Synthesis of novel fused tricyclic quinolones: 4a,5-dihydro-1H-[1,2,4]triazino[1,6-a]quinoline-2,4,6(3H)-triones

Article abstract of DOI:10.1002/jhet.5570390608

A versatile methodology to build the 1H-[1,2,4]triazino[1,6-a]quinoline-2,4,6(3H)-trione structure from methyl 6-fluoro4-oxo-1,4-dihydro-2-quinolinecarboxylate was developed. The method involves an N-amination followed by condensation of an aroyl isocyana

Full text of DOI:10.1002/jhet.5570390608

Nov-Dec 2002
Synthesis of Novel Fused Tricyclic Quinolones:
1161
4a,5-Dihydro-1H-[1,2,4]triazino[1,6-a]quinoline-2,4,6(3H)-triones
Dolorès Edmont, Christophe Marot and Jacques Chenault*
Institut de Chimie Organique et Analytique, Université d'Orléans, B. P. 6759, 45067 Orléans cedex 2, France
Received December 27, 2001
A versatile methodology to build the 1H-[1,2,4]triazino[1,6-a]quinoline-2,4,6(3H)-trione structure from
methyl 6-fluoro4-oxo-1,4-dihydro-2-quinolinecarboxylate was developed. The method involves an N-ami-
nation followed by condensation of an aroyl isocyanate to form an alpha semicarbazidocarboxylate that
readily cyclizes to the fused [1,2,4]triazino ring under ammonia/ethanol condition. Also, the reactivity of the
[1,2,4]triazino ring thus obtained was studied.
J. Heterocyclic Chem., 39, 1161(2002).
Among the different quinolones carboxylic families of
at reflux, as previously described [10]. The intermediate,
methyl 1-amino-6-fluoro-4-oxo-1,4-dihydro-2-quino-
linecarboxylate 2, was obtained through a high yield N-
amination reaction at low temperature via the use of O-
mesitylenesulfonylhydroxylamine (MSH) [11].
antibacterial agents there is a series of potent tricyclic and
tetracyclic compounds containing a three- or four-atom
bridge connecting the N1-C8 vicinal positions of
quinolones [1]. These series include oxolinic acid [2],
tioxacin [3], flumequin [4], ofloxacin [5], and other differ-
ent tricyclic quinolones, which contain a three-atom bridge
connecting the C2 to either the N1 [6a-c] or the C3 [6d].
So, we are interested in preparing novel fused tricyclic
quinolones that are non carboxylic at the C3 position, and
contain a four-atom bridge connecting the N1 with the C2
incorporated into the [1,2,4]triazino ring. In this paper, we
report first the synthesis of the 8-fluoro-1H-[1,2,4]-tri-
azino[1,6-a]quinoline-2,4,6(3H)-trione, followed by the
study of the reactivity of the [1,2,4]triazino-3,5-dione ring
obtained.
Scheme 2
Historically, the [1,2,4]triazino-3,5-dione ring has been
obtained from a [4+2] combination [7] between alpha
hydrazino carboxylates and imidates [8], or by cyclization
of alpha semicarbazido carboxylic acids derivatives [9].
Therefore, we chose to use methyl 1-amino-6-fluoro-4-
oxo-1,4-dihydro-2-quinolinecarboxylate as the starting
material. Our approach [4+2] is shown in Scheme 1, where
the C-N moiety, we envisaged the synthesis of a semicar-
bazide, allows for an intramolecular cyclization to gener-
ate the triazino ring.
Scheme 1
The key to the successful synthesis lies in the prepara-
tion of the methyl 1-amino-6-fluoro-4-oxo-1,4-dihydro-2-
quinoline carboxylate. The starting synthon 1 was obtained
by condensation dimethyl acetylenedicarboxylate with
4-fluoro aniline, followed by a cyclization in diphenylether
A) DMF, K CO , MSH, -10/0°C, 73%; B) KNCO, H O, 8 N HCl; C)
2
3
2
MeC H SO NCO, DMF, 25°C, 73%; D) DMF, MeONa, 65°C, 76%.
