One-pot synthesis of novel s-triazine-containing polyphenols and imidazotriazinium salts

Article abstract of DOI:10.1007/s00706-013-0939-1

Study of the reaction of aminoacetal containing 1,3,5-triazine moiety with phenols is reported. Reaction conditions leading to the formation of either polyphenols modified with 1,3,5-triazine moiety or previously unknown 6-arylimidazo[1,2-a][1,3,5]triazin-5-ium salts with good yields are determined. Formation of triazinium salts proceeds via the dearylation of initially formed triazine-containing polyphenols.

Full text of DOI:10.1007/s00706-013-0939-1

Monatsh Chem (2013) 144:1027–1030
DOI 10.1007/s00706-013-0939-1
ORIGINAL PAPER
One-pot synthesis of novel s-triazine-containing polyphenols
and imidazotriazinium salts
•
Almir S. Gazizov Natalya I. Kharitonova
•
•
Alexander R. Burilov Michail A. Pudovik
•
Oleg G. Sinyashin
Received: 2 October 2012 / Accepted: 27 January 2013 / Published online: 9 April 2013
Ó Springer-Verlag Wien 2013
Abstract Study of the reaction of aminoacetal containing
1,3,5-triazine moiety with phenols is reported. Reaction
conditions leading to the formation of either polyphenols
modified with 1,3,5-triazine moiety or previously unknown
6-arylimidazo[1,2-a][1,3,5]triazin-5-ium salts with good
yields are determined. Formation of triazinium salts pro-
ceeds via the dearylation of initially formed triazine-
containing polyphenols.
Following the studies in this field, we have pointed our
attention to acetals containing 1,3,5-triazine moiety.
Derivatives of sym-triazine attract careful attention of
researchers due to the wide range of biological activity. In
particular, it was reported on anti-protozoa [13], antiviral
[14], antimicrobial [15–19], antimalarial [20, 21], and
anticancer [22] activities of these compounds; their use as
modulators of estrogenic receptors [23] and inhibitors of
cycline-dependent kinases [24].
Keywords Arenes Á Heterocycles Á Cyclizations Á
Resorcinol Á Amino aldehyde
Results and discussion
Introduction
Initial acetal was synthesized from the easily available
cyanuric chloride. Its reaction with two equivalents of
morpholine with alkali yields 6-chloro-1,3,5-triazine-2,4-
diamine (1) [25]. Further reaction of this compound with
N-methylaminoacetaldehyde dimethyl acetal made it possi-
ble to synthesize target N-(2,2-dimethoxyethyl)-N-methyl-
4,6-dimorpholino-1,3,5-triazin-2-amine (2, Scheme 1).
Reaction of acetal 2 with 2-methylresorcinol in boiling
ethanol in the presence of hydrochloric acid gives rise to
the formation of the mixture of two main products. Anal-
ysis of spectral data made it possible to establish that one of
them is the product of condensation of acetal 2 with two
molecules of 2-methylresorcinol and has the structure
of 4,4’-[2-[(4,6-dimorpholino-1,3,5-triazin-2-yl)(methyl)-
amino]ethane-1,1-diyl]bis(2-methylbenzene-1,3-diol) (3a).
The latter product corresponded to unexpected 6-(2,4-
dihydroxy-3-methylphenyl)-8-methyl-2,4-dimorpholino-
7,8-dihydro-6H-imidazo[1,2-a][1, 3, 5]triazin-5-ium chlo-
ride (4a, Scheme 2). The structure of the compound 4a
was unambiguously confirmed by 2D HSQC and HMBC
experiments. In HMBC spectrum, resonance of methyne
group proton at 4.23 ppm shows cross-peak to resonance
Condensation of resorcinol with aldehydes and acetals is
intensively studied for recent decades [1] and represents a
convenient method of synthesis of polyphenol compounds
of both polymer [2] and macrocyclic structure [3, 4].
Despite the fact that a broad range of aliphatic and aro-
matic aldehydes is involved in reaction, until recently,
insufficient attention was devoted to the reactions of
resorcinol with aldehydes containing functional groups at
a-carbon atom [5, 6].
Earlier, within the study of the reaction of resorcinol
with a-substituted acetals [7–9], we devised the method of
synthesis of polyphenols modified by nitrogen- [10, 11]
and phosphorus-containing [12] groups, which enables one
to synthesize the target products with high yields.
A. S. Gazizov (&) Á N. I. Kharitonova Á A. R. Burilov Á
M. A. Pudovik Á O. G. Sinyashin
A.E. Arbuzov Institute of Organic and Physical Chemistry,
Kazan Scientific Centre, Russian Academy of Sciences,
Kazan, Russia
e-mail: agazizov@iopc.ru
123

