sym-triazines. 8. Synthesis and some reactions of 4,6-disubstituted 2-(1H-pyrrolyl)-1,3,5-triazines

Article abstract of DOI:10.1007/s10593-008-0050-4

We have studied the reaction of 2,5-dimethoxytetrahydrofuran with 4,6-disubstituted 2-amino-1,3,5-triazines with the aim of obtaining novel coupled polyheterocyclic systems with potential bioactivity. Reaction conditions were optimized. A series of novel 4,6-disubstituted 2-(1H-1-pyrrolyl)-sym- triazines was obtained. It was found that the product yields depended on the nature of the substituent in the 4 and 6 positions of the triazine ring and on the reaction conditions.

Full text of DOI:10.1007/s10593-008-0050-4

Chemistry of Heterocyclic Compounds, Vol. 44, No. 3, 2008
sym-TRIAZINES. 8*. SYNTHESIS
AND SOME REACTIONS
OF 4,6-DISUBSTITUTED 2-(1H-
PYRROLYL)-1,3,5-TRIAZINES
A. A. Chesnyuk1, S. N. Mikhailichenko2, V. N. Zaplishnyi2, L. D. Konyushkin3, and S. I. Firgang3
We have studied the reaction of 2,5-dimethoxytetrahydrofuran with 4,6-disubstituted 2-amino-1,3,5-
triazines with the aim of obtaining novel coupled polyheterocyclic systems with potential bioactivity.
Reaction conditions were optimized. A series of novel 4,6-disubstituted 2-(1H-1-pyrrolyl)-sym-triazines
was obtained. It was found that the product yields depended on the nature of the substituent in the 4 and
6 positions of the triazine ring and on the reaction conditions.
Keywords: 4,6-disubstituted 2-amino-1,3,5-triazines, 2,5-dimethoxytetrahydrofuran, 4-substituted
2-amino-(1,3,5-triazinyl)-6-iminotriphenylphosphoranes, 4-substituted 2-(1H-1-pyrrolyl)-6-(1,2,3-
triazol-1-yl)-1,3,5-triazines.
In continuing our study of the synthesis of conjugated heterocyclic systems it seemed reasonable to
prepare novel compounds containing 1,3,5-triazine, pyrrole, and 1,2,3-triazole rings together. We have
previously reported the synthesis of sym-triazine derivatives containing 1,2,3-triazole fragments [2, 3]. The aim
of this work is the targeted synthesis of novel and potentially bioactive 4,6-disubstituted 2-(1H-1-pyrrolyl)-
1,3,5-triazine derivatives and to study their properties and reactions.
It is known [4] that 4,6-dichloro-2-(N-pyrrolyl)-1,3,5-traizines are formed in about 37% yield as a result
of the reaction of 2,4,6-trichloro-1,3,5-triazine with pyrrole or pyrrolyl potassium (lithium) in the presence of
AlCl3. However, this method is only suitable for the substitution of the first chlorine in cyanuric chloride.
In [5] it was reported that the primary amino group of alkyl and arylamines can be used as the nitrogen
component in the construction of a pyrrole ring via reaction with 2,5-dimethoxytetrahydrofuran. The latter can
be used as a latent 1,4-dicarbonyl compound giving high yields of the corresponding N-alkyl- or N-aryl-
pyrroles.
_______
* For Communication 7 see [1].
_________________________________________________________________________________________
1Kuban State Agrarian University, Krasnodar 350044, Russia; e-mail: alex_ch2003@list.ru, e-mail:
2
vlad_zplv@mail.ru. University of Toronto at Scarborough, 1265 Military Trial, Toronto, ON. Canada, MIC
3
1A4; e-mail: mikhay@utsc.utoronto.ca. N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences, Moscow 119991; e-mail: LeonidK@chemical-block.com. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 3, pp. 440-451, March, 2008. Original article submitted March 16, 2006;
revision submitted October 8, 2007.
0009-3122/08/4403-0339©2008 Springer Science+Business Media, Inc.
339

