Reactions of resorcinol derivatives with 1-methyl-3-phenylimidazol-2-one as a new method for the synthesis of 5-arylimidazolidin-2-ones

Article abstract of DOI:10.1016/j.mencom.2008.01.020

Substituted imidazolidin-2-ones have been synthesised by the interaction of imidazol-2-one with 2-methylresorcinol and pyrogallol in a chloroform solution in the presence of trifluoroacetic acid.

Full text of DOI:10.1016/j.mencom.2008.01.020

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 54–55
Reactions of resorcinol derivatives with
1-methyl-3-phenylimidazol-2-one as a new method
for the synthesis of 5-arylimidazolidin-2-ones
Alexander R. Burilov, Maxim S. Khakimov, Almir S. Gazizov, Mikhail A. Pudovik,*
Victor V. Syakaev, Dmitry B. Krivolapov and Alexander I. Konovalov
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Centre of the Russian Academy of
Sciences, 420088 Kazan, Russian Federation. Fax: +7 8432 73 2253; e-mail:pudovik@iopc.knc.ru
DOI: 10.1016/j.mencom.2008.01.020
Substituted imidazolidin-2-ones have been synthesised by the interaction of imidazol-2-one with 2-methylresorcinol and pyrogallol
in a chloroform solution in the presence of trifluoroacetic acid.
Imidazol-2-ones and imidazolidin-2-ones are important bio-
logically active compounds. Imidazol-2-ones are in vivo anti-
16
15
O
oxidants,1 which can be formed under physiological conditions by
the interaction of angeotensin I with ascorbate.2 Imidazol-2-one
is a structural basis of the nucleotide antibiotic Nikkomycin X.
Imidazol-2-ones play a role in intraocular pressure regulation,3
they also exhibit anticonvulsant activity.4 The derivatives of
imidazolidin-2-ones are used as proteingenase modulators.5
The general method of the synthesis of imidazolidin-2-one
derivatives is the interaction of functionalised α-aminocarbonyl
compounds with isocyanates.6–8 Thus, the first stage of the
reaction is the formation of appropriate ureas, which are cyclised
under acid catalysis conditions. The synthesis of imidazolidin-
2-one derivatives can be performed by the condensation of
ethylenediamine with phosgene,9 bis(trichloromethyl) carbonate,10
diethyl carbonate,11 di(tret-butyl) carbonate12 and 1,1'-carbonyl-
diimidazole.13 1-Methyl-3-phenylimidazol-2-one 2 was syn-
thesised by the cyclization of acetal 1 in an acid medium8
(Scheme 1).
17
6
14
1
Me
2
N
N
5
3
R
4
8
7
HO
OH
CF3CO2H/CHCl3
60 °C, 30 h
9
2 +
HO
12
10
11
13 R
OH
3 R = Me
4 R = OH
Scheme 2
methyl group in the HMBC spectrum indicates the addition of
2-methylresorcinol to the C(5) carbon atom of a heterocyclic
ring. One-dimensional DPFGSE-NOE experiments with com-
pound 3 exhibited a twice larger NOE cross-peak intensity for
the C(5)H group proton (2%) compared to that of the C(8)H
group (1%) and practically complete absence of NOE for
CH(3)N group protons (NOE < 0.01%) after saturation of H(6)
revealed the addition of 2-methylresorcinol fragment to the
5-position of the heterocyclic ring.
Me
O
According to the X-ray– data,‡ compound 4 forms triclinic
crystals in spatial group P1. In the symmetrically independent
part of a crystal cell, there are two independent molecules of
imidazolidinone 4 and two molecules of water. The configura-
tion of the C(5) atom for molecules A and B in the asym-
metrical part of a crystal cell is identical. Five-membered
heterocyclic rings in both molecules are flat to within 0.025(3)
and 0.087(3) Å, respectively. The torsion angles of phenyl
substituents in compound 4 equal –9.7(4), 16.2(4)° and –19.9(4),
–30.4 (3)° for molecules A and B, respectively.
