A new route to substituted pyrimido[5,4-e]-l,2,4-triazine-5,7(1H,6H)-diones and facile extension to 5,7(6H,8H) isomers

Article abstract of DOI:10.1055/s-0029-1217030

A new route to substituted pyrimido[5,4-e]-l,2,4-triazine-5,7(lH,6H)-diones is outlined. The synthesis proceeds via preformed hydrazone intermediates, which are then condensed with an activated chlorouracil to build up the entire molecular framework, foll

Full text of DOI:10.1055/s-0029-1217030

4022
PAPER
A New Route to Substituted Pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones
and Facile Extension to 5,7(6H,8H) Isomers
New
R
oute to Pyri
n
mido[5,4-
e
]-
j
1,2,4-t
a
ndiones ette J. Turbiak, H. D. Hollis Showalter*
Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109-1065, USA
Fax +1(734)6478430; E-mail: showalh@umich.edu
Received 27 May 2009; revised 23 July 2009
methyluracil according to the published method.4 The ad-
dition to 8 required catalysis with aluminum trichloride
for those hydrazones formed from arylhydrazines. The re-
sultant 6-(2-arylidene-1-substituted-hydrazinyl)-3-meth-
Abstract: A new route to substituted pyrimido[5,4-e]-1,2,4-tria-
zine-5,7(1H,6H)-diones is outlined. The synthesis proceeds via pre-
formed hydrazone intermediates, which are then condensed with an
activated chlorouracil to build up the entire molecular framework,
followed by a reductive ring closure to provide the parent series. yl-5-nitrouracils 9 were then cyclized to 3-(4-aryl)-6-
The route has been extended to the isomeric pyrimido[5,4-e]-1,2,4-
methyl-1-substituted-pyrimido[5,4-e]-1,2,4-triazine-
triazine-5,7(6H,8H)-dione class via the use of methylhydrazine as
5,7(1H,6H)-diones 10 upon treatment with zinc dust (4
hydrazine surrogate, followed by regiospecific alkylation of the N8-
equiv) and ammonium chloride (2 equiv) while exposed
H pyrimidotriazinediones with a range of alkyl and alkaryl substit-
to the air and with vigorous stirring in refluxing 50%
uents. This new methodology permits the generation of a wide
aqueous ethanol. The N1-substituted pyrimidotriazinedi-
ones were then isolated cleanly, usually in >60% yield, by
washing with aqueous 1 M hydrochloric acid. Other sol-
vents and combinations thereof were tried for the zinc-
mediated cyclization, but the yields were considerably di-
minished. Further, additional standard methods were
evaluated to reduce the nitro group and promote cycliza-
tion. These included standard hydrogenation over palladi-
um on carbon, transfer hydrogenation (Pd/C, ammonium
formate), tin in ethyl acetate, tin(II) chloride dihydrate in
ethanol, iron in glacial acetic acid, and zinc/hydrochloric
acid in ethanol, but none provided clean product.
range of compounds with variable substitution at the N1, C3, and N8
positions for a heterocyclic scaffold with demonstrated pharmaco-
logical activity.
Key words: pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones, py-
rimido[5,4-e]-1,2,4-triazine-5,7(6H,8H)-diones, heterocycles, hy-
drazones, cyclizations
Pyrimido[5,4,e]-1,2,4-triazine-5,7-diones such as the nat-
ural products toxoflavin (1) and fervenulin (2) (Figure 1)
exhibit antibiotic and other useful pharmacological activ-
ity, motivating interest in their exploration since the early
1960s.1 While a variety of analogues have been synthe-
sized and evaluated within both templates, one subclass
conspicuously absent is that with aryl substituents at the
N1-position, 3, whereas analogues with similar substitu-
ents at N8, 4, have been reported.2 We recently have re-
ported on a novel synthesis of compounds related to 1,
including hitherto inaccessible N1-phenyl analogues 3.3 In
this paper, we report on the further application of this syn-
thesis to a variety of N1-alkyl and N1-aryl compounds, and
an efficient process for extending this synthesis to the
generation of compounds within the isomeric fervenulin
series.
