Synthesis of N-(4-oxo(thioxo)-1,3,5-triazinan-1-yl)arylamides using samarium-containing catalysts

Article abstract of DOI:10.1007/s10593-014-1525-0

An effective method has been developed for the synthesis of N-(4-oxo(thioxo)-1,3,5-triazinan-1-yl)-arylamides by heterocyclization of (thio)carbamides with hydrazides of aromatic carboxylic acids and bis(N,N-dimethylamino)methane, using samarium salts as

Full text of DOI:10.1007/s10593-014-1525-0

Chemistry of Heterocyclic Compounds, Vol. 50, No. 5, August, 2014 (Russian Original Vol. 50, No. 5, May, 2014)
SYNTHESIS OF N-(4-OXO(THIOXO)-1,3,5-TRIAZINAN-
1-YL)ARYLAMIDES USING SAMARIUM-CONTAINING
CATALYSTS
1
1
1
1
*
R. R. Hairullina , A. R. Geniyatova , A. G. Ibragimov , and U. M. Dzhemilev
An effective method has been developed for the synthesis of N-(4-oxo(thioxo)-1,3,5-triazinan-1-yl)-
arylamides by heterocyclization of (thio)carbamides with hydrazides of aromatic carboxylic acids and
bis(N,N-dimethylamino)methane, using samarium salts as catalysts.
Keywords: aromatic carboxylic acid hydrazides, bis(N,N-dimethylamino)methane, N,N'-bis[(dimethyl-
amino)methyl]thiocarbamide, N-(4-oxo(thioxo)-1,3,5-triazinan-1-yl)arylamides, samarium chloride,
catalysis, heterocyclization.
The current methods for the synthesis of 5-substituted 1,3,5-triazinan-2-ones(thiones) by
cyclocondensation of (thio)carbamides with formaldehyde and primary alkyl- [1-3], aryl- and hetarylamines
[1-4], as well as the thermal condensation of primary amines with bis(N,N'-hydroxymethyl)urea [1, 5] have
several limitations due to the use of aqueous formaldehyde, performing the reaction at elevated temperature, and
the low selectivity during the formation of the target heterocycles. The interest in compounds of 1,3,5-triazinane
series is motivated by such applications as pesticides [6], promising antitumor [7-9], antiviral, and antibacterial
agents [10].
The practical significance of substituted 1,3,5-triazinan-2-ones(thiones) and the lack of preparative
procedures for the synthesis of these compounds stimulated the search for an effective method for obtaining
new N-(4-oxo(thioxo)-1,3,5-triazinan-1-yl)arylamides by catalytic cycloaminomethylation of aromatic
carboxylic acid hydrazides with (thio)carbamide and bis(N,N-dimethylamino)methane (bisamine). The method
developed is based on our recently performed cycloaminomethylation of primary alkylamines with N,N'-bis-
[(dimethylamino)methyl](thio)carbamide, which led to 5-alkyl-1,3,5-triazinan-2-ones(thiones) [11].
In the case of isonicotinic acid hydrazide reaction with thiourea and bisamine, we established that using a
CuCl2·2H2O catalyst, which showed the highest activity in cycloaminomethylation [11] and cyclothiomethylation
reactions [12], led to the formation of N-(4-thioxo-1,3,5-triazinan-1-yl)isonicotinamide (1) in <15% yield. Other
catalysts based on the halides and complexes of Rb, Cs, Sm, Fe, Zn, and Yb were tried in order to increase the
yield of compound 1 in the heterocyclization reaction (Table 1).
_______
*To whom correspondence should be addressed, e-mail: ink@anrb.ru.
1Institute of Petroleum Chemistry and Catalysis, Russian Academy of Sciences, 141 Oktyabrya Ave., Ufa
450075, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 777-781, May, 2014. Original
article submitted February 14, 2014.
0009-3122/14/5005-0715©2014 Springer Science+Business Media New York
715

