Unexpected reductive transformation of 1-substituted 5-hydroxy-4,5-diphenyl-1H-imidazol-2(5H)-ones and their cyclic analogs by the reaction with thiourea and hydrochloric acid

Article abstract of DOI:10.1016/j.tetlet.2017.04.061

An unexpected reductive transformation of 1-substituted 5-hydroxy-4,5-diphenyl-1H-imidazol-2(5H)-ones (imidazolones) and their cyclic analogs to give 1-substituted 4,5-diphenyl-1H-imidazol-2(5H)-ones (imidazolinones) upon reaction with thiourea and hydroc

Full text of DOI:10.1016/j.tetlet.2017.04.061

Accepted Manuscript
Unexpected reductive transformation of 1-substituted 5-hydroxy-4,5-diphen-
yl-1H-imidazol-2(5H)-ones and their cyclic analogs by the reaction with thio-
urea and hydrochloric acid.
Vladimir V. Baranov, Maria M. Antonova, Valentina A. Karnoukhova,
Angelina N. Kravchenko
PII:
S0040-4039(17)30514-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.061
TETL 48853
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 March 2017
13 April 2017
19 April 2017
Please cite this article as: Baranov, V.V., Antonova, M.M., Karnoukhova, V.A., Kravchenko, A.N., Unexpected
reductive transformation of 1-substituted 5-hydroxy-4,5-diphenyl-1H-imidazol-2(5H)-ones and their cyclic analogs
by the reaction with thiourea and hydrochloric acid., Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/
j.tetlet.2017.04.061
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Unexpected reductive transformation of 1-substituted 5-hydroxy-
4,5-diphenyl-1H-imidazol-2(5H)-ones and their cyclic analogs by the
reaction with thiourea and hydrochloric acid.
Vladimir V. Baranova,b,*, Maria M. Antonovaa, Valentina A. Karnoukhovac, and Angelina N.
Kravchenkoa
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky
prosp., Moscow, 119991, Russian Federation, Fax: +7 499 135 5328, Phone: +7 499 137 2944
e-mail: ase1313@mail.ru
b
Рeoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St.,
Moscow, 117198 Russian Federation
c
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28
Vavilova St., Moscow, 119991, Russian Federation
Abstract
An unexpected reductive transformation of 1-substituted 5-hydroxy-4,5-diphenyl-1H-imidazol-
2(5H)-ones (imidazolones) and their cyclic analogs to give 1-substituted 4,5-diphenyl-1H-
imidazol-2(5H)-ones (imidazolinones) upon reaction with thiourea and hydrochloric acid was
discovered.
Keywords: Imidazolinones, Imidazolones, Thiourea, Reductive transformation, Heterocycles
1-Substituted 1H-imidazol-2(3Н)-ones (imidazolinones) 1 are biologically active
compounds possessing antioxidant,1,2 cytotoxic,3 antifungal,4 anticonvulsant,2 antiinflammatory,
antitumor, cardiotonic,5 or receptor agonist5,6 properties. Various methods for the synthesis of
imidazolinones 1 have been described in the literature.7 Previously, these compounds were used
for the formation of 1-substituted 5-hydroxy-4,5-diphenyl-1H-imidazol-2(5H)-ones
(imdazolones) 2 in nitric acid, and a wide range of imidazothiazoles 3 and glycolurils 4 were

