A new facile method for the synthesis of 3-imidazolylpropionic acid N-oxides

Article abstract of DOI:10.1007/s10593-019-02431-7

[Figure not available: see fulltext.] A facile and efficient method for the preparation of 3-imidazolylpropionic acid N-oxides has been developed. It involves condensation of 2-unsubstituted imidazole N-oxide with an aldehyde and Meldrum's acid followed b

Full text of DOI:10.1007/s10593-019-02431-7

DOI 10.1007/s10593-019-02431-7
Chemistry of Heterocyclic Compounds 2019, 55(2), 147–155
A new facile method for the synthesis
of 3-imidazolylpropionic acid N-oxides
1
1
1,2
Anton V. Kutasevich *, Valery P. Perevalov , Vitaly S. Mityanov ,
2
2
2
Boris V. Lichitsky , Andrey N. Komogortsev , Mikhail M. Krayushkin ,
Tatyana Yu. Koldaeva , Vladimir S. Miroshnikov
1
1
1
Department of Fine Organic Synthesis and Chemistry of Dyes,
D. I. Mendeleyev University of Chemical Technology of Russia,
9
Miusskaya Sq., Moscow 125047, Russia; е-mail: kutasevich@muctr.ru
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
7 Leninsky Ave., Moscow 119991, Russia
2
4
Published in Khimiya Geterotsiklicheskikh Soedinenii,
019, 55(2), 147–155
Submitted January 10, 2019
Accepted February 11, 2019
2
A facile and efficient method for the preparation of 3-imidazolylpropionic acid N-oxides has been developed. It involves condensation of
2
-unsubstituted imidazole N-oxide with an aldehyde and Meldrum's acid followed by hydrolysis and decarboxylation of the
corresponding adduct. This method tolerates a broad variation in the structure of starting aldehydes as well as N-oxides.
Keywords: CH acids, imidazole N-oxides, Meldrum's acid, CH functionalization, multicomponent reaction.
Among nitrogen heterocycles, imidazole occupies a
special place as a key structural element of many natural
compounds and drugs. The imidazole core is a part of the
regulators of the most important physiological processes,
nucleic acids, and proteins. It is in the structure of such
vital drugs as econazole, losartan, ethimozole, azomycin,
which are on the list of the best-selling drugs. Therefore,
new approaches for the imidazole cycle functionalization
and modification are an important task in organic chemistry.
Special attention is drawn to the original methodologies
that open new ways toward compounds with functional
groups and fragments that are difficult or impossible to
introduce with known reactions. Reactions that lead to the
formation of carbon–carbon bond from simple precursors
enable the direct synthesis and simple assembly of valuable
synthetic organic building blocks, biologically active
compounds, and natural product scaffolds.4–7
cross-coupling reactions.4 The synthetic methods and
chemical properties of 2-unsubstituted imidazole N-oxides
are described in recent reviews.1
1,12
In our previous works, we have described C(2)-functio-
nalization of 2-unsubstituted imidazole N-oxides via
condensation with aldehydes and various CH acids.1 In
the present study, we developed synthetic protocol suitable
for the preparation of 3-imidazolylpropionic acid N-oxides
by acid hydrolysis of the products of condensation of
imidazole N-oxide with Meldrum's acid and an aldehyde.
We have applied this reaction to the broad scope of
aldehydes and various imidazole N-oxides.
3,14
1–3
It was found that compounds 4a–s, which are products
of condensation of 2-unsubstituted imidazole N-oxides 1a–j
with aldehydes 2a–q and Meldrum's acid (3) could be
smoothly converted into corresponding N-oxides of
3-imidazolylpropionic acids 5a–s by refluxing in 10%
aqueous HCl (Scheme 1). In all cases, the pure reaction
product in the hydrochloride form can be isolated as a
crystalline solid by simple evaporation to dryness of the
reaction mixture. Hydrochloride formation has been
confirmed by the elemental analysis. These hydrochlorides
can be easily transformed into bases by the treatment with
N-oxides of 2-unsubstituted imidazoles are important
precursors for the preparation of various classes of imidazole
derivatives. These compounds are used in nucleophilic kine-
8
substitution reactions, act as 1,3-dipoles in reactions with
various dipolarophiles such as thioketones and dimethyl
9
,10
acetylenedicarboxylate,
and are used in Pd-catalyzed
0
009-3122/19/55(2)-0147©2019 Springer Science+Business Media, LLC
147

Chemistry of Heterocyclic Compounds 2019, 55(2), 147–155
Scheme 1. Synthesis of compounds 5a–s
O–
N+
R1
R1
Me
Me
O
O–
R1
Me Me
O–
O
O
O
N+
N+
1
.HCl, , 15 min
R2
O
O
Me
Me
+
+
OH
O
N
Alk
N
Alk
N
Alk
Me
MeCN
, 5 h
2. NaOAc, rt, 10 min
2
a–q
O
O
R2
5a–s
R2
O
1
a–j
3
4
a–s
–
–
–
–
O
N
OH
O
O
N
OH
O
N
OH
O
O
N
OH
Me
Me
+
Me
Me
+
Me
Me
+
Me
Me
+
O
O
N
N
N
N
Me
Me
SMe
5
a (88%)
5b (89%)
from 4b (53%)
5c (79%)
from 4c (69%)
5d (94%)
from 4d (60%)
from 4a (63%)
–
–
–
–
O
N
OH
O
O
N
O
N
OH
O
O
N
OH
O
OH
O
Me
Me
+
Me
Me
+
Me
Me
+
Me
Me
+
N
N
N
N
Cl
Cl
NO2
HO
S
OMe
5
e (96%)
5
f (90%)
5g (98%)
from 4g (76%)
5h (82%)
from 4h (67%)
from 4e (55%)
from 4f (67%)
–
–
–
O
N
OH
O
O
N
OH
O
N
OH
O
O–
N+
Me
Me
+
Me
Me
+
Me
Me
+
Me
O
OH
N
N
N
N
Me
N
O
OMe
O
Br
NH2
O
OH
OMe
k (76%)
OMe
O
5
5l (94%)
from 4l (85%)
5
i (74%)
from 4i (61%)*
5j (75%)
from 4j (66%)
OMe
from 4k (84%)
O
–
–
–
Me
O
N
OH
O
O
N
OH
O
O
N
OH
O
Me
Me
+
Me
Me
+
–
Me
Me
+
O
N
OH
+
N
N
N
O
O
N
Me
H C
2
Me
Me
5p (90%)
from 4p (29%)
O
Me
OH
OMe
O
Me
MeO
from 4o (83%)
OMe
5
m (79%)
from 4m (42%)
5n (69%)
from 4n (69%)
5o (78%)
–
–
O
N
OH
O
O
N
OH
–
O
N
OH
O
Me
Me
+
Me
Me
+
Me
Me
+
O
N
N
N
O
Me
Me Me
N
OMe
Me
Me
5r (94%)
from 4r (54%)
5s (91%)
from 4s (84%)
Cl
5
q (86%)
from 4q (27%)
*
For the preparation of product 4i, 4-acetamidobenzaldehyde was used, acetyl group fully hydrolyzes in HCl.
1
48

Chemistry of Heterocyclic Compounds 2019, 55(2), 147–155
crude products were used for the further reaction with
α-hydroxyimino ketone in EtOH without purification.
Under these conditions, triazinanes are known to undergo
dissociation, and the formed monomeric formaldehyde imines
(
N-methyleneamines) react with α-hydroxyimino ketones
to give imidazole N-oxides. 1-(Hydroxyimino)-1-(p-tolyl)-
propan-2-one (6) was used for the synthesis of compound
1
h (Scheme 2).
In summary, a new facile synthetic method for the
preparation of 3-imidazolylpropionic acids was developed.
The possibility of introducing into this reaction a broad
scope of aldehydes and imidazole N-oxides, combined with
simple and chromatography-free procedure, makes it a
useful synthetic method for imidazole N-oxide functio-
nalization. The developed synthetic protocol opens a
simple and quick access to imidazole derivatives which are
difficult to synthesize in another way.
1
Figure 1. Fragment of H NMR spectra of compound 5b (upper)
6
and its hydrochloride (lower) in DMSO-d .
