One-pot diastereoselective synthesis of functionalized 4,5-dihydropyrroles by reactions of arylglyoxals, β-dicarbonyl compounds, and aromatic amines

Article abstract of DOI:10.1007/s10593-019-02544-z

[Figure not available: see fulltext.] A multicomponent reaction of arylglyoxal hydrates, acetylacetone or acetoacetic ester, aniline or its 3(4)-substituted analogs in 1:1:2 ratio occurred upon stirring in methanol, giving 4-arylamino-5-hydroxypyrroline derivatives containing 4,5-dihydroxypyrrolines as impurities.

Full text of DOI:10.1007/s10593-019-02544-z

DOI 10.1007/s10593-019-02544-z
Chemistry of Heterocyclic Compounds 2019, 55(9), 827–833
One-pot diastereoselective synthesis
of functionalized 4,5-dihydropyrroles
by reactions of arylglyoxals, β-dicarbonyl compounds,
and aromatic amines
1
1
1,2
Nadezhda N. Kolos *, Sergey A. Karpan , Irina V. Omelchenko ,
1
2
Natal'ya V. Chechina , Feodor G. Yaremenko
1
V. N. Karazin Kharkiv National University,
4
Svobody Sq., Kharkiv 61022, Ukraine; е-mail: kolos_n@ukr.net
2
Scientific-Technological Complex ''Institute of Monocrystals ," National Academy of Sciences of Ukraine,
0 Nauky Ave., Kharkiv 61072, Ukraine
6
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
019, 55(9), 827–833
Submitted March 21, 2019
Accepted May 19, 2019
2
A multicomponent reaction of arylglyoxal hydrates, acetylacetone or acetoacetic ester, aniline or its 3(4)-substituted analogs in 1:1:2 ratio
occurred upon stirring in methanol, giving 4-arylamino-5-hydroxypyrroline derivatives containing 4,5-dihydroxypyrrolines as impurities.
Keywords: acetylacetone, acetoacetic ester, arylglyoxal hydrates, 4,5-dihydropyrroles, domino reactions.
1
3
Pyrrole derivatives containing two aryl groups at
adjacent positions are found among various classes of
natural and synthetic compounds that show different types
malonodinitrile ). The active electrophilic component in
the latter type of reactions is acetylenedicarboxylate.
14
In an earlier study we developed a simple and effective
approach to the synthesis of tetrasubstituted pyrroles. These
reactions were performed with arylglyoxal hydrates, β-di-
carbonyl compounds (acetylacetone or acetoacetic ester),
and anilines containing halogen substituents at the оrtho
position. The reactants were mixed in 1:1:2 molar ratio in
MeOH with a catalytic amount of HOAc, and the mixtures
were refluxed for 30 min. As a result, 3-acetyl-5-aryl-(3-car-
bonylethoxy)-1-phenyl-2-{[(phenyl)amino]methyl}pyrroles
І were synthesized (Scheme 1).
1
of biological and pharmacological activity. It is known
2
that 1,5-diarylpyrroles act as estrogen receptor ligands, as
3
well as inhibitors of cyclooxygenase-2 receptors and
4
,5
cannabinoid receptors. Derivatives of 4,5-dihydropyrrole
are also of some interest. Enantioselective synthesis of
these compounds has been accomplished by a domino
6
reaction of N-activated aziridines with malonodinitrile,
while trans-4,5-disubstituted 4,5-dihydropyrroles have
7
been obtained in Baylis–Hillman reaction or by reaction
between α,β-unsaturated imines and allyl carbonates.8
The assembly of pyrrole ring via multicomponent
reactions starting from arylglyoxals and arylamines has not
yet been thoroughly studied, and there is a continuing
interest in this type of heterocyclization processes.
Syntheses of polysubstituted pyrroles by Ugi reaction using
anilines, isocyanides, and cyanoacetic (or phosphonoacetic)
The substituents in aniline and arylglyoxal moieties
practically did not affect the reaction duration and product
yields. At the same time, m-(p)-nitroanilines did not form
Scheme 1
9
acid have been reported. A series of publications have
been devoted to the synthesis of pyrrole 1,5-diaryl
derivatives through four-component condensation reactions
of arylglyoxals, arylamines, СН acids (barbituric acid,
10
11
12
acetylacetone, cyclic β-diketones, 4-hydroxycoumarin,
0
009-3122/19/55(9)-0827©2019 Springer Science+Business Media, LLC
827

Chemistry of Heterocyclic Compounds 2019, 55(9), 827–833
Scheme 2
the target products and were recovered from the reaction
mixture. Unsubstituted aniline under the described
experimental conditions formed a complex product mixture
5а, which were successfully separated by column
chromatography. The yield of product 5а, as a rule, did not
exceed 10%. Prolonging the reaction duration to 2.5 h had
no effect on the yield of the major product (Table 1, entry 6).
Raising the reaction temperature reduced the target
product yield both in polar and nonpolar solvents. The
reaction in hexane did not result in the formation of any
new products.
(
according to TLC analysis), which could not be effectively
separated by recrystallization.
The aim of this work was to study three-component
heterocyclization reactions involving aniline, its m-(p)-sub-
stituted derivatives, arylglyoxal hydrates, and β-dicarbonyl
compounds. We studied these condensation reactions by
varying the solvents, reaction temperature and time in the
case when aniline, acetylacetone, and phenylglyoxal
hydrate were selected as starting materials in 2:1:1 ratio.
The results obtained during the optimization of reaction
conditions for the synthesis of compound 4а (Scheme 1)
are presented in Table 1. It was found that stirring the
reactants for 40 min in alcohols (MeOH, EtOH) containing
catalytic amounts of HOAc or HCl at room temperature led
to the formation of heterogeneous white crystalline
precipitate consisting of two products – compounds 4а and
Compounds 4b–k were obtained analogously (Scheme 2,
Table 2). Along with the main products, also in these cases
the formation of impurities – diols 5 was observed. It
should be noted that the reaction proceeded even with
1 equiv of aniline, but the yield in that case was reduced
nearly by one half. The same conditions were used with
p-nitroaniline, giving a low yield of product 4k.
