Synthesis of 5-Amino-3-methylimidazolidine-2,4-dione and 1,3,5-triazine derivatives as analogues of the alkaloids naamidine A and G

Article abstract of DOI:10.1055/s-0030-1258963

A simple two-step synthesis of 5-amino-3-methylimidazolidine-2,4-dione is described. Addition of this amine to cyanuric chloride followed by reaction with 4-methoxyphenol or 4-alkoxy-anilines gives analogues of the imidazole alkaloids naamidine A and G with a 1,3,5-triazine core

Full text of DOI:10.1055/s-0030-1258963

4312
PAPER
Synthesis of 5-Amino-3-methylimidazolidine-2,4-dione and 1,3,5-Triazine
Derivatives as Analogues of the Alkaloids Naamidine A and G
5
-Amino-3-methyl
e
imidazolidi
l
ne-2,4
e-dione and
n
T
riazine
D
erivative
M
s
. Witchard,a Keith G. Watson*a,b
a
Walter and Eliza Hall Institute of Medical Research, Biotechnology Centre, La Trobe R&D Park, Bundoora, 4 Research Avenue,
Victoria 3086, Australia
Fax +61(3)93452211; E-mail: kwatson@wehi.edu.au
Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
b
Received 17 September 2010; revised 27 September 2010
known. However, a recent paper by Ohta10 describes the
amination of 3-methylparabanic acid (5) with various aryl-
amines to give 5-(N-arylamino)-3-methylimidazole-2,4-
diones 6. We used the method of Ohta to prepare 5-benzyl-
amino-3-methylimidazole-2,4-dione (7) which we hoped
would debenzylate under catalytic hydrogenation condi-
tions to give the amine 4 (Scheme 1).
Abstract: A simple two-step synthesis of 5-amino-3-methylimida-
zolidine-2,4-dione is described. Addition of this amine to cyanuric
chloride followed by reaction with 4-methoxyphenol or 4-alkoxy-
anilines gives analogues of the imidazole alkaloids naamidine A
and G with a 1,3,5-triazine core.
Key words: antitumor agents, imidazolidine, naamidine alkaloids,
nucleophilic addition, s-triazine
However, it was found that transfer hydrogenation of 7
with ammonium formate in the presence of palladium on
charcoal as catalyst gave 5-benzylamino-3-methylimida-
zolidine-2,4-dione (8), whilst prolonged hydrogenation at
atmospheric pressure lead to the formation of 5-amino-3-
methylimidazolidine-2,4-dione (9). The assignment of the
reduced structure 9 is based on the 1H spectrum in CD3CN
which, in addition to the N-methyl peak at 2.87 ppm,
showed a one proton doublet at 4.68 ppm for the CH at the
5-position. The 13C NMR spectrum confirmed the assign-
ment showing a strong peak at 64 ppm for the C5 carbon
and peaks at 24, 158, and 175 ppm for the N-methyl and
carbonyl carbons. The only previous report of the synthe-
sis of the amine 9 appears to be a 1926 paper11 involving
a three-step diacetylation, methylation, and deacetylation
sequence from 5-aminohydantoin which itself can be ob-
Several imidazole alkaloids have been isolated from the
bright yellow sponge Leucetta chagosensis including na-
amidines A (1) and G (2) (Figure 1).1 These alkaloids pos-
sess novel, drug-like structures and indeed have been
reported to show various types of potentially useful bio-
logical activity. For example, naamidine A (1) exhibits
antitumor activity in a mouse xenograft model2 and re-
mains under active investigation as an anticancer agent.3
There are at least two reported total syntheses4 of naami-
dine A (1) and also a very recent report5 of the total syn-
thesis of naamidine G (2). We have also reported the
synthesis and biological evaluation of analogues of 1 and
2 in which the central imidazole ring is replaced by a thi-
azole.6
It occurred to us that one interesting type of analogue of
naamidines 1 and 2 would be compounds 3 in which the
central imidazole ring is replaced with a 1,3,5-triazine
core possessing two substituted phenyl rings attached via
amino or ether linkages and an aminoimidazole-2,4-dione
as the third substituent. In support of this idea it was noted
that other workers have recently reported that a bis-anili-
notriazine derivative has promising in vivo antitumor ac-
tivity.7 We thus set out to prepare compounds of general
structure 3 using stepwise reaction of cyanuric chloride.