6
4
2

1162
D. Edmont, C. Marot and J. Chenault
Vol. 39
Our initial attempts to obtain the semicarbazide moiety
the deprotection in one pot from 7 using the same condi-
tions (aqueous 16 N ammonia and ethanol) in excellent
yield (77%) (Scheme 3).
using potassium isocyanate under aqueous acidic condi-
tions [12] resulted in failure, the starting material 2 being
recovered unchanged (Scheme 2). As an alternative route,
we envisaged the formation of an N-protected semicar-
bazide by a nucleophilic addition of the N-amino com-
pound 2 onto an isocyanate, the last step of the synthesis
being a N-deprotection. As the para-toluene sulfonyl iso-
cyanate is commercially available, we expected that the
sulfonamide bond would be easy to deprotect. Thus, com-
pound 2, when treated with the para-toluene sulfonyl iso-
cyanate in DMF readily gave 4 in 73% yield. This reaction
is exothermic. The triazino ring of 5 was formed by
intramolecular cyclization using commercially available
sodium methoxide in DMF (Scheme 2).
However, all our attempts to effect N-desulfonylation
[13] did not take place: as example, heating in solvents
such as ethanol or 1-butanol resulted in degradation.
Reductive conditions such as tributyltin hydride [14] or
naphthalene-sodium complex [15] result in deprotection
but also bring about the nitrogen-nitrogen bond.
In order to assess the reactivity of the [1,2,4]triazino moi-
ety, different reactions were envisaged. Chloration [17]
using phosphorus oxychloride as reactant and solvent, read-
ily gave the dichloro compound 9 in 95% yield (Scheme 4).
In the proton magnetic resonance spectrum, we observed a
chemical shift of the H5 signal at low field (6.61 ppm to
8.54 ppm), and the mass spectrum confirmed the presence
+
of two chloro atoms with peaks m/z 284 [M] (100%), m/z
+
+
286 [M+2] (64%) and m/z 288 [M+4] (10%).
Standard alkylation of 6 in the presence of sodium
hydride and iodoethane gave a mixture of N- and O-alky-
lated products 10 and 11 in 19% and 78% yield, respec-
tively. This reaction revealed that a competitive alkylation
takes place due to the prototropic equilibrium shown in
Scheme 5.
Scheme 4
Another protective group was envisaged: the benzoyl
moiety. To this end the synthesis of the benzoyl isocyanate
was achieved from benzamide using oxalyl chloride [16].
Scheme 3
A) benzoyl isocyanate, DMF, 25°C, 71%; B) DMF, MeONa, 65°C, 61%;
C) EtOH, 16N NH OH, 25°C, 37%; D) EtOH, 16 N NH OH, 25°C, 77%.
4
4
A) POCl , reflux, 30 min, 95%; B) (7), DMF, NaH, EtI, 25°C, 19 and
78%; C) DMF, triton B, methyl acrylate, 100°C, 67%.
Nucleophilic addition of 2, with this isocyanate, fol-
lowed by intramolecular cyclization of the resulting adduct
readily afforded the N-protected tricyclic compound 8,
with an overall yield of 43% (Scheme 3). Debenzoylation
of 8 with aqueous 16 N ammonia and ethanol afforded the
desired compound 6 but in only poor yields (37%). After
optimization of this step we achieving the cyclization and
3
On the other hand, a Michaël addition with methyl acry-
late in presence of triton B at 100 °C led to the selective
introduction of the methyl propanoate group onto the nitro-
gen atom N3. Different magnetic resonance experiments

Nov-Dec 2002
Synthesis of Novel Fused Tricyclic Quinolones
1163
such as proton, carbon, NOESy and HMQC, confirmed the
three structures10, 11 and 12.
framework of our SAR studies. Further work including
biological activity and other reactions are under way in our
laboratory.
