Synthesis of highly functional imidazole derivatives via assembly of 2-unsubstituted imidazole N-oxides with CH-acids and arylglyoxals

Article abstract of DOI:10.1016/j.tet.2020.130947

A novel and convenient method for the synthesis of a wide range of polyfunctional imidazole derivatives based on the three-component condensation of imidazole N-oxides with CH-acids and arylglyoxals has been developed. This reaction proceeds smoothly in moderate-to-good yields with a wide range of starting materials.

Full text of DOI:10.1016/j.tet.2020.130947

Journal Pre-proof
Synthesis of highly functional imidazole derivatives via assembly of 2-unsubstituted
imidazole N-oxides with CH-acids and arylglyoxals
Valery P. Perevalov, Vitaly S. Mityanov, Boris V. Lichitsky, Andrey N. Komogortsev,
Ludmila G. Kuz'mina, Tatyana Yu. Koldaeva, Vladimir S. Miroshnikov, Anton V.
Kutasevichaa
PII:
S0040-4020(20)30037-5
https://doi.org/10.1016/j.tet.2020.130947
TET 130947
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 December 2019
Revised Date: 28 December 2019
Accepted Date: 8 January 2020
Please cite this article as: Perevalov VP, Mityanov VS, Lichitsky BV, Komogortsev AN, Kuz'mina LG,
Koldaeva TY, Miroshnikov VS, Kutasevichaa AV, Synthesis of highly functional imidazole derivatives via
assembly of 2-unsubstituted imidazole N-oxides with CH-acids and arylglyoxals, Tetrahedron (2020),
doi: https://doi.org/10.1016/j.tet.2020.130947.
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Synthesis of highly functional imidazole
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a
a,b
b
b
Valery P. Perevalov , Vitaly S. Mityanov , Boris V. Lichitsky , Andrey N. Komogortsev , Ludmila G.
c
a
a
a*
Kuz’mina , Tatyana Yu. Koldaeva , Vladimir S. Miroshnikov and Anton V. Kutasevich
a Department of Fine Organic Synthesis and Chemistry of Dyes, D. Mendeleyev University of Chemical
Technology of Russia, Miusskaya Sq., 9, Moscow 125047, Russian Federation.
е-mail: kutasevich.anton@gmail.com.
b N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Pr., 47, Moscow
119991, Russian Federation.
c Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Science, Leninskii Pr., 31,
Moscow 117907, Russian Federation

1
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of highly functional imidazole derivatives via assembly of 2-unsubstituted
imidazole N-oxides with CH-acids and arylglyoxals.
a
a,b
b
b
Valery P. Perevalov , Vitaly S. Mityanov , Boris V. Lichitsky , Andrey N. Komogortsev , Ludmila G.
c
a
a
a*
Kuz’mina , Tatyana Yu. Koldaeva , Vladimir S. Miroshnikov and Anton V. Kutasevich
*
—
——
*
∗
Corresponding author.
E-mail addresses: mityanovvs@yandex.ru (V.S. Mityanov),
kutasevich.anton@gmail.com (A.V. Kutasevich).

1
a
Department of Fine Organic Synthesis and Chemistry of Dyes, D. Mendeleyev University of Chemical Technology of Russia, Miusskaya Sq., 9, Moscow 125047,
Russian Federation.
е-mail: kutasevich.anton@gmail.com.
b
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Pr., 47, Moscow 119991, Russian Federation.
Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Science, Leninskii Pr., 31, Moscow 117907, Russian Federation
c
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel and convenient method for the synthesis of a wide range of polyfunctional imidazole
derivatives based on the three-component condensation of imidazole N-oxides with CH-acids
and arylglyoxals has been developed. This reaction proceeds smoothly in moderate-to-good
yields with a wide range of starting materials.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
multicomponent reaction
CH-functionalization
imidazole N-oxide
arylglyoxal
CH-acid
1
. Introduction
Given the synthetic availability of N-oxides of 1H-imidazoles,
Table 1. Scope of products 4.
they can be considered as valuable building blocks in the
synthesis of various functional heterocycles [1] including
biologically active substances [2]. The presence of N-oxide
moiety in the imidazole derivatives substantially changes the
reactivity of the parent heterocycle. It becomes possible to carry
out selective CH-functionalization by cine-nucleophilic
substitution [1d, 3a] of the hydrogen atom, as well as transition
metal catalyzed reactions [1b, 3d] with preservation of N-oxide
function. Of interest are the [3+2] dipolar cycloaddition reactions
Ph
O
[
4]. However, only the one example of CH-functionalization of
N
O
O
imidazole N-oxides is known in the literature, based on Michael’s
addition, as a result of three-component condensation described
in a series of our recent articles [5].
In continuation of our ongoing interest in the synthesis and
functionalization of 2-unsubstituted imidazole N-oxides, we have
significantly expanded the range of compounds available using
our method, introducing the hydrate of arylglyoxals to the three-
component reaction.
N
O
S
d (64%)
4
O
O
N
Ph
O
O
O
O
O
N
2
. Results and discussion
N
O
N
O
We have shown that N-oxides of 2-unsubstituted imidazoles
O
N
enter condensation reaction with hydrates of arylglyoxal 2 and
various CH-acids 3 with the formation of the products 4 (Scheme
1
O
O
O
4
g (37%)
4h (31%)
, Table 1).
O
R1
O
O
R2
R3
R3
R2
N
HO
HO
O
N
OMe
O
O
O
HN
MeCN or
MeCN/H O,
R4
O
O
MeO
N
R1
N
O
2
O
N
NH
O
R4
1
2
3
4
N
O
Scheme 1. Condensation of 2-unsubstituted imidazole N-
oxides with CH-acids and arylglyoxals.
O
S
4k (58%)

2
Tetrahedron
or acid does not allow these CH-acids to be introduced into the
investigated reaction.
Scheme 3. Reaction of imidazole N-oxide and arylglyoxal
with acyclic β-dicarbonyl compounds.
This method is operationally simple and does not require
chromatographical purification of the target compounds. For this
transformation, aromatic and heteroaromatic glyoxals in the form
of stable hydrates were used. However, using glyoxal itself and
methylglyoxal in the form of aqueous solutions led to a complex
mixture of substances, it was not possible to isolate the
corresponding products.
It is known that compounds of type 9 containing a 1,4-
dicarbonyl moiety relatively easy undergo Paal-Knorr-type
cyclization to fused furans 10 when heated in the acid (formic
acid or a mixture of hydrochloric and acetic acids) [7].
However, despite the structural similarity of compounds 4 and
9
, with prolonged heating in formic acid or a mixture of
hydrochloric and acetic acids, they do not change.
We assumed that a stronger acid is required for cyclization.
Indeed, carrying out the reaction with compound 4r in the
concentrated sulfuric acid at ambient temperature resulted in
cyclization to furocoumarin. However, this process is
accompanied by sulfonation of the electron-donating
methoxyphenyl ring (Scheme 4).
Arylglyoxals are more active electrophiles than aldehydes and
when interacting with CH-acids they do not form stable enones
but give addition products of 2 equivalents of CH-acid to
arylglyoxal.
This is because the initially formed hydroxyketone 5 very
easily eliminates water with the formation of a highly active
Michael acceptor 6 which rapidly attaches the second mole of the
CH-acid (Scheme 2).
Scheme 4. Cyclization of compound 4r in the concentrated
sulfuric acid.
At the same time, the use of trifluoromethanesulfonic acid as a
cyclizing agent makes it possible to obtain furocoumarins and
furopyranones 12 in high yields (Scheme 5).
Scheme 2. Condensation of arylglyoxals with two moles of
CH-acid.
In the present work, we used the scope of common CH-acids,
similar to that described earlier for reactions with aldehydes: CH-
acids such as barbituric acid, dimedone, Meldrum's acid,
hydroxy-6-methylpyranone, 4-hydroxycoumarin and 4-hydroxy-
7
,7-dimethyl-7,8-dihydro-2H-chromene-2,5(6H)-dione
(2f)
(which was not used earlier). When using acyclic CH-acids such
as acetylacetone 8a, dimethyl malonate 8b, ethyl acetoacetate 8c
in the same conditions, the reaction does not occur (Scheme 3). It
is known that aromatic CH-acids such as phenols can interact
with arylglyoxals only in the presence of a base, which converts
them to the ionic form [6]. However, the addition of either base