Experimental
IR spectra were recorded on a Shimadzu IRAffinity-1
NaOH, NaOAc solution, or even by boiling in water in an
open flask. It should be noted that there are differences in
1
1
13
H NMR spectra of hydrochlorides and corresponding
FTIR spectrophotometer in KBr pellets. H and C NMR
spectra were recorded on a Bruker Avance 300 spectro-
meter (300 and 75 MHz, respectively) or on a JEOL 400
bases (Fig. 1). Protonation of imidazole ring enhances its
acceptor properties and the proton signals of the groups
associated with it are shifted to a weak field.
spectrometer (400 and 151 MHz, respectively) in DMSO-d ,
6
A wide variety of both 2-unsubstituted 1-alkylimidazole
N-oxides and aldehydes, including aromatic, aliphatic, and
formaldehyde (as 37% water solution) can be used in this
reaction. Assembling different combinations of these
building blocks we were able to prepare a library of
functionalized imidazolylpropionic acids 5a–s (Scheme 1).
with TMS as internal standard. High-resolution mass
spectra were registered on a Bruker MicrOTOF ESI-TOF
mass spectrometer. The TLC analysis was performed on
Merck Silica Gel 60 F254 precoated plates. Melting points
were determined on a Kofler hot stage.
All reagents were purchased from commercial suppliers
and used without further purification unless otherwise
noted. (Hydroxyimino)-1-(p-tolyl)propan-2-one (6) was
obtained according to the literature procedure.16 Synthesis
9
14
14
14
15
Starting imidazole N-oxides 1a, 1b, 1c, 1e, 1i,
were obtained according to the literature procedures,
imidazole N-oxides that are not yet described in the
literature (compounds 1d,f,g,h,j) were obtained in analogy
to the mentioned procedures (Scheme 2). 1,3,5-Triazinanes
were synthesized by reaction of the corresponding amine
with paraformaldehyde in MeOH at room temperature. The
1
3
of compounds 4a–g is described in our previous work.
9
14
14
14
15
Imidazole N-oxides 1a, 1b, 1c, 1e, 1i, were obtained
according to the literature procedures.
Synthesis of compounds 4h–s (General method).
A solution of imidazole N-oxide 1h–s (1 mmol), Meldrum's
acid (3) (150 mg, 1 mmol), and the appropriate aldehyde 2
Scheme 2. Synthesis of imidazole N-oxides 1d,f,g,h,j
(
1 mmol) in MeCN (5 ml) was refluxed for 5 h. The
solvent was removed under reduced pressure, and the
residue was crystallized from i-PrOH or it's mixture with
H O to give the corresponding product. All products 4h–s
2
exist in the form of enols with a strong hydrogen bond
between the proton of the hydroxy group of the Meldrum's
acid and the oxygen of the N-oxide moiety. For all
compounds 4h–s, this proton could be observed in the
1
H NMR spectra as a singlet in the 14.65–16.58 ppm
region.
2-[(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-yl)(4-methoxy-
phenyl)methyl]-4,5-dimethyl-1-(thiophen-2-ylmethyl)-1H-
imidazole N-oxide (4h). Yield 315 mg (67%), white solid,
mp 195–197°C. IR spectrum, ν, cm : 3395, 2993, 1651,
1
4
(
–
1
620, 1450, 1357, 1280, 1195, 1111, 1010, 848, 756, 663,
1
55. H NMR spectrum (300 MHz), δ, ppm (J, Hz): 15.85
1H, s, OH); 7.61 (1H, d, J = 4.9, H thiophene); 7.23 (1H,
d, J = 2.9, H thiophene); 7.08–7.05 (1H, m, H thiophene);
.83 (4H, s, H Ar); 6.05 (1H, s, CH); 5.79 (1H, d, J = 16.7,
CH ); 5.67 (1H, d, J = 16.5, CH ); 3.71 (3H, s, OCH );
6
2
2
3
1
49

Chemistry of Heterocyclic Compounds 2019, 55(2), 147–155
1
2
.33 (3H, s, CH
3
); 2.10 (3H, s, CH
3
); 1.62 (6H, s, 2CH
3
).
1015, 931,857, 778, 590, 511, 458. H NMR spectrum
(300 MHz), δ, ppm (J, Hz): 14.65 (1H, s, OH); 7.02 (2H, d,
J = 12.1, H Ar); 6.87 (1H, d, J = 8.4, H Ar); 6.65 (1H, s,
1
3
C NMR spectrum (75 MHz), δ, ppm: 167.0; 158.1;
1
1
40.4; 137.2; 127.7; 127.6; 127.5; 127.3; 122.9; 122.6;
13.8; 101.8; 73.2; 55.0; 43.2; 34.1; 25.4; 8.5; 6.6.
H Ar); 6.62 (1H, s, H Ar); 6.01 (2H, s, OCH
2
O); 5.87 (1H,
); 5.29 (1H, d, J = 16.5,
); 3.69 (3H, s, OCH ); 2.14 (3H, s,
); 1.56 (6H, s, 2CH
+
Found, m/z: 471.1584 [M+H] . C24
m/z: 471.1589.
H
27
N
2
O
6
S. Calculated,
s, CH); 5.46 (1H, d, J = 16.5, CH
2
CH
CH
2
); 3.74 (3H, s, OCH
); 2.10 (3H, s, CH
3
3
13
2
-[(4-Acetamidophenyl)(2,2-dimethyl-4,6-dioxo-1,3-
3
3
3
). C NMR
dioxan-5-yl)methyl]-4,5-dimethyl-1-phenethyl-1H-imidazole
N-oxide (4i). Yield 308 mg (61%), white solid, mp 192–
spectrum (151 MHz), δ, ppm: 190.3; 148.8; 147.9; 147.6;
147.0; 127.9; 122.7; 120.5; 116.0; 115.8; 113.5; 110.5;
–
1
1
1
1
94°C. IR spectrum, ν, cm : 3425, 3302, 3263, 3116,
108.4; 107.2; 106.1; 101.3; 56.5; 55.9; 55.5; 48.2; 36.1;
+
681, 1651, 1604, 1535, 1512, 1365, 1311, 1257, 1195,
25.5; 8.7; 6.6. Found, m/z: 617.1129 [M+H] . C28
H
30BrN
2
O .
9
1
157, 1111, 1002, 925, 763, 570. H NMR spectrum
Calculated, m/z: 617.1134.
(
300 MHz), δ, ppm (J, Hz): 15.65 (1H, s, OH); 9.90 (1H, s,
2-[(4-Carboxyphenyl)(2,2-dimethyl-4,6-dioxo-1,3-dioxan-
5-yl)methyl]-1-cyclopentyl-4,5-dimethyl-1H-imidazole
N-oxide (4m). Yield 156 mg (42%), white solid, mp 195–
NH); 7.45 (2H, d, J = 8.4, H Ar); 7.32–7.24 (5H, m, H Ph);
6
.82 (2H, d, J = 8.4, H Ar); 5.90 (1H, s, CH); 4.56–4.38
2H, m, CH ); 3.02 (2H, t, J = 7.5, CH ); 2.18 (3H, s, CH );
); 1.62 (6H, s, 2CH ).
–1
(
2
2
3
197°C. IR spectrum, ν, cm : 3425, 2931, 2669, 2553,
2
.07 (3H, s, CH
3
); 2.02 (3H, s, CH
3
3
1681, 1604, 1419, 1257, 1203, 1111, 995, 925, 779, 555.
1
3
1
C NMR spectrum (75 MHz), δ, ppm: 168.2; 166.9; 140.1;
H NMR spectrum (300 MHz), δ, ppm (J, Hz): 15.79 (1H,
1
1
38.0; 136.9; 130.7; 129.2; 128.7; 127.1; 122.9; 122.5;
s, OH); 7.89 (2H, d, J = 7.8, H Ar); 7.17 (2H, d, J = 7.8,
19.0; 101.8; 73.0; 46.1; 35.5; 34.5; 25.6; 24.0; 8.2; 6.7.
H Ar); 6.07 (1H, s, CH); 5.12–4.99 (1H, m, CH); 2.33–1.91
+
13
Found, m/z: 506.2286 [M+H] . C28
H
32
N
3
O
6
. Calculated, m/z:
(14H, m, 2CH
3
, 4CH
2
); 1.60 (6H, s, 2CH
3
). C NMR
5
06.2291.
-[(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-yl)(4-hydroxy-
-methoxyphenyl)methyl]-1-(furan-2-ylmethyl)-4,5-di-
spectrum (75 MHz), δ, ppm: 167.1; 166.7; 142.1; 139.2;
2
129.5; 129.4; 126.8; 123.3; 123.1; 101.8; 72.2; 57.8;
3
35.5; 31.2; 30.6; 30.2; 25.4; 24.5; 24.4; 9.8; 6.6. Found,
+
methyl-1H-imidazole N-oxide (4j). Yield 310 mg (66%),
m/z: 457.1969 [M+H] . C24
H
29
N
2
7
O . Calculated, m/z:
–
1
white solid, mp 196–198°C. IR spectrum, ν, cm : 3395,
457.1974.
