A practical and easy synthesis of 2,4,6-trisubstituted-s-triazines

Article abstract of DOI:10.1055/s-2004-815927

Triflic anhydride was found to be efficient for the cyclotrimerization of dialkylcyanamides under mild conditions. The same reaction can be applied to aryl nitriles and thiocyanates.

Full text of DOI:10.1055/s-2004-815927

SHORT PAPER
503
A Practical and Easy Synthesis of 2,4,6-Trisubstituted-s-triazines
A
P
ractica
l
and Ea
n
sy
S
ynthesis
t
of 2,4,
o
6-Trisubstitu
n
ted-
s
-triazine
i
s
o Herrera,a Roberto Martínez-Alvarez,*a Pedro Ramiro,a Mourad Chioua,a Rachid Chiouab
a
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Complutense, 28040 Madrid, Spain
Fax +34(91)3944103; E-mail: rma@quim.ucm.es
b
Departement de Chimie, Faculté des Sciences, Université Abdelmalek Essaâdi, Tétouan, Morocco
Received 21 November 2003; revised 5 January 2004
R1
N
R1
N
Abstract: Triflic anhydride was found to be efficient for the cyclo-
trimerization of dialkylcyanamides under mild conditions. The
same reaction can be applied to aryl nitriles and thiocyanates.
N
R2
R2
R1
R2
Tf2O / CH2Cl2
N
CN
N
N
Key words: s-triazines, cyanamides, triflic anhydride, cyclotrimer-
ization, Lewis acid
N
R2
R1
1
2
Scheme 1
Triazine derivatives are interesting compounds with bio-
logically important properties1–3 and are also recognized
to be powerful chelating agents which can be used as liq-
uid crystals,4 metal complexes,5 and as new hydrogena-
tion catalyts.6 However, despite a growing interest, there
are some problems in the practical preparation of them.
The common methods leading to s-triazines include oxi-
dation of aromatic aldehydes and cyclotrimerization of ni-
triles. The first involves long reaction times and achieves
low yields7 while the latter needs rather harsh conditions
of pressure (1000 atm) and temperature (200 ºC).8,9 Lan-
thanum and yttrium triflate have been found to catalyze
the reaction between ammonia and aromatic nitriles to af-
ford 2,4,6-triaryl-s-triazines at lower pressure although
high temperatures are necessary to carry out the process.10
Samarium iodide catalyzes the cyclotrimerization of aryl
nitriles.11 The use of hexylamine as co-catalyst permits
the use of milder reaction conditions.12 Different Brønsted
and Lewis acids and mixtures of them have been em-
ployed to promote the cyclotrimerization of nitriles and
cyanamides.9 Strong bases are also used in this reaction
but the conditions would destroy other functional groups
present in the system.9 Both acidic and basic conditions
require high pressure as well high temperature. On the
other hand, 2,4,6-tris-(dialkylamino)-s-triazines are usu-
ally prepared directly by refluxing cyanuric chloride with
varying excesses of the corresponding dialkylamines in an
appropriate solvent.13
It is reported that dimethylcyanamide reacts with triflic
anhydride forming an unstable isourea derivative, which
undergoes a Chapman rearrangement affording a bistri-
flylurea 315 (Scheme 2)
We have found that when dialkylcyanamides 1a–d were
reacted with triflic anhydride in dichloromethane at room
temperature, the corresponding s-triazines 2a–d were iso-
lated in good yield (Table 1).
Table 1 Cyclotrimerization of Dialkylcyanamides 1
Entry
R1, R2
Conditions Product 2 Yield (%)
1
2
3
4
CH3
r.t., 12 h
r.t., 12 h
r.t., 12 h
r.t., 12 h
2a
2b
2c
2d
67
81
89
73
-(CH2)5-
-(CH2)2-O(CH2)2-
-(CH2)4-
The reaction involves the formation of the bistriflyl-
isourea intermediate 3,15 which reacts quickly with two
molecules of cyanamide affording the triazine 2
(Scheme 2).
R1
R2
OTf
Tf2O
R1
R2
N
C
N
CN
N-Tf
3
1
Quite recently, we have reported that the synthesis of py-
rimidines from ketones and cyanamides in the presence of
triflic anhydride lead to the formation of triazines instead
to the expected pyrimidines.14 Herein, we describe a facile
and efficient one-pot reaction for the preparation of 2,4,6-
tris-(dialkylamino)-s-triazines 2 which involves the cy-
clotrimerization of dialkylcyanamides 1 in the presence of
triflic anhydride (Scheme 1).
2 x 1
R1
N
R1
N
N
R2
R2
N
N
N
R2
R1
2
SYNTHESIS 2004, No. 4, pp 0503–0505
x
x
.
x
x
.2
0
0
4
Advanced online publication: 26.01.2004
DOI: 10.1055/s-2004-815927; Art ID: T12403SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