3
refluxing in toluene with a Dean-Stark trap in the presence of
p-toluenesulfonic acid as a catalyst (Scheme 6).
Scheme 6. Cyclization of compound 4b.
We were unable to obtain furane derivatives from compounds
containing a fragment of barbituric or Meldrum’s acid due to
4
their instability under-discussed conditions.
3
. Conclusion
In conclusion, a novel method for C2-functionalization of
imidazole N-oxides based on condensation with arylglyoxals and
CH-acids was developed. It makes it easy to generate structurally
diverse imidazole derivatives including pharmacologically
interesting molecules containing furocoumarin and furopyranone
fragments. A method is operationally simple and not requires
column chromatography for isolation target products in pure
form. Thus, the developed method can be considered as a useful
synthetic protocol for the preparation of various types of
polyfunctional heterocyclic compounds.
4
. Experimental
All the reagents were purchased from commercial suppliers
and used without further purification. Imidazole N-oxides 1a
4a], 1b [4a], 1c [9a], 1d [9b], 1e [9c], 1f [5c], 1g [5b] and 4-
hydroxy-7,7-dimethyl-7,8-dihydro-2H-chromene-2,5(6H)-dione
2f) [9d] were prepared according to the reported procedures.
Preparation of imidazole N-oxides 1h,i,j,k described in
[
Scheme 5. Cyclization of compounds 4 in trifluoromethane-
sulfonic acid
(
The structure of all newly synthesized compounds was proved
by a complex of physicochemical methods, including X-ray
analysis for cyclic derivative 12a (figure 1).
1
13
supporting info. H and C NMR spectra were recorded on a
Bruker Avance 300 MHz, Bruker Avance 400 MHz or a Bruker
AV-600 600 MHz spectrometer in DMSO-d , chemical shift
6
1
13
values for H and C NMR spectra are reported in parts per
million (ppm) with the solvent resonance as the internal standard.
High-resolution mass spectra (HRMS) were registered on Bruker
MicrOTOF ESI-TOF mass spectrometer. The TLC analysis was
performed with Merck Silica Gel 60 F254 precoated plates. IR
spectra were recorded on a Shimadzu IRAffinity-1 FTIR
spectrophotometer. The melting points were determined on a
Kofler hot stage.
Single crystals of 12a C N O were grown from ethyl acetate
30
2
6
solution. A suitable crystal was selected and mounted on a 'CCD
area detector' SMART APEX-II diffractometer. The crystal was
kept at 296 K during data collection. Using Olex2 [10a], the
structure was solved with the ShelXT [10b] structure solution
program using Intrinsic Phasing and refined with the olex2.refine
[
10c] refinement package using Gauss-Newton minimisation.
Figure 1. ORTEP representation of compound 12a.
Crystal Data for C N O (M =510.55 g/mol): triclinic, space
30
2
6
group P 1 (no. 2), a = 9.3741(6) Å, b = 10.4032(6) Å, c =
4.3572(9) Å, α = 79.912(2)°, β = 79.046(2)°, γ = 72.546(2)°,
It should be noted that such compounds containing a
furocoumarin core are known to have a wide spectrum of
biological activity, including antifungal, anti-inflammatory and
antiproliferative activity [8].
These conditions turned out to be unsuitable for compounds 4
containing a fragment of dimedone. Carrying out the reaction in
sulfuric or trifluoromethanesulfonic acid resulted in complex and
non-separable mixtures of products. We have shown by the
example of compound 4b that cyclization can be carried out by
1
3
-1
V = 1300.84(14) Å , Z = 2, T = 296 K, ꢀ(Mo Kα) = 0.092 mm ,
3
Dcalc = 1.3033 g/cm , 21481 reflections measured (4.6° ≤ 2θ ≤
5
3.7°), 5552 unique (Rint = 0.0493, R = 0.0449) which were used
σ
in all calculations. The final R was 0.0503 (I≥2σ(I)) and wR
1
2
was 0.1509 (all data).
CCDC – 1969028 contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.camm.ac.uk/data_requesr/cif,
or
e-mailing