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A. S. Gazizov et al.
MeO
OMe
Scheme 1
Cl
MeNHCH2CH(OMe)2
K2CO3
Me
N
N
N
R =
N
O
N
N
MeCN, reflux, 8 h
R
N
R
R
N
R
1
2
Scheme 2
R
N
N
R
R1
HO
R1
N
N
HO
OH
OH
Cl
Me
OH
2
R1
BuOH, HCl (aq)
reflux, 72 h
R
BuOH, HCl (aq),
60 °C, 8 h
N
N
Me
N
HO
OH
OH
N
R1
R
3a, 3b
4a, 4b
R1 = Me (a), OH (b)
R =
N
O
of carbon atom of triazole ring at 153.42 ppm, which
proves the imidazole ring formation. Same proton has
also the cross-peak with resonance of carbon atom of
resorcinol fragment at 156.15 ppm. At the same time, no
cross-peaks are observed for the resonances of protons of
methylene group and triazine ring carbon atoms. So, the
methylene group does not adjoin the triazine ring and
obtained data suggests the 6-arylsubstituted heterocycle
formation.
boiling under the same conditions; this proves the absence
of equilibrium between two products. Thus, it can be
suggested that polyphenol 3a is the product of kinetic
control of reaction, while triazinium salt 4a represents the
product of thermodynamic control.
Reaction of acetal 2 with pyrogallol proceeds according
to analogous scheme. However, it should be noted that, in
this case, reaction results in the formation of hardly sepa-
rable mixture of compounds 3b and 4b even under
relatively mild conditions and we did not succeed in iso-
lating individual polyphenol 3b.
There are only several publications describing the syn-
thesis of triazinium salts [26–28] or indicating on the
possibility of their formation as unstable intermediates [29,
30]. There are no data on the synthesis of aryl-substituted
compounds of this type in published data.
Assuming the data obtained, we suggested the fol-
lowing scheme of reaction (Scheme 2). On the first step,
reaction of acetal 2 with phenol takes place with the
formation of polyphenol 3, dearylation of which at ele-
vated temperature gives triazinium salt 4 as product. It
should be noted that there are no analogous transforma-
tions in published data.
Further study of this reaction showed that decrease in
temperature and in time of reaction increases the fraction
of product of dimerization in reaction mixture, while
increase in temperature and time of reaction provides the
formation of triazinium salt. When performing reaction in
boiling butanol for 72 h, triazinium salt 4a was isolated as
the only product. Decrease in temperature to 60°C and time
of reaction to eight hours made it possible to synthesize
polyphenol 3a with the yield of 60 %.
Thus, as a result of the studies performed, we devised a
convenient single-step method of synthesis of polyphenols
containing 1,3,5-triazine fragment, as well as novel aryl-
substituted imidazotriazinium salts according to the reac-
tion of triazine-containing acetals with polyatomic phenols.
It was established that the formation of triazinium salts
proceeds according to dearylation and subsequent intra-
molecular heterocyclization of polyphenols.
Long-term boiling of the dimer 3a obtained in butanol
with hydrochloric acid also gives rise to the formation of
compound 4a. Triazinium salt 4a remains unchanged at
123

