Selective modification of bifunctional heterocyclic compounds containing amino and thioamide groups in acetic acid medium

Article abstract of DOI:10.1002/jhet.5570450446

(Chemical Equation Presented) In acetic acid medium, 2-chloro-4,6- dimorpholin-4-yl-[1,3,5]triazine undergoes amination by bifunctional heterocyclic compounds containing both amino and thioamide groups. The reactions are high-yielding and selective; the t

Full text of DOI:10.1002/jhet.5570450446

Jul-Aug 2008
1215
Selective Modification of Bifunctional Heterocyclic Compounds
Containing Amino and Thioamide Groups in Acetic Acid Medium
Kirill A. Kolmakov*
Department of Chemistry, University of Toronto, Toronto, ON, M5S 3H6, Canada
E-mail: kkolmako@chem.utoronto.ca
Received July 10, 2007
H
NH
N
N
N
R
AcOH
R'X, S-alkylation
Compound
libraries
S
base
N
N
no base, reflux
N
N
NH
H2N
N
R
R
Reagent
N
N
S
Substrates
Cl
N
R = N-Morpholyl
H
R' = Alk, Bz, CH2CONHAr
R'X, S-alkylation
H
N
R
N
N
R
AcOH
S
Compound
libraries
base
S
no base, reflux
N
N
H2N
NH
S
S
R
In acetic acid medium, 2-chloro-4,6-dimorpholin-4-yl-[1,3,5]triazine undergoes amination by
bifunctional heterocyclic compounds containing both amino and thioamide groups. The reactions are high-
yielding and selective; the thioamide functions are unaffected under the requisite conditions. The reactions
do not proceed in satisfactory yields in other solvents and, thus, require acetic acid. The resulting
thioamides, consisting of multiple biologically relevant residues, are easily alkylated at the sulfur (thiol-
thione) centers to furnish new thioethers in subsequent steps.
J. Heterocyclic Chem., 45, 1215 (2008).
INTRODUCTION
heterocycles (triazoles or thiazoles) in scaffolds that also
contain a 1,3,5-triazine group.
Heterocyclic compounds with two or more functional
groups are highly attractive for combinatorial chemistry
because the reactive sites can, in principle, be modified in
a stepwise fashion, providing access to large compound
libraries. To take advantage of multiple reactive sites for
combinatorial applications, it is necessary to develop
high-yielding synthetic protocols, by which a given
functional group can be selectively modified. Here we
report the first examples of amination of a chloro-
substituted 1,3,5-triazine moiety, using heterocyclic
substrates containing both amino and thioamide groups.
The latter exhibit thiol-thione tautomerism, and are highly
reactive towards electrophiles. When the reactions are
conducted in acetic acid, the amino groups are selectively
modified, in high yield, while the thioamide (thiol-thione)
functions are unaffected.
Sulfur- and nitrogen-containing heterocycles, partic-
ularly 1,2,4-triazoles and benzothiazoles, have received
considerable attention owing to their biological activities
and are common scaffolds in drug discovery [1]. Cyanuric
chloride (2,4,6-trichloro[1,3,5]triazine, 1, Scheme 1) is a
useful, inexpensive reagent whose 1,3,5-triazine moiety is
also a part of many biologically active and medicinally
significant compounds [2]. Cyanuric chloride can undergo
stepwise nucleophilic substitution at its three C-Cl sites,
[3] making it a versatile reagent for generating function-
alized triazine cores. We have sought to incorporate
biologically relevant nitrogen- and sulfur-containing
Scheme 1
O
Cl
N
N
N
N
N
N
N
N
Morpholine
Cl
Cl
1
2
Acetone, r.t.
Cl
O
NH
N
5
NH
S
N
N
a
S
2
N
R
b
HN
94 %
R = Me
R
AcOH
reflux,1h
H2N
3
N
N
N
N
N
O
O
H
H
N
N
2
a
S
S
S
S
HN
AcOH
reflux, 1 h
H2N
b
88 %
4
6
N
N
a -- substrates and products
are drawn in thione form
b -- isolated yields
N
N
N
O
O
Alkylation c
H
N
Thione
S
Thiol
-
N
Z
Z
'
N
Z
OH
H+
RX
Z
Z
'
'
SH (S- )
SR
Z
Z = N-R
Z' = N
(
(
3
3
and
and
5
5
)
)
or S
or C
(
4
and
and
6
6
)
,
R = Alk, Bz, etc.
c -- see Scheme 3
(
4
)

1216
K. Kolmakov
Vol 45
In our approach, amine-substituted triazoles or thiazoles
core, was obtained via previously reported synthetic route
that involved the condensation of 4-nitrobenzoic acid
hydrazide and methyl isothiocyanate followed by base-
assisted cyclization [7].
are coupled to a 1,3,5-triazine core by amination reactions
at the C-Cl group of the 1,3,5-triazine moiety. Morpholine
groups occur in a huge number of biologically potent
compounds, often in conjunction with a 1,3,5-triazine
core (see [2a,b]). As a triazine-containing reagent, we
chose 2-chloro-4,6-dimorpholin-4-yl-[1,3,5]triazine (2),
which is readily obtained by reaction of 1 with 2 equiv. of
morpholine in acetone (Scheme 1) [3b]. The replacement
of the chlorine atom in compound 2 by nucleophiles,
including aliphatic amines requires harder conditions or
microwave irradiation [3c,d,e]. The characteristic feature
of all known recipes for the chlorine substitution in
compounds 1 and 2 is the use of bases or hydrogen
chloride acceptors [3a-e].