Scheme 5
EXPERIMENTAL
Melting points (uncorrected) were determined on a Köfler appa-
ratus. Infrared (ir) spectra were recorded on a Perkin-Elmer Paragon
FT-IR 1000 spectrophotometer with 4 cm-1 resolution, only the
1
most significant ir absorptions are given. H nmr spectra were
recorded at 250 MHz and 13C nmr spectra were recorded at 62.89
MHz on a Brucker AM-250 MHz instrument. Chemical shifts are
expressed in parts per million (ppm). Mass spectra were recorded
on a Perkin-Elmer SCIEZ API 3000 spectrometer (ion spray).
Methyl 1-Amino-6-fluoro-4-oxo-1,4-dihydro-2-quinolinecar-
boxylate (2).
To a solution of 1 (3 g, 14 mmol) dissolved in 27 ml of DMF
with 4.7 g (35 mmol) of potassium carbonate, 1 g of MSH was
added every quarter of an hour, until all of the precursor disap-
peared. The temperature was maintained between –10/0 °C. The
mixture was poured into 500 ml of ice cold water. The precipitate
so formed was then collected by filtration, washed and dried in a
steam room at 100 °C to give 2 as a white solid (73%), mp 224
°C; ir (KBr): 3351 (NH2), 1735, 1608 (C=O) cm-1; 1H nmr (250
MHz, DMSO-d6): d 3.88 (s, 3, OCH3), 6.13 (s, 1, H3), 6.39 (s, 2,
At the same time, a molecular modeling study was per-
formed. The four prototropic forms were modeled and
optimized with SYBYL (v.6.4) [18] via MOPAC [19],
using AM1. Two other methods, ab initio, were also used
in order to find the stability of each form (Spartan and
Games). The results in Table 1 showed, without ambiguity,
that 6a and 6d are the most stable forms from an energetic
standpoint and that the nitrogen atom N3 is more elec-
tronegative than N1 in both forms.
NH2), 7.73-7.8 (m, 2, H5, H7), 7.93 (dd, 1, J8,F = 4.0 Hz, J8,7
10.0 Hz, H8);13C nmr (62.89 MHz, DMSO-d6): d 55.70 (OCH3),
108.06 (C3), 111.93 (d, JC,F = 22.64 Hz, C5), 122.79 (d, JC,F
=
=
8.17 Hz, C8), 123.66 (d, JC,F = 25.15 Hz, C7), 129.84 (Cq),
141.64 (Cq), 50.65 (Cq), 161.53 (d, JC,F = 243.38 Hz, C6),
165.55 (C=O), 177.65 (C=O); HRMS (EI+) 236.0455 (M+; calc.
for C11H9FN2O3, 236.0219).
Anal. Calcd. for C11H9FN2O3: C, 55.94; H, 3.84; N, 11.86.
Found: C, 55.82; H, 3.86; N, 11.71.
Table 1
Methyl 6-Fluoro-1-[({[(4-methylphenyl) sulfonyl]amino}-
carbonyl)amino]-4-oxo-1,4-dihydro-2-quinolinecarboxylate (4).