4
Tetrahedron
o
data_request@ccdc.cam.ac.uk or by contacting The Cambridge
Yield 64% (method A), off-white solid, m.p. 188-190 C. IR
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
IEZ, UK.
(KBr): 3426, 3094, 2955, 2376, 1651, 1605, 1450, 1420, 1250,
1
1049, 879, 810, 663, 563, H NMR (300 MHz, DMSO-d ) δ 7.84
6
(
6
d, J = 4.9 Hz, 1H), 7.46 – 7.25 (m, 3H), 7.16 (d, J = 7.4 Hz, 2H),
.93 (t, J = 4.4 Hz, 1H), 6.80 (s, 1H), 6.26 (s, 1H), 5.51 (d, J =
16.5 Hz, 1H), 5.24 (d, J = 16.3 Hz, 1H), 2.34 – 1.92 (m, 10H),
General procedure of preparation compounds 4a-t.
Method A. A mixture of appropriate imidazole N-oxide (2
mmol), CH-acid (2 mmol) and arylglyoxal (2 mmol) was
refluxed for 5 h. The solvent was removed under reduced
pressure and the residue was crystallized from IPA or its mixture
with water to give the corresponding product.
13
0.96 (s, 6H). C NMR (151 MHz, DMSO-d ) δ 183.77, 141.28,
6
135.14, 134.77, 133.99, 130.96, 128.93, 128.03, 127.94, 126.72,
123.41, 123.00, 106.20, 47.56, 31.18, 8.66, 6.74. HRMS-ESI:
+
Calculated for
C
H
29
N
2
O
4
S
[M+H] : 465.1848. Found:
26
4
65.1843.
Method B. A mixture of appropriate imidazole N-oxide (2
mmol), arylglyoxal (2 mmol) and barbituric acid 2a (2 mmol) in
mixture MeCN (5 mL) and water (2 mL) was refluxed for 8 h.
The solvent was removed under reduced pressure and the residue
was crystallized from IPA to give the corresponding product.
4.1.5.
1-benzyl-2-(1-(4,4-dimethyl-2,6-dioxocyclohexyl)-2-
(2,5-dimethylthiophen-3-yl)-2-oxoethyl)-4,5-dimethyl-1H-
imidazole N-oxide (4e).
o
Yield 67% (method A), white solid, m.p. 133-136 C. IR
(KBr): 3426, 3063, 3032, 2955, 2924, 2886, 2816, 2739, 2361,
2345, 1952, 1667, 1605, 1558, 1489, 1450, 1373, 1358, 1335,
4
.1.1. 2-(1-(4,4-dimethyl-2,6-dioxocyclohexyl)-2-oxo-2-(p-
tolyl)ethyl)-1,4,5-trimethyl-1H-imidazole N-oxide (4a).
1
7
312, 1234, 1204, 1126, 1096, 1057, 1003, 957, 910, 887, 833,
95, 779, 733, 702, 648, 617, 594, 563, 463. H NMR (300 MHz,
o
Yield 72% (method A), white solid, m.p. 200-201 C. IR (KBr):
3
1
1
426, 2939, 2870, 2361, 1697, 1605, 1450, 1366, 1258, 1180,
DMSO-d ) δ 7.44 – 7.25 (m, 3H), 7.18 (d, J = 6.7 Hz, 2H), 6.05
1
6
003, 964, 864, 771, 733, 617, 594, 548, 486, 447. H NMR (300
(s, 1H), 5.98 (s, 1H), 5.41 (d, J = 16.6 Hz, 1H), 5.18 (d, J = 16.6
MHz, DMSO-d ) δ 16.87 (br.s, 1H), 7.51 (d, J = 7.8 Hz, 2H),
.19 (d, J = 7.9 Hz, 2H), 6.37 (s, 1H), 3.71 (s, 3H), 2.31 (s, 3H),
.19 – 2.13 (m, 7H), 1.94 (s, 3H), 0.94 (s, 6H). C NMR (101
MHz, DMSO-d ) δ 154.10, 142.60, 139.43, 134.93, 133.61,
31.43, 128.86, 127.47, 122.74, 122.10, 117.50, 115.07, 106.42,
1.17, 22.96, 21.03, 8.29, 6.65. HRMS-ESI: Calculated for
6
Hz, 1H), 2.41 (s, 3H), 2.14 (s, 3H), 2.13 – 1.97 (m, 8H), 0.90 (s,
6H). C NMR (101 MHz, DMSO-d
1
1
1
7
2
13
13
6
) δ 187.97, 152.41, 145.20,
35.29, 135.00, 134.53, 134.15, 129.09, 128.09, 126.75, 123.87,
6
23.14, 122.54, 106.74, 47.29, 40.82, 31.12, 29.30, 26.44, 14.79,
4.49, 8.63, 6.88. HRMS-ESI: Calculated for C H N O S
1
3
2
8
33
2
4
+
+
[M+H] : 493.2161. Found: 493.2156.
C H N O [M+H] : 397.2127. Found: 397.2122.
23
29
2
4
4
.1.6. 1-benzyl-2-(2-(4-bromophenyl)-1-(4,4-dimethyl-2,6-
4
.1.2. 1-benzyl-2-(1-(4,4-dimethyl-2,6-dioxocyclohexyl)-2-oxo-2-
dioxocyclohexyl)-2-oxoethyl)-7-(hydroxyimino)-4,5,6,7-
tetrahydro-1H-benzo[d]imidazole N-oxide (4f).
(p-tolyl)ethyl)-4,5-dimethyl-1H-imidazole N-oxide (4b).
o
Yield 89% (method A), white solid, m.p. 194-196 C. IR (KBr):
o
Yield 54% (method A), white solid, m.p. 188-190 C. IR
KBr): 3171, 3063, 2893, 2376, 1697, 1582, 1389, 1258, 1072,
011, 918, 802, 710, 679, 579, 478, 417. H NMR (300 MHz,
DMSO-d ) δ 11.54 (s, 1H), 7.52 – 7.29 (m, 3H), 7.06 (d, J = 8.7
Hz, 2H), 6.32 (s, 1H), 6.15 (d, J = 15.8 Hz, 1H), 5.40 (d, J = 15.8
Hz, 1H), 2.76 – 2.66 (m, 2H), 2.59 – 2.45 (m, 2H), 2.29 – 2.09
m, 4H), 1.90 – 1.80 (m, 3H), 0.93 (s, 6H). C NMR (151 MHz,
3
1
1
6
410, 3071, 3032, 2963, 2870, 2361, 1697, 1643, 1589, 1574,
512, 1497, 1450, 1420, 1373, 1335, 1304, 1281, 1234,
(
1
1
204,1157, 1111, 1057, 1034, 988, 949, 864, 802, 764, 733, 702,
1
6
64, 625, 594, 563, 463. H NMR (300 MHz, DMSO-d ) δ 16.58
6
(br.s, 1H), 7.50 – 7.30 (m, 3H), 7.26 – 7.11 (m, 4H), 7.03 (d, J =
7
1
0
1
1
3
.8 Hz, 2H), 6.30 (s, 1H), 5.52 (d, J = 16.6 Hz, 1H), 5.22 (d, J =
13
(
6.6 Hz, 1H), 2.27 (s, 3H), 2.21 – 2.04 (m, 7H), 1.97 (s, 3H),
13
DMSO-d
6
) δ 190.59, 147.08, 137.52, 134.96, 131.29, 130.91,
28.93, 128.86, 128.16, 127.03, 126.33, 120.08, 106.16, 49.60,
5.44, 38.30, 31.12, 22.21, 20.07, 18.22. HRMS-ESI: Calculated
.93 (s, 6H). C NMR (151 MHz, DMSO-d ) δ 194.46, 191.43,
6
1
4
42.49, 135.10, 133.48, 128.98, 128.66, 128.07, 127.20, 126.73,
23.01, 122.61, 106.64, 101.84, 49.19, 47.37, 45.74, 38.56,
1.11, 20.94, 8.54, 6.70. HRMS-ESI: Calculated for C H N O
+
for C H BrN O [M+H] : 592.1447. Found: 592.1442.
30
31
3
5
29
33
2
4
+
[
M+H] : 473.2440. Found: 473.2435.
4.1.7.
2-(2-(benzo[d][1,3]dioxol-5-yl)-1-(4,4-dimethyl-2,6-
dioxocyclohexyl)-2-oxoethyl)-1-methyl-5-(pyridin-3-yl)-1H-
imidazole N-oxide (4g).
4
.1.3. 2-(2-(benzo[d][1,3]dioxol-5-yl)-1-(4,4-dimethyl-2,6-
dioxocyclohexyl)-2-oxoethyl)-1-benzyl-4,5-dimethyl-1H-
imidazole N-oxide (4c)
o
Yield 37% (method A), pale grey solid, m.p. 168-170 C. IR
o
(KBr): 3426, 2955, 1682, 1605, 1443, 1250, 1111, 1034, 795,
Yield 81% (method A), white solid, m.p. 176-179 C. IR
KBr): 3426, 3055, 2970, 2932, 2886, 2785, 1682, 1597, 1520,
1
7
1
1
17, 571. H NMR (400 MHz, DMSO-d ) δ 8.76 (d, J = 2.3 Hz,
H), 8.70 (d, J = 3.2 Hz, 0H), 8.04 (d, J = 8.0 Hz, 1H), 7.74 (s,
H), 7.58 (dd, J = 8.0, 4.9 Hz, 1H), 7.22 – 7.16 (m, 2H), 6.90 (d,
6
(
1
1
6
2
6
466, 1420, 1366, 1335, 1312, 1288, 1258, 1211, 1196, 1157,
111, 1049, 1011, 988, 949, 949, 934, 880, 841, 772, 718, 664,
25, 563, 263. H NMR (300 MHz, DMSO-d ) δ 7.46 – 7.37 (m,
H), 7.37 – 7.27 (m, 1H), 7.17 (d, J = 6.2 Hz, 3H), 6.95 (s, 1H),
.73 – 6.61 (m, 2H), 6.26 (s, 1H), 6.05 (s, 2H), 5.50 (d, J = 16.7
Hz, 1H), 5.23 (d, J = 16.6 Hz, 1H), 2.05 (d, J = 23.3 Hz, 10H),
.91 (d, J = 7.7 Hz, 6H). C NMR (101 MHz, DMSO-d ) δ
90.10, 150.76, 147.39, 135.17, 130.30, 129.06, 128.08, 126.61,
23.11, 122.80, 122.69, 112.46, 111.90, 107.41, 107.27, 101.90,
7.51, 46.63, 31.48, 31.20, 27.68, 8.61, 6.83. HRMS-ESI:
1
J = 8.6 Hz, 1H), 6.43 (s, 1H), 6.12 – 6.07 (m, 2H), 3.83 (s, 3H),
6
13
2
1
1
.22 (s, 4H), 0.98 (s, 6H). C NMR (151 MHz, DMSO-d ) δ
6
89.74, 150.88, 150.28, 149.51, 147.51, 137.92, 136.73, 130.36,
27.71, 123.74, 123.15, 122.82, 117.73, 107.73, 107.43, 101.90,
13
54.89, 49.33, 40.43, 39.52, 38.52, 32.99, 31.22, 31.22. HRMS-
0
1
1
4
+
6
ESI: Calculated for C H N O [M+H] : 476.1821. Found:
26
26
3
6
4
76.1816.
4.1.8. 1-benzyl-2-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-
(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-oxoethyl)-4,5-
+
Calculated for C H N O [M+H] : 503.2182. Found: 503.2177.
29
31
2
6
dimethyl-1H-imidazole N-oxide (4h).
4
.1.4.
oxo-2-(thiophen-2-yl)ethyl)-4,5-dimethyl-1H-imidazole N-oxide
4d).
1-benzyl-2-(1-(4,4-dimethyl-2,6-dioxocyclohexyl)-2-
o
Yield 31% (method A), white solid, m.p. 241-243 C. IR
(KBr): 3441, 2993, 2153, 1666, 1605, 1512, 1389, 1296, 1258,
(
1
1
204, 1065, 895, 818, 779, 710, 586, 455. H NMR (400 MHz,

