Synthesis, characterization and reactions of 2-deoxo-5-deazaalloxazines

Article abstract of DOI:10.1016/S0968-0896(01)00194-8

5-Deazaflavins and their homologues have been known as potential riboflavin antagonists, bioreductives, and compounds with potent antitumor activity 2-Amino-4-methylquinoline-3-carbonitrile (2) was prepared as unreported starting material for several interesting 2-deoxo-5-deazalloxazine derivatives. Cyclization of 2 using formamide afforded the 2,4-deoxo-5-dea-zaalloxazine derivative 7, which was subjected to deamination with nitrous acid to give the 2-deoxo-5-deazaalloxazine (8). The compound 8 was also obtained via 13 by treating the latter with refluxing formic acid or formamide and used as a recursor for synthesis of several 2-deoxo-5-deazaalloxazines 18, 19 , 20, 21 and 22. The pharmacological and biological properties of these compounds are still under investigation. Copyright

Full text of DOI:10.1016/S0968-0896(01)00194-8

Bioorganic & Medicinal Chemistry 9 (2001) 2993–2998
Synthesis, Characterization and Reactions of
2-Deoxo-5-deazaalloxazines
Abd El-Wareth A. O. Sarhan,a,* Zeinab A. Hoziena and Hosney A. H. El-Sherief b
aChemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
bPharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut 71525, Egypt
Received 16 April 2001; accepted 28 May 2001
Abstract—5-Deazaflavins and their homologues have been known as potential riboflavin antagonists, bioreductives, and com-
pounds with potent antitumor activity. 2-Amino-4-methylquinoline-3-carbonitrile (2) was prepared as unreported starting material
for several interesting 2-deoxo-5-deazalloxazine derivatives. Cyclization of 2 using formamide afforded the 2,4-deoxo-5-dea-
zaalloxazine derivative 7, which was subjected to deamination with nitrous acid to give the 2-deoxo-5-deazaalloxazine (8). The
compound 8 was also obtained via 13 by treating the latter with refluxing formic acid or formamide and used as a precursor for
synthesis of several 2-deoxo-5-deazaalloxazines 18, 19, 20, 21 and 22. The pharmacological and biological properties of these
compounds are still under investigation. # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
From the chemical, biological and pharmaceutical point
of view, a series of 5-deazaflavins and related com-
pounds have been studied.1ꢀ3 It is interesting that some
of the 5-deazaflavin, derivatives where the nitrogen
atom existing in the isoalloxazine ring at N(10) is
replaced by carbon atom, revealed potential biological
activity including antitumor and antiviral activities.4
5-Deazaflavins were synthesized as potential riboflavin
antagonists and were also found to be multifunctional
and reactive and to serve as cofactors for several flavins,
naturally occurring F 420.6 Some heterocyclic com-
It is known that 5-deazaflavin cofactor is an essential
co-enzyme, and is involved in the reduction of CO2 to
methane in the biological system.1 5-Deazaflavin cata-
lyzes the splitting of thymidine dimer as photo-
reactivating coenzyme.5
pounds containing a quinoline moiety are of importance
owing to their industrial drugs and biological activities,
especially antimalaria,7 antibacterial,8,9 analgesic
agents.10 They also show moderate activity against
Aspergillus niger11 and higher activity towards tumor
cells.12 A series of nitro-5-deazaflavins, possessing a
nitro groupat C(6)–C(9) have been designed and syn-
thesized as a novel class of bioreductive hetero-aromatic
nitro compounds, and their cytotoxicities towards
L1210 and KB cells have been evaluated. The redox
systems of nitro-5-deazaflavins showed much more
*Corresponding author. Fax: +20-88-31-2564; e-mail: elwareth@acc.
aun.eun.eg
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00194-8