MOPAC
(AM1)
Charge
Spartan
3-21G*
Energie
(Hartree)
Games
3-21G*
Charge
Under nitrogen, to a solution of 2 (3 g, 12.71 mmol) in 25 ml of
freshly distilled DMF, was added dropwise 2.6 ml (16.52 mmol)
of para-toluene sulfonyl isocyanate. After 6 hours at room tem-
perature, the reaction mixture was evaporated and the crude prod-
uct was purified by column chromatography eluting with 9:1
CH2Cl2/MeOH to afford a pale yellow solid (73%), mp 208-210
°C; ir (KBr): 3230 (NH), 1737, 1698, 1633 (C=O) cm-1; 1H nmr
(250 MHz, DMSO-d6): d 2.47 (s, 3, CH3), 3.70 (s, 3, OCH3),
6.47 (s, 1, H3), 7.38-7.42 (m, 3, H7, phenyl), 7.66-7.78 (m, 4, H5,
H8, phenyl), 10.52 (s, 1, NH), 12.06 (s, 1, NH); 13C nmr (62.89
MHz, DMSO-d6): d 19.48 (CH3), 51.81 (OCH3), 108.13 (d, JC,F
= 20.12 Hz, C5), 108.29 (C3), 117.45 (d, JC,F = 7.79 Hz, C8),
120.63 (d, JC,F = 25.15 Hz, C7), 125.81 (2C, phenyl), 127.73
(2C, phenyl), 127.97 (Cq), 135.24 (Cq), 136.89 (Cq), 142.54
(Cq), 142.76 (Cq), 149.63 (C=O), 157.54 (d, JC,F = 244.64 Hz,
C6), 159.76 (C=O), 173.99 (C=O); HRMS (EI+) 433.1730 (M+;
calc. for C19H16FN3O6S, 433.2163).
Energie
(Kcal)
Energie
(Hartree)
N
N
1
3
6a
6b
6c
6d
-45.47
-29.05
-32.40
-46.07
-0.22
-0.27
-0.19
-0.15
-0.36
-0.26
-0.21
-0.33
-902.3705
-902.3330
-902.3374
-902.3656
-902.3680
-902.3322
-902.3373
-902.3654
So this molecular modeling study corroborated the reac-
tivity that we observed for the alkylation of compound 6.
In summary, we have synthesized a new class of fused
tricyclic quinolone that contain a four-atom bridge con-
necting the N1 with the C2 incorporated into the triazino
ring. The route required 5 steps from commercially avail-
able arylamines with an overall yield of 33%. We have
selectively alkylated the nitrogen atom N3 by a Michaël
addition whereas a standard alkylation gave a mixture of
N- and O-alkylated product and O-alkylated product. This
reactivity offers routes to a wide variety of analogues in
order to perform some structural modifications within the
8-Fluoro-3-[(4-methylphenyl)sulfonyl]-1H-[1,2,4]triazino[1,6-a]-
quinoline-2,4,6(3H)-trione (5).
Under nitrogen, to a solution of 4 (4.5 g, 10 mmol) in 20 ml of
freshly distilled DMF, was added 1.43 g (25 mmol) of sodium

1164
D. Edmont, C. Marot and J. Chenault
Vol. 39
methoxide. After 4 hours of heating at 76 °C, the reaction mix-
ture was added to 50 ml of cold water. Some traces of 4 were
removed by filtration under millipore. The filtrate was acidified
with cold aqueous 3 N HCl. The precipitate was collected by fil-
tration, washed with cold water, diethyl ether and dried under
vacuum to give 5 as a pale yellow solid (76%), mp > 264 °C. The
compound can be recrystallised from water; ir (KBr): 3293 (NH),
138.41 (Cq), 144.79 (Cq), 153.11 (C=O), 154.97 (d, JC,F = 233.95
Hz, C8), 162.28 (C=O), 167.28 (C=O), 175.60 (C=O); HRMS (EI+)
351.0580 (M+; calc. for C18H10FN3O4, 351.0931).
Anal. Calcd. for C18H10FN3O4: C, 61.54; H, 2.87; N, 11.96.
Found: C, 61.33; H, 2.91; N, 12.11.
8-Fluoro-1H-[1,2,4]triazino[1,6-a]quinoline-2,4,6(3H)-trione
(6).