5
DMSO-d ) δ 7.37 – 7.20 (m, 4H), 7.15 – 7.04 (m, 3H), 6.81 (d, J
4.1.13. 2-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-
6
=
=
8.5 Hz, 1H), 6.07 (s, 1H), 5.65 (d, J = 16.8 Hz, 1H), 5.41 (d, J
(4-methoxyphenyl)-2-oxoethyl)-1,4,5-trimethyl-1H-imidazole N-
oxide (4m).
16.8 Hz, 1H), 4.31 – 4.19 (m, 4H), 2.16 (s, 3H), 2.04 (s, 3H),
13
1
1
1
4
.30 (s, 6H). C NMR (101 MHz, DMSO-d ) δ 192.41, 165.23,
47.55, 142.95, 135.04, 128.95, 128.74, 127.66, 126.29, 123.43,
23.29, 121.41, 116.78, 116.67, 100.91, 71.43, 64.51, 63.92,
o
6
Yield 71% (method A), white solid, m.p. 229-232 C. IR
(
1
KBr): 3442, 3087, 2906, 2842, 1911, 1696, 1635, 1442, 1366,
511, 1366, 1311, 1244, 1169, 1025, 996, 891, 845, 786, 708,
8.39, 42.49, 25.66, 8.51, 6.91. HRMS-ESI: Calculated for
1
+
614, 546, 508. H NMR (300 MHz, DMSO-d
6
) δ 7.62 (d, J = 8.8
C H N O [M+H] : 521.1924. Found: 521.1918.
28
29
2
8
Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.18 (s, 1H), 5.78 (s, 1H), 3.81
13
4
.1.9. 1-benzyl-2-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-
-(4-methoxyphenyl)-2-oxoethyl)-4,5-dimethyl-1H-imidazole N-
oxide (4i).
(s, 3H), 3.79 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H), 1.98 (s, 3H). C
2
NMR (151 MHz, DMSO-d ) δ 165.44, 162.68, 160.09, 134.63,
6
129.81, 128.23, 123.46, 122.41, 118.04, 113.70, 104.35, 94.20,
72.40, 55.39, 40.61, 18.93, 8.33, 6.57. HRMS-ESI: Calculated
o
Yield 65% (method A), white solid, m.p. 182-184 C. IR
+
for C H N O [M+H] : 399.1556. Found: 399.1551.
21
23
2
6
(
KBr): 3426, 3001, 2376, 1674, 1605, 1512, 1465, 1342, 1250,
1
1
203, 1173, 1111, 1026, 871, 841, 779, 702, 586, 455. H NMR
4.1.14. 1-benzyl-2-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-
yl)-2-(4-methoxyphenyl)-2-oxoethyl)-4,5-dimethyl-1H-imidazole
N-oxide (4n).
(400 MHz, DMSO-d ) δ 7.59 (d, J = 8.4 Hz, 2H), 7.38 – 7.24 (m,
6
3
1
3
H), 7.11 (d, J = 7.5 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.10 (s,
H), 5.65 (d, J 16.8 Hz, 1H), 5.44 (d, J = 16.8 Hz, 1H), 3.78 (s,
H), 2.15 (s, 2H), 2.07 (s, 2H), 1.32 (s, 5H). C NMR (101 MHz,
o
13
Yield 67% (method A), white solid, m.p. 108-113 C. IR
(
1
1
KBr): 3426, 2924, 2376, 1697, 1597, 1458, 1350, 1258, 1173,
DMSO-d ) δ 165.40, 162.74, 134.98, 129.76, 128.76, 128.28,
1
6
026, 995, 849, 702, 602, 555. H NMR (400 MHz, DMSO-d ) δ
6
1
4
27.72, 126.40, 123.44, 123.17, 113.55, 100.96, 71.45, 55.43,
8.33, 42.26, 25.58, 8.50, 6.84. HRMS-ESI: Calculated for
6.90 (br. s, 1H), 7.50 – 7.34 (m, 3H), 7.29 – 7.18 (m, 4H), 6.73
+
(d, J = 8.5 Hz, 2H), 6.08 (s, 1H), 5.85 (s, 1H), 5.62 (d, J = 16.5
Hz, 1H), 5.26 (d, J = 16.6 Hz, 1H), 3.77 (s, 3H), 2.24 (s, 3H),
C H N O [M+H] : 493.1974. Found: 493.1969.
27
29
2
7
13
4
.1.10. 1-(2-hydroxyethyl)-2-(2-(4-methoxyphenyl)-2-oxo-1-
2,4,6-trioxohexahydropyrimidin-5-yl)ethyl)-4,5-dimethyl-1H-
imidazole N-oxide (4j).
2.11 (s, 3H), 1.99 (s, 3H). C NMR (101 MHz, DMSO-d ) δ
6
(
172.68, 165.57, 162.61, 160.27, 136.36, 134.94, 129.60, 129.14,
128.31, 128.04, 126.97, 123.42, 123.36, 113.54, 109.55, 104.08,
94.52, 55.40, 47.78, 40.79, 18.99, 8.71, 6.76. HRMS-ESI:
o
Yield 64% (method B), white solid, m.p. 235-238 C. IR
+
Calculated for C H N O [M+H] : 475.1869. Found: 475.1864.
27
27
2
6
(
KBr): 3472, 3163, 2885, 1697, 1605, 1474, 1358, 1258,
1
1
1
173,1026, 833, 548, 447. H NMR (300 MHz, DMSO-d ) δ
7.06 (br. s, 1H), 10.25 (s, 2H), 7.75 (d, J = 8.8 Hz, 2H), 6.93 (d,
4.1.15.
1-(carboxymethyl)-2-(1-(4-hydroxy-6-methyl-2-oxo-
6
2H-pyran-3-yl)-2-oxo-2-(p-tolyl)ethyl)-4,5-dimethyl-1H-
J = 8.9 Hz, 2H), 6.32 (s, 1H), 5.20 (s, 1H), 4.51 – 4.23 (m, 2H),
imidazole N-oxide (4o).
13
3
.80 (s, 3H), 3.78 – 3.57 (m, 2H), 2.24 (s, 3H), 2.08 (s, 3H).
C
o
Yield 87% (method A), white solid, m.p. 241-243 C. IR