1
The most characteristic signals in Н NMR spectra of
products 4a–k were the doublet of methine group proton at
position 4, as well as the doublet (J = 4.0 Hz) and singlet of
amino and hydroxy groups belonging to the ring positions
Table 1. Optimization of reaction conditions for the synthesis of
compound 4a
Table 2. Yields of 4-arylamino-5-hydroxypyrroles 4a–k
Temperature, Time,
Ar1
Ar2
Entry
Solvent
Catalyst
Yield, %
Compound
R
Yield, %
°
C
min
1
2
3
4
5
6
7
8
9
MeOH
MeOH
EtOH
HOAc
HCl
65
20
80
45
20
20
20
81
20
101
20
45
30
35
18
80
23
60
79
80
62
18
38
31
34
–
4а
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
OEt
Me
OEt
OEt
OEt
Me
Me
Me
Me
Me
79
46
72
63
81
67
70
77
75
81
47
4
b
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
15
4
c
4-O
2
2
NC
NC
6
6
H
4
4
EtOH
15
4
d
4-O
H
MeOH
MeOH
i-PrOH
MeCN
MeCN
Dioxane
Dioxane
Hexane
40
4
e
2-FC
3-FC
4-FC
2-FC
2-FC
2-FC
6
6
6
6
6
6
H
4
H
4
H
4
H
4
H
4
H
4
150
20
4f
30
4
g
40
30
60
4
h
3-ClC
6
H
4
4
1
1
1
0
1
2
4
i
4-ClC
6
H
24 h
4j
4-BrC
6 4
H
1
3
Hexane
HOAc
20
24 h
–
4k
4-O NC H
6
2-FC H4
2
6
4
8
28

Chemistry of Heterocyclic Compounds 2019, 55(9), 827–833
4
and 5, which were observed at 5.9 and 6.3 ppm,
respectively. These signals disappeared as a result of
deuterium exchange, while the Н-4 proton signal became a
singlet. It is interesting to note that the methylene group
protons of the ester fragment were manifested as two
multiplets, indicating their non-equivalence due to steric
hindrance in the molecule, which was attributed to the
presence of arylamino group. The strongest peaks in mass
spectra of products 4b,d–f, obtained on the basis of
+
acetoacetic ester, were those of the [M+Н–H
2
O] ion.
The structures of compounds 4а–k were confirmed by
X-ray structural analysis that was performed for compound
4
а (Fig. 1). The obtained results indicated that the 4-aryl-
amino group and the hydroxy group at position 5 of the
pyrroline ring were in a cisoid sp-configuration (torsion
angle O(1)–C(1)–C(2)–N(2) was equal to –7.0(4)°, the
N(1)–C(1)–C(2)–N(2) angle was equal to –125.9(2)°).
3
Since the spin-spin coupling constant J was practically the
same for compounds 4a–k and 5a, it can be concluded that
the hydroxy groups in compound 5a are also in a cisoid
relationship.
Figure 1. The molecular structure of compound 4а with atoms
The pyrroline ring in compound 4а has a planar confi-
guration, but the length of the N(1)–C(5) bond (1.429(4) Å)
is closer to the average value for nonconjugated bonds
represented by thermal vibration ellipsoids of 50% probability.
(
1.426 Å),15 rather than conjugated bonds (1.371 Å).15
Along with the rotation of substituent at the N(1) atom by
4.8(9)° relative to the pyrroline ring plane, this observa-
Diol 5а was synthesized17 by stirring 4-(phenylamino)-
pent-3-en-2-one and phenylglyoxal hydrate in aqueous
medium at room temperature for 10 min. We also
performed a reaction between aniline, acetylacetone, and
phenylglyoxal in water at 2:1:1 ratio of reactants, obtaining
a complex mixture of products, primarily consisting of the
starting materials due to their low solubility. According to
HPLC-MS analysis of the reaction mixture, the formation
of 4,5-dihydroxypyrroline 5а and trace amounts of
4-arylamino derivative 4а could be also confirmed.
5
tion pointed to the lack of π-conjugation between the benzene
ring and N(1) atom. The rotation can be likely attributed to
the repulsion between substituents at N(1), С(4), and С(3)
atoms (shortened contact С(5)···С(11) 2.97 Å at the sum of
1
6
van der Waals radii 3.42 Å and Н(13)···С(9) (2.61 Å) at
1
6
the sum of van der Waals radii 2.87 Å ), forcing the
benzene rings into a nearly coplanar orientation. At the same
time, the length of the N(1)–C(4) bond was 1.359(4) Å,
indicating the presence of a substantial π-conjugation in
the N(1)–C(4)–C(3) fragment (the average bond length
17,18
4-Arylamino derivatives 4a–k were obtained
as a
result of condensation between enamino ketones and
arylglyoxals in the presence of 1 mol of arylamine. The
cyclization was performed in the presence of catalytic
1
.355 Å). The N(2) atom had a flattened pyramidal
configuration (sum of valence angles equal to 354(2)°) and
showed significant conjugation with the phenyl
a
amounts of FeCl or other Lewis acids, which according to
3
17
substituent (N(2)–C(17) 1.383(4) Å). The configuration of
this substituent facilitated a weak attractive С–Н···π
interaction Н(22)···С(11) 2.82 Å (the sum of van der Waals
radii 2.87 Å).16 The molecules in crystal formed chains
along the [1 0 0] direction via О(1)–H(1)···O(2)' hydrogen
bonds (H···O 1.92 Å, OHO angle 169°) and N(2)–H(2)···O(2)'
hydrogen bonds (H···O 2.35 Å, NHO angle 139°) .
