Regioselective synthesis of imidazo[1,2-a][1,3,5]triazines and 3,4-dihydroimidazo[1,2-a][1,3,5]triazines from [1,3,5]triazin-2,4-diamines

Article abstract of DOI:10.1016/j.tet.2013.03.039

An efficient and practical procedure was developed to prepare novel imidazo[1,2-a][1,3,5]triazines and 3,4-dihydroimidazo[1,2-a][1,3,5]triazines with a good regioselectivity and high yields, starting from dicyandiamide and the corresponding arylamines. Mechanistic studies for the subsequent cyclocondensation with chloroacetaldehyde support a pathway, which begins with the displacement of the chloro atom activated by an adjacent CO group, followed by cyclization and dehydration.

Full text of DOI:10.1016/j.tet.2013.03.039

Tetrahedron 69 (2013) 3867e3871
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective synthesis of imidazo[1,2-a][1,3,5]triazines and
3,4-dihydroimidazo[1,2-a][1,3,5]triazines from [1,3,5]triazin-2,4-
diamines
*
Pascal Dao, Christiane Garbay, Huixiong Chen
ꢀ
ꢀ
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601, CNRS, Universite Paris Descartes, PRES Sorbonne Paris Cite, 45 rue
ꢁ
des Saints-Peres, 75270 Paris Cedex 06, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and practical procedure was developed to prepare novel imidazo[1,2-a][1,3,5]triazines and
3,4-dihydroimidazo[1,2-a][1,3,5]triazines with a good regioselectivity and high yields, starting from di-
cyandiamide and the corresponding arylamines. Mechanistic studies for the subsequent cyclo-
condensation with chloroacetaldehyde support a pathway, which begins with the displacement of the
chloro atom activated by an adjacent CO group, followed by cyclization and dehydration.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 21 December 2012
Received in revised form 28 February 2013
Accepted 12 March 2013
Available online 14 March 2013
Keywords:
Nitrogen heterocycles
Cyclization
Regioselectivity
Reaction mechanisms
1. Introduction
[1,3,5]triazines, which are very attractive heterocyclic units and
could exhibit important biological properties. The current study
1,3,5-Triazine derivatives and their analogues of dihydro-1,3,5-
triazines, one group of compounds known for a long period of
time, have a wide array of biological activities, including antican-
cer,1 anti-angiogenesis,2 anti-HIV,3 antimalarial,4 antibacterial,5
and antimicrobial activity.6
was aimed at the synthesis of these compounds and their reduced
analogues by starting from [1,3,5]triazin-2-ylamine derivatives 2
(Scheme 1), which are synthesized in two steps from the
microwave-assisted reaction of cyanoguanidine with amines and
further with esters.14
Fused heterocyclic 1,3,5-triazine structures have also been de-
veloped and used as important core structures in many chemo-
therapeutic agents due to their interesting pharmacological
properties. Many such fused heterocyclic compounds, as imidazo
[1,5-a][1,3,5]triazines, imidazo[1,2-a][1,3,5]triazines, pyrazolo[1,5-
a][1,3,5]triazines, [1,2,4]triazolo[2,3-a][1,3,5]triazines, and benzi-
midazo[1,2-a][1,3,5]triazines, have been synthesized by several
methods.7e10 The imidazo[1,5-a][1,3,5]triazine derivatives have
been reported as potential agents against influenza A and re-
spiratory syncytial virus.11 The pyrazolo[1,5-a][1,3,5]triazines have
been used as good corticotropin-releasing factor antagonists, which
makes them drug candidates for depressing and anxiety.12 How-
ever, only a few of imidazo[1,2-a][1,3,5]triazine derivatives have
been documented in the literature.13
Scheme 1. Reagents and conditions: (a) morpholine/dioxane/MW, 90 ꢀC, 15 min; (b)
R1CO2Et/MeONa/THF/MW, 70 ꢀC, 20 min; (c) 2-chloroacetaldehyde/DMSO, 120 ꢀC; (d)
H2/PtO2, 20 h.