Scheme 2
NH
NH
N
N
1) (NH4)2S / H2O, 80oC
2) H+
S
S
N
N
Me
Me
84 %, isolated
7
O2N
3
H2N
In our initial attempts to aminate compound 2 with
amine-containing heterocycles 3 and 4 (Scheme 1), we
screened a variety of high-boiling organic solvents (DMF,
1,4-dioxane, ethanol, acetonitrile, benzene, dichloroethane)
and we employed sodium acetate or pyridine as HCl
acceptors. Of the solvents examined for this
transformation, noticeable conversion to the desired
aminated products (5 or 6, Scheme 1) was observed only
in DMF; for the other solvents we screened, the reaction
did not proceed, even upon prolonged reaction times at
elevated temperatures. While the desired aminated species
were formed in DMF in low yields, selectivity was poor
(several products, including S-alkylation products were
detected in the product mixture) and the reaction was slow
(< 30 % conversion after 1 h at 150 °C). Dimethyl-
sulfoxide (DMSO) is unsuitable as a solvent for these
reactions because it reacts with the chloride 2, to form,
presumably, hydroxy compound 11 (see Scheme 4 below)
[9]. Ultimately, we discovered that the desired amination
reactions (amination of 2 with 3 or 4) readily proceed in
glacial acetic acid. Despite being a potentially attractive
solvent by virtue of its high polarity/boiling point and its
environmental compatibility, acetic acid has limited
application in organic synthesis (as compared to that of
many other solvents). Particularly, no attempts to perform
amination reactions in acetic acid medium have been
reported so far. Initial tests showed that the desired
modification, indeed, occurs in acetic acid. Moreover, the
reaction proceeded even in the absence of CH3COONa, or
other proton acceptors, which simplifies product
purification. Upon heating 2 in acetic acid solutions of 3
or 4, reaction starts immediately, as evidenced visually by
the evolution of HCl from the boiling solutions and the
formation of precipitates. Amination products 5 or 6 are
formed in excellent yields, on a convenient timescale (1 h
at 118 °C) (see Scheme 1 and Experimental Section)
when the reactions are carried out in acetic acid.
Importantly, the thioamide groups in substrates 3 and 4
are not affected under these conditions. Further, product
isolation is extremely convenient: the desired products,
compounds 5 and 6, precipitate from acetic acid and can
be isolated by simple filtration. The identity of N-
substituted products 5 and 6 was verified by spectroscopic
Our approach relies on selective modification of the
amino group (NH2) in heterocyclic substrates (3 and 4)
that also contain thioamide functions as a part of the ring
system. It is known that cyanuric chloride (1) reacts with
some thioamides at the thioamide sulfur. For example,
substitution of all three chlorine atoms in 1 is achieved
with thiourea as a nucleophile [4].
We have devised a method to induce amination at the
C-Cl site of 2, without affecting the thioamide groups of
the triazole or benzothiazole reagents. This method has
allowed us to generate new heterocyclic molecules that
contain multiple residues with potential biological activity
(1,2,4-triazole or benzothiazole, 1,3,5-triazine and
morpholine groups). Two known bifunctional (amine- and
thioamide-containing) heterocyclic compounds were
chosen as representative substrates for reaction with 2: 5-
(4-aminophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazole-3-
thione (3) and 6-amino-3H-benzothiazole-2-thione (4)
(Scheme 1). As a scaffold in combinatorial chemistry,
compound 3 is of special interest because it has an
additional variable N-R site incorporated in the 1,2,4-
triazole ring (R = Me). Heterocyclic compounds that
contain thioamide groups (Scheme 1) undergo alkylation
in basic media to give thioethers (S-alkylation products)
(Scheme 1, bottom). Numerous data [5] indicate that
thiolate anions of a general formula –N=C(Z)–S– (see
Scheme 1), generated from compounds containing
fragment –NH–C(Z)=S in heterocyclic rings (Z = N,O,S),
act as strong nucleophiles. On the other hand, in the solid
state and in neutral solutions these compounds exist
predominantly in thione (thioamide) form[6,7,8].
RESULTS AND DISCUSSION
6-Amino-benzothiazole-2-thiol (4) was prepared from
readily accessible benzothiazole-2-thione by nitration,
followed by reduction, according to the reported
procedure [6]. Our synthesis of compound 3 also involved
reduction of a nitro group in the final step (Scheme 2). Its
precursor, nitro compound 7, containing 1,2,4-triazole

Jul-Aug 2008
Selective Modification of Bifunctional Heterocyclic Compounds
1217
methods (IR, NMR), mass spectrometry and elemental
analysis (see Experimental Section).
especially with aromatic amines. Synthetic routes to
trisubstituted 1,3,5-triazine derivatives generally involve
long reaction times and elevated temperatures [3a,3e].
The only reported synthesis of compound 10a was
undertaken in 1998 by Shibuya and co-workers [2a],
starting from N-formanilide and N,N'-dimorpholino-
cyanamide. According to the authors, this approach was
chosen to avoid slow, low-yielding substitution reactions
at the C-Cl groups of cyanuric chloride. Compound 10b
(Ar = 4-NO2(C6H4), Scheme 4), a potential anti-malarial
drug, was synthesized by Agarwal [2b] and co-workers,
by amination of cyanuric chloride with 1 equiv of 4-
NO2(C6H4)NH2, followed by amination of the remaining
two C-Cl sites with morpholine in refluxing THF. If the
two morpholine groups were installed first, it is likely that
the third amination step, using less nucleophilic 4-
NO2(C6H4)NH2, would be prohibitively slow in
commonly used solvents, such as THF.
S-Alkylation products of general structures 8 and 9
were obtained from compounds 5 and 6 respectively
(Scheme 3) to demonstrate the possibility of substitution
(S-alkylation) at the second reactive site (thioamide
group). This reactivity provides a convenient route to
derivatives of 5 and 6 with potential biological activity.