1
1723, 1614 (C=O) cm-1; H nmr (250 MHz, DMSO-d6): d 2.27
(s, 3, CH3), 6.12 (s, 1, H5), 7.26 (s, 1, NH), 7.33 (d, 2, J = 8.0
Hz, phenyl), 7.67 (d, 2, J = 8.0 Hz, phenyl), 7.69-7.75 (m, 2, H7,
H9), 7.98 (dd, 1, J10,F = 4.26 Hz, J10,9 = 9.44 Hz, H10); 13C
nmr (62.89 MHz, DMSO-d6): d 21.84 (CH3), 106.25 (C5),
110.16 (d, JC,F = 22.64 Hz, C7), 121.16 (d, JC,F = 8.17 Hz, C10),
121.94 (d, JC,F = 25.15 Hz, C9), 126.38 (Cq), 126.56 (2C,
phenyl), 127.97 (Cq), 130.24 (2C, phenyl), 139.93 (Cq), 142,36
(Cq), 142.80 (Cq), 149.76 (C=O), 159.83 (d, JC,F = 243.38 Hz,
C8), 164.73 (C=O), 175.80 (C=O); HRMS (EI+) 401.2144 (M+;
calc. for C18H12FN3O5S, 401.1743).
To a solution of 7 (23 g, 60.05 mmol) in 300 ml of absolute
ethanol, was added 915 ml of aqueous 16 N ammonia. After 48
hours at room temperature, the precipitate was collected by filtra-
tion, washed with diethyl ether and dried under vacuum to afford
a pale yellow solid (77%), mp >264 °C; The compound can be
recrystallised from water; ir (KBr): 3125, 3079 (NH), 1675,
1598, 1566 (C=O) cm-1; uv: (water): l max 226 nm (e 25118-
31622); l max 242 nm (e 31622-39810); l max 275 nm (e
1
19952-25118); l max 410 nm (e 10000-12589); H nmr (250
MHz, DMSO-d6): d 6.61 (s, 1, H5), 7.1 (s, 1, NH), 7.63 (ddd, 1,
J9,7 = 3.0 Hz, J9,F = 9.0 Hz, J9,10 = 9.0 Hz, H9), 7.81 (dd, 1,
J7,9 = 3.0 Hz, J7,F = 9.0 Hz, H7), 8.70 (dd, 1, J10,F = 5.0 Hz,
J10,9 = 9.0 Hz, H10), 10.73 (s, 1, NH); 13C nmr (62.89 MHz,
DMSO-d6): d 103.96 (C5), 110.61 (d, JC,F = 22.64 Hz, C7),
121.91 (d, JC,F = 25.15 Hz, C9), 124.35 (d, JC,F = 7.54 Hz,
C10), 131.86 (Cq), 136.03 (Cq), 137.11 (Cq), 153.63 (C=O),
161.47 (d, JC,F = 251.37 Hz, C8), 161.14 (C=O), 173.15 (C=O);
HRMS (EI+) 247.0404 (M+; calc. for C11H6FN3O3, 247.0393).
Anal. Calcd. for C11H6FN303: C, 53.45; H, 2.45; N, 17.00.
Found: C, 53.68; H, 2.36; N, 16.92.
Anal. Calcd. for C18H12FN3O5S: C, 53.86; H, 3.01; N, 10.47.
Found: C, 53.91; H, 2.92; N, 10.51.
Methyl 1-{[(Benzoylamino)carbonyl]amino}-6-fluoro-4-oxo-
1,4-dihydro-2-quinolinecarboxylate (7).
Under nitrogen, to a solution of 2 (10 g, 42.37 mmol) in 85 ml
of freshly distilled DMF, was added dropwise 8 g (55.08 mmol)
of benzoyl isocyanate. After 6 hours at room temperature, the
reaction mixture was evaporated and the crude product was puri-
fied by column chromatography eluting with 9:1 CH2Cl2/MeOH
to afford a pale yellow solid (71 %), mp 108-110 °C; ir (KBr):
2,4-Dichloro-8-fluoro-6H-[1,2,4]triazino-[1,6-a]quinolin-6-one
(9).