O
O
N
Me
O
N
N
Me
O
N
N
N
N
N
N
N
Me
2
Me
1
O
O
6
N
6
N
R
N
Me
O
R
N
Me
O
3
3
1
N
8
N
N
N
N
N
Ar
3
Ar
4
5,7(1H,6H)-dione
5,7(6H,8H)-dione
The strategy and range of analogues synthesized within
Figure 1 Structures of natural and synthetic pyrimidotriazinediones
the
pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-dione
(toxoflavine) series is shown in Table 1. First, monosub-
stituted hydrazines 5, either as the free base or hydrochlo-
ride salt, were condensed under reflux with aromatic
aldehydes 6 in ethanol or tetrahydrofuran to form hydra-
zones 7, which usually precipitated out of solution upon
cooling. The resulting hydrazones 7 were then treated
with 6-chloro-3-methyl-5-nitrouracil (8), which had been
formed by nitration of commercially available 6-chloro-3-
For Ar and R = aryl, the method was amenable to a variety
of substituents on either ring (Table 1, entries 1–8). Both
electron-donating and electron-withdrawing substituents
were tolerated on either component and there was varia-
tion in overall yield depending on the combination of moi-
eties examined. However, the hydrazone formed from 2-
pyridylhydrazine was unreactive, perhaps due to catalyst
deactivation via complexation of the adjacent pyridyl ni-
trogen with aluminum trichloride. An attempt to conduct
this reaction in the absence of catalyst and at higher tem-
peratures led only to recovered hydrazone.
SYNTHESIS 2009, No. 23, pp 4022–4026
x
x.
x
x
.
2
0
0
9
Advanced online publication: 12.10.2009
DOI: 10.1055/s-0029-1217030; Art ID: M02809SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
New Route to Pyrimido[5,4-e]-1,2,4-triazine-5,7-diones
4023
In optimizing the reaction sequence, it was found that hy- however, in the subsequent cyclization of 9 to 10 with
drazones 7, where R = aryl, did not need to be isolated in zinc and ammonium chloride, demethylation at N1 was a
a separate step (Table 1, Method A) and that yields of 9 significant side reaction. Varying the reaction time and
were often improved by forming the hydrazone in situ. temperature could minimize this, but it was never com-
Hence, this became the preferred method. In the improved pletely suppressed. Hence, for R = methyl, the preferred
protocol (Table 1, Method B), 6-chloro-3-methyl-5-ni- method of synthesis would be one of the standard methods
trouracil (8) and aluminum trichloride were added after 1– commonly used to make N1-methylpyrimidotriazinedi-
2 hours of reaction time between the arylhydrazine 5 and ones,5 but for most other R substituents, our new method-
arylaldehyde 6 in an appropriate solvent. After a solvent ology is advantageous with regard to both synthesis time
screen that included standard chlorinated solvents (no re- and efficiency. Moreover, for Methods B and C, the se-
action) and acetonitrile (modest reaction), tetrahydrofuran quence of in situ formation of hydrazone 7 followed by
was found to provide superior yields. In addition to aryl- condensation with chloronitrouracil 8 and subsequent cy-
hydrazines, the methodology was investigated for a vari- clization to 10 can be carried out with yields comparable
ety of alkylhydrazines 5 (R = alkyl), and here the to or better than when 7 is isolated separately.