2
1
993, 1651, 1620, 1512, 1419, 1357, 1280, 1195, 1111,
010, 848, 756, 663, 455. H NMR spectrum (300 MHz),
1-Benzyl-2-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-
(4-methyl-2-oxo-2H-chromen-7-yl)methyl]-4,5-dimethyl-
1H-imidazole N-oxide (4n). Yield 355 mg (69%), white
1
δ, ppm (J, Hz): 15.85 (1H, s, OH); 8.94 (1H, s, H Ar); 7.74
–1
(
1H, s, H Ar); 6.70–6.64 (2H, m, H Ar); 6.52 (1H, s, CH);
.44–6.39 (2H, m, H Ar); 6.13 (1H, s, H Ar); 5.66 (1H, d,
J = 16.6, CH ); 5.48 (1H, d, J = 16.6, CH ); 3.60 (3H, s,
OCH ); 3.36 (3H, s, CH ); 2.33 (3H, s, CH ); 2.08 (3H, s,
CH ); 1.64 (6H, s, 2CH ). C NMR spectrum (75 MHz),
solid, mp 194–196°C. IR spectrum, ν, cm : 3444, 2985,
6
2931, 1728, 1674, 1620, 1504, 1419, 1388, 1365, 1249,
1
1195, 1165, 1111, 995, 972, 856, 779, 732. H NMR
2
2
3
3
3
spectrum (300 MHz), δ, ppm (J, Hz): 15.81 (1H, s, OH);
7.64 (1H, d, J = 8.1, H Ar); 7.44–7.34 (3H, m, H Ar); 7.26
(2H, d, J = 7.8, H Ar); 6.87–6.84 (2H, m, H Ar); 6.35 (1H,
1
3
3
3
δ, ppm: 167.1; 147.9; 147.5; 145.5; 144.6; 140.8; 126.6;
1
3
C
22.7; 119.3; 115.4; 111.0; 109.9; 101.8; 73.3; 55.5; 41.1;
s, H Ar); 6.03 (1H, s, CH); 5.60 (1H, d, J = 17.1, CH
5.51 (1H, d, J = 17.1, CH ); 2.38 (3H, s, CH ); 2.28 (3H, s,
CH ); 2.15 (3H, s, CH ); 1.60 (6H, s, 2CH
2
);
+
4.2; 25.4; 8.4; 6.6. Found, m/z: 471.1762 [M+H] .
2
3
13
24
2
H
27
N
2
O
8
. Calculated, m/z: 471.1767.
3
3
3
). C NMR
-[(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-yl)(4-methoxy-
spectrum (75 MHz), δ, ppm: 166.8; 159.6; 152.9; 141.1;
139.6; 135.1; 129.1; 128.2; 126.5; 125.5; 123.6; 123.2;
122.7; 118.5; 114.4; 114.0; 101.9; 72.6; 48.0; 35.0; 25.45;
phenyl)methyl]-4,5-dimethyl-1-(2-morpholinoethyl)-1H-
imidazole N-oxide (4k). Yield 409 mg (85%), white solid,
mp 179–181°C. IR spectrum, ν, cm : 3425, 2931, 1666,
–
1
+
17.95; 8.59; 6.76. Found, m/z: 517.1969 [M+H] .
1
9
651, 1620, 1512, 1357, 1303, 1257, 1203, 1118, 1033,
33, 825, 763, 524. H NMR spectrum (300 MHz), δ, ppm
C
29
H
29
N
2
O . Calculated, m/z: 517.1974.
7
1
2-[(3,4-Dimethoxyphenyl)(2,2-dimethyl-4,6-dioxo-1,3-
(
J, Hz): 15.69 (1H, s, OH); 7.12 (2H, d, J = 8.7, H Ar);
dioxan-5-yl)methyl]-1,5-dimethyl-4-(4-methylphenyl)-
6
.91 (2H, d, J = 8.7, H Ar); 5.98 (1H, s, CH); 4.62–4.52
1H-imidazole N-oxide (4o). Yield 429 mg (83%), white
–1
(
1H, m, CH
2
); 4.17–4.11 (1H, m, CH
); 3.43–3.27 (4H, m, 2CH ); 2.75–2.54 (4H, m,
); 2.38–2.31 (2H, m, CH ); 2.26 (3H, s, CH ); 2.10
); 1.63 (6H, s, 2CH ). C NMR spectrum
2
); 3.74 (3H, s,
solid, mp 196–198°C. IR spectrum, ν, cm : 3422, 2932,
OCH
3
2
1662, 1653, 1507, 1410, 1373, 1265, 1199, 1111, 1061,
1
2
CH
2
2
3
1031, 1010, 831, 806, 769. H NMR spectrum (300 MHz),
1
3
(
(
3H, s, CH
3
3
δ, ppm (J, Hz): 15.59 (1H, s, OH); 7.32 (4H, s, H Ar); 6.93
(1H, d, J = 8.3, H Ar); 6.83–6.77 (2H, m, H Ar); 6.04 (1H,
75 MHz), δ, ppm: 166.9; 158.0; 141.0; 128.2; 128.0;
1
4
22.6; 122.3; 113.6; 101.7; 73.2; 65.7; 57.9; 55.0; 53.6;
s, CH); 3.87 (3H, s, CH
OCH ); 2.34 (3H, s, CH
2CH ). C NMR spectrum (75 MHz), δ, ppm: 166.8;
3
); 3.74 (3H, s, OCH
3
); 3.68 (3H, s,
+
2.2; 34.2; 25.6; 8.253; 6.7. Found, m/z: 488.2391 [M+H] .
3
3
); 2.33 (3H, s, CH
3
); 1.65 (6H, s,
13
C
25
1
H
34
N
3
O
7
. Calculated, m/z: 488.2396.
3
-(1,3-Benzodioxol-5-ylmethyl)-2-[(2-bromo-4,5-di-
148.6; 147.8; 141.2; 138.8; 129.4; 129.2; 128.8; 126.4;
125.3; 124.4; 119.4; 117.3; 111.8; 111.4; 110.0; 101.6;
methoxyphenyl)(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-
methyl]-4,5-dimethyl-1H-imidazole N-oxide (4l). Yield
73.0; 55.6; 55.5; 34.6; 32.2; 25.5; 20.8; 20.7; 9.2.
+
5
24 mg (85%), off-white solid, mp 194–196°C. IR spectrum,
Found, m/z: 495.2126 [M+H] . C27
31
H N
2
O . Calculated, m/z:
7
–1
ν, cm : 3451, 3004, 1671, 1599, 1501, 1257, 1206, 1037,
495.2131.
1
50

Chemistry of Heterocyclic Compounds 2019, 55(2), 147–155
2
-[(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-yl)(4-methoxy-
s, CH
1.50 (6H, s, 2CH
J = 6.4, CH
3
); 2.12–2.04 (1H, m, CH
2
); 1.62–1.55 (1H, m, CH );
2
2
1
,3-dimethylphenyl)methyl]-4,5-dimethyl-1-(prop-2-en-
3
); 1.29–1.23 (1H, m, CH); 0.62 (3H, d,
13
-yl)-1H-imidazole N-oxide (4p). Yield 128 mg (29%),
3
); 0.55 (3H, d, J = 6.4, CH ). C NMR
3
–1
off-white solid, mp 170–172°C. IR spectrum, ν, cm :
spectrum (75 MHz), δ, ppm: 166.7; 141.1; 134.2; 132.6;
3
1
425, 2931, 2376, 1666, 1620, 1458, 1442, 1381, 1342,
129.0; 127.9; 122.8; 122.6; 101.5; 75.0; 46.7; 36.9; 28.6;
1
257, 1203, 1103, 925, 771. H NMR spectrum (400 MHz),
25.5; 25.1; 22.4; 21.3; 8.3; 6.8. Found, m/z: 449.1838
+
δ, ppm (J, Hz): 14.82 (1H, s, OH); 7.13 (1H, d, J = 8.8,
H Ar); 6.83 (1H, d, J = 8.8, H Ar); 5.90–5.83 (1H, m, CH);
[M+H] . C23
H
30ClN
2
O . Calculated, m/z: 449.1843.
5
Synthesis of compounds 5a–s (General procedure).