O
Me
N
N
N
NH
O
N
Me
MeO
O
N
H
A
N
A
N
N
X
Me
1 X = OH
For introduction of the 3-methylimidazole-2,4-dione ring
system we initially thought that 5-amino-3-methylimida-
zole-2,4-dione (4) (Figure 1) might be suitable for addi-
tion to cyanuric chloride. Compound 4 was reported in
1920, under the name 3-methylallantoxaidin,8 however,
more recent consideration of the chemistry has lead to the
conclusion that the original structural assignment was in-
correct.9 Thus, it appears that compound 4 is actually un-
2 X = OMe
N
N
O
MeO
X
3 X = OH or OMe; A = O or NH
H
H2N
N
N
N
N
R
O
O
N
O
O
Me
Me
SYNTHESIS 2010, No. 24, pp 4312–4316
Advanced online publication: 09.11.2010
x
x.
x
x
.
2
0
1
0
4
6
Figure 1 Naamidine A (1), naamidine G (2), triazine targets 3, and
imidazoles 4 and 6
DOI: 10.1055/s-0030-1258963; Art ID: Z23410SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
5-Amino-3-methylimidazolidine-2,4-dione and Triazine Derivatives
4313
H
N
microanalysis of the product revealed that we had only re-
formed the starting 3-methylparabanic acid (5). It thus ap-
pears that compound 4 may not be stable under aqueous
acidic conditions, possibly because it exists predominant-
ly in the 5-imino form which is readily hydrolyzed.
MeO
O
O
d
X
a
4
H
N
O
N
N
N
O
Me
5
O
Me
a
10
Given the novelty of amino compound 9 and its similarity
to 4, we decided to go ahead with the preparation of triaz-
ine derivatives incorporating the reduced 5-amino-3-meth-
ylimidazolidine-2,4-dione (9). Reaction of cyanuric
chloride with amine 9 was carried out in anhydrous aceto-
nitrile at 0–20 °C in the presence of sodium bicarbonate
(Scheme 2). The crude dichlorotriazine product 11 was
isolated by chromatography in 78% yield and, being fairly
unstable towards hydrolysis, was not fully characterized,
but reacted immediately with 4-methoxyphenol in aceto-
nitrile, using potassium carbonate as the base and stirring
for 18 hours at room temperature. A mixture of products
was obtained and the bis-ether 12 was isolated in low
yield by column chromatography.
H
N
H
H2N
O
N
N
N
c
O
O
N
O
Me
Me
7
9
b
c
H
N
H
N
O
N
O
Me
8
To prepare the amino-linked compounds, the dichlorotri-
azine 11 was first reacted with one equivalent of 4-meth-
Scheme 1 Synthesis of 5-amino-3-methylimidazolidine-2,4-dione
(9). Reagents and conditions: (a) imidazole, Et3N, DMAP, Me3SiCl,
(4-MeO)PhCH2NH2, CHCl3, 56–62%; (b) Pd/C, HCO2NH4, MeOH, oxyaniline in acetonitrile at room temperature for 25
45%; (c) H2, Pd/C, EtOH–EtOAc, 90%; (d) TFA, CH2Cl2, or CAN,
MeCN–H2O.
hours, using sodium bicarbonate as base. These condi-
tions allowed clean monosubstitution to give intermediate
13 in high yield with one remaining chlorine atom on the
triazine ring. Reaction of 13 with three different anilines
tained in four steps from parabanic acid.12 As an alterna-
tive approach to making the desired amino compound 4
was carried out in dimethylformamide with gentle warm-
we prepared the 5-(4-methoxybenzyl)amino-3-methylim-
ing and in the presence of a base such as potassium or ce-
idazole-2,4-dione (10) again using the Ohta method.10 At-
sium carbonate to give the triaminotriazines 14–16 in
tempted removal of the methoxybenzyl group with
modest yields after chromatographic purification.