As part of our programme investigating fused ring 1,3,5-triazine
derivatives, we are particularly interested in the imidazo[1,2-a]
2. Results and discussion
In the initial condensation of 4-methyl-6-morpholino-1,3,5-
triazin-2-amine 2a with 4.2-fold excess of 2-chloroacetaldehyde
in DMSO, surprisingly, we obtained only one isomeric product 3a
* Corresponding author. Tel.: þ33 1 42 86 4085; fax: þ33 1 42 86 4082; e-mail
address: huixiong.chen@parisdescartes.fr (H. Chen).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.039

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P. Dao et al. / Tetrahedron 69 (2013) 3867e3871
with high yield. In theory, it was possible from this cyclo-
condensation to obtain a pair of isomeric products (3a and 3a0),
which differ on the position of the imidazole ring (Fig. 1), because
the starting compound 2a is differently substituted in the 4 and 6
positions. NOE experiments unambiguously established the struc-
ture, because positive NOE effects were obtained between protons
H9 and methyl group for 3a and not with NeCH2 of the morpholine
ring (3a0). The same results were also obtained for compounds
3bee. This regioselectivity is probably due to steric hindrance of
the morpholino group, which prevents the approach of 2-
chloroacetaldehyde. The excellent regioselectivity is observed if
this morpholino group is replaced by other secondary amines.
However, the use of primary amines, such as aniline derivatives led
to the other regioisomer as a minority (not published results).
Fig. 1. NOE studies of 3a (similar NOESY is observed for 3bee).
Naturally, it was interesting to elucidate the mechanism of
this reaction. The steps for the two mechanisms to be suggested
are shown in Scheme 2 for the cyclocondensation of 2a with
2-chloroacetaldehyde as the initial step, which gives imidazo
[1,2-a][1,3,5]triazine 3a as the final product. We followed
changes during reaction, which were monitored by 1H NMR
spectroscopy (DMSO-d6) at 60 ꢀC. Since hydrogen chloride is
generated during the reaction, the various bases (2a, D, E, and
3a) are in equilibrium with the protonated forms.
The changes in the 1H NMR spectra, illustrated in Fig. 2 show
a much greater complexity at intermediate times than at the end of
the reaction, together with the disappearance of the signals due to
2a and intermediates. The data show clearly that one intermediate
E is formed, that is, concurrent with the formation of product 3a.
This relatively long-lived intermediate was also isolated and char-
acterized by means of 1H and 2D-NOE spectra. 1H NMR (Table 1)
indicates that the intermediate EHþ has the structure shown in
Scheme 2. The most characteristic data for 1H NMR spectra is the
presence in the region 4.0e5.7 ppm of three pairs of doublet of
doublets signals. Two doublets of doublets were assigned to the
intrinsically non-equivalent CH2 protons of the five-membered
ring, that shows the typical large coupling (J¼12.4 Hz) of geminal
protons. The third doublet of doublets, assigned also to the five-
membered ring was due to vicinal proton-proton coupling between
CH and two protons of CH2. Furthermore, positive NOE effects were
also obtained between the two protons H9 and CH3 of EHþ and not
with NeCH2 of the morpholino ring. However, the intermediates C
and D were not detectable.
As shown in the 0-min spectrum, we could observe that the
hydrate form of 2-chloroacetaldehyde is formed and these two
compounds are in equilibrium with each other. The 1-min spec-
trum shows the emergence of the imidazole and methyl groups of
the final product (3aHþ). These signals become deshielded by the
acid liberated during the consumption of the intermediate EHþ. The
two signals at 4.1 and 4.4 ppm and the third one at 5.6 ppm,
assigned to protons adjacent to nitrogens of five-membered ring in
structure E, fail to move downfield significantly during the course
of the reaction. This intermediate therefore exists primarily in the
Scheme 2. Possible mechanism for the cyclocondensation of 2a into 3a.
protonated form EHþ since E must be a stronger base than 2a. The
intensity of the signals of 2a, EHþ and 3a changes in function of the
reaction time. When no further changes occur, all of the signals
can be assigned to product 3a and remaining of excess of
2-chloroacetaldehyde.