504
A. Herrera et al.
SHORT PAPER
2,4,6-Trimorpholin-4-yl-1,3,5-triazine (2c)
White powder; yield: 89%; mp 263–264 ºC (EtOH).
and thiocyanates with triflic anhydride. Thus, acetonitrile IR (KBr): 2960, 2858, 1544, 1479 cm–1.
In order to extend this synthetic procedure to other classes
of nitriles, we have investigated the reaction of alkyl, aryl,
1H NMR (300 MHz, CDCl3): = 3.10–3.17 (m, 12 H, CH2N), 3.58–
3.66 (m, 12 H, CH2O).
13C NMR (75.47 MHz, CDCl3): = 48.7 (CH2N), 65.5 (CH2O),
165.2 (C arom).
4a, benzonitrile 4b, and methylthiocyanate 4c, as model
compounds, afford the corresponding s-triazines 5. Reac-
tion conditions and yields are collected in Table 2.
Table 2 Cyclotrimerization of Nitriles
MS (EI): m/z (%) = 336 (M+·,100), 306 (M – CH2O, 78), 279 (54).
R
N
R
Tf2O
Anal. Calcd for C15H24N6O3: C, 53.56; H, 7.19; N, 24.98. Found: C,
53.19; H, 7.25; N, 24.24.
R-CN
N
N
CH2Cl2
R
2,4,6-Tripyrrolidin-1-yl-1,3,5-triazine (2d)
White needles; yield: 73%; mp 178–179 (EtOH).
4
5
IR(KBr): 2930, 2850, 1535, 1480 cm–1.
Entry
R
Conditions Product 5
Yield a (%)
1H NMR (300 MHz, CDCl3): = 1.83–1.91 (m, 12 H, CH2), 3.48–
3.56 (m, 12 H, CH2N).
13C NMR(75.47 MHz, CDCl3): = 25.3 (CH2), 45.8 (CH2N), 163.2
(C arom).
1
2
3
CH3
C6H5
CH3-S
r.t., 12 h
r.t., 12 h
r.t., 12 h
5a
5b
5c
89
91
88
MS (EI): m/z (%) = 288 (M+·,100), 260 (M – C2H4, 85), 232 (42),
219 (M – C4H7N, 25).
In conclusion, we have disclosed a practical synthesis of
trisubstituted s-triazines from easily available starting ma-
terials under mild conditions. In light of its operational
simplicity and efficiency, this reliable method is expected
to have a broad utility due to the scope of applications of
the s-triazines.
Anal. Calcd for C15H24N6: C, 62.47; H, 8.39; N, 29.14. Found: C,
62.88; H, 7.99; N, 28.93.
2,4,6-Trimethyl-1,3,5-triazine (5a)
White needles; yield: 89%; mp 54–55 ºC (purified by vacuum sub-
limation).10
IR (KBr): 1548, 1436 cm–1.
1H NMR (300 MHz, CDCl3): = 2.54 (s)
13C NMR (75.47 MHz, CDCl3): = 25.4 (CH3), 175.9 (C arom).
MS (EI): m/z (%) = 123 (M+·,100), 108 (M – CH3, 85).
Reaction of Cyanamides and Nitriles with Triflic Anhydride;
General Procedure
Tf2O16 (0.5 g, 1.7 mmol) was added to a solution of the correspond-
ing cyanamide 1a–d (5.1 mmol) or nitrile 4a–c (5.1 mmol) in