One-pot synthesis of novel s-triazine-containing polyphenols
1029
vꢀ = 1,609, 3,271 cm-1; MALDI TOF: m/z calcd for
C28H36N6O6 (M?) 552.26, found 552.27.
Experimental
Commercially available compounds were used without
further purification. Solvents were purified according to
standard procedures. The NMR spectra were recorded on
an Avance 600 instrument with the working frequency of
6-(2,4-Dihydroxy-3-methylphenyl)-8-methyl-2,4-
dimorpholino-7,8-dihydro-6H-imidazo[1,2-a][1, 3, 5]-
triazin-5-ium chloride (4a, C21H29ClN6O4)
To the solution of 1.30 g (3.53 mmol) N-(2,2-dimethoxy-
ethyl)-N-methyl-4,6-dimorpholino-1,3,5-triazin-2-amine (2)
and 0.83 g (6.69 mmol) 2-methylresorcinol in 20 cm3 1-
butanol 1.5 cm3 concentrated hydrochloric acid was added
at room temperature. Reaction mixture was refluxed for
72 h, cooled, and transferred to 200 cm3 diethyl ether.
Precipitate formed was filtered off, washed multiple times
with diethyl ether, and dried in vacuum (0.01 torr, 40 °C,
2 h) to give 1.18 g (72 %) 4a. M.p.: 199–200°C; 1H NMR
(600 MHz, CD3OD): d = 2.05 (s, 3H, CH3-Caryl), 3.15 (s,
3H, CH3-N), 3.22-3.24 (m, 4H, morpholine), 3.87-3.90 (m,
4H, morpholine), 3.77 (m, 8H, morpholine), 4.23
(t, J = 10.67 Hz, 1H, CH), 3.70 (dd, J = 10.39 Hz,
5.39 Hz, 1H, CH2), 5.50 (dd, J = 10.79 Hz, 4.92 Hz, 1H,
CH2), 6.35 (d, J = 8.25 Hz, 1H, CHaryl), 6.88 (d, J =
8.33 Hz, 1H, CHaryl) ppm; 13C NMR (150 MHz, DMSO-
d6): d = 8.89 (CH3-Caryl), 30.73 (CH3-N), 42.50, 45.16
(CH2-N, morpholine), 53.91, 54.93 (CH2), 63.08, 65.36
(CH2-O, morpholine), 79.17 (CH), 106.49 (CHaryl), 109.45
(Caryl-CH3), 112.09 (Caryl-CH), 116.37 (CHaryl), 146.81,
153.42 (Ctriazine), 154.43 (Ctriazine-N?), 156.15, 156.34
1
600.13 MHz for H and 150.90 MHz for 13C. Signals of
residual protons of solvent in 1H NMR spectra were used as
references for the measurements of chemical shift. IR
spectra were recorded on a Vector 22 (Bruker) spectrom-
eter. Results of elemental analyses (C, H, N, Cl) were
found to be in good agreement ( 0.3 %) with the calcu-
lated values. 2-Chloro-4,6-dimorpholino-1,3,5-triazine (1)
was prepared according to known procedure, m.p. 173°C
(Ref. [25] 173–174°C).
N-(2,2-Dimethoxyethyl)-N-methyl-4,6-dimorpholino-1,3,5-
triazin-2-amine (2, C16H28N6O4)
To the solution of 5.00 g (17.48 mmol) 2-chloro-4,6-
dimorpholino-1,3,5-triazine (1) and 2.08 g (17.48 mmol)
N-methylaminoacetaldehyde dimethyl acetal in 70 cm3
acetonitrile, 5 g potassium carbonate was added. Reaction
mixture was refluxed for 8 h, filtered, and evaporated in
1
vacuo to give 5.60 g (87.5 %) 2. M.p.: 140°C; H NMR
(600 MHz, CDCl3): d = 3.12 (s, 3H, CH3-N), 3.38 (s, 6H,
CH3-O), 3.62 (d, J = 5.37 Hz, 2H, CH2), 3.66-3.70
(m, 8H, morpholine), 3.73 (m, 8H, morpholine), 4.56
(t, J = 5.00 Hz, 1H, CH) ppm; 13C NMR (150 MHz,
CDCl3): d = 36.82 (CH3-N), 43.67 (CH2-N, morpholine),