trifluoroacetic acid in dichloromethane did not give any
identifiable product. Initially we thought that oxidative re-
A recent publication13 has reported that a variety of bis-(4-
methoxybenzylamino)-1,3,5-triazines, together with the
moval of the methoxybenzyl group with ceric ammonium
analogous purine derivative myoseverin, are active as mi-
nitrate in aqueous acetonitrile had given compound 4, but
crotubulin destabilizing agents. Given the structural simi-
Cl
N
Cl
N
N
Cl
a
O
O
H
N
H
N
O
N
O
Cl
N
b
N
Me
N
Me
N
N
HN
N
N
HN
MeO
O
O
O
Cl
11
12
c
MeO
O
H
N
H
N
H
N
H
N
N
N
d
N
Me
N
Me
N
N
HN
N
N
HN
MeO
MeO
O
O
NH
Cl
13
14 X = OMe
15 X = OH
16 X = OBn
X
Scheme 2 Synthesis of imidazolidine–aminotriazine conjugates 12–16. Reagents and conditions: (a) 9, NaHCO3, MeCN, 0–20 °C, 78%; (b)
4-methoxyphenol, K2CO3, MeCN, 20 °C, 13%; (c) 4-methoxyaniline, NaHCO3, MeCN, 96%; (d) 4-substituted phenol, inorganic base, DMF,
20–35 °C, 33–62%.
Synthesis 2010, No. 24, 4312–4316 © Thieme Stuttgart · New York

4314
H. M. Witchard, K. G. Watson
PAPER
a clear colorless oil, which was purified by chromatography on sil-
ica gel (CHCl3, then 1% MeOH–CHCl3), to give the product as a
colorless solid; yield: 300 mg (45%).
1H NMR (300 MHz, CDCl3): d = 7.27 (br s, 5 H, C6H5), 5.93 (s, 1
H, NH), 4.84 (s, 1 H, CH), 3.89 (d, J = 12.9 Hz, 1 H, CH2), 3.78 (d,
J = 12.9 Hz, 1 H, CH2), 2.99 (s, 3 H, CH3), 2.5 (br, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 172.3, 156.6, 138.5, 128.7, 128.4,
127.7, 69.1, 48.5, 24.4.
MS (ESI): m/z (%) = 220 (100, [M + H]+).
larity between these compounds and our triazines 12 and
14, we are exploring the tubulin-binding properties of our
imidazolidine–aminotriazine conjugates.
Melting point determinations were carried out on a Barnstead Elec-
trothermal A9200 Digital Melting Point apparatus and are uncor-
rected. Microanalyses were performed by the Campbell
Microanalytical Laboratory, Department of Chemistry, University
of Otago, Dunedin, New Zealand. Electrospray ionization (ESI)
mass spectra were determined in positive ion mode using a Micro-
mass Platform II Mass Spectrometer or a Thermo Electron LCQ
Advantage MAX ion trap. 1H and 13C NMR spectra were recorded
at 300 MHz and 75.4 MHz, respectively, using a Bruker DRX 300
or a Bruker Advance DPX 300 spectrometer equipped with a Sili-
Anal. Calcd for C11H13N3O2: C, 60.26; H, 5.98; N, 19.17. Found: C,
60.10; H, 5.96; N, 19.26.
5-Amino-3-methylimidazolidine-2,4-dione (9)
To a solution of 7 (400 mg, 1.84 mmol) in EtOH–EtOAc (50 mL,
1:1) was added Pd/C catalyst (10%, 195 mg). The flask was evacu-
ated and filled with H2 three times and then stirred under a H2 atmo-
sphere at r.t. for 23 h. The reaction mixture was filtered through
Celite and the filtrate was evaporated to give the product 9 as a col-
orless solid; yield: 214 mg (90%); mp 122–125 °C.
IR (KBr): 3375, 1713, 1470 cm–1.
1H NMR (300 MHz, CD3CN): d = 6.31 (br s, 1 H, NH), 4.68 (d,
J = 1.5 Hz, 1 H, CH), 2.87 (s, 3 H, CH3).
