A new method for the synthesis of 5-bromo(aryl)methylene-substituted hydantoins

Article abstract of DOI:10.1007/s10593-008-0167-5

It has been shown that bromination of 5-aryl-5-benzylidene-3,5-dihydro-4H- 2-methylthioimidazol-4-one in methylene chloride at room temperature leads to the addition of bromine at the double bond, but the the reaction of 5-aryl-3,5-dihydro-4H-2-methylthio-5-(2-pyridylmethylene)imidazol-4-one gave complex compound of the starting materials. After boiling both of the compounds obtained in ethanol the corresponding 5-[bromo(aryl)methylene]imidazolidine-2,4- diones were obtained.

Full text of DOI:10.1007/s10593-008-0167-5

Chemistry of Heterocyclic Compounds, Vol. 44, No. 9, 2008
A NEW METHOD FOR THE SYNTHESIS
OF 5-BROMO(ARYL)METHYLENE-
SUBSTITUTED HYDANTOINS*
R. L. Antipin, E. K. Beloglazkina, A. G. Magouga, A. N. Chernysheva, and N. V. Zyk
It has been shown that bromination of 5-aryl-5-benzylidene-3,5-dihydro-4H-2-methylthioimidazol-4-one
in methylene chloride at room temperature leads to the addition of bromine at the double bond, but the
the reaction of 5-aryl-3,5-dihydro-4H-2-methylthio-5-(2-pyridylmethylene)imidazol-4-one gave complex
compound of the starting materials. After boiling both of the compounds obtained in ethanol the
corresponding 5-[bromo(aryl)methylene]imidazolidine-2,4-diones were obtained.
Keywords: 5-aryl-3,5-dihydro-4H-2-methylthioimidazol-4-ones, hydantoins, imidazoline-2,4-diones,
bromination, addition-elimination.
In recent years hydantoins (4-oxoimidazolidin-2-ones) and 2-thiohydantoins (4-oxoimidazolidine-
2-thiones) have been actively investigated in connection with the wide spectrum of their biological activity.
Apart from this hydantoins and thiohydantoins are precursors in the synthesis of a wide range of organic
compounds, for example, amino acids [1-5].
We have shown previously that 3-methyl-5-benzylidenethiohydantoin reacts with bromine in acetic
acid, adding Br2 at the C=C double bond, with further substitution of one of the bromine atoms by an ethoxy
group on reaction with ethanol [6, 7].
In this work the possibility of obtaining 5-bromo(aryl)methylene-substituted hydantoins by the
bromination of 2-aryl- and hetarylmethylene-substituted 2-thiohydantoins has been demonstrated. The 5-aryl-
3,5-dihydro-4H-2-methylthioimidazol-4-ones were obtained by a previously described method [8]. Bromination
of S-alkylated derivatives of 2-thiohydantoin were carried out by slow addition of a solution of 1.1 equiv of
bromine in CH2Cl2 to a solution of compound 1 or 2 in the same solvent. From the bromination of 2-methylthio-
5-(phenylmethylene)-3-phenyl-3,5-dihydro-4H-imidazol-4-one we isolated the product of the addition of
bromine to the double bond of the 2-thiohydantoin 3, which degraded on standing. In the case of the S-alkylated
derivative of 2-thiohydantoin containing a pyridomethylene substituent at position 5, a complex of 2-methyl-
1
thio-5-(2-pyridylmethylene)-3.5-dihydro-4H-imidazol-4-one with bromine 4 was formed. In the H NMR
spectrum signals of aromatic systems of this compound are shifted to the weak-field region. Boiling both
compounds 3 and 4 in ethanol gave compounds 5 and 6, containing a bromoarylmethylene unit.
_______
* Dedicated to Academician B. A. Trofimov on his 70th jubilee.
__________________________________________________________________________________________
M. V. Lomonosov Moscow State University, Moscow 119992, Russia; e-mail:
majouga@org.chem.msu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1406-1408,
September, 2008. Original article submitted May 15, 2008
0009-3122/08/4409-1135©2008 Springer Science+Business Media, Inc.