hydrazones 7 formed in situ were found to be sufficiently
reactive with chlorouracil 8 that activation with aluminum
trichloride was unnecessary. Table 1 (Method C; entries
9–13) summarizes reactions for successful alkylhydra-
zines. In addition to those shown, the hydrazones of meth-
ylhydrazine also reacted quickly and efficiently with 8;
There are some shortcomings to this methodology, how-
ever. The reaction between hydrazones 7 and 6-chloro-3-
methyl-5-nitrouracil (8) was the more general of the last
two steps. An example where the desired Michael-type
addition to 8 did not occur included the hydrazone of tert-
butylhydrazine. For the cyclization of 9 to 10, reaction
Table 1 Substituted Pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones 10 from Condensation of 6-Chloro-3-methyl-5-nitrouracil (8) with
Hydrazones 7 Followed by Reductive Ring Closure of 9
O
O
O
Ar
O2N
Me
O
Ar
N
Me
O
H
N
Δ
AlCl3 (R = Ar)
O
Zn, NH4Cl
H2O–EtOH
Δ
H
N
N
+
N
R
NH2
Ar
H
THF or
EtOH
R
N
N
N
N
R
N
H
N
R
N
O2N
Me
O
5
6
7
N
Ar
9a–m
10a–m
Cl
N
H
8
Entry
Ar
R
Product
9a
Yielda (%)
30,b 72c
41,b 65c
33,b 53c
82c
Product
Yield (%) from 9 Overall yield (%)
1
2
4-HOC6H4
Ph
10a
10b
10c
10d
10e
10f
58
78d
72d
82
79
61
76
40
70
62
56
62d
51
17,b 41c
32,b 51c
24,b 38c
67
4-MeOC6H4
4-ClC6H4
Ph
Ph
9b
9c
3
4
4-HOC6H4
4-MeOC6H4
4-FC6H4
4-FC6H4
4-FC6H4
9d
9e
5
71c
56
6
5-methyl-2-furyl
4-MeOC6H4
4-FC6H4
9f
38c
23
7
4-BrC6H4
9g
31c
10g
10h
10i
24
8
4-MeOC6H4
(CH2)2OH
(CH2)2OH
(CH2)2OH
9h
9i
73c
29
9
4-MeC6H4
66e
46
10
11
12
13
14
3-ClC6H4
9j
68e
10j
42
3,4-(MeO)2C6H3
4-MeOC6H4
4-MeOC6H4
various
9k
9l
70e
10k
10l
39
(CH2)2CHMe2
52e
32
i-Pr
9m
80e
10m
41
e
Me
–
a Overall yield for first two steps.
b Hydrazone isolated in separate step prior to reaction with 8 with AlCl3 catalysis (Method A).
c Hydrazone formation in situ and subsequent reaction with 8 with AlCl3 catalysis (Method B).
d Ref. 3.
e See Table 2. Hydrazone formation in situ and subsequent reaction with 8 without AlCl3 catalysis (Method C).
Synthesis 2009, No. 23, 4022–4026 © Thieme Stuttgart · New York

4024
A. J. Turbiak, H. D. H. Showalter
PAPER
Table 3 N8-Substituted Pyrimido[5,4-e]-1,2,4-triazine-5,7(6H,8H)-
diones 11 from Regiospecific Alkylation of 10
conditions were robust for aryl and some alkyl substitu-
ents at the N1-position. However, problems were encoun-
tered for both benzyl and methyl (as described above)
substituents. While N1-methylpyrimidotriazinediones
could be isolated to some extent, despite the competing
demethylation, no desired N1-benzylpyrimidotriazinedi-
ones 10 could be detected as debenzylation appeared to
rapidly follow cyclization. A similar outcome was ob-
served for R = (CH2)2NEt2 with N1–C bond cleavage like-
ly occurring via an aziridinium intermediate.
X
X
O
O
N
N
Me
O
N
Me
O
RBr
N
N
N
N
Cs2CO3
acetone
N
R
N
10
N
H
11a–j
Entry Substrate
X
R
Product Yield (%)
1
2
10q
10s
10n
10n
10p
10q
10n
10s
10p
10s
Cl
Pr
11a
11b
11c
11d
47
22
43
39
71
57
66
81
91
87
The demethylation that occurred when R = Me in the for-
mation of 10 could be used to advantage, however, when
the goal was an N8-H pyrimidotriazinedione. While hy-
drazine itself could be used in the initial condensation
with aldehydes 6 to form hydrazones 7 (R = H), subse-
quent reaction of these with chlorouracil 8 followed by re-
ductive ring closure with zinc and ammonium chloride
never provided clean N1(N8)-H pyrimidotriazinediones.
