An efficient, "green" approach to aryl amination of cyanuric chloride using acetic acid as solvent

Article abstract of DOI:10.1002/jhet.5570450236

(Chemical Equation Presented) Acetic acid is an inexpensive and environmentally friendly solvent for facile, clean and high-yielding aryl amination of cyanuric chloride with aromatic amines, including nitroanilines. Aryl animation in acetic acid medium and isolation protocol are greatly simplified as compared to previously reported procedures. Under proper conditions, it is possible to attach the same or different aniline residues in a controlled way to obtain in excellent yields symmetrical and unsymmetrical 1,3,5-triazine derivatives, respectively.

Full text of DOI:10.1002/jhet.5570450236

Mar-Apr 2008
533
An Efficient, “Green” Approach to Aryl Amination of Cyanuric
Chloride Using Acetic Acid as Solvent
Kirill A. Kolmakov∗
Department of Chemistry, University of Toronto, 80 St. George St., Toronto, Ontario, M5S 3H6, Canada.
E-mail: kkolmako@chem.utoronto.ca
Received August 7, 2007
Cl
N
Cl
2 ArNH2
Ar-HN
N
Cl
Ar-HN
ArNH2
N
NH-Ar
N
N
N
N
N
N
AcOH,r.t.,
AcONa
AcOH, reflux
~ 90%
NH-Ar
74 - 96%
Cl
NH-Ar
3 ArNH2
(Including Ar = 2- or 4- NO2(C6H4))
AcOH, no base, reflux, 15 - 30 min
Acetic acid is an inexpensive and environmentally friendly solvent for facile, clean and high-yielding
aryl amination of cyanuric chloride with aromatic amines, including nitroanilines. Aryl amination in acetic
acid medium and isolation protocol are greatly simplified as compared to previously reported procedures.
Under proper conditions, it is possible to attach the same or different aniline residues in a controlled way to
obtain in excellent yields symmetrical and unsymmetrical 1,3,5-triazine derivatives, respectively.
J. Heterocyclic Chem., 45, 533 (2008).
published routes [1-6] to aminated 1,3,5-triazine rings
have employed toxic organic solvents such as 1,4-dioxane
or dimethylforamide (DMF).
INTRODUCTION
It has been known for 60 years that amines react with
cyanuric chloride (2,4,6-trichloro-1,3,5-triazine (1,
Scheme I)), providing access to amine-functionalized
1,3,5-triazine compounds [1]. 1,3,5-Triazine rings with
aryl amine substituents (e.g., 2 and 3, Scheme I) are of
particular interest because many of these compounds are
biologically active [2]. Also, compounds with the general
Scheme I
Aryl Amination of Cyanuric Chloride (1) with Aromatic Amines in
Acetic Acid Medium
Cl
N
Cl
Ar-HN
2 ArNH2
N
Cl
Ar-HN
ArNH2
N
NH-Ar
structure
3 (Scheme I) are potentially useful as
N
N
1
N
N
N
N
AcOH, r.t.,
AcONa.
AcOH,
reflux
inexpensive and non-toxic UV-absorbents [3] and
pigments [4]. Finally, dendritic polymers, with potential
materials applications, can be built from aromatic amine-
functionalized 1,3,5-triazine rings [5].
3a-g
2a-g
Cl
NH-Ar
NH-Ar
ArNH2
AcOH,
H2O,
3 ArNH2, AcOH, no base, reflux, 15 min
Ar = C6H5 (2a, 3a),
Despite the merits of 1,3,5-triazine molecules with two
or three aryl amine groups attached to the ring, existing
syntheses of such compounds leave much to be desired.
Compared to the reactions of aliphatic amines (AlkNH2),
[2,3] amination of 1 with less nucleophilic aromatic
amines (anilines, ArNH2) is more difficult to achieve,
especially if trisubstituted (3) products are desired [3,9].
The difficulty is exacerbated if the aromatic group of the
amine bears an electron-withdrawing group (e.g., 4-
nitroaniline, 4-NO2(C6H4)NH2), which further decreases
the nucleophilicity of the amine. Thus, established
synthetic routes to molecules of type 2 and 3 (Scheme I)
generally involve long reaction times, elevated
temperatures [1c] and give moderate yields after
purification [5]. Further, all reported amination reactions
of compound 1 utilize bases (normally heterogeneous) to
remove hydrogen chloride generated as a byproduct,
which complicates isolation of the aminated product.
No “green” (environmentally innocuous) syntheses of
these compounds have been reported: previously
~15oC
4-Me(C6H4) (2b, 3b),
4-MeO(C6H4) (2c, 3c),
2-F(C6H4) (2d, 3d),
Cl
N
Cl
Ar'NH2
Ar'-HN
N
Cl
N
N
5
2-NO2(C6H4) (2e, 3e)
4-NO2(C6H4) (2f, 3f),
4-CO2H(C6H4) (2g,3g).
Ar = C6H5 (4, 5, 6a,b),
Ar' = 4-Me(C6H4) (6a),
Ar' = 4-NO2(C6H4)(6b).
N
N
AcOH, r.t.,
AcONa.
6a,b
NH-Ar
NH-Ar
AcOH
reflux
ArNH2
Ar-NHCOCH3
4
In 2003, Sha and Dong [3] reported that the aryl
amination reactions of 1 are drastically accelerated by
microwave radiation, such that compounds of type 3 can
be obtained in greatly reduced reaction times, compared
to conventional approaches. As an illustrative example, it
was claimed that 1 reacts with 3 equiv of 4-nitroaniline to
give product 3f (Ar = 4-NO2(C6H4), see Scheme I/Table 2
for structures) in minutes, while a previously reported
synthesis (see below) of this compound required hours at
elevated temperatures [5] to obtain complete reaction [1c].