50.65 (CH2), 54.28 (CH3-O), 66.61 (CH2-O, morpholine),
103.46 (CH), 164.51, 165.26, 165.56 (Ctriazine) ppm.
(Caryl-OH) ppm; IR: vꢀ = 1,605, 1,672, 1,753, 3,181 cm-1
MALDI TOF: m/z calcd for C21H29ClN6O4 (M?-Cl)
429.22, found 429.22.
;
8-Methyl-2,4-dimorpholino-6-(2,3,4-trihydroxyphenyl)-
7,8-dihydro-6H-imidazo[1,2-a][1, 3, 5]triazin-5-ium chlo-
ride (4b, C20H27ClN6O5)
4,4’-[2-[(4,6-Dimorpholino-1,3,5-triazin-2-yl)(methyl)amino]-
ethane-1,1-diyl]bis(2-methylbenzene-1,3-diol)
(3a, C28H36N6O6)
To the solution of 0.50 g (1.36 mmol) N-(2,2-dimethoxy-
ethyl)-N-methyl-4,6-dimorpholino-1,3,5-triazin-2-amine (2)
and 0.34 g (2.70 mmol) pyrogallol in 10 cm3 1-butanol
1.0 cm3 concentrated hydrochloric acid was added at room
temperature. Reaction mixture was refluxed for 72 h,
cooled, and transferred to 200 cm3 diethyl ether. Precip-
itate formed was filtered off, washed multiple times with
diethyl ether, and dried in vacuum (0.01 torr, 40 °C, 2 h) to
give 0.3 g (47 %) 4b. M.p.: 112–113°C; 1H NMR
(600 MHz, CD3OD): d = 3.15 (s, 3H, CH3-N), 3.22-3.30
(m, 4H, morpholine), 3.87–3.90 (m, 4H, morpholine),
3.75–3.79 (m, 8H, morpholine), 4.24 (t, J = 10.62 Hz, 1H,
CH), 3.72 (dd, J = 10.50 Hz, 4.88 Hz, 1H, CH2), 5.47
(dd, J = 10.74, 5.47 Hz, 1H, CH2), 6.32 (d, J = 8.30 Hz,
1H, CHaryl), 6.57 (d, J = 8.30 Hz, 1H, CHaryl) ppm; 13C
NMR (150 MHz, CD3OD): d = 28.55 (CH3-N), 41.79,
44.80 (CH2-N, morpholine), 53.17, 53.97 (CH2), 62.00,
64.06 (CH2-O, morpholine), 76.58 (CH), 104.99 (CHaryl),
113.83 (Caryl-CH), 117.87 (CHaryl), 142.97, 144.51, 147.12,
152.90 (Ctriazine), 154.45 (Ctriazine-N?), 155.08 (Caryl-OH)
To the solution of 1.50 g (4.07 mmol) N-(2,2-dimethoxy-
ethyl)-N-methyl-4,6-dimorpholino-1,3,5-triazin-2-amine (2)
and 1.00 g (8.06 mmol) 2-methylresorcinol in 20 cm3 1-
butanol 2 cm3 concentrated hydrochloric acid was added at
room temperature. Reaction mixture was heated at 60°C
for 8 h, cooled, and transferred to 200 cm3 diethyl ether.
Precipitate formed was filtered off, washed multiple times
with chloroform, and dried in vacuum (0.01 torr, 40 °C,
2 h) to give 1.28 g (60 %) 3a. M.p.: 193–194°C; 1H NMR
(600 MHz, CD3OD): d = 2.05 (s, 6H, CH3-Caryl), 3.12
(s, 3H, CH3-N), 3.74 (m, 16H, morpholine), 4.24 (d, J =
7.57 Hz, 2H, CH2), 5.04 (t, J = 7.93 Hz, 1H, CH), 6.33 (d,
J = 8.30 Hz, 2H, CHaryl), 6.92 (d, J = 8.30 Hz, 2H,
CHaryl) ppm; 13C NMR (150 MHz, CD3OD): d = 7.67
(CH3-Caryl), 35.62 (CH3-N), 44.87, 45.28 (CH2-N, mor-
pholine), 53.73 (CH2-N), 65.98 (CH2-O), 106.84 (CHaryl),
111.67 (Caryl-CH3), 120.28 (Caryl-CH), 125.10 (CHaryl),
152.91 (Caryl-OH), 154.34, 154.49 (Ctriazine-N) ppm; IR:
123

1030
A. S. Gazizov et al.
ppm; IR: vꢀ = 1,604, 1,673, 1,753, 3,173 cm-1; MALDI
TOF: m/z calcd for C20H27ClN6O5 (M?) 466.17, found
466.17.
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