Chemical properties of pyrimidoquinoxaline 6-oxides

Article abstract of DOI:10.1002/jhet.5570430644

The reactivity of some representative 5-arylpyrimidoquinoxaline 6-oxides 1 was investigated. Reduction with sodium borohydride afforded the corresponding N-deoxy compounds 2. Reaction with methyl iodide in excess led selectively to N-methyl derivatives 3.

Full text of DOI:10.1002/jhet.5570430644

Nov-Dec 2006
1703
Chemical Properties of Pyrimidoquinoxaline 6-oxides
Ma. Beatriz García, Liliana R. Orelli and Isabel A. Perillo*
Department of Organic Chemistry. Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Junín
956 (1113), Buenos Aires, Argentina. E-mail: iperillo@ffyb.uba.ar
Received February 1, 2006
NH2
N
N
R
N
O
R
BH4Na
NaOH 10%
N
N
R
N
O
N
O
N
2
1
4
CH3I
N
N
I
N
O
R
3
The reactivity of some representative 5-arylpyrimidoquinoxaline 6-oxides 1 was investigated. Reduction
with sodium borohydride afforded the corresponding N-deoxy compounds 2. Reaction with methyl iodide
in excess led selectively to N-methyl derivatives 3. The preference for N vs. O-alkylation is analyzed
considering electronic effects. Alkaline hydrolysis of compounds 1 involved initial nucleophilic attack to
the amidine carbon (C4a), and subsequent regioselective ring opening leading to 4-(3-aminopropyl)-2-aryl-
quinoxaline-3-one 1-oxides 4. The regioselectivity observed in alkaline hydrolysis is also discussed.
J. Heterocyclic Chem., 43, 1703 (2006).
Introduction.
individual component or from the interaction of both. Due
to the biological activity of the parent heterocycles, the
investigation of new structurally related compounds is also
interesting. Among them, derivatives bearing the quinoxa-
linone core are of particular interest as an important
pharmacophore in numerous biologically active
compounds [3].
Amidinoquinoxaline N-oxides have received attention
due to their pharmacological properties, acting as
antibacterials, antiamoebics and antineoplastics [1]. The
first reported synthetic procedure for 5-aryl-2,3-dihydro-
1H-pyrimido[1,2-a]quinoxaline 6-oxides involves
a
displacement-cyclization reaction of 2-benzyl-1,4,5,6-
tetrahydropyrimidines with 2-nitrohalobenzenes, and leads
in general to poor yields (30% or less) of the desired
heterocycles [1a,b]. More recently, we reported an
alternative synthetic procedure by ring closure of N-acyl-
N´-(2-nitrophenyl)-1,3-propanediamines with ethyl poly-
phosphate (PPE) followed by spontaneous hetero-
cyclization [2]. This method allowed for the preparation of
5-aryl derivatives with high yields and was extended to the
corresponding 5-alkyl (and aralkyl) pyrimidoquinoxalines
as well as to the homologous 6-aryldiazepinoquinoxalines,
a novel heterocyclic nucleus. To our knowledge, the
reactivity of pyrimidoquinoxaline N-oxides has not been
studied yet. The chemical features of such system are
interesting due to its polyfunctionality, resulting from the
presence of two heterocyclic moieties: pyrimidine as
tetrahydro derivative and quinoxaline N-oxide. The
chemical behaviour of the heterocycles under study could
thus result alternatively from the reactivity of each
In the present paper we have investigated the reduction,
methylation and alkaline hydrolysis of some representative
5-arylpyrimidoquinoxaline 6-oxides 1 (Scheme 1).
Results and Discussion.
Reactions of pyrimidoquinoxaline 6-oxides 1a-d are
summarized in Scheme 1. Treatment of compounds 1 with
sodium borohydride led to pyrimidoquinoxalines 2 as the
main products. However, variable amounts of colateral
products are observed probably resulting from
overreduction. This behaviour was also reported by
Haddadin in the deoxygenation of quinoxaline N,N´-
dioxides with sodium borohydride [4].