534
K. Kolmakov
Vol 45
While microwave-assisted routes to 2 and 3 might be
promising, there are some drawbacks to the approach of
Sha and Dong. For instance, microwave-assisted
syntheses do not allow the selective formation of mono-
(5) and diaminated (2) products; the triaminated products
(3) form quickly to the exclusion of partially substituted
derivatives. Also, isolation of aminated products requires
(a) removal of high-boiling solvents (DMF or dioxane)
under reduced pressure, (b) extraction of the solid residue
with water to remove NaCl and NaHCO3, and (c)
recrystallization. It should be reiterated that similarly
difficult purification procedures are common to all
previously reported syntheses of aryl amine-
functionalized 1,3,5-triazine compounds, where high-
boiling solvents and HCl acceptors are required. Finally,
the authors did not provide NMR spectroscopic data for
compound 3f and reported a melting point range of 154-
160°C. Compound 3f was originally made by Takagi and
co-workers [5] by refluxing 1 and 4-NO2(C6H4)NH2 in
dioxane for 17 h, in the presence of K2CO3. The isolated
reagents are generated in the course of solvent-free
reactions, which must be separated from unreacted aniline
(used in excess) and aminated products.
Having ruled out solvent-free protocols, we began the
search for a new solvent for the aryl amination reactions
of 1. In our view, amination of 1 is a special case of
nucleophilic aromatic substitution. Polar solvents
normally favor this type of reaction [8]. However,
converting 1 to its trisubstituted aryl amine derivatives
(compounds of type 3) is generally slow [1c] in
conventional polar (and toxic) organic solvents such as
DMF, THF, and dioxane [5], even at elevated
temperature. Note that DMSO, a polar and high-boiling
solvent, reacts vigorously [9] with 1 and, therefore, can be
ruled out as a solvent for these amination reactions. In the
context of “green” solvents, water is an obvious choice,
especially when high polarity is desired. However, water
is also unsuitable as a solvent for these aryl amination
reactions because the C-Cl bonds of 1 undergo hydrolysis
[1c] at rates competitive with the desired amination
reactions [10]. Also, the low solubility of the aniline
reagents and the aminated products, led to further
complications when water was used as solvent.
1
compound was characterized by H NMR spectroscopy
and was reported to have a melting point (presumably
with decomposition) above 300°C. Our NMR data and
melting point range for compound 3f, synthesized by our
new method (see below), agree with those presented by
Takagi et al [5]. In light of these discrepancies, the
efficacy of the microwave-assisted synthesis of 3f is
subject to scrutiny.
As shown above, potential solvents for the aryl
amination reactions of 1 should be polar and high-boiling
in order to facilitate the second or third substitution steps.
Ideally, the solvent would also be inexpensive and
inoffensive to the environment (i.e., “green”).
With these considerations in mind, we tested
CH3COOH/CH3COONa as a solvent system for the aryl
amination of 1, where acetic acid would serve as solvent
and sodium acetate would act as an acceptor of HCl.
Initial results showed aryl amination of 1 does, indeed,
occur in this medium. In fact, we discovered that the
reaction in acetic acid proceeds even in the absence of
CH3COONa. Further, an excess of ArNH2, which could
potentially serve as an HCl acceptor, is not required.
Upon combination of 1 with aromatic amines, reaction
occurs immediately, as evidenced visually by the
evolution of HCl. The progress of the reactions was
monitored by TLC or HPLC. While mono- (5) and
disubstituted (2) aryl amine derivatives of 1 are readily
formed at or below room temperature, we found it
necessary to heat (100°C) the reaction mixtures to obtain
trisubstituted aryl amine species (3). For example, in the
reaction between 1 and 3 equiv of aniline, conversion to
trisubstituted 3a (Ar = Ph) was not complete (60-70 %
conversion) after 24 h at ambient temperature (20-25°C).
However, 3a was formed in high yield (up to 96%,
isolated, see Table 1 and Experimental Section) by
heating the reaction mixture to reflux (118°C) for 15 min
or for 30 min at 100 °C. Table 1 compares the reactions of
1 with aniline (PhNH2) or less reactive 2-nitroaniline (2-
NO2(C6H4)NH2)) in various solvents. Note that, in
contrast to conventional approaches, we did not use base
Our goal was to develop a new, more efficient approach
to aryl amination of cyanuric chloride (1) with various
aromatic amines in a controlled fashion. In particular, we
sought to reduce reaction times, especially for the final
third stage of substitution, simplify product isolation and
increase yields. Also, we were motivated to find green,
cost-effective routes to symmetrical and unsymmetrical
aminated 1,3,5-triazine compounds, which are amenable
to large-scale industrial processes. In this regard,
protocols that do not require solvent, or that use non-
toxic, inexpensive solvent(s), are particularly desirable.
RESULTS AND DISCUSSION
We first investigated solvent-free methods to generate
amine-functionalized 1,3,5-triazine products but found
this approach to be unfeasible. Problems with solvent-free
syntheses include the large exotherms associated with
amination of 1, which pose safety concerns, especially
when large-scale reactions are considered. Also, we found
it impossible to achieve selectivity, with regard to the
degree of amine substitution (i.e., mixtures of mono- (5),
di- (2) or tri-substituted products (3) were generated), in
the absence of solvent. Further complications arise when
the aniline starting material is a high-melting solid, or
when high-melting solids are generated by the first or
second substitution step. Finally, HCl salts of the aniline

Mar-Apr 2008
Aryl Amination of Cyanuric Chloride Using Acetic Acid as Solvent
535
(to accept HCl) in these reactions. It is seen that, in all of
the reactions examined, conversion to trisubstituted
products (3a or 3e) is fastest in acetic acid, compared to
conventional, high-boiling organic solvents. The
advantage of using acetic acid is more pronounced in the
reactions of less nucleophilic 2-nitroaniline.
observe the precipitation of HCl salts of aryl amine
reagents in the course of amination of 1. Presumably, the
formation of aryl amine hydrochlorides is reversible in
acetic acid. It is known that the acid strength of HCl is
considerably lower in acetic acid medium than in water
[8,11]. Also, the HCl salts are very likely to possess
high solubility in polar protonic solvents. Note that the
basicity of amino groups in compounds 2, 3, 5 and 6 is
considerably decreased when attached to the 1,3,5-
triazine core because of the electron withdrawing nature
of this group. Hence, the aminated products, generated
by amination of 1, are not expected to be protonated by
HCl to a significant extent [10]. As a result, yields are
not negatively affected.