N
O
O
Me
Me
NH
1
9
8
7
O
CF3COOH/CHCl3
60 °C, 4 h
10
6
3
1
Me
2
N
N
– 2 MeOH
5
4
2
Scheme 1
The molecules of compound 4 in a crystal are stabilised by a
system of intra- and intermolecular O–H···O hydrogen bonds.
We found that the interaction of compound 2 with 2-methyl-
resorcinol or pyrogallol in a chloroform solution in the presence
of trifluoroacetic acid results in the formation of imidazolidin-
2-ones 3, 4 (Scheme 2). Note that trimethoxybenzene and
dimethoxybenzene did not react with compound 2 under these
conditions.
The structures of the compounds obtained were confirmed
by 1H and 13C NMR spectroscopy, elemental analysis and mass
spectrometry.† The HSQC and HMBC experiment was carried
out to elucidate the structure of 3. The presence of a cross-peak
between protons of the MeN group and the C(5) carbon atom
and the absence of a cross-peak with the carbon C(4) of the
C(6B)
O(2B)
N(1B)
C(18B) C(2B)
C(13B)
O(10A)
C(10A)
C(9A)
C(17B)
C(5B)
C(7B)
C(8A)
O(12B)
C(12B)
N(3B)
C(15B)
C(16B)
C(4B)
C(11A)
C(7A)
C(14B)
O(2A)
C(8B)
C(9B)
O(11A)
C(6A)
C(11B)
C(12A)
O(11B)
N(1A)
N(3A)
C(5A)
C(18A)
C(10B)
C(17A)
C(16A)
O(10B)
O(12A)
C(14A)
C(15A)
Figure 1 Molecular structure of compound 4.
– 54 –
© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 54–55
Thus, the interaction of resorcinol derivatives with imidazolone
References
2 is a new convenient method for the synthesis of 5-aryl-
1
R. C. Smith, J. C. Reeves, R. C. Dage and R. A. Schnetter, Biochem.
imidazolidin-2-one derivatives.
Pharmacol., 1987, 36, 1457.
2
3
K. Uchida and S. Kawakishi, Arch. Biochem. Biophys., 1990, 20, 283.
T. Matsugui, M. Kageyama, K. Nishimura, H. Giles and E. Shirasawa,
Eur. J Pharmacol., 1995, 275, 245.
S. Cortes, Z. Liao, D. Watson and H. Kohn, J. Med. Chem., 1985,
28, 601.
L. Zhao, L. Qiao, S. B. Rong and A. P. Kozikowski, Tetrahedron Lett.,
2000, 41, 8711.
J. O. Cole and A. R. Ronzio, J. Am. Chem. Soc., 1944, 66, 1584.
P. Fritsch, Chem. Ber., 1893, 26, 427.
V. V. Golovko, A. I. Stanitskaya, Yu. A. Baskakov and Yu. G. Putsykin,
Khim. Geterotsikl. Soedin., 1982, 1339 [Chem. Heterocycl. Compd.
(Engl. Transl.), 1986, 22, 1084].
This work was supported by the Russian Foundation for
Basic Research (grant no. 05-03-33008).
4
5
†
The 1H and 13C NMR spectra were recorded on an Avance 600 instru-
ment with working frequencies of 600.13 (1H) and 150.90 (13C) MHz.
The IR spectra were recorded on a Vector 22 (Bruker) spectrometer.
Mass spectra were measured on a MAT-212 (Finnigan) instrument.
1-Methyl-1-(2,2-dimethoxyethyl)-3-phenylurea 1. A solution of 3.0 g
(25.2 mmol) of phenylisocyanate in 3 ml of benzene was added dropwise
to a solution of 3.0 g (25.2 mmol) of N-methylaminoacetaldehyde dimethyl
acetal in 6 ml of benzene. The reaction mixture was stirred for 1 h at
30 °C; the solvent was removed, and the residue was crystallised from
benzene. Yield, 65%; mp 66–68 °C. 1H NMR ([2H6]acetone) d: 3.04 (s,
3H), 3.41 (s, 6H), 3.43 (d, 2H, 3JHH 5.30 Hz), 4.55 (t, 1H, 3JHH 5.30 Hz),
6.93 (m, 1H), 7.21 (m, 2H), 7.48 (m, 2H), 7.86 (s, 1H). Found (%): C,
60.07; H, 7.82; N, 11.38. Calc. for C12H18N2O3 (%): C, 60.49; H, 7.61;
N, 11.76.