H
5 mol% SmCl36H2O
, EtOH
N
X
O
H2N
H2N
O
X
NH2
+ 2
+
NMe2
Me2N
N
NH
R
N
– 2 Me2NH
R
N
H
H
1–5
1 R = 4-Py; 2 R = 4-MeOC6H4; 3 R = 3-Py; 4 R = 3-MeOC6H4; 5 R = 2-MeOC6H4;
1–4 X = S; 5 X = O
TABLE 1. The Effects of Catalyst and Solvent on the Yield of Compound 1*
Catalyst
Solvent
Yield, %
Catalyst
Solvent
Yield, %
SmCl3·6H2O
SmCl3·6H2O
SmCl3·6H2O
SmCl3·6H2O
SmCl3·6H2O
EtOH
40
15
0
YbF3
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
25
33
32
20
20
13
EtOH–CHCl3 , 1:1
CHCl3
FeCl3·6H2O
ZnCl2·2H2O
Cs2CO3
C6H14
0
n-BuOH
38
22
RbNO3
Sm(NO3)3·6H2O EtOH
CuCl2·2H2O
_______
*Reaction conditions: a 1:2:1:0.05 ratio of 4-PyC(O)NHNH2–bisamine–
thiocarbamide–catalyst, refluxing for 8 h.
According to the obtained results (Table 1), the highest catalytic activity in this reaction was shown by
SmCl3·6H2O at a 1:2:1:0.05 molar ratio of RC(O)NHNH2–bisamine–thiocarbamide–[М], while using refluxing
EtOH as solvent. The yield of the heterocycle 1 under these conditions reached 40% after 8 h.
The thiocarbamide reaction with bisamine and the hydrazides of meta- and para-methoxybenzoic and
nicotinic acids, catalyzed by 5 mol% of SmCl3·6H2O in EtOH, led to the corresponding N-(4-thioxo-1,3,5-tri-
azinan-1-yl)arylamides 2-4 in 49-75% yields. The formation of compounds 2-4 was not observed in aprotic
solvents (hexane, CHCl3) in the absence of a catalyst. Hydrazides of 2-furan- and 2-thiophenecarboxylic acids,
as well as methyl, ethoxy, and tert-butyl carbazates were unreactive under the developed reaction conditions.
In order to expand the applicability of this method for the synthesis of compounds 2-4, we explored the
heterocyclization of hydrazides with carbamide and bisamine under the developed conditions. The hydrazide of
ortho-methoxybenzoic acid gave 2-methoxy-N-(4-oxo-1,3,5-triazinan-1-yl)benzamide (5) in 30% yield. The
hydrazides of meta- and para-methoxybenzoic, as well as nicotinic and isonicotinic acids were not reactive
under these conditions.
1
The structure of compounds 1-5 was proved by one-dimensional Н and 13С NMR spectra, two-
dimensional homo- (COSY, NOESY) and heteronuclear (HSQC, HMBC) NMR spectra, and by mass
spectroscopy. The characteristic 1H and 13C NMR signals of the NCH2N fragment of 1,3,5-triazinane ring were
observed at δН 3.79-4.85 and δС 62.2-74.6 ppm [2-5, 11]. The 13C NMR signals of the (thio)carbonyl group
correlated with the methylene protons of the NCH2N fragment in the two-dimensional HMBC spectra of
compounds 1-5.
S
10 mol% SmCl36H2O
Me2N
N
N
NMe2
H
H
80°C, EtOH
1–4
+
O
– 2Me2NH
NH2
R
N
H
Based on the previously obtained results regarding the synthesis of 5-alkyl-1,3,5-triazinane-2-thiones
[11], we performed the heterocyclization of hydrazides of aromatic carboxylic acids with N,N'-bis-[(dimethyl-
716