Table 1
Aryl Amination of Cyanuric Chloridea 1 in some high-boiling solvents at
100°C in the absence of base.
Yields b (%) of Compounds 3a or 3ec
(See Scheme I) in Reaction of 1 with 3 equiv of:
Solvent
Aniline
2-Nitroaniline
In our study, we investigated seven anilines, with a
range of electronic properties, as substrates for the
amination of 1 in acetic acid. For all seven substrates,
including 4-aminobenzoic acid, 2- and 4-nitroanilines, we
were able to selectively synthesize both di- (2a-g) and tri-
substituted (3a-g) aryl amine 1,3,5-triazine compounds
(Table 2) in high yields. As stated above, both of these
classes of molecules are of interest for biological and/or
Acetic acid
DMF
1,4-Dioxane
1-Butanol
Toluene
93
68
43
25
22
73
22
15
12
9
a – 3 equiv (3 mmol) of the aniline were added to 1 equiv
(1 mmol) of 1 in the solvent (5 ml of 0.2 M solution) and then heated
for 30 min at 100°C (no base added).
b – The yields of 3 were evaluated with 5 % accuracy by HPLC.
c – the rest of the chloride 1 formed disubstituted products 2.
materials applications. Compounds of type
2 are
interesting reagents for combinatorial syntheses because
they contain a reactive functional group CCl. Another
reason to prepare compounds 2 was that, since the final
third stage of substitution in 1 is normally difficult to
achieve [1,5], we needed authentic samples of di-
substituted compounds to check the purity of the
corresponding tri-substituted compounds (3) by means of
chromatographic analysis and spectroscopic study (see
Experimental Section for details). Additionally, as
reagents for possible combinatorial syntheses, other two
new compounds of type 2 were prepared from 2,4- and
3,5-dimethylanilines (2h and 2i, respectively).
Clearly, if acetic acid is to be used as a solvent for the
aryl amination reactions of 1, then 1 must be reasonably
stable in this medium. That is, if acetic acid induces
cleavage of the C-Cl bonds in 1, the rate of the
decomposition pathway (solvolysis) must be much
smaller than the rate of the desired amination reactions.
It was reported [1c] that 1 undergoes solvolysis when
refluxed in a large excess of acetic acid. However, we
found that 1 is stable in acetic acid at room temperature;
1
the H or 13C NMR spectra of 1 in CD3COOD solution
Of the substrates examined in the aryl amination
reactions of 1, nitro-substituted anilines (2-NO2(C6H4)NH2
and 4-NO2(C6H4)NH2) were the least reactive, as expected
on the basis of their decreased nucleophilicity. The
challenge in synthesizing compounds 2e and 3e (Ar =
2-NO2(C6H4)) from 2-nitroaniline is related to the low
nucleophilicity of the aniline substrate (2-
NO2(C6H4)NH2), which is impeded not only by the
electron-withdrawing effect of the nitro group but also by
steric hindrance in the vicinity of the nitrogen atom (see
Table 1 for structures). It should be noted that compounds
2e and 3e (Ar = 2-NO2(C6H4)) have not been reported
are invariant over 2 days at ambient temperature. When
solutions of 1 are heated to reflux (118°C, 1 h) in acetic
acid, solvolysis gives 70-80 % conversion to acetyl
chloride and cyanuric acid (identified by mass
spectrometry). Further experiments established that
solvolysis of 1 is negligible, even at high temperatures,
if a nucleophile, such as ArNH2, is present, because
amination occurs at a larger rate than the decomposition
pathway. Another concern was the potential reactivity of
hydrogen chloride (generated upon amination of 1)
towards acetic acid and aniline substrates. N-Acetyl
anilines (4) were formed only in trace amounts; we
propose that these acylated byproducts arise from the
slight excess (5-10%) of aniline reagents used in
preparative scale syntheses of compounds of type 3.
Indeed, aniline forms N-acetyl aniline 4 (Ar = Ph) with a
high yield (> 80%) when refluxed in a large excess of
acetic acid for 1 h in the absence of cyanuric chloride 1
(Scheme I). Perhaps most importantly, we did not
previously, while
a considerable amount of other
compounds of types 2 and 3, with a wide range of
substituents in benzene rings, have been synthesized by
conventional methods [2]. Having obtained good results
with the least reactive amine, we believe that, apart from
the representative substrates (Table 2), our approach can
be extended to aromatic amines of greater diversity.

536
K. Kolmakov
Vol 45
Table 2
with boiling water to remove the acetic acid. As seen in
Table 2, isolated yields for all compounds range from
good to excellent, for the reactions conducted in acetic
acid. Even though the second and the third steps of the
substitution do proceed in the absence of bases, as we
established, better isolated yields of compounds 2 were
achieved when sodium acetate was used as HCl acceptor,
and some water was added to assist product precipitation
and thus omit recrysctallization from suitable solvents.
Aryl Amination of Cyanuric Chloride 1 with Aromatic Amines in Acetic
Acid Medium.
Product structure
Compd
Ar
Yielda,
(%),
Method
№
Ac Bd
2ab
2bb
2cb
2db
2e
2fb
2gb
2h
C6H5
4-CH3(C6H4)
4-CH3O(C6H4)
2-F(C6H4)
2-NO2(C6H4)
4-NO2(C6H4)
4-CO2H(C6H4)
2,4-Di-CH3(C6H3)
3,5-Di-CH3(C6H3)
96 65
94 74
97 67
92 62
29 68
76 72
74 69
95 70
93 76
(Compare conditions for Methods
A
and
B
in
Ar-HN
N
Cl
Experimental Section). Method A, which utilizes
CH3COONa, requires shorter time to complete the
reactions and, as seen in Table 2, gives better yields for all
the aniline substrates, except 2-nitroaniline. In fact, both
procedures are homogeneous, and crystalline solids start
to precipitate soon after the reagents are combined. In
Method A, sodium chloride (byproduct) remains in the
solution.