Treatment of compounds 1 with methyl iodide in excess
led exclusively to the N-alkyl derivatives 3. Although
steric effects cannot be ruled out, the observed N vs. O
selectivity can be explained considering the resonance
stabilization of the resulting amidinium system and the
electron releasing effect of the oxygen atom (Scheme 2,

1704
B. García, L. Orelli and I. Perillo
Vol 43
Scheme 1
NH2
N
N
R
N
O
R
BH4Na
NaOH 10%
N
N
R
N
O
N
O
N
2
1
4
CH3I
N
N
I
N
O
3
R
Compd.1-4
R
a
b
c
C6H5
4-ClC6H4
4-CH3OC6H4
4-NO2C6H4
d
structures I and II, respectively). The last effect can also
account for the absence of N,O-dialkylation products.
Treatment of compounds 1 with an excess 10% aqueous
sodium hydroxide solution led to 4-(3-aminopropyl)-2-
arylquinoxaline-3-one 1-oxides 4.
According to previous data regarding cyclic amidines
[5] and quinoxalines [6], the existence of two electrophilic
sites can be anticipated in compounds 1, namely C4a and
C5. Accepting that alkaline hydrolysis of cyclic amidines
[5b] and heterocyclic N-oxides [6] involves formation and
cleavage of carbinolamines as reaction intermediates, a
total of three products could, in principle, be expected
(Scheme 3). The higher stabilization of isomer 4 could in
part account for the observed regioselectivity. On the other
hand, isolation of compounds 4 as the sole reaction
products would result from initial hydroxyde attack on
C4a and subsequent regioselective cleavage of C4a ꢀ N4
bond in the reaction intermediate. The higher electro-
philicity of C4a if compared to C5 would be the
consequence of electron delocalization involving both the
N-oxide moiety and the 5-aryl substituent. The observed
regioselective cleavage of the reaction intermediate can be
rationalized considering the different basicities of the two
potential leaving groups. It is accepted that, due to their
strong basicity, nitrogen anions (RR´Nꢀ) are poor
nucleofuges and require proton transfer previous or
simultaneous to their departure [7]. C4a ꢀ N4 cleavage
would then be the consequence of a thermodynamically
Scheme 2
Scheme 3
NH2
I
CH3
I
CH3
N
O
R
N
N
R
N
N
R
N
O
N
O
I
N
O
4
N
NH
OH
R
II
I
N
O
2I
NH NH
N
N
N
R
CH3
N
N
R
CH3
N
N
O
N
O
4a
5
HO
N
R
N
N
R
O
4'
CH3I
N
O
1
R
OCH3
3
N
N
R
N
O
1
N
N
N
N
N
OH
O
I
OH
NH
OH
N
R
R
OCH3
4''

Nov-Dec 2006
Chemical Properties of Pyrimidoquinoxaline 6-oxides
1705
H, aromatics), 7.11 (dt, J1 = 7.6 Hz, J2 = 1.1 Hz, 1 H, aromatic),
6.99 (dd, J1 = 8.2 Hz, J2 = 1.1 Hz, 1 H, aromatic), 3.86 (t, J = 6.4
Hz, 2 H, CH2N), 3.61 (t, J = 5.5 Hz, 2 H, CH2N), 2.02-2.10 (m, 2
H, CH2-CH2-CH2) ppm. MS: m/z= 295 (M.+).
Anal. Calcd. for C17H14ClN3: C, 69.03; H, 4.77; N, 14.21.
Found: C, 69.18; H, 4.75; N, 14.24.
favored proton transfer from the solvent to the most basic
nitrogen (N4), which becomes the best leaving group [8].
This behavior is opposite to that previously observed in
the alkaline hydrolysis of N-aryltetrahydropyrimidines
[5b], in which the less basic amino group is liberated. In
the case of tetrahydropyrimidines, the observed regio-
selectivity was explained on the basis of stereoelectronic
effects which might not be operating for pyrimido-
quinoxaline 6-oxides due to geometry restrictions.
5-(4-Methoxyphenyl)-2,3-dihydro-1H-pyrimido[1,2-a]quinoxal-
ine (2c).