In the case of two compounds the authors in [6] have shown that pyrazolinotriazines containing a
primary amino group in their composition can form pyrroles with 2,5-dimethoxytetrahydrofuran in 72 and 83%
yields by refluxing for 10 h in a mixture of dioxane and acetic acid.
The starting mono- and diamino sym-triazines 1a-m were prepared by a known method [7]. The
physico-chemical and spectroscopic characteristics of some of them are given in Tables 1 and 2.
Studies have shown that the reaction conditions prove to have a marked effect on the reaction time and
on the yield of the target compounds. It was found that shortening of the reaction time and improved yields of
the 4,6-disubstituted 2-(1H-1-pyrrolyl)-1,3,5-triazines 2a-m can be achieved by refluxing the reagents in
toluene solution in the presence of P2O5 using
a
molar ratio of amino-sym-triazine
1
to
2,5-dimethoxytetrahydrofuran to P2O5 of 1:1.2:1. The reaction was carried out according to the scheme:
O
NH2
N
N
MeO
OMe
N
N
N
N
P2O5, toluene
R1
N
R2
R1
R2
2a–m
1a–m
N
PPh3
2i, j
+
N
N
PPh3
R1
N
N
3a,b
N
N
O
N
N
R3
2i–m
+
N
R1
N
N
R3
4a–h
1,2 a R1 = NPh2, R2 = NMe2; b R1 = NPh2, R2 = NEt2; c R1 = NPh2, R2 = CN; d R1 = NPh2, R2 =1-morpholino;
e R1 = NPh2, R2 =1-piperidino; f R1 = Ph, R2 = NH2; g R1 = Ph, R2 =1-pyrrolyl; h R1 = OMe, R2 = 1-morpholino;
i R1 = NPh2, R2 = N3; j R1 = NEt2, R2 = N3; k R1 = NPr2, R2 = N3; l R1 = N(Me)CH2Ph, R2 = N3; m R1 = NMePh, R2 = N3;
3 a R1 = NPh2, b R1 = NEt2; 4 a R1 = NPh2, R3 =Ac; b R1 = NEt2, R3 =Ac; c R1 = NPr2, R3 =Ac;d R1 = N(Me)CH2Ph, R3 =Ac;
e R1 = NPh2,R3 = COOEt; f R1 = NPr2, R3 = COOEt; g R1 = N(Me)CH2Ph, R3 = COOEt; h R1 = NMePh, R3 = COOEt
With an equimolar ratio of reagents the reaction time was increased from 1-2 to 2.5-4 h and the yield of
target products was lowered by 7-10%. The use of absolute toluene as solvent ensures good solubility of the
starting materials and a quite high reaction mixture temperature and leads to high (73-93%) yields of the target
products 2a-m. With the use of a lower boiling solvent (benzene) the reaction time is increased by 3-3.5 h. It
should be noted that carrying out the synthesis in glacial acetic acid in agreement with [6, 8] needs more
prolonged heating (up to 10 h). The yields of compounds 2a-h did not exceed 45-55% but those containing an
azide group 2i-m (Tables 1 and 2) were in fact less (up to 30%) and this is evidently associated with side
reactions which lead to rapid tarring.
340