1
3240 (NH), 1739, 1721, 1681, 1618 (C=O) cm-1; H nmr (250
MHz, DMSO-d6): d 3.81 (s, 3, OCH3), 6.51 (s, 1, H3), 7.50-7.56
(m, 3, phenyl), 7.65 (ddd, 1, J7,F = 9.5 Hz, J7,5 = 3.0 Hz, J7,8
=
Compound 6 (1 g, 4.05 mmol) in 10 ml of phosphorus oxy-
chloride was heated under reflux during half an hour. After evap-
oration, the crude product was poured into 500 ml of ice cold
water. The precipitate formed was then collected by filtration,
washed with water until pH 6, dried under vacuum to afford a
yellow solid (95%), mp 218-220 °C. The compound can be
recrystallised from DMF; ir (KBr): 1656 (C=N), 1620 (C=O) cm-
1; uv: (ethanol): l max 256 nm (e 39810); l max 286 nm (e
19952-25118); l max 388 nm (e = 12589-15848); m/z = 284
9.0 Hz, H7), 7.77 (dd, 1, J5,F = 9.0 Hz, J5,7 = 3.0 Hz, H5), 7.8
(dd, 1, J8,7 = 9.0 Hz, J8,F = 5.0 Hz, H8), 8.01-8.05 (m, 2,
phenyl), 11.35 (s, 1, NH), 11.46 (s, 1, NH); 13C nmr (62.89 MHz,
DMSO-d6): d 54.38 (OCH3), 110.3 (d, JC,F = 22.64 Hz, C5),
111.15 (C3), 122.37 (d, JC,F = 8.17 Hz, C8), 124.62 (d, JC,F
=
25.15 Hz, C7), 129.29 (Cq), 130.91 (2C, phenyl), 131.07 (2C,
phenyl), 134.31 (phenyl), 135.67 (Cq), 141.10 (Cq), 145.94 (Cq),
155.77 (C=O), 161.56 (d, JC,F = 244.64 Hz, C6), 163.87 (C=O),
169.97 (C=O), 178.16 (C=O); HRMS (EI+) 383.1735 (M+; calc.
for C19H14FN3O5, 383.1352).
1
[M]+ (100%); 286 [M+2]+ (64%); 288 [M+4]+ (10%); H nmr
(250 MHz, DMSO-d6): d 8.15 (ddd, 1, J9,10 = 10.0 Hz, J9,F
=
9.0 Hz, J9,7 = 3.0 Hz, H9), 8,28 (dd, 1, J7,9 = 3.0 Hz, J7,F = 9.0
Hz, H7), 8.54 (s, 1, H5), 9.10 (dd, 1, J10,9 = 10.0 Hz, J10,F = 5.0
3-Benzoyl-8-fluoro-1H-[1,2,4]triazino[1,6-a]quinoline-
2,4,6(3H)-trione (8).
Hz, H10); 13C nmr (62.89 MHz, DMSO-d6): d 111.20 (d, JC,F
=
25.53 Hz, C7), 120.73 (C5), 124.22 (d, JC,F = 9.94 Hz, C10),
125.02 (d, JC,F = 25.97 Hz, C9), 126.27 (Cq), 129.89 (Cq),
134.50 (Cq), 135.74 (Cq), 143.29 (Cq), 162.79 (C=O), 163.79 (d,
JC,F = 254.26 Hz, C8); HRMS (EI+) 284.0481 (M+; calc. for
C11H4Cl2FN3O, 284.0765).
Anal. Calcd. for C11H4Cl2FN3O: C, 46.51; H, 1.42; N, 14.79.
Found: C, 46.47; H, 1.36; N, 14.85.