1
This compound was obtained as an oil (55%). H NMR
(300 MHz, CDCl3, 25ºC): ꢀ = 8.00 (dd, J1 = 8.2 Hz, J2 = 2.0
Hz, 2 H, aromatics), 7.65 (dd, J1 = 7.9 Hz, J2 = 1.4 Hz, 1 H,
aromatic), 7.33 (dt, J1 = 7.9 Hz, J2 = 1.4 Hz, 1 H, aromatic),
7.09 (t, J = 7.6 Hz, 1 H, aromatic), 6.98 (d, J1 = 7.6 Hz, 1 H,
aromatic), 6.94 (dd, J1 = 8.2 Hz, J2 = 2.0 Hz, 2 H, aromatic),
3.86 (t, J = 6.4 Hz, 2 H, CH2N), 3.84 (s, 3 H, CH3O), 3.62 (t,
J = 5.5 Hz, 2 H, CH2N), 2.02-2.12 (m, 2 H, CH2-CH2-CH2)
ppm. MS: m/z= 291 (M.+).
EXPERIMENTAL
Melting points were taken on a Büchi capillary apparatus and
are uncorrected. 1H NMR spectra were recorded on a Bruker MSL
300 MHz spectrometer. Deuteriochloroform or methanol-d4 was
used as the solvents, and the standard concentration of the
samples was 20 mg/mL. Chemical shifts are reported in ppm (ꢀ)
relative to TMS as an internal standard. Deuterium oxide was
employed to confirm exchangeable protons (ex). Splitting
multiplicities are reported as singlet (s), broad signal (bs), doublet
(d), double doublet (dd), triplet (t), double triplet (dt), quartet (q),
pentet (p) and multiplet (m). Electron impact mass spectra were
recorded with a GC-MS Shimadzu QP-1000 spectrometer
operating at 20 eV. TLC analyses were carried out on Silica gel
60 F254. Column chromatographies were performed on Silica gel
60, with typically 30-50 g of stationary phase per gram substance.
Reagents, solvents and starting materials were purchased from
standard sources and purified according to literature procedures.
5-Aryl-2,3-dihydro-1H-pyrimido[1,2-a]quinoxaline 6-oxides
1a-d were synthesized as previously reported [2].
Anal. Calcd. for C18H17N3O: C, 74.20; H, 5.88; N, 14.42.
Found: C, 74.43; H, 5.86; N, 14.37.
5-(4-Nitrophenyl)-2,3-dihydro-1H-pyrimido[1,2-a]quinoxaline (2d).
This compound was obtained in 64% yield. M.p.: 124-126ºC
1
(ethanol). H NMR (300 MHz, CDCl3, 25ºC): ꢀ = 8.18-8.28 (m,
4 H, aromatics), 7.67 (dd, J1 = 7.9 Hz, J2 = 1.3 Hz, 1 H,
aromatic), 7.38-7.43 (m, 1 H, aromatic), 7.14 (dt, J1 = 7.6 Hz, J2
= 1.3 Hz, 1 H, aromatic), 7.02 (d, J1 = 8.3 Hz, 1 H, aromatic),
3.89 (t, J = 6.4 Hz, 2 H, CH2N), 3.62 (t, J = 5.5 Hz, 2 H, CH2N),
2.04-2.09 (m, 2 H, CH2-CH2-CH2) ppm. MS: m/z= 306 (M.+).
Anal. Calcd. for C17H14N4O2: C, 66.66; H, 4.61; N, 18.29.
Found: C, 66.82; H, 4.59; N, 18.31.
5-Aryl-4-methyl-2,3-dihydro-1H-pyrimido[1,2-a]quinoxalinium
iodide 6-oxides (3). General Procedure.
5-Aryl-2,3-dihydro-1H-pyrimido[1,2-a]quinoxalines (2).
General Procedure.
A mixture of the corresponding 5-aryl-2,3-dihydro-1H-
pyrimido[1,2-a]quinoxaline 6-oxide 1 (1 mmol) and methyl
iodide (0.426 g, 3 mmol) in anhydrous methylene chloride
(10 mL) was refluxed protected from moisture. The reaction
was monitored by TLC (chloroform:methanol 9:1) until
disappearance of the starting material. The solution was
evaporated in vacuo and the residue purified by recrystalization
to yield compounds 3a-d.