The obtained results allow to propose that the interaction
of reactants at room temperature included the formation of
enamino ketone intermediate А, which reacted with
arylglyoxal (leading to intermediate С), followed by the
formation of pyrrolines 5 (Scheme 2), which we isolated as
minor products, in agreement with published reports.17 In
the presence of excess arylamine, apparently, both enamino
ketone А and imine В were formed. Nucleophilic addition
of imine В to enamino ketone A and cyclization led to
products 4a–k. Most likely, one of the stereocenters was
established at the Michael adduct formation stage, while
the other was fixed during the ring closure.
the authors of that publication promoted the dehydration
of intermediate С, followed by addition of an arylamine
molecule at the activated double bond and cyclization. In
18
another work, dihydropyrrolines 4 were synthesized
under the conditions of microwave activation in the
presence of added water, with HOAc acting as reaction
promoter. The use of 4-(arylamino)pent-3-en-2-ones and
various arylamines in the reaction allowed to vary the
substituents at positions 1 and 4 of the dihydropyrroline
ring.
Stirring a reaction mixture containing 2 mol of aniline,
acetylacetone, and p-methylphenylglyoxal in MeOH for 4 h
led to the formation of pyrrole 6а. Dehydration of minor
product – diol 5а was not observed under the given
conditions, even though such reaction is well known for the
intermediate 4,5-dihydroxypyrroles and proceeds both in
19
aqueous medium at room temperature and upon heating
in МеOH.1
4,20–22
The attempts to perform dehydration of
compound 4i in the presence of p-toluenesulfonic acid were
8
29

Chemistry of Heterocyclic Compounds 2019, 55(9), 827–833
promoted the formation of α-hydroxy ketone – a product
arising from the alkylation of β-dicarbonyl compounds by
arylglyoxal, while subsequent transformations involving
2
3
mol of оrtho-substituted anilines allowed to obtain
-acetyl-5-aryl-(3-carbonylethoxy)-1-phenyl-2-{[(phenyl)-
amino]methyl}pyrroles.
Experimental
IR spectra were recorded on an Agilent Technologies
Cary 630 FT-IR spectrometer by diffuse reflectance
1
13
method for samples in KBr pellets. Н and C NMR
spectra were acquired on a Varian MR-400 spectrometer
(
400 and 100 MHz, respectively) in DMSO-d , with TMS
6
13
as internal standard. The assignment of С NMR signals
was based on spectra for
a series of analogous
compounds.1 HPLC-MS analyses were performed using
7,18
Figure 2. Molecular structure compound 7а with atoms represented by
thermal vibration ellipsoids of 50% probability.
an Agilent LC/MSD SL system: Zorbax SB-C18 column,
1
.8 µm, 4.6 mm; solvents: a) MeCN–H
2
O + 0.1 %
COOH; chemical
CF COOH; b) 0.1% aqueous CF
3
3
accompanied by pyrroline ring opening and liberation of
the respective p-chloroaniline salt, while TLC analysis
indicated the presence of о-fluorophenylglyoxal and
acetylacetone in the filtrate. Pyrroline ring opening
occurred at the N(1)–C(2) bond, followed by fragmentation
of the molecule, which was in agreement with literature
precedents on the destruction of 4,5-dihydropyrroles.23
During the crystal growth experiments for X-ray
structural analysis of compound 4а from МеОН, another
compound 7а – 3-acetyl-5-hydroxy-4-methoxy-2-methyl-
ionization in the presence of hydrogen. Mass spectrum of
compound 6а was recorded on a Finnigan МАТ INCOS-50
instrument (EI, 70 eV). Elemental analysis was performed
on an EuroVector EА 3000 elemental analyzer. Melting
points were determined on a Kofler bench. The reaction
progress and purity of the obtained compounds were
controlled by TLC using Silufol UV-254 plates with 1:1
PhMe–EtOAc and 10:1 СHCl –2-PrOH mobile phases,
3
visualization in iodine vapor.
Synthesis of compounds 4а–k, 5а, 6а (General
method). A mixture of the appropriate arylamine 1а–e
(2.0 mmol), acetylacetone 2а (0.1 ml, 1.0 mmol) or
acetoacetic ester 2b (0.15 ml, 1.1 mmol), arylglyoxal
hydrate 3а–e (1.0 mmol), and 3-4 drops of НОАс in
MeOH (8 ml) was stirred on a magnetic stirrer for 40 min
(the stirring time was 4 h during the synthesis of compound
6а). The precipitate was filtered off and separated by silica
gel column chromatography, eluent 1:1 hexane–EtOAc.
1-[5-Hydroxy-2-methyl-1,5-diphenyl-4-(phenylamino)-
4,5-dihydro-1H-pyrrol-3-yl]ethan-1-one (4a). Yield
0.30 g (79%), white powder, mp 155–156°С (MeOH)
1
,5-diphenyl-4,5-dihydropyrrole was also isolated. It
should be noted that, according to the data of X-ray
structural analysis (Fig. 2), the configuration of substituent at
the С(4) atom was inverted (the N(1)–C(1)–C(2)–О(2) torsion
angle was equal to +97.7(2)°) and, thus, the relative
configuration of hydroxy and methoxy substituents was
changed to anticlinal (the О(2)–C(1)–C(2)–О(1) angle was
equal to –145.6(2)°). We established that maintaining (or
refluxing) compound 4а in МеОН did not give rise to
noticeable amounts of product 7а. At the same time,
stirring of compound 4а in MeOH with an equivalent
amount of silica gel for 5 h allowed to obtain 4-methoxy-
pyrroline 7а in a low yield. These results indicated that the
1
7
–1
(mp 156–157°С ). IR spectrum, ν, cm : 3378 (NH), 3120
1
(OH), 1615 (C=O), 1200, 1110, 930. H NMR spectrum,
S
N
2 nucleophilic substitution occurred at position 4 of the
δ, ppm (J, Hz): 1.93 (3H, s, CH
3
); 2.26 (3H, s, CH ); 4.45
3
3
3
ring. We also observed the formation of methoxy
derivative during HPLC-MS analysis of wet precipitate of
compound 4а. It is likely that under these conditions
nucleophilic substitution of 4-hydroxy group occurred in
the minor product – diol 5а with a methoxy group in the
presence of silica gel, which can be expected according to
the literature.24 At the same time, HPLC-MS analysis of
purified and dried samples did not show any new products.