The S-alkylation of the thioamides (thiol-thiones) 5 and 6
can be performed under mild conditions and the reactions
are complete after 2-4 h at ambient temperature. The
reactions and isolation protocols are simple and are
therefore amenable to automation. Three carbon-based
electrophiles of general structure RCH2X (Scheme 3)
were taken as examples: methyl iodide, benzyl chloride
and 2-chloro-N-p-tolylacetamide (R = 4-Me(C6H4)NH-
(CO)CH2). Members of the latter class of electrophile
(chloroacetic acid amides) are readily accessible from
aromatic amines and are widely used in combinatorial
chemistry [5,10]. Six new compounds were obtained in a
parallel-synthetic fashion with excellent yields (see
Scheme 4
O
O
Scheme
3
and Experimental Section), and were
N
N
N
N
N
N
characterized by NMR, IR, mass spectrometry, and
elemental analysis.
N
N
N
N
Ar-NH2
Ar-HN
Cl
AcOH, reflux
10a,b
2
Scheme 3
O
AcOH, reflux
N
N
O
O
N
N
N
SR
N
N
RX
N
5 b
Ar = C6H (10a),
or 4-O2N(C6H4) (10b)
5
HO
KOH,
MeCN, HN
H2O, r.t.
N
Compd.;
Yield a, %
Me
11
R
8a,b,c
N
Me
8a 88
8b 93
O
N
N
N
PhCH2
O
O
N
p -Tol NH(CO)CH2 8c 97
However, with acetic acid as the solvent, the
introduction of a third amine substituent to 2 is easily
achieved: compounds 10a and 10b were obtained in 90 %
and 58 % yields respectively, by treating 2 with PhNH2 or
4-NO2(C6H4)NH2 in refluxing acetic acid (Scheme 4).
The lower yield of 10b is the result of a side reaction in
which 2 undergoes solvolysis by acetic acid to furnish 11
(Scheme 4). The hydroxy compound 11 was identified by
means of 1H NMR and mass-spectrometry [11].
RX
KOH,
MeCN,
H2O, r.t.
6 b
SR
S
HN
N
Me
PhCH2
9a 92
9b 94
9a,b,c
N
N
p -TolNH(CO)CH2 9c 96
N
N
O
O
a -- isolated yields
b
-- see Scheme1 for srtuctures
In addition to the experiments with substrates 3 and 4 in
acetic acid medium, it seemed reasonable to explore the
reactivity of chloride 2 towards “regular”, monofunctional
aromatic amines (anilines) in the same solvent. Aniline
and less nucleophilic 4-nitroaniline were taken as
representative substrates. The reaction between 2 and
amines can be considered as the final third stage of
nucleophilic substitution in cyanuric chloride (1).
Replacement of the chlorine atom in 2 gives trisubstituted
1,3,5-triazine compounds of type 10 (see Scheme 4). The
final substitution stage, to introduce a third nucleophilic
substituent on 1,3,5-triazine core, is difficult to achieve,
The reactions between 2 and more nucleophilic amine
substrates (e.g., aniline) are much faster and product loss via
solvolysis is minimal. Note that solvolysis of cyanuric
chloride 1 (Scheme 1) in boiling acetic acid was observed
previously and has been used as a convenient method for the
preparation of cyanuric acid [3a]. In dry acetic acid, acetyl
chloride is formed as byproduct. In the course of the reaction
between 2 and substrates 3 and 4, the solvolysis occurs to a
much lesser extent. Importantly, the side-product 11 is
soluble in aqueous acetic acid and does not contaminate
target compounds 5 and 6. Solvolysis of 2 was only observed
in the reaction with less nucleophilic 4-NO2(C6H4)NH2,

1218
K. Kolmakov
Vol 45
Laboratories, Guelph ON, Canada. NMR spectra were recorded
on Varian spectrometer at 300 MHz (1H) and 75 MHz (13C).
Acetic acid (Aldrich, 99.7 %, ACS reagent grade) was freshly
distilled and subjected to fractional crystallization for initial
experiments. Later, in all the synthetic procedures described
below acetic acid was used without purification. All other
solvents were purified by conventional methods. All the
syntheses described below were performed without protection
from air or moisture, unless otherwise noted.
2-Chloro-4,6-dimorpholin-4-yl-[1,3,5]triazine (2) was
prepared according to the classical procedure [3b] from
cyanuric chloride and morpholine (purity was checked by means
of 1H NMR and TLC).
6-Amino-3H-benzothiazole-2-thione (4) was obtained in
high yield and purity (checked by means of NMR and HPLC)
according to the known procedure from commercially available
2-mercaptobenzothiazole. The melting point (260–262 °C) and
1H MNR agreed with reported [6].
5-(4-Aminophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazole-3-
thione (3). Nitro compound 7 (4-methyl-5-(4-nitrophenyl)-2,4-
dihydro-[1,2,4]triazole-3-thione (Scheme 2)), was prepared
according to the previously described procedure, starting from 4-
nitrobenzoic acid hydrazide [7]. The reduction of 7 to the
corresponding amine 3 was accomplished as follows:
because amination is much slower in that case. The results as
a whole indicate that acetic acid, as solvent, favors the
reaction of chloride 2 with aromatic amines and makes it
possible to utilize weak nucleophiles, such as 4-nitroaniline,
and substrates 3 and 4 in amination of 2.