N
N
NH-Ar
2i
3ab
3bb
3c
93
96
94
89
86
92c
88
C6H5
Ar-HN
N
NH-Ar
4-CH3(C6H4)
4-CH3O(C6H4)
2-F(C6H4)
2-NO2(C6H4)
4-NO2(C6H4)
4-CO2H(C6H4)
Meanwhile, we found that the final third stage of
substitution in 1, when performed in acetic acid, is very
slightly influenced by the addition of CH3COONa or
pyridine. As we expected, all the di-substituted
compounds 2 formed the corresponding tri-substituted
compounds 3 with high (≥ 90%) yields simply upon
heating (118°C) with 1 equiv of the corresponding aniline
substrates in acetic acid for 15 min (Scheme I). Clearly, it
is more convenient to prepare compounds 3 straight from
cyanuric chloride (1) by heating it with 3 equiv of the
aniline substrates in acetic acid to reflux (see
Experimental Section for General Procedure).
3db
3e
N
N
NH-Ar
3fb
3gb
Ar / Ar'
6ab
C6H5 /
4-CH3(C6H4)
Ar-HN
N
Cl
98
91
N
N
C6H5 /
4-NO2(C6H4)
NH-Ar'
6b
a – yields refer to isolated products with purity ≥ 98% (HPLC).
b – known compounds; see ref. [3,5,6,12]. c − see Expt. Section
for details. d − yields after recrystallization.
In addition to compounds of type 2 and 3, where the
aryl amine groups attached to the 1,3,5-triazine scaffold
are identical, we were able to apply our acetic acid
method to the syntheses of unsymmetrical 6-chloro-N,N'-
diaryl-[1,3,5]triazine-2,4-diamines (type 6). With three
different groups (CCl, NHAr and NHAr') on the 1,3,5-
triazine moiety, these molecules are very interesting for
combinatorial applications; again, it should be possible to
generate libraries of new amine-substituted 1,3,5-triazines
with potential biological activity and/or materials
applications. We made these unsymmetrical species (type
6) by installation of a single aryl amine group of the
triazine ring, to give compounds of type 5, followed by
another aryl amine substitution step to generate molecules
with the general structure 6. We found that both
substitution steps can be accomplished in acetic acid, with
The compounds synthesized in this study are
summarized in Table 2. All products were characterized
by 1H/13C NMR, and IR spectroscopy, high resolution
mass spectrometry and by melting point determination. In
addition, elemental analyses were done to all new
compounds. Our melting point data for known
compounds (2a, 2b, 2c, 2d, 2f, 2g, 3a, 3b, 3d, 3f, 3g, and
6a) agreed with literature reports [3,5,6,12]. As seen in
Experimental Section, one can easily distinguish the tri-
substituted derivatives (3) from the di-substituted ones (2)
by means of 13C NMR spectroscopy. In particular, for
compounds 2, the characteristic signals belonging to
carbon atoms C6, attached to the chlorine (see Table 2 for
structures), were observed in the low-field (163 – 165
ppm) area. Despite the informativity nature of the method,
none of those compounds has been characterized by 13C
NMR spectroscopy so far. Products of type 2, 3 and 6
were conveniently isolated by filtration; in all cases these
species are only sparingly soluble in acetic acid. Thus,
purification requires only washing the solid precipitates
high selectivity/yields, as seen in Table
2
(see
Experimental Section for conditions). While mono-
substituted compounds 5 are accessible by classical
procedures (via temperature-controlled reactions between
1 and ArNH2 in acetone/water [1]), our alternative
syntheses in acetic acid have the advantages of higher
yields and greater ease of work-up.

Mar-Apr 2008
Aryl Amination of Cyanuric Chloride Using Acetic Acid as Solvent
537
uncorrected. Acetic acid (Aldrich, ACS reagent grade, 99.7%)
was freshly distilled and subjected to fractional crystallization
for initial experiments. Later, in all the procedures described
below acetic acid was used without purification.
CONCLUSIONS
In summary, we have developed efficient synthetic
approaches to mono- (5), di- (symmetrical (2) and
unsymmetrical (6) and tri- (3) aryl amine functionalized
1,3,5-triazines. Under proper conditions, it is possible to
selectively add different anilines in a controlled fashion to
cyanuric chloride (1) to get unsymmetrical triazines in
excellent yields; even with non-nucleophillic anilines.
This approach utilizes acetic acid as solvent, which is
inexpensive and non-toxic (environmentally friendly) and,
therefore, amenable to large-scale industrial processes.
Low flammability is also very important. Also, acetic acid
is volatile, miscible with water and most organic solvents.
Therefore, it is much easier to completely remove residual
acetic acid from solid reaction products than such popular
“green” solvents as polyethylene glycol or ionic liquids
[7]. Further, in the context of industrial applications, the
acetic acid could easily be recycled: once the acetic acid-
insoluble aminated products are removed from the
reaction medium by filtration, only HCl-saturated acetic
acid remains. The hydrogen chloride can be removed
from the solvent conveniently under reduced pressure or
by boiling/bubbling air through the liquid. Further
purification (if necessary) can be achieved by means of
fractional freezing/thawing (freezing point of acetic acid =
17°C). The chemistry described here is exceptionally
clean; all products were isolated in good to excellent
yields, with shorter reaction times, compared to
conventional approaches. Importantly, in our method,
purification/isolation of aminated products is greatly
simplified, relative to previously reported syntheses of
aminated triazine compounds. Because hydrogen chloride
acceptors are not required, and aryl amine products are
insoluble in acetic acid, product isolation requires only
filtration. On-going investigations are focused on
determining why acetic acid is superior to conventional
polar organic solvents in the aryl amination.
General Procedure for Aryl Amination of Cyanuric
Chloride with 3 Equiv of Aromatic Amines in Acetic Acid
Medium to Give Compounds of Type 3. (See Table 2 for the
yields). Cyanuric chloride 1 (1.84 g, 0.01 mol) was added in one
portion to a stirred solution of the aromatic amine (aniline)
substrate (0.033 mol) in 75 mL of glacial acetic acid (AcOH),
and the mixture was heated (30 min, steam bath (100°C) or 15
min, reflux (118°C)) immediately after the addition of aniline.