NMR (101 MHz, DMSO-d ) δ 191.47, 164.99, 162.74, 150.68,
6
(
KBr): 3426, 2924, 2345, 1852, 1697, 1605, 1450, 1358, 1234,
1
5
36.97, 130.04, 128.20, 123.19, 122.15, 113.57, 84.43, 59.58,
5.46, 47.24, 8.54, 6.83. HRMS-ESI: Calculated for C H N O
1
9
95, 856, 771, 586, 439. H NMR (400 MHz, DMSO-d ) δ 7.61
6
20
23
4
7
+
(d, J = 7.9 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 6.21 (s, 1H), 5.84 –
.79 (m, 1H), 5.27 (d, J = 18.5 Hz, 1H), 5.02 (d, J = 18.5 Hz,
[
M+H] : 431.1566. Found: 431.1561.
5
1
3
4
.1.11. 1-(2,2-dimethoxyethyl)-4,5-dimethyl-2-(2-oxo-2-
1H), 2.30 (s, 3H), 2.11 – 2.06 (m, 6H), 1.94 (s, 3H). C NMR
(thiophen-2-yl)-1-(2,4,6-trioxohexahydropyrimidin-5-yl)ethyl)-
(151 MHz, DMSO-d ) δ 172.58, 168.29, 165.37, 160.12, 142.97,
6
1
H-imidazole N-oxide (4k).
135.35, 133.07, 128.75, 127.87, 123.78, 122.80, 104.08, 94.79,
77.04, 46.01, 21.03, 18.92, 8.12, 6.59. HRMS-ESI: Calculated
o
Yield 58% (method B), grey solid, m.p. 238-241 C. IR (KBr):
140, 2985, 2762, 1697, 1666, 1604. 1450, 1411, 1357, 1280,
+
for C H N O [M+H] : 427.1505. Found: 427.1500.
22
23
2
7
3
1
5
2
7
2
242, 1126, 1072, 956, 1033, 856, 833, 802, 779, 748, 648, 624,
4.1.16. 2-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-(4-
methoxyphenyl)-2-oxoethyl)-4,5-dimethyl-1-(2-(pyridin-2-
yl)ethyl)-1H-imidazole N-oxide (4p).
1
78, 540, 509, 432. H NMR (400 MHz, DMSO-d ) δ 10.41 (s,
6
H), 7.94 (d, J = 4.9 Hz, 1H), 7.50 (d, J = 2.6 Hz, 1H), 7.18 –
.10 (m, 1H), 6.20 (s, 1H), 4.69 – 4.63 (m, 1H), 4.41 – 4.27 (m,
H), 3.34 (s, 3H), 3.24 (s, 3H), 2.24 (s, 3H), 2.09 (s, 3H).
o
13
Yield 46% (method A), off-white solid, m.p. 175-179 C. IR
C
(
1
KBr): 3425, 2932, 1681, 1697, 1604, 1515, 1473, 1357, 1250,
234, 1172, 1033, 995, 910, 871, 841, 786, 756, 586, 524. H
NMR (101 MHz, DMSO-d ) δ 184.83, 165.12, 150.55, 140.47,
1
8
1
6
37.06, 134.67, 132.17, 128.18, 123.89, 122.43, 109.51, 101.93,
3.84, 56.02, 54.64, 46.61, 41.03, 8.47, 6.76. HRMS-ESI:
NMR (400 MHz, DMSO-d ) δ 17.21 (br.s, 1H), 8.44 (d, J = 4.3
6
+
Hz, 1H), 7.77 – 7.68 (m, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.28 (d, J
Calculated for C H N O S [M+H] : 451.1287. Found: 451.1282
19
23
4
7
=
7.7 Hz, 1H), 7.25 – 7.18 (m, 1H), 6.92 (d, J = 8.9 Hz, 2H), 6.27
4
.1.12.
2-(2-(4-methoxyphenyl)-2-oxo-1-(2,4,6-
(s, 1H), 5.81 (s, 1H), 4.72 – 4.55 (m, 2H), 3.79 (s, 3H), 3.13 (s,
2H), 2.14 (s, 3H), 2.12 (s, 3H), 1.96 (s, 3H). C NMR (151 MHz,
13
trioxohexahydropyrimidin-5-yl)ethyl)-1,5-dimethyl-4-(p-tolyl)-
H-imidazole N-oxide (4l).
1
DMSO-d ) δ 189.65, 173.28, 165.61, 162.67, 160.40, 156.79,
6
o
149.21, 136.85, 129.93, 128.18, 123.73, 123.13, 122.87, 122.18,
Yield 84% (method B), off-white solid, m.p. 285-290 C. IR
KBr): 3426, 3209, 1720, 1605, 1504, 1381, 1358, 1258, 1165,
1
13.66, 104.52, 95.07, 55.45, 44.22, 40.97, 37.43, 23.04, 19.05,
(
+
1
8.27, 6.76. HRMS-ESI: Calculated for C27
90.1978. Found: 490.1973.
H N O [M+H] :
28 3 6
1
2
2
3
1
1
026, 810, 787, 555. H NMR (400 MHz, DMSO-d ) δ 10.33 (s,
H), 7.69 (d, J = 8.8 Hz, 2H), 7.28 (s, 4H), 6.95 (d, J = 8.8 Hz,
H), 6.31 (s, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 2.30 (s, 3H), 2.32 (s,
H). C NMR (151 MHz, DMSO-d ) δ 190.81, 164.83, 162.68,
50.55, 143.38, 138.61, 137.58, 129.82, 129.12, 128.39, 125.36,
6
4
4.1.17. 2-(2-(2,5-dimethylthiophen-3-yl)-1-(4-hydroxy-6-
methyl-2-oxo-2H-pyran-3-yl)-2-oxoethyl)-1-(2-methoxybenzyl)-
4,5-dimethyl-1H-imidazole N-oxide (4q).
13
6
24.69, 122.45, 122.19, 113.63, 83.18, 55.39, 32.13, 20.81, 9.15.
HRMS-ESI: Calculated for C H N O [M+H] : 477.1774.
o
+
Yield 67% (method A), white solid, m.p. 222-225 C. IR
25
25
4
6
(
KBr): 3441, 2924, 2354, 1682, 1497, 1358, 1288, 1165, 1119,
Found: 477.1769.