Under nitrogen, to a solution of 7 (2.9 g, 7.57 mmol) in 20 ml of
freshly distilled DMF, was added 1.1 g (18.92 mmol) of sodium
methoxide. After 4 hours of heating at 76 °C, the reaction mixture
was added to 50 ml of cold water. Some traces of 7 were removed
by filtration under millipore. The filtrate was acidified with cold
aqueous 3N HCl. The precipitate was collected by filtration, washed
with cold water, diethyl ether and dried under vacuum to give 8 as a
pale yellow solid (61%), mp 220 °C; ir (KBr): 3274 (NH), 1730,
Standard Alkylation Procedure.
1
1701, 1609, 1566 (C=O) cm-1; H nmr (250 MHz, DMSO-d6): d
6.48 (s, 1, H5), 7.53-7.63 (m, 3, phenyl), 7.69 (dd, 1, J7,F = 10.5
Hz, J7,9 = 3.5 Hz, H7), 7.82 (ddd, 1, J9,7 = 3.5 Hz, J9,10 = 9.5 Hz,
J9,F = 9.0 Hz, H9), 7.96 (dd, 1, J10,9 = 9.5 Hz, J10,F = 5.0 Hz,
H10), 8.03-8.10 (m, 2, phenyl), 11.37 (s, 1, NH); 13C nmr (62.89
MHz, DMSO-d6): d 108.93 (d, JC,F = 25.15 Hz, C7), 109.36 (C5),
119.48 (d, JC,F = 8.17 Hz, C10), 121.68 (d, JC,F = 25.15 Hz, C9),
126.45 (Cq), 128.16 (4C, phenyl), 131.64 (phenyl), 132.96 (Cq),
To a solution of6 (300 mg, 1.21 mmol) in 20 ml of freshly dis-
tilled DMF, was added 48 mg (1.21 mmol) of sodium hydride.
When hydrogen emission ceased, 0.12 ml of ethyl iodide was
added dropwise. After 24 hours at room temperature, the reaction
mixture was neutralized with aqueous ammonium chloride and
evaporated under vacuum. The residue was adsorbed onto silica
gel and chromatographed by eluting with 9:1 and 8:2

Nov-Dec 2002
Synthesis of Novel Fused Tricyclic Quinolones
1165
CH2Cl2/MeOH to give two yellow solids 10 and 11, respectively
Anal. Calcd. for C14H10FN3O5: C, 52.67; H, 3.16; N, 13.16.
with 19% and 78% yields.
Found: C, 52.73; H, 3.09; N, 12.98.
2-Ethoxy-3-ethyl-8-fluoro-3H-[1,2,4]-triazino[1,6-a]quinoline-
4,6-dione (10).
Acknowledgements.
We thank A. Petit and his collaborator for realization and ana-
lyze of NMR spectrum.
This compound has mp 190-192 °C; Rf (9:1 CH2Cl2/MeOH)
1
0.87; ir (KBr): 1710, 1655 (C=O) cm-1; H nmr (250 MHz,
DMSO-d6): d 1.19 (t, 3, J = 7.0 Hz, NCH2CH3), 1.42 (t, 3, J =
7.0 Hz, OCH2CH3), 3.92 (q, 2, J = 7.0 Hz, NCH2CH3), 4.53 (q,
REFERENCES AND NOTES
2, J = 7.0 Hz, OCH2CH3), 6.66 (s, 1, H5), 7.77 (ddd, 1, J9,10
=
10.0 Hz, J9,F = 8.0 Hz, J9,7 = 3.0 Hz, H9), 7.83 (dd, 1, J7,9 = 3.0
Hz, J7,F = 9.0 Hz, H7), 8.50 (dd, 1, J10,9 = 10.0 Hz, J10,F = 5.0
Hz, H10); 13C nmr (62.89 MHz, DMSO-d6): d 12.84
(NCH2CH3), 13.81 (OCH2CH3), 36.82 (NCH2CH3), 65.61
(OCH2CH3), 103.69 (C5), 109.70 (d, JC,F = 25.53 Hz, C7),
120.58 (Cq), 122.22 (d, JC,F = 25.97 Hz, C9), 127.65 (Cq),
133.45 (d, JC,F = 9.94 Hz, C10), 135.02 (Cq), 147.29 (Cq),
155.79 (C=O), 166.94 (d, JC,F = 245.26 Hz, C8), 173.34 (C=O);
HRMS (EI+) 303.0990 (M+; calc. for C15H14FN3O3, 303.1019).