Hence, methylhydrazine could be used as a surrogate to
attain the same objective. Table 2 lists several examples
where 3-aryl-substituted pyrimidotriazinediones were
made in this two-pot three-step process. Here, slightly
lower yields were obtained in the ring closure/demethyla-
tion step when there was an electron-donating substituent
at the 4-position of the aryl substituent (Table 2, entries 6
and 7), whereas the highest yields were obtained with the
strongly electron-withdrawing fluoro group at the same
position (Table 2, entries 3 and 8). Both of these observa-
tions are consistent with the ease with which demethyla-
tion of N1-methylpyrimidotriazinediones occurred. This
involves a likely mechanism of SN2 nucleophilic attack of
the N1-methyl group by solvent followed by C–N bond
cleavage with the core pyrimidotriazinedione heterocycle
serving as a leaving group.
a
OMe
H
(CH2)2NEt2
(CH2)2OH
(CH2)2Ph
3
4
H
5
F
4-t-BuC6H4CH2 11e
6
Cl
2-FC6H4CH2
3-FC6H4CH2
4-FC6H4CH2
11f
11g
11h
7
H
8
OMe
F
9
3,4-F2C6H3CH2 11i
3,4-F2C6H3CH2 11j
10
OMe
a Chloride reacted instead of bromide.
The demethylated pyrimidotriazinediones could then be
alkylated to produce a variety of novel N8-substituted py-
rimidotriazinedione analogues, as shown in Table 3. This
reaction, which has been previously documented in the lit-
erature,6 can be subjected to conditions that provide either
N1- or N8-alkyl products or mixtures thereof. Our condi-
tions, which involve the use of cesium carbonate as base,
Table 2 N8-H Pyrimido[5,4-e]-1,2,4-triazine-5,7(6H,8H)-diones 10 from Methylhydrazine as a Hydrazine Surrogate
O
O
O
O2N
Me
O
Ar
N
N
Me
O
Table 1
scheme
N
Zn, NH4Cl
H2O–DMF
Δ
N
H
N
+
Ar
H
N
Me
NH2
N
N
N
H
N
H
5
6
Ar
Me
9n–u
10n–u
Entry
Ar
Ph
Producta
9n
Yield (%)
Product
10n
10o
Yield (%) from 9 Overall yield (%)
1
2
3
4
5
6
7
8
75
82
87
78
72
90
85
84
50
61
79
63
65
43
47
86
38
50
68
49
46
38
40
72
3-FC6H4
4-FC6H4
9o
9p
10p
10q
10r
4-ClC6H4
9q
3-MeOC6H4
4-MeOC6H4
9r
9s
10s
3-F-4-MeOC6H3
4-F-3-MeOC6H3
9t
10t
9u
10u
a Hydrazone formation in situ and subsequent reaction with 8 without AlCl3 catalysis (Method C).
Synthesis 2009, No. 23, 4022–4026 © Thieme Stuttgart · New York

PAPER
New Route to Pyrimido[5,4-e]-1,2,4-triazine-5,7-diones
4025
1H NMR (DMSO-d6): d = 3.14 (s, 3 H), 7.42 (d, J = 7.7 Hz, 2 H),
7.50 (m, 3 H), 7.58 (m, 3 H), 7.70 (d, J = 7.7 Hz, 2 H), 11.90 (br s,
1 H).
13C NMR (DMSO-d6): d = 27.72, 112.52, 122.27, 127.83, 128.78,
129.11, 130.22, 131.17, 132.73, 134.97, 135.29, 142.61, 145.53,
157.75.
provide N8 products exclusively for a wide range of alkyl
and alkaryl substituents. While yields are variable, these
were not optimized except for 11i and 11j.