A solution of the corresponding pyrimidoquinoxaline 6-
oxide 1 (1 mmol) in dry ethanol (10 mL) was treated with
sodium borohydride (0.151 g, 4 mmol) and refluxed for 30
minutes. The solvent was then evaporated in vacuo and the
residue treated with water (10 mL) and extracted with
methylene chloride (2 X 20 mL). The organic layers were
combined, washed with water (5 mL), dried with sodium
sulfate and filtered. The solvent was then evaporated in
vacuo, affording compounds 2, which were purified by flash
chromatography (chloroform:methanol 10:0 to 8:2).
5-Phenyl-4-methyl-2,3-dihydro-1H-pyrimido[1,2-a]quinoxalin-
ium iodide 6-oxide (3a).
This compound was obtained in 60% yield. M.p.: 253-254ºC
(isopropanol). 1H NMR (300 MHz, CDCl3, 25ºC): ꢀ = 8.54 (dd, J
= 8.2 Hz, 1 H, aromatic), 7.68-7.78 (m, 3 H, aromatics), 7.38-
7.57 (m, 5 H, aromatics), 4.79 (t, J = 6.4 Hz, 2 H, CH2N), 3.92 (t,
J = 5.5 Hz, 2 H, CH2N), 2.78 (s, 3 H, CH3N), 2.60-2.78 (m, 2 H,
CH2-CH2-CH2) ppm. MS: m/z= 277 (M.+-ICH3) [10].
5-Phenyl-2,3-dihydro-1H-pyrimido[1,2-a]quinoxaline (2a) [9].
1
This compound was obtained as an oil (62%). H NMR (300
MHz, CDCl3, 25ºC): ꢀ = 7.94-7.98 (m, 2 H, aromatics), 7.67 (dd, J1
= 7.9 Hz, J2 = 1.5 Hz, 1 H, aromatic), 7.33-7.43 (m, 4 H, aromatics),
7.11 (dt, J1 = 7.6 Hz, J2 = 1.0 Hz, 1 H, aromatic), 7.00 (d, J = 8.3
Hz, 1 H, aromatic), 3.87 (t, J = 6.4 Hz, 2 H, CH2N), 3.62 (t, J = 5.5
Hz, 2 H, CH2N), 2.03-2.11 (m, 2 H, CH2-CH2-CH2) ppm.
Anal. Calcd. for C18H18IN3O: C, 51.57; H, 4.33; N, 10.02.
Found: C, 51.75; H, 4.32; N, 9.99.
5-(4-Chlorophenyl)-4-methyl-2,3-dihydro-1H-pyrimido[1,2-a]-
quinoxalinium iodide 6-oxide (3b).
5-(4-Chlorophenyl)-2,3-dihydro-1H-pyrimido[1,2-a]quinoxaline
(2b).
This compound was obtained in 65% yield. M.p.: 238-239ºC
1
(isopropanol). H NMR (300 MHz, CDCl3, 25ºC): ꢀ = 8.48 (d, J
= 7.2 Hz, 1 H, aromatic), 7.76-7.83 (m, 2 H, aromatics), 7.61-
1
This compound was obtained as an oil (56%). H NMR (300
MHz, CDCl3, 25ºC): ꢀ = 7.98 (d, J = 8.2 Hz, 2 H, aromatics),
7.65 (dd, J1 = 7.9 Hz, J2 = 1.5 Hz, 1 H, aromatic), 7.30-7.40 (m, 3
7.66 (m, 3 H, aromatics), 7.56 (dd, J1 = 6.7 Hz, J2 = 2.3 Hz, 2 H,

1706
B. García, L. Orelli and I. Perillo
Vol 43
aromatics), 4.74 (t, J = 6.4 Hz, 2 H, CH2N), 3.78 (t, J = 5.5 Hz, 2
H, CH2N), 2.82 (s, 3 H, CH3N), 2.59-2.63 (m, 2 H, CH2-CH2-
CH2) ppm. MS: m/z= 311 (M.+-ICH3).
Anal. Calcd. for C18H17ClIN3O: C, 47.65; H, 3.78; N, 9.26.