1
con Graphics workstation. H NMR spectra were recorded in the
specified deuterated solvent, and referenced to the residual nondeu-
terated solvent signal. Chemical shifts (d) in ppm were measured
relative to the internal standard. Analytical TLC analyses were car-
ried out on Merck silica gel 60 F254 precoated aluminum plates with
a thickness of 0.2 mm. All column chromatography was performed
under ‘flash’ conditions on Merck Silica gel 60 (230–400 mesh).
Chromatography solvent mixtures were measured by volume. Or-
ganic solvent extracts were dried with anhyd MgSO4, and the sol-
vent removed under reduced pressure with a Büchi rotary
evaporator. All compounds were judged to be of greater than 95%
1H NMR (300 MHz, D2O): d = 4.95 (s, 1 H, CH), 2.96 (s, 3 H, CH3).
13C NMR (75 MHz, D2O): d = 175.6, 158.5, 64.0, 24.3.
1
purity based upon H NMR and TLC analysis. Starting materials
and reagents were purchased from Sigma-Aldrich Pty Ltd and were
used as received.
Anal. Calcd for C4H7N3O2: C, 37.21; H, 5.46; N, 32.54. Found: C,
38.20; H, 5.34; N, 31.13.
1-Methylimidazolidine-2,4,5-trione (5)
5-(4-Methoxy)benzylamino-3-methylimidazole-2,4-dione (10)
To a solution of 5 (1.02 g, 7.97 mmol), imidazole (596 mg, 8.77
mmol), N,N-dimethylaminopyridine (cat.), and Et3N (2.33 mL, 16.7
mmol) in CHCl3 (15 mL) was added Me3SiCl (2.13 mL, 16.7 mmol)
dropwise at r.t. under a N2 atmosphere. The reaction mixture was
stirred for 2 h and 4-methoxybenzylamine (1.14 mL, 8.77 mmol)
was added and the mixture was stirred for a further 20 h. The mix-
ture was diluted with CHCl3 (30 mL), washed with H2O (2 × 20
mL), and the CHCl3 extracts were dried and evaporated. The crude
product was purified by column chromatography on silica gel
(CH2Cl2–EtOAc, ratio decreasing from 10:1 to 5:1) to give the
product 10 as a colorless solid; yield: 1.10 g (56%); mp 141–143 °C.
1H NMR (300 MHz, CDCl3): d = 7.35 (br s, 1 H, NH), 7.24 (d,
J = 8.6 Hz, 2 H, ArH), 6.83 (d, J = 8.6 Hz, 2 H, ArH), 4.60 (br s, 2
H, CH2), 3.76 (s, 3 H, OCH3), 3.02 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 165.1, 163.5, 162.0, 159.4, 129.6,
126.8, 114.0, 54.9, 46.2, 24.8.
1-Methylimidazolidine-2,4,5-trione (1-methylparabanic acid, 5)
was prepared following a literature procedure;14 yield: 94%; mp
146–149 °C (Lit.14,15 mp 153–155 °C, 145–148 °C).
1H NMR (300 MHz, DMSO-d6): d = 11.96 (br s, 1 H, NH), 2.91 (s,
3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 159.2, 158.5, 154.8, 24.2.
5-Benzylamino-3-methylimidazole-2,4-dione (7)
To a solution of 1- methylparabanic acid (5; 800 mg, 6.25 mmol),
imidazole (467 mg, 6.87 mmol), N,N-dimethylaminopyridine (5
mg, cat.), and Et3N (1.82 mL, 13.1 mmol) in CHCl3 (13 mL) was
added Me3SiCl (1.67 mL, 13.1 mmol) dropwise at r.t. under a N2 at-
mosphere, and the reaction mixture was stirred for 2 h. Benzyl-
amine (0.75 mL, 6.87 mmol) was added and the mixture was stirred
for a further 22.5 h. The mixture was diluted with CHCl3 (20 mL),
washed with H2O (2 × 20 mL), and the CHCl3 extracts were dried
and evaporated. The crude product was purified by column chroma-
tography (silica gel; CH2Cl2–EtOAc, with ratio decreasing from
10:1 to 3:1) to give 7 as a colorless solid; yield: 838 mg (62%); mp
152–154 °C.