341

342

343

A steric effect is also an important factor influencing the rate of this reaction. Hence the most reactive
are the amino-sym-triazines 1a,c,f,h which contain a low bulk substituent (OCH3, N(CH3)2 etc) at positions 4 or
6 of the triazine ring. The greatest reaction times were found in the case of the use of the starting compounds
1d,e which contain diphenylamine, piperidine, or morpholine substituents together. At the same time, and
against expectations, the presence of small volume acceptor groups which lower the nucleophilicity of the
amino group (nitrile or azide) markedly increase the rate of formation of the final products. Hence the 2-amino-
6-cyano(azido)-sym-triazines give the corresponding pyrrolyl-sym-triazines 2c,i-m in good yields (73-93%)
even after short (0.5-1 h) refluxing in toluene in the presence of P2O5. This is likely connected on one hand with
the absence of sterically hindering substituents in the composition of the starting materials and on the other with
the use of an aprotoic solvent. It will be recalled that the yields of compounds 2i-m do not exceed 30% when the
reaction is carried out in acetic acid medium (method B, Experimental section).
The composition and structure of the pyrrole sym-triazine derivatives 2a-m were confirmed by IR and
1H NMR spectroscopic and mass-spectrometric data.
The IR spectra of the mono(di)-N-pyrrolyl-sym-triazines 2a-m contain varying intensity maximum
absorptions at 1510-1625 cm-1 which are characteristic stretching vibrations of a sym-triazine ring [9] and
substituent in the 4,6 sym-triazine ring positions. The spectra of all of the synthesized compounds also show the
disappearance of broad absorption stretching bands in the region 3470-3270 cm-1 which are assigned to the
stretching of the primary amino groups in the sym-triazines 1a-m [10] (Table 1).
1
The H NMR spectra of the synthesized 1,3,5-triazines 2a-m show all of the proton signals for the
substituent groups in positions 4 and 6 of the triazine ring and this is a reliable confirmation of the structure of
the compounds obtained (Table 1). It was an interesting experimental fact that the signals for the H-2-5 protons
in the majority of the N-substituted pyrroles 1g, 2a-m, 3a,b, 4a-h appear as triplets with a spin-spin coupling of
2.3 Hz in the range 7.12-7.92 ppm and of intensity two proton units. The signals for the H-3 and H-4 protons in
the spectra of the compounds also appear as a triplet in the range 6.07-6.38 ppm, shifted to higher field and
typical of N-substituted pyrroles of this type [10].
The mass spectroscopic molcular ions observed in the spectra of compounds 2a-m also confirm their
structure.
With the aim of broadening the series of sym-triazine derivatives [2, 11] it was of interest to synthesize
iminotriphenylphosphoranes which also contain a pyrrole fragment in their structure. The 4-azido-2-(1H-1-
pyrrolyl)-1,3,5-triazines 2i,j were used as starting materials. The reactions were carried out in benzene solution
at 10-15ºC and their completion was monitored by the finish of nitrogen evolution.
The synthesized iminophosphorano-sym-triazines 3a,b (Tables 1 and 2) are colorless, fine crystalline
materials.
The IR spectra of compounds 3a,b show absorption bands in the region 1530-1615 cm-1 which are
characteristic of C=C stretching vibrations and, in comparison with the spectra of the starting azides 2i-m, the
disappearance of the characteristic azide group band at 2100-2105 cm-1.
The 1H NMR spectra of the compounds 3a,b also show characteristic signals for the protons of all of the
substituents in the sym-triazine ring and also multiplet signals for the protons of all three phenyl residues in
quite a narrow region (7.40-7.75 ppm) corresponding to fifteen proton units. The mass-spectroscopic data for
compounds 3a,b also confirm their structure.
Bearing in mind the high growth stimulating and antidotal activity [12, 13] of the triazine-triazole
biheterocyclic systems previously obtained by us [1, 2] it seemed reasonable to study the possibility of
preparing novel sym-triazine derivatives which contain triazole and pyrrole rings together.
With this in view we carried out the reaction of the pyrrolyl-sym-triazines 2i-m with acetylacetone and
acetoacetic ester in DMF solution in the presence of triethylamine. The target compounds 4a-h were obtained in
high (68-80%) yields (see Scheme and Tables 1 and 2).
344