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A. A. O. Sarhan et al. / Bioorg. Med. Chem. 9 (2001) 2993–2998
potent antitumor activities than other 5-deazaflavins
bearing no nitro group.12 5-Deazaflavins (5-deazaiso-
alloxazines), have been synthesized as potential
riboflavin antagonists.13
On the other hand, refluxing of 2 with formamide for
20 h afforded 4-amino-5-methyl-pyrimido[4,5-b]quino-
line (7), which converted into 5-methyl-3H-2-deoxo-5-
deazaalloxazine (8) in good yield by treatment with
nitrous acid in acetic acid. The reaction of 2 with phenyl
isothiocyanate in pyridine gave 4-amino-5-methyl-3-
phenyl-2-thioxopyrimido[4,5-b]quinoline (9). The IR
spectrum of compound 9 revealed the absorption bands
at n 3400, 3300 (NH2), 1640 (C¼N), 1580 (C¼C),
1140 cmꢀ1 (C¼S). The 1H NMR (DMSO-d6) showed
signals at d 3.0 (s, 3H, CH3), 4.1 (br, 2H, NH2,
exchangeable on deuteration), and 7.5–8.3 ppm (m, 9H,
aromatic–H). The MS exhibited peaks at 320 (6.3)
[M++2], 319 (23.9) [M++1], and 318 (100) [M+].
In 1977, Senga et al. prepared a number of isoalloxazine
derivatives via treatment of uracil derivatives with aro-
matic amines in the presence of dimethylformamide
dimethylacetal.14 The importance of isoalloxazine in
riboflavin and its coenzyme derivatives FMV and FAD
was studied several years ago.15
The reaction of 2 with benzoyl chloride gave a separable
mixture of 5-methyl-2-phenyl-2-deoxo-5-deazaallox-
azine (10) (63% yield) and 5-methyl-2-phenyl-1,3-oxa-
zino[4,5-b]quinoline-4-one (11) (34% yield). The
compound 10 was independently obtained from 11 by
treatment with ammonium acetate in refluxing acetic
acid. Alkylation of 10 with ethyl iodide in dimethylfor-
mamide in the presence of K2CO3 afforded the
corresponding 12 (Scheme 2).
Results and Discussion
The synthetic methods of pyrimidoquinoline derivatives
using pyrimidine moiety11,16ꢀ18 or quinoline moi-
ety8,10,19 as starting materials have appeared in the lit-
erature. The synthetic pathway and biological
properties of alloxazine derivative have been discussed
recently in literature.20 Here, we present a synthetic
route to 2-amino-4-methylquinolin-3-carbonitrile (2),
which is converted into a number of 2-deoxy-5-dea-
zaalloxazine. 2-Amino-4-methylquinolin-3-carbonitrile
(2) was prepared in 73% yield from 2-aminoacetophe-
none (1) by treatment with malononitrile in refluxing
pyridine.
Hydrolysis of 2 using 60% H2SO4 gave 2-amino-4-
methylquinoline-3-carboxamide (13) in 90% yield. On
cyclization using glacial acetic acid, 13 gave a mixture of
2,5-dimethyl-2-deoxo-5-deazaalloxazine (14) (63%
yield)
and
2-acetylamino-4-methylquinoline-3-car-
boxylic acid (15) (35% yield). The latter 15 being iso-
lated from the derivative 14 by acidification of the
filtrate of 14 with acetic acid. In addition, reaction of 13
with phenyl isothiocyanate in refluxing pyridine affor-
ded the product 16. Furthermore, refluxing of 13 with
formamide or formic acid afforded the 5-methyl-2-
deoxo-5-deazaalloxazine derivative (8) in good yield
(61%) (Scheme 3).
An
attempt
to
obtain
4-methyl-2-ethoxy-
methylideneaminoquinoline-3-carbonitrile (4) via con-
densation of 2 with triethyl orthoformate in refluxing
acetic anhydride was unsuccessful, and the N-acetyl
derivative 3 was obtained in 83% yield. On the other
hand, acetylation of 2 using a 4:1 mixture of acetic
anhydride and pyridine produced the N,N-diacetyl
derivative 5 as pale brown crystals in 69% yield. Con-
densation of 2 with benzaldehyde or p-nitrobenzalde-
hyde in ethanol containing a few drops of piperidine as
a basic catalyst gave the corresponding arylidene deri-
vatives 6a and 6b in 60 and 78% yields, respectively
(Scheme 1).
Treatment of 5-methyl-2-deoxo-5-deazaalloxazine (8)
with hydrazine hydrate in refluxing ethanol afforded the
N-amino derivative (17) in 43% yield (Scheme 4). The
IR spectrum of the product (17) revealed absorptions at
n 3320 and 3400 cmꢀ1 (NH2) and 1660 cmꢀ1 (CON).
The NMR spectrum of compound 17 showed a signal at
d 7.8 ppm (NH2, exchangeable on deuteration.
Scheme 1.
Scheme 2.