MS (ESI): m/z (%) = 248 (15, [M + H]+), 121 (100).
Anal. Calcd for C12H13N3O3: C, 58.29; H, 5.30; N, 16.99. Found: C,
58.54; H, 5.29; N, 16.87.
1H NMR (300 MHz, CD3CN): d = 7.95 (v br s, 1 H, NH), 7.41–7.27
(m, 5 H, C6H5), 4.64 (s, 2 H, CH2), 2.95 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 165.0, 163.6, 161.9, 134.7, 128.6,
128.2, 128.1, 46.7, 24.8.
Attempted Preparation of 5-Imino-3-methylimidazolidine-2,4-
dione (4)
A solution of 10 (1.10 g, 4.45 mmol) and ceric ammonium nitrate
(4.88 g, 8.91 mmol) in MeCN–H2O (4:1; 30 mL) was stirred at r.t.
for 19 h. The reaction mixture was diluted with EtOAc (40 mL),
washed with H2O (2 × 20 mL), and the EtOAc extracts were dried
and evaporated. The crude product was purified by column chroma-
tography on silica gel (CH2Cl2–EtOAc, 3:1) to give 5 as a pale
cream solid; yield: 516 mg (91%); mp 155–156 °C (Lit.14 mp 153–
155 °C).
MS (ESI): m/z (%) = 218 (79, [M + H]+), 91 (100).
Anal. Calcd for C11H11N3O2: C, 60.82; H, 5.10; N, 19.34. Found: C,
60.80; H, 5.06; N, 19.28.
5-Benzylamino-3-methylimidazolidine-2,4-dione (8)
A solution of 7 (650 mg, 3.0 mmol) and ammonium formate (1.5 g,
24 mmol) in MeOH (40 mL) was stirred at r.t. under an atmosphere
of N2. Pd/C (10%, 100 mg) was added to the solution and the result-
ant suspension was stirred vigorously at r.t. for 48 h. The suspension
was filtered and the filtrate was concentrated by evaporation to give
1H NMR (300 MHz, CD3OD): d = 3.05 (s, 3 H, CH3).
Anal. Calcd for C4H4N2O3: C, 37.51; H, 3.15; N, 21.87. Found: C,
38.03; H, 3.17; N, 21.42.
Synthesis 2010, No. 24, 4312–4316 © Thieme Stuttgart · New York

PAPER
5-Amino-3-methylimidazolidine-2,4-dione and Triazine Derivatives
4315
5-(4,6-Dichloro[1,3,5]triazin-2-ylamino)-3-methylimidazoli-
dine-2,4-dione (11)
13C NMR (75 MHz, DMSO-d6): d = 171.5, 165.3, 164.0, 156.5,
154.5, 132.8, 121.9, 113.6, 61.8, 55.1, 24.0.
An ice-cold suspension of 9 (266 mg, 2.06 mmol), cyanuric chloride
(415 mg, 2.27 mmol), and NaHCO3 (191 mg, 2.27 mmol) in MeCN
(15 mL) was stirred with ice-cooling under a N2 atmosphere for 1 h,
and then allowed to stir at r.t. for 22 h. The solvent was evaporated,
and residue was extracted with EtOAc (2 × 20 mL). The EtOAc ex-
tracts were dried, filtered, and evaporated, and the crude product
was purified by column chromatography on silica gel (CH2Cl2–
EtOAc ratio increasing from 10:1 to 1:1) to afford 11 as a pale
cream solid; yield: 448 mg (78%).
1H NMR (300 MHz, CD3CN): d = 7.50 (br s, 1 H, NH), 6.56 (br s,
1 H, NH), 5.60 (dd, J = 7.8, 1.8 Hz, 1 H, CH), 2.97 (s, 3 H, CH3).
MS (ESI): m/z (%) = 277 (10, [M + H]+), 259 (46), 241 (100).
MS (ESI): m/z (%) = 451 (100, [M + H]+).
Anal. Calcd for C21H22N8O4: C, 55.99; H, 4.92; N, 24.88. Found: C,
57.02; H, 5.52; N, 23.22.