TABLE 2. Physico-chemical Characteristics of Synthesized Compounds
1a-e,g,i-m, 2a-m, 3a,b, and 4a-h
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
H
4
N
5
1
2
3
6
7
C17H18N6
66.94
66.65
68.48
68.24
66.84
66.65
65.68
65.50
69.61
69.34
65.99
65.81
59.34
59.20
40.49
40.38
5.89
5.92
6.77
6.63
4.44
4.20
5.87
5.79
6.37
6.40
4.72
4.67
4.15
3.98
5.89
5.81
27.17
27.43
24.75
25.13
28.72
29.15
24.01
24.12
24.02
24.26
29.27
29.52
36.60
36.82
53.70
53.81
202-203
165
65
1a
1b
1c
1d
1e
1g
1i
C19H22N6
C16H12N6
C19H20N6O
C20H22N6
C13H11N5
C15H12N8
C7H12N8
70
186-187
202-203
211-212
153-154
147-148
121-122
110-111
98-99
86
73
68
76
80
83
1j
C9H16N8
45.55
45.75
51.70
51.56
7.00
6.83
4.87
4.72
47.25
47.42
43.55
43.72
71
1k
1l
C11H12N8
C14H12N8
C21H20N6
C23H24N6
C20H14N6
C23H22N6O
C24H24N6
C13H11N5
C17H13N5
C12H15N5O2
C19H14N8
C11H14N8
C13H18N8
C15H14N8
C14H12N8
C37H29N6P
C29H29N6P
C24H20N8O
C16H20N8O
76
49.68
49.58
70.64
70.76
71.71
71.85
71.13
70.99
69.50
69.32
72.54
72.70
65.68
65.81
70.93
71.06
55.01
55.16
64.45
64.40
50.90
51.15
54.27
54.53
54.27
54.53
57.30
57.53
75.58
75.49
70.66
70.71
4.28
4.16
5.74
5.66
6.37
6.29
4.03
4.17
5.62
5.57
6.15
6.10
4.77
4.67
4.47
4.56
5.89
5.79
4.07
3.98
5.70
5.46
6.67
6.34
4.82
4.61
4.30
4.14
4.80
4.96
6.01
5.93
46.04
46.26
23.49
23.58
22.00
21.86
24.71
24.84
20.97
21.09
21.33
21.20
29.54
29.52
24.49
24.38
26.70
26.81
31.58
31.62
43.72
43.38
39.45
39.13
36.85
36.58
38.40
38.83
14.35
14.28
17.00
17.06
177-178
168-170
116-117
214-215
173-174
142-143
153-155
185-187
89-90
70
1m
2a
2b
2c
2d
2e
2f
73 (method А)
82
91
85
77
76
79
85
93
77
72
73
77
87
80
75
80
2g
2h
2i
126-128
—*
2j
—
2k
2l
—*
104-105
185-186
156-157
240-241
135-136
2m
3а
3b
4a
4b
65.87
66.04
56.56
56.56
4.75
4.62
6.50
6.56
25.56
25.68
32.80
32.92
345

TABLE 2 (continued)
1
2
3
4
5
6
7
4c
C18H24N8O
C20H20N8O
C25H22N8O2
C19H26N8O2
C21H22N8O2
C20H20N8O2
58.55
58.68
61.80
61.84
64.21
64.36
57.16
57.27
60.35
60.27
59.22
59.39
6.50
6.56
5.27
5.19
4.60
4.75
6.66
6.58
5.44
5.30
5.08
4.98
30.53
30.42
28.99
28.85
24.18
24.02
28.01
28.12
26.83
26.78
27.86
27.71
95-96
71
71
73
70
68
78
4d
4e
4f
62-63
174-175
84-85
4g
4h
110-111
215-216
_______
* oil
It has been found that the rate of the reaction depends significantly on both the structure of the starting
azide and on the activity of the dicarbonyl compound. The presence of steric hindrance in the composition of the
starting azide increases the reaction time from 0.5-1 h to 10 h when the more active acetylacetone is used and to
48 h in the case of the acetoacetate ester [2].
The synthesized polyheterocyclic systems 4a-h are white, fine crystalline powders which show good
solubility in polar organic solvents and aromatic hydrocarbons. The purity of the compounds obtained was
confirmed using TLC and the composition and structure through the results of elemental analysis and from IR,
1H NMR, and mass-spectroscopic data (Table 1).
Hence we have studied the addition-cyclization reactions of different mono- and diamino sym-triazine
derivatives 1a-m with 2,5-dimethoxytetrahydrofuran. The dependence of the reaction time on the structure of
the substituent occurring in the composition of the amino-1,3,5-triazines and achievement of optimum
conditions (P2O5, toluene) for the synthesis of the N-substituted pyrrolyl-sym-triazines containing different
substituents are discussed.
As a result, a series of sym-triazine derivatives containing pyrrole, triazole, or iminophosphorane
fragments together and with high bioactivity potential has been prepared for the first time.
EXPERIMENTAL
IR spectra were recorded for sample suspensions in vaseline oil on a Specord IR-75 spectrophotometer.
1H NMR spectra were taken on a Bruker DRX-500 (500 MHz) radiofrequency spectrometer using DMSO-d6
and with TMS as internal standard. Mass spectra were recorded on a Finnigan MAT INCOS50 instrument with
70 eV ionization energy. Elemental analysis of the synthesized compounds was carried out on a Carlo-Erba
1106 analyzer. Monitoring of the reaction course and the purity of the products obtained was carried out using
TLC on Silufol UV-254 plates with acetone–hexane (1:1) as eluent.
All of the reagents used were purified by crystallization from a suitable solvent or fractionally distilled
immediately before use. Solvents were purified and dried by known methods [14].
4-Dimethylamino-6-diphenylamino-2-(1H-1-pyrrolyl)-1,3,5-triazine (2a). A. A suspension of
2-amino-4-dimethylamino-6-diphenylamino-1,3,5-triazine 1a (1.0 g, 3.26 mmol), P2O5 (0.46 g, 3.26 mmol), and
absolute toluene (10 ml) was heated to reflux and 2,5-dimethoxytetrahydrofuran (0.51 g, 3.91 mmol) was added
with stirring. The reaction product was refluxed for 1.5-2 h, cooled and then filtered, and the filtrate was
evaporated to dryness. The residue was washed with water, dried to constant weight, dissolved in methylene
346