The consideration of donor-acceptor properties of
solvents might help to explain why acetic acid is superior
to other solvents in the amination of 2. Among the
solvents screened (DMF, 1,4-dioxane, acetonitrile,
ethanol, benzene, chlorinated hydrocarbons), acetic acid,
in addition to being very polar, possesses the highest
acceptor number value (about 53, see ref. [12]) and
consequently the lowest nucleophilicity. On the other
hand, “nucleuophilic” solvents, i.e. DMF or alcohols,
must strongly solvate reagent 2 and thus compete with the
substrates. As a result, the reaction rate is insufficiently
low. Also importantly, under acidic conditions the thione
forms of substrates 3 and 4 predominate, which
completely suppresses the undesirable substitution at the
sulfur (thiol-thione) centers. All these make acetic acid
the solvent of choice for the title reaction. In contrast to
conventional procedures for the chlorine substitution in
1,3,5-triazine derivatives 1 and 2, the use of HCl
acceptors in the amination of 2 in acetic acid medium
becomes unnecessary, which simplifies product isolation.
Our method of preparing compound 10a is superior to the
previously reported multi-step synthesis [2a], which
involves prolonged heating under elevated pressure.
Sodium sulfide nanohydrate (Na2S ꢀ 9H2O, 144 g, 0.60 mol)
and NH4Cl (32.5 g, 0.60 mol) were successively dissolved in
500 mL of water. Then compound 7 (40 g, 0.17 mol) was added
upon stirring, and the mixture heated to 70 °C. The solid
dissolved completely, and an exothermic reaction started to give
a raise in temperature up to 95–100 °C. Heating was ceased, and
about 50 mL of cold water was poured straight into the solution
to prevent it from boiling off. For TLC analysis, a small portion
(1 mL) of the solution was acidified with AcOH to pH = 5 ꢁ 6
and diluted with 5-fold excess of acetone. The analysis of the
probe showed the absence of the starting nitro compound 7. The
rest of the solution was then acidified with 60 mL (~1.0 mol) of
AcOH in 200 mL of water (CAUTION! H2S!), the precipitate
separated and washed to neutral pH with cold water (~100 mL ꢀ
2). The crude amine 3 was dissolved in 1 L of water containing
40 mL (0.47 mol) of conc. HCl upon heating to 80 °C. The
solution was cooled to room temperature and an insoluble
material (mostly elementary sulfur) was filtered off. The pure
compound (28.7 g, 84 %) was precipitated as pale yellow
needles when 83 g (0.60 mol) of CH3COONa ꢀ 3H2O was added
to the acidic solution. The melting point (176–178°C), IR and 1H
NMR spectra of 3 were in a good accordance with that reported
by S. Rollas and co-workers, who originally prepared this
compound via a different route [8]. IR (KBr): 3360-2800 (br.
CONCLUSION
Clean and high-yielding procedures for selective
modification of amino groups in two bifunctional
heterocyclic substrates (3 and 4) have been developed.
These amination reactions require acetic acid as solvent,
as they do not proceed in other high-boiling organic
solvents. The thioamide groups in substrates 3 and 4 are
stable towards the conditions used for amination, although
they can be easily alkylated in a subsequent step. New
compounds 5, 6, 8a-c and 9a-c contain multiple residues
with potential biological activity. We also showed that the
1,3,5-triazine compound 2 undergoes amination by
aromatic amines, including weakly nucleophilic 4-
nitroaniline, when acetic acid is used as solvent.
1
m), 1610, 1516, 1485, 1448, 1340, 1300, 1148 cm-1. H NMR
(300 MHz, DMSO-d6): ꢂ 3.51 (s, 3H, N-CH3), 5.46 (s, 2H,
NH2), 6.72 (d, J=9Hz, 2HAr), 7.33 (d, J=9Hz, 2HAr), 13.52 (s,
1H, NH) ppm.
EXPERIMENTAL
General. All chemicals were purchased from Aldrich
Chemical Company. Progress of the reactions was monitored by
HPLC or TLC on silica gel SIL G/UV 254 plates and
chloroform/acetone (10:1) as mobile phase. HPLC was
performed using 5500 Varian Vista chromatograph equipped
with Waters Symmetry C-18 reverse-phase column (4.6/150
mm, 5 μ particle size, methanol/water (80:20 vol.) as mobile
phase). Mass-spectra were recorded on Micromass 70S-250
sector mass spectrometer, IR – on Shimadzu FTIR 8700
spectrometer. Elemental analyses were carried out at Guelph
Modification of bifunctional heterocyclic substrates 3 and
4 in acetic acid medium; General procedure. 0.01 mol of the
amine substrate (3 or 4) was dissolved in 75 mL of glacial acetic
acid upon boiling, and chloride 2 (3.58 g, 0.0125 mol) was
carefully added in few portions. The solution was refluxed for 1
h (until no trace of starting compounds was detected by means
of TLC). Hot solutions with precipitates were quenched with
equal volume of water and cooled to room temperature. The
precipitates were separated by filtration and washed twice with
30 mL of boiling water. For further purification, the moist

Jul-Aug 2008
Selective Modification of Bifunctional Heterocyclic Compounds
1219
products were dissolved in a mixture of DMF (25 mL) and Et3N
(3.6 mL 0.025 mol) upon heating and stirring. The solutions
were diluted with 150 mL of water and filtered to separate a
small amount of insoluble material. Compounds 5 and 6 with
purity > 98 % (NMR, HPLC) were isolated after the solutions
were acidified with 2.5 mL (0.04 mol) of AcOH and boiled for 5
min for better aggregation the precipitates filtered, thoroughly
washed with hot water and dried in air.