In summary, we have discovered a facile route to pyrimi-
do[5,4-e]-1,2,4-triazine-5,7-diones with variable substitu-
tion at the N1, C3, and N8 positions, including previously
undisclosed N1-aryl variants. We also have exemplified
the use of methylhydrazine as a surrogate for hydrazine to
provide an entry to a variety of N1(N8)-unsubstituted con-
geners, which can be mildly and regioselectively func-
tionalized at the N8-position with alkyl and alkaryl
halides. We expect this chemistry to find wide application
toward the discovery of novel pharmacological agents.
MS: m/z = 422.1 (M + Na).
6-(2-Arylidene-1-substituted-hydrazinyl)-3-methyl-5-nitropy-
rimidine-2,4(1H,3H)-diones 9 via In Situ Generation of Hydra-
zone 7; General Procedure for Methods B and C
Method B: A mixture of aryl- or alkylhydrazine 5 and arylaldehyde
6 (1.1 equiv) was dissolved in anhyd THF (0.3 M) and the soln was
heated at reflux for 1.5 h. The soln was cooled to r.t, and chlorou-
racil 8 (0.9 equiv) was added, followed by AlCl3 (1.0 equiv). The
mixture was returned to reflux for 4 h and then cooled on ice for sev-
eral hours. The formed precipitate was collected by filtration, rinsed
with THF and EtOH, and dried.
All starting materials were obtained from commercial suppliers and
were used without further purification. THF was distilled prior to
use over Na/benzophenone. Reactions were run under a blanket of
N2 unless specified otherwise. Glassware was oven-dried before use
for reactions run under anhydrous conditions. Melting points were
determined in open capillary tubes on a Laboratory Devices Mel-
Temp apparatus and are uncorrected. The NMR spectra were re-
corded on a Bruker instrument at 500 MHz for 1H, 125 MHz for 13C,
and 470 MHz for 19F spectra. Mass spectra were recorded on a Mi-
cromass TofSpec-2E Matrix-Assisted, Laser-Desorption, Time-of-
Flight mass spectrometer.
Method C: The same initial steps for Method B were followed, ex-
cept that the catalyst was omitted. A precipitate began to form with-
in 5–10 min after addition of 8. The mixture was heated for an
additional 20–45 min. Further processing as per Method B provided
product 9.
6-[2-(4-Fluorobenzylidene)-1-(4-methoxyphenyl)hydrazinyl]-3-
methyl-5-nitropyrimidine-2,4(1H,3H)-dione (9h)
Fluorescent yellow powder; yield: 556 mg (73%); mp 228–229 °C.
1H NMR (DMSO-d6): d = 3.15 (s, 3 H), 3.86 (s, 3 H), 7.14 (d,
J = 8.85 Hz, 2 H), 7.23 (dd, J = 8.85 Hz, J¢ = 8.85 Hz, 2 H), 7.33 (d,
J = 8.8 Hz, 2 H), 7.46 (s, 1 H), 7.75 (dd, J = 8.3 Hz, J¢ = 5.7 Hz, 2
H).
13C NMR (DMSO-d6): d = 27.66, 55.99, 115.83, 124.39, 126.33,
129.68, 130.12, 131.64, 143.71, 147.29, 149.11, 158.83, 160.83,
162.18, 165.48.
All known compounds had spectroscopic (NMR and MS) and phys-
ical properties identical to those given in the literature. There are
preparative procedures in the literature for the synthesis of hydra-
zones 7a,7 7b8 and 7c9 of Table 1, (hydrazinyl)nitropyrimidinedi-
ones 9n,10 9q10 and 9s10 of Table 2, pyrimidinotriazines 10n,10 10q10
and 10s10 of Table 2, and alkylated pyrimidinotriazines 11a11 and
11c12 of Table 3.
2-Substituted 1-(4-Arylidene)hydrazines 7; General Procedure
for Method A
A mixture of aryl- or alkylhydrazine 5, arylaldehyde 6 (1.1 equiv),
and abs EtOH (0.5–0.7 M) was heated at reflux for 90 min. The soln
was left standing at r.t. for several hours and the formed precipitate
was collected by filtration, rinsed thoroughly with EtOH, and dried.