The products precipitated from solution as white or yellow
solids and were recovered by filtration. The solid products were
washed with boiling water (approximately 20 mL x 3) to neutral
pH and dried at 90°C in air to afford compounds 3 with high
purity (≥ 98 %; HPLC, NMR). See below for characterization
data/spectral assignments. Analytical samples of compounds 3
were recrystallized from suitable solvents (see below), boiled
with water to completely remove the solvents and dried under
vacuum.
N,N',N''-Triphenyl-[1,3,5]triazine-2,4,6-triamine (3a).
Colorless crystals; mp 229−230°C (isopropanol); reported mp
232 °C [3]; ir (KBr): 3260, 1570, 1521, 1230 cm-1; 1H nmr
(DMSO-d6): δ 7.12 (t, J = 7.5 Hz, 1H, Ph), 7.70 (d, J = 7.5Hz,
2H, Ph), 7.34 (t, J = 7.8Hz, 2H, Ph), 10.31 (s, 1H, NH); 13C
NMR (DMSO-d6): δ 122.47, 124.87, 128.97, 129.17, 137.62;
MS (EI, 70 e V): m/z (%) = 354 (100, M+), 262 (25, M+− Ph-
NH); HRMS (EI) Calcd. for (M+) C21H18N6 354.1593. Found:
354.1601.
N,N',N''-Tri-p-tolyl-[1,3,5]triazine-2,4,6-triamine (3b).
Colorless crystals; mp 236−237°C (isopropanol); reported
1
238−239 °C [3]; ir (KBr): 3260, 1570, 1521, 1230 cm-1; H nmr
(DMSO-d6): δ 2.36 (s, 3H, CH3), 7.52 (d, J = 6,6Hz, 2H, p-
C6H4), 7.13 (d, J = 6,6Hz, 2H, p-C6H4), 10.34 (s, 1H, NH); 13C
NMR (DMSO-d6): δ 21.11 (CH3), 122.41 (br.), 129.41, 134.14,
134.88; MS (EI, 70 e V): m/z (%) = 396 (100, M+), 305 (25, M+−
Tol), 106 (45, M+− Tol-NH); HRMS (EI) Calcd. for (M+)
C24H24N6 396.2062. Found: 396.2059.
N,N',N''-Tris-(4-methoxyphenyl)-[1,3,5]triazine-2,4,6-tri-
amine (3с). Colorless crystals; mp 214−216 °C (isopropanol); ir
(KBr): 3230, 1580, 1510, 1240 cm-1; 1H nmr (DMSO-d6): δ 3.78
(s, 3H, OCH3), 6.87 (m, 2H, p-C6H4), 7.54 (m, 2H, p-C6H4),
10.29, (s, 1H, NH); 13C nmr (DMSO-d6): δ 55.41 (OCH3),
113.95, 122.87, 124.05, 130.49, 156.81 (CAr-OCH3); MS (EI, 70
e V): m/z (%) = 444 (100, M+), 429 (35, M+− CH3), 412 (5, M+−
OCH3), 322 (10, M+− NHPh-OCH3); HRMS (EI) Calcd. for
(M+) C24H24N6O3 444.1910, Found: 444.1915; Anal. Calcd.: C,
64.85; H, 5.44; N, 18.91. Found: C, 64.51; H, 5.49; N, 18.74.
N,N',N''-Tris-(2-fluorophenyl)-[1,3,5]triazine-2,4,6-tri-
amine (3d). Colorless crystals; mp 169−170°C (isopropanol);
reported 173−174 °C [3]; ir (KBr): 3230, 1580, 1530, 1255 cm-1;
1H nmr (DMSO-d6): δ 7.21 – 7.84 (m, 3HAr), 7.85 (m, 1HAr),
8.61 (s, 1H, NH); 13C nmr (DMSO-d6): δ 115.43, 115.69,
124.20, 124.05, 127.28, 127.43, 168.21 (C-F); MS (EI, 70 e V):
m/z (%) = 408 (25, M+), 389 (100, M+ − F), 370 (20, M+ − 2F),
298(10, M+− NH-Ph-F); HRMS (EI) Calcd. for (M+) C21H15F3N6
408.1310. Found: 408.1312.
EXPERIMENTAL
General. All chemicals were purchased from Aldrich
Chemical Company and used as received. Progress of the
reactions was monitored by HPLC or TLC on silica gel SIL
G/UV 254 plates. The chromatograms were developed in
chloroform/hexanes (4:1 v/v) or chloroform/acetone (15:1 v/v)
(for reactions involving nitro- substituted derivatives). HPLC
was performed using 5500 Varian Vista chromatograph
equipped with Waters Symmetry C-18 reverse-phase column
(4.6/150 mm, 5µ particle size, methanol/water 80:20 v/v as
liquid phase). Mass-spectra were recorded on Micromass 70S-
250 sector mass and IR
− on Shimadzu FTIR 8700
spectrometers. NMR spectra were taken using Varian
spectrometer at 300 MHz (H1) and 75 MHz (C13). Elemental
analyses were carried out at Guelph Laboratories, Guelph ON,
Canada. Melting points were measured in capillary tubes and are
N,N',N''-Tris-(2-nitrophenyl)-[1,3,5]triazine-2,4,6-triamine
(3e). Yellow crystals (isopropanol); t. decomp. ≥ 300 °C; ir
(KBr): 3360, 1620, 1590, 1510, 1330, 1240 cm-1; 1H nmr
(DMSO-d6): δ 7.31 (m, 1HAr), 7.68 (m, 1HAr), 8.05

538
K. Kolmakov
Vol 45
1
(m, 2HAr), 9.88 (s, 1H, NH). 13C nmr (DMSO-d6): δ 104.79,
115.40, 119.59, 125.70, 131.04, 135.37, 146.62; MS (EI, 70 e
V): m/z (%) = 489 (30, M+), 443 (100, M+− NO2), 397 (10, M+−
2NO2), 351 (12, M+− 3NO2); HRMS (EI) Calcd. for (M+)
C21H15N9O6 489.1145. Found 489.1150; Anal. Calcd.: C, 51.54;
H, 3.09; N, 25.76. Found: C, 51.33; H, 2.92; N, 25.48.