7.83 (d, J=9Hz, 2HAr), 9.22 (s, 1H, NH) ppm. 13C NMR ꢁ (75
MHz, DMSO-d6): ꢁ 15.09 (SCH3), 31.61 (N-CH3), 43.43, 66.05
(CH2, Morph.), 119.30, 119.79, 128.63, 129.04, 141.93, 151.29,
164.07, 164.76 (8CAr) ppm. MS (EI, 70 eV): m/z (%) = 469
(100) [M+], 454 (20) [M+ – CH3], 422 (30) [M+ – CH3S], 393 (20)
[M+ – CH3S – NCH3], 410 (10), 205 (10). HRMS (EI) calc. for
[M+] C27H31N9O2S 469.2008, observed 469.2011. Anal. Calc. C
53.71; H 5.80; N 26.85. Found: C 53.57; H 5.66; N 26.69.
5-[4-(4,6-Di-morpholin-4-yl-[1,3,5]triazin-2-ylamino)phenyl]-
4-methyl-2,4-dihydro-[1,2,4]triazole-3-thione (5) was isolated
as a colorless crystalline product; yield 94 %; mp 296ꢀ298 °C.
Very slightly soluble in most organic solvents, except DMF and
DMSO; readily soluble in aqueous KOH. IR (KBr): 3440, 3000-
2800 br. m, 1610, 1575, 1508, 1440, 1390, 1410, 1390, 1360,
1255, 1110 cm-1. 1H NMR (300 MHz, DMSO-d6): ꢁ 3.54 (s, 3H,
CH3), 3.64 – 3.76 (m, 16H, Morph), 7.78 (d, 2HAr), 7.87
(d, J=9Hz, 2HAr), 13.84 (s, 1H, NH) ppm . 13C NMR (75 MHz,
DMSO-d6): ꢁ 31.79 (N-CH3), 43.46, 66.10 (CH2, Morph.),
118.59, 119.24, 128.91, 142.70, 151.57, 164.09, 164.74 (7CAr),
167.30 (C=S) ppm. MS (EI, 70 eV): m/z (%) = 455 (100) [M+],
423 (60) [M+ – S], 407 (30) [M+ – SCH3], 394 (20) [M+ – S –
NCH3], 205 (20). HRMS (EI) calc. for [M+] C20H25N9O2S
455.1852, observed 455.1849. Anal. Calc. C 52.73; H 5.53; N
27.67. Found: C 52.36; H 5.31; N 27.52.
[4-(5-Benzylsulfanyl-4-methyl-4H-[1,2,4]triazol-3-yl)phenyl]-
(4,6-di-morpholin-4-yl-[1,3,5]triazin-2-yl)-amine (8b).
Colorless solid, yield 93 %, mp 158ꢀ160 °C, IR (KBr): 3440,
3000-2800 (br. m), 1604, 1572, 1523, 1500, 1481, 1446, 1410,
1
1361, 1258, 1113 cm-1. H NMR (300 MHz, DMSO-d6): ꢁ 3.48
(s, 3H, N-CH3), 3.64 – 3.76 (m, 16H, Morph), 4.36 (s, 2H,
SCH2) 7.32 (m 5H, Ph) 7.52 (d, J=9Hz, d, 2HAr), 7.83 (d,
J=9Hz, d, 2HAr), 9.23 (s, 1H, NH) ppm . 13C NMR ꢁ (75 MHz,
DMSO-d6): ꢁ = 31.67 (N-CH3), 37.51 (SCH2), 43.44, 66.10
(CH2, Morph.), 119.32, 119.79, 127.61, 128.58, 128.69, 129.04,
137.32, 142.06, 149.73, 155.46, 164.10, 164.76 (12 CAr) ppm.
MS (EI, 70 e V): m/z (%) = 545 (100, M+), 454 (10, M+ –
PhCH2), 422 (40, M+ – PhCH2S), 393 (20, M+ – PhCH2S –
NCH3), 410 (5), 205 (10). HRMS (EI) calc. for [M+]
C27H31N9O2S 545.2321, observed 545.2349. Anal. Calc. C
59.43; H 5.73; N 23.10. Found: C 59.11; H 5.54; N 22.76.
6-(4,6-Di-morpholin-4-yl-[1,3,5]triazin-2-ylamino)-3H-benzo-
thiazole-2-thione (6) was isolated as a colorless crystalline
product; yield 88 %, decomp. t ~ 220–230 °C. Very slightly
soluble in most organic solvents, except DMF and DMSO;
readily soluble in aqueous KOH, triethylamine, and ammonia.
IR (KBr): 3440, 3100-2800 br. m, 1600, 1580, 1528, 1514,
2-{5-[4-(4,6-Di-morpholin-4-yl-[1,3,5]triazin-2-ylamino)-
phenyl]-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl}-N-p-tolyl-
acetamide (8c). Colorless solid, yield 97 %, mp 174ꢀ176 °C,
IR (KBr): 3440, 3000-2800 (br. m), 1660 (shoulder, C=O),
1610, 1570, 1520, 1500, 1481, 1446, 1410, 1362, 1258, 1113
1
cm-1. H NMR (300 MHz, DMSO-d6): ꢁ 2.32 (s, 3H, CH3Ar),
1
1485, 1444, 1400, 1360, 1258, 1330, 1223, 1110, 1030 cm-1. H
3.48 (s, 3H, N-CH3), 3.64 – 3.76 (m, 16H, Morph), 4.02 (s, 2H,
SCH2), 7.05 – 7.84 (m, 8HAr), 9.22 (s, 1H, NH), 10.25 (s, 1H,
NMR (300 MHz, DMSO-d6): ꢁ 3.62–3.76 (m, 16H, Morph),
7.19 (d, J=7Hz, 2HAr), 7.65 (d, J=7Hz, 2HAr), 7.86 (s, 1HAr),
12.69 (s, 1H, NH) ppm. 13C NMR (75 MHz, DMSO-d6):
ꢁ 43.46, 66.10 (CH2, Morph.), 111.97, 112.31, 119.65, 129.74,
135.98, 137.39, 163.98, 164.69 (8 CAr), 188.32 (C=S) ppm. MS
(EI, 70 eV): m/z (%) = 431 (50) [M+], 399 (100) [M+ – S], 265
(30), 181 (20), 166 (25). HRMS (EI) calc. for [M+]
C18H21N7O2S2 431.1198, observed 431.1186. Anal. Calc. C
50.10; H 4.90; N 22.27. Found: C 49.78; H 4.71; N 22.04.