The gradual downfield shift of the methyl group signal of 2a
occurs only if 2a is in rapid equilibrium with another species having
higher chemical shifts. This condition is satisfied by the formation
of acid, which is possible only when D and/or E are formed in
significant amount. Formation of C does not generate Hþ. Therefore,
the most likely species in equilibrium with E is DHþ, which could
probably proceed via slower formation of D than its conversion to
EHþ. However, the above data could not exclude another mecha-
nism, which could proceed via path b.
To gain further support for the mechanism, which is favoured
through path a, the methylation of 2a by iodomethane was per-
formed (Scheme 3). As it could be expected, this reaction produced
5 as a single product. The structure of 5 was unambiguously char-
acterized by a combined application of 1H, 13C NMR, (1He13C)
HSQC, (1He13C) HMBC, and 2D-NOE. Positive NOE effects were
observed between protons of the two methyl groups.
These results suggest that the mechanism through path b in
Scheme 2 is improbable. The fact that path a is favoured over path
b could be explained by a lower energy of the transition state for
the displacement of the chloro atom when activated by an adjacent

P. Dao et al. / Tetrahedron 69 (2013) 3867e3871
3869
was unsuccessful. To our surprise, when the reaction was carried
out with 10% of PtO2, not only the nitro group is reduced to an
amine but also the triazine ring is reduced to dihydrotriazine ring,
to form a new heterocyclic system, which, to our knowledge, has
not yet been described in the literature. Similar results have been
obtained for 3aed, which gave 4aed with good yields.
In conclusion, we have developed an efficient and simple ap-
proach to imidazo[1,2-a][1,3,5]triazines with excellent regiose-
lectivity. A mechanism for the cyclocondensation between 4-methyl-
6-morpholino-1,3,5-triazin-2-amine 2a and 2-chloroacetaldehyde
was proposed and discussed on the basis of experimental results. By
means of NMR spectroscopy the structure was established of a stable
intermediate product, 4,7-dimethyl-2-morpholino-6,7,8,8a-tetrahy-
droimidazo[1,2-a][1,3,5]-triazin-7-ol, whose dehydration yielded the
above imidazo[1,2-a][1,3,5]triazines. We have also described the
synthesis of the hydrogenated analogues of imidazo[1,2-a][1,3,5]tri-
azines, 3,4-dihydroimidazo[1,2-a][1,3,5]triazines as a new heterocy-
clic system.
Fig. 2. Partial 500 MHz 1H NMR spectra of a DMSO-d6 solution recorded 1, 2, 3, 5 min at
60 ꢀC after mixing 4-methyl-6-morpholino-1,3,5-triazin-2-amine 2a with chlor-
oacetaldehyde. The bottom scan is the sum of separately recorded spectra of the two
starting materials at 27 ꢀC. The top scan was recorded when no further changes occurred
(20 min) at 60 ꢀC. Relevant assignments are as follows: bottom scan: 2.31 (s): CH3 protons
of 2a; 4.46 (s): CH2 protons of B; 4.88 (t): CH proton of B0 signals; 6.74 (broad peak): NH2
protons of 2a and 9.51 (s): CHO of B. Signals connected by dotted lines on intermediate
times (2, 3, 5 min): 2aþ2aHþ: CH3 (s) of protonated and non-protonated species; EHþ:
CH3 (s), CH9a (dd), CH9b (dd) and CH8 (dd). Top scan: 2.78 (s): CH3 protons of 3aHþ, 7.62
(d): CH8 proton of imidazole ring, 7.86 (d): CH9 proton of imidazole ring.
3. Experimental section
3.1. General
All commercial materials were used without further purifica-
tion. Microwave irradiation was carried out with a microwave
monomode reactor (IR detector for temperature). Melting points
were determined on a Kofler apparatus as uncorrected values.
Analytical thin-layer chromatography was performed on precoated
Table 1
1H NMR chemical shifts (
d
, ppm) of compounds EHþa and 5b
250
UV light. Column chromatography was performed using Silica gel
60 (40e63
m). 1H NMR and 13C NMR spectra were measured on
250 MHz or 500 MHz spectrometer in DMSO-d6 or CDCl3 or CD3CN
with chemical shift ( ) given in parts per million (ppm) relative to
mm layer thickness silica gel 60 F254 plates and visualized with
m
d
TMS as internal standard and recorded at 23 ꢀC. MS (ESI) was de-
termined by using a Q-Tof1 spectrometer with Z-spray source.
High-resolution mass spectra (HRMS) were performed on Q-TOF
Micro micromass positive ESI (CV¼30 V).
EH+
5
CH3
NCH3
2.43 (s)
2.52 (s)
3.45 (s)
3.77 (t)
3.2. General method for the synthesis of compounds 2
b
a
-CH2
-CH2
3.71 (t)
3.84 (t), 3.94 (t)
3.77 (t), 3.86 (t)
8.30 (s), 8.83 (s)
A mixture of sodium methoxide (1.5 mmol) prepared from Na
and methanol, arylbiguanide hydrochloride (1 mmol) 1,14 and ester
(3 mmol) in dry THF (5 mL) was introduced into a round-bottomed
flask equipped with a condenser and a magnetic stirring bar. The
flask was placed in the microwave cavity and exposed to microwave
irradiation for 20 min at 70 ꢀC using irradiation power of 100 W. On
cooling to room temperature, the mixture was evaporated under
vacuum, and the residue was subjected to flash chromatography
(silica gel, 5% methanol/CH2Cl2) to afford the desired product as
a white solid.
NH2
Ha
Hb
Hc
OH
NH
4.08 (dd)
4.37 (dd)
5.68 (dd)
5.04 (br s)
(s)
a
In CD3CN.
In DMSO-d6.
b
3.2.1. 6-Methyl-4-morpholino-1,3,5-triazin-2-amine (2a). White solid,
mp 192 ꢀC (lit.,15 192 ꢀC), 181.6 mg (93%). 1H NMR (250 MHz, DMSO):
d
2.11 (s, 3H), 3.57 (t, J¼4.8 Hz, 4H), 3.66 (t, J¼4.8 Hz, 4H), 6.73 (s, 2H).
13C NMR (500 MHz, DMSO):
d 176.3, 168.6, 166.5, 68.0, 45.0, 27.0. MS
(ESI) m/z 196.1 [MþH]þ.
Scheme 3.
3.2.2. 4-Morpholino-1,3,5-triazin-2-amine (2b). White solid, mp
221 ꢀC (lit.,16 215e216 ꢀC), 177.5 mg (98%). 1H NMR (250 MHz,
CO group in 2-chloroacetaldehyde. The nitrogen of the triazinic ring
serves as a nucleophilic site for the first step of the mechanism and
not the amine function. This is due to the delocalization of its
doublet in the triazinic ring.
DMSO):
d
3.6 (t, J¼4.8 Hz, 4H), 3.64 (t, J¼4.8 Hz, 4H), 6.87 (s, 2H),
8.04 (s, 1H). 13C NMR (500 MHz, DMSO):
d 166.2, 165.7, 163.9, 65.9,
43.0. MS (ESI) m/z 182.1 [MþH]þ.
Initially, the reduction of the 4-(4-(2-nitrophenyl)-3,4-
dihydroimidazo[1,2-a][1,3,5]triazin-2-yl)morpholine 3e by hydro-
genation in the presence of Pd/C or Ni using standard procedures
3.2.3. 4-Morpholino-6-p-tolyl-1,3,5-triazin-2-amine (2c). White solid,
mp 167 ꢀC (lit.,17 165e166 ꢀC), 196.5 mg (72.5%). 1H NMR (250 MHz,
DMSO):
d
2.36 (s, 3H), 3.64 (t, J¼4.7 Hz, 4H), 3.78 (t, J¼4.7 Hz, 4H),

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P. Dao et al. / Tetrahedron 69 (2013) 3867e3871
6.89 (s, 2H), 7.27 (d, J¼8.2 Hz, 4H), 8.19 (d, J¼8.2 Hz, 4H). 13C NMR
d 156.9, 156.1, 150.2, 148.9, 134.0, 133.7, 133.3, 129.1, 128.7, 124.8,
(500 MHz, DMSO):
d
169.6, 167.1, 164.9, 141.1, 134.2, 128.7, 127.8, 66.0,
107.4, 65.6, 43.9, 36.9. MS (ESI) m/z 341.1 [MþH]þ. ESI-HRMS m/z
43.1, 21.0. MS (ESI) m/z 272.1 [MþH]þ.
calcd for C16H17N6Oþ3 [MþH]þ 341.1362, found 341.1355.
3.2.4. 4-Morpholino-6-(2-benzyl)-1,3,5-triazin-2-amine (2d). White
3.4. General method for the synthesis of compounds 4
solid, mp 150 ꢀC, 271 mg (100%). 1H NMR (250 MHz, DMSO):
d
2.13
(3H, s, CH3), 3.57 (t, J¼4.8 Hz, 4H), 3.65 (t, J¼4.8 Hz, 4H), 3.67 (s, 2H),
6.81 (s, 2H), 7.27 (m, 5H). 13C NMR (500 MHz, DMSO):
178.0, 168.8,
To a solution of compound 3 (0.2 mmol) in methanol (10 mL),
10% platinum oxide (5 mg) is added under a nitrogen atmosphere.
The reaction vessel is charged with hydrogen and evacuated three
times until the reaction is under a hydrogen atmosphere. The re-
action is stirred overnight. The reaction mixture is filtered through
a pad of Celite and washed with methanol. The filtrate is concen-
trated to a small volume, and purified by flash chromatography.
d
166.7, 139.9, 130.9, 130.1, 128.1, 67.8, 46.7, 45.0. MS (ESI) m/z 272.1
[MþH]þ.
3.2.5. 4-Morpholino-6-(2-nitrobenzyl)-1,3,5-triazin-2-amine
(2e). White solid, mp 154 ꢀC, 261.1 mg (82.6%). 1H NMR (250 MHz,
DMSO): d 2.18 (3H, s), 3.53 (8H, s), 4.17 (2H, s), 6.79 (2H, s), 7.51 (2H,
m), 7.66 (1H, td, J¼7.5, 1.4 Hz), 7.98 (1H, dd, J¼8, 1.7 Hz). 13C NMR
3.4.1. 4-(4-Methyl-3,4-dihydroimidazo[1,2-a][1,3,5]triazin-2-yl)-
(500 MHz, DMSO):
d
174.4, 166.6, 164.3, 149.6, 133.3, 131.8, 128.0,
morpholine (4a). Light-yellow solid, mp 260 ꢀC dec, 42.5 mg (96%).
124.3, 65.8, 43.0, 40.5. MS (ESI) m/z 317.1 [MþH]þ.
1H NMR (250 MHz, DMSO):
d
1.5 (d, J¼5.65 Hz, 3H), 3.4 (t, J¼4.54 Hz,
4H), 3.62 (t, J¼4.54 Hz, 4H), 5.48 (q, J¼5.7 Hz, 1H), 6.69 (s, 1H), 6.81
3.3. General method for the synthesis of compounds 3
(s, 1H), 7.28 (br s, 1H). 13C NMR (500 MHz, DMSO):
d 153.6, 147.6,
123.3, 110.6, 65.7, 61.6, 44.9, 22.3. MS (ESI) m/z 222.1 [MþH]þ. ESI-
A solution of compound 2 (0.5 mmol) and 2-chloroacetaldehyde
(50% in H2O, 0.2 mL, 2.1 mmol) in DMSO was stirred at 120 ꢀC for
7 h. After being cooled, the solvent was removed under reduced
pressure and the residue was treated with NaHCO3 saturated
aqueous solution. This alkaline mixture was extracted with CH2Cl2
(3ꢁ20 mL). The combined extracts were dried (Na2SO4), reduced to
a small volume and purified by flash chromatography.
HRMS m/z calcd for C10H16N5Oþ [MþH]þ 222.1355, found 222.1347.
3.4.2. 4-(3,4-Dihydroimidazo[1,2-a][1,3,5]triazin-2-yl)morpholine
(4b). Light green solid, mp 228 ꢀC, 38.5 mg (93%). 1H NMR
(250 MHz, DMSO):
d
3.39 (t, J¼4.7 Hz, 4H), 3.61 (t, J¼4.7 Hz, 4H),
5.17 (s, 2H), 6.61 (d, J¼1.5 Hz, 1H), 6.65 (d, J¼1.5 Hz, 1H), 7.48 (br s,
1H). 13C NMR (500 MHz, DMSO):
d 153.7, 148.3, 126.0, 111.0, 65.8,
54.4, 44.9. MS (ESI) m/z 208.1 [MþH]þ. ESI-HRMS m/z calcd for
3.3.1. 4-(4-Methylimidazo[1,2-a][1,3,5]triazin-2-yl)morpholine
C9H14N5Oþ [MþH]þ 208.1198, found 208.1187.
(3a). White solid, mp 196 ꢀC, 91 mg (83.1%). 1H NMR (250 MHz,
DMSO):
d
2.68 (s, 3H), 3.65 (t, J¼4.8 Hz, 4H), 3.76 (t, J¼4.8 Hz, 4H),
3.4.3. 4-(4-p-Tolyl-3,4-dihydroimidazo[1,2-a][1,3,5]triazin-2-yl)-
7.27 (d, J¼1.5 Hz, 1H), 7.57 (d, J¼1.5 Hz, 1H). 13C NMR (500 MHz,
morpholine (4c). Light- yellow, mp 216 ꢀC, 55.3 mg (93%). 1H NMR
DMSO):
d
159.1, 158.7, 152.1, 134.4, 109.7, 67.8, 46.1, 22.3. MS (ESI)
(250 MHz, DMSO):
d
2.32 (s, 3H), 3.60 (t, J¼4.8 Hz, 4H), 3.64 (t,
m/z 220.1 [Mþ1]þ. ESI-HRMS m/z calcd for C10H14N5Oþ [MþH]þ
J¼4.8 Hz, 4H), 6.74 (d, J¼3.05 Hz, 1H), 6.9 (d, J¼2.45 Hz, 1H), 7.13 (d,
220.1198, found 220.1189.
J¼2.52 Hz, 1H), 7.27 (s, 4H), 8.84 (d, J¼2.64 Hz, 1H). 13C NMR
(500 MHz, DMSO):
d 154.2, 146.5, 139.5, 135.4, 129.6, 126.3, 114.8,
3.3.2. 4-(Imidazo[1,2-a][1,3,5]triazin-2-yl)morpholine (3b). Light-
113.1, 66.6, 65.5, 44.8, 20.7. MS (ESI) m/z 298.1 [MþH]þ. ESI-HRMS
yellow solid, mp 180 ꢀC, 85.3 mg (83.2%). 1H NMR (250 MHz,
m/z calcd for C16H20N5Oþ [MþH]þ 298.1668, found 298.1657.
DMSO):
d
3.62 (t, J¼4.7 Hz, 4H), 3.72 (t, J¼4.7 Hz, 4H), 7.22 (d,
J¼1.3 Hz, 1H), 7.47 (d, J¼1.3 Hz, 2H), 9.21 (s, 1H). 13C NMR (500 MHz,
3.4.4. 4-(4-Benzyl-3,4-dihydroimidazo[1,2-a][1,3,5]triazin-2-yl)-
DMSO):
d
156.8, 149.3, 148.3, 133.1, 108.3, 65.8, 44.2. MS (ESI) m/z
morpholine (4d). Yellow solid, mp 203 ꢀC, 52.9 mg (89%). 1H NMR
206.0 [Mþ1]þ. ESI-HRMS m/z calcd for C9H12N5Oþ [MþH]þ
(250 MHz, DMSO):
d
2.92 (dd, J¼4.0, 13.6 Hz, 1H), 3.0 (dd, J¼4.0,
206.1042, found 206.1037.
13.6 Hz, 1H), 3.3 (t, J¼4.3 Hz, 4H),3.52 (t, J¼4.37 Hz, 4H), 5.8 (t,
J¼4.3 Hz, 1H), 6.61 (s, 1H), 6.72 (s, 1H), 7.0 (dd, J¼1.4, 7.1 Hz, 1H), 7.22
3.3.3. 4-(4-p-Tolylimidazo[1,2-a][1,3,5]triazin-2-yl)morpholine
(m, 4H). 13C NMR (500 MHz, DMSO):
d 154.5, 149.6, 137.0, 131.9, 129.9,
(3c). Light-yellow solid, mp 174 ꢀC, 119.7 mg (81.1%). 1H NMR
128.5, 127.2, 112.8, 67.7, 46.8, 44.9. MS (ESI) m/z 298.1 [MþH]þ. ESI-
(250 MHz, DMSO):
d
2.43 (s, 3H), 3.68 (t, J¼4.7 Hz, 4H), 3.81 (t,
HRMS m/z calcd for C16H20N5Oþ [MþH]þ 298.1668, found 298.1655.
J¼4.7 Hz, 4H), 7.33 (d, J¼1.3 Hz, 1H), 7.44 (d, J¼8.2 Hz, 1H), 7.61 (d,
J¼1.3 Hz, 2H), 7.9 (d, J¼8.2 Hz, 2H). 13C NMR (500 MHz, DMSO):
3.4.5. 4-(4-(2-Nitrobenzyl)-3,4-dihydroimidazo[1,2-a][1,3,5]triazin-
d
156.8, 155.4, 151.2, 142.6, 133.5, 129.5, 128.8, 128.7, 108.2, 65.9,
2-yl)morpholine (4e). Yellow solid, mp 206 ꢀC, 58.7 mg (94%). 1H
44.2, 21.1. MS (ESI) m/z 296.1 [MþH]þ. ESI-HRMS m/z calcd for
NMR (250 MHz, DMSO):
d
2.73 (dd, J¼14, 4.7 Hz,1H), 2.92 (dd, J¼14,
C16H18N5Oþ [MþH]þ 296.1511, found 296.1506.
4.7 Hz, 1H), 3.34 (t, J¼4.3 Hz, 4H), 3.58 (t, J¼4.3 Hz, 4H), 4.97 (br s,
2H), 5.67 (t, J¼5.6 Hz, 1H), 6.46 (t, J¼7.5 Hz, 1H), 6.57 (s, 1H), 6.64 (d,
J¼7.5 Hz, 1H), 6.68 (s, 1H), 6.69 (d, J¼7.5 Hz, 1H), 6.87 (s, 1H), 6.94 (t,
3.3.4. 4-(4-Benzylimidazo[1,2-a][1,3,5]triazin-2-yl)morpholine
(3d). Light-yellow solid, mp 152 ꢀC, 134.3 mg (91%). 1H NMR
J¼7.5 Hz, 1H). 13C NMR (500 MHz, DMSO):
d 151.5, 146.8, 139.2,
(250 MHz, DMSO):
d
3.64 (t, J¼4.7 Hz, 4H), 3.72 (t, J¼4.7 Hz, 4H),
128.0, 127.6, 124.9, 118.9, 116.2, 115.0, 111.1, 65.8, 44.9, 40.4. MS (ESI)
m/z 313.2 [MþH]þ. ESI-HRMS m/z calcd for C16H21N6Oþ [MþH]þ
313.1777, found 313.1769.
4.38 (s, 1H), 7.27 (d, J¼1.9 Hz, 1H), 7.28e7.43 (m, 5H), 7.69 (d,
J¼1.9 Hz, 1H), 7.9 (d, J¼8.2 Hz, 2H). 13C NMR (500 MHz, DMSO):
d
156.1, 156.7, 150.5, 134.0, 133.0, 129.2, 128.5, 127.1, 107.5, 65.8, 44.1.
MS (ESI) m/z 296.1 [MþH]þ. ESI-HRMS m/z calcd for C16H18N5Oþ
3.4.6. 2-Amino-1,6-dimethyl-4-morpholino-1,3,5-triazinium iodide
5. A mixture of compound 2 (100 mg, 0.51 mmol) and methyl io-
dide (1 mL, 16 mmol) and DMF (1 mL) was heated at reflux for 6 h.
The mixture was cooled, the solvent removed under reduced
pressure and the residue was crystallized from methanol and ether.
White solid, mp 183 ꢀC, 99.2 mg (93%). 1H NMR (250 MHz,
[MþH]þ 296.1511, found 296.1503.
3.3.5. 4-(4-(2-Nitrobenzyl)imidazo[1,2-a][1,3,5]triazin-2-yl)morpho-
line (3e). Light-yellow solid, mp 196 ꢀC, 129.9 mg (76.4%). 1H NMR
(250 MHz, DMSO):
d 3.53 (s, 8H), 4.88 (s, 2H), 7.38 (s, 1H), 7.81 (m,
2H), 7.67 (m, 2H), 8.16 (d, J¼8 Hz, 1H). 13C NMR (500 MHz, DMSO):
DMSO):
d
2.52 (s, 3H), 3.45 (s, 3H), 3.66 (m, 4H), 3.77 (t, J¼4.8 Hz,

P. Dao et al. / Tetrahedron 69 (2013) 3867e3871
3871
2H), 3.86 (t, J¼4.8 Hz, 2H), 8.30 (s, 1H), 8.83 (s, 1H). 13C NMR
3. Daeyaert, F. F. D.; De Corte, B.; De Jonge, M. R.; Heeres, J.; Ho, C. Y.; Janssen, P. A. J.;
Kavash, R.W.; Koymans, L. M. H.; Kukla, M. J.; Ludovici, D. W. PCT Int. Appl., 1999,
WO 9950256 A1 19991007.
4. Agarwal, A.; Srivastava, K.; Puri, S. K.; Chauhan, P. M. S. Bioorg. Med. Chem. Lett.
2005, 15, 531e533.
(500 MHz, DMSO):
d 167.3, 158.6, 156.8, 65.8, 65.5, 44.2, 43.9, 34.4,
22.8. MS (ESI) m/z 210.1 [MþH]þ. ESI-HRMS m/z calcd for
C9H16N5Oþ [MþH]þ 210.1349, found 210.1341.
5. Solankee, A.; Kapadia, K.; Solankee, S.; Patel, G. J. Indian Chem. Soc. 2009, 868,
837e840.
Acknowledgements
ꢀ
6. Solankee, A.; Kapadia, K.; Ana, C.; Sokovic, M.; Doytchinova, I.; Geronikaki, A.
Eur. J. Med. Chem. 2010, 452, 510e518.
7. Han, B.; Jaun, B.; Krishnamurthy, R.; Eschenmoser, A. Org. Lett. 2004, 6,
3691e3694.
8. Tam, S. Y. K.; Klein, R. S.; Wempen, I.; Fox, J. J. J. Org. Chem. 1979, 44,
4547e4553.
We thank Dr. Le Corre Laurent for the use of microwave reactor,
Dr. Bertho Gildas for the use of NMR spectrometer and Assia
Hessani for the mass spectra recording.
9. Federico, S.; Paoletta, S.; Cheong, S. L.; Pastorin, G.; Cacciari, B.; Stragliotto, S.;
Klotz, K. N.; Siegel, J.; Gao, Z. G.; Jacobson, K. A.; Moro, S.; Spalluto, G. J. Med.
Chem. 2011, 54, 877e889.
Supplementary data
10. Lalezari, I.; Nabahi, S. J. Heterocycl. Chem. 1980, 17, 1121e1123.
11. Golankiewicz, B.; Januszczyk, P.; Ikeda, S.; Balzarini, J.; De Clercq, E. J. Med.
Chem. 1995, 38, 3558e3565.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.03.039.
12. Elnagdi, M. H.; El-Moghayar, M. R. H.; Fleita, D. H.; Hafez, E. A. A.; Fahmy, S. M. J.
Org. Chem. 1976, 41, 3781e3784.
References and notes
13. Kobe, J.; Stanovnik, B.; Tisler, M. Chem. Commun. (London) 1968, 22, 1456.
14. Dao, P.; Laporte, A.; Garbay, C.; Chen, H. Tetrahedron 2012, 68, 3856e3860.
15. Chen, H.; Dao, P.; Laporte, A.; Garbay, C. Tetrahedron Lett. 2010, 51,
3174e3176.
1. Brzozowski, Z.; Saczewski, F.; Gdaniec, M. Eur. J. Med. Chem. 2000, 35,
1053e1056.
16. Takagi, K.; Ueda, T. Chem. Pharm. Bull. 1969, 17, 1061e1064.
17. Colautti, A.; Maurich, V. Farmaco Sci. 1973, 28, 531e538.
2. Ono, M.; Kawahara, N.; Goto, D.; Wakabayashi, Y.; Ushiro, S.; Yoshida, S.; Izumi, H.;
Kuwano, M.; Sato, Y. Cancer Res. 1996, 56, 1512e1516.