It was used directly in the next step.
19F NMR (DMSO-d6): d = –107.2.
MS: m/z = 414.1 (M + H).
6-[1-Isopropyl-2-(4-methoxybenzylidene)hydrazinyl]-3-meth-
yl-5-nitropyrimidine-2,4(1H,3H)-dione (9m)
Pastel yellow powder; yield: 74 mg (80%); mp 280–285 °C (dec).
1H NMR (DMSO-d6): d = 1.40 (d, J = 6.1 Hz, 6 H), 3.20 (s, 3 H),
3.79 (s, 3 H), 4.76 (m, 1 H), 6.97 (d, J = 8.3 Hz, 2 H), 8.15 (d,
J = 8.2 Hz, 2 H), 12.25 (s, 1 H).
1-(4-Chlorobenzylidene)-2-phenylhydrazine (7c)9
Pale peach powder; yield: 290 mg (52%); mp 124–126 °C.
1H NMR (DMSO-d6): d = 6.76 (t, J = 7.3 Hz, 1 H), 7.07 (d, J = 8.2
Hz, 1 H), 7.22 (dd, J = 7.5 Hz, J¢ = 8.1 Hz, 2 H), 7.44 (d, J = 8.2 Hz,
2 H), 7.66 (d, J = 8.5 Hz, 2 H), 7.85 (s, 1 H), 10.45 (s, 1 H).
13C NMR (DMSO-d6): d = 22.04, 27.57, 49.37, 55.59, 95.54,
113.88, 124.76, 129.86, 143.21, 147.78, 151.18, 158.64, 160.04.
MS: m/z = 362.1 (M + H), 384.0 (M + Na).
13C NMR (DMSO-d6): d = 112.52, 119.42, 127.60, 129.13, 129.59,
6-[2-(4-Fluoro-3-methoxybenzylidene)-1-methylhydrazinyl]-3-
methyl-5-nitropyrimidine-2,4(1H,3H)-dione (9u)
Pastel yellow powder; yield: 295 mg (84%); mp 218–222 °C.
132.52, 135.29, 135.43, 145.54.
MS: m/z = 231.1 (M + H).
1H NMR (DMSO-d6): d = 3.15 (s, 3 H), 3.41 (s, 3 H), 3.95 (s, 3 H),
7.35 (m, 1 H), 7.55 (m, 1 H), 7.90 (d, J = 8.5 Hz, 1 H), 8.71 (s, 1 H),
11.30 (br s, 1 H).
13C NMR (DMSO-d6): d = 27.63, 34.98, 56.34, 111.01, 116.49,
122.42, 131.20, 131.65, 142.36, 149.47, 157.62.
6-(2-Arylidene-1-substituted-hydrazinyl)-3-methyl-5-nitropy-
rimidine-2,4(1H,3H)-diones 9; General Procedure for Method
A
Hydrazone 7 was suspended in anhyd THF (0.3M), and treated with
AlCl3 (1.0 equiv) and chlorouracil 8 (0.9 equiv). The mixture was
heated at reflux for 4 h, during which time it became homogeneous
and usually a darker color in appearance. The mixture was cooled
on ice for several hours and the thus formed precipitate was collect-
ed by filtration, rinsed successively with THF and EtOH, and dried.
19F NMR (DMSO-d6): d = –129.7.
MS: m/z = 350.1 (M – H).
Anal. Calcd for C14H14FN5O5: C, 47.87; H, 4.02; N, 19.94. Found:
C, 47.82; H, 3.89; N, 19.87.
6-[2-(4-Chlorobenzylidene)-1-phenylhydrazinyl]-3-methyl-5-
nitropyrimidine-2,4(1H,3H)-dione (9c)
Yellow powder; yield: 95 mg (63%); mp 210–212 °C (dec).
