Unexpected cyclization of n-aryl-n-carboxy-ethyl-β-alanines to 5,6-dihydrouracils

Full text of DOI:10.1007/s10593-012-1105-0

Chemistry of Heterocyclic Compounds, Vol. 48, No. 7, October, 2012 (Russian Original Vol. 48, No. 7, July, 2012)
LETTERS TO THE EDITOR
UNEXPECTED CYCLIZATION OF N-ARYL-N-CARBOXY-
ETHYL--ALANINES TO 5,6-DIHYDROURACILS
K. Anusevicius1, R. Vaickelioniene1, and V. Mickevicius1*
Keywords: N-aryl-substituted -alanines, 5,6-dihydrouracils, N,N-disubstituted amino acids, 2-thio-
5,6-dihydrouracils.
1-Substituted 5,6-dihydrouracils show certain biological activity which includes antitumor [1] and anti-
retroviral [2, 3] properties. 5,6-Dihydrouracil derivatives have also been used as adrenoblocking agents [4]. It is
known that 1-aryl-5,6-dihydrouracils and their 2-thio analogs are prepared by the reaction of N-aryl--alanines
or their esters with urea or alkali metal thiocyanates in acidic medium [5-8]. The reactions are generally
performed in refluxing acetic acid with subsequent acidification of the reaction mixture with hydrochloric acid,
in order to cyclize the intermediate N-aryl-N-carbamoyl(thiocarbamoyl)--alanines.
We have found that N-aryl-N-carboxyethyl--alanines can be used in the synthesis of 1-aryl-5,6-di-
hydrouracils or their 2-thio analogs.
O
X
OH
(NH2)2CO or
X
N
NH2
H
KSCN, AcOH
HCl
N
Ar
N
Ar
N
Ar
O
, 20 h
OH
6
5
OH
O
4, 5 a–d
O
1a–d
2, 3 a–d
1–5 a Ar = 4-FC6H4, b Ar = 4-BrC6H4, c Ar = 4-HOC6H4, d Ar = 4-Et2NC6H4;
2, 4 a–d X = O, 3, 5 a–d X = S
The reactions are carried out under the same conditions as in the synthesis of 5,6-dihydrouracils from
N-aryl-substituted -alanines. It is likely that initially the N,N-disubstituted amino acids 1a-d are dealkylated to
the N-aryl-substituted -alanines, which are further transformed to the (thio)ureido acids 2, 3 a-d, which readily
cyclize to the derivatives 4, 5 a-d in the presence of hydrochloric acid. The advantage of this method is the
possibility of synthesizing the 1-substituted 5,6-dihydrouracils and their 2-thio analogs not only from pure
N-aryl-substituted -alanines, but also from their mixtures with N-aryl-N-carboxyethyl--alanines, which are
often formed when treating aromatic amines with acrylic acid.
______
*To whom correspondence should be addressed, e-mail: Vytautas.Mickevicius@ktu.lt.
1Kaunas University of Technology, 19 Radvilenu Sq., Kaunas LT 50254, Lithuania.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1187-1189, July, 2012. Original
article submitted January 17, 2012.
0009-3122/12/4807-1105©2012 Springer Science+Business Media New York
1105