Method А. A solution of compound 4a–s (1 mmol) in 10%
HCl (6 ml) was stirred under reflux for 15 min, then
5
.79 (1H, s, CH); 5.27 (1H, d, J = 10.4, CH=CH ); 5.18
2
(
1H, d, J = 11.4, CH=CH
3H, s, OCH ); 2.22 (3H, s, CH
3H, s, CH ); 1.78 (3H, s, CH
3
2
); 4.88 (2H, t, J = 5.6, CH
2
); 3.75
); 2.05
(
3
3
); 2.07 (3H, s, CH
3
mixture was concentrated under reduced pressure. H O
2
(
3
3
); 1.58 (6H, s, 2CH
3
).
(10 ml) and NaOAc (210 mg, 2.5 mmol) were added to the
residue and stirring was continued for 10 min. Precipitate
1
C NMR spectrum (75 MHz), δ, ppm: 166.6; 156.1; 140.8;
1
1
34.6; 130.9; 126.4; 126.3; 124.2; 122.7; 122.3; 118.9;
was filtered off and washed with cold H O (10 ml).
2
07.6; 101.4; 73.3; 55.3; 47.1; 33.6; 25.6; 15.3; 11.9; 8.2; 6.5.
Method B (for highly water-soluble compounds). A solution
of compound 4a–s (1 mmol) in 10% HCl (6 ml) was stirred
under reflux for 15 min, then mixture was concentrated
+
Found, m/z: 443.2177 [M+H] . C24
H
31
N
2
O . Calculated, m/z:
6
4
43.2182.
2
-{[4-(Diethylamino)phenyl](2,2-dimethyl-4,6-dioxo-
under reduced pressure. H
2.5 mmol) were added to the residue and stirring was
continued for 10 min. Then H O was removed under
reduced pressure, and CHCl (15 ml) was added to the
residue. Inorganic salts were filtered and washed with
CHCl (5 ml). Resulting solution was concentrated under
2
O (10 ml) and NaOAc (210 mg,
1
,3-dioxan-5-yl)methyl}-4,5-dimethyl-1-phenethyl-1H-
imidazole N-oxide (4q). Yield 140 mg (27%), pale-brown
2
–1
solid, mp 152–154°C. IR spectrum, ν, cm : 3448, 2970, 2931,
3
1
9
1
666, 1651, 1620, 1519, 1357, 1257, 1203, 1157, 1111, 1002,
1
25, 779. H NMR spectrum (400 MHz), δ, ppm (J, Hz):
3
5.78 (1H, s, OH); 7.33–7.26 (5H, m, H Ph); 6.73 (2H, d,
reduced pressure to give the corresponding product.
3-(1-Benzyl-4,5-dimethyl-3-oxido-1H-imidazol-2-yl)-
propanoic acid (5a). Yield 242 mg (88%, method B),
J = 8.4, H Ar); 6.56 (2H, d, J = 8.4, H Ar); 5.86 (1H, s,
CH); 4.55–4.49 (1H, m, CH
2
); 4.41–4.35 (1H, m, CH
); 3.01 (2H, t, J = 7.2, CH ); 2.15
); 1.61 (6H, s, 2CH ), 1.06
). C NMR spectrum (75 MHz),
2
);
–1
3
(
(
.29 (4H, q, J = 6.8, 2CH
2
2
white solid, mp 162–164°C. IR spectrum, ν, cm : 3410,
3H, s, CH
3
); 2.07 (3H, s, CH
3
3
2939, 2831, 1697, 1681, 1589, 1496, 1458, 1419, 1257,
1
3
1
6H, t, J = 7.5, 2CH
3
1234, 1157, 1141, 1026, 987, 864, 763, 732, 624. H NMR
δ, ppm: 166.9; 146.3; 140.4; 136.8; 129.1; 128.7; 127.7;
spectrum (300 MHz), δ, ppm (J, Hz): 7.38–7.29 (3H, m,
1
3
[
27.0; 122.6; 122.2; 122.1; 111.4; 101.6; 73.3; 46.0; 43.5;
H Ph); 7.04 (2H, d, J = 7.1, H Ph); 5.29 (2H, s, CH
2
); 2.96–
); 2.06 (6H, s,
). C NMR spectrum (75 MHz), δ, ppm: 173.3;
5.6; 33.9; 25.5; 12.4; 8.0; 6.6. Found, m/z: 520.2806
2.92 (2H, m, CH
2
); 2.39–2.35 (2H, m, CH
2
+
13
M+H] . C30
1
H
38
N
3
O
5
. Calculated, m/z: 520.2811.
3CH
3
-Cyclopentyl-2-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-
136.3; 135.8; 128.9; 127.6; 126.0; 123.8; 120.4; 46.6; 31.6;
+
5
1
-yl)(3-ethoxy-4-methoxyphenyl)methyl]-4,5-dimethyl-
18.3; 8.3; 7.0. Found, m/z: 275.1390 [M+H] . C15
Calculated, m/z: 275.1396.
H
19
N
2
O .
3
H-imidazole N-oxide (4r). Yield 160 mg (33%), pale-
yellow solid, mp 195–197°C. IR spectrum: 3425, 2931,
3-(1-Benzyl-4,5-dimethyl-3-oxido-1H-imidazol-2-yl)-
3-phenylpropanoic acid (5b). Yield 311 mg (89%,
1
1
(
720, 1666, 1604, 1512, 1419, 1365, 1257, 1172, 1134,
1
–1
111, 1033, 918, 864, 763, 601. H NMR spectrum
method A), white solid, mp 217–219°C. IR spectrum, ν, cm :
400 MHz), δ, ppm (J, Hz): 15.82 (1H, s, OH); 6.90 (1H, d,
3425, 2924, 2399, 2376, 1712, 1651, 1543, 1496, 1458,
1396, 1342, 1265, 1211, 1165, 1026, 964, 840, 763, 732,
J = 8.0, H Ar); 6.59–6.57 (2H, m, H Ar); 5.96 (1H, s, CH);
1
5
.09 (1H, t, J = 8.8, CH); 3.89 (2H, q, J = 6.4, OCH
2
); 3.73
694, 617. H NMR spectrum (300 MHz), δ, ppm (J, Hz):
(
3H, s, OCH
CH
3
); 2.33 (3H, s, CH
3
); 2.23–1.93 (11H, m, CH
3
,
7.28–7.22 (8H, m, H Ph); 7.01 (2H, s, H Ph); 5.46 (2H, s,
4
2
); 1.61 (6H, s, 2CH
3
), 1.28 (6H, t, J = 6.8, 2CH
3
).
CH
CH
CH
2
); 5.10–5.05 (1H, m, CH); 3.50 (1H, dd, J = 17.4, J = 9.3,
1
3
C NMR spectrum (75 MHz), δ, ppm: 148.0; 147.7; 139.9;
2
); 3.13 (1H, dd, J = 17.3, J = 6.5, CH ); 2.22 (3H, s,
2
13
1
5
29.0; 123.2; 122.6; 119.0; 112.1; 112.0; 101.6; 72.9; 63.7;
3
); 2.05 (3H, s, CH ). C NMR spectrum (75 MHz),
3
7.7; 55.5; 34.8; 31.0; 30.3; 25.4; 24.6; 24.5; 14.6; 9.8; 6.7.
δ, ppm: 171.9; 140.9; 136.6; 134.4; 128.8; 127.9; 127.8;
+
Found, m/z: 487.2439 [M+H] . C26
H
35
N
2
O
7
. Calculated, m/z:
127.7; 126.3; 124.9; 123.4; 47.9; 36.6; 36.4; 8.5; 7.2.
+
4
87.2444.
1
Found, m/z: 351.1701 [M+H] . C21
H
23
N
2
O . Calculated, m/z:
3
-(4-Chlorobenzyl)-2-[1-(2,2-dimethyl-4,6-dioxo-1,3-
351.1709.
dioxan-5-yl)-3-methylbutyl]-4,5-dimethyl-1H-imidazole
N-oxide (4s). Yield 242 mg (54%), white solid, mp 177–
3-(1-Benzyl-4,5-dimethyl-3-oxido-1H-imidazol-2-yl)-
3-[4-(methylsulfanyl)phenyl]propanoic acid (5c). Yield
312 mg (79%, method A), white solid, mp 190–192°C.