6
7
8
9
Ch. Trapesonzjanz, Chem. Ber., 1892, 25, 3271.
10 L. Cotarca, P. Delogu, A. Nardelli and V. Sunjic, Synthesis, 1996, 553.
11 J. S. Madalengoita, J. J. Tepe, K. A. Werbovetz, E. K. Lehnert and
T. L. Macdonald, Bioorg. Med. Chem., 1997, 5, 1807.
12 H. J. Knillker and T. Braxmeier, Tetrahedron Lett., 1998, 39, 9407.
13 H. A. Staab, Angew. Chem., Int. Ed. Engl., 1962, 1, 351.
14 A. Altomare, G. Cascarano, C. Giacovazzo and D. Viterbo, Acta
Crystallogr., Sect. A, 1991, 47, 744.
15 L. J. Farrugia, J. Appl. Crystallogr., 1999, 32, 837.
16 L. H. Straver and A. J. Schierbeek, MOLEN. Structure Determination
System, Nonius B.V. Delft, Netherlands, 1994, vols. 1, 2.
17 A. L. Spek, Acta Crystallogr., Sect. A, 1990, 46, 34.
1-Methyl-3-phenylimidazol-2-one 2. A mixture of 4 g (16.8 mmol)
of 1-(2,2-dimethoxyethyl)-1-methyl-3-phenylurea 1, 2.1 g (18.4 mmol) of
trifluoroacetic acid in 25 ml of chloroform was heated at 60 °C for 4 h.
The solvent was removed, and the dry residue was washed with 50 ml of
diethyl ether. Yield, 90%; mp 117 °C. 1H NMR (CDCl3) d: 3.28 (s, 3H),
6.29 (d, 1H, 3J 2.93 Hz), 6.54 (d, 1H, 3J 2.93 Hz), 7.21 (t, 1H, 3J 7.33 Hz),
7.38 (t, 2H, 3J 7.92 Hz), 7.59 (d, 2H, 3J 8.21 Hz). 13C NMR (CD3OD) d:
1
1
29.40 [C(6), JCH 139.13 Hz], 109.83 [C(5), JCH 197.92 Hz], 113.29
1
1
[C(4), JCH 196.61 Hz], 121.78 [C(8), JCH 159.77 Hz], 125.94 [C(10),
1
1JCH 159.22 Hz], 128.91 [C(9), JCH 158.66 Hz], 137.17 [C(7)], 152.20
[C(2)]. Found (%): C, 68.60; H, 5.93; N, 15.78. Calc. for C10H10N2O
(%): C, 68.95; H, 5.79; N, 16.08.
5-(2,4-Dihydroxy-3-methylphenyl)-1-methyl-3-phenylimidazolidin-2-one
3. A mixture of 2-methylresorcinol (0.39 g, 3.1 mmol), trifluoroacetic
acid (0.35 g, 3.1 mmol), compound 2 (0.54 g, 3.1 mmol) and chloroform
(3 ml) was heated at 60 °C for 30 h. The solvent was removed; the crystal
product was recrystallised from benzene. Yield, 81%; mp 158–159 °C.
1H NMR (CD3OD) d: 2.09 [s, 3H, C(13)H], 2.69 [s, 3H, C(6)H], 3.62,
2
3
4.93 [dd, 2H, C(4)H, JHH 7.01 Hz, JHH 9.12 Hz], 4.16 [t, 1H, C(5)H,
3JHH 9.12 Hz], 6.40 [d, 1H, C(9)H, JHH 8.41 Hz], 6.83 [d, 1H, C(8)H,
3JHH 8.41 Hz], 7.01 [m, 1H, C(17)H], 7.27 [m, 2H, C(16)H], 7.51 [m,
2H, C(15)H]. 13C NMR (CD3OD) d: 8.57 [C(13), 1JCH 127.39 Hz], 29.29
[C(6), JCH 134.66 Hz], 51.75 [C(4), JCH 149.68 Hz], 55.54 [C(5),
1JCH 140.96 Hz], 108.13 [C(9), 1JCH 158.40 Hz], 113.08 [C(11)], 118.29
[C(7)], 119.02 [C(15), 1JCH 158.40 Hz], 123.39 [C(17), 1JCH 156.94 Hz],
125.50 [C(8), JCH 156.94 Hz], 129.5 [C(16), JCH 156.94 Hz], 141.58
[C(14)], 157.06, 155.18 [C(10), C(12)], 160.09 [C(2)]. IR (n/cm–1):
3330, 1680, 1600. Found (%): C, 68.07; H, 6.35; N, 9.38. Calc. for
C17H18N2O (%): C, 68.44; H, 6.08; N, 9.39. MS (EI), m/z: 298.