CH2Cl2 (20 mL) and stirred for 12 h at r.t. The reaction mixture was
carefully neutralized with aq sat. soln of NaHCO3. After extraction
with CH2Cl2 (3 × 50 mL), the combined extracts were washed with
brine and dried (MgSO4). Evaporation of the solvent provided a sol-
id, which was recrystallized twice from the appropriate solvent.
2,4,6-Triphenyl-1,3,5-triazine (5b)
White powder; yield: 91%; mp 230–231 ºC (CHCl3–EtOH).10
IR (KBr): 1522, 1367, 743, 683 cm–1.
1H NMR (300 MHz, CDCl3): = 7.53–7.64 (m, 9 H), 8.77–8.82 (m,
6 H).
13C NMR (75.47 MHz, CDCl3): = 128.6, 129.0, 132.5 (CH arom),
136.2, 171.6 (C arom).
MS(EI): m/z (%) = 309 (M+·,57), 103 (C7H5N, 100).
N,N,N ,N ,N ,N -Hexamethyl-1,3,5-triazine-2,4,6-triamine (2a)
White powder; yield: 67%; mp 174–175 ºC (EtOH).
IR (KBr): 2885, 1370 cm–1.
1H NMR (300 MHz, CDCl3): = 3.25 (s, CH3N).
13C NMR (75.47 MHz, CDCl3): = 40.0 (CH3N), 159.6 (C arom.).
MS (EI): m/z (%) = 210 (M+·,100), 195 (M – CH3, 63).
2,4,6-Tris(methylthio)-1,3,5-triazine (5c)
Pale yellow powder; yield: 88%; mp 175–176 ºC (EtOH).
IR (KBr): 1481, 1244 cm–1.
1H NMR (300 MHz, CDCl3): = 2.52 (s, SCH3).
13C NMR (75.47 MHz, CDCl3): = 13.3 (SCH3), 179.7 (C arom).
MS (EI): m/z (%) = 219 (M+·,100), 204 (M – CH3, 12), 158 (54).
Anal. Calcd for C9H18N6: C, 51.41; H, 8.63; N, 39.97. Found: C,
51.22; H, 8.77; N, 39.58.
2,4,6-Tripiperidin-1-yl-1,3,5-triazine (2b)
Anal. Calcd for C6H9N3S3: C, 32.85; H, 4.14; N, 19.16; S, 43.86.
Found: C, 32.33; H, 3.88; N, 18.88; S, 43.11.
White needles; yield: 81%; mp 215–216 ºC (EtOH).
IR (KBr): 2931, 2848, 1533, 1481 cm–1.
1H NMR (300 MHz, CDCl3): = 1.50–1.65 (m, 18 H, CH2), 3.65–
3.75 (m, 12 H, CH2N).
Acknowledgment
13C NMR (75.47 MHz, CDCl3): = 25.1, 25.8 (CH2), 44.1 (CH2N),
165.3 (C arom).
MS (EI): m/z (%) = 330 (M+·, 100), 301 (M – C2H5, 91), 247 (M –
This work has been supported by the DGESIC (Spain, Grant
BQU2002-00406). R. Chioua thanks the AECI (Spain) for a fel-
lowship (PR 120/00-8980). We also thank CAIs of UCM (Madrid,
Spain) for determining NMR, MS, and CHN analysis.
C5H9N, 75).
Anal. Calcd for C18H30N6: C, 65.42; H, 9.15; N, 25.43. Found: C,
65.28; H, 8.99; N, 24.83.
Synthesis 2004, No. 4, 503–505 © Thieme Stuttgart · New York

SHORT PAPER
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