Found: C, 47.59; H, 3.79; N, 9.23.
7.70 (dt, J1 = 7.0 Hz, J2 = 1.5 Hz, 1 H, aromatic), 7.55 (dd, J1 =
7.0 Hz, J2 = 2.8 Hz, 1 H, aromatic), 7.38-7.49 (m, 3 H,
aromatics), 4.42 (t, J = 7.1 Hz, 2 H, CH2N), 2.83 (t, J = 6.4 Hz, 2
H, CH2N), 1.90-1.99 (m, 2 H, CH2-CH2-CH2), 1.6 (b.s., ex., 2 H,
NH2) ppm. MS: m/z= 329 (M.+).
Anal. Calcd. for C17H16ClN3O2: C, 61.91; H, 4.89; N, 12.74.
Found: C, 62.01; H, 4.91; N, 12.69.
5-(4-Methoxyphenyl)-4-methyl-2,3-dihydro-1H-pyrimido[1,2-a]-
quinoxalinium iodide 6-oxide (3c).
4-(3-Aminopropyl)-2-(4-methoxyphenyl)quinoxaline-3-one
1-oxide (4c).
This compound was obtained in 68% yield. M.p.: 242-244ºC
1
(isopropanol). H NMR (300 MHz, CDCl3, 25ºC): ꢀ = 8.44 (d, J
This compound was obtained as an oil (81%). 1H NMR (300
MHz, CDCl3, 25ºC): ꢀ = 8.55 (dd, J1 = 8.5 Hz, J2 = 1.5 Hz, 1
H, aromatic), 7.85 (dd, J1 = 8.7 Hz, J2 = 1.0 Hz, 2 H,
aromatics), 7.66-7.74 (m, 1 H, aromatic), 7.53 (d, J = 7.9, 1 H,
aromatic), 7.40 (dt, J1 = 7.4 Hz, J2 = 1.0 Hz, 1 H, aromatic),
7.01 (d, J = 8.7 Hz, 2 H, aromatics), 4.43 (t, J = 7.1 Hz, 2 H,
CH2N), 3.87 (s, 3 H, CH3O), 2.83 (t, J = 6.4 Hz, 2 H, CH2N),
1.92-1.97 (m, 2 H, CH2-CH2-CH2), 1.6 (b.s., ex., 2 H, NH2)
ppm. MS: m/z= 325 (M.+).
= 8.1 Hz, 1 H, aromatic), 7.86 (d, J = 7.6 Hz, 2 H, aromatics),
7.56-7.65 (m, 3 H, aromatics), 7.03 (d, J = 7.6 Hz, 2 H,
aromatic), 4.72 (t, J = 5.5 Hz, 2 H, CH2N), 3.80-3.91 (m, 5 H,
CH3O-CH2N), 2.78 (s, 3 H, CH3N), 2.58-2.64 (m, 2 H, CH2-CH2-
CH2) ppm. MS: m/z= 307 (M.+-ICH3).
Anal. Calcd. for C19H20IN3O2: C, 50.79; H, 4.49; N, 9.35.
Found: C, 50.85; H, 4.50; N, 9.32.
5-(4-Nitrophenyl)-4-methyl-2,3-dihydro-1H-pyrimido[1,2-a]-
quinoxalinium iodide 6-oxide (3d).
Anal. Calcd. for C18H19N3O3: C, 66.45; H, 5.89; N, 12.91.
Found: C, 66.24; H, 5.86; N, 12.95.
This compound was obtained in 63% yield. M.p.: 240-242ºC
(isopropanol). 1H NMR (300 MHz, CD3OD, 25ºC): ꢀ = 8.56 (d, J
= 8.2, 1 H, aromatic), 8.52 (dd, J1 = 7.9 Hz, J2 = 2.2 Hz, 2 H,
aromatic), 8.00-8.09 (m, 2 H, aromatics), 7.97 (dd, J1 = 7.9 Hz, J2
= 2.2 Hz, 2 H, aromatics), 7.77 (d, J1 = 8.3 Hz, 1 H, aromatic),
4.58 (t, J = 6.4 Hz, 2 H, CH2N), 3.56 (t, J = 4.4 Hz, 2 H, CH2N),
2.73 (s, 3 H, CH3N), 2.52-2.56 (m, 2 H, CH2-CH2-CH2) ppm.