3
Received: 3rd July 2007; Com. 07/2972
1
1
‡
X-ray crystallography of 4: C16H16N2O4·H2O, M = 318.32, triclinic,
–
space group P1, a = 10.663(3), b = 11.0674(18) and c = 14.8613(13) Å,
a = 81.88(1), b = 75.28(2) and g = 65.64(2)°, V = 1543.9(5) Å3, Z = 4
1
1
(two independent molecules and two solvent water molecules), dcalc =
= 1.37 g cm–3. Cell parameters and intensities of 6268 independent reflec-
tions (3909 with I ³ 2s) were measured on an Enraf-Nonius CAD-4
diffractometer in the w/2q-scan mode, q £ 74.20°, using CuKα radiation
with a graphite monochromator. The intensity falling was not observed
at three control measurements. Absorption correction was not applied
[µ(CuKα) = 8.59 cm–1]. The structure was solved by a direct method
using the SIR program14 and refined by the full matrix least-squares
using the SHELX-97 program package. All non-hydrogen atoms were
refined anisotropically. The positions of the hydrogen atoms were idealised.
The final divergence factors are R = 0.047, Rw = 0.104 based on 3909
reflections with F2 ³ 2s2. All calculations were performed on a PC using
the WinGX program.15 Cell parameters, data collection and data reduc-
tion were performed on an Alpha Station 200 computer using MoLEN.16
Figures of molecules were performed with the program PLATON.17
CCDC 643328 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2008.
5-(2,3,4-Trihydroxyphenyl)-1-methyl-3-phenylimidazolidin-2-one 4.
Compound 4 was obtained from 2 and pyrogallol by analogous pro-
cedure. Yield, 81%; mp 150–151 °C. 1H NMR (CD3OD) d: 2.67 [s, 3H,
C(6)H], 3.61 [dd, 2H, C(4)H, 1J 8.88 Hz, 2J 6.79 Hz], 4.07 [t, 1H,
1
1
2
C(5)H, J 9.40 Hz], 4.87 [dd, C(4)H, J 9.66 Hz, J 7.05 Hz], 6.41 [d,
1
1H, C(9)H, J 8.36 Hz], 6.51 [d, 1H, C(8)H, 1J 8.36 Hz], 6.97 [t, 1H,
C(17)H, 1J 7.31 Hz], 7.25 [t, 2H, C(16)H, 1J 8.09 Hz], 7.48 [d, 2H,
C(15)H, 1J 7.84 Hz]. 13C NMR (CD3OD) d: 29.57 [C(6), 1JCH 137.84 Hz],
1
1
51.86 [C(4), JCH 145.95 Hz], 55.39 [C(5), JCH 145.40 Hz], 108.34
1
1
[C(9), JCH 161.43 Hz], 118.40 [C(8), JCH 158.66 Hz], 118.49 [C(7)],
119.29 [C(15), 1JCH 159.22 Hz], 123.70 [C(17), 1JCH 160.32 Hz], 129.84
[C(16), 1JCH 158.66 Hz], 141.85 [C(14)], 134.49 [C(11)], 147.23, 146.18
[C(10), C(12)], 160.30 [C(2)]. IR (n/cm–1): 3337, 1692, 1653. Found (%):
C, 63.50; H, 5.89; N, 9.01. Calc. for C16H16N2O4 (%): C, 63.99; H, 5.37;
N, 9.33.
– 55 –