Thus, we have developed a method for the synthesis of
polysubstituted cis-4-arylamino-5-hydroxy-4,5-dihydropyr-
roles by a [3+2] diаstereoselective three-component reaction
of arylglyoxal hydrates, arylamines, and β-dicarbonyl
compounds in alcohols at room temperature. It was
established that temperature was a crucial factor in our
studied reactions: the key step at room temperature was the
formation of enamino ketone, while heating of the reactants
(1H, d, J = 4.2, CH); 5.88 (1H, d, J = 4.2, NH); 6.27 (1H,
s, OH); 6.52–6.75 (3H, m, H Ar); 6.97–7.47 (12H, m,
13
H Ar). C NMR spectrum, δ, ppm: 15.3 (CH
3
); 28.7 (CH );
3
68.5 (CH); 94.2 (CH); 108.1; 113.4; 117.0 (2C); 123.6
(2C); 126.7 (2C); 127.5 (2C); 128.6 (2C); 129.1 (2C); 135.9
(2C); 137.8; 146.3; 148.0; 159.4; 192.6 (C=O). Mass spectrum,
+
m/z (Irel, %): 385 [M+Н] (100), 367 (14), 338 (16), 337
(66), 295 (11), 94 (14). Found, %: С 78.02; Н 6.38; N 7.22.
C
25
H
24
N O2. Calculated, %: С 78.10; Н 6.29; N 7.29.
2
Ethyl 5-hydroxy-2-methyl-1,5-diphenyl-4-(phenyl-
amino)-4,5-dihydro-1Н-pyrrole-3-carboxylate
(4b).
Yield 0.19 g (46%), white powder, mp 117–118°С
1
(MeOH). H NMR spectrum, δ, ppm (J, Hz): 0.93 (3H, t,
J = 8.0, CH
CH
5.62 (1H, d, J = 4.4, NH); 6.17 (1H, s, ОH); 6.48–6.67
2
CH
3
); 2.20 (3H, s, CH
3
); 3.87–3.92 (1H, m,
3
2
); 3.97–4.02 (1H, m, CH ); 4.29 (1H, d, J = 4.4, CH);
2
3
8
30

Chemistry of Heterocyclic Compounds 2019, 55(9), 827–833
1
3
+
+
(
3H, m, H Ar); 7.10–7.46 (12H, m, H Ar). C NMR spectrum,
δ, ppm: 14.4 (CH ); 14.8 (CH ); 58.4 (CH ); 69.1 (CH);
2.3 (CH); 114.7; 118.0 (2С); 125.4 (2C); 127.0; 128.6
2С); 128.8 (2C); 128.9 (2С); 130.0 (2С); 130.1 (2С);
433 [M+Н] (78), 415 [M+Н–H
2
O] (100), 360 (20); 340
3
3
2
(65). Found, %: С 72.12; Н 5.66; N 6.80. C26
Calculated, %: С 72.21; Н 5.83; N 6.48.
H
25FN
2
O
3.
9
(
Ethyl 5-(3-fluorophenyl)-5-hydroxy-2-methyl-1-phenyl-
4-(phenylamino)-4,5-dihydro-1Н-pyrrole-3-carboxylate
(4f). Yield 0.29 g (67%), white powder, mp 124–125°С
1
37.8; 144.1; 149.7; 160.2; 165.9 (C=O). Mass spectrum, m/z
+
+
(
(
I
rel, %): 415 [M+Н] (60), 397 [M+Н–H
2
O] (100), 323
1
25), 322 (13). Found, %: С 75.51; Н 6.43; N 6.58.
(MeOH). H NMR spectrum, δ, ppm (J, Hz): 0.94 (3H, t,
C
26
1
H
26
N
2
O
3
. Calculated, %: С 75.34; Н 6.32; N 6.76.
-[5-Hydroxy-2-methyl-5-(4-nitrophenyl)-1-phenyl-
-(phenylamino)-4,5-dihydro-1H-pyrrol-3-yl]ethan-1-one
4c). Yield 0.31 g (72 %), yellow powder, mp 162–164°С
J = 8.0, CH
CH
5.63 (1H, d, J = 4.2, NH); 6.33 (1H, s, OH); 6.46–6.57
2
CH
3
); 2.18 (3H, s, CH
3
); 3.86–3.90 (1H, m,
3
2
); 3.99–4.03 (1H, m, CH ); 4.33 (1H, d, J = 4.2, CH);
2
3
4
13
(
(3H, H Ar); 6.92–7.45 (11H, m, H Ar). C NMR spectrum,
–
1
(
MeOH). IR spectrum, ν, cm : 3388 (NH), 3100 (OH),
δ, ppm (J, Hz): 14.3 (CH
3
); 14.8 (CH
3
); 58.5 (CH ); 68.9
2
2
1
9
615 (C=O), 1600, 1520 (NO
2
), 1375 (NO
2
), 1220, 1100,
);
); 4.69 (1H, d, J = 4.0, CH); 5.92 (1H, d,
(CH); 93.7 (CH); 112.5; 114.6 (2C); 115.2 (d, JCF = 17.8,
1
2
60. H NMR spectrum, δ, ppm (J, Hz): 1.99 (3H, s, CH
3
CH (CF)); 116.1 (d, JCF = 17.0, CH (CF)); 121.7 (d,
3
4
2
.25 (3H, s, CH
3
JCF = 2.7, C Ar); 127.2; 128.2 (2C); 128.9; 129.0 (2C);
3
3
J = 4.0, NH); 6.45 (1H, s, OH); 6.60–6.75 (6H, m, H Ar);
129.1 (2C); 131.1 (d, JCF = 7.8, C Ar); 133.6; 137.6; 147.1
3 1
7
.15–7.28 (4H, m, H Ar); 7.72 (2H, d, J = 8.0, H Ar); 8.22 (2H,
(d, JCF = 6.6, C Ar); 157.9; 161.6 (d, JCF = 242.0, CF);
13
+
d, J = 8.0, H Ar). C NMR spectrum, δ, ppm: 15.4 (CH
3
);
165.8 (C=O). Mass spectrum, m/z (Irel, %): 433 [M+Н]
+
2
8.8 (CH
3
); 68.6 (CH); 94.2 (CH); 109.1; 112.4; 116.1
(64), 415 [M+Н–H
2
O] (100), 340 (60). Found, %:
(
(
(
2C); 121.6; 126.9 (2C); 128.2 (2C); 128.6 (2C); 129.1
2C); 130.3 (2C); 137.8; 146.3; 146.7; 147.4; 159.5; 193.3
С 72.30; Н 5.64; N 6.90. C26
С 72.21; Н 5.83; N 6.48.