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Compounds 5 and 6 are hydantoins, i.e., hydrolysis of the methylthio group occurs in the course of the reaction.
A similar substitution of an SMe group by an oxygen atom has been described previously in the literature [9],
but it usually takes place under more vigorous conditions.
Ph
N
SMe
O
Br
N
Br
EtOH
H2O, ∆
Ph
Br2
CH2Cl2
R = Ph
3
Ph
N
Ph
N
O
O
SMe
O
N
N
Ph
N
H
Br
SMe
2Br2
Br2
O
R
EtOH
H2O, ∆
R
CH2Cl2
R = 2-Py
5, 6
1, 2
N
·
N
4
1, 5 R = Ph, 2, 6 R = 2-Py
So we have developed a suitable method for the preparation of 5-[bromo(aryl)methylene]imidazoline-
2,4-diones starting from the available 5-arylmethylene-3,5-dihydro-4H-2-methylthioimidazol-4-ones. The
reaction occurs by addition-elimination, accompanied by hydrolysis of the methylthio groups. Note that this
hydrolysis does not require the use of an acid catalyst as described in the literature examples [9], which gives
this reaction promise for the transformation of substrates which are sensitive to the presence of acids.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker AVANCE instrument (400 MHz) with HMDS as internal
standard. Elemental analyses of the compounds synthesized were carried out on a Carlos-Erba CHN analyzer.
5-Bromo-5-[(bromo)benzyl]-2-methylthio-3-phenyl-3,5-dihydro-4H-imidazol-4-one (3). A solution
of bromine (0.06 g, 0.37 mmol) in CH2Cl2 (10 ml) was added with stirring at room temperature to a solution of
2-methylthio-5-phenylmethylene-3-phenyl-3,5-dihydro-4H-imidazol-4-one (1) in methylene chloride (10 ml),
stirring was continued for 2 h, monitored by TLC. Compound 3 (0.12 g, 83%) was obtained as a yellow oil
1
which crystallized on standing in the air after evaporation of the solvent in vacuum. Mp 172°C. H NMR
spectrum (CDCl3), δ, ppm: 7.45 (10H, m, C6H5), 5.94 (1H, s, CHBr), 2.89 (3H, s, SCH3). Found, %: C 45.01;
H 3.23; N 6.07. C17H14Br2N2OS. Calculated, %: C 44.90; H 3.08; N 6.16.
Complex of 2-Methylthio-5-(2-pyridyl)methylene-3-phenyl-3,5-dihydro-4H-imidazol-4-one (2) and
Bromine (4). The reaction was carried out as for the preparation of compound 3. Complex compound 4 was
obtained as a yellow powder from compound 2 (0.2 g, 0.68 mmol) and bromine (0.13 g, 0.75 mmol); mp 144°C
1
(decomp.) H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 9.03 (1H, dd, J6,4 = 1, J6,5 = 5, H-6 Py); 8.84 (1H, dd,
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J3,5 = 1, J3,4 = 8, H-3, Py); 8.23 (1H, ddd, J4,6 = 1, J4,3 = 8, J4,5 = 8, H-4 Py); 7.68 (1H, ddd, J5,3 = 1, J5,6 = 5, J5,4 = 8,
H-5 Py); 7.14 (5H, m, C6H5); 6.95 (1H, s, CH=); 2.56 (3H, s, SCH3). Found, % C 31.33; H 2.41; N 7.06.
C16H13Br4N3OS. Calculated, %: C 31.22; H 2.11; N 6.82.
5-[Bromo(phenyl)methylene]-3-phenylimidazolidine-2,4-dione (5). Ethanol (5 ml) was added to
compound 3 (0.1 g, 0.22 mmol). The mixture was boiled for 1-2 min, a light-yellow precipitate which formed on
1
cooling was filtered and dried in air. Yield 0.06 g (80%) of compound 5. Mp 211-213°C. HNMR spectrum
(CDCl3), δ, ppm: 10.21 (1H, s, NH); 6.98 (10H, m, C6H5). Found, %: C 56.10; H 3.21; N 8.24. C16H11BrN2O2.
Calculated, %: C 55.98; H 3.21; N 8.16.
5-[bromo(2-pyridyl)methylene]-3-phenylimidazolidine-2,4-dione (6) was made analogously to
1
compound 5 from compound 4 (0.1 g, 0.16 mmol) with a yield of 0.05 g (89%); mp 192-195°C. H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 11.78 (1H, s, NH); 8.66 (1H, dd, J6,5 = 4.9, J6,3 = 1, H-6 Py); 8.25 (1H, dd,
J3,4 = 8, J3,5 = 1, H-3 Py); 7.93 (1H, ddd, J4,6 = 1, J4,5 = 7.7, J4,3 = 8, H-4 Py); 7.42 (6H, m, C6H6+Py). Found, %:
C 52.20; H 3.09; N 11.99. C15H10BrN3O2. Calculated, %: C 52.33; H 2.91; N 12.21.
This project was carried with financial help from RFFI (grant No. 08-03-00707).
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