amino)methyl]thiocarbamide, the synthesis of which we have previously described for the first time
[11]. We established that the heterocyclization of isonicotinic acid hydrazide with this reagent in EtOH at a
1:1:0.05 molar ratio of 4-PyC(O)NHNH2–N,N'-bis[(dimethylamino)methyl]thiocarbamide–Sm(NO3)3·6H2O
required 8 h at 80°С temperature and gave the 1,3,5-triazinane-4-thione 1 in a 41% yield. Using 10 mol% of
SmCl3·6H2O as catalyst gave a 63% yield of compound 1.
The reaction of nicotinic and isonicotinic, as well as meta- and para-methoxybenzoic acid hydrazides
with N,N'-bis[(dimethylamino)methyl]thiocarbamide led to the selective formation of N-(4-thioxo-1,3,5-
triazinan-1-yl)arylamides 1-4 in 38-63% yields. The reaction did not occur in the absence of a catalyst.
A likely route for the heterocyclization of carboxylic acid hydrazides [1-5, 11, 13] involves catalytic
activation of N,N'-bis[(dimethylamino)methyl]thiocarbamide [14], subsequent nucleophilic addition of an aryl
hydrazide to the carbocation formed under the reaction conditions, and concludes with the formation of the
respective 1,3,5-triazinane-4-thiones 1-4.
O
H
:N
H
S
NH2
S
H
N
Ar
N
H
..
N
H
+
Me2N
N
NMe2
Ar
Me2N
N
N+ CH2
H
H
H
O
[Sm]
..
Me2N [Sm]
– Me2NH
S
S
+
..
HN
O
NH+
CH2
HN
N
NMe2
H
..
1–4
NH
[Sm]
[Sm]
NH
HN
– Me2NH
– [Sm]
– Me2NH
Ar
NH
O
:
N
Me
Me
Ar
Thus, we have developed an effective method for the synthesis of previously difficult to obtain N-(4-oxo-
(thio)-1,3,5-triazinan-1-yl)arylamides, based on our study of samarium chloride-catalyzed heterocyclization of
aryl hydrazides with bis(N,N-dimethylamino)methane and (thio)carbamide, as well as with N,N'-bis[(dimethyl-
amino)methyl]thiocarbamide.
EXPERIMENTAL
1Н and 13С NMR spectra were acquired on a Bruker Avance 400 spectrometer (400 and 100 MHz,
respectively) in DMSO-d6 according to the standard procedures of Bruker, with TMS as the standard. The
mixing time for the NOESY experiments was 0.3 s. Mass spectra were recorded on a Bruker AUTOFLEX III
MALDI TOF/TOF instrument. Elemental analysis was performed with a Сarlo Erba 1106 elemental analyzer.
Melting points were determined on PHMK 80/2617 apparatus. The reaction progress was controlled by TLC on
Sorbfil plates (PTLC-AF-B), visualization with iodine vapor. Column chromatography was performed with
KSK silica gel (100-200 µm), eluent 1:2 hexane–acetone. Commercially available aryl hydrazides, catalysts,
and bis(N,N-dimethylamino)methane were used (Sigma-Aldrich, Acros Organics).
Heterocyclization of Aryl Hydrazides with (Thio)carbamide and Bis(N,N-dimethylamino)-
methane (General Method A). A mixture of bis(N,N-dimethylamino)methane (0.205 g, 2.00 mmol) and
(thio)carbamide (1 mmol) in EtOH (5 ml) was stirred for 30 min at room temperature, followed by dropwise
addition of the corresponding aryl hydrazide (1.00 mmol) in EtOH (5 ml) and SmCl3·6H2O (0.018 g,
717