S-alkylation of compounds 5 and 6; General procedure for
the preparation of compound libraries (compounds 8 and 9).
Reactions were set up in a parallel-synthesis fashion using 20 mL
capacity vials, and were performed on a 0.30-mmol scale in two
groups of three reactions. The solutions of 0.32 mmol of the thiols
5 or 6 and 0.45 mmol of KOH in a mixture MeCN-H2O (1:1 vol.,
5 mL) were added in one portion to 5 mL of MeCN containing
0.30 mmol of the alkylating reagents (methyl iodide, benzyl
chloride or 2-chloro-N-p-tolylacetamide). The resulting solutions
were left for 4 h at 20ꢀ25 °C and then diluted with equal volume
of water. (Bulky precipitates were formed within 5-15 min after
the reagents were combined.) Crystalline solids were collected by
filtration, washed with water (10 mL ꢂ 2) to neutral pH and dried
in air to afford thioethers 8a-a and 9a-c in excellent yields and
with high purity (> 98 %, according to NMR and HPLC).
NH) ppm . 13
C
NMR (75 MHz, DMSO-d6): ꢁ 20.51
(CH3Ar), 31.90 (N-CH3), 37.77 (SCH2), 43.47, 66.10 (CH2,
Morph.), 119.25, 119.33, 119.69, 128.69, 129.26, 132.65,
136.31, 142.06, 149.96, 155.51, 164.10, 164.77 (12CAr), 165.65
(C=O) ppm. MS (EI, 70 eV): m/z (%) = 602 (100) [M+], 511
(20) [M+ – TolNH], 422 (30) [M+ – TolNH(CO)CH2S], 205 (10).
HRMS (EI) calc. for [M+] C29H34N10O3S 602.2536, observed
602.2562. Anal. Calc. C 57.79; H 5.69; N 23.24. Found: C
57.44; H 5.54; N 23.08.
(4,6-Di-morpholin-4-yl-[1,3,5]triazin-2-yl)-(2-methyl-
sulfanyl-benzothiazol-6-yl)-amine (9a). Colorless solid, yield
92 %, mp 173–174 °C, IR (KBr): 3430, 3100-2800 (br. m),
1593, 1564, 1527, 1503, 1477, 1443, 1406, 1360, 1258, 1113
1
cm-1. H NMR (300 MHz, DMSO-d6): ꢁ 2.74 (s, 3H, SCH3),
3.62 – 3.80 (m, 16H), 7.71 – 7.78 (m, 2HAr) 8.24 (s, 1HAr) 9.22
(s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): ꢁ 15.57
(SCH3), 43.41, 66.05 (CH2, Morph.), 111.30, 119.36, 120.64
(br.), 135.01, 137.25, 147.96, 164.06, 164.74 (9CAr) ppm. MS
(EI, 70 eV): m/z (%) = 578 (100) [M+], 430 (20) [M+ – PhCH2],
398 [20, M+ – PhCH2S], 181 (15). HRMS (EI) calc. for [M+]
C19H23N7O2S2 445.1355, observed 445.1361. Anal. Calc. C
51.22; H 5.20; N 22.01. Found: C 50.96; H 5.08; N 21.93.
(2-Benzylsulfanyl-benzothiazol-6-yl)-(4,6-di-morpholin-4-
yl-[1,3,5]triazin-2-yl)-amine (9b). Colorless solid, yield 94 %,
mp 178ꢀ180 °C, IR (KBr): 3430, 3100-2800 (br. m), 1595,
(4,6-Di-morpholin-4-yl-[1,3,5]triazin-2-yl)-[4-(4-methyl-5-
(8a).
methylsulfanyl-4H-[1,2,4]triazol-3-yl)-phenyl]-amine
1
Colorless solid, yield 88 %, mp 149ꢀ151 °C, IR (KBr): 3440,
3000-2800 (br .m), 1602, 1570, 1523, 1500, 1481, 1446, 1410,
1564, 1527, 1500, 1477, 1443, 1406, 1360, 1258, 1113 cm-1. H
NMR (300 MHz, DMSO-d6): ꢁ 3.58–3.76 (m, 16H, Morph.),
4.52 (s, 2H, SCH2), 7.32 – 7.70 (m, 7HAr), 8.26 (s, 1HAr), 9.23 (s,
1H, NH) ppm . 13C NMR (75 MHz, DMSO-d6): ꢁ 36.84 (SCH2),
43.43, 66.10 (CH2, Morph.), 111.32, 119.41, 120.91, 127.63,
1
1361, 1258, 1113 cm-1. H NMR (300 MHz, DMSO-d6): ꢁ =
2.63 (s, 3H, SCH3), 3.52 (s, 3H, N-CH3), 3.64 – 3.76 (m,
16H, Morph), 7.32 (m 5H, Ph) 7.52 (d, J=9Hz, d, 2HAr),

1220
K. Kolmakov
Vol 45
128.63, 129.10, 135.29, 136.70, 137.56, 147.70, 162.93, 164.08,
164.74, (13 CAr) ppm. MS (EI, 70 eV): m/z (%) = 578 (100)
[M+], 430 (20) [M+ – PhCH2], 398 (20) [M+– PhCH2S], 181(15).