5-[4-(4-Hydroxyphenylamino)-6-(4-methoxyphenylami-
no)[1,3,5]triazin-2-ylamino]-3-methylimidazolidine-2,4-dione
(15)
A suspension of 13 (76 mg, 0.21 mmol), 4-aminophenol (50 mg,
0.46 mol), and KOAc (25 mg, 0.25 mmol) in anhyd DMF (3 mL)
was stirred under a N2 atmosphere at 35 °C for 22 h. The reaction
mixture was diluted with H2O (25 mL), and the crude product was
extracted with EtOAc (2 × 20 mL). The organic layer was dried and
evaporated and the crude product was purified by column chroma-
tography on silica gel (CH2Cl2–EtOAc starting with a solvent ratio
of 10:1 and increasing the polarity to CH2Cl2–MeOH, 10:1) to af-
ford 15 as a fawn solid; yield: 24 mg (33%).
1H NMR (300 MHz, CD3CN): d = 7.49 (br d, J = 8.7 Hz, 2 H, ArH),
7.37 (br s, 4 H, NH and ArH), 6.87 (d, J = 8.7 Hz, 2 H, ArH), 6.75
(d, J = 8.7 Hz, 2 H, ArH), 6.70 (s, 1 H, OH), 6.48 (s, 1 H, NH), 6.09
(br d, 1 H, NH), 5.67 (d, J = 7.8 Hz, 1 H, CH), 3.78 (s, 3 H, OCH3),
2.88 (s, 3 H, NCH3).
5-[4,6-Bis-(4-methoxyphenoxy)[1,3,5]triazin-2-ylamino]-3-
methylimidazolidine-2,4-dione (12)
A suspension of 11 (80 mg, 0.29 mmol), 4-methoxyphenol (39 mg,
0.32 mmol), and K2CO3 (88 mg, 0.64 mmol) in MeCN (5 mL) was
stirred at r.t. under a N2 atmosphere for 18 h. The reaction mixture
was diluted with EtOAc (20 mL) and H2O (30 mL), and the organic
layer was separated, and dried. The solvent was evaporated, and the
crude product was purified by column chromatography on silica gel
(CH2Cl2–EtOAc ratio increasing from 10:1 to 1:2). Recrystalliza-
tion from MeCN gave 12 as a colorless solid; yield: 17 mg (13%).
1H NMR (300 MHz, acetone-d6): d = 7.81 (d, J = 8.1 Hz, 1 H, NH),
7.40 (s, 1 H, NH), 7.08 (d, J = 9.0 Hz, 2 H, ArH), 7.07 (d, J = 9.0
Hz, 2 H, ArH), 6.92 (d, J = 9.0 Hz, 4 H, ArH), 5.73 (d, J = 8.1 Hz,
1 H, CH), 3.81 (s, 6 H, OCH3), 2.77 (s, 3 H, NCH3).
13C NMR (75 MHz, CD3CN): d = 171.4, 166.3, 156.9, 156.0, 153.2,
122.9, 114.9, 113.8, 62.2, 55.3, 24.0.
MS (ESI): m/z (%) = 437 (100, [M + H]+).
Anal. Calcd for C20H20N8O4·MeOH: C, 53.84; H, 5.16; N, 23.92.
Found: C, 54.11; H, 4.89; N, 24.26.
MS (ESI): m/z (%) = 453 (100, [M + H]+).
5-[4-(4-Benzyloxyphenylamino)-6-(4-methoxyphenylami-
no)[1,3,5]triazin-2-ylamino]-3-methylimidazolidine-2,4-dione
(16)
Anal. Calcd for C21H20N6O6: C, 55.75; H, 4.46; N, 18.58. Found: C,
55.46; H, 4.66; N, 18.39.
A suspension of 13 (93 mg, 0.26 mmol), 4-benzyloxyaniline hydro-
chloride (132 mg, 0.56 mmol), Cs2CO3 (184 mg, 0.56 mmol) in an-
hyd DMF (5 mL) was stirred under a N2 atmosphere at 30 °C for 19
h. The reaction mixture was diluted with H2O (25 mL) and the aque-
ous mixture was extracted with EtOAc (2 × 20 mL). The organic
layer was dried and evaporated, and the crude product was purified
by column chromatography on silica gel (CH2Cl2–EtOAc starting
with a solvent ratio of 10:1 and increasing the polarity to CH2Cl2–
MeOH, 20:1). The main fractions from the column were combined
and the crude product was recrystallized from hexane–CH2Cl2–
EtOAc gave 16 as a cream solid; yield: 90 mg (62%).
