
ꢀ(2,4ꢀDichlorophenyl)ꢀ3ꢀ(5ꢀmethylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀ
pyrazolꢀ4ꢀyl)propionic acid amide (9d). The yield was 55%, m.p.
2
3
2
3
(t, 1 H, CH, J = 7.0 Hz); 6.65 (s, 1 H, H—N—H); 6.76 (d, 2 H,
H , J = 8.3 Hz); 7.19 (d, 2 H, H , J = 8.3 Hz); 7.24 (s, 1 H,
Ar
Ar
1
13
2
32—235 C. H NMR (DMSOꢀd ), : 2.07 (s, 3 H, CH ); 2.78
H—N—H); 11.20 (br.s, 2H, NH). C NMR (DMSOꢀd ),
6
3
6
(
(
d, 2 H, CH , J = 7.7 Hz); 4.40 (t, 1 H, CH, J = 7.7 Hz); 6.75
: 13.85, 30.78, 34.81, 39.40, 54.86, 60.43, 104.69, 113.09, 128.40,
133.32, 136.49, 157.15, 158;75, 169.26, 173.03. MS (ESI), m/z:
2
s, 1 H, H—N—H); 7.32 (s, 1 H, H—N—H); 7.33—7.65 (m, 3 H,
HAr); 10.53 (br.s, 2 H, NH). 13C NMR (DMSOꢀd ), : 10.35,
found: 348.1554 [M + H] . C H N O . Calculated: [M + H] =
+
6
17 21
3
5
3
2.26, 38.94, 101.19, 126.89, 128.38, 130.80, 130.94, 133.37,
= 348.1559.
1
36.86, 140.84, 159.70, 172.33. Found (%): C, 49.88; H, 4.08;
{4ꢀ[2ꢀCarbamoylꢀ1ꢀ(4ꢀchlorophenyl)ethyl]ꢀ5ꢀoxoꢀ2,5ꢀdiꢀ
N, 13.51. C H Cl N O (314.17). Calculated (%): C, 49.70;
hydroꢀ1Hꢀpyrazolꢀ3ꢀyl}acetic acid ethyl ester (9j). The yield was
13
13
2
3
2
1
H, 4.17; N, 13.37.
ꢀ(5ꢀMethylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ3ꢀ(3,4,5ꢀ
57%; m.p. 192—194 C. H NMR (DMSOꢀd ), : 1.10 (t, 3 H,
6
3
CH , J= 7.0 Hz); 2.65 (dd, 1 H, H—C—H, J = 14.8 Hz, J = 7.0 Hz);
3
trimethoxyphenyl)propionic acid amide (9e). The yield was 89%,
2.86 (dd, 1 H, H—C—H, J = 14.8 Hz, J = 8.2 Hz); 3.52 (m, 2 H,
CH ); 3.97 (q, 2 H, CH , J = 7.0 Hz); 4.21 (t, 1 H, CH, J = 7.0 Hz);
1
m.p. 246—248 C. H NMR (DMSOꢀd ), : 2.06 (s, 3 H, CH );
6
3
2
2
2
.69 (dd, 1 H, H—C—H, J = 14.5 Hz, J = 7.6 Hz); 2.83 (dd, 2 H,
6.69 (s, 1 H, H—N—H); 7.31 (m, 5 H, H + H—N—H); 11.12
Ar
13
H—C—H, J = 14.5 Hz, J = 6.5 Hz); 3.60 (s, 3 H, OCH ); 3.72
(br.s, 2 H, NH). C NMR (DMSOꢀd ), : 13.82, 30.75, 35.10,
3
6
(
s, 6 H, OCH ); 4.13 (t, 1 H, CH, J = 7.7 Hz); 6.65 (s, 1 H,
39.62, 60.47, 103.93, 127.59, 129.37, 130.08, 133.49, 143.49,
158.78, 169.20, 172;70. MS (ESI), m/z: found: 352.1059 [M + H] .
3
+
H—N—H); 7.18 (s, 1 H, H—N—H); 7.25 (s, 2 H, H ); 10.48
(
Ar
br.s, 2 H, NH). 13C NMR (DMSOꢀd ), : 10.19, 36.34, 40.05,
C H ClN O . Calculated: [M + H] = 352.1064.
6
16 18
3
4
5
1
5.64, 59.83, 103.39, 104.70, 135.44, 136.33, 141.06, 152.34,
59.28, 172.99. MS (ESI), m/z: found: 336.1554 [M + H] .
3ꢀ(5ꢀBenzylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ3ꢀ(4ꢀmethꢀ
oxyphenyl)propionic acid amide (9k). The yield was 53%, m.p.
+
1
C H N O . Calculated: [M + H] = 336.1559.
