Catalytic cycloaminomethylation of ureas and thioureas with N,N-bis(methoxymethyl)alkanamines

Article abstract of DOI:10.1134/S1070428015010200

An efficient procedure has been developed for the synthesis of 5-alkyl-1,3,5-triazinan-2-ones, 5-alkyl-1,3,5-triazinane-2-thiones, and 2,6-dialkylhexahydro-2,3a,4a,6,7a,8a-hexaazacyclopenta[def]fluorene-4,8(1H,5H)-diones by reactions of urea, thiourea, an

Full text of DOI:10.1134/S1070428015010200

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 1, pp. 116–120. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © R.R. Khairullina, A.R. Geniyatova, E.S. Meshcheryakova, L.M. Khalilov, A.G. Ibragimov, U. M. Dzhemilev, 2015, published in
Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 1, pp. 118–122.
Catalytic Cycloaminomethylation of Ureas and Thioureas
with N,N-Bis(methoxymethyl)alkanamines
R. R. Khairullina, A. R. Geniyatova, E. S. Meshcheryakova, L. M. Khalilov,
A. G. Ibragimov, and U. M. Dzhemilev
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences,
pr. Oktyabrya 141, Ufa, 450075 Bashkortostan, Russia
e-mail: ink@anrb.ru
Received June 24, 2014
Abstract—An efficient procedure has been developed for the synthesis of 5-alkyl-1,3,5-triazinan-2-ones, 5-al-
kyl-1,3,5-triazinane-2-thiones, and 2,6-dialkylhexahydro-2,3a,4a,6,7a,8a-hexaazacyclopenta[def]fluorene-
4,8(1H,5H)-diones by reactions of urea, thiourea, and tetrahydroimidazo[4,5-d]imidazole-2,5-(1H,3H)-dione
with N,N-bis(methoxymethyl)alkanamines in the presence of SmCl3 ·6H2O as catalyst.
DOI: 10.1134/S1070428015010200
One of the most widely known method for the syn-
thesis of substituted 1,3,5-triazinan-2-ones is based on
the Mannich reaction of ureas with primary amines and
formaldehyde or of primary amines with N,N-bis-
(hydroxymethyl)urea [1–5]. The use in this reaction of
aqueous formaldehyde at elevated temperature reduces
the selectivity for triazinan-2-ones [2–4].
bacterial agents [11], pesticides [12], fuel bioprotec-
tors, and lubricating oils [13]. The choice of N,N-bis-
(methoxymethyl)alkanamines as aminomethylating
agents toward urea and thiourea was determined by
high reactivity of the latter in the catalytic heterocy-
clizations of α,ω-diols [14] and dithiols [15] to N- and
S-heterocycles.
We have recently synthesized 5-substituted
1,3,5-triazinan-2-ones and 1,3,5-triazinane-2-thiones
by catalytic cycloaminomethylation of ureas and
thioureas with N,N,N′,N′-tetramethylmetanediamine
and primary amines [6], as well as with aromatic
carboxylic acid hydrazides [7]. In continuation of our
studies in this line, in the present work we examined
reactions of urea and its derivatives (thiourea,
glycoluril) with N,N-bis(methoxymethyl)alkanamines
in the presence of catalysts based on d and f elements
with the goal of developing catalytic methods for
the selective synthesis of substituted 1,3,5-triazinanes.
These compounds are promising as building blocks for
the preparation of antitumor [8–10], antiviral, and anti-
The reaction of urea with an equimolar amount
of N,N-bis(methoxymethyl)cyclohexan-1-amine was
used as model process to evaluate the catalytic activ-
ity of various catalysts based on d and f elements (Fe,
Co, Pd, Ti, Zr, Cu, Sm, Yb). It was found that 5 mol %
of SmCl3 · H2O (CHCl3–EtOH, 1 : 2 by volume;
60°C, 6 h) ensured the best yield of 5-cyclohexyl-
1,3,5-triazinan-2-one (1a, 52%). The yield of 1a in
aliphatic (hexane, cyclohexane) and aromatic (ben-
zene, toluene) solvents was lower than <10%, and it
did not exceed 5% in the absence of a catalyst. Under
the given conditions, the reactions of urea and thio-
urea with N,N-bis(methoxymethyl)alkanamines in
the presence of 5 mol % of SmCl3 ·6H2O selectively
Scheme 1.
H
N
X
X
Alk
[Sm]
+
MeO
N
OMe
–2MeOH
N
NH
H2N
NH2
Alk
1a–1c, 2a–2d
[Sm] = SmCl3·6H2O; 1, X = O; 2, X = S; Alk = cyclo-C6H11 (a), t-Bu (b), HO(CH2)2 (c), i-Pr (d).
116