H
25FN O3. Calculated, %:
2
+
C=O). Mass spectrum, m/z (Irel, %): 430 [M+Н] (100),
1-[5-(4-Fluorophenyl)-5-hydroxy-2-methyl-1-phenyl-
4-(phenylamino)-4,5-dihydro-1H-pyrrol-3-yl]ethan-
1-one (4g). Yield 0.28 g (70%), white powder, mp 135–
4
12 (68), 355 (14), 338 (16), 337 (66), 295 (11), 94 (14).
Found, %: С 69.52; Н 5.68; N 9.72. C25
H
23
N
3
O
4.
1
Calculated, %: С 69.92; Н 5.40; N 9.78
136°С (MeOH). H NMR spectrum, δ, ppm (J, Hz): 1.90
3
Ethyl [5-hydroxy-2-methyl-5-(4-nitrophenyl)-1-phenyl-
(3Н, s, CH
3
); 2.19 (3Н, s, CH
3
); 4.45 (1H, d, J = 4.4, CH);
3
4
-(phenylamino)-4,5-dihydro-1Н-pyrrol-3-yl]carboxylate
5.85 (1H, d, J = 4.4, NH); 6.34 (1H, s, OH); 6.50–6.74
13
(
4d). Yield 0.29 g (63%), yellow powder, mp 155–156°С
(3H, m, H Ar); 6.90–7.50 (11H, m, H Ar). C NMR
–
1
(
MeOH). IR spectrum, ν, cm : 3396 (NH), 3150 (br. OH),
spectrum, δ, ppm (J, Hz): 15.1 (CH
3
); 29.1 (CH ); 68.3
3
2
1
645 (C=O), 1580, 1520 (NO
2
), 1400, 1350 (NO
100, 975. H NMR spectrum, δ, ppm (J, Hz): 0.94 (3H, t,
CH ); 2.19 (3H, s, CH ); 3.84–3.87 (1H, m,
); 3.90–3.94 (1H, m, CH ); 4.33 (1H, d, J = 4.0, CH);
.68 (1H, d, J = 4.0, NH); 6.51 (1H, s, OH); 6.56–6.70
6H, m, H Ar); 7.14–7.25 (4H, m, H Ar); 7.70 (2H, d,
2
), 1210,
(CH); 94.5 (CH); 107.5; 114.0; 115.5 (2C, d, JCF = 17.2,
1
4
1
CH (CF)); 117.7; 127.6 (d, JCF = 2.8, C Ar); 128.1; 128.9
3
J = 8.0, СH
2
3
3
(2C); 129.4 (2C); 131.7 (2C); 137.8; 140.1 (2C, d, JCF = 6.2,
3
1
CH
5
(
2
2
CH (CF)); 149.0; 160.2; 161.1; 163.0 (d, JCF = 244.2,
3
C Ar); 192.5 (C=O). Mass spectrum, m/z (Irel, %): 403
+
[M+Н] (100), 385 (32), 310 (12). Found, %: С 74.50;
1
3
J = 8.0, H Ar); 8.21 (2H, d, J = 8.0, H Ar). C NMR
Н 5.71; N 6.75. C25
Н 5.76; N 6.96.
H
2
23FN О2. Calculated, %: С 74.61;
spectrum, δ, ppm: 14.4 (CH
3
); 14.8 (CH
CH); 93.9 (CH); 114.4; 118.0 (2C); 124.3 (2C); 127.0
2C); 127.4; 129.0 (2C); 129.1 (2C); 129.3 (2C); 131.5;
37.4; 147.5; 149.4; 151.3; 160.2; 165.8 (C=O). Mass
3
); 58.5 (CH
2
); 68.5
(
(
1
1-{1-(3-Chlorophenyl)-4-[(3-chlorophenyl)amino]-
5-(2-fluorophenyl)-5-hydroxy-2-methyl-4,5-dihydro-1H-
pyrrol-3-yl}ethan-1-one (4h). Yield 0.36 (77%), white
+
+
–1
spectrum, m/z (Irel, %): 460 [M+Н] (36), 442 [M+Н–H
100), 396 (18), 367 (13), 350 (15), 349 (67), 94 (11).
Found, %: С 67.99; Н 5.53; N 9.06. C26 5. Calculated,
: С 67.96; Н 5.48; N 9.14.