Synthesis 2009, No. 23, 4022–4026 © Thieme Stuttgart · New York

4026
A. J. Turbiak, H. D. H. Showalter
PAPER
8-(3-Fluorobenzyl)-6-methyl-3-phenylpyrimido[5,4-e]-1,2,4-
Pyrimidotriazinediones 10; General Procedure
Table 1: To a suspension of 9 in 50% aq EtOH (0.2 M) was added
Zn dust (4.0 equiv) and NH4Cl (2.0 equiv). The vigorously stirred
suspension was heated at reflux overnight with exposure to the air.
The mixture was cooled to r.t. and diluted with aq 1 M HCl (1–3 mL
per mmol of Zn used). After stirring at r.t. for 1 h, the formed pre-
cipitate was collected by filtration, washed successively with aq 1
M HCl and EtOH, and dried to provide 10.
triazine-5,7(6H,8H)-dione (11g)
Yield: 47 mg (66%); mp 229–232 °C.
1H NMR (DMSO-d6): d = 3.40 (s, 3 H), 5.60 (s, 2 H), 7.11 (t, J = 7.2
Hz, 1 H), 7.31 (m, 2 H), 7.39 (m, 1 H), 7.63 (d, J = 2.6 Hz, 3 H),
8.43 (m, 2 H).
13C NMR (DMSO-d6): d = 29.31, 45.42, 114.42, 123.70, 127.67,
129.77, 130.80, 131.99, 134.42, 139.46, 149.93, 150.19, 159.99,
160.20, 160.51.
Table 2: The same procedure as described above was followed ex-
cept that reaction was carried out in 50% aq DMF (0.08–0.1 M).
MS: m/z = 364.1 (M + H).
1-(4-Fluorophenyl)-3-(4-methoxyphenyl)-6-methylpyrimi-
do[5,4-e]-1,2,4-triazine-5,7(1H,6H)-dione (10e)
Bright red-orange solid; yield: 188 mg (79%); mp 310–315 °C
(dec).
1H NMR (DMSO-d6): d = 3.29 (s, 3 H), 3.86 (s, 3 H), 7.14 (d,
J = 8.8 Hz, 2 H), 7.51 (t, J = 8.7 Hz, 2 H), 7.82 (dd, J1 = 8.8 Hz,
J2 = 4.9 Hz, 2 H), 8.14 (d, J = 8.8 Hz, 2 H).
Acknowledgment
A.J.T. gratefully acknowledges financial support of the American
Chemical Society Division of Medicinal Chemistry, Sheila B.
Cresswell, and Fred and Dee Lyons Graduate Fellowships. This
publication was also made possible by grant number GM007767
from NIGMS. Its contents are solely the responsibility of the au-
thors and do not necessarily represent the official views of NIGMS.
13C NMR (DMSO-d6): d = 26.03, 52.04, 112.45, 115.67, 117.07,
119.19, 124.06, 124.19, 128.12, 129.45, 144.84, 154.96, 162.24.
19F NMR (DMSO-d6): d = –105.6.
References
MS: m/z = 380.1 (M + H), 402.1 (M + Na).
(1) (a) Lacrampe, J. F. A.; Connors, R. W.; Ho, C. Y.;
Richardson, A.; Freyne, E. J. E.; Buijnsters, P. J. J.; Bakker,
A. C. WO 2004,007,498, 2004. (b) Nagamatsu, T.;
Yamasaki, H.; Hirota, T.; Yamato, M.; Kido, Y.; Shibata,
M.; Yoneda, F. Chem. Pharm. Bull. 1993, 41, 362. (c)Liao,
T.; Baiocchi, F.; Cheng, C. C. J. Org. Chem. 1966, 31, 900.
(d) Levenberg, B.; Linton, S. N. J. Biol. Chem. 1966, 241,
846.
(2) Nagamatsu, T.; Yamasaki, H.; Yoneda, F. Heterocycles
1994, 37, 1147.
(3) Turbiak, A. J.; Showalter, H. D. H. Tetrahedron Lett. 2009,
50, 1996.
(4) Black, H. T. J. Heterocycl. Chem. 1987, 24, 1373.