Anal. Calcd. for C13H10FN3O3: C, 56.73; H, 3,66; N, 15.27.
Found: C, 56.68; H, 3.52; N, 15.34.
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2-Ethoxy-8-fluoro-3H-[1,2,4]triazino[1,6-a]quinoline-4,6-dione
(11).
This compound has mp >264 °C; Rf (9:1 CH2Cl2/MeOH) 0.10;
ir (KBr): 3400 (NH), 1721, 1650 (C=O) cm-1; 1H nmr (250 MHz,
DMSO-d6): d 1.29 (t, 3, J = 7.0 Hz, OCH2CH3), 4.53 (q, 2, J =
7.0 Hz, OCH2CH3), 6.61 (s, 1, H5), 7.65 (ddd, 1, J9,10 = 9.0 Hz,
J9,F = 8.0 Hz, J9,7 = 3.0 Hz, H9), 7.82 (dd, 1, J7,9 = 3.0 Hz, J7,F
= 9.0 Hz, H7), 8.57 (dd, 1, J10,9 = 9.0 Hz, J10,F = 5.0 Hz, H10);
13C nmr (62.89 MHz, DMSO-d6): d 14.37 (OCH2CH3), 62.01
(OCH2CH3), 101.69 (C5), 108.92 (d, JC,F = 22.07 Hz, C7),
120.24 (d, JC,F = 25.34 Hz, C9), 120.62 (Cq), 120.76 (Cq),
125.70 (Cq), 128.89 (Cq), 135.26 (d, JC,F = 12.82 Hz, C10),
150.04 (C=O), 158.80 (d, JC,F = 238.98 Hz, C8), 172.75 (C=O);
HRMS (EI+) 275.0705 (M+; calc. for C13H10FN3O3, 275.0706).
Anal. Calcd. for C13H10FN3O3: C, 56.73; H, 3,66; N, 15.27.
Found: C, 56.56; H, 3.70; N, 15.57.
Methyl 3-(8-Fluoro-2,4,6-trioxo-1,2,4,6-tetrahydro-3 H-
[1,2,4]triazino[1,6-a]-quinolin-3-yl)propanoate (12).
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To a solution of 6 (214 mg, 0.87 mmol) in 20 ml of DMF and
20 ml of methyl acrylate heated at 100 °C, was added a catalytic
amount of triton B. After 3 hours, the reaction mixture was evap-
orated under vacuum. The residue was poured into an ice cold
aqueous 3 N HCl. The precipitate was collected by filtration,
washed with water until pH 6, with diethyl ether then dried under
vacuum. Purification by column chromatography (8:2
CH2Cl2/MeOH) gave a pale yellow solid (67%), mp >264 °C; ir
1
(KBr): 3368 (NH), 1753, 1691, 1618 (C=O) cm-1; H nmr(250
MHz, DMSO-d6): d 2.65 (t, 2, J = 7.8 Hz, CH2), 3.61 (s, 3,
OCH3), 4.18 (t, 2, J = 7.8 Hz, NCH2), 7.46 (s, 1, H5), 7.92-8.02
(m, 2, H7, H9), 9.01 (dd, 1, J10,F = 4.4 Hz, J10,9 = 9.4 Hz, H10);
13C nmr, DEPT 135 (62.89 MHz, DMSO-d6): d 31.45 (CH2),
36.06 (NCH2), 51.45 (OCH3); HRMS (EI+) 333.0887 (M+; calc.
for C15H12FN3O5, 333.0872).
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