Ethyl [5-(2-fluorophenyl)-5-hydroxy-2-methyl-1-phenyl-
2
O]
powder, mp 150–152°С (MeOH). IR spectrum, ν, cm :
(
3385 (NH), 3170 (br. OH), 1607 (C=O), 1485, 1400, 1280,
1
H
25
N
3
O
950, 1100, 770. H NMR spectrum, δ, ppm (J, Hz): 1.93
3
%
(3H, s, CH
3
); 2.24 (3H, s, CH
3
); 4.57 (1H, d, J = 4.8, CH);
3
6.15 (1H, d, J = 4.8, NH); 6.28–6.42 (3H, m, H Ar); 6.46
4
-(phenylamino)-4,5-dihydro-1Н-pyrrol-3-yl]carboxylate
(1H, s, OH); 6.73–7.23 (7H, m, H Ar); 7.64–7.72 (2H, m,
H Ar). 1 C NMR spectrum, δ, ppm (J, Hz): 15.5 (CH
3
(
4e). Yield 0.35 g (81%), white powder, mp 135–136°С
3
);
1
(
MeOH). H NMR spectrum, δ, ppm (J, Hz): 0.96 (3H, t,
29.0 (CH
3
); 69.7 (CH); 93.5; 108.9; 110.7; 111.6; 115.3 (d,
2
J = 8.0, CH
2
CH
3
); 2.08 (3H, s, CH
3
); 3.86–3.90 (1H, m,
J
CF = 16.9, C (CF); 122.8; 123.7; 123.8; 125.7 (d,
3
4
2
CH
5
(
2
); 3.98–4.02 (1H, m, CH
2
); 4.56 (1H, d, J = 4.0, CH);
J
CF = 3.8, C Ar); 126.7 (d, JCF = 12.6, CH); 129.7; 130.1;
3
3
3
.63 (1H, d, J = 4.0, NH); 6.49 (1H, s, OH); 6.54–6.74
130.5; 130.8 (d, JCF = 4.2, C Ar); 131.8 (d, JCF =8.6,
1
3
3H, m, H Ar); 6.78–7.50 (11H, m, H Ar). C NMR
C Ar); 133.3; 139.3; 149.7; 157.4; 159.1; 160.6 (d,
1
spectrum, δ, ppm (J, Hz): 13.7 (CH ); 14.3 (CH ); 58.0
3
3
JCF = 245.0, C Ar); 193.5 (C=O). Mass spectrum, m/z
+ + +
(
CH
2
); 67.7 (CH); 91.9 (CH); 114.1 (2С); 116.0 (d,
(Irel, %): 473 [M+Н] (60), 472 [M+Н] (25), 471 [M+Н]
2
4
J
CF = 17.1, CH (CF)); 117.7; 123.9 (d, JCF = 3.0, C Ar);
(100), 346 (31), 345 (24), 344 (89), 302 (10). Found, %:
2
1
26.9; 128.3 (2C); 128.4 (d, JCF = 11.7, C Ar); 128.5 (2C);
С 63.78; Н 4.48; N 5.91. C25
С 63.70; Н 4.49; N 5.94.
H
21Cl
2
FN O2. Calculated, %:
2
3
1
28.6 (2C); 130.2 (d,
JCF = 8.0, C Ar); 130.4 (d,
3
J
CF = 6.0, C Ar); 133.0; 137.3; 148.8; 158.3; 160.4 (d,
1-{1-(4-Chlorophenyl)-4-[(4-chlorophenyl)amino]-
1
J
CF = 244.0, CF); 165.4 (C=O). Mass spectrum, m/z (Irel, %):
5-(2-fluorophenyl)-5-hydroxy-2-methyl-4,5-dihydro-1H-
8
31

Chemistry of Heterocyclic Compounds 2019, 55(9), 827–833
pyrrol-3-yl}ethan-1-one (4i). Yield 0.35 g (75%), white
128.4 (2C); 128.8 (2C); 136.7; 144.3; 148.6; 159.8 (C=C);
–1
+
powder, mp 148–150°С (MeOH). IR spectrum, ν, cm :
191.9 (C=O). Mass spectrum, m/z (Irel, %): 310 [M+Н] (100),
3
9
397 (NH), 3130 (br. OH), 1608 (C=O), 1490, 1405, 1285,
292 (41), 249 (15). Found, %: С 73.70; Н 6.23; N 4.49.
1
60, 1100, 790. H NMR spectrum, δ, ppm (J, Hz): 1.90
C
19
H
19NO . Calculated, %: С 73.77; Н 6.19; N 4.53.
3
3
(
3H, s, CH
3
); 2.22 (3H, s, CH
3
); 4.53 (1H, d, J = 4.0, CH);
1-[2-Methyl-1-phenyl-4-(phenylamino)-5-(p-tolyl)-
1H-pyrrol-3-yl]ethan-1-one (6а). Yield 0.21 g (55%),
6
.00 (1H, d, J = 4.0, NH); 6.40 (1H, s, ОН); 6.72–6.99 (6H,
1
m, H Ar); 7.18 (2H, d, J = 8.0, H Ar); 7.22 (2H, d, J = 8.0,
white powder, mp 169–170°С (MeOH).
H NMR
13
H Ar); 7.65–7.70 (2H, m, H Ar). C NMR spectrum, δ, ppm
J, Hz): 15.5 (CH ); 28.9 (CH ); 70.0 (CH); 93.6; 108.7;
13.4; 115.3 (d, JCF = 18.0, C (CF)); 119.2; 125.9 (d,
spectrum, δ, ppm (J, Hz): 2.13 (3H, s, CH ); 2.28 (6H, s,
3
(
3
3
2CH ); 6.47–6.53 (3H, m, H Ar); 6.92 (2H, d, J = 8.0,
3
2
1
H Ar); 6.95 (2H, d, J = 8.0, H Ar); 7.04–7.27 (5H, m, H Ar,
4
2
13
J
CF = 4.0, C Ar); 126.9 (d, JCF = 10.4, C Ar); 128.3 (2C);
NH); 7.35–7.40 (3H, m, H Ar). C NMR spectrum, δ, ppm:
3
1
28.9 (2C); 129.0 (2C); 129.7 (2C); 130.7 (d, JCF = 3.4, C Ar);
13.5 (CH
3
); 21.1 (СН
3
); 30.4 (CH ); 112.9; 116.7; 119.0;
3
3
1
31.2 (d, JCF = 8.2, C Ar); 136.8; 147.3; 157.7; 160.4 (d,
122.4 (2C); 128.0; 128.7 (2C); 128.8; 129.0 (2C); 129.4
(2C); 129.6 (2C); 129.9 (2C); 130.7; 135.5; 136.4; 137.6;
1
J
CF = 246.0, CF); 193.2 (C=O). Mass spectrum, m/z (Irel, %):
+ + +
+
4
73 [M+Н] (65), 472 [M+Н] (27), 471 [M+Н] (100),
149.5; 194.9 (C=O). Mass spectrum, m/z (Irel, %): 380 [M]
3
62 (12), 347 (10), 346 (36), 344 (99), 302 (10). Found, %:
(100), 154 (16), 76 (5). Found, %: С 82.15; Н 6.28; N 7.30.
С 63.46; Н 4.38; N 6.01. C25
С 63.70; Н 4.49; N 5.94.
H
21Cl
2
FN
2
O
2. Calculated, %:
C
26
H
24
2
N O. Calculated, %: С 82.07; Н 6.36; N 7.36.
