Preparation of aminotriazole- thione derivatives from N-aryl- N-carboxyethyl-β-alanines

Article abstract of DOI:10.1007/s10593-010-0416-2

Depending on the substituents in the aryl moiety, the fusion of N-aryl-N-ethoxycarbonyl-β-alanines with thiocarbohydrazide gives di- or monotriazole derivatives, namely, 4-amino-(2-{[2-(4-amino-5-thioxo-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl)ethyl]anilino}e

Full text of DOI:10.1007/s10593-010-0416-2

Chemistry of Heterocyclic Compounds, Vol. 45, No. 10, 2009
PREPARATION OF AMINOTRIAZOLE-
THIONE DERIVATIVES FROM N-ARYL-
N-CARBOXYETHYL-β-ALANINES
I. Tumosienė1 and Z. J. Beresnevičius1*
Depending on the substituents in the aryl moiety, the fusion of N-aryl-N-ethoxycarbonyl-β-alanines with
thiocarbohydrazide gives di- or monotriazole derivatives, namely, 4-amino-(2-{[2-(4-amino-5-thioxo-
4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]anilino}ethyl)-4,5-dihydro-1H-1,2,4-triazole-5-thiones, 1-[2-(4-amino-
5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]-2,3-dihydroquinolin-4(1H)-ones,
4-amino-3-[2-(4-
methylanilino))ethyl]-4,5-dihydro-1H-1,2,4-triazole-5-thione and 4-amino-3-[2-(4-ethoxyanilino)-
ethyl]-4,5-dihydro-1H-1,2,4-triazole-5-thione. A ditriazolethione derivative was also obtained from the
diethyl ester of N-ethoxycarbonyl-N-(4-ethoxyphenyl)- β-alanine.
Keywords: dihydroxyquinolone, carboxyalanine, triazole, cyclization.
In previous work on the synthesis of compounds with two identical pyrazole, oxadiazole, or triazole
rings [1], we synthesized 4-amino-3-(2-{[2-(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]anilino}-
ethyl)-2,4-dihydro-3H-1,2,4-triazole-5-thione (2a) and its methyl derivative 2b, by the action of hydrazine on
the corresponding 1,3,4-oxadiazole-2(3H)-thione derivative. In a continuation of this study and searching for a
shorter synthetic pathway to the desired products, which hold interest as potential bioactive compounds, we
carried out the reaction of carboxylic acids with thiocarbohydrazide already reported by Mekuskiene et al. [2, 3].
In a detailed study of this reaction for N-aryl-N-ethoxycarbonyl-β-alanines (1), we established that both the
reaction conditions and the substituent in the N-aryl moiety affect the result of this reaction.
The fusion of diacid 1a with thiocarbohydrazide gave ditriazole derivative 2a in 80% yield. In the case
of N-(4-methylphenyl-N-ethoxycarbonyl-β-alanine (1b), 4-amino-3-[2-(4-methylanilino)ethyl]-4,5-di-hydro-
1H-1,2,4-triazole-5-thione (3b) was obtained as the result of the dealkylation of alanine 1b along with
ditriazolethione 2b. Triazolethione 3b was isolated from the filtrate by column chromatography. The dealkyla-
tion of N-aryl-N-carboxyethyl-β-alanines in cyclization reactions to give hydroxyquinolinone derivatives has
been noted by Kantminene [4].
The alkoxy group in the aryl fragment in carboxylic acids 1c and 1d facilitates internal acylation to give
6-alkoxy-1-[2-(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]-2,3-dihydroquinolin-4(1H)-ones 4.
Decarboxylation also occurs in the fusion of alanine 1d with thiocarbohydrazide to give 4-amino-3-[2-(4-
ethoxyanilino)ethyl]-4,5-dihydro-1H-1,2,4-triazole-5-thione (3d). The presence of a quinoline system in
_______
* To whom correspondence should be addressed, e-mail: zigmuntas.beresnevicius@ktu.lt.
1Kaunas University of Technology, LT-30254 Kaunas, Lithuania.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1564-1567, October, 2009.
Original article submitted March 6, 2009.
0009-3122/09/4510-1257©2009 Springer Science+Business Media, Inc.
1257