4,4',4'-([1,3,5]-Triazine-2,4,6-triyltriimino)tribenzoic acid
(3g). Colorless crystals (isopropanol); t. decomp. ≥ 330 °C;
reported mp 378−380 °C [12]; ir (KBr): 3300 – 3100 (br. m), 1610,
1560, 1530, 1330, 1240 cm-1; 1H nmr (DMSO-d6): δ 7.96 (d, J = 8
Hz, 2H, p-C6H4), 8.12 (d, J = 8 Hz, 2H, p-C6H4), 10.11 (br. s, 1H,
NH); 13C nmr (DMSO-d6): δ 120.44, 122.31, 124.14, 135.14,
139.71, 192.30 (CO2H); MS (EI, 70 e V): m/z (%) = 486 (15, M+),
442 (100, M+ − CO2), 398 (10, M+ − 2 CO2); HRMS (EI) Calcd. for
(M+) C24H18N6O6 486.1288, Found: 486.1281.
N,N',N''-Tris-(4-nitrophenyl)-[1,3,5]triazine-2,4,6-triamine
(3f) was prepared as follows: The solution of 1 (1.84 g, 0.01
mol) in 30 mL of AcOH was added within 3 min to a boiling
solution of 6.20 g (0.045 mol) of 4-nitroaniline in 60 mL of
AcOH. The mixture was refluxed for 30 min, a yellow
precipitate was filtered and boiled with ~ 100 mL of water to
remove the solvent to give 92% of 3f as yellow crystalline
powder (analytical sample was recrystallized from DMF −
isopropanol). Properties: t. decomp. ≥ 300 °C (as reported
previously [5]); ir (KBr): 3340, 1630, 1590, 1510, 1340, 1240
cm-1; 1H nmr (DMSO-d6): δ 8.11 (d, J = 8 Hz, 2H, p-
C6H4), 8.17 (d, J = 8 Hz, 2H, p-C6H4), 10.23 (s, 1H, NH); (in
accordance with reported [5]). 13C nmr (DMSO-d6): δ 119.99,
120.44, 124.99, 125.06, 146.61; MS (EI, 70 e V): m/z (%) = 489
(12, M+), 443 (100, M+− NO2), 397 (7, M+− 2 NO2); HRMS (EI)
Calcd. for (M+) C21H15N9O6 489.1145, Found: 489.1149.
General Procedure for Aryl Amination of Cyanuric
Chloride with 2 Equiv of Aromatic Amines in Acetic Acid
Medium to Give Compounds of Type 2. (See Table 2 for the
yields). Method A. (With sodium acetate as HCl acceptor, and
water added. Provides excellent yields for all the compounds 2,
except ortho-nitro derivative 2e; See Table 2)
A solution of 1 (18.4 g, 0.1 mol) in 300 mL of AcOH and
solutions of 0.21 mol of the aniline substrates with 34 g (0.25
mol) of sodium acetate trihydrate (CH3COONa × 3H2O) in the
mixture of 100 mL of AcOH and 100 mL of H2O were
combined at r.t. and then slightly cooled to maintain the
temperature below 25°C. The resulting solutions were left for
2−4 h or overnight (for compound 2f (Ar = 4-NO2(C6H4)); the
completion of the reactions was checked by TLC. The
precipitates were separated by filtration and washed with boiling
water (150 mL × 2) to neutral pH. All the chlorides of type 2
were isolated with high purity (≥ 98 %; HPLC, NMR) after
filtration. Analytical samples were recrystallized from suitable
solvents and dried under vacuum.
191°C [5]; H nmr (DMSO-d6): δ 7.03 (t, J = 7.8 Hz, 1H, Ph),
7.28 (t, J = 7.8 Hz, 2H, Ph), 7.70 (br. s, 2H, Ph), 10.16 (s,1H,
NH); 13C nmr (DMSO-d6): δ 121.31, 123.43, 128.55, 139.00,
164.31(C-Cl).
6-Chloro-N,N'-di-p-tolyl-[1,3,5]triazine-2,4-diamine (2b).
Colorless crystals; mp 199−201 °C (isopropanol); reported
204−206 °C [6]; ir (KBr): 3260, 1570, 1521, 1230 cm-1; H nmr
1
(DMSO-d6): δ 2.36 (s, 3H, CH3), 7.21 (d, J = 6,3 Hz , 2H, p-
C6H4), 7.61 (d, J = 6,3 Hz, 2H, p-C6H4), 10.38 (s,1H, NH);13C nmr
(DMSO-d6) δ 20.53 (CH3), 121.11, 129.03 (br.), 123.69, 135.81,
163.87 (C-Cl); MS (EI, 70 e V): m/z (%) = 325 (100, M+), 234
(15, M+ − Tol), 290 (55, M+− Cl), 219 (10, M+ − Tol-NH); HRMS
(EI) Calcd. for (M+) C17H16ClN5 325.1094. Found 325.1096.
6-Chloro-N,N'-bis-(4-methoxyphenyl)-[1,3,5]triazine-2,4-
diamine (2c). Colorless crystals; mp 198−189°C (isopropanol);
reported 202−203 °C [6]; ir (KBr): 3230, 1580, 1510, 1240 cm-1;
1H nmr (DMSO-d6): δ 3.81(s, 3H, OCH3), 6.93 (d, J = 9 Hz, 2H,
p-C6H4), 7.61 (d, J = 9 Hz, 2H, p-C6H4), 10.35 (s, 1H, NH); 13C
nmr (DMSO-d6): δ 55.31 (OCH3), 113.79, 122.31, 122.85,
131.31, 155.74, (CAr-OCH3), 163.84 (CCl); MS (EI, 70 e V): m/z
(%) = 357 (100, M+), 342 (35, M+ − CH3), 322 (30, M+ − Cl),
234 (10, M+ − NH-Ph-OCH3); HRMS (EI) Calcd. for (M+)
C17H16ClN5O2: 357.0993. Found 357.0988.