1H and 13C NMR spectra were recorded on a Varian Unity Inova spectrometer (300 and 75 MHz,
respectively) using DMSO-d6 with TMS as internal standard. Elemental analysis was carried out on a CE-440
instrument (EAI Exeter Analytical, Inc.), and melting points were determined on an APA II instrument
(Kleinfeld Labortechnik Gmbh).
1-Aryl-5,6-dihydrouracils 4a-d (General Method). A mixture of the corresponding N-aryl-N-
carboxyethyl--alanine 1a-d (10 mmol) and urea (0.90 g, 15 mmol) in glacial acetic acid (15 ml) was refluxed
for 20 h, 10% HCl (40 ml) was added, and the product was refluxed for a further 30 min. The mixture was
cooled, and the precipitated crystals were filtered off, washed with water, and crystallized from the
corresponding solvent. In order to isolate compound 4d from the reaction mixture, the liquid fractions were
evaporated on a rotary evaporator. The residue was dissolved in water (30 ml), NaOAc (0.25 g) was added, and
the mixture was stirred for 10 min. The crystals formed were filtered off, washed with water, and crystallized
from MeOH.
1-(4-Fluorophenyl)-5,6-dihydrouracil (4a). Yield 0.87 g (42%). White crystals, mp 238-239ºC
(EtOH) (mp 238-239ºC [6]). The 1H NMR spectrum agreed with that given in the study [6].
1-(4-Bromophenyl)-5,6-dihydrouracil (4b). Yield 1.53 g (57%). Light-brown crystals, mp 228-229ºC
(MeOH). 1H NMR spectrum, , ppm (J, Hz): 2.70 (2Н, t, J = 6.6, 5-CН2); 3.78 (2Н, t, J = 6.6, 6-CН2); 7.30 (2Н,
d, J = 8.7, Н-2',6'); 7.57 (2Н, d, J = 8.7, Н-3',5'); 10.44 (1Н, s, NН). Found, %: C 44.55; H 3.43; N 10.34.
C10H9BrN2O2. Calculated, %: C 44.63; H 3.37; N 10.41.
1-(4-Hydroxyphenyl)-5,6-dihydrouracil (4c). Yield 1.18 g (57%). White crystals, mp 265-266ºC
(CH3COOH) (mp 265-266ºC [8]). The 1H NMR spectrum agreed with that given in the study [8].
1-(4-Diethylaminophenyl)-5,6-dihydrouracil (4d). Yield 0.94 g (36%). Light-gray crystals, mp
1
183-184ºC (MeOH). H NMR spectrum, , ppm (J, Hz): 1.08 (6Н, t, J = 6.9, 2СH3CH2); 2.67 (2Н, t, J = 6.7,
5-CН2); 3.32 (4Н, q, J = 6.8, 2СН3CH2); 3.65 (2Н, t, J = 6.7, 6-CН2); 6.63 (2Н, d, J = 9.0, Н-3',5'); 7.07 (2Н, d,
J = 9.0, Н-2',6'); 10.22 (1Н, s, NН). 13C NMR spectrum, , ppm: 12.3 (2СН3CH2); 31.1 (С-5); 43.7 (С-6); 45.1
(2СН3CH2); 111.2 (С-3',5'); 126.7 (С-2',6'); 129.9 (С-1'); 145.7 (С-4'); 152.3 (2-С=O); 170.6 (4-С=O). Found,
%: C 64.42; H 7.41; N 15.95. C14H19N3O2. Calculated, %: C 64.35; H 7.33; N 16.08.
1-Aryl-2-thio-5,6-dihydrouracils (5a-d) (General Method). Obtained by the method for preparation
of compounds 4a-d, but using potassium thiocyanate instead of urea. Compound 5d was isolated similarly to
compound 4d.
1-(4-Fluorophenyl)-2-thio-5,6-dihydrouracil (5a). Yield 0.94 g (42%). White crystals, mp 291-292ºC
(EtOH) (mp 291-292ºC [6]). The 1H NMR spectrum agreed with that given in the study [6].
1-(4-Bromophenyl)-2-thio-5,6-dihydrouracil (5b). Yield 0.88 g (31%). White crystals, mp 234-235ºC
(MeOH). 1H NMR spectrum, , ppm (J, Hz): 2.81 (2Н, t, J = 7.0, 5-CН2); 3.90 (2Н, t, J = 6.8, 6-CН2); 7.34 (2Н,
d, J = 8.7, Н-2',6'); 7.64 (2Н, d, J = 8.7, Н-3',5'); 11.33 (1Н, s, NН). 13C NMR spectrum, , ppm: 30.3 (С-5); 48.5
(С-6); 120.2 (С-4'); 129.4 (С-2',6'); 131.9 (С-3',5'); 144.2 (С-1'); 166.9 (С=O); 179.4 (С=S). Found, %: C 42.21;
H 3.09; N 9.91. C10H9BrN2OS. Calculated, %: C 42.12; H 3.18; N 9.82.
1-(4-Hydroxyphenyl)-2-thio-5,6-dihydrouracil (5c). Yield 1.62 g (73%). White crystals, mp
309-311ºC (DMSO) (mp 309-311ºC [8]). The 1H NMR spectrum agreed with that given in the study [8].
1-(4-Diethylaminophenyl)-2-thio-5,6-dihydrouracil (5d). Yield 0.64 g (23%). Yellow crystals, mp
1
206-207ºC (MeOH). H NMR spectrum, , ppm (J, Hz): 1.09 (6Н, t, J = 6.9, 2СН3CH2); 2.76 (2Н, t, J = 6.9,
5-CН2); 3.34 (4Н, q, J = 6.9, 2СН3CH2); 3.83 (2Н, t, J = 6.9, 6-CН2); 6.63 (2Н, d, J = 8.9, Н-3',5'); 7.07 (2Н, d,
J = 8.9, Н-2',6'); 11.10 (1Н, s, NН). Found, %: C 60.72; H 6.81; N 15.07. C14H19N3OS. Calculated, %: C 60.62;
H 6.90; N 15.15.
REFERENCES
1.
D. J. T. Porter, J. A. Harrington, M. R. Almond, G. T. Lowen, and T. Spector, Biochem. Pharmacol.,
1106

48, 775 (1997).
2.
M. W. Embrey, J. S. Wai, T. W. Funk, C. F. Homnick, D. S. Perlow, S. D. Young, J. P. Vacca,
D. J. Hazuda, P. J. Felock, K. A. Stillmock, M. V. Witmer, G. Moyer, W. A. Schleif, L. J. Gabryelski,
L. Jin, I.-W. Chen, J. D. Ellis, B. K. Wong, J. H. Lin, Y. M. Leonard, N. N. Tsou, and L. Zhuang,
Bioorg. Med. Chem. Lett., 15, 4550 (2005).
3.
4.
R. W. Buckheit, Jr., T. L. Hartman, K. M. Watson, S. G. Chung, and E. H. Cho, Antimicrob. Agents
Chemother., 52, 225 (2008).
M. Eltze, R. Boer, M. C. Michel, P. Hein, R. Testa, W. R. Ulrich, N. Kolassa, and K. H. Sanders,
Naunyn-Schmiedeberg's Arch. Pharmacol., 363, 649 (2001).
5.
6.
R. Vaickelioniene, V. Mickevicius, and G. Mikulskiene, Molecules, 10, 407 (2005).
R. Vaickelioniene and V. Mickevicius, Khim. Geterotsikl. Soedin., 862 (2006). [Chem. Heterocycl.
Compd., 42, 753 (2006)].
7.
8.
M. S. Malinovskii, L. N. Polovina, Z. F. Solomko, N. M. Prikhodko, T. S. Babkova, and
L. N. Chekunova, Pharm. Chem. J., 21 (1972).
R. S. Baltrushis, Z.-I. G. Beresnevicius, and V. Yu. Mickevicius, Khim. Geterotsikl. Soedin., 1251
(1982). [Chem. Heterocycl. Compd., 18, 967 (1982)].
1107