5-Hydroxy-4-methoxy-2-methyl-1,5-diphenyl-4,5-dihydro-
1
-{1-(4-Bromophenyl)-4-[(4-bromophenyl)amino]-
1Н-pyrrol-3-yl)ethan-1-one (7а). A mixture of compound
4а (0.38 g, 1 mmol) and silica gel (0.6 g, 1 mmol) in
MeOH (20 ml) was stirred at 50°С for 5 h. The reaction
mixture was evaporated on a rotary evaporator, triturated
with MTBE (5 ml), the crystals that formed were filtered
5
-(2-fluorophenyl)-5-hydroxy-2-methyl-4,5-dihydro-1H-
pyrrol-3-yl}ethan-1-one (4j). Yield 0.45 g (81%), white
–1
powder, mp 148–149°С (MeOH). IR spectrum, ν, cm :
3
1
388 (NH), 3120 (br. OH), 1610 (C=O), 1490, 1408, 1280,
1
080, 765, 630. H NMR spectrum, δ, ppm (J, Hz): 1.91
off and recrystallized from MeOH. Yield 0.1 g (32%),
3
1
(
3H, s, CH
3
); 2.22 (3H, s, CH
3
); 4.52 (1H, d, J = 4.8, CH);
white powder, mp 184–186°С (MeOH).
H NMR
3
6
.03 (1H, d, J = 4.8, NH); 6.36 (1H, s, ОН); 6.71–6.87
spectrum, δ, ppm (J, Hz): 1.92 (3H, s, CH
CH ); 3.43 (3H, s, ОCH ); 4.27 (1H, s, СH); 6.26 (1H, s,
ОH); 6.50–6.70 (3H, m, H Ar); 7.15–7.40 (7H, m, H Ar).
3
); 2.22 (3H, s,
(
3H, m, H Ar); 6.92 (2H, d, J = 8.0 H Ar); 7.13 (2H, d,
3
3
1
3
J = 8.0, Н Ar); 7.37–7.69 (5H, m, H Ar). C NMR
spectrum, δ, ppm (J, Hz): 15.5 (CH ); 29.0 (CH ); 70.0
CH); 93.2; 106.7; 114.1; 115.4 (d, JCF = 19.0, CH); 119.6;
13
3
3
C NMR spectrum, δ, ppm: 15.1 (CH
3
); 29.0 (CH ); 57.3
3
2
(
(OCH ); 96.6 (CH); 108.9; 114.0 (2C); 125.3 (2C); 126.7;
3
4
2
1
25.9 (d, JCF = 3.6, C Ar); 126.4 (d, JCF = 11.2, C Ar);
127.3; 128.0 (2C); 129.8 (2C); 137.3; 137.8; 143.8; 161.0;
3
+
1
1
29.3 (2C); 129.7; 130.8 (d, JCF = 3.7, C Ar); 131.1 (2C);
193.0 (C=O). Mass spectrum, m/z (Irel, %): 324 [M+Н]
3
31.5 (d, JCF = 8.6, C Ar); 131.9 (2С); 132.5 (2C); 138.5;
(65), 306 (60), 293 (10), 292 (15). Found, %: С 74.20;
1
1
59.7; 160.6 (d, JCF = 245.6, C Ar); 193.2 (C=O). Mass
Н 6.38; N 4.30. C20
Н 6.55; N 4.33.
H
21NO . Calculated, %: С 74.28;
3
+
+
spectrum, m/z (Irel, %): 562 [M+Н] (47), 560 [M+Н] (100),
+
5
3
C
59 [M+Н] (50), 544 (35), 542 (90), 541 (30), 496 (18),
27 (15). Found, %: С 53.63; Н 3.68; N 4.98.
4-Chloroaniline p-toluenesulfonate. A mixture of com-
pound 4е (0.11 g, 0.25 mmol) and p-toluenesulfonic acid
(0.02 g, 0.1 mmol) in PhMe (5 ml) was stirred for 2 h at
80°С. The precipitate that formed was filtered off, washed
with PhMe, and air-dried. Yield 0.02 g (57%), white
25
1
H
21Br
2
FN O2. Calculated, %: С 53.60; Н 3.78; N 5.00.
2
-{5-(2-Fluorophenyl)-5-hydroxy-2-methyl-1-(4-nitro-
phenyl)-4-[(4-nitrophenyl)amino]-4,5-dihydro-1H-pyrrol-
-yl}ethan-1-one (4k). Yield 0.23 g (47%), yellow powder,
25
1
3
crystals, mp 228–230°С (MeOH) (mp 230°С ). H NMR
–
1
mp 152–154°С (MeOH). IR spectrum, ν, cm : 3350 (NH),
spectrum, δ, ppm (J, Hz): 2.29 (3H, s, CH ); 7.11 (2H, d,
3
3
120 (br. OH), 1612 (C=O), 1525 (NO
2
), 1500, 1410, 1352
J = 6.2, H Ar); 7.21 (2H, d, J = 6.2, H Ar); 7.45–7.48 (4H,
m, H Ar).
1
(
NO
2
), 1100, 952, 745. H NMR spectrum, δ, ppm (J, Hz):
3
2
.03 (3H, s, CH
3
); 2.28 (3H, s, CH
3
); 4.85 (1H, d, J = 4.6,
X-ray structural analysis of compounds 4а and 7а
was performed on an Xcalibur-3 diffractometer (MoKα
radiation, ССD detector, graphite monochromator, ω-scan-
ning) at room temperature (295–303 K). The structures
CH); 6.53–6.56 (2H, m, NH, OH); 6.68–7.03 (3H, m,
H Ar); 7.45–7.53 (4H, m, H Ar); 7.75–7.80 (3H, m, H Ar);
8
4
.16 (2H, d, J = 8.0, H Ar). Mass spectrum, m/z (Irel, %):
+
2
93 [M+H] (100), 475 (60), 356 (13), 355 (54). Found, %:
were solved directly by F using a full-matrix method of
С 61.02; Н 4.28; N 11.30. C25
С 60.97; Н 4.30; N 11.38.