CATALYTIC CYCLOAMINOMETHYLATION OF UREAS AND THIOUREAS
117
Scheme 2.
O
8a
7a
8
H
N
H
N
7
5
1
3
N
N
Alk
N
[Sm]
2
N
6
N
8b
8c
2
+
O
O
Alk
Alk
MeO
OMe
–4MeOH
N
H
N
H
N
N
4
3a
4a
O
3a–3d
Alk = cyclo-C6H11 (a), t-Bu (b), HO(CH2)2 (c), i-Pr (d); [Sm] = SmCl3·6H2O.
afforded 5-alkyl-1,3,5-triazinan-2-ones 1a–1c and 5-al-
kyl-1,3,5-triazinane-2-thiones 2a–2d in 30–58%
yield (Scheme 1).
azinane fragments, the heterocyclization was carried
out with glycoluril {tetrahydroimidazo[4,5-d]imidaz-
ole-2,5(1H,3H)-dione}. Under analogous conditions
(5 mol % SmCl3 ·6 H2O, 60°C, CHCl3–EtOH, 6 h),
glycoluril reacted with N,N-bis(methoxymethyl)cyclo-
hexanamine at a molar ratio of 1:2 to produce ~81% of
2,6-dicyclohexylhexahydro-1H,5H-2,3a,4a,6,7a,8a-
hexaazacyclopenta[def]fluorene-4,8-dione (3a). The
yield of 3a in the absence of a catalyst did not exceed
15%. Glycoluril was also brought into reaction with
The structure of compounds 1a–1c and 2a–2d was
1
determined by H and 13C NMR spectroscopy and
MALDI–TOF mass spectrometry, as well as by com-
paring their physicochemical characteristics with
those of authentic samples. In order to extend the
scope of catalytic cycloaminomethylation and obtain
new fused aza heterocycles containing 1,3,5-tri-
C13
C47
C14
C46
C13
C48
C31
C12
C14
C9
C43
C12
C6
C26
N2
C11
O5
O4
C16
N1
C6
C11
C13
C14
O2
O2
C9
N1
C44
C9
N8
N1
C27
C12
N10
C7
C3
8
N4
C
C32
N5
N4
N6
N11
C8
N5
C3
C10
7
C
C21
C23
C10
3a
3b
O7
C19
C22
C21
C20
C18
C14
O3
C13
C17
N5
C12
N3
C16
O1
C11
C1A
O1
O8
N6
C19
C14
O2
N9
C11
N10
C10
N6
C15
C1B
N4
C13
C1С
C15
C12
N2
N7
N5
N4
N8
C16
C13
C18
C16
3d
3с
Structures of molecules 3a–3d according to the X-ray diffraction data. Non-hydrogen atoms are shown as thermal vibration ellipsoids
with a probability of 50%.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 1 2015