6-Chloro-N,N'-bis-(2-fluorophenyl)-[1,3,5]triazine-2,4-di-
amine (2d). Colorless crystals; mp 144−146 °C (isopropanol); ir
(KBr): 3230, 1580, 1530, 1255 cm-1; 1H nmr (DMSO-d6): δ
7.22-7.41 (m, 3HAr), 7.96 (br. s, 1ΗAr) 8.72 (s, 1H, NH); 13C nmr
(DMSO-d6): δ 115.69, 115.95, 124.22, 125.23, 125.38, 126.97
(br), 164.91, (C-Cl), 168.91 (C-F); MS (EI, 70 e V): m/z (%) =
333 (100 M+), 314 (55, M+- F), 298 ( 40, M+− Cl), 223 (10, M+−
NHPh-F); HRMS (EI) Calcd. for (M+) C15H10ClF2N5:
333.05927. Found: 333.05980.
6-Chloro-N,N'-bis-(2-nitrophenyl)-[1,3,5]triazine-2,4-di-
amine (2e). Colorless crystals; mp 199 −201 °C (isopropanol); ir
(KBr): 3360, 1620, 1590, 1510, 1330, 1240 cm-1; 1H nmr
(DMSO-d6): δ 7.56 (m, 1HAr), 7.78 (m, 1HAr), 8.05(m, 2ΗAr),
11.42 (s, 1Η, NH); 13C nmr (DMSO-d6): δ 125.66, 127.76,
128.04, 129.99, 134.47, 144.13, 164.89, (C-Cl); MS (EI, 70 e
V): m/z (%) = 387 (100, M+), 341 (65, M+- NO2), 351 (10, M+ −
Cl), 249 (10, M+ − NHPh-NO2); HRMS (EI) Calcd. for (M+)
C15H10ClN7O4 387.04829, Found: 387.04963; Anal. Calc.: C,
46.46; H, 2.60; N, 25.29; Found: C, 46.13; H, 2.48; N, 24.89.
Chloro-N,N'-bis-(4-nitrophenyl)-[1,3,5]triazine-2,4-di-
amine (2f). Colorless crystals; mp 264−266°C (acetone),
reported 273 °C [3]; ir (KBr): 3340, 1630, 1590, 1510, 1340,
1
1240 cm-1; H nmr (DMSO-d6): δ 7.90 (d, J = 9.3Hz, 2H, p-
C6H4), 8.22 (d, J = 9.3Hz, 2H, p-C6H4), 10.44 (s, 1H, NH); (in
accordance with reported ) [3]; 13C nmr (DMSO-d6): δ 120.36,
121.08, 125.05, 125.12, 143.85, 164.32 (C-Cl); MS (EI, 70 e V):
m/z (%) = 387 (100, M+), 351 (45, M+− Cl), 341 (60, M+ − NO2),
249 (30, M+ − NHPh-NO2); HRMS (EI) Calcd. for (M+)
C15H10ClN7O4 387.04829. Found: 387.04997.
4,4'-[(6-Chloro-1,3,5-triazine-2,4-diyl)diimino]dibenzoic
acid (2g). Colorless crystals (isopropanol); t. decomp. ≥ 330 °C;
reported mp 345−348°C [12]; ir (KBr): 3300 – 3100 (br. m),
1610, 1560, 1530, 1330, 1240 cm-1; H nmr (DMSO-d6): δ 7.88
(d, J = 8 Hz, 2H, p-C6H4), 8.06 (d, J = 8 Hz, 2H, p-C6H4),
10.10 (br. s, 1H, NH); 13C nmr (DMSO-d6): δ 120.44, 122.56,
124.14, 135.11, 139.83, 164.66 (C-Cl), 192.30 (CO2H); MS (EI,
70 e V): m/z (%) = 385 (10, M+), 350 (30, M+ − Cl), 341 (100,
M+ − CO2); HRMS (EI) Calcd. for (M+) C17H12ClN5O4 385.0578,
Found: 385.0569.
Method B. (In glacial acetic acid, with no HCl acceptors
added. Provides good yield for 6-chloro-N,N'-bis-(2-nitro-
phenyl)-[1,3,5]triazine-2,4-diamine (2e) and for the rest of
compounds 2; See Table 2).
Solutions of 1 (1.84 g, 0.01 mol) in 30 mL of AcOH and the
aniline substrates (0.02 mol, (2 equiv each)) in 30 mL of AcOH
were combined at room temperature and then left overnight. The
precipitates were collected and recrystallized from isopropyl
alcohol or acetone to afford pure (≥ 98 %; HPLC, NMR)
compounds.
1
6-Chloro-N,N'-diphenyl-[1,3,5]triazine-2,4-diamine (2a).
Colorless crystals; mp 197−198 °C (benzene); reported mp

Mar-Apr 2008
Aryl Amination of Cyanuric Chloride Using Acetic Acid as Solvent
539
135.93, 138.62, 164.66 (C-Cl) MS (EI, 70 e V): m/z (%) = 311
(100, M+), 276 (25, M+- Cl), 219 (10, M+− Tol), 205 (7, M+−
Tol-NH); HRMS (EI) Calcd. for (M+) C16H14ClN5 311.093.
Found: 311.0929.