HRMS (EI) calc. for [M+] C25H27N7O2S2 521.1668, observed
521.1659. Anal. Calc. C 57.56; H 5.22; N 18.80. Found: C
57.48; H 5.14; N 18.68.
ChemDiv, Inc. for the financial support at the early stage of this
work, and is also grateful to D. J. Harrison (University of
Toronto) for help in preparing the final manuscript.
REFERENCES AND NOTES
2-[6-(4,6-Di-morpholin-4-yl-[1,3,5]triazin-2-ylamino)-benzo-
thiazol-2-ylsulfanyl]-N-p-tolylacetamide (9c). Colorless solid,
yield 96 %, mp 181ꢀ182 °C, IR (KBr): 3440, 3100-2800 (br. m),
1660 (shoulder, C=O), 1606, 1564, 1502, 1527, 1477, 1442,
[1] For various examples of 1,2,4-triazole-3-thiones, 3H-
benzothiazoles and their biological activities see: [a] Mukergee, A. K.;
Ashare, R. Chem. Reviews 1991, 91, 1–24. [b] Wang, Z. Y.; Shi, H. X.;
Shi, H. J. J. Heterocycl. Chem. 2001, 38, 355–357. [c] Chaaban, I.; Oji,
O. O. J. Indian Chem. Soc. 1984, 61, 523. [d] Oruc, E. E.; Rollas, S.;
Kabasakal, L.; Uysal, M. K. Drug Metabolism and Drug Interactions
1999, 15, 127–140. [e] Zahradnik, P.; Sidorova, E.; Frydrych, Z.;
Sevcik, B.; Ceskoslovenska farmacie 1988, 37, 440–442, [f] El-Sherief,
H. A.; Mahmoud, A. M.; Abdel-Rahman, A. E.; El-Naggar, G. M. J.
Indian Chem. Soc. 1983, 60, 58–60.
[2] For the syntheses of biologically active compounds
containing 1,3,5 - triazine core see: [a] Shibuya, I.; Oishi, A.; Yasumoto,
M. Heterocycles 1998, 48, 1659–1662. [b] Agarwal, A.; Srivastava, K.;
Puri, S. K.; Chauhan, Prem M. S. Bioorg. Med. Chem. Lett. 2005, 15,
531–533. [c] Borkoveca, A. B.; De Milo, A. B. J. Med. Chem. 1967, 10,
457. [d] Heitmeier, D. E.; Gray, A. P. J. Med. Chem. 1964, 7, 288. [e]
Irikura, T.; Abe, K.; Okamura, K.; Higo, A.; Maeda, A.; Morinaga, F.;
Hatae, S. J. Med. Chem. 1970, 13, 1081. [f] Goodrow, M. H.; Harrison,
R. O.; Hammock, B. D. J. Agric. Food Chem. 1990, 38, 990–996.
[3] For the nucleophilic substitution in cyanuric chloride and in
2-chloro-4,6-dimorpholin-4-yl-[1,3,5]triazine see: [a] Smolin E. M.;
Rapoport, L. s-Triazines and derivatives Weissberger A.; Ed. The
Chemistry of Heterocyclic Compounds; Interscience, NY-L, 1959, Vol.
13, pp. 53–56. [b] Pearlman, W. M.; Banks, C. K. J. Am. Chem. Soc.
1948, 70, 3726–3728. [c] Kurteva, V. B.; Afonso, C. A. M. Green
Chemistry 2004, 6, 183–187 [d] Mikhailichenko, S. N.; Chesnyuk, A.
A.; Suslov, V. I.; Shkrebets, A. I.; Yukhonenko, M. M.; Zaplishny, V. N.
Izvestiya Vysshikh Uchebnykh Zavedenii, Khimiya i Khimicheskaya
Tekhnologiya 2002, 45, 136–141. [e] Freiberg, R.; Bulka, E. J. Prakt.
Chem. 1985, 327, 471–478.
[4] For the reactions of thioamides with cyanuric chlorides see:
Pollak, A.; Stanovnik, B.; Tiꢀler, M. Can. J. Chem. 1966, 44, 829–832.
[5] For the alkylation of 3H-Benzothiazole-2-thione see: [a]
Kumar, R. V.; Kumar, K.; Gopal, K. R. J. Heterocycl. Chem. 2005, 42,
153–156. [b] Hu, Y.; Chen, Z. C.; Le, Z .G.; Zheng, Q. G. Syn. Comm.
2004, 34, 2039–2046. [c] Orio O. A.; Gaspio, N. B. Annali dell 'Istituto
Superiore di Sanita 1967, 3, 392–394. For the alkylation of 1,2,4-
triazole-3-thiones see: [d] Andersen, H. S.; Kampen, G. C.; Christensen,
I. T.; Mogensen, J. P.; Larsen, A. R. US Pat. 2003-467362 20030502,
2004; Chem. Abstr. 2004, 141, 366233. [e] Klimesova, V.; Zahajska, L.;
Waisser, K.; Kaustova, J.; Mollmann, U. Farmaco 2004, 59, 279.
[6] For the preparation and properties of 6-amino-3H-
benzothiazole-2-thione see: [a] Drozdov, N. S.; Stavrovskaya, V. I.
Zhurnal Obshchei Khimii 1937, 7, 2813–2818. [b] Sidoova, E.;
Odlerova, Z.; Spaldonova, R. Chem. Papers 1985, 39, 543–551.
[7] Kubota S.; Uda, M. Chem. Pharm. Bull. 1975, 23, 955–956.
[8] Rollas, S.; Kalyoncuogly, N.; Sur-Altiner, D.; Yegenogly,
Y.Pharmazie 1993, 48, 308–309.