KHAIRULLINA et al.
118
Crystallographic data and structure refinement parameters for compounds 3a–3d
Parameter
3a
3b
3c
3d
Formula
C20H32N6O2
388.507
C16H28N6O2
336.433
C12H20N6O4
312.325
C14H24N6O2
308.380
Molecular weight
Crystal system
Space group
a, Å
Monoclinic
C2/c
Monoclinic
P21/c
Orthorhombic
P22121
Monoclinic
P21/n
15.3964(13)
16.434(2)00
7.8035(6)
90.00
12.8000(7)0
12.2472(7)0
22.6270(17)
90.00
06.38723(15)
12.4481(3)00
16.8336(3)00
90.00
13.2014(11)
7.7892(5)
14.9799(10)
90.00
b, Å
c, Å
α, deg
β, deg
(0)097.341(7)
(0)092.962(6)
90.00
(0)095.016(7)
γ, deg
V, Å3
90.00
1958.2(4)
4
90.00
3542.3(4)
6
90.00
1338.42(5)
4
90.00
1534.47(19)
5
Z
dcalc, mg/mm3
1.182
1.312
1.638
1.257
F(000)
736.0
1464.0
62.44
660.0
605.0
2Θmax, deg
62.26
62.16
61.9
Total number of reflections
3508
12706
3871
8253
Number of independent reflections
2105 (0.0181)
7299 (0.0273)
3077 (0.0094)
4408 (0.0162)
(Rint)
Goodness of fit S
R/wR [I ≥ 2σ (I)]
R/wR
1.138
0.976
0.820
1.006
0.0624/0.1604
0.0835/0.1840
0.24/–0.32
0.0650/0.1616
0.1335/0.2159
0.14/–0.15
0.0327/0.0948
0.0350/0.0987
0.22/–0.24
0.0477/0.1310
0.0637/0.1465
0.24/–0.25
Residual electron density peaks,
min/max, e Å–3
some other N,N-bis(methoxymethyl)alkanamines.
We thus obtained 2,6-dialkylhexahydro-1H,5H-
2,3a,4a,6,7a,8a-hexaazacyclopenta[def]fluorene-4,8-
diones 3b–3d in 60–80% yield (Scheme 2).
bered imidazole rings (see figure). The five-membered
ring planes in 3a–3d form dihedral angles of 71.62,
71.46, 108.52, and 71.11°, respectively, and have
an envelope conformation with the C=O carbon atom
deviating by 0.205–0.229 Å from the plane formed by
the other atoms. The triazinane rings adopt a chair
conformation. The alkyl substituents in 3a, 3c, and 3d
occupy axial positions and are oriented syn. One tert-
butyl group in 3b is axial, while the other occupies
an intermediate position between axial and equatorial.
Obviously, the large size of tert-butyl groups prevents
them from being oriented strictly axially.
1
The structure of 3a–3d was proved by H and
13C NMR data (including two-dimensional techniques),
IR and mass spectra, and X-ray analysis. In the
13C NMR spectra of 3a–3d, carbonyl carbon atoms of
the tetracyclic skeleton characteristically resonated at
δC 158.98–159.67 ppm, and signals from the CH2 and
CH group were observed at δC 57–61 and 64–66 ppm,
2
respectively. The geminal coupling constant J be-
tween the axial and equatorial protons of the methy-
lene groups was equal to 12–13 Hz.
Thus, catalytic cycloaminomethylation of urea and
its derivatives with N,N-bis(methoxymethyl)alkan-
amines provides an efficient method for the selective
synthesis of 5-alkyl-1,3,5-triazinan-2-ones, 5-alkyl-
1,3,5-triazinane-2-thiones, and 2,6-dialkylhexahydro-
1H,5H-2,3a,4a,6,7a,8a-hexaazacyclopenta[def]fluo-
rene-4,8-diones.
According to the X-ray diffraction data, the hexa-
hydro-1H,5H-2,3a,4a,6,7a,8a-hexaazacyclopenta[def]-
fluorene-4,8-dione fragment in molecules 3a–3d has
a bowl-like structure, where two vicinal triazinane
rings are fixed by paired urea bonds closing five-mem-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 1 2015