compounds 4 is indicated by the aromatic proton singlet at 6.81-6.83 ppm in the 1H NMR spectra. The 1H NMR
spectra of all products 2-4 have signals for the N-NH group as singlets at 13.53 ppm. The primary amino group
protons of the dihydroquinoline derivatives of aminotriazolethiones 4 appear as two singlets at 5.56-5.61 ppm.
O
O
R
14, 15
6
OR1
3
2
N
R
N
9
OR1
10
11
O
1a–d, 5c
NH2
4c,d
N
N
13
H
N
N
H
S
11
S
N
H
N
N
N
S
9
NH2
N
8
7
N
N
R
12, 13
4
1
NH2
S
NH2
N
H
R
N
N
H
2a–c
3b,d
1, 2 a R = H; 1–3 b R = Me; 1, 2, 4, 5 c R= MeO; 1, 3, 4 d R = EtO; 1a–d R1 = H, 5c R1 = Et
Triazolethione 2c was also obtained from the diethyl ester of diacid 5c by heating this compound at
reflux [5] with thiocarbohydrazide in methanolic sodium methylate with subsequent acidification of the reaction
mixture.
EXPERIMENTAL
1
The H and 13C NMR spectra were taken on a Varian 300 Inova spectrometer at 300 and 75 MHz,
respectively, in DMSO-d6 with TMS as the internal standard. The IR spectra were taken on a Perkin-Elmer
Spectrum Bx FT-IR spectrometer for KBr pellets. The chemical ionization mass spectra were taken on a Waters
Micromas ZQ 2000 mass spectrometer. The reaction course and purity of the products were monitored by
thin-layer chromatography on Silufol 254 and Silufol UV-254 plates.
4-Amino-3-(2-{[2-(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]anilino}ethyl)-4,5-di-
hydro-1H-1,2,4-triazole-5-thione (2a). A mixture of N-ethoxycarbonyl-N-phenyl-β-alanine (1a) (2.37 g,
10 mmol) and thiocarbohydrazide (2.12 g, 20 mmol) was heated for 90 min at 160°C. The melt was cooled and
dissolved in ethanol (50 ml). The precipitate formed upon cooling was filtered off and crystallized from ethanol
to give 1.87 g (79%) 2a; mp 200-201°C (mp 200-201°C [1]).
4-Amino-3-(2-{[2-(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]-4-methylanilino}ethyl)-
4,5-dihydro-1H-1,2,4-triazole-5-thione (2b) and 4-amino-3-[2-(4-methylanilino))ethyl]-4,5-dihydro-
1H-1,2,4-triazole-5-thione (3b). A mixture of β-alanine 1b (5.02 g, 20 mmol) and thiocarbohydrazide (4.25 g,
40 mmol) was heated at 160°C for 90 min. The melt was cooled and dissolved in ethanol (50 ml). The
precipitate formed upon cooling was filtered off and crystallized from ethanol to give 4.85 g (62%) 2b;
mp 165-166°C (mp 165-166°C [1]).
1258