1
1406, 1360, 1258, 1113 cm-1. H NMR (300 MHz, DMSO-d6):
ꢁ 2.32 (s, 3H, CH3Ar), 3.53 – 3.67 (m, 16H, Morph), 4.31 (s,
2H, SCH2), 7.11 – 7.71 (m, 6HAr), 8.26 (s, 1HAr), 9.22 (s, 1H,
NH), 10.25 (s, 1H, HNCO) ppm. 13C NMR (75 MHz, DMSO-
d6): ꢁ 20.54 (CH3Ar), 37.86 (SCH2), 43.45, 66.12 (CH2,
Morph.), 111.41, 119.27, 119.43, 120.84, 129.31, 132.70,
135.40, 136.34, 137.57, 147.64, 163.02, 164.09, 164.76 (13 CAr),
165.14 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 578 (60) [M+],
472 (30) [M+ ꢀ TolNH], 430 (10) [M+ ꢀ TolNH(CO)CH2], 398
(100) [M+– TolNH(CO)CH2S], 181 (10). HRMS (EI) calc. for
[M+] C27H30N8O3S2 578.1882, observed 578.1889. Anal. Calc. C
56.04; H 5.23; N 19.36. Found: C 55.78; H 5.03; N 19.14.
2-Chloro-N-p-tolylacetamide was obtained from p-toluidine
and chloroacetyl chloride [10]. The melting point (161°C) and
1H NMR spectrum agreed with reported.
Amination of 2-chloro-4,6-dimorpholin-4-yl-[1,3,5]triazine (2)
with aromatic amines in acetic acid medium.
4,6-Di-morpholin-4-yl-[1,3,5]triazin-2-yl)-phenylamine (10a).
Chloride 2 (286 mg, 1 mmol) and aniline (102 mg, 1.1 mmol) were
refluxed for 45 min in 3 mL of AcOH. The solution was quenched
with 20 mL of brine, a colorless precipitate was collected, washed
with water and dried to afford 308 mg (90 %) of chromatographi-
cally (HPLC, TLC) pure compound with mp 173ꢀ174 °C, which is
1
close to that reported in [4] (168ꢀ169 °C). H NMR (300 MHz,
DMSO-d6): ꢁ 3.60 – 3.76 (m, 16H, Morph), 6.89 (t, J = 7.5 Hz,
2HAr), 7.20 (t, J = 8 Hz, 2HAr), 7.63 (d, J = 7.5 Hz, 1HAr), 9.02 (s,
1H, NH) ppm. 13C NMR (75 MHz, DMSO-d6): ꢁ 43.77, 66.52
(CH2, Morph.), 119.95, 121.77, 128.68, 140.75, 164.42, 165.13
(6CAr) ppm. MS (EI, 70 eV): m/z (%) = 342 (100) [M+], 265 (20)
[M+ – Ph], 256 (25) [M+ – Morph]. HRMS (EI) calc. for [M+]
C17H22N6O2 342.1804, observed 342.1803.
4,6-Di-morpholin-4-yl-[1,3,5]triazin-2-yl)-4-nitrophenyl-
amine (10b). 4-Nitroaniline (138 mg, 1 mmol) and chloride 2
(357 mg, 1.25 mmol) were refluxed for 1 h in 3 mL of AcOH
under argon atmosphere. The solution was quenched with 20 mL
of brine; the precipitate was filtered, dissolved in 6 ml of
acetone and diluted with a solution of KOH (30 mg, 0.5 mmol)
and NaCl (2g) in 20 mL of H2O. The solid was collected and
dried. For further purification it was dissolved in 1.5 mL of
pyridine, and boiling benzene (~5 mL) was added. 224 mg (58
%) of the pure compound with m.p. 256–259 °C was isolated
upon cooling. 1H NMR (300 MHz, DMSO-d6): ꢁ 3.60 – 3.76 (m,
16H, Morph), 7.93 (d, J = 9 Hz, 2HAr), 8.13 (d, J = 9 Hz, 2HAr),
9.75 (s, 1H, NH) ppm. 13C NMR (75 MHz, DMSO-d6):
ꢁ 43.89, 66.54 (CH2, Morph.), 118.92, 124.97, 140.92, 147.57,
164.37, 165.06 (6CAr) ppm. MS (EI, 70 eV): m/z (%) = 387
(100) [M+], 341(40) [M+ – NO2], 301 (30) [M+ – Morph.], 255
(30) [M+ – NO2 – Morph.]. HRMS (EI) calc. for [M+]
C17H21N7O4 387.1655, observed 387.1649.
[9] For the reaction of sulfoxides with cyanuric chloride see:
Olah, G. A.; Fung, B. G.; Gupta, B.; Narang, S .C. Synthesis 1980, 221.
[10] Matulenko, M. A.; Surber, B.; Fan, L.; Kolasa, T.; Nakane,
M.; Terranova, M. A.; Uchic, M. E.; Miller, L. N.; Chang, R.; Donnelly-
Roberts, D. L.; Namovic, M. T.; Morel, R. B.; Brioni J. D.; Stewart, A.
O. Bioorg. Med. Chem. 2004, 12, 3471–3483.
[11] For properties of compd. 11 see: Mikhailichenko, S. N.;
Chesniyuk, A. A.; Zavodnik, V. E.; Firgand, S. I.; Konyushkin, L. D.;
Zaplishny, V. N. Chem. Heterocycl. Comp. 2002, 38, 292–299.
[12] For electronic properties of organic solvents see: [a] Mayer,
U.; Gutmann, V.; Gerger, W. Monatshefte für Chemie, 1975, 106, 1235–
1257. [b] Umemura, Y.; Kanno, H.; Takahashi, S. J. Raman
Spectroscopy 1998, 27, 527–531.
Acknowledgement. The author thanks the University of
Toronto Chemistry Department (Canada) for fellowship support,