CATALYTIC CYCLOAMINOMETHYLATION OF UREAS AND THIOUREAS
119
EXPERIMENTAL
Cycloaminomethylation of tetrahydroimidazo-
[4,5-d]imidazole-2,5(1H,3H)-dione (glycoluril) with
N,N-bis(methoxymethyl)alkanamines (general pro-
cedure). A mixture of 20 mmol of N,N-bis(methoxy-
methyl)alkanamine in 2 mL of chloroform, 0.5 mmol
of SmCl3·6H2O, and 10 mmol of glycoluril in 4 mL of
ethanol was stirred for 6 h at 60°C. 2,6-Dialkyl-
hexahydro-2,3a,4a,6,7a,8a-hexaazacyclopenta[def]-
fluorene-4,8(1H,5H)-diones 3a–3d were isolated from
the reaction mixtures by silica gel column chroma-
tography.
The progress of reactions was monitored by TLC
1
using Sorbfil plates. The H and 13C NMR spectra
were recorded on a Bruker Avance-400 spectrometer at
400.13 and 100.62 MHz, respectively, using DMSO-d6
as solvent and reference (δ 2.50, δC 39.50 ppm). The IR
spectra were recorded on a Bruker Vertex 70v
spectrometer from samples dispersed in mineral oil.
The mass spectra were obtained on a Bruker Autoflex
III MALDI–TOF spectrometer with α-cyano-4-hy-
droxycinnamic or 2,5-dihydroxybenzoic acid as
matrix; samples were prepared by the dried drop tech-
nique (chloroform, 1:10). The melting points were de-
termined on a PHMK 80/2617 melting point apparatus.
Pure compounds were isolated by column chroma-
tography on KSK silica gel (50–160 μm). The spectral
parameters of compounds 1 and 2 coincided with those
reported in [6].
2,6-Dicyclohexylhexahydro-2,3a,4a,6,7a,8a-hexa-
azacyclopenta[def]fluorene-4,8(1H,5H)-dione (3a).
Yield 81%, colorless crystals, mp 214–216°C, Rf 0.60
(acetone). IR spectrum, ν, cm–1: 2923–2854, 1708,
1463, 1443–1377, 1235, 1161, 1046, 954, 869, 745.
1H NMR spectrum, δ, ppm: 1.15–1.17 m (10H, CH2),
1.50 br.s (2H, CH2), 1.68 br.s (4H, CH2), 2.06 br.s
(4H, CH2), 2.46 br.s (2H, CH), 3.99 d and 4.98 d (8H,
2
Cycloaminomethylation of urea and thiourea
with N,N-bis(methoxymethyl)alkanamines (gen-
eral procedure). A mixture of 10 mmol of N,N-bis-
(methoxymethyl)alkanamine in 1 mL of chloroform,
0.5 mmol of SmCl3·6H2O, and 10 mmol of urea or
thiourea in 2 mL of ethanol was stirred for 6 h at 60°C.
5-Alkyl-1,3,5-triazinan-2-ones 1a–1c and 5-alkyl-
1,3,5-triazinane-2-thiones 2a–2d were isolated by
silica gel column chromatography.
1-H, 3-H, 5-H, 7-H, J = 13.2 Hz), 5.29 s (2H, 8b-H,
8c-H). 13C NMR spectrum, δC, ppm: 24.38 (CH2),
25.88 (CH2), 30.16 (CH2), 54.35 (2-CH, 6-CH), 57.26
(C1, C3, C5, C7), 65.39 (C8b, C8c), 158.98 (C4, C8).
Mass spectrum: m/z 427.237 [M + K]+. Calculated:
M 388.507.
2,6-Di-tert-butylhexahydro-2,3a,4a,6,7a,8a-hexa-
azacyclopenta[def]fluorene-4,8(1H,5H)-dione (3b).
Yield 78%, colorless crystals, mp 158–160°C, Rf 0.70
(acetone). IR spectrum, ν, cm–1: 2924–2854, 1706,
1464, 1350, 1264, 1207, 1164, 1016–926, 867, 813–
5-Cyclohexyl-1,3,5-triazinan-2-one (1a). Yield
52%, colorless crystals, mp 203–205°C; published data
[6]: mp 204–205°C.
1
738. H NMR spectrum, δ, ppm: 1.06 m (18H,
5-tert-Butyl-1,3,5-triazinan-2-one (1b). Yield
48%, colorless crystals, mp 183–184°C; published data
[6]: mp 182–184°C.
t-Bu), 3.84 d and 4.73 d (8H, 1-H, 3-H, 5-H, 7-H,
2J = 12.4 Hz), 5.41 s (2H, 8b-H, 8c-H). 13C NMR
spectrum, δC, ppm: 27.00 (CH3), 52.72 [C(CH3)3],
56.11 (C1, C3, C5, C7), 64.26 (C8b, C8c), 159.16
(C4, C8). Mass spectrum: m/z 375.398 [M + K]+. Cal-
culated: M 336.433.
5-(2-Hydroxyethyl)-1,3,5-triazinan-2-one (1c).
Yield 35%, colorless crystals, mp 174–176°C; pub-
lished data [6]: mp 173–176°C.
2 , 6 - B i s ( 2 - h y d r o x y e t h y l ) h e x a h y d r o -
2,3a,4a,6,7a,8a-hexaazacyclopenta[def]fluorene-
4,8(1H,5H)-dione (3c). Yield 70%, colorless crystals,
mp 217–220°C, Rf 0.60 (acetone). IR spectrum, ν,
cm–1: 3443, 2922–2843, 1713, 1619, 1172, 1125, 1047,
5-Cyclohexyl-1,3,5-triazinane-2-thione (2a).
Yield 58%, colorless crystals, mp 172–173°C; pub-
lished data [6]: mp 172–174°C.
5-tert-Butyl-1,3,5-triazinane-2-thione (2b). Yield
50%, colorless crystals, mp 170–172°C; published
data [6]: mp 169–172°C.
1
721. H NMR spectrum, δ, ppm: 2.64 t (4H, 2-CH2,
6-CH2), 3.39–3.44 m (4H, CH2OH), 4.25 d and 4.58 d
2
5-(2-Hydroxyethyl)-1,3,5-triazinane-2-thione
(2c). Yield 44%, colorless crystals, mp 161–162°C;
published data [6]: mp 160–162°C.
(8H, 1-H, 3-H, 5-H, 7-H, J = 13.5 Hz), 5.57 s (2H,
8b-H, 8c-H). 13C NMR spectrum, δC, ppm: 53.32
(2-CH2, 6-CH2), 59.48 (CH2OH), 60.42 (C1, C3, C5,
C7), 64.71 (C8b, C8c), 159.67 (C4, C8). Mass spectrum,
m/z: 335.292 [M + Na]+, 351.258 [M + K]+. Calcu-
lated: M 312.325.
5-Isopropyl-1,3,5-triazinane-2-thione (2d). Yield
30%, colorless crystals, mp 152–155°C; published data
[6]: mp 153–155°C.
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KHAIRULLINA et al.
120
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(acetone). IR spectrum, ν, cm–1: 2923–2855, 1713,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 1 2015