(5) (a) Nagamatsu, T.; Yamasaki, H.; Hirota, T.; Yamato, M.;
Kido, Y.; Shibata, M.; Yoneda, F. Chem. Pharm. Bull. 1993,
41, 362. (b) Yoneda, F.; Nagamatsu, T. Chem. Pharm. Bull.
1975, 23, 2001. (c) Yoneda, F.; Nagamatsu, T.; Shinomura,
K. J. Chem. Soc., Perkin Trans. 1 1976, 713.
Anal. Calcd for C19H14FN5O3: C, 60.16; H, 3.72; N, 18.46. Found:
C, 59.88; H, 3.50; N, 18.19.
1-(2-Hydroxyethyl)-6-methyl-3-(4-methylphenyl)pyrimido[5,4-
e]-1,2,4-triazine-5,7(1H,6H)-dione (10i)
Bright reddish-orange powder; yield: 57 mg (70%); mp 199–201 °C
(dec).
1H NMR (DMSO-d6): d = 2.41 (s, 3 H), 3.34 (s, 3 H), 3.93 (t, J = 5.2
Hz, 2 H), 4.53 (t, J = 5.3 Hz, 2 H), 4.98 (br s, 1 H), 7.39 (d, J = 7.3
Hz, 2 H), 8.21 (d, J = 7.3 Hz, 2 H).
13C NMR (DMSO-d6): d = 21.50, 28.75, 57.15, 58.09, 127.07,
130.28, 132.64, 141.67, 146.92, 149.95, 151.75, 154.59, 159.49.
MS: m/z = 314.1 (M + H).
3-(4-Methoxyphenyl)-6-methylpyrimido[5,4-e]-1,2,4-triazine-
5,7(6H,8H)-dione (10s)10
Mustard yellow powder; yield: 897 mg (43%); mp >325 °C.
(6) (a) Nagamatsu, T.; Yamasaki, H. J. Chem. Soc., Perkin
Trans. 1 2001, 130. (b) Yoneda, F.; Nagamatsu, T.
J. Heterocycl. Chem. 1974, 11, 271. (c) Yoneda, F.;
Nagamatsu, T. Tetrahedron Lett. 1973, 14, 1577.
(7) Dabideen, D. R.; Cheng, K. F.; Aljabari, B.; Miller, E. J.;
Pavlov, V. A.; Al-Abed, Y. J. Med. Chem. 2007, 50, 1993.
(8) Yao, H. C.; Resnick, P. J. Org. Chem. 1965, 30, 2832.
(9) Deng, X.; Mani, N. S. J. Org. Chem. 2008, 73, 2412.
(10) Yoneda, F.; Nagamatsu, T. Synthesis 1975, 177.
(11) Yoneda, F.; Higuchi, M.; Nitta, Y. J. Heterocycl. Chem.
1980, 17, 869.
1H NMR (TFA-d): d = 3.55 (s, 3 H), 3.90 (s, 3 H), 7.09 (d, J = 7.2
Hz, 2 H), 8.31 (d, J = 7.2 Hz, 2 H).
13C NMR (TFA-d): d = 19.49, 45.95, 116.54, 121.91, 132.06,
138.08, 147.51, 150.95, 161.72, 166.36.
MS: m/z = 284.1 (M – H).
8-Alkylpyrimido[5,4-e]-1,2,4-triazine-5,7(6H,8H)-diones 11;
General Procedure
A mixture of 3-arylpyrimidotriazinedione 10, Cs2CO3 (1.5 equiv),
alkyl halide (1.2 equiv), and acetone (0.1 M) was stirred at r.t. over-
night (bromides) or heated to 50 °C in a sealed vessel overnight
(chlorides). The mixture was diluted with H2O, and refrigerated for
3–4 h. The resulting precipitate was collected, washed with H2O,
and dried to provide 11.
(12) Yoneda, F.; Nagamatsu, T. J. Heterocycl. Chem. 1974, 11,
271.
Synthesis 2009, No. 23, 4022–4026 © Thieme Stuttgart · New York