MS: m/z= 322 (M.+-ICH3).
4-(3-Aminopropyl)-2-(4-nitrophenyl)quinoxaline-3-one 1-oxide
(4d).
This compound was obtained in 60% yield. M.p.: 149-
1
151ºC (ethanol). H NMR (300 MHz, CDCl3, 25ºC): ꢀ = 8.52
(dd, J1 = 8.5 Hz, J2 = 1.5 Hz, 1 H, aromatic), 8.34 (dd, J1 = 8.9
Hz, J2 = 2.0 Hz, 2 H, aromatics), 8.02 (dd, J1 = 8.9 Hz, J2 = 2.0
Hz, 2 H, aromatics), 7.75 (dt, J1 = 8.5 Hz, J2 = 1.5 Hz, 1 H,
aromatic), 7.61 (dd, J1 = 8.6 Hz, J2 = 1.0 Hz, 1 H, aromatic),
7.44 (dt, J1 = 7.2 Hz, J2 = 1.0 Hz, 1 H, aromatic), 4.45 (t, J =
7.2 Hz, 2 H, CH2N), 2.85 (t, J = 6.4 Hz, 2 H, CH2N), 1.87-
1.98 (m, 2 H, CH2-CH2-CH2), 1.5 (b.s., ex., 2 H, NH2) ppm.
MS: m/z= 340 (M.+).
Anal. Calcd. for C18H17IN4O3: C, 46.57; H, 3.69; N, 12.07.
Found: C, 43.47; H, 3.68; N, 12.10.
4-(3-Aminopropyl)-2-arylquinoxaline-3-one 1-oxides (4).
General Procedure.
The corresponding pyrimidoquinoxaline 6-oxide 1 (1 mmol) was
dissolved in a minimum volume of methanol and diluted with water
(final volume: 10 mL). The solution was treated with aqueous 10%
sodium hydroxide (10 mL), and refluxed until disappearance of the
strarting material, as disclosed by TLC (chloroform:methanol 8:2).
The reaction mixture was then extracted with methylene chloride (2
ꢁ 20 mL). The organic phases were pooled, washed with water,
dried over sodium sulfate and filtered. The solvent was then
eliminated in vacuo at rt. Compounds 4 were purified by flash
chromatography employing mixtures of methylene chloride:
isopropylamine 100:0 to 20:1).
Anal. Calcd. for C17H16N4O4: C, 59.99; H, 4.74; N, 16.46.
Found: C, 60.15; H, 4.76; N, 16.50.
Acknowledgements.
This work was financially supported by Universidad de
Buenos Aires and by CONICET (postdoctoral fellowship M. B.
G.). We are grateful to Bioq. Gloria B. Garbarino for the
preparation of some synthetic intermediates.
REFERENCES AND NOTES
4-(3-Aminopropyl)- 2-phenylquinoxaline-3-one 1-oxide (4a).
1
This compound was obtained as an oil (89%). H NMR (300
[1a] P. C. Parthasarathy, B. S. Joshi, M. R. Chaphekar, D. H.
Gawad, L. Anandan, M. A. Likhate, M. Hendi, S. Mudaliar, S. Iyer, D.
K. Ray and V. B. Srivastava, Indian J. Chem. Sect. B, 22, 1250 (1983);
[b] G. J. Ellames, K. R. Lawson, A. A. Jaxa-Chamiec and R. M. Upton,
EP 0,256,545 (1988), Chem. Abstr., 108, 204642 (1988); [c] G. E.
Adams, E. M. Fielden, M. A. Naylor and I. J. Stratford, UK Pat. Appl.
GB 2,257,360 (1993); Chem. Abstr., 118, 183400 (1993).
MHz, CDCl3, 25ºC): ꢀ = 8.52 (d, J = 8.3 Hz, 1 H, aromatic),
7.53-7.76 (m, 3 H, aromatics), 7.31-7.50 (m, 5 H, aromatics),
4.40 (t, J = 6.6 Hz, 2 H, CH2N), 2.83 (t, J = 6.4 Hz, 2 H, CH2N),
2.5 (b.s., ex., 2 H, NH2), 1.94-2.01 (m, 2 H, CH2-CH2-CH2) ppm.