chloride (10-15 ml), and passed through a silica gel column (1 cm, LC 5/40 µ grade). Additional purification
was carried out by crystallization from ethanol. Yield of compound 2a 0.85 g (73%).
Compounds 2b-i were prepared similarly. The end of the reaction was determined by TLC in each
specific case.
B. A solution of compound 1a (1.0 g, 3.26 mmol) in glacial acetic acid (8 ml) was heated to reflux and
2,5-dimethoxytetrahydrofuran (0.51 ml, 3.91 mmol) was added with stirring. The reaction product was refluxed
for 3-3.5 h, cooled, and diluted with cold water (30 ml). The precipitate formed was separated, washed with
water to neutral reaction of sparge water, and dried. Purification by method A gave the product compound 2a
(0.55 g, 47%).
4-Diethylamino-2-(1H-1-pyrrolyl)-6-(1,3,5-triazin-2-yl)-iminotriphenylphosphorane (3b). Triphenyl-
phosphine (1.01 g, 3.87 mmol) was added in small portions to a stirred solution of 6-azido-4-diethylamino-
2-(1H-1-pyrrolyl)-1,3,5-triazine 2j (1.0 g, 3.87 mmol) in absolute benzene (15 ml). The reaction product was
stirred to the completion of gas bubble formation and left overnight at room temperature. The precipitate formed
was filtered off and the mother liquor was evaporated to give an additional amount of product. The precipitates
were combined, washed with cold hexane, and dried in air to constant weight. Purification by crystallization
from ethanol gave compound 3b (1.33 g, 80%) as white crystals.
Compound 3a was prepared under the same conditions.
6-(4-Acetyl-5-methyl-1,2,3-triazol-1-yl)-4-dipropylamino-2-(1H-1-pyrrolyl)-1,3,5-triazine (4c). A
solution of acetylacetone (0.72 ml, 6.98 mmol) and triethylamine (0.97 ml, 6.98 mmol) in dry DMF (5 ml) was
added dropwise to a solution of 6-azido-4-dipropylamino-2-(1H-1-pyrrolyl)-1,3,5-triazine 2k (1.0 g, 3.49 mmol)
in DMF (10 ml) stirred at room temperature. The reaction product was stirred at the same temperature for 3 h
and then introduced as a fine jet with stirring into cold water (100 ml). The precipitate of the target product was
filtered off, repeatedly washed with water, and dried to give compound 4c (0.91 g, 71%). The product did not
need further purification.
Compounds 4a,b,d were prepared similarly.
4-Dipropylamino-6-(4-ethoxycarbonyl-5-methyl-1,2,3-triazol-1-yl)-2-(1H-1-pyrrolyl)-1,3,5-triazine
(4f). A solution of acetoacetic ester (0.89 ml, 6.98 mmol) and triethylamine (0.97 g, 6.98 mmol) in DMF (5 ml)
was added to a solution of 4-dipropylamino-6-azido-2-(1H-1-pyrrolyl)-1,3,5-triazine 2k (1.0 g, 3.49 mmol) in
dry DMF (10 ml) with stirring at room temperature. The reaction product was stirred at 30-40ºC for 48 h and
treated similarly to compound 4c to give the target product 4f (0.97 g, 70%) which did not need further
purification.
Compounds 4e,g,h were synthesized similarly.
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