6
Tetrahedron
1
o
1
034, 764, 594, 548, 494, 424. H NMR (400 MHz, DMSO-d )
Yield 56%, off-white solid, m.p. 245-248 C. IR (KBr): 3449,
6
δ 7.39 – 7.30 (m, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 7.4
Hz, 1H), 6.93 – 6.85 (m, 1H), 6.05 (s, 1H), 5.89 (s, 1H), 5.80 (d,
J = 1.1 Hz, 1H), 5.35 (d, J = 16.8 Hz, 1H), 5.21 (d, J = 16.8 Hz,
1736, 1636, 1605, 1474, 1281, 1088, 1034, 972, 895, 756, 702,
1
625. H NMR (400 MHz, DMSO-d ) δ 8.05 (d, J = 7.2 Hz, 1H),
6
7.89 (d, J = 2.5 Hz, 1H), 7.72 – 7.63 (m, 1H), 7.57 – 7.46 (m,
2H), 7.34 (d, J = 6.2 Hz, 1H), 7.13 (d, J = 7.0 Hz, 3H), 7.02 –
1
2
H), 3.78 (s, 3H), 2.45 (s, 3H), 2.14 (d, J = 5.9 Hz, 6H), 2.07 (s,
H), 2.07 (s, 1H), 2.01 (s, 3H). C NMR (151 MHz, DMSO-d6)
13
13
6.91 (m, 3H), 3.80 (s, 2H), 2.31 (s, 3H), 2.21 (s, 3H). C NMR
δ 186.46, 165.51, 160.00, 156.74, 146.22, 134.76, 134.70,
(101 MHz, DMSO-d ) δ 158.38, 156.80, 156.24, 156.21, 152.13,
6
1
1
1
33.68, 129.77, 127.76, 123.99, 123.48, 123.11, 122.37, 121.28,
20.42, 111.37, 104.09, 94.43, 55.44, 44.21, 43.17, 18.90, 14.91,
4.50, 8.50, 6.75. HRMS-ESI: Calculated for C H N O S
136.55, 134.04, 131.92, 129.54, 128.72, 128.54, 127.96, 126.68,
126.61, 126.42, 125.71, 125.37, 121.17, 117.20, 112.57, 111.59,
111.32, 102.84, 96.86, 55.72, 48.80, 8.88, 7.23. HRMS-ESI:
27
29
2
6
+
+
[
M+H] : 509.1746. Found: 509.1741.
Calculated for C H N O S [M+H] : 573.1331. Found:
30
25
2
8
5
73.1326.
4.3. General procedure of preparation compounds 12a-g
00 mg of appropriate compound 4 was dissolved in 3 ml (5
4
.1.18. 1-benzyl-2-(1-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-
(
4-methoxyphenyl)-2-oxoethyl)-4,5-dimethyl-1H-imidazole N-
oxide (4r).
3
o
Yield 71% (method A), white solid, m.p. 187-190 C. IR
KBr): 3426, 1666, 1605, 1512, 1458, 1350, 1265, 1165, 1111,
026, 748, 702, 548, 463. H NMR (400 MHz, DMSO-d ) δ 7.82
d, J = 6.5 Hz, 1H), 7.56 (t, J = 7.0 Hz, 1H), 7.38 – 7.18 (m, 9H),
g) of trifluoromethanesulfonic acid and stirred at room
temperature for 5 h. Then reaction mixture was poured on 100 ml
of water, formed precipitate was filtered and washed with cold
water. In case of compound 12e no precipitate is formed. The
(
1
(
1
6
6
5
.76 (d, J = 8.9 Hz, 2H), 6.30 (s, 1H), 5.64 (d, J = 16.7 Hz, 1H),
.36 (d, J = 16.7 Hz, 1H), 3.75 (s, 3H), 2.21 (s, 3H), 2.06 (s, 3H).
resulting solution was neutralized by aqueous NH and extracted
3
by CHCl (3x15 ml). The extract was dried over anhydrous
3
1
3
C NMR (101 MHz, DMSO-d ) δ 163.92, 163.32, 162.68,
6
sodium sulfate. The solvent was removed under reduced pressure
1
1
1
52.37, 134.77, 132.01, 129.62, 128.98, 128.17, 127.97, 126.73,
24.36, 123.76, 123.49, 123.34, 119.11, 118.57, 115.86, 113.59,
to obtain pure 12e.
4
.3.1.
1-benzyl-2-(2-(4-methoxyphenyl)-4-oxo-4H-furo[3,2-
12.42, 95.67, 55.38, 47.97, 41.52, 8.65, 6.77. HRMS-ESI:
+
c]chromen-3-yl)-4,5-dimethyl-1H-imidazole N-oxide (12a).
Calculated for C H N O [M+H] : 511.1869. Found: 511.1864.
30
27
2
6
o
Yield 87%, off-white solid, m.p. 126-129 C. IR (KBr): 3425,
4
.1.19. 2-(2-(2,5-dimethylthiophen-3-yl)-1-(4-hydroxy-2-oxo-
H-chromen-3-yl)-2-oxoethyl)-4,5-dimethyl-1-phenethyl-1H-
imidazole N-oxide (4s).
1
7
735, 1635, 1304, 1527, 1481, 1257, 1180, 1033, 979, 894, 840,
56, 702, 640, 516. H NMR (400 MHz, DMSO-d ) δ 8.09 (d, J
2
1
6
=
7.7 Hz, 1H), 7.75 – 7.66 (m, 1H), 7.54 (t, J = 7.5 Hz, 2H), 7.26
(d, J = 8.4 Hz, 2H), 7.12 – 7.01 (m, 3H), 6.85 (d, J = 6.3 Hz, 4H),
.18 (d, J = 16.3 Hz, 1H), 5.10 (d, J = 16.3 Hz, 1H), 3.75 (s, 3H),
o
Yield 49% (method A), pale gray solid, m.p. 173-176 C. IR
(
KBr): 3425, 2908, 1689, 1651, 1558, 1489, 1357, 1280, 1226,
5
1
13
1
134, 1033, 879, 840, 771, 702, 671, 601, 555, 493. H NMR
2.34 (s, 3H), 2.22 (s, 3H). C NMR (151 MHz, DMSO-d ) δ
190.43, 188.38, 177.86, 172.59, 168.30, 165.37, 160.12, 142.98,
6
(400 MHz, DMSO-d ) δ 17.72 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H),
6
7
1
.58 (t, J = 7.7 Hz, 1H), 7.36 – 7.23 (m, 5H), 7.19 – 7.06 (m,
H), 6.69 (s, 1H), 6.22 (s, 1H), 4.62 – 4.52 (m, 1H), 4.46 – 4.34
1
35.35, 133.08, 128.76, 127.88, 123.79, 122.81, 104.09, 94.80,
77.05, 46.03, 40.86, 21.03, 18.93, 8.13, 6.60.
(m, 1H), 2.97 – 2.83 (m, 2H), 2.26 (s, 3H), 2.14 (s, 3H), 2.06 (s,
+
13
HRMS-ESI: Calculated for C H N O [M+H] : 493.1763.
30 25 2 5
Found: 493.1758.
3
1
1
1
H). C NMR (151 MHz, DMSO-d ) δ 186.86, 169.54, 164.21,
6
52.51, 148.20, 146.62, 136.83, 134.95, 134.32, 133.66, 132.15,
29.10, 128.48, 126.84, 124.56, 124.21, 123.63, 123.55, 122.84,
4
.3.2. 2-(2-(2,5-dimethylthiophen-3-yl)-4-oxo-4H-furo[3,2-
19.32, 115.99, 46.20, 43.64, 35.53, 15.11, 14.62, 8.14, 6.81.
c]chromen-3-yl)-4,5-dimethyl-1-phenethyl-1H-imidazole N-oxide
(12b).
+
HRMS-ESI: Calculated for C H N O S [M+H] : 529.1797.
Found: 529.1792.
30
29
2
5
o
Yield 89%, white solid, m.p. 146-148 C. IR (KBr): 438,
4
.1.20. 2-(1-(4-hydroxy-7,7-dimethyl-2,5-dioxo-5,6,7,8-
2
7
925, 1746, 1636, 1499, 1454, 1346, 1275, 1153, 1032, 968, 896,
58, 702, 637, 518. H NMR (400 MHz, DMSO-d ) δ 8.11 (d, J
1
tetrahydro-2H-chromen-3-yl)-2-(4-methoxyphenyl)-2-oxoethyl)-
1
6
,4,5-trimethyl-1H-imidazole N-oxide (4t).
=
–
7.5 Hz, 1H), 7.74 (t, J = 7.1 Hz, 1H), 7.62 – 7.53 (m, 2H), 7.08
6.99 (m, 2H), 6.92 – 6.84 (m, 3H), 6.24 (s, 1H), 4.20 (br. s,
Yield 47% (method A), pale yellow solid, m.p. 229-
o
1H), 3.92 (br. s, 1H), 2.64 (br. s, 2H), 2.44 (s, 3H), 2.31 (s, 3H),
2.29 (s, 3H), 2.14 (s, 3H). C NMR (101 MHz, DMSO-d ) δ
6
2
1
30 (dec.) C. IR (KBr): 3448, 1697, 1681, 1512, 1365, 1311,
13
1
257, 1172, 1026, 848, 766, 601, 555, 455. H NMR (400 MHz,
1
1
1
56.52, 152.22, 139.80, 137.85, 136.73, 131.95, 130.44, 128.71,
28.53, 128.22, 126.43, 125.80, 125.38, 125.22, 123.63, 122.91,
21.20, 117.12, 111.64, 110.38, 90.85, 46.83, 34.70, 17.78,
DMSO-d ) δ 7.63 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H),
6
6
–
3
1
9
1
.19 (s, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 2.78 – 2.57 (m, 2H), 2.34
2.21 (m, 2H), 2.19 (s, 3H), 2.00 (s, 3H), 1.00 (s, 3H), 0.97 (s,
13
14.68, 14.16, 8.26, 7.22. HRMS-ESI: Calculated for
H). C NMR (101 MHz, CD Cl ) δ 193.30, 172.78, 172.35,
2
2
+
C H N O S [M+H] : 511.1691. Found: 511.1686.
30
27
2
4
62.82, 129.93, 129.01, 128.17, 123.91, 122.29, 113.79, 111.79,
4.28, 55.48, 52.42, 41.40, 41.02, 31.95, 31.25, 27.75, 27.42,
4
.3.3. 1-benzyl-2-(2-(4-methoxyphenyl)-6-methyl-4-oxo-4H-
8.59, 8.39, 6.69. HRMS-ESI: Calculated for C H N O
26
29
2
7
furo[3,2-c]pyran-3-yl)-4,5-dimethyl-1H-imidazole N-oxide (12c).
+
[
M+H] : 481.1974. Found: 481.1969.
o
Yield 78%, pale yellow solid, m.p. 87-89 C. IR (KBr): 3448,
4
.2. 1-benzyl-2-(2-(4-methoxy-3-sulfophenyl)-4-oxo-4H-
1
740, 1607, 1582, 1497, 1264, 1179, 1032, 969, 837, 638, 517.
1
furo[3,2-c]chromen-3-yl)-4,5-dimethyl-1H-imidazole N-oxide
H NMR (400 MHz, DMSO-d ) δ 7.26 (d, J = 8.9 Hz, 2H), 7.22
6
(11).
–
7.10 (m, 3H), 7.07 – 6.97 (m, 2H), 6.97 – 6.90 (m, 3H), 5.22 (s,
13
2
H), 3.81 (s, 3H), 2.36 (s, 3H), 2.33 (s, 3H), 2.25 (s, 3H).
C
3
00 mg (0.52 mmol) of compound 4r was dissolved in 3 ml
NMR (101 MHz, DMSO-d ) δ 161.81, 161.16, 161.08, 157.71,
6
(5.5 g) of 94% sulfuric acid and stirred at room temperature for 5
1
1
55.41, 133.95, 129.90, 128.66, 128.11, 127.41, 126.87, 126.47,
25.78, 118.91, 114.96, 108.66, 95.58, 55.49, 48.79, 19.75, 8.90,
h. Then reaction mixture was poured on 100 ml of ice-cold water,
formed precipitate was filtered and washed with cold water.