–
1
1
1
1
6
79°C. IR spectrum, ν, cm : 3410, 2954, 2900, 1651,
635, 1496, 1450, 1419, 1365, 1350, 1273, 1257, 1203,
172, 1134, 1118, 1033, 1010, 987, 925, 848, 786, 732,
–1
IR spectrum, ν, cm : 3425, 2924, 2376, 1720, 1705, 1643,
1496, 1458, 1435, 1342, 1265, 1219, 1126, 1049, 1010,
1
1
63. H NMR spectrum (400 MHz), δ, ppm (J, Hz): 16.58
894, 879, 810, 694, 648, 586. H NMR spectrum (300 MHz),
(
1H, s, OH); 7.47 (2H, d, J = 8.4, H Ar); 7.13 (2H, d, J = 8.4,
δ, ppm (J, Hz): 7.27–7.21 (5H, m, H Ph); 7.07 (2H, d, J = 8.1,
H Ar); 5.58 (1H, d, J = 17.2, CH
2
); 5.38 (1H, d, J = 17.2,
); 2.17 (3H,
H Ar); 6.87 (2H, s, H Ar); 5.28 (1H, d, J = 17.2, CH ); 5.17
2
CH ); 4.34–4.30 (1H, m, CH); 2.18 (3H, s, CH
2
3
(1H, d, J = 17.2, CH ); 4.73 (1H, dd, J = 10.6, J = 5.5,
2
1
51

Chemistry of Heterocyclic Compounds 2019, 55(2), 147–155
CH); 3.75 (1H, dd, J = 15.7, J = 10.7, CH
J = 14.9, J = 5.2, CH ); 2.40 (3H, s, CH
CH ); 1.98 (3H, s, CH
δ, ppm: 172.2; 136.9; 136.6; 135.9; 135.6; 128.6; 128.0;
27.4; 126.3; 126.0; 124.7; 121.3; 46.6; 36.9; 14.8; 8.6; 7.1.
2
); 2.77 (1H, dd,
); 2.09 (3H, s,
). C NMR spectrum (75 MHz),
J = 17.1, CH
m, CH); 3.76–3.67 (1H, m, CH
J = 5.2, CH ); 2.10 (3H, s, CH
2
); 5.10 (1H, d, J = 17.1, CH
); 2.68 (1H, dd, J = 14.4,
); 1.95 (3H, s, CH ).
2
); 4.72–4.67 (1H,
2
3
2
1
3
3
3
2
3
3
13
C NMR spectrum (75 MHz), δ, ppm: 172.3; 157.7; 141.3;
1
136.3; 135.6; 129.6; 128.6; 127.5; 126.0; 124.7; 121.3;
+
Found, m/z: 397.1580 [M+H] . C22
97.1586.
-(1-Benzyl-4,5-dimethyl-3-oxido-1H-imidazol-2-yl)-
-methylhexanoic acid (5d). Yield 310 mg (94%, method A),
H
25
N
2
O
3
S. Calculated, m/z:
117.9; 114.2; 46.7; 37.6; 8.6; 7.1. Found, m/z: 367.1652
+
3
[M+H] . C21
H
23
N
2
O . Calculated, m/z: 367.1657.
4
3
3-[4,5-Dimethyl-3-oxido-1-(thiophen-2-ylmethyl)-1H-
imidazol-2-yl]-3-(4-methoxyphenyl)propanoic acid (5h).
Yield 316 mg (82%, method A), white solid, mp 199–201°C.
5
–
1
white solid, mp 200–202°C. IR spectrum, ν, cm : 3425,
954, 2345, 1697, 1504, 1458, 1419, 1350, 1203, 1103,
–1
2
IR spectrum, ν, cm : 3425, 2962, 2931, 2515, 1720, 1651,
1
9
02, 871, 709, 671, 594, 524. H NMR spectrum (300 MHz),
δ, ppm (J, Hz): 7.39–7.29 (3H, m, H Ph); 7.04 (2H, d, J = 7.3,
H Ph); 5.28 (1H, d, J = 17.4, CH ); 5.24 (1H, d, J = 17.4,
CH ); 3.30 (2H, br. s, CH
.43 (1H, m, CH); 2.10 (3H, s, CH
.59–1.43 (2H, m, CH ); 1.23–1.14 (1H, m, CH(CH
1612, 1512, 1458, 1404, 1342, 1257, 1165, 1118, 1026,
1
910, 825, 725, 601, 547. H NMR spectrum (300 MHz),
2
δ, ppm (J, Hz): 7.52 (1H, d, J = 4.8, H thiophene); 7.24
(2H, d, J = 8.2, H Ar); 6.97–6.94 (2H, m, H thiophene);
2
2
); 2.99–2.90 (1H, m, CH); 2.54–
2
1
0
3
); 2.06 (3H, s, CH
3
);
);
6.81 (2H, d, J = 8.2, H Ar); 5.72 (1H, d, J = 16.8, CH
2
);
); 5.14–5.08 (1H, m, CH); 3.71
); 3.43 (1H, dd, J = 17.4, J = 8.9, CH ); 3.14
(1H, dd, J = 17.4, J = 6.7, CH ); 2.21 (6H, s, 2CH ).
2
3
)
2
5.61 (2H, d, J = 16.8, CH
(3H, s, OCH
2
.60 (3H, d, J = 6.4, CH
3
); 0.50 (3H, d, J = 6.4, CH
3
).
3
2
1
3
C NMR spectrum (75 MHz), δ, ppm: 172.8; 136.9; 136.2;
2
3
1
3
1
2
28.7; 127.5; 125.8; 124.0; 120.5; 46.5; 36.2; 29.3; 24.9;
C NMR spectrum (75 MHz), δ, ppm: 171.9; 158.6;
+
2.4; 21.5; 8.5; 7.0. Found, m/z: 331.2016 [M+H] .
140.9; 136.6; 129.0; 128.4; 127.4; 127.1; 127.0; 124.8;
C
19
H
3
27
N
2
O
3
. Calculated, m/z: 331.2022.
123.0; 114.1; 55.1; 43.5; 36.6; 35.7; 8.5; 7.2. Found, m/z:
+
-(1-Benzyl-4,5-dimethyl-3-oxido-1H-imidazol-2-yl)-
-(2,4-dichlorophenyl)propanoic acid (5e). Yield 402 mg
96%, method A), white solid, mp 182–184°C. IR spectrum,
387.1373 [M+H] .
387.1378.
C
20
H
23
N
2
4
O S. Calculated, m/z:
3
(
3-(4-Aminophenyl)-3-[4,5-dimethyl-3-oxido-1-(2-phenyl-
ethyl)-1H-imidazol-2-yl]propanoic acid (5i). Yield 280 mg
(74%, method A), white solid, mp 228–230°C. IR spectrum,
–
1
ν, cm : 3425, 2360, 1690, 1635, 1473, 1342, 1203, 1103,
1
1
033, 987, 864, 817, 702, 640, 509. H NMR spectrum
300 MHz), δ, ppm (J, Hz): 7.59 (1H, d, J = 8.1, H Ar);
.32–7.27 (2H, m, H Ar); 7.13 (3H, s, H Ar); 6.79 (2H, s,
H Ar); 5.16 (2H, s, CH ); 4.88–4.87 (1H, m, CH ); 3.82–
.73 (1H, m, CH ); 2.74–2.70 (1H, m, CH); 2.12 (3H, s,
CH ); 2.08 (3H, s, CH
–1
(
ν, cm : 3410, 2624, 1651, 1612, 1519, 1342, 1296, 1172,
1
7
1033, 825, 764, 709, 609, 532. H NMR spectrum
2
2
(300 MHz), δ, ppm (J, Hz): 7.28–7.21 (3H, m, H Ar); 7.11–
7.05 (4H, m, H Ar); 6.51 (2H, d, J = 8.1, H Ar); 4.66–4.61
3
2
1
3
3
3
). C NMR spectrum (75 MHz),
(1H, m, CH); 4.19–4.10 (1H, m, CH
CH
(2H, m, CH
1.83 (3H, s, CH ). C NMR spectrum (151 MHz), δ, ppm:
2
); 3.96–3.87 (1H, m,
); 2.67–2.61
); 2.03 (3H, s, CH );
δ, ppm: 171.7; 135.7; 135.0; 133.9; 132.6; 132.3; 131.0;
2
); 3.72 (1H, dd, J = 14.4, J = 11.5, CH
); 2.56–2.50 (1H, m, CH
2
1
4
C
28.6; 128.3; 127.7; 127.2; 125.5; 125.4; 124.8; 121.6;
2
2
3
+
13
6.8; 36.0; 34.3; 8.5; 7.2. Found, m/z: 419.0924 [M+H] .
3
21
H
3
21Cl
2
N
2
O
3
. Calculated, m/z: 419.0930.