The ethanolic filtrate was evaporated and the residue was subjected to chromatography on a silica gel 60
column using 1:1 acetone–hexane as the eluent to give 0.9 g (18%) 3b as an oil, Rf 0.5 (1:1 acetone–hexane).
1H NMR spectrum, δ, ppm (J, Hz): 2.19 (3H, s, 4-CH3); 2.89 (2H, t, J = 7.2, CH2CN); 3.37 (2H, t, J = 7.2,
CH2N); 5.52 (2H, br.s, NH2); 5.59 (1H, s, NH-Ar); 6.54 (2H, d, J = 8.1, H-2,6 Ar); 6.91 (2H, d, J = 8.1,
H-3,5 Ar); 13.54 (1H, s, NNH). Mass spectrum (20 eV), m/z (Irel, %): 250 [M+H]+ (70). Found, %: C 52.85;
H 6.12; N 28.10. C11H15N5S. Calculated, %: C 52.99; H 6.06; N 28.09.
4-Amino-3-(2-{[2-(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]-4-methoxyanilino}-
ethyl)-4,5-dihydro-1H-1,2,4-triazole-5-thione (2c). Thiocarbohydrazide (13.27 g, 125 mmol) was added to a
solution of sodium methylate obtained from metallic sodium (5.35 g, 23.25 mmol) in absolute methanol (50 ml)
and heated at reflux for 15 min. Then, diethyl ester 5c (12.1 g, 41 mmol) was added and heated at reflux for 4 h.
The reaction mixture was cooled and 20 ml water was added. Then, acetic acid was added to bring the solution
to pH 4. The precipitate formed was filtered off, washed with water, and crystallized from DMF–H2O to give
1
10.68 g (64%) 2c; mp 212-213°C. IR spectrum, ν, cm-1: 1240 (C=S), 3233 (NH2). H NMR spectrum, δ, ppm
(J, Hz): 2.86 (4H, t, J = 7.3, CH2CN); 3.60 (4H, t, J = 7.3, CH2N); 3.68 (3H, s, CH3O); 5.61 (4H, s, 2NH2); 6.83
(4H, s, H Ar); 13.53 (2H, s, 2NH). 13C NMR spectrum, δ, ppm: 22.56 (C-8); 47.64 (C-7); 55.24 (C-11); 114.20
(C-2, C-6); 114.80 (C-3, C-5); 140.97 (C-1); 150.45 (C-9); 151.18 (C-4); 165.93 (C-10). Mass spectrum
(20 eV), m/z (Irel, %): 408 [M+H]+ (100). Found, %: C 44.59; H 5.34; N 30.95. C15H21N9OS2. Calculated, %:
C 44.21; H 5.19; N 30.93.
1-[2-(4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]-6-methoxy-2,3-dihydroquinolin-
4(1H)-one (4c). Analogously to the preparation of triazolethione 2b, diacid 1c (2.67 g, 10 mmol) and
thiocarbohydrazide (2.65 g, 25 mmol) gave 2.41 g (76%) dihydroquinolone 4c; mp 142-143°C (2-propanol).
1H NMR spectrum, δ, ppm (J, Hz): 2.81 (2H, t, J = 6.3, CH2CN); 2.85-2.90 (4H, m, 2CH2); 3.67 (3H, s, CH3O);
3.78 (2H, t, J = 6.3, CH2N); 5.56 (1H, s, NH2); 5.59 (1H, s, NH2); 6.57 (1H, d, J = 8.7, H-8 Ar); 6.72 (1H, d,
J = 8.7, H-7 Ar); 6.83 (1H, s, H-5 Ar); 13.53 (1H, s, NH). 13C NMR spectrum, δ, ppm: 18.11, 22.54 (C-2, C-3);
23.85 (C-10); 47.34 (C-9); 55.42 (C-14); 113.25 (C-8); 114.17 (C-5); 115.41 (C-7); 142.37 (C-8a); 149.99,
150.41, 150.63 (C-4a, C-6, C-11); 165.79, 165.86 (C-4, C-13). Mass spectrum (15 eV), m/z (Irel, %): 320
(M+H]+ (50). Found, %: C 52.61; H 5.34; N 21.89. C14H17N5O2S. Calculated, %: C 52.65; H 5.37; N 21.93.
1-[2-(4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]-6-ethoxy-2,3-dihydroquinolin-
4(1H)-one (4d) and 4-amino-3-[2-(4-ethoxyanilino)ethyl]-4,5-dihydro-1H-1,2,4-triazole-5-thione (3d).
Analogously to the preparation of triazolethione 2b, acid 1d (1.41 g, 5 mmol) and thiocarbohydrazide (1.06 g,
10 mmol) gave 1.15 g (69%) dihydroquinolone 4d; mp 92-93°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.27 (3H, t,
J = 6.9, CH3CH2O); 2.88 (2H, t, J = 7.2, CH2CN); 3.31-3.57 (4H, m, 2CH2); 3.61 (2H, m, CH2N); 3.92 (2H, q,
J = 6.9, CH3CH2O); 5.59 (0.67H, s, NH2); 5.61 (1.33H, s, NH2); 6.56 (1H, d, J = 8.7, H-8 Ar); 6.73 (1H, d,
13
J = 8.7, H-7 Ar); 6.81 (1H, s, H-5 Ar); 13.53 (1H, s, NH). C NMR spectrum, δ, ppm: 14.82 (C-15); 18.29,
22.56 (C-2, C-3), 24.56 (C-10), 47.59 (C-9), 63.21 (C-14), 113.22 (C-8), 114.16 (C-5), 115.35 (C-7), 142.35
(C-8a); 149.98, 150.39, 150.65 (C-4a, C-6, C-11); 165.83, 165.85 (C-4, C-13). Mass spectrum (15 eV), m/z
(Irel, %): 334 [M+H]+ (40). Found, %: C 54.14; H 5.73; N 21.04. C15H19N5O2S. Calculated, % C 54.04; H 5.74;
N 21.01.
Triazolethione 3d was isolated from the filtrate analogously to 3b. The yield of 3b was 0.21 g (15%);
1
mp 179-180°C. IR spectrum, ν, cm-1: 1299 (C=S), 3185 (NH2). H NMR spectrum, δ, ppm (J, Hz): 1.28 (3H, t,
J = 6.9, CH3CH2O); 2.87 (2H, t, J = 7.2, CH2CN); 3.33 (2H, t, J = 7.2, CH2N); 3.91 (2H, q, J = 6.9, CH3CH2O);
5.31 (2H, s, NH2); 5.59 (1H, s, NH-Ar); 6.56 (2H, d, J = 9.0, H-2, 6 Ar); 6.72 (2H, d, J = 9.0, H-3,5 Ar); 13.52
13
(1H, s, NNH). C NMR spectrum, δ, ppm: 14.84 (C-13); 24.57 (C-8); 47.99 (C-7); 63.21 (C-12); 113.24 (C-2,
C-6); 115.36 (C-3, C-5); 142.35 (C-1); 150.66 (C-9); 152.10 (C-4); 165.85 (C-11). Mass spectrum (20 eV), m/z
(Irel, %): 280 [M+H]+ (100). Found, %: C 51.54; H 6.19; N 25.03. C12H17N5OS. Calculated, %: C 51.59; H 6.13;
N 25.07.
1259

REFERENCES
1.
J. Tumosene and Z. I. Bersnevičius, Khim. Geterotsikl. Soedin., 1353 (2007) [Chem. Heterocycl. Comp.,
43, 1148 (2007)].
2.
3.
G. Mekuskiene, S. Tumkevičius, and P. Vainilavičius, J. Chem. Res. (S), 213 (2002).
G. Mekuskiene, and P. Vainilavičius, Khim. Geterotsikl. Soedin., 1088 (2007). [Chem. Heterocycl.
Comp., 43, 919 (2007)].
4.
5.
K. Kantminene, Dis. Doc. Chem. Sci., Kaunas (1998).
N. Demirbas, A. Demirbas, S. A. Karaoglu, and E. Êelik, ARKIVOC, (i), 75 (2005).
1260