7
+
7
.25. HRMS-ESI: Calculated for C H N O [M+H] : 457.1763.
4.4. 1-benzyl-2-(6,6-dimethyl-4-oxo-2-(p-tolyl)-4,5,6,7-
tetrahydrobenzofuran-3-yl)-4,5-dimethyl-1H-imidazole N-oxide
27
25
2
5
Found: 457.1758.
(13).
4
.3.4. 2-(2-(2,5-dimethylthiophen-3-yl)-6-methyl-4-oxo-4H-
furo[3,2-c]pyran-3-yl)-1-(2-methoxybenzyl)-4,5-dimethyl-1H-
Solution of 450 mg (1 mmol) of compound 4b and 85 mg (0.5
imidazole N-oxide (12d).
mmol) of p-TSA in 50 ml of toluene was refluxed with Dean-
Stark trap for 12 h. The resulted solution was washed with 5%
solution of potassium carbonate (20 mL) and dried over
anhydrous sodium sulfate. The solvent was removed under
reduced pressure, and the residue was purified by column
chromatography on silica gel (eluent: ethyl acetate then
methanol) to give the corresponding product 13.
o
Yield 81%, pink solid, m.p. 164-165 C (dec.). IR (KBr):
3
1
448, 2924, 2623, 1735, 1620, 1581, 1496, 1442, 1303, 1249,
211, 1157, 1026, 964, 756, 640, 516. H NMR (400 MHz,
1
DMSO-d ) δ 7.24 – 7.08 (m, 1H), 6.97 (s, 1H), 6.81 (d, J = 8.3
6
Hz, 1H), 6.72 – 6.54 (m, 2H), 6.07 (s, 1H), 5.06 (d, J = 15.8 Hz,
1
2
H), 4.94 (d, J = 15.8 Hz, 1H), 3.57 (s, 3H), 2.35 (s, 3H+3H),
.33 (s, 3H), 2.32 (s, 3H), 2.28 (s, 3H). C NMR (151 MHz,
13
o
Yield 75%, pale yellow solid, m.p. 47-49 C. IR (KBr):3426,
DMSO-d ) δ 161.61, 160.82, 157.32, 156.43, 152.18, 138.96,
3032, 2955, 2924, 2855, 2376, 1721, 1682, 1636, 1597,
1543,1512, 1458, 1427, 1342, 1304, 1234, 1180, 1119, 1072,
1049, 1018, 918, 818, 702, 671, 633, 586, 548, 494, 455. H
6
1
1
1
37.28, 129.78, 129.38, 128.58, 126.02, 125.38, 123.37, 122.86,
21.05, 119.89, 110.87, 107.76, 97.63, 95.25, 55.22, 45.12,
1
9.65, 14.60, 14.19, 8.72, 7.12. HRMS-ESI: Calculated for
NMR (300 MHz, DMSO-d ) δ 7.43 – 7.34 (m, 2H), 7.19 (d, J =
6
+
C H N O S [M+H] : 491.1640. Found: 491.1635.
7.9 Hz, 2H), 7.09 – 6.91 (m, 3H), 6.71 (d, J = 7.5 Hz, 2H), 4.98
27
27
2
5
(
2
d, J = 16.6 Hz, 1H), 4.68 (d, J = 16.5 Hz, 1H), 3.03 – 2.83 (m,
H), 2.38 (s, 2H), 2.32 (s, 3H), 2.10 (s, 3H), 1.15 – 1.07 (m, 6H).
13
4
.3.5. 2-(2-(2,5-dimethylthiophen-3-yl)-6-methyl-4-oxo-4H-
furo[3,2-c]pyran-3-yl)-4,5-dimethyl-1-(2-(pyridin-2-yl)ethyl)-1H-
imidazole N-oxide (12e).
C NMR (101 MHz, DMSO-d ) δ 192.74, 165.98, 165.98,
6
1
54.10, 135.89, 129.26, 128.22, 127.33, 126.18, 125.70, 125.56,
o
Yield 62%, pale yellow solid, m.p. 209-209 C (dec.). IR
125.21, 121.51, 119.80, 100.62, 51.59, 47.16, 34.79, 28.06,
(
1
KBr): 3425, 3016, 1735, 1612, 1581, 1527, 1435, 1334, 1257,
27.70, 20.86, 8.74, 7.42. HRMS-ESI: Calculated for C29
[M+H] : 455.2334. Found: 455.2329.
H
31
N
2
O
3
1
+
180, 1026, 964, 840, 756, 609. H NMR (600 MHz, DMSO-d )
6
δ 8.26 – 8.22 (m, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.39 (t, J = 7.6
Hz, 1H), 7.02 (s, 1H), 7.01 – 6.94 (m, 3H), 6.71 (d, J = 7.7 Hz,
Acknowledgments
1
H), 4.17 – 4.09 (m, 1H), 4.09 – 4.02 (m, 1H), 3.77 (s, 3H), 2.72
13
(t, J = 6.8 Hz, 2H), 2.34 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H).
C
This work was supported by Russian Foundation of Basic
Research (grant 18-33-00162 mol_a).
NMR (151 MHz, DMSO-d ) δ 161.01, 160.75, 160.34, 157.89,
6
1
1
3
56.86, 154.25, 148.87, 136.25, 127.79, 125.02, 123.14, 122.11,
21.72, 120.24, 114.42, 108.76, 99.80, 95.51, 55.32, 43.65,
7.55, 19.64, 8.35, 7.38. HRMS-ESI: Calculated for C H N O
References
27
26
3
5
+
[
M+H] : 472.1872. Found: 472.1867.
[1] (a) G. Mloston, H. Heimgartner, Curr. Org. Chem. 20 (2016) 1359,
DOI:10.2174/1385272820666151210000010;
(b) L. Campeau, D. R. Stuart, J. Leclerc, E. Villemure, H. Sun, S. Lasserre,
N. Guimond, M. Lecavallier, K. Fagnou, J. Am. Chem. Soc. 131 (2009)
4
.3.6. 2-(2-(4-methoxyphenyl)-6-methyl-4-oxo-4H-furo[3,2-
c]pyran-3-yl)-1,4,5-trimethyl-1H-imidazole N-oxide (12f).
3
291, DOI:10.1021/ja808332k;
o
Yield 59%, pale yellow solid, m.p. 239-240 C (dec.). IR
(c) A. H. Sandtorv, W. Törnroos, H. Bjørsvik, European J. Org. Chem. 16
(2015) 3506. DOI:10.1002/ejoc.201500328;
(
KBr): 3442, 2751, 1873, 1606, 1582, 1489, 1445, 1303, 1256,
1
(
d) E. I. Adiulin, A. V. Kutasevich, V. S. Mityanov, I. I. Tkach, T. Y.
Koldaeva, Chem. Heterocycl. Compd. 51 (2015) 500, DOI:10.1007/s10593-
15-1727-0.
2] (a) M. Gaba, C. Mohan, Med. Chem. Res. 25 (2016) 173,
1
236, 1182, 1028, 971, 949, 837, 797, 637, 515. H NMR (600
MHz, DMSO-d ) δ 7.36 (d, J = 8.9 Hz, 2H), 7.11 (s, 1H), 7.06 (d,
J = 8.9 Hz, 2H), 3.82 (s, 3H), 3.55 (s, 2H), 2.39 (s, 3H), 2.37 (s,
3
1
1
3
6
0
[
13
H), 2.30 (s, 3H). C NMR (151 MHz, DMSO-d ) δ 161.86,
DOI:10.1007/s00044-015-1495-5;
(b) M. Boiani, H. Cerecetto, A. Gerpe, A. Denicola, D. Montero, A. Escario,
6
61.27, 161.08, 157.62, 155.42, 129.53, 127.46, 126.11, 125.38,
21.75, 119.14, 115.01, 108.58, 95.55, 55.44, 39.93, 39.80,
Arch.
DOI:10.1002/ardp.200300840.
3] (a) H. Mossaraf, K. Pradhan, A. K. Nanda. Tet. Lett. 58 (2017) 3772,
Pharm.
Pharm.
Med.
Chem.
337
(2004)
259,
9.66, 39.52, 39.38, 39.24, 39.10, 32.48, 19.70, 8.44, 7.03.
[
+
HRMS-ESI: Calculated for C H N O [M+H] : 381.1450.
Found: 381.1445.
21
21
2
5
DOI: 10.1016/j.tetlet.2017.08.047;
(b) L. Campeau, M. Bertrand-Laperle,J. Leclerc,E. Villemure,S. Gorelsky, K.
Fagnou.
DOI:10.1021/ja808332k.10.1021/ja7107068.
[4] (a) G. Mloston, T. Gendek, H. Heimgartner, Helv. Chim. Act. 81 (1998)
1585, DOI: 10.1002/(SICI)1522-2675(19980909)81:9<1585::AID-
HLCA1585>3.0.CO;2-N;
(b) R. Loska, P. Bukowska, Org. Biomol. Chem. 13 (2015) 9872,
DOI:10.1039/x0xx00000x;
J.
Am.
Chem.
Soc.
130
(2008)
3276,
4
.3.7. 2-(2-(4-methoxyphenyl)-7,7-dimethyl-4,9-dioxo-6,7,8,9-
tetrahydro-4H-furo[3,2-c]chromen-3-yl)-1,4,5-trimethyl-1H-
imidazole N-oxide (12g).
o
Yield 73%, pale yellow solid, m.p. C. IR (KBr): 3441, 2962,
766, 1689, 1604, 1573, 1496, 1396, 1357, 1296, 1180, 1157,
026, 972, 840, 640, 570, 516. H NMR (400 MHz, DMSO-d6) δ
.37 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 9.0 Hz, 2H), 3.81 (s, 3H),
.55 (s, 3H), 3.00 – 2.84 (m, 2H), 2.62 – 2.50 (m, 2H), 2.36 (s,
H), 2.30 (s, 3H), 1.13 (s, 3H), 1.11 (s, 3H). C NMR (101 MHz,
1
1
7
3
3
1
(c) R. Loska, K. Szachowicz, D. Szydlik, Org. Lett. 15 (2013) 5706,
DOI:10.1021/ol402735m.
[
5] (a) V. S. Mityanov, A. V. Kutasevich, M. M. Krayushkin, B. V. Lichitsky,
A. A. Dudinov, A. N. Komogortsev, L. G. Kuzmina, Tetrahedron Lett. 57
(2016) 5315, DOI:10.1016/j.tetlet.2016.10.061;
13
DMSO-d ) δ 192.34, 172.51, 161.30, 157.04, 156.37, 156.07,
(b) V. S. Mityanov, A. V. Kutasevich, M. M. Krayushkin, B. V. Lichitsky, A.
A. Dudinov, A. N. Komogortsev, T. Y. Koldaeva, V. P. Perevalov,
Tetrahedron. 73 (2017) 6669, DOI:10.1016/j.tet.2017.10.026;
6
1
9
29.15, 127.50, 126.38, 125.56, 119.01, 115.22, 109.95, 107.05,
5.31, 55.54, 50.63, 32.55, 32.37, 27.89, 27.21, 8.55, 7.14.
(c) A. V. Kutasevich, V. P. Perevalov, V. S. Mityanov, B. V. Lichitsky, A. N.
+
HRMS-ESI: Calculated for C H N O [M+H] : 463.1869.
26
27
2
6
Komogortsev, M. M. Krayushkin, T. Y. Koldaeva, V. S. Miroshnikov, Chem.
Heterocycl. Compd. 55 (2019) 147, DOI:10.1007/s10593-019-02431-7.
Found: 463.1864.
[
6] B. Eftekhari-Sis, M. Zirak, A. Akbari, Chem. Rev., 113, (2013) 2958,
DOI:10.1021/cr300176g.