6-Chloro-N,N'-bis-(2,4-dimethylphenyl)-[1,3,5]triazine-2,4-
diamine (2h). Colorless crystals; mp 213−214 °C (isopropanol);
ir (KBr): 3260, 1570, 1520, 1230 cm-1; 1H nmr (DMSO-d6):
δ 2.31, 2.36 (2s, 6H, 2CH3), 7.15 (s, 1HAr), 7.23 (m, 1HAr), 7.63
(m, 1HAr) 10.38 (s, 1H, NH); 13C nmr (DMSO-d6): δ 20.32
(CH3), 20.81(CH3), 121.13, 129.05 (br), 132.69, 135.86, 163.87
(C-Cl); MS (EI, 70 e V): m/z (%) = 353 (100, M+), 318 (40, M+ −
Cl), 248 (20, M+− C6H4(CH3)2), 233 (10, M+− C6H3(CH3)2NH);
HRMS (EI) Calcd. for (M+) C19H20ClN5 353.1407. Found:
353.1398. Anal. Calcd.: C, 64.49; H, 5.70; N, 19.79. Found C,
64.16; H, 5.58; N, 19.58.
6-Chloro-N-(4-nitro-phenyl)-N'-phenyl-[1,3,5]triazine-2,4-
diamine (6b). Yellow crystals; mp 221−2 °C (acetone); ir (KBr):
1
3320, 1630, 1590, 1510, 1340, 1240 cm-1; H nmr (Acetone-d6):
δ 7.22 (m, 1HAr), 7.77 (m, 2HAr), 7.45 (m, 2HAr), 8.10 (m, 2HAr),
8.25 (m, 2HAr), 9.30 (br. s, 1H, NH), 9.69 (br. s, 1H, NH); 13C
nmr (Acetone-d6): δ = 119.87, 122.85 (br.), 124.54, 128.77,
138.11, 142.81, 145.04, 164.65(C-Cl); MS (EI, 70 e V): m/z (%)
= 342 (100, M+), 297 (70, M+− NO2), 307 (10, M+− Cl); HRMS
(EI) Calcd. for (M+) C15H11ClN6O2 342.0623. Found: 342.0632;
Anal. Calcd.: C, 52.56; H, 3.23; N, 24.52. Found: C, 52.24; H,
3.31; N, 24.63.
6-Chloro-N,N'-bis-(3,5-dimethylphenyl)-[1,3,5]triazine-2,4-
diamine (2i). Colorless crystals; mp 189−191°C (isopropanol);
ir (KBr): 3260, 1570, 1520, 1230 cm-1; 1H nmr (DMSO-d6):
δ 2.34 (s, 6H, 2CH3), 7.34 (s, 1HAr), 7.63 (s, 2HAr), 10.34 (s, 1H,
NH). 13C nmr (DMSO-d6):
δ
21.23 (CH3), 121.13,
Acknowledgement. The author would like to thank
University of Toronto Chemistry Department for fellowship
support, and is also very grateful to Daniel J. Harrison
(University of Toronto) for his help in preparing the final
manuscript, and to Dr. Maxim Karpov (St. Petersburg State
University) for good advice.
129.05(br), 132.69, 135.56, 163.91(C-Cl); MS (EI, 70 e V): m/z
(%) = 353 (100, M+), 318 (50, M+ − Cl), 248 (15, M+−
C6H4(CH3)2), 233 (10, M+− C6H3(CH3)2NH); HRMS (EI) Calcd.
for (M+) C19H20ClN5 353.1407. Found: 353.1394. Anal. Calc.: C,
64.49; H, 5.70; N, 19.79. Found C, 64.09; H, 5.56; N, 19.61.
4,6-Dichloro-[1,3,5]triazin-2-yl-phenylamine (5). To
a
stirred solution of 1 (9.2 g, 0.05 mol) in 150 mL of acetic acid
4.65 g (0.05 mol) of aniline in a mixture of 20 mL of AcOH and
80 mL of H2O was added dropwise within 15 min at 15-17°C
(not letting AcOH to freeze). The reaction mixture was left for
1h at this temperature and then diluted with 1 L of brine. The
solid was collected, dried in the open air and recrystallized from
400 ml of heptane (insoluble impurities were filtered off the hot
solution) to afford 67 % of pure compound 5 whose melting
point (136-137°C) was in accordance with previously reported
[1,10]. We found that the compound reacted with DMSO and
therefore NMR spectrum was taken in acetone-d6: 1H nmr
(Acetone-d6): δ 7.25 (t, J = 9 Hz, 1H, Ph) 7.46 (t, J = 8 Hz, 2H,
Ph), 7.77 (br. s, 2H, Ph), 9.90 (br. s, 1H, NH); 13C nmr
(Acetone-d6): δ 121.62, 125.19, 128.93, 137.07, 164.56 (C-Cl)
REFERENCES
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Practice, Oxford University Press: New York, 1998.
[8] C.Reichardt, Solvents and solvent effects in Organic
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“Unsymmetrical” derivatives
− 6-Chloro-N,N'-diaryl-
[1,3,5]triazine-2,4-diamines (6a, 6b). (See Table 2 for the
yields). Compound 5 (1.20 g , 5 mmol) was dissolved in the
mixture of 40 mL of AcOH and 10 mL of H2O. The aromatic
amines (5.5 mmol) and 0.81 g (6 mmol) of CH3COONa × 3H2O
was then added. The solution was stirred until the solids
dissolved and left overnight. Crystalline products were filtered,
washed with boiling water (10 mL × 3) and dried to afford pure
compounds 6a and 6b. Analytical samples were recrystallized
from isopropanol.
6-Chloro-N-phenyl-N'-p-tolyl-[1,3,5]triazine-2,4-diamine
(6a). Colorless crystals; mp 178−179 °C (isopropanol); reported
mp 176.5 − 177.5 °C [6]; ir (KBr): 3260, 1570, 1521, 1230 cm-1;
1H nmr (Acetone-d6): δ 2.34 (s, CH3), 7.22−7.13 (m, 3H, Ph),
7.39 (t, J = 8Hz, 2H, Ph), 7.81 (d, J = 7Hz, 2H, p-C6H4), 7.66
(d, J = 8Hz, 2H, p-C6H4), 9.04 (br. s, 2H, NH); 13C nmr
(Acetone-d6): 20.06 (CH3), 121.20 (br), 123.70, 128.26, 133.25,
[12] Pogosyan, G. M.; Zaplishnyi, V.N.; Asaturyan, I. A.,
Armyanskii Khimicheskii Zhurnal 1977, 30, 342.