172.6; 148.0; 137.4; 136.6; 129.0; 128.5; 128.0; 127.4;
-(1-Benzyl-4,5-dimethyl-3-oxido-1H-imidazol-2-yl)-
-(4-nitrophenyl)propanoic acid (5f). Yield 355 mg (90%,
method A), pale-yellow solid, mp 191–193°C. IR spectrum,
126.8; 123.8; 121.0; 114.2; 45.1; 39.2; 37.3; 35.1; 7.9; 7.1.
+
3
Found, m/z: 380.1969 [M+H] . C22
H
26
N
3
O . Calculated, m/z:
3
380.1974.
–
1
ν, cm : 3361, 2844, 2472, 2348, 1510, 1496, 1448, 1286,
3-[1-(Furan-2-ylmethyl)-4,5-dimethyl-3-oxido-1H-
imidazol-2-yl]-3-(4-hydroxy-3-methoxyphenyl)propanoic
acid (5j). Yield 290 mg (75%, method A), yellow solid,
1
1
192, 1165, 1026, 964, 840, 793, 732, 704, 654. H NMR
spectrum (300 MHz), δ, ppm (J, Hz): 7.97 (2H, d, J = 8.6,
–
1
H Ar); 7.56 (2H, d, J = 8.6, H Ar); 7.17–7.15 (3H, m,
mp 177–179°C. IR spectrum, ν, cm : 3410, 2962, 2931,
1720, 1689, 1651, 1604, 1519, 1450, 1427, 1381, 1342,
1273, 1149, 1126, 1064, 1033, 902, 887, 802, 756, 663,
H Ph); 6.87 (2H, s, H Ph); 5.31 (2H, s, CH ); 4.93 (1H, dd,
2
J = 10.2, J = 5.5, CH); 3.83 (1H, dd, J = 16.0, J = 10.1,
1
CH
CH
2
); 2.90 (1H, dd, J = 16.0, J = 5.4, CH
2
); 2.09 (3H, s,
601. H NMR spectrum (300 MHz), δ, ppm (J, Hz): 7.56
1
3
3
); 2.04 (3H, s, CH
3
). C NMR spectrum (75 MHz),
(1H, s, H Ar); 7.01 (1H, s, H Ar); 6.72–6.69 (1H, m, H Ar);
6.62–6.59 (1H, m, H Ar); 6.37 (1H, s, H Ar); 6.30–6.29
δ, ppm: 172.0; 147.4; 146.3; 135.8; 134.4; 129.0; 128.5;
1
7
27.3; 125.9; 124.9; 123.4; 121.4; 46.6; 37.1; 36.9; 8.6;
.1. Found, m/z: 396.1554 [M+H] . C21
(1H, m, H Ar); 5.34 (1H, d, J = 16.8, CH
J = 16.8, CH
3.60 (5H, m, OCH
CH
2
); 5.15 (1H, d,
+
H
22
N
3
O
5
. Calcu-
2
); 4.79 (1H, dd, J = 10.3, J = 5.5, CH); 3.71–
lated, m/z: 396.1559.
3
, CH
); 2.17 (3H, s, CH
2
); 2.83 (1H, dd, J = 15.2, J = 5.5,
13
3
-(1-Benzyl-4,5-dimethyl-3-oxido-1H-imidazol-2-yl)-
-(3-hydroxyphenyl)propanoic acid (5g). Yield 358 mg
98%, method A), white solid, mp 224–226°C. IR spectrum,
2
3
); 2.02 (3H, s, CH ). C NMR
3
3
spectrum (75 MHz), δ, ppm: 173.5; 149.5; 148.7;
(
147.0; 144.5; 138.0; 131.1; 125.6; 122.7; 121.0; 116.6;
–
1
ν, cm : 3070, 2345, 1874, 1851, 1813, 1651, 1604, 1458,
113.3; 111.9; 110.1; 56.8; 41.6; 39.8; 38.1; 9.6; 8.1.
1
+
1
342, 1234, 1157, 1087, 995, 771, 702. H NMR spectrum
Found, m/z: 387.1551 [M+H] . C20
z: 387.1556.
H
23
N
2
O . Calculated, m/
6
(
(
300 MHz), δ, ppm (J, Hz): 7.23–7.21 (3H, m, H Ar); 7.00
1H, t, J = 8.1, H Ar); 6.88–6.82 (3H, m, H Ar); 6.70 (1H,
3-{4,5-Dimethyl-1-[2-(morpholin-4-yl)ethyl]-3-oxido-
1H-imidazol-2-yl}-3-(4-methoxyphenyl)propanoic acid
d, J = 8.0, H Ar); 6.57 (1H, d, J = 8.0, H Ar); 5.26 (1H, d,
1
52

Chemistry of Heterocyclic Compounds 2019, 55(2), 147–155
+
(
5k). Yield 306 mg (76%, method B), white solid, mp 101–
Found, m/z: 433.1758 [M+H] . C25
H
25
N
2
O . Calculated, m/z:
5
–
1
1
1
5
03°C. IR spectrum, ν, cm : 3442, 1930, 2587, 1723,
433.1763.
653, 1514, 1354, 1255, 1182, 1099, 1031, 985, 873, 759,
3-(3,4-Dimethoxyphenyl)-3-[1,5-dimethyl-4-(4-methyl-
phenyl)-3-oxido-1H-imidazol-2-yl]propanoic acid (5o).
Yield 320 mg (78%, method A), pale-brown solid, mp 192–
1
55. H NMR spectrum (300 MHz), δ, ppm (J, Hz): 7.37
(
4
2H, d, J = 8.1, H Ar); 6.90 (2H, d, J = 8.1, H Ar); 5.03–
–
1
.98 (1H, m, CH); 4.30 (2H, br. s, CH
); 3.60 (4H, br. s, CH ); 3.13–3.05 (2H, m, CH
); 2.26 (3H, s, CH ); 2.17 (3H, s,
2
); 3.73 (3H, s,
194°C. IR spectrum, ν, cm : 3425, 2931, 1720, 1705,
OCH
3
2
2
);
1589, 1519, 1458, 1419, 1350, 1265, 1149, 1026, 817, 763,
1
2
.65–2.57 (6H, m, CH
2
3
609. H NMR spectrum (300 MHz), δ, ppm (J, Hz): 7.45
1
3
CH
3
). C NMR spectrum (75 MHz), δ, ppm: 172.1; 158.7;
(2H, d, J = 7.8, H Ar); 7.28 (2H, d, J = 7.8, H Ar); 7.26
1
5
29.4; 128.9; 124.2; 123.1; 114.3; 109.7; 68.1; 65.1; 55.2;
(1H, s, H Ar); 7.19–6.87 (2H, m, H Ar); 4.84 (1H, dd,
+
2.8; 36.8; 35.9; 8.3; 7.0. Found, m/z: 404.2180 [M+H] .
J = 10.6, J = 5.6, CH); 3.72–3.65 (7H, m, 2CH
3
O, CH
2
);
);
C
21
H
3
30
N
3
O
5
. Calculated, m/z: 404.2185.
3.52 (3H, s, CH
2.35 (3H, s, CH
3
); 2.79 (1H, dd, J = 14.6, J = 5.5, CH
2
13
-[1-(1,3-Benzodioxol-5-ylmethyl)-4,5-dimethyl-3-oxido-
H-imidazol-2-yl]-3-(2-bromo-4,5-dimethoxyphenyl)-
propanoic acid (5l). Yield 502 mg (94%, method A),
3
); 2.19 (3H, s, CH
3
). C NMR spectrum
1
(75 MHz), δ, ppm: 172.2; 148.9; 148.1; 137.7; 137.0;
131.7; 129.4; 128.7; 127.0; 123.8; 123.1; 119.4; 112.1;
–
1
white solid, mp 195–197°C IR spectrum, ν, cm : 3215,
111.5; 55.5; 37.2; 31.0; 20.9; 9.2. Found, m/z: 411.1914
+
3
9
(
037, 2823, 2481, 1605, 1594, 1497, 1262, 1159, 1031,
[M+H] . C23
H
27
N
2
O . Calculated, m/z: 411.1920.