prepared from compounds 2 upon reaction with KSCN and AcOH or urea and HCl, respectively
(Scheme 1).8
Scheme 1. Preparation of imidazothiazoles 3 and glycolurils 4 from imidazolinones 1.
Herein, the reaction of imidazolones 2a-h and their cyclic analogs (7-hydroxy-7,7a-
diphenyltetrahydroimidazo[5,1-b]oxazol-5(6H)-one (imidazooxazolone) 5 and 8-hydroxy-8,8a-
diphenyltetrahydro-2H-imidazo[5,1-b][1,3]oxazin-6(7H)-one (imidazooxazinone)
6
with
thiourea and hydrochloric acid was studied.
We began our investigation by studying the model reaction of imidazolone 2a with
thiourea (Table 1). However, the expected thioglycoluril 7 was not formed; imidazolinone 1a
and the hydrochloric salt of formamidine disulfide were obtained in 33% yield (Entry 1). The
failure of thioglycoluril 7 formation could be explained by the rapid reaction of thiourea as an S-
nucleophile (see below). The reaction conditions were next optimized using MeCN or MeOH as
solvents and different amounts of thiourea (1, 2 or 3 eq.) and hydrochloric acid (0.5, 1 or 2
mL/1.5 mmol of 2a) (Table 1). Optimal conditions for the synthesis of imidazolinone 1a (85%)
were heating a solution of imidazolone 2a, thiourea (2 eq.) and HCl (1 mL, 35%/1.5 mol of 2a)
in MeCN at reflux for 1 min. (Table 1, entry 2).
Table 1. Screening conditions for the reaction of imidazolone 2a with thiourea and hydrochloric
acid.

Thiourea
Yield 1a
Entry
Solvent
HCl 35% (mL)
(eq.)
(%)
33
85
48
83
84
-
1
2
3
4
5
6
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
1
1
1
2
2
2
3
2
0.5
2
1
1
Reagents and conditions: 2a (1.5 mmol), thiourea, solvent (15 mL), 60 °C, then 35% HCl dropwise, reflux, 1 min.
The reaction was extended to the synthesis of a series of imidazolinones 1a-i, which were
obtained in 79-89% yield (Table 2, entries 1-9). In contrast, imidazolinone 1j was obtained in
only 10% yield even after heating at reflux for 24 h (Entry 10). The low yield of imidazolinone
1j could be explained by the difficulty of the six-membered ring-opening process in
imidazooxazinone 6.9
Table 2. Synthesis of imidazolinones 1a-j.
Yield 1
Entry Reagent
R
Product
(%)
85a
79a
84a
80a
89a
87a
80a
84a
1
Me
Et
2a
1a
1b
1c
1d
1e
1f
2
2b
3
Pr
2c
4
Bu
2d
5
Bn
2e
6
(CH2)2OAc
(CH2)3OAc
(CH2)4OAc
2f
7
2g
1g
1h
8
2h

9
(CH2)2OH
(CH2)3OH
82a
10b
5
6
1i
1j
10
aReagents and conditions: 2a-h, 5 (1.5 mmol), thiourea (3 mmol), MeCN (15 mL), 60 °C, then 35% HCl (1mL) dropwise,
reflux, 1 min.
b
6 (1.5 mmol), thiourea (3 mmol), MeCN (15 mL), 35% HCl (1mL), reflux, 24 h.
Plausible mechanisms for the formation of imidazolinones 1 are shown in Scheme 2.
Initially, formation of cation A (for compounds 2a-h), followed by nucleophilic attack of
thiourea as an S-nucleophile gives intermediate B. Protonation of intermediate B on the –OH
group leads to the elimination of water with the formation of cation C. Cation C and a second
molecule of thiourea are assembled with NH2…S=C H-bonds to give intermediate D, which is
converted to intermediate E with cis-orientation of the thiourea moieties. Formamidine disulfide
is then eliminated from intermediate E and imidazolinones 1 are formed. Under heating, bicyclic
compounds 5, 6 eliminate H2O to form intermediate F.10 The mechanisms for the formation of
imidazolinones 1 from imidazolones 2 or intermediates F should be similar, however protonation
of intermediate H with opening of the O-containing ring is required for the formation of cation
C.
Scheme 2. Plausible mechanisms for the formation of imidazolinones 1 from imidazolones 2 and
cyclic analogs 5,6.