H
21FN
4
O
6
. Calculated, %:
least squares in anisotropic approximation for non-
2
6
hydrogen atoms with the OLEX2 software
using
SHELXT and SHELXL modules.2
7,28
The hydrogen atom
1-(2-Methyl-1,5-diphenyl-4,5-dihydro-1H-pyrrol-3-yl)-
ethan-1-one (5a). Yield 0.03 g (11%), white powder, mp 132–
positions were determined by difference synthesis of
electron density map and refined according to the riding
model with Uiso = 1.2Uequiv (1.5Uequiv for methyl group).
The positions of hydrogen atoms in hydroxy and amino
groups were determined in isotropic approximation. The
crystallographic data, atomic coordinates, and geometric
parameters of the structures of compounds 4а and 7а were
1
9
1
1
32°С (MeOH) (mp 134°С ). H NMR spectrum, δ, ppm
J, Hz): 1.89 (3Н, s, CH ); 2.21 (3Н, s, CH ); 4.41 (1H, d,
J = 4.0, CH); 5.83 (1H, d, J = 4.0, OH); 6.23 (1H, s, ОH);
.51–6.57 (3H, m, H Ar); 6.95–7.45 (7H, m, H Ar).
(
3
3
3
3
6
1
3
C NMR spectrum, δ, ppm: 14.6 (CH
3
); 28.6 (CH ); 68.0
3
(
CH); 97.2 (CH); 107.0; 113.5; 117.2 (2C); 126.9 (2C);
8
32

Chemistry of Heterocyclic Compounds 2019, 55(9), 827–833
deposited at the Cambridge Crystallographic Data Center
12. Feng, X.; Wang, Q.; Lin, W.; Dou, G.-L.; Huang, Z.-B.; Shi,
D.-Q. Org. Lett. 2013, 15, 2542.
(
deposits CCDC 1889580 and CCDC 1889581,
1
1
3. Mehrabi, H.; Alizadeh-Bami, F.; Ranjbar-Karimi, R. J. Iran.
Chem. Soc. 2018, 15, 1961.
respectively).
4. Kolos, N. N.; Zubar, V. V.; Omelchenko, I. V.; Musatov, V. I.
Chem. Heterocycl. Compd. 2016, 52, 237. [Khim. Geterotsikl.
Soedin. 2016, 52, 237.]
A Supplementary information file containing the crystal
structure parameters for compounds 4а and 7а and
experimental details of X-ray structural analysis is
available at the journal website http://link.springer.com/
journal/10593.
1
5. Structure Correlation; Bürgi, H.-B.; Dunitz, J. D., Eds.; VCH:
Weinheim, 1994, Vol. 2, p. 741.
16. Zefirov, Yu. V.; Zorkii, P. M. Russ. Chem. Rev. 1989, 58,
4
21. [Usp. Khim. 1989, 58, 713.]
References
17. Masoudi, M.; Anary-Abbasinejad, M.; Mohammadi, M. J.
Iran. Chem. Soc. 2016, 13, 315.
1
2
. Bellina, F.; Ross, R. Tetrahedron 2006, 62, 7213.
. Nishiguchi, G. A.; Rodriguez, A. L.; Katzenellenbogen, J. A.
Bioorg. Med. Chem. Lett. 2002, 12, 947.
18. Tong, G.; Xu, H.; Fan, W.; Jiang, B.; Wang, S.; Tu, S. Chin. J.
Chem. 2013, 31, 1039.
3
. Penning, T.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.;
Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.;
Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.;
Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.;
Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med.
Chem. 1997, 40, 1347.
19. Khalili, B.; Jajarmi, P.; Eftekhari-Sis, B.; Hashemi, M. M. J.
Org. Chem. 2007, 73, 2090.
20. Zhang, Z.; Wang, D.; Wang, B.; Liu, Q.; Liu, T.; Zhang, W.;
Yuan, B.; Zhao, Z.; Han, D.; Zhang, G. Tetrahedron 2013, 69,
9063.
21. Feliciano, A. S.; Caballero, E.; Pereira, J. A. P.; Puebla, P.
Tetrahedron 1989, 45, 6553.
4
5
. Francisco, M. E. Y.; Seltzman, H. H.; Gilliam, A. F.;
Mitchell, R. A.; Rider, S. L.; Pertwee, R. G.; Stevenson, L. A.;
Thomas, B. F. J. Med. Chem. 2002, 45, 2708.
22. Caballero, E.; Puebla, P.; Domercq, M.; Medarde, M.;
Lo ́p ez, J.-L.; Feliciano, A. S. Tetrahedron 1994, 50, 7849.
23. Bhat, S. I.; Trivedi, D. R. Tetrahedron Lett. 2013, 54, 5577.
24. Santoro, S.; Battistelli, B.; Gjoka, B.; Si, C.-w. S.; Testaferri, L.;
Tiecco, M.; Santi, C. Synlett 2010, 1402.
. Bailly, C. Curr. Med. Chem.: Anti-Cancer Agents 2004, 4,
363.
6
7
8
9
. Ghorai, M. K; Tiwari, D. P. J. Org. Chem. 2013, 78, 2617.
. Xiang, J.; Xie, H.; Li, Z.; Dang, Q.; Bai, X. Org. Lett. 2015, 17, 3818.
. Li, H.; Luo, J.; Li, B.; Yi, X.; He, Z. Org. Lett. 2017, 19, 5637.
. Eftekhari-Sis, B.; Zirak, M.; Akbari, A. Chem. Rev. 2013,
25. Fahmy, A. F. M.; Aly, N. F.; Nada, A.; Aly, N. Y. Bull.
Chem. Soc. Jpn. 1977, 50, 2678
26. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.;
Puschmann, H. J. Appl. Crystallogr. 2009, 42, 339.
27. Sheldrick, G. M. Acta Crystallogr., Sect. C: Cryst. Struct.
Commun. 2015, C71, 3.
1
13, 2958.
10. Dommaraju, Y.; Prajapati, D. Mol. Diversity 2015, 19, 173.
1. Wang, H.; Liu, X.; Feng, X.; Huang, Z.; Shi, D. Green Chem.
1
28. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found.
Crystallogr. 2008, A64, 112.
2
013, 15. 3307.
8
33