5
1
82, 844, 793, 654. H NMR spectrum (300 MHz), δ, ppm
3-[4,5-Dimethyl-3-oxido-1-(prop-2-en-1-yl)-1H-imidazol-
2-yl]-3-(4-methoxy-2,3-dimethylphenyl)propanoic acid
(5p). Yield 322 mg (90%, method A), white solid, mp 198–
J, Hz): 7.26 (1H, s, H Ar); 6.93 (1H, s, H Ar); 6.67 (1H, d,
J = 8.4, H Ar); 6.31–6.29 (2H, m, H Ar); 5.95 (1H, s, СH
.89 (1H, s, СH ); 5.02 (2H, s, CH ); 4.78 (1H, dd,
J = 10.8, J = 4.5, CH); 3.92–3.83 (1H, m, CH ); 3.70 (3H,
s, OCH ); 3.62 (3H, s, OCH ); 2.65 (1H, dd, J = 15.2,
J = 4.4, CH ); 2.12 (3H, s, CH ); 2.04 (3H, s, CH
2
);
–
1
5
2
2
200°C. IR spectrum, ν, cm : 3425, 2931, 1720, 1651,
2
1620, 1489, 1458, 1381, 1257, 1219, 1056, 1010, 979, 910,
1
3
3
802, 725, 501. H NMR spectrum (400 MHz), δ, ppm
13
2
3
3
). C NMR
(J, Hz): 6.90 (1H, d, J = 6.6, H Ar); 6.77 (1H, d, J = 6.6,
spectrum (75 MHz), δ, ppm: 171.8; 148.8; 148.7; 147.3;
H Ar); 5.49–5.40 (1H, m, CH); 4.98 (1H, d, J = 7.8, CH );
2
1
1
3
46.4; 135.0; 130.4; 128.7; 124.8; 121.6; 119.1; 115.3;
4.77 (1H, dd, J = 11.2, J = 4.8, CH
CH ); 4.45 (1H, dd, J = 18.7, J = 3.3, CH
J = 17.7, J = 5.0, CH ); 3.71 (3H, s, OCH ); 3.56–3.50 (1H,
); 2.19 (3H, s,
); 2.07 (3H, s,
2
); 4.67 (1H, d, J = 12.9,
12.4; 112.1; 108.0; 106.1; 101.1; 55.9; 55.7; 46.6; 37.4;
2
2
); 4.14 (1H, dd,
+
7.2; 8.5; 7.2. Found, m/z: 533.0918 [M+H] . C24
H
26BrN
2
O
7
.
2
3
Calculated, m/z: 533.0923.
m, CH); 2.59 (1H, dd, J = 13.9, J = 4.8, CH
2
3
-(4-Carboxyphenyl)-3-(1-cyclopentyl-4,5-dimethyl-
CH
CH
3
); 2.13 (3H, s, CH
3
3
); 2.08 (3H, s, CH
3
13
3
-oxido-1H-imidazol-2-yl)propanoic acid (5m). Yield
). C NMR spectrum (75 MHz), δ, ppm: 172.0; 156.2;
2
93 mg (79%, method A), white solid, mp 200–202°C.
136.3; 134.5; 131.5; 129.8; 125.2; 124.8; 124.1; 121.6;
–
1
IR spectrum, ν, cm : 3432, 2965, 2593, 1716, 1609, 1423,
116.8; 108.6; 55.4; 45.9; 35.1; 14.6; 12.0; 8.1; 7.1.
+
1
4
344, 1271, 1213, 1105, 1012, 967, 830, 792, 668, 586, 529,
Found, m/z: 359.1965 [M+H] . C20
H
27
N
2
4
O . Calculated, m/z:
1
50. H NMR spectrum (300 MHz), δ, ppm (J, Hz): 7.81
359.1970.
(
(
2H, d, J = 8.1, H Ar); 7.41 (2H, d, J = 8.1, H Ar); 5.07
1H, dd, J = 9.7, J = 5.7, CH); 4.80–4.74 (1H, m, CH); 3.73
3-(4-Diethylaminophenyl)-3-[4,5-dimethyl-3-oxido-
1-(2-phenylethyl)-1H-imidazol-2-yl]propanoic acid (5q).
Yield 346 mg (86%, method A), white solid, mp 199–201°C.
(
1H, dd, J= 15.4, J = 10.2, CH
2
); 2.93 (1H, dd, J = 15.5, J = 5.4,
); 2.07 (3H, s, CH ); 1.90–1.54 (8H,
). C NMR spectrum (75 MHz), δ, ppm: 171.8;
–1
CH
2
); 2.21 (3H, s, CH
3
3
IR spectrum, ν, cm : 3410, 2931, 1720, 1705, 1612, 1519,
13
m, 4CH
2
1458, 1373, 1342, 1265, 1195, 1149, 1118, 1072, 1033, 1010,
1
1
1
66.8; 141.8; 140.2; 130.1; 129.8; 127.8; 125.7;
918, 817, 709. H NMR spectrum (400 MHz), δ, ppm
22.6; 58.0; 35.9; 35.7; 30.2; 30.0; 24.7; 24.5; 10.1; 7.2.
(J, Hz): 7.28–7.20 (5H, m, H Ph); 7.06 (1H, d, J = 5.1, H Ar);
6.61 (1H, d, J = 6.6, H Ar); 4.71–4.67 (1H, m, CH); 4.17–
+
Found, m/z: 373.1758 [M+H] . C20
m/z: 373.1763.
H
25
N
2
O . Calculated,
5
4.09 (1H, m, CH); 3.95–3.88 (1H, m, CH
2
); 3.74–3.67 (1H,
); 2.72 (1H, dd, J = 14.5,
); 2.50–2.43 (2H, m, CH ); 2.05 (3H, s, CH );
). C NMR
3
-(1-Benzyl-4,5-dimethyl-3-oxido-1H-imidazol-2-yl)-
m, CH
J = 5.0, CH
1.88 (3H, s, CH
2
); 3.30–3.25 (4H, m, 2CH
2
3
-(4-methyl-2-oxo-2H-chromen-7-yl)propanoic acid (5n).
2
2
3
13
Yield 298 mg (69%, method A), white solid, mp 199–201°C.
3
); 1.02 (6H, t, J = 5.1, 2CH
3
–
1
IR spectrum, ν, cm : 3425, 2924, 1720, 1689, 1620, 1558,
spectrum (75 MHz), δ, ppm: 172.4; 146.6; 137.3; 136.2;
1
8
7
496, 1458, 1419, 1388, 1334, 1165, 1111, 1064, 1026,
128.9; 128.4; 128.2; 126.7; 126.5; 123.8; 121.1; 111.8;
1
71, 702. H NMR spectrum (300 MHz), δ, ppm (J, Hz):
45.0; 43.5; 37.2; 35.1; 12.3; 7.9; 7.0. Found, m/z: 436.2595
+
.54 (1H, d, J = 8.7, H Ar); 7.32 (2H, s, H Ar); 7.12 (3H, s,
[M+H] . C26
H
34
N
3
O . Calculated, m/z: 436.2600.
3
H Ar); 6.86–6.84 (2H, m, H Ar); 6.32 (1H, s, CH
2
); 5.30
3-(1-Cyclopentyl-4,5-dimethyl-3-oxido-1H-imidazol-
2-yl)3-(3-ethoxy-4-methoxyphenyl)propanoic acid (5r).
Yield 343 mg (94%, method A), white solid, mp 204–206°C.
(
(
2H, s, CH
2
); 4.90 (1H, dd, J = 10.0, J = 5.4, CH); 3.84
); 2.90 (1H, dd, J = 15.6,
); 2.10 (3H, s, CH ); 2.02
). C NMR spectrum (75 MHz), δ, ppm:
1H, dd, J = 15.3, J = 10.3, CH
2
–1
J = 5.4, CH
2
); 2.35 (3H, s, CH
3
3
3
IR spectrum, ν, cm : 3425, 2962, 1720, 1705, 1512, 1458,
13
(
3H, s, CH
1442, 1419, 1342, 1249, 1141, 1026, 833, 779, 586.
1
1
1
1
82.4; 172.0; 159.6; 152.8; 152.6; 144.2; 135.7; 134.9;
28.4; 127.1; 125.8; 125.5; 124.9; 123.6; 121.4;
18.4; 115.5; 114.0; 46.6; 37.6; 37.0; 17.9; 8.6; 7.1.
H NMR spectrum (400 MHz), δ, ppm (J, Hz): 7.14 (1H, s,
H Ar); 6.86 (1H, d, J = 6.3, H Ar); 6.79 (1H, d, J = 6.3,
H Ar); 4.85–4.77 (2H, m, CH
2
); 3.97–3.90 (2H, m, CH );
2
1
53

Chemistry of Heterocyclic Compounds 2019, 55(2), 147–155
+
3
.82–3.76 (1H, m, CH); 3.70 (3H, s, CH
3
O); 2.75–2.70
); 1.96–
7.0. Found, m/z: 193.0976 [M+H] . C10
lated, m/z: 193.0977.