Compounds 1a-i have been described in the literature,8,9b,10-13 but compounds 1b-d were
not sufficiently characterized. The structures of compounds 1b-d,j were confirmed by 1H, 13C
NMR spectroscopy, HRMS and single-crystal X-Ray diffraction (Fig. 1).14
Figure 1. X-ray crystal structures of compounds 1b, 1c, 1d, 1j. Hydrogen atoms connected to
carbon atoms are omitted for clarity.
In conclusion, the unexpected formal red-ox transformation of imidazolones 2a-h and
their cyclic analogs (imidazooxazole 5 and imidazooxazine 6) to give imidazolinones 1a-j upon
reaction with thiourea and hydrochloric acid was discovered.
Acknowledgment
The publication was financially supported by the Ministry of Education and Science of the
Russian Federation (the Agreement number 02.a03.21.0008).
Supplementary data
Supplementary data (1H, 13C NMR spectral data for compounds 1b-d,j) associated with this
article can be found in the online version, at
References and Notes
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Watanabe, T.; Ishibashi, A.; Yuki, S.; Tanaka, M. Bioorg. Med. Chem. Lett. 2008, 18, 1478.
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K.; Itoh, K. Chem. Pharm. Bull. 2000, 48, 1935.
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(6) (a) Carling, W. R.; Moore, K. W. US 5698573, 1995; Chem. Abstr. 1995, 123, 55879. (b)
Diness, F.; Meldal, M. Chem. Eur. J. 2009, 15, 7044. (c) Diness, F.; Meldal, M.
Biopolуmers 2010, 94, 236.
(7) (a) Antonova, M. M.; Baranov, V. V.; Kravchenko, A. N. Chem. Heterocycl. Compd. 2015,
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A. N. Synlett. 2017, DOI: 10.1055/s-0036-1588932 (in press). (b) Antonova, M. M.;
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(14) Crystallographic data for 1b-d and 1j have been deposited at the Cambridge
Crystallographic Data Centre (CCDC) with the reference numbers 1532152-1532155. These
data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html.
(15) 1-Substituted 4,5-diphenyl-1H-imidazol-2(3H)-ones 1a-i; General Procedure
A mixture of the corresponding 1-substituted 4,5-diphenyl-1H-imidazol-2(3H)-one 2a-i (1.5
mmol), thiourea (0.228 g, 3 mmol) and MeCN (15 mL) was heated to 60 °C, then HCl (1
mL) was added dropwise. The reaction mixture was then heated at reflux for 1 minute. The
white precipitate containing the hydrochloric salt of formamidine disulfide was filtered off.
Compound 1a-i precipitated from the filtrate after 24 h and was filtered off then washed
with MeCN.
1-(3-hydroxypropyl)-4,5-diphenyl-1H-imidazol-2(3H)-one 1j.

A mixture of 8-hydroxy-8,8a-diphenyltetrahydro-2H-imidazo[5,1-b][1,3]oxazin-6(7H)-one
6 (0.465 g, 1.5 mmol), thiourea (0.228 g, 3.0 mmol), HCl (1 mL) and MeCN (15 mL) was
heated at reflux for 24 h. The white precipitate was filtered off. Compound 1j precipitated
from the filtrate after 24 h and was filtered off then washed with MeCN. Colorless crystals;
yield: 0.044 g (10%); mp 237 – 240 °C (MeCN). 1H NMR (300 MHz, DMSOd6): δ = 1.42–
1.57 (m, 2H, CH2), 3.22–3.32 (m, 2H, CH2), 3.44–3.54 (m, 1H, CH2), 7.09–7.24 (m, 5H,
Ph), 7.34–7.44 (m, 2H, Ph), 7.45–7.58 (m, 3H, Ph), 10.80 (m, 1H, NH). 13C NMR (75 MHz,
DMSOd6): δ = 32.23, 37.85, 58.10 (CH2) 117.22, 120.51, 125.32, 126.42, 128.33, 128.90,
129.08, 129.72, 130.74 (Ph-C=C-Ph), 153.19 (C=O). HRMS (ESI-TOF): m/z [M + H]+
calcd for C18H18N2O2+H: 295.1442; found: 295.1438.

Highlights
• Unexpected reduction of imidazolones and analogs into imidazolinones was discovered
• 10 examples of imidazolinones were synthesized
• Plausible mechanisms for the formation of imidazolinones were proposed
The structures were confirmed by 1H, 13C NMR spectroscopy, HRMS and X-Ray
•