MS: m/z= 295 (M.+).
Anal. Calcd. for C17H17N3O2: C, 69.14; H, 5.80; N, 14.23.
Found: C, 68.95; H, 5.78; N, 14.27.
[2] M. B. García, L. R. Orelli, M. L. Magri and I. A. Perillo,
Synthesis, 2687 (2002).
[3a] R. E. Ten Brimk, W. B. Im, V. H. Sethy, A. H. Tang and D.
B. J. Carter, J. Med. Chem., 37, 758 (1994); [b] E. J. Jacobosen, R. E.
Ten Brimk, L. S. Stelzer, K. L. Belonga, D. B. J. Carter, W. B. Im, V. H.
Sethy, A. H. Tang and P. F. VonVoigtlander and J. D. Petke J. Med.
Chem., 39, 158 (1996); [c] E. J. Jacobosen, R. E. Ten Brimk, K. L.
Belonga, D. B. J. Carter, H. K. Im, W. B. Im, V. H. Sethy, A. H. Tang, P.
4-(3-Aminopropyl)-2-(4-chlorophenyl)quinoxaline-3-one 1-
oxide (4b).
1
This compound was obtained as an oil (75%). H NMR (300
MHz, CDCl3, 25ºC): ꢀ = 8.53 (dd, J1 = 8.5 Hz, J2 = 1.5 Hz, 1 H,
aromatic), 7.79 (dd, J1 = 8.7 Hz, J2 = 2.3 Hz, 2 H, aromatics),

Nov-Dec 2006
Chemical Properties of Pyrimidoquinoxaline 6-oxides
1707
[7a] E. S. Hand and W. P. Jencks, J. Am. Chem. Soc., 84, 3505
(1962); [b] D. Becke, Adv. Heterocycl. Chem., 1, 167 (1969); [c] C. L.
Perrin and O. Nuñez, J. Am. Chem. Soc., 109, 522 (1987).
[8] H. Slebocka-Tilk, A. J. Bennet, J. W. Keillor, R. S. Brown, J.
Peter Guthrie and A. Jodhan, J. Am. Chem. Soc., 112, 8507 (1990); S.
Vincent, C. Mioskowski and L. Lebeau, J. Org. Chem., 64, 991 (1999).
[9] H. Otsumasu, JP 1969 18020 (1969); Chem. Abstr., 81,
183400 (1974).
[10] The electron impact mass spectra of 1,2-diaryl-3-methyl-
1,4,5,6-tetrahydropyrimidinium salts previously reported by us show
thermal decomposition originating the corresponding amidines and
methyl iodide [11].
F. VonVoigtlander, J. D. Petke, W. Z. Zhong and J. W. Mickelson J.
Med. Chem., 42, 1123 (1999); [d] D. S. Lawrence, J. E. Copper and C. D.
Smith J. Med. Chem., 44, 594 (2001); [e] A. Carta, M. Loriga, S. Zanetti
and L. A. Sechi Il Farmaco, 58, 1251 (2003); [f] S. Piras, M. Loriga and
G. Paglietti Il Farmaco, 59, 185 (2004); [g] D. A. Dudley and J. J.
Edmunds, US Pat. Appl. 6,916,805 (2005); Chem. Abstr., 131, 640844
(1999).
[4] M. J. Haddadin, H. N. Alkaysi and S. E. Saheb, Tetrahedron,
26, 1115 (1970).
[5a] B. M. Fernández, I. A. Perillo and S. Lamdan, J. Chem. Soc.,
Perkin Trans. 2, 1416 (1974); [b] L. R. Orelli, F. Niemevz, M. B. García
and I. A. Perillo, J. Heterocyclic. Chem., 36, 105 (1999).
[6] T. W. M. Spence and G. Tennant, Chem. Commun., 5, 194
(1969).
[11] L. R. Orelli, M. E. Hedrera and I. A. Perillo, Instr. Sci.
Technol., 25, 207 (1997).