H
13
N
2
O . Calcu-
2
(
1H, m, CH); 2.19 (3H, s, CH ); 2.06 (3H, s, CH
3
3
13
1.47 (8H, m, 4CH
2
); 1.28 (3H, t, J = 5.1, CH
2
CH
3
). C NMR
1-(1,3-Benzodioxol-5-ylmethyl)-4,5-dimethyl-1H-imidazole
N-oxide (1f). Yield 1.50 g (61%), white solid, mp 140–
spectrum (75 MHz), δ, ppm: 172.5; 148.0; 147.9; 136.4;
–1
1
5
33.0; 125.2; 120.5; 119.1; 112.3; 112.1; 63.7; 56.5;
142°C. IR spectrum, ν, cm : 3448, 3008, 2360, 1651,
5.4; 37.5; 30.5; 30.0; 24.6; 24.5; 14.6; 10.1; 7.0. Found,
1504, 1450, 1248, 1188, 1033, 925, 810, 771, 740, 694,
+
1
m/z: 403.2227 [M+H] . C22
H
31
N
2
O
5
. Calculated, m/z:
632, 509. H NMR spectrum (300 MHz), δ, ppm (J, Hz):
4
03.2232.
-[1-(4-Chlorobenzyl)-4,5-dimethyl-3-oxido-1H-imidazol-
-yl]-5-methylhexanoic acid (5s). Yield 332 mg (91%,
8.24 (1H, s, H imidizole); 6.88 (1H, d, J = 8.1, H Ar); 6.83–
3
6.82 (1H, m, H Ar); 6.71–6.68 (1H, m, H Ar); 6.00 (2H, s,
2
CH
CH
2
); 4.96 (2H, s, CH
3
2
); 2.04 (3H, s, CH ); 1.96 (3H, s,
3
–1
13
method A), white solid, mp 228–230°C. IR spectrum, ν, cm :
). C NMR spectrum (125 MHz), δ, ppm: 147.6;
3
1
410, 2931, 2870, 1697, 1635, 1489, 1458, 11442, 1427,
146.8; 130.1; 125.4; 123.9; 120.7; 108.3; 107.7; 101.1;
+
411, 1357, 1334, 1211, 1157, 1111, 1018, 894, 817, 725,
47.7; 8.4; 6.9. Found, m/z: 247.1077 [M+H] . C13
Calculated, m/z: 247.1082.
H
15
N
2
O .
3
1
671, 655, 624. H NMR spectrum (400 MHz), δ, ppm (J, Hz):
7
5
3
.42 (2H, d, J = 6.3, H Ar); 7.08 (2H, d, J = 6.3, H Ar);
.38 (1H, d, J = 13.2, CH ); 5.26 (1H, d, J = 13.2, CH );
.30 (1H, br. s, CH); 2.99–2.92 (1H, m, CH ); 2.54–2.44
); 2.04 (3H, s, CH ); 1.58–
1-Cyclopentyl-4,5-dimethyl-1H-imidazole N-oxide (1g).
Yield 0.83 g (46%), gray solid, mp 56–57°C. Hygroscopic!
2
2
–1
2
IR spectrum, ν, cm : 3402, 2962, 1651, 1627, 1527, 1450,
(
1H, m, CH
2
); 2.07 (3H, s, CH
3
3
1411, 13811, 1342, 1219, 1188, 1141, 1080, 1033, 732,
1
1
.42 (2H, m, CH
2
); 1.19–1.12 (1H, m, CH); 0.60 (3H, d,
624, 586. H NMR spectrum (300 MHz), δ, ppm (J, Hz):
1
3
J = 4.8, CH
3
); 0.49 (3H, d, J = 4.8, CH
3
). C NMR
8.27 (1H, s, H imidazole); 4.44–4.40 (1H, m, CH); 2.13 (3H,
spectrum (75 MHz), δ, ppm: 173.0; 137.4; 135.4; 132.2;
s, CH
3
); 2.07–2.03 (2H, m, CH
2
); 1.96 (3H, s, CH );
3
13
1
28.7; 127.9; 124.3; 120.4; 46.0; 36.0; 29.5; 25.0; 22.4;
1.75–1.58 (6H, m, 3CH ). C NMR spectrum (75 MHz),
2
+
2
1.7; 8.6; 7.1. Found, m/z: 365.1626 [M+H] . C19
H
26ClN
2
O
3
.
δ, ppm: 124.7; 121.7; 120.9; 56.2; 32.3; 23.2; 8.6; 6.9.
+
Calculated, m/z: 365.1631.
Found, m/z: 181.1335 [M+H] . C10
H
17
2
N O. Calculated, m/z:
1
,5-Dimethyl-4-(p-tolyl)-1H-imidazole N-oxide (1h).
181.1340.
A mixture of 1-(hydroxyimino)-1-(p-tolyl)propan-2-one (6)
1-(4-Chlorobenzyl)-4,5-dimethyl-1H-imidazole N-oxide
(1j). Yield 0.92 g (39%), gray solid, mp 190–192°C.
(
(
1.80 g, 10 mmol) and 1,3,5-trimethyl-1,3,5-triazinane
–1
0.45 g, 3.5 mmol) in i-PrOH (20 ml) was refluxed for 4 h.
IR spectrum, ν, cm : 3405, 2977, 1628, 1492, 1386, 1331,
1
Solvent was removed under reduced pressure, and the
1188, 1141, 1084, 1014, 982, 803, 738, 614, 484. H NMR
residue was crystallized from Me
2
2
CO–Et O, 2:1 mixture.
spectrum (300 MHz), δ, ppm (J, Hz): 8.28 (1H, s,
H imidazole); 7.43 (d, J = 8.1, H Ar); 7.20 (d, J = 8.1, H Ar);
Yield 1.20 g (59%), white solid, mp 190–192°C.
–
1
IR spectrum, ν, cm : 3258, 3253, 3125, 2278, 1597, 1512,
5.10 (2H, s, CH
2
); 2.01 (3H, s, CH
3
); 1.96 (3H, s, CH ).
3
13
1
437, 1382, 1345, 1308, 1250, 1186, 1147, 1033, 819, 796,
C NMR spectrum (75 MHz), δ, ppm: 135.6; 132.5; 128.9;
1
7
18, 668, 600. H NMR spectrum (300 MHz), δ, ppm (J, Hz):
.21 (1H, s, H imidazole); 7.53 (2H, d, J = 8.0, H Ar); 7.23
2H, d, J = 8.0, H Ar); 3.55 (3H, s, CH ); 2.33 (3H, s, CH );
). C NMR spectrum (75 MHz), δ, ppm:
36.8; 128.9; 128.5; 125.3; 125.1; 122.6; 31.8; 20.9; 9.1.
128.8; 125.7; 124.3; 121.0; 47.3; 8.3; 7.0. Found, m/z:
+
8
237.0788 [M+H] . C12
H
14ClN O. Calculated, m/z: 237.0794.
2
(
3
3
13
Supplementary information file containing 1H and
C NMR spectra and HRMS of all synthesized compounds
is available at the journal website at http://link.springer.com/
journal/10593.
2
.21 (3H, s, CH
3
13
1
+
Found, m/z: 203.1183 [M+H] . C12
15 2
H N O. Calculated, m/z:
2
03.1184.
Synthesis of N-oxides 1d,f,g,j (General method). Paraform-
aldehyde (0.30 g, 10 mmol) was added to a solution of
amine (10 mmol) in MeOH (20 ml). The reaction mixture
was stirred at room temperature for 8 h. Then solvent was
removed under reduced pressure, EtOH (20 ml) and butane-
This work was supported by Russian Foundation of
Basic Research (grant 18-33-00162 mol_a).
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1d). Yield 1.03 g (54%), white solid, mp 74–76°C.
2
CO (10 ml), filtered, and
2
1
4
(
–
1
IR spectrum, ν, cm : 3376, 3255, 3109, 3032, 1651, 1627,
1
9
(
504, 1442, 1396, 1381, 1327, 1226, 1141, 1072, 1010,
1
18, 756, 663, 609. H NMR spectrum (300 MHz), δ, ppm
5
6
J, Hz): 8.15 (1H, s, H imidazole); 7.63 (1H, s, H furan);
6
1
1
.44 (2H, s, H furan); 5.12 (2H, s, CH
2
); 2.12 (3H, s, CH
). C NMR spectrum (125 MHz), δ, ppm:
49.4; 143.5; 125.4; 124.0; 121.0; 110.8; 108.9; 41.2; 8.2;
3
);
. Trofimov, B. A.; Andriyankova, L. V; Belyaeva, K. V;
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13
.96 (3H, s, CH
3
1
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1
1
. Mloston, G.; Gendek, T.; Heimgartner, H. Helv. Chim. Acta
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55