203—204 C. H NMR (DMSOꢀd ), : 2.64 (dd, 1 H, H—C—H,
16
21
3
5
6
3
ꢀ(5ꢀMethylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ3ꢀphenylꢀ
J = 14.7 Hz, J = 7.1 Hz); 2.83 (dd, 1 H, H—C—H, J = 14.7 Hz,
propionic acid amide (9f). The yield was 74%, m.p. 236—238 C.
J = 8.8 Hz); 3.67 (s, 3 H, OMe); 3.80 (m, 2 H, CH ); 4.21 (t, 1 H,
CH, J = 7.5 Hz); 6.65 (s, 1 H, H—N—H); 6.68—7.26 (m, 10 H,
2
1
H NMR (DMSOꢀd ), : 2.03 (s, 3 H, CH ); 2.71 (dd, 1 H,
6
3

1
088
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 5, May, 2015
Lichitskii et al.
HAr + H—N—H); 10.41 (br.s, 2 H, NH). 13C NMR (DMSOꢀd ),
2. Y. Zhang, R. Benmohamed, H. Huang, T. Chen, C. Voisine,
R. I. Morimoto, D. R. Kirsch, R. B. Silverman, J. Med.
Chem., 2013, 26, 2665.
3. A. M. Shestopalov, A. A. Shestopalov, L. A. Rodinovskaya,
Synthesis, 2008, 1, 1.
6

: 30.31, 35.13, 40.33, 54.85, 103.88, 113.07, 125.99, 128.19,
28.27, 128.39, 137.03, 138.93, 138.97, 157.09, 159.25, 173.04.
Found (%): C, 68.55; H, 5.89; N, 12.09. C H N O (351.41).
1
2
0
21
3
3
Calculated (%): C, 68.36; H, 6.02; N, 11.96.
ꢀ(5ꢀBenzylꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ3ꢀmethꢀ
ylbutanoic acid methyl ester 12. Pyrazole 6b (0.35 g, 2 mmol),
3
4. M. Peuchmaur, Y. Wong, Comb. Chem. High Throughput
Screen., 2008, 11, 587.
5
4
ꢀisopropylideneꢀ2,2ꢀdimethylꢀ1,3ꢀdioxaneꢀ4,6ꢀdione 11 (0.74 g,
mmol), and triethylamine (0.23 g, 2.3 mmol) were mixed in
5. B. V. Lichitskii, A. O. Osipov, A. N. Komogortsev, A. A.
Dudinov, M. M. Krayushkin, Russ. Chem. Bull. (Int. Ed.),
2014, 63, 457 [Izv. Akad. Nauk, Ser. Khim., 2014, 457].
6. Z. Xiao, M. Lei, L. Hu, Tetrahedron Lett., 2011, 52, 7099.
7. EP Pat. 1953148 A1, 2008, 165.
8. J. T. Reeves, D. R. Fandrick, Z. Tan, J. J. Song, S. Rodriguꢀ
ez, B. Qu, S. Kim, O. Niemeier, Z. Li, D. Byrne, S. Campꢀ
bell, A. Chitroda, P. DeCroos, T. Fachinger, V. Fuchs, N. C.
Gonnella, N. Grinberg, N. Haddad, B. Jager, H. Lee, J. C.
Lorenz, S. Ma, B. A. Narayanan, L. J. Nummy, A. Premasiꢀ
ri, F. Roschangar, M. Sarvestani, S. Shen, E. Spinelli, X. Sun,
R. J. Varsolona, N. Yee, M. Brenner, C. H. Senanayake,
J. Org. Chem., 2013, 78, 3616.
methanol (5 mL). The reaction mixture was refluxed for 2 h and
concentrated, the residue was recrystallized from aqueous methꢀ
anol. A precipitate formed was filtered and washed with aqueous
methanol on the filter. The yield was 43%, m.p. 188—190 C.
1
H NMR (DMSOꢀd ), : 1.24 (s, 6 H, 2 CH ); 2.59 (s, 2 H, CH );
6
3
2
3
.44 (s, 3 H, OCH ); 3.96 (s, 2 H, CH ); 7.06 (d, 2 H, H ,
3 2 Ar
J = 7.4 Hz); 7.18 (m, 1 H, H ); 7.28 (m, 2 H, H ); 11,01 (br.s, 2 H,
NH). C NMR (DMSOꢀd ), : 27.79, 31.78, 32.68, 45.12, 50.60,
1
Found (%): C, 66.44; H, 6.87; N, 9.61. C H N O (288.35).
Calculated (%): C, 66.65; H, 6.99; N, 9.72.
Ar
Ar
13
6
06.34, 125.91, 127.60, 128.24, 136.67, 139.87, 159.39, 171;60.
16
20
2
3
9
. S. Guillon, Y. L. Janin, Chem. Eur. J., 2010, 16, 4669.
References
1
. H. Yoshida, H. Yanai, Y. Namiki, K. FukatsuꢀSasaki,
N. Furutani, Tada CNS Drug Rev., 2006, 12, 9.
Received March 16, 2015;
In revised form April 7, 2015