0.05 mmol). The reaction mixture was stirred for 5 h at 80°С, evaporated, the residue was purified by silica gel
column chromatography, yielding the pure N-(4-oxo(thio)-1,3,5-triazinan-1-yl)arylamides 1-5.
Heterocyclization of Aryl Hydrazides with N,N'-Bis(dimethylaminomethyl]thiocarbamide (General
Method B). A mixture of N,N'-bis(dimethylaminomethyl)thiocarbamide [11] (0.190 g, 1.0 mmol) in EtOH (3
ml) and SmCl3·6H2O (0.036 g, 0.1 mmol) was stirred for 30 min at room temperature, followed by dropwise
addition of the corresponding aryl hydrazide (1.0 mmol) in EtOH (5 ml). The reaction mixture was stirred for 5
h at 80°С, evaporated, the residue was purified by silica gel column chromatography, yielding the pure N-(4-
oxo-1,3,5-triazinan-1-yl)arylamides 1-4.
N-(4-Thioxo-1,3,5-triazinan-1-yl)isonicotinamide (1). Yield 0.095 g (40%, method A), 0.09 g (38%,
method B). White crystals. Mp 240-242°С (EtOH), Rf 0.66 (acetone). 1H NMR spectrum, δ, ppm: 4.29 (4H, br.
s, 2CH2); 7.66 (2H, br. s, Н-3,5 Py); 8.16 (2H, br. s, NHC(S)NH); 8.67 (2H, br. s, Н–2,6 Py); 10.41 (1H, br. s,
13
СОNH). C NMR spectrum, δ, ppm: 62.2 (CH2); 122.3 (С-3,5 Py); 141.2 (С-4 Py); 150.4 (С-2,6 Py); 164.0
(СОNH); 176.3 (С(S)). Mass spectrum, m/z (Irel, %): 223 [M-CH2]+ (35), 236 [M-H]+ (100), 276 [M+K]+ (15).
Found, %: С 45.59; Н 4.86; N 29.97; S 13.39. C9H11N5OS. Calculated, %: С 45.56; Н 4.67; N 29.51; S 13.51.
4-Methoxy-N-(4-thioxo-1,3,5-triazinan-1-yl)benzamide (2). Yield 0.130 g (49%, method А), 0.110 g
(41%, method B). White crystals. Mp 187-190°С (EtOH), Rf 0.55 (acetone). 1H NMR spectrum, δ, ppm (J, Hz):
3.59 (3H, br. s, CH3); 3.79 (4H, br. s, 2CH2); 6.98 (2H, d, J = 8.4, H-2,6 Ar); 7.77 (2H, d, J = 8.4, H-3,5 Ar);
13
8.15 (2H, br. s, NHC(S)NH); 9.75 (1H, br. s, CONH). C NMR spectrum, δ, ppm: 55.8 (CH3); 62.5 (CH2);
113.8 (С-2,6 Ar); 126.1 (С-1 Ar); 130.1 (С-3,5 Ar); 162.2 (С-4 Ar); 165.3 (СONH); 176.3 (С(S)). Mass
spectrum, m/z (Irel, %): 289 [M+Na]+ (100), 305 [M+K]+ (80). Found, %: С 49.54; Н 5.37; N 21.05; S 12.14.
C11H14N4O2S. Calculated, %: С 49.61; Н 5.30; N 21.04; S 12.03.
N-(4-Thioxo-1,3,5-triazinan-1-yl)nicotinamide (3). Yield 0.180 g (75%, method A), 0.150 g (63%,
1
method B). White crystals. Mp 180-185°С (EtOH), Rf 0.74 (acetone). H NMR spectrum, δ, ppm (J, Hz): 4.85
(4H, br. s, 2CH2); 7.49-7.51 (1H, m, Н-5 Py); 8.07-8.12 (2H, m, Н-2,4 Py); 8.71-8.73 (1H, m, Н-6 Py); 8.98
13
(2H, br. s, NHC(S)NH); 10.29 (1H, br. s, CONH). C NMR spectrum, δ, ppm: 68.1 (CH2); 123.9 (С-5 Py);
129.6 (С-3 Py); 135.8 (С-4 Py); 149.1 (С-6 Py); 152.6 (С-2 Py); 164.4 (СONH); 183.6 (С(S)). Mass spectrum,
m/z (Irel, %): 276 [M+K]+ (100). Found, %: С 45.64; Н 4.66; N 29.82; S 13.94. C9H11N5OS. Calculated, %:
С 45.56; Н 4.67; N 29.51; S 13.51.
3-Methoxy-N-(4-thioxo-1,3,5-triazinan-1-yl)benzamide (4). Yield 0.190 g (74%, method А), 0.170 g
1
(67%, method B). White crystals. Mp 189-192°С (EtOH), Rf 0.79 (acetone). H NMR spectrum, δ, ppm: 3.82
(3H, br. s, CH3); 4.24 (4H, br. s, 2CH2); 7.27-7.32 (2H, m, H-2,6 Ar); 7.39-7.45 (2Н, m, H-4,5 Ar); 8.04 (2H,
13
br. s, NHC(S)NH); 9.90 (1H, br. s, СОNH). C NMR spectrum, δ, ppm: 55.7 (CH3); 74.6 (CH2); 113.0 (С-5
Ar); 117.0 (С-4 Ar); 117.9 (С-6 Ar); 120.0 (С-2 Ar); 130.0 (С-1 Ar); 155.9 (С-3 Ar); 159.6 (СONH); 184.3
(С(S)). Mass spectrum, m/z (Irel, %): 289 [M+Na]+ (100), 305 [M+K]+ (10). Found, %: С 49.39; Н 5.74;
N 21.27; S 11.99. C11H14N4O2S. Calculated, %: С 49.61; Н 5.30; N 21.04; S 12.03.
2-Methoxy-N-(4-oxo-1,3,5-triazinan-1-yl)benzamide (5). Yield 0.075 g (30%, method А). White
1
crystals. Mp 187-190°С (EtOH), Rf 0.79 (acetone). H NMR spectrum, δ, ppm (J, Hz): 3.89 (3H, br. s, CH3);
4.17 (4H, br. s, 2CH2); 6.99-7.05 (2H, m, H-5,6 Ar); 7.42-7.47 (1H, m, H-3 Ar); 7.14-7.82 (1H, m, H-4 Ar);
13
9.73 (3H, br. s, 3NH). C NMR spectrum, δ, ppm: 57.8 (CH3); 70.8 (CH2); 112.4 (С-3 Ar); 121.0 (С-5 Ar);
121.9 (С-1 Ar); 131.1 (С-6 Ar); 113.0 (С-4 Ar); 158.7 (С-2 Ar); 159.7 (СONH); 163.8 (СO(NH)2). Mass
spectrum, m/z (Irel, %): 273 [M+Na]+ (100). Found, %: С 52.86; Н 5.56; N 22.83. C11H14N4O3. Calculated, %:
С 52.79; Н 5.64; N 22.39.
The work received financial support from the Russian Foundation for Basic Research (projects 13-03-
12027 ofi_m, 14-03-00240 _a, 14-03-97023 r_povolzhye_a, and 14-03-31360 mol_a), and from the Federal
Agency of Science and Innovations (grant by the President of the Russian Federation NSh-2136.2014.3).
718

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