1H NMR (300 MHz, CD3CN): d = 7.58–7.30 (m, 11 H, ArH, C6H5,
and NH), 6.94 (d, J = 8.7 Hz, 2 H, ArH), 6.87 (d, J = 8.7 Hz, 2 H,
ArH), 6.49 (br s, 1 H, NH), 6.14 (br, 1 H, NH), 5.67 (d, J = 7.2 Hz,
1 H, CH), 5.09 (s, 2 H, CH2), 3.78 (s, 3 H, OCH3), 2.88 (br s, 3 H,
NCH3).
5-[4-Chloro-6-(4-methoxyphenylamino)[1,3,5]triazin-2-ylami-
no]-3-methylimidazolidine-2,4-dione (13)
A suspension of 11 (228 mg, 0.82 mmol), 4-methoxyaniline (111
mg, 0.90 mmol), and NaHCO3 (76 mg, 0.90 mmol) in MeCN (7
mL) was stirred at r.t. under a N2 atmosphere for 25 h. The solvent
was evaporated, and the crude product was extracted with EtOAc
(2 × 20 mL). The organic layer was dried and evaporated and the
crude product was purified by column chromatography on silica gel
(CH2Cl2–EtOAc starting with 10:1 and increasing the polarity to
pure EtOAc) to afford 13 as a cream solid; yield: 288 mg (96%).
1H NMR (300 MHz, acetone-d6): d = 8.88 (br d, 1 H, NH), 7.9–7.7
(br m, 2 H, NH), 7.51 (d, J = 8.7 Hz, 2 H, ArH), 6.88 (d, J = 8.7 Hz,
2 H ArH), 5.82 (br d, 1 H, CH), 3.79 (s, 3 H, OCH3), 2.95 and 2.73
(2 s, 3 H, NCH3).
MS (ESI): m/z (%) = 364 (100, [M + H]+).
13C NMR (75 MHz, CDCl3): d = 164.3, 156.6, 155.4, 137.2, 131.5,
5-[4,6-Bis-(4-methoxyphenylamino)[1,3,5]triazin-2-ylamino]-3-
methylimidazolidine-2,4-dione (14)
128.6, 128.0, 127.5, 123.2, 115.1, 114.1, 70.3, 62.4, 55.5, 24.7.
MS (ESI): m/z (%) = 527 (100, [M + H]+).
A suspension of 13 (50 mg, 0.14 mmol), 4-methoxyaniline (25 mg,
0.21 mmol), and K2CO3 (48 mg, 0.34 mmol) in anhyd DMF (5 mL)
was stirred under a N2 atmosphere for 18.5 h. The reaction mixture
was diluted with H2O (30 mL) and the crude product was extracted
with EtOAc (2 × 20 mL). The organic layer was dried and evaporat-
Anal. Calcd for C27H26N8O4: C, 61.59; H, 4.98; N, 21.28. Found: C,
61.50; H, 5.10; N, 21.22.
ed, and the crude product was purified by column chromatography Acknowledgment
on silica gel (CH2Cl2–EtOAc starting with a solvent ratio of 10:1
and increasing the polarity to CH2Cl2–MeOH, 10:1) to afford 14 as
We thank the CRC for Cellular Growth Factors for funding.
a pale cream solid; yield: 36 mg (58%).
1H NMR (300 MHz, acetone-d6): d = 8.14 (br s, 2 H, NH), 7.60 (br
s, 4 H, ArH), 7.43 (br s, 1 H, NH), 6.91 (br d, 1 H, NH), 6.85 (d,
J = 9.0 Hz, 4 H, ArH), 5.91 (d, J = 7.8 Hz, 1 H, CH), 3.77 (s, 6 H,
OCH3), 2.86 and 2.73 (2 s, total 3 H, NCH3).
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