8
Tetrahedron
[
7] (a) M. M. Krayushkin. Yu. O. Gorbunov, V. S. Mityanov V. G.
Melekhina, Russ. Chem. Bull. 67 (2018) 304,
DOI:10.1080/10426500490464186;
b) Y. Gorbunov, N. Komogortsev, V. S. Mityanov, B. V. Lichitskii, A. A.
Pharmazie. 46 (1991) 412, DOI:10.1002/chin.199211167.
(d) H. Junek, E. Ziegler, U. Herzog, Monatshefte fur Chemie. 102 (1971)
1096, DOI:10.1007/BF00909936.
[10] (a) O. V.Dolomanov, L. J. Bourhis, R. J Gildea, J. A. K. Howard, H.
(
Dudinov, K. A. Lyssenko, Krayushkin, Russ. Chem. Bull. 67 (2018) 504.
DOI:10.1007/s11172-018-2101-z.
Puschmann.
10.1107/S0021889808042726.
(b) G.M. Sheldrick, Acta
10.1107/S2053273314026370
(c) O. V. Dolomanov, L. J. Bourhis, R. J Gildea, J. A. K. Howard, H.
Puschmann. Acta Cryst. A71 (2015) 59б DOI:
J.
Appl.
Cryst.
42
(2009)
339,
DOI:
[
8] (a) Y. Dong, Q. Shi, H. C. Pai, C. Y. Peng, S. L. Pan, C. M. Teng, K.
Cryst.
A71
(2015)
3,
DOI:
Nakagawa-Goto, D. Yu, Y. N. Liu, P. C. Wu, K. F. Bastow, S. L. Morris-
Natschke, A. Brossi, J. Y. Lang, J. L. Hsu, M. C. Hung, E. Y. H. P. Lee, K.
H. Lee, J. Med. Chem. 53 (2010) 2299, DOI:10.1021/jm1000858;
(b) T. A. Fattah, A. Saeed, Y. M. Al-Hiari, V. Kasabri, I. M. Almasri, S.
10.1107/S2053273314022207.gler E, Herzog U. Monatshefte fur Chemie.
AlAlawi, F. A. Larik, P. A. Channar, J. Mol. Struct. 1179 (2019) 390,
DOI:10.1016/j.molstruc.2018.11.014;
1971; 102: 1096–1100.
(
c) S. Sardari, Y. Mori, K. Horita, R. G. Micetich, S. Nishibe, M.
Daneshtalab, Bioorganic Med. Chem. 7 (1999) 1933, DOI:10.1016/S0968-
896(99)00138-8;(d) X. Wang, K. Nakagawa-Goto, M. Kozuka, H. Tokuda,
Supplementary Material
0
H. Nishino, K. H. Lee, Pharm. Biol. 44 (2006) 116,
DOI:10.1080/13880200600592178.
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
[
9] (a) H. Cerecetto, A. Gerpe, M. González, Y. Fernández Sainz, O. E. Piro,
E. E. Castellano, Synthesis (Stuttg). 16 (2004) 2678, DOI:10.1055/s-2004-
31212.
8
(
(
(
b) G. Mloston, P. Mucha, A. Linden, H. Heimgartner, Helv. Chim. Act. 90
2007), 1765, DOI: 10.1002/hlca.200790186.
c) R. Hossbach, H. Lettau, P. Nuhn, R. Schneider, P. Stenger, B. Stiebitz,

C2-functionalization of imidazole N-oxide.
Multicomponent reaction with arylglyoxals

Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐
The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: