Studies on pyrrolidinones: Chemistry of dimethoxytriazines

Article abstract of DOI:10.1055/s-0033-1338298

The synthesis of dimethoxytriazine-containing N-aryl substituted pyrrolidinones is realized for the first time. Three new modes of reactivity for these substrates possessing a 4,6-dimethoxy-1,3,5-triazine unit are discussed. Their treatment with acid lead

Full text of DOI:10.1055/s-0033-1338298

PAPER
▌1333
paper
Studies on Pyrrolidinones: Chemistry of Dimethoxytriazines
Chemistry of Dimethoxytriazines
Liliana Lucescu,a Philippe Gautret,b,c Souhila Oudir,b,c Benoît Rigo,b,c Dalila Belei,a Elena Bîcu,a Alina Ghinet*a,b,c
a
Department of Organic Chemistry, ‘Al. I. Cuza’ University of Iasi, Faculty of Chemistry, Bd. Carol I nr. 11, 700506 Iasi, Romania
b
Université Lille Nord de France, 59000 Lille, France
c
UCLille, EA 4481 (GRIIOT), Laboratoire de Pharmacochimie, HEI, 13 rue de Toul, 59046 Lille, France
Fax +33(328)384804; E-mail: alina.ghinet@hei.fr
Received: 30.01.2013; Accepted after revision: 11.03.2013
N
N
Abstract: The synthesis of dimethoxytriazine-containing N-aryl
substituted pyrrolidinones is realized for the first time. Three new
modes of reactivity for these substrates possessing a 4,6-dimethoxy-
1,3,5-triazine unit are discussed. Their treatment with acid leads to
complete O-demethylation of the methoxy groups, while similar re-
action in a basic medium leads to partial O-demethylation. In con-
trast, heating in the presence of dimethyl sulfate as the catalyst
induces migration of the methyl groups from the oxygen atoms to
the triazine nitrogens (Hilbert–Johnson transposition). These new
scaffolds may demonstrate biological potential.
X
Y
O
O
N
O
N
R
R
2 R = Me, Cl, Y = Me, SO2Me
1 R = H, X = CN
OMe
N
OMe
N
N
N
O
Key words: arylation, cleavage, carboxylic acids, zinc, ring closure
O
N
N
N
N
OMe
OMe
R1
The s-triazine (1,3,5-triazine) moiety is a widespread het-
erocyclic system, which can be utilized as a synthetic
pharmacophore with considerable therapeutic potential.1
While less studied than pyrimidines, the biological impor-
tance of triazines has made them attractive synthetic tar-
gets. Many derivatives of this class of compounds have
been synthesized, mainly for their antifungal2 and
herbicidal3 properties. We have previously reported that
several N-benzylpyrrolidinones, such as 14 and 2,5 exhibit
antifungal activities, and have investigated the synthesis
of heterocyclic compounds 3 containing an N-benzylpyr-
rolidinone group linked to a 4,6-dimethoxy-1,3,5-triazine
moiety, with potential biostatic properties6 (Figure 1). In
continuation of this research, we were interested by the
possibility of attaching 1,3,5-triazinone and 1,3,5-triazine-
dione cores to pyrrolidinones (at C-5). Herein, we report
the synthesis of novel triazines 3 and 4, the total or partial
hydrolysis of their methoxy groups, and the Hilbert–
Johnson transposition of these compounds.
R2
R
3 R1, R2 = H, Me, Cl
4
Figure 1 Structures of N-benzylpyrrolidinones 1, 2 and 3
the novel dimethoxytriazines 3c, 4a and 4b (Scheme 1).
Acid chlorides 7a and 7b were obtained via the copper-
catalyzed N-arylation of methyl DL-pyroglutamate
(8),10,11 saponification of the intermediate esters 9a10 and
9b thus obtained, and then treatment of the acids 10a and
10b with thionyl chloride (Scheme 1).
There are no reports on the synthesis of 2-alkyltriazine-
4,6-diones in the literature. In the field of dialkoxytri-
azines substituted at C-2 by an amino12 or
a
propargyloxy13 group, reflux of the substrate in dilute hy-
drochloric acid or heating at 180 °C led to the formation
of the corresponding di- (or tri)-carbonyl compound. In
the dimethoxypyrimidine series, many different reagents
have been utilized to realize such total hydrolysis
(Me3SiX14 in the presence of NaI,15 CH3COX16 which is
considered to be better,15b or heating in aqueous HCl,17
which is described18 as the superior method). Neverthe-
less, with dimethoxypyridine19 or pyrimidine,20 partial hy-
drolysis can occur, sometimes accompanied by migration
of one of the methyl groups from oxygen to nitrogen. We
studied the hydrolysis of dimethoxytriazine 3a in 20%
aqueous hydrochloric acid (4 equiv, reflux, 3 h), which re-
sulted in complete decomposition of the substrate. How-
ever, heating the same compound at reflux temperature in
aqueous hydrochloric acid (1.8%) for five hours furnished
a 71% yield of triazinedione 11a after recrystallization
from water. Thus, hydrolysis of compounds 3b, 3c, 4a and
4b was realized under these conditions to afford products
11b, 11c, 12a and 12b in moderate to good yields
Important methods described thus far for the synthesis of
dimethoxytriazines involve the Grignard or palladium-
catalyzed coupling of 2-chloro-4,6-dimethoxytriazine,7 or
the reaction of a very large excess of an activated carbox-
ylic acid with zinc dimethyl imidodicarbonimidate (5).8
We previously reported that performing this reaction in
the presence of pyridine and 4 Å molecular sieves allowed
the use of only a stoichiometric amount of acid chloride,
affording the known dimethoxytriazines 3a and 3b.6 The
same reaction applied to the condensation of acid chlo-
rides 6c,9 7a and 7b furnished moderate to good yields of
SYNTHESIS 2013, 45, 1333–1340
Advanced online publication: 28.03.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338298; Art ID: SS-2013-Z0079-OP
© Georg Thieme Verlag Stuttgart · New York

1334
L. Lucescu et al.
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OMe
N
MeO
N
N
N
NH
NH
(i)
Zn
COCl
O
O
+
N
N
2
OMe
MeO
R3
R3
R1
R1
R2
R2
6a R1 = Me, R2, R3 = H
6b R1, R2 = H, R3 = Cl
5
3a R1 = Me, R2, R3 = H 72%
3b R1, R2 = H, R3 = Cl 80%
3c R1 = H, R2–R3 = OCH2O 85%
6c R1 = H, R2–R3 = OCH2O
OMe
N
(i)
N
5
COCl
O
O
N
N
+
N
OMe
R1
R1
R2
R2
7a R1–R2 = OCH2O
4a R1–R2 = OCH2O 67%
7b R1 = H, R2 = COMe
4b R1 = H, R2 = COMe 35%
(iv)
(iii)
(ii)
CO2H
O
CO2Me
CO2Me
O
O
N
N
N
H
R1
R1
R2
R2
10a R1–R2 = OCH2O 99%
9a R1–R2 = OCH2O 85%
8
10b R1 = H, R2 = COMe 69%
9b R1 = H, R2 = COMe 65%
Scheme 1 Reagents and conditions: (i) py, powdered 4 Å MS, CH2Cl2, r.t., 24 h; (ii) aryl halide (1–1.5 equiv), CuI (0.5 equiv), N,N′-dimeth-
ylethylenediamine (1 equiv), Cs2CO3 (2 equiv), 1,4-dioxane, inert atm, 50–60 °C, 6–20 h; (iii) aq NaOH (2 M, 2 equiv), 80 °C, 1–10 h, then
HCl; (iv) SOCl2 (2 equiv), CH2Cl2, inert atm, reflux, 2–24 h, quant.
(Scheme 2). Interestingly, during these reactions with hy- (Scheme 3); no by-products were isolated from these re-
drochloric acid, partial hydrolysis or migration of a meth- actions.
yl group were not detected.
1,3-Dimethyl-1,3,5-triazine-2,4-diones represent other
As with the total hydrolysis of alkoxytriazines, the litera- potential biocides; these interesting compounds can be
ture proved to be very scarce concerning partial reactions. obtained by Hilbert–Johnson oxygen to nitrogen migra-
To the best of our knowledge, the only reports concerned tion of dimethoxytriazines. The mechanism of the reac-
heating 2,4,6-tripropargyloxy-1,3,5-triazines (50 °C, 1 h) tion was proved, in the pyrimidine series, to occur via a
in aqueous sodium hydroxide (5%), which led to hydroly- sequence of alkylation–dealkylation steps,21 at 160–
sis of one of the three ether groups,13b and the analogous 190 °C in the presence of p-toluenesulfonic acid (PTSA)
reaction in the 2,4-dimethoxy-1,3-pyrimidine series re- derivatives,22 or at lower temperatures by using alkylating
quired heating the substrate at reflux temperature in aque- agents,23 or sodium iodide in N,N-dimethylformamide.24
ous sodium hydroxide (5 M) for 48 hours to give moderate Again, very few reports have appeared concerning the tri-
yields of methoxypyrimidone, accompanied by the com- azine series: 2,3-dimethoxy-1,3,5-triazine25 and 1-amino-
pletely hydrolyzed product.20 Modification of these con- 3,5-dialkoxytriazines,22b were transposed at high temper-
ditions led us to heat dimethoxytriazines 3a–c and 4b at ature (160–250 °C), the reaction being favored by the ac-
reflux temperature in the presence of potassium hydroxide tion of p-toluenesulfonic acid. In addition, the reaction of
(1–2 equiv) in methanol for 20–28 hours to give 62–87% 2-chloro-3,5-dimethoxytriazine with sodium diethoxy di-
yields of 2-methoxy-1,3,5-triazin-6-ones 13a–c and 14b thiophosphonate led to the product of oxygen to nitrogen
Synthesis 2013, 45, 1333–1340
© Georg Thieme Verlag Stuttgart · New York

PAPER
Chemistry of Dimethoxytriazines
1335
OMe
N
OMe
N
O
O
Me
N
N
N
N
N
HN
N
NMe
O
NH
O
O
O
O
N
N
O
N
N
N
(i)
OMe
OMe
R3
R3
R3
R1
R1
R3
R1
R1
R2
R2
R2
R2
3a R1 = Me, R2, R3 = H
15a R1 = Me, R2, R3 = H 52%
3a R1 = Me, R2, R3 = H
3b R1, R2 = H, R3 = Cl
11a R1 = Me, R2, R3 = H 71%
11b R1, R2 = H, R3 = Cl 83%
11c R1 = H, R2–R3 = OCH2O 85%
3c R1 = H, R2–R3 = OCH2O
15c R1 = H, R2–R3 = OCH2O 46%
3c R1 = H, R2–R3 = OCH2O
Scheme 4 Reagents and conditions: (i) Me2SO4 (1 equiv), toluene,
reflux, 24–48 h.
O
HN
OMe
N
NH
N
Products 3b, 11a,c and 13b,c were selected by the Nation-
al Cancer Institute (NCI) for biological screening on a 60-
cell line panel. They were tested initially at a single dose
(10 μM), but did not satisfy the predetermined threshold
inhibition criteria, and did not progress to the five-dose
screen in order to determine their GI50 (concentration that
causes 50% growth inhibition) values. However, at this
concentration (10 M), chlorotriazines 3b and 13b showed
modest cellular growth inhibition of leukemia cell lines
(3b: 38.9% inhibition of SR; 13b: 33.4% inhibition of
K562), of ovarian cancer cell lines (3b: 42.7% inhibition
of IGROV1 and 43.8% inhibition of OVCAR-8), and of a
renal cancer cell line (13b: 35.3% inhibition of CAKI-1).
All the other tested compounds were devoid of biological
activity on tumor cell lines.
O
N
N
O
N
N
(i)
O
OMe
R1
R1
R2
R2
4a R1–R2 = OCH2O
12a R1–R2 = OCH2O 81%
4b R1 = H, R2 = COMe
12b R1 = H, R2 = COMe 47%
Scheme 2 Reagents and conditions: (i) aq HCl (1.8%, 2 equiv), re-
flux, 5 h.
OMe
N
OMe
NH
O
N
N
N
N
(i)
O
O
N
N
In conclusion, the 2-alkyl-3,5-dimethoxy-1,3,5-triazine
system represents a rarely encountered heterocyclic scaf-
fold. We have demonstrated that partial or total hydrolysis
of the methoxy groups, and a Hilbert–Johnson oxygen to
nitrogen migration of the methyl groups can be realized
easily by using dilute potassium hydroxide or hydrochlo-
ric acid, or by catalysis with dimethyl sulfate. These reac-
tions allowed the preparation of a variety of potential
biocides, formed from pyrrolidinones substituted at the 5-
position with a triazine scaffold. The antifungal properties
of these compounds will be reported in due course.
OMe
R3
R3
R1
R1
R2
R2
3a R1 = Me, R2, R3 = H
3b R1, R2 = H, R3 = Cl
3c R1 = H, R2–R3 = OCH2O
13a R1 = Me, R2, R3 = H 80%
13b R1, R2 = H, R3 = Cl 87%
13c R1 = H, R2–R3 = OCH2O 73%
OMe
OMe
N
N
(i)
N
NH
O
N
N
O
N
N
OMe
O
All starting materials were commercially available. Thin-layer
chromatography (TLC) was performed on Macherey Nagel silica
gel plates containing a fluorescent indicator, and were made visual
under a UV lamp at 254 nm and 366 nm. Column chromatography
was accomplished on silica gel (40–60 μm; Macherey Nagel). Melt-
ing points were measured on an MPA 100 OptiMelt apparatus and
are uncorrected. IR spectra were recorded on a Varian 640-IR FT-
IR spectrometer. NMR spectra were acquired at 200 MHz (1H
NMR) on a Varian Gemini 2000 spectrometer, or at 400 MHz (1H
NMR) and 100 MHz (13C NMR) on a Varian 400 MHz Premium
Shielded spectrometer. Chemical shifts (δ) are expressed in parts
per million relative to TMS as the internal standard. LC–MS was
accomplished using an HPLC combined with a Surveyor MSQ
(Thermo Electron) equipped with an APCI source. Elemental anal-
ysis of new compounds were recorded by ‘Pôle Chimie Moléculai-
re’, Faculté de Sciences Mirande, Université de Bourgogne, Dijon,
France. Many of the products obtained during this study were diffi-
cult to obtain in perfectly anhydrous form; similar problems have
been reported previously with triazine compounds.27
O
O
4b
14b 62%
Scheme 3 Reagents and conditions: (i) KOH (1–2 equiv), MeOH,
reflux, 20–28 h.
migration.26 Taking the above into account, dimethoxytri-
azines 3a and 3c were heated at reflux temperature in tol-
uene in the presence of dimethyl sulfate for 24–48 hours
to give 1,3-dimethyl-1,3,5-triazines 15a and 15c (Scheme
4); again, no by-products were isolated from these reac-
tions.
© Georg Thieme Verlag Stuttgart · New York
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1336
L. Lucescu et al.
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Methyl N-Arylpyroglutamates 9a,b; General Procedure
(d, J = 2.7 Hz, 1 H, ArH), 6.771 (s, 1 H, ArH), 7.06 (dd, J = 1.8, 0.9
Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3–DMSO-d6): δ = 23.2 (CH2), 30.6
(CH2), 62.4 (CH), 101.2 (CH2), 105.0 (CH), 107.9 (CH), 115.6
(CH), 132.3 (C), 145.3 (C), 147.7 (C), 173.4 (C), 174.4 (C).
To a suspension of methyl DL-pyroglutamate (1 equiv), CuI (0.5
equiv), Cs2CO3 (2 equiv), and the appropriate aryl halide (1.0–1.5
equiv) in 1,4-dioxane under an N2 atmosphere was added dropwise
the coupling ligand, N,N′-dimethylethylenediamine (DMEDA) (1
equiv) via a syringe. The mixture was then stirred at 50 °C or 60 °C
for 12 or 20 h, turning blue very quickly.10 After cooling to r.t., the
mixture was filtered to remove insoluble salts and the filter cake
was washed with CH2Cl2. The filtrate was concentrated in vacuo
and the residue was partitioned between H2O and CH2Cl2. The or-
ganic layer was dried over MgSO4 and evaporated to dryness. The
residue was purified by column chromatography on silica gel
(EtOAc–n-heptane) to afford pure compound 9a or 9b.
Anal. Calcd for C12H11O5N: C, 57.83; H, 4.45; N, 5.62. Found: C,
57.57; H, 4.31; N, 5.93.
N-(4-Acetylphenyl)pyroglutamic Acid (10b)
The general procedure was followed using ester 9b (2.40 g, 9.19
mmol) and aq NaOH [0.73 g, 18.35 mmol in H2O (9.2 mL), 2 M].
The mixture was stirred at 80 °C for 1 h. The solid obtained by fil-
tration was washed with H2O and dried to give acid 10b.
Methyl N-(Benzo[1,3]dioxol-5-yl)pyroglutamate (9a)
Yield: 1.57 g (69%); white solid; mp (H2O) 207–210 °C.
The general procedure was followed using methyl DL-pyrogluta-
mate (2.0 g, 14 mmol), 5-bromo-1,3-benzodioxole (2.5 mL, 21
mmol), Cs2CO3 (9.1 g, 28 mmol), CuI (1.3 g, 7 mmol) and DMEDA
(1.5 mL, 14 mmol) in 1,4-dioxane (40 mL). The mixture was stirred
at 60 °C for 12 h. The residue was separated by chromatography on
silica gel (EtOAc–n-heptane, 3:2) to afford pure product 9a as a
white powder (3.13 g, 85%). The physicochemical properties were
identical to those reported in the literature.10
IR (neat): 3349, 1707, 1668, 1598, 1581, 1442, 1385, 1328, 1287,
1213, 1186, 1108, 901, 823 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 1.70–1.82 (m, 1 H,
CH2CH2CH), 1.83–1.97 (m, 1 H, CH2CH2CH), 2.17–2.32 (m, 2 H,
CH2CH2CH), 2.24 (s, 3 H, COCH3), 6.43 (d, J = 8.8 Hz, 2 H, ArH),
6.59–6.64 (m, 1 H, CH2CH2CH), 7.56 (d, J = 8.8 Hz, 2 H, ArH),
12.32 (s, 1 H, COOH).
13C NMR (100 MHz, DMSO-d6): δ = 26.9 (CH3), 27.5 (CH2), 30.5
(CH2), 54.9 (CH), 111.7 (C), 126.0 (2 CH), 130.8 (2 CH), 152.6 (C),
174.2 (C), 174.6 (C), 195.6 (C).
Methyl N-(4-Acetylphenyl)pyroglutamate (9b)
The general procedure was followed using methyl DL-pyrogluta-
mate (2.91 g, 20.32 mmol), 1-(4-iodophenyl)ethanone (5.00 g,
20.32 mmol), Cs2CO3 (13.24 g, 40.64 mmol), CuI (1.96 g, 10.16
mmol) and DMEDA (2.18 mL, 20.32 mmol) in 1,4-dioxane (50
mL). The mixture was stirred at 50 °C for 20 h. The residue was sep-
arated by chromatography on silica gel (EtOAc–n-heptane, 1:1) to
afford pure product 9b.
Anal. Calcd for C13H13NO4: C, 63.15; H, 5.30; N, 5.66. Found: C,
62.97; H, 5.12; N, 5.60.
Acid Chlorides 6a–c and 7a,b; General Procedure
A mixture of carboxylic acid 10a or 10b (1 equiv) and SOCl2 (2
equiv) in CH2Cl2 was heated at reflux temperature under an inert
atm for 2–24 h. The resulting pale yellow soln was concentrated in
vacuo to give the crude acid chloride 6a–c, 7a or 7b as a pale yellow
solid in quant. yield, which was used without further purification in
the subsequent step.
Yield: 3.45 g (65%); white solid; mp (EtOAc) 96–99 °C; Rf = 0.23
(EtOAc–n-heptane, 1:1).
IR (neat): 1738, 1712, 1669, 1599, 1377, 1346, 1261, 1197, 1177,
840 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.20–2.29 (m, 1 H, CH2CH2CH),
2.48–2.56 (m, 1 H, CH2CH2CH), 2.58 (s, 3H, COCH3), 2.59–2.64
(m, 1 H, CH2CH2CH), 2.72–2.84 (m, 1 H, CH2CH2CH), 3.76 (s, 3
H, COOCH3), 4.82 (m, 1 H, CH2CH2CH), 7.63 (d, J = 8.8 Hz, 2 H,
ArH), 7.96 (d, J = 8.8 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 23.1 (CH2), 26.5 (CH3), 31.0
(CH2), 52.9 (CH3), 61.0 (CH), 119.8 and 119.9 (2 rotamers, 2 CH),
129.4 and 129.5 (2 rotamers, 2 CH), 133.5 (C), 142.4 (C), 171.9 (C),
174.4 (C), 196.9 (C).
The physicochemical properties of acid chlorides 6a–c were identi-
cal to those reported in the literature.6
1-(1,3-Benzodioxol-5-yl)-5-oxoprolyl Chloride (7a)
1H NMR (400 MHz, CDCl3): δ = 2.35–2.44 (m, 1 H, CH2CH2CH),
2.56–2.80 (m, 3 H, CH2CH2CH), 4.90–4.97 (m, J = 4.7, 2.9, 1.9 Hz,
1 H, CH2CH2CH), 5.99 (s, 2 H, OCH2O), 6.72 (dd, J = 8.4, 2.0 Hz,
1 H, ArH), 6.81 (d, J = 8.2 Hz, 1 H, ArH), 7.05 (d, J = 2.0 Hz, 1 H,
ArH).
1-(4-Acetylphenyl)-5-oxoprolyl Chloride (7b)
1H NMR (400 MHz, CDCl3): δ = 2.22–2.40 (m, 1 H, CH2CH2CH),
2.43–2.81 (m, 3 H, CH2CH2CH), 2.59 (s, 3 H, COCH3), 4.80 (m, 1
H, CH2CH2CH), 7.66 (d, J = 8.6 Hz, 2 H, ArH), 8.00 (d, J = 8.6 Hz,
2 H, ArH).
Anal. Calcd for C14H15NO4·0.2H2O: C, 63.48; H, 5.86; N, 5.29.
Found: C, 63.76; H, 6.16; N, 5.53.
Pyroglutamic Acids 10a,b; General Procedure
A mixture of ester 9a or 9b (1 equiv) and aq NaOH (2 M, 2 equiv)
was stirred at 80 °C for 1 or 10 h (until the starting ester had dis-
solved completely, which was equivalent to sodium carboxylate
formation). After cooling to r.t., the stirred soln was acidified to
pH 5–6 by slow addition of concd HCl. The solid obtained by filtra-
tion was washed with distilled H2O and dried to give pure acid 10a
or 10b.
Dimethoxytriazines 3a–c and 4a,b; General Procedure
Under an inert atm, a soln of acid chloride 6a–c, 7a or 7b (1 equiv)
in anhyd CH2Cl2 was added dropwise over 30 min to a stirred mix-
ture of zinc dimethyl imidodicarbonimidate (5) (0.5–0.75 equiv)
and powdered 4 Å MS in distilled py (15 mL). After the addition
was complete, the mixture was stirred at r.t. for 24 h. The mixture
was filtered, the solid washed with CH2Cl2 and the filtrate concen-
trated in vacuo. The residue was co-evaporated with toluene (3 × 5
mL) in order to remove py. The remaining slurry was dissolved in
CH2Cl2 (10 mL), washed with HCl (1 M, 3 × 10 mL), and then aq
sat. NaHCO3 soln (10 mL). Following evaporation, the obtained
residue was crystallized or purified by column chromatography,
then recrystallized from an appropriate solvent to give pure di-
methoxytriazine 3a–c, 4a or 4b.
N-(Benzo[1,3]dioxol-5-yl)pyroglutamic Acid (10a)
The general procedure was followed using ester 9a (0.80 g, 2.59
mmol) and aq NaOH [0.17 g, 4.25 mmol in H2O (2.2 mL), 2 M].
The mixture was stirred at 80 °C for 10 h. The solid obtained by fil-
tration was washed with H2O and dried to give acid 10a.
Yield: 0.75 g (99%); white solid; mp (H2O) 156–158 °C; Rf = 0.24
(CH2Cl2).
1H NMR (200 MHz, CDCl3): δ = 2.15–2.30 (m, 1 H, CH2CH2CH),
2.44–2.81 (m, 3 H, CH2CH2CH), 4.63 (dd, J = 8.9, 3.1 Hz, 1 H,
CH2CH2CH), 5.81 (br s, 1 H, COOH), 5.96 (s, 2 H, OCH2O), 6.767
The physicochemical properties of triazines 3a–c were identical to
those reported in the literature.6
Synthesis 2013, 45, 1333–1340
© Georg Thieme Verlag Stuttgart · New York

PAPER
Chemistry of Dimethoxytriazines
1337
1-Benzo[1,3]dioxol-5-yl-5-(4,6-dimethoxy[1,3,5]triazin-2-
yl)pyrrolidine-2-one (4a)
13C NMR (100 MHz, DMSO-d6): δ = 19.1 (CH3), 23.9 (CH2), 29.2
(CH2), 43.2 (CH2), 58.5 (CH), 126.3 (CH), 128.0 (CH), 128.9 (CH),
130.7 (CH), 134.4 (2 C), 137.0 (C), 168.9 (2 C), 175.0 (C).
The general procedure was followed using acid chloride 7a (0.54 g,
2.02 mmol), zinc derivative 5 (0.50 g, 1.54 mmol), py (20 mL) and
CH2Cl2 (3 mL) in the presence of powdered 4 Å MS (2.00 g). The
residue obtained upon evaporation was purified by column chroma-
tography (EtOAc–n-heptane, 7:3) to provide pure triazine 4a.
Anal. Calcd for C15H16N4O3·H2O: C, 56.60; H, 5.70; N, 17.60.
Found: C, 56.19; H, 5.79; N, 17.93.
6-[1-(4-Chlorobenzyl)-5-oxopyrrolidin-2-yl]-1,3,5-triazine-
2,4(1H,3H)-dione (11b)
The general procedure was followed using dimethoxytriazine 3b
(1.00 g, 2.87 mmol) and HCl (1.8%, 8.5 mL). Pure compound 11b
was obtained after filtration.
Yield: 0.5 g (67%); white solid; mp (EtOAc–n-heptane) 114–
116 °C; Rf = 0.26 (EtOAc–n-heptane, 7:3).
1H NMR (200 MHz, CDCl3): δ = 2.04–2.20 (m, 1 H, CH2CH2CH),
2.52–2.96 (m, 3 H, CH2CH2CH), 4.01 (s, 6 H, 2 OCH3), 5.05–5.12
(m, 1 H, CH2CH2CH), 5.92 (s, 2 H, OCH2O), 6.72 (dd, J = 12.7, 8.5
Hz, 2 H, ArH), 7.12 (d, J = 1.8 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 25.1 (CH2), 30.7 (CH2), 55.5 (2
CH3), 65.3 (CH), 101.3 (CH2), 105.2 (CH), 107.9 (CH), 115.9 (CH),
132.3 (C), 145.2 (C), 147.7 (C), 172.9 (2 C), 174.8 (C), 181.9 (C).
Yield: 763 mg (83%); white solid; mp (H2O) 167–169 °C.
IR (neat): 3364, 2945, 1759, 1665, 1611, 1491, 1458, 1394, 1360,
1248, 997, 791 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.03–2.09 (m, 1 H,
CH2CH2CH), 2.32–2.39 (m, 3 H, CH2CH2CH), 4.00 (d, J = 15.2
Hz, 1 H, ArCH2N), 4.26 (dd, J = 9.2, 3.6 Hz, 1 H, CH2CH2CH),
4.77 (d, J = 15.6 Hz, 1 H, ArCH2N), 7.28 (d, J = 8.8 Hz, 2 H, ArH),
7.42 (d, J = 8.8 Hz, 2 H, ArH), 11.32 (s, 1 H, CONHCN), 12.22 (s,
1 H, CONHCO).
13C NMR (100 MHz, DMSO-d6): δ = 23.7 (CH2), 29.1 (CH2), 44.1
(CH2), 58.6 (CH), 128.9 (2 CH), 130.3 (2 CH), 132.4 (C), 136.1 (2
C), 168.9 (2 C), 175.3 (C).
Anal. Calcd for C16H16N4O5: C, 55.81; H, 4.68; N, 16.27. Found: C,
56.11; H, 4.51; N, 15.90.
1-(4-Acetylphenyl)-5-(4,6-dimethoxy-1,3,5-triazin-2-yl)pyrro-
lidin-2-one (4b)
The general procedure was followed using acid chloride 7b (1.64 g,
6.19 mmol), zinc derivative 5 (1.01 g, 3.09 mmol), py (20 mL) and
CH2Cl2 (3 mL) in the presence of powdered 4 Å MS (3.00 g). The
residue obtained upon evaporation was purified by column chroma-
tography on silica gel (EtOAc–n-heptane, 7:3) to afford pure com-
pound 4b.
Anal. Calcd for C14H13ClN4O3·1.5H2O: C, 48.35; H, 4.64; N, 16.11.
Found: C, 48.31; H, 4.25; N, 16.12.
6-[1-(1,3-Benzodioxol-5-ylmethyl)-5-oxopyrrolidin-2-yl]-1,3,5-
triazine-2,4(1H,3H)-dione (11c)
The general procedure was followed using dimethoxytriazine 3c
(0.71 g, 1.95 mmol) and HCl (1.8%, 7.5 mL). Pure compound 11c
was obtained after filtration.
Yield: 738 mg (35%); white solid; mp (EtOAc) 137–139 °C;
Rf = 0.13 (EtOAc–n-heptane, 1:1).
IR (neat): 1695, 1678, 1549, 1502, 1457, 1366, 1272, 1257, 1108,
1072, 1025, 932, 831 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.14–2.22 (m, 1 H, CH2CH2CH),
2.17 (s, 3 H, COCH3), 2.61–2.72 (m, 2 H, CH2CH2CH), 2.82–2.95
(m, 1 H, CH2CH2CH), 3.99 (s, 6 H, 2 OCH3), 5.23–5.30 (m, 1 H,
CH2CH2CH), 7.67 (d, J = 8.4 Hz, 2 H, ArH), 7.89 (d, J = 8.4 Hz, 2
H, ArH).
13C NMR (100 MHz, CDCl3): δ = 24.9 (CH2), 26.1 (CH3), 31.2
(CH2), 55.5 (2 CH3), 63.1 (CH), 120.0 (2 CH), 129.3 (2 CH), 133.1
(C), 142.7 (C), 172.9 (C), 175.1 (2 C), 181.5 (C), 196.9 (C).
Yield: 548 mg (85%); white solid; mp (H2O) 219–221 °C.
IR (neat): 3080, 2929, 2760, 1754, 1687, 1658, 1604, 1498, 1455,
1245, 1029, 915, 793, 665, 631, 530 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 1.95–2.05 (m, 1 H,
CH2CH2CH), 2.19–2.43 (m, 3 H, CH2CH2CH), 3.83 (d, J = 14.9
Hz, 1 H, ArCH2N), 4.15 (dd, J = 8.5, 2.9 Hz, 1 H, CH2CH2CH),
4.65 (d, J = 14.9 Hz, 1 H, ArCH2N), 5.97 (dd, J = 3.1, 0.8 Hz, 2 H,
OCH2O), 6.67 (dd, J = 7.8, 1.6 Hz, 1 H, ArH), 6.77 (d, J = 1.6 Hz,
1 H, ArH), 6.83 (d, J = 7.8 Hz, 1 H, ArH), 11.27 (s, 1 H, CONHCN),
12.14 (s, 1 H, CONHCO).
Anal. Calcd for C17H18N4O4·0.5H2O: C, 58.11; H, 5.45; N, 15.95.
Found: C, 58.11; H, 5.49; N, 15.81.
13C NMR (100 MHz, DMSO-d6): δ = 23.7 (CH2), 29.3 (CH2), 44.5
(CH2), 58.5 (CH), 101.4 (CH2), 101.6 (CH), 109.0 (CH), 121.9
(CH), 130.7 (C), 147.0 (C), 148.8 (2 C), 169.0 (C), 175.1 (2 C).
O-Demethylated Derivatives 11a–c and 12a,b; General Proce-
dure
A suspension of dimethoxytriazine 3a–c, 4a or 4b (1 equiv) in aq
HCl (1.8%, 2 equiv) was heated at reflux temperature for 5 h. After
cooling to r.t., the precipitate formed was filtered and washed with
H2O to afford pure triazinedione 11a–c, 12a or 12b.
Anal. Calcd for C15H14N4O5: C, 54.55; H, 4.27; N, 16.96. Found: C,
54.79; H, 4.44; N, 16.99.
6-[1-(Benzo[1,3]dioxol-5-yl)-5-oxopyrrolidin-2-yl]-1,3,5-tri-
azine-2,4(1H,3H)-dione (12a)
The general procedure was followed using dimethoxytriazine 4a
(0.15 g, 0.44 mmol) and HCl (1.8%, 6 mL). Pure compound 12a
was obtained after filtration.
6-[1-(2-Methylbenzyl)-5-oxopyrrolidin-2-yl]-1,3,5-triazine-
2,4(1H,3H)-dione (11a)
The general procedure was followed using dimethoxytriazine 3a
(1.00 g, 3.05 mmol) and HCl (1.8%, 10.5 mL). Pure compound 11a
was obtained after filtration.
Yield: 113 mg (81%); white solid.
Yield: 650 mg (71%); white solid; mp (H2O) 136–137 °C.
1H NMR (400 MHz, DMSO-d6): δ = 2.25–2.36 (m, 1 H,
CH2CH2CH), 2.40–2.63 (m, 3 H, CH2CH2CH), 5.00–5.03 (m, 1 H,
CH2CH2CH), 6.28 (s, 2 H, OCH2O), 7.08 (dd, J = 8.4, 1.9 Hz, 1 H,
ArH), 7.17 (d, J = 8.4 Hz, 1 H, ArH), 7.45 (d, J = 1.9 Hz, 1 H, ArH),
10.15 (s, 1 H, NH), 11.61 (s, 1 H, NH).
IR (neat): 3500, 3386, 1727, 1686, 1662, 1611, 1433, 1413, 1244,
1156, 953, 905, 795, 540 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 1.98–2.07 (m, 1 H,
CH2CH2CH), 2.20 (s, 3 H, ArCH3), 2.25–2.45 (m, 3 H,
CH2CH2CH), 3.89 (d, J = 15.2 Hz, 1 H, ArCH2N), 4.10 (dd, J = 8.7,
2.6 Hz, 1 H, CH2CH2CH), 4.72 (d, J = 15.2 Hz, 1 H, ArCH2N), 7.07
(d, J = 7.2 Hz, 1 H, ArH), 7.10–7.18 (m, 3 H, ArH), 11.25 (s, 1 H,
CONHCN), 12.09 (s, 1 H, CONHCO).
Anal. Calcd for C14H12N4O5: C, 53.17; H, 3.82; N, 17.71. Found: C,
53.43; H, 4.05; N, 17.40.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1333–1340

1338
L. Lucescu et al.
PAPER
6-[1-(4-Acetylphenyl)-5-oxopyrrolidin-2-yl]-1,3,5-triazine-
2,4(1H,3H)-dione (12b)
The general procedure was followed using dimethoxytriazine 4b
(0.26 g, 0.75 mmol) and HCl (1.8%, 10 mL). Pure compound 12b
was obtained after filtration.
OCH3), 4.21 (m, 1 H, CH2CH2CH), 4.95 (d, J = 15.1 Hz, 1 H,
ArCH2N), 7.12 (d, J = 8.2 Hz, 2 H, ArH), 7.26 (d, J = 8.2 Hz, 2 H,
ArH).
Anal. Calcd for C15H15ClN4O3: C, 53.82; H, 4.52; N, 16.74. Found:
C, 54.12; H, 4.80; N, 17.01.
Yield: 112 mg (47%); white solid; mp (H2O) 170–173 °C.
4-[1-(1,3-Benzodioxol-5-ylmethyl)-5-oxopyrrolidin-2-yl]-6-
methoxy-1,3,5-triazin-2(1H)-one (13c)
IR (neat): 3547, 3476, 1717, 1677, 1616, 1599, 1421, 1356, 1267,
1222, 1039, 848, 772, 620, 547 cm–1.
The general procedure was followed using dimethoxytriazine 3c
(0.50 g, 1.40 mmol) and KOH (0.156 g, 2.79 mmol) in MeOH (10
mL). The reaction mixture was heated at reflux temperature for 28
h. The obtained white solid was filtered and dried to provide mono
O-demethylated product 13c.
1H NMR (400 MHz, DMSO-d6): δ = 2.33–2.40 (m, 1 H,
CH2CH2CH), 2.58–2.69 (m, 1 H, CH2CH2CH), 2.67 (s, 3 H,
COCH3), 2.72–2.80 (m, 2 H, CH2CH2CH), 5.24 (dd, J = 8.4, 2.8 Hz,
1 H, CH2CH2CH), 7.79 (d, J = 8.4 Hz, 2 H, ArH), 8.09 (d, J = 8.4
Hz, 2 H, ArH), 11.49 (s, 1 H, CONHCN), 12.66 (s, 1 H, CONHCO).
13C NMR (100 MHz, DMSO-d6): δ = 23.8 (CH2), 27.0 (CH3), 31.0
(CH2), 60.4 (CH), 119.7 (2 CH), 129.6 (2 CH), 132.9 (C), 142.8 (2
C), 168.6 (C), 175.2 (C), 197.1 (C).
Yield: 350 mg (73%); yellow solid; mp (Et2O) 230–232 °C.
IR (neat): 2955, 1663, 1560, 1489, 1444, 1363, 1242, 1203, 1099,
1035, 835, 772, 650 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 1.79–1.90 (m, 1 H,
CH2CH2CH), 2.13–2.29 (m, 2 H, CH2CH2CH), 2.31–2.42 (m, 1 H,
CH2CH2CH), 3.58 (d, J = 14.9 Hz, 1 H, ArCH2N), 3.56 (s, 3 H,
OCH3), 3.99 (dd, J = 8.6, 3.2 Hz, 1 H, CH2CH2CH), 4.73 (d,
J = 14.9 Hz, 1 H, ArCH2N), 5.97 (s, 2 H, OCH2O), 6.60 (dd, J = 7.8,
1.5 Hz, 1 H, ArH), 6.70 (d, J = 1.5 Hz, 1 H, ArH), 6.81 (d, J = 7.8
Hz, 1 H, ArH).
13C NMR (100 MHz, DMSO-d6): δ = 24.4 (CH2), 30.0 (CH2), 44.4
(CH2), 53.2 (CH), 61.8 (CH3), 101.3 (CH2), 108.6 (CH), 108.7
(CH), 121.5 (CH), 131.2 (C), 146.8 (C), 147.8 (C), 172.1 (C), 175.1
(2C), 177.4 (C).
Anal. Calcd for C15H14N4O4·MeOH·H2O: C, 52.74; H, 5.53; N,
15.3. Found: C, 52.79; H, 5.12; N, 15.18.
Mono O-Demethylated Derivatives 13a–c and 14b; General
Procedure
Dimethoxytriazine 3a–c or 4b (1 equiv) was added to a soln of KOH
(1–2 equiv) in MeOH and the resulting mixture heated at reflux
temperature for 19–28 h. After cooling to r.t., the solvent was evap-
orated in vacuo and the residue dissolved in CH2Cl2. All insoluble
salts were removed by filtration and the filtrate was concentrated in
vacuo. Et2O was then added to the crude residue and the obtained
precipitate was collected by filtration to give pure product 13a–c or
14b.
LC–MS (APCI+): m/z 345.1 [M + H]+.
4-[1-(4-Acetylphenyl)-5-oxopyrrolidin-2-yl]-6-methoxy-1,3,5-
triazin-2(1H)-one (14b)
6-Methoxy-4-[1-(2-methylbenzyl)-5-oxopyrrolidin-2-yl]-1,3,5-
triazin-2(1H)-one (13a)
The general procedure was followed using dimethoxytriazine 4b
(0.35 g, 1.02 mmol) and KOH (0.114 g, 2.04 mmol) in MeOH (10
mL). The reaction mixture was heated at reflux temperature for 19
h. The obtained white solid was filtered and dried to provide mono
O-demethylated product 14b.
The general procedure was followed using dimethoxytriazine 3a
(0.50 g, 1.52 mmol) and KOH (0.085 g, 1.52 mmol) in MeOH (10
mL). The reaction mixture was heated at reflux temperature for 24
h. The obtained white solid was filtered and dried to provide mono
O-demethylated product 13a.
Yield: 208 mg (62%); yellow solid.
Yield: 380 mg (80%); yellow solid.
1H NMR (400 MHz, DMSO-d6): δ = 2.18–2.24 (m, 1 H,
CH2CH2CH), 2.45–2.68 (m, 3 H, CH2CH2CH), 3.43 (s, 3 H,
COCH3), 3.58 (s, 3 H, OCH3), 4.97–5.02 (m, 1 H, CH2CH2CH),
7.70 (d, J = 8.2 Hz, 2 H, ArH), 7.91 (d, J = 8.2 Hz, 2 H, ArH).
IR (neat): 3080, 2929, 2760, 1754, 1687, 1658, 1604, 1498, 1455,
1245, 1029, 915, 793, 665, 631, 530 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 1.77–1.90 (m, 1 H,
CH2CH2CH), 2.12–2.32 (m, 2 H, CH2CH2CH), 2.16 (s, 3 H,
ArCH3), 2.35–2.45 (m, 1 H, CH2CH2CH), 3.67 (s, 3 H, OCH3), 3.71
(d, J = 15.2 Hz, 1 H, ArCH2N), 3.93 (dd, J = 8.5, 2.9 Hz, 1 H,
CH2CH2CH), 4.84 (d, J = 15.2 Hz, 1 H, ArCH2N), 6.99 (d, J = 7.2
Hz, 1 H, ArH), 7.08–7.18 (m, 3 H, ArH).
13C NMR (100 MHz, DMSO-d6): δ = 19.1 (CH3), 24.6 (CH2), 29.9
(CH2), 42.6 (CH2), 53.2 (CH), 61.8 (CH3), 126.3 (CH), 127.7 (CH),
128.7 (CH), 130.6 (CH), 135.0 (C), 136.6 (C), 172.2 (C), 175.0 (2
C), 177.8 (C).
LC–MS (APCI+): m/z 329.1 [M + H]+.
Hilbert–Johnson Transposition; General Procedure
A soln of dimethoxytriazine 3a or 3c (1 equiv) and Me2SO4 (1
equiv) in toluene was heated at reflux temperature for 23 or 48 h.
After cooling to r.t., the mixture was concentrated in vacuo and the
crude residue was treated with Et3N (1 equiv) and H2O. The organic
compounds were extracted into CH2Cl2. After evaporation of the
solvent, the resulting solid was recrystallized from absolute EtOH
to afford the pure product 15a or 15c.
LC–MS (APCI+): m/z 315.1 [M + H]+.
1,3-Dimethyl-6-[1-(2-methylbenzyl)-5-oxopyrrolidin-2-yl]-
1,3,5-triazine-2,4(1H,3H)-dione (15a)
4-[1-(4-Chlorobenzyl)-5-oxopyrrolidin-2-yl]-6-methoxy-1,3,5-
triazin-2(1H)-one (13b)
The general procedure was followed using dimethoxytriazine 3a
(0.72 g, 2.20 mmol) and Me2SO4 (0.28 g, 2.20 mmol) in toluene (15
mL). The mixture was heated at reflux temperature for 23 h. After
recrystallization, the obtained white precipitate was filtered to pro-
vide pure product 15a.
The general procedure was followed using dimethoxytriazine 3b
(0.25 g, 0.72 mmol) and KOH (0.040 g, 0.72 mmol) in MeOH (8
mL). The reaction mixture was heated at reflux temperature for 24
h. The obtained white solid was filtered and dried to provide mono
O-demethylated product 13b.
Yield: 374 mg (52%); yellow solid; mp (EtOH) 113–116 °C.
Yield: 209 mg (87%); yellow solid.
IR (neat): 1727, 1655, 1591, 1453, 1417, 1365, 1287, 1238, 1160,
986, 788, 752 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.92–2.01 (m, 1 H, CH2CH2CH),
2.27 (s, 3 H, ArCH3), 2.36–2.58 (m, 2 H, CH2CH2CH), 2.64–2.68
(m, 1 H, CH2CH2CH), 3.10 (s, 3 H, NCH3), 3.36 (s, 3 H, NCH3),
4.15 (d, J = 14.4 Hz, 1 H, ArCH2N), 4.28 (dd, J = 9.0, 3.1 Hz, 1 H,
IR (neat): 3043, 2756, 1755, 1667, 1489, 1423, 1212, 1088, 915,
799, 672 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.02–2.10 (m, 1 H,
CH2CH2CH), 2.32–2.45 (m, 2 H, CH2CH2CH), 2.61–2.76 (m, 1 H,
CH2CH2CH), 3.84 (d, J = 15.1 Hz, 1 H, ArCH2N), 3.86 (s, 3 H,
Synthesis 2013, 45, 1333–1340
© Georg Thieme Verlag Stuttgart · New York

PAPER
Chemistry of Dimethoxytriazines
1339
CH2CH2CH), 4.99 (d, J = 14.8 Hz, 1 H, ArCH2N), 6.96 (d, J = 7.2
Hz, 1 H, ArH), 7.09–7.12 (m, 1 H, ArH), 7.15–7.22 (m, 2 H, ArH).
13C NMR (100 MHz, DMSO-d6): δ = 19.1 (CH3), 22.9 (CH2), 28.9
(CH3), 29.0 (CH2), 31.0 (CH3), 43.3 (CH2), 57.5 (CH), 126.2 (CH),
127.8 (CH), 128.6 (CH), 130.6 (CH), 134.7 (C), 136.9 (C), 151.7
(C), 154.7 (C), 166.5 (C), 175.1 (C).
Folgaria, Italy, September 8–12, 1998; Società Chimica
Italiana (Divisione di Chimica Organica): Rome, 1998,
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C.; Menicagli, R.; Samaritani, S.; Pini, D.; Rapaccini, S. M.;
Salvadori, P. Restaurator 1999, 97.
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H. WO 9720825, 1997; Chem. Abstr. 1997, 127, 95296.
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1998, 37, 510.
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Anal. Calcd for C17H20N4O3·H2O: C, 58.95; H, 6.40; N, 16.17.
Found: C, 58.92; H, 6.41; N, 15.76.
6-[1-(1,3-Benzodioxol-5-ylmethyl)-5-oxopyrrolidin-2-yl]-1,3-di-
methyl-1,3,5-triazine-2,4(1H,3H)-dione (15c)
The general procedure was followed using dimethoxytriazine 3c
(0.69 g, 1.90 mmol) and Me2SO4 (0.24 g, 1.90 mmol) in toluene (15
mL). The reaction mixture was heated at reflux temperature for 48
h. After recrystallization, the obtained white precipitate was filtered
to provide pure product 15c.
Yield: 212 mg (46%); yellow solid; mp (EtOH) 167–169 °C.
IR (neat): 1730, 1658, 1593, 1489, 1441, 1366, 1282, 1246, 1162,
1031, 919, 789 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 1.98–2.15 (m, 1 H,
CH2CH2CH), 2.22–2.34 (m, 2 H, CH2CH2CH), 2.35–2.40 (m, 1 H,
CH2CH2CH), 3.16 (s, 3 H, NCH3), 3.23 (s, 3 H, NCH3), 3.77 (d,
J = 14.8 Hz, 1 H, ArCH2N), 4.67 (d, J = 14.4 Hz, 1 H, ArCH2N),
4.67 (d, J = 9.6 Hz, 1 H, CH2CH2CH), 5.96 (s, 2 H, OCH2O), 6.72–
6.74 (m, 1 H, ArH), 6.81–6.84 (m, 2 H, ArH).
13C NMR (100 MHz, DMSO-d6): δ = 22.3 (CH2), 28.9 (CH3), 29.0
(CH2), 31.1 (CH3), 44.7 (CH2), 57.5 (CH), 101.4 (CH2), 108.6 (CH),
109.0 (CH), 121.9 (CH), 131.2 (C), 146.9 (C), 147.8 (C), 151.8 (C),
154.8 (C), 166.6 (C), 175.2 (C).
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Shorshnev, S. V.; Klyuev, N. A. Pharm. Chem. J. 2004, 38,
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(14) Pomeisi, K.; Holy, A.; Pohl, R.; Horska, K. Tetrahedron
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(15) (a) Kraljevic, T. G.; Kristafor, S.; Suman, L.; Kralj, M.;
Ametamey, S. M.; Cetina, M.; Raic-Malic, S. Bioorg. Med.
Chem. 2010, 18, 2704. (b) Kraljevic, T. G.; Petrovic, M.;
Anal. Calcd for C17H18N4O5·1.5H2O: C, 52.57; H, 5.54; N, 14.43.
Found: C, 52.59; H, 5.10; N, 14.18.
Acknowledgment
The authors gratefully acknowledge the ‘Ministerul Educaţiei,
Cercetării, Tineretului şi Sportului’ (Romania) for a scholarship (L.
L.), and the NCI (National Cancer Institute) (USA) for biological
evaluation of several compounds on their 60-cell panel.
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