A. A. O. Sarhan et al. / Bioorg. Med. Chem. 9 (2001) 2993–2998
2995
Furthermore, on refluxing 8 with a mixture of phos-
phorus pentachloride and phosphorus oxychloride for
4 h, the corresponding 4-chloro derivative (18) was
obtained in 60% yield. In addition, heating 8 with
phosphorus pentasulfide in pyridine gave the corre-
sponding compound (19) in good yield (74%). The
derivative (19) was also obtained in 74% yield via reac-
tion of 18 with thiourea in refluxing ethanol. Nucleo-
philic substitution of the compound 18 using sodium
methoxide in methanol gave the methoxy derivative 20
in 44% yield (Scheme 5).
Treatment of 18 with hydrazine hydrate in ethanol gave
the hydrazino derivative (21) in 73% yield. The hydra-
zino compound (21) was then cyclized using formic acid
to afford the corresponding 12-methyl-1,2,4-triazo-
lo[30,40:6,1]pyrimido[4,5-b]quinoline (22) in 66% yield
(Scheme 6).
The structures of all new compounds were confirmed by
means of spectral analysis such as IR, NMR, and MS
spectra. Elemental analyses of all compounds were in
satisfactory agreement with the calculated values.
The structure of compound 17 was supported by GC–
MS spectroscopy, and the spectrum showed the exact
molecular ion peak at 226 [M+]. The elemental analysis
of 17 was also in agreement with the calculated value.
Experimental
All melting points were determined in open glass capil-
1
laries and are uncorrected. The H NMR spectra were
measured in CDCl3 or DMSO-d6 using TMS as an
internal standard on an EM 360 90 MHz NMR spec-
trometer. Elemental analyses were carried out on a Per-
kin-Elmer 240C microanalyser. Mass spectra were
measured on GC/MS Finnigan mat SCQ 7000, Digital
DEC 3000, EI eV 70.
2-Amino-4-methylquinoline-3-carbonitrile (2). A mixture
of 2-aminoacetophenone (1) (10 mmol) and mal-
ononitrile (10 mmol) in dry pyridine (50 mL) was
refluxed for 2 h. After cooling, the precipitate thus
formed was collected by filtration and washed with eth-
anol. The crude product was recrystallized from DMF
to give 1 as pale brown crystals (73% yield), mp 297–
299 ꢁC; IR (KBr): n 3400, 3300 (NH2), 2200 (CN), 1620
Scheme 3.
(C¼N), 1600 (C¼C) cmꢀ1
.
1H NMR (DMSO-d6):
d=2.90 (s, 3H, CH3), 3.90 (br, 2H, NH2, exchangeable
with D2O), 7.30–8.00 ppm (m, 4H, Ar-H). MS m/e (%)
184 [M++1] (9), 183 [M+] (100). Anal. calcd for
C11H9N3 (183.2): C, 72.11; H, 4.95; N, 22.93. Found: C,
72.00; H, 4.68; N, 23.09.
Scheme 4.
2-Acetylamino-4-methylquinoline-3-carbonitrile (3).
A
mixture of 2 (10 mmol), ethyl orthoformate (10 mmol)
and acetic anhydride (10 mL) was refluxed for 3 h. The
reaction mixture was concentrated under reduced pres-
sure to one third of its original volume and then poured
onto ice/water mixture. The resulting precipitate was
filtered and recrystallized from benzene to give the cor-
responding monoacetylated derivative (3) (83% yield),
mp138–140 ꢁC. IR (KBr): n 3250 (NH), 2220 (CN),
1680 (COCH3), 1600 (C¼N), 1580 cmꢀ1 (C¼C). 1H
NMR (CDC13): d 2.20 (s, 3H, CH3CO), 3.00 (s, 3H,
CH3), 7.40–8.30 ppm [m, 5H, (4H, Ar-H and 1H, NH
after deuteration became integrated 4H]. Anal. calcd for
C13H11N3O (225.2): C, 69.33; H, 4.92; N, 18.66. Found:
C, 69.63; H, 4.69; N, 18.67.
Scheme 5.
2-Diacetylamino-4-methylquinoline-3-carbonitrile (5). A
sample of 2 (10 mmol) was heated in a 1:4 mixture acetic
anhydride (5 mL) and pyridine (20 mL) mixture at 80 ꢁC
for 1 h. After cooling, the reaction mixture was poured
onto ice, and the precipitate thus formed was collected
and recrystallized from dilute acetic acid to give pale
Scheme 6.

2996
A. A. O. Sarhan et al. / Bioorg. Med. Chem. 9 (2001) 2993–2998
ꢁ
brown crystals (69% yield), mp130–135 C. IR (KBr): n
2200 (CꢂN), 1700 (C¼O), 1600 (C¼N), 1560 (C¼C)
water. The solid product thus formed was collected by
filtration and recrystallized from ethanol to give 8 as
white needle crystals in 78% yield, mp >340 ꢁC. IR
(KBr): n 3350 (OH), 3200 (NH), 1650 (C¼O), 1580
cmꢀ1. H NMR (DMSO-d6): d 2.50 (s, 6H, 2 CH3CO),
3.10 (s, 3H, CH3), 6.90–7.30 ppm (m, 4H, Ar–H). Anal.
calcd for C15H13N3O2 (267.3): C, 67.40; H, 4.90; N,
15.72. Found: C, 67.42; H, 4.87, N, 15.73.
1
1
(C¼N), 1510 (C¼C) cmꢀ1. H NMR (DMSO-d6): d 3.1
(s, 3H, CH3), 7.2–7.4 (m, 4H, Ar–H), 7.8 (s, 1H, NH),
8.0 ppm (s, 1H, CH-2). MS m/e (%) 213 [M++2] (10),
212 [M++1] (1.4), 211 [M+] (1.8), 199 (13.3), 198 (100),
143 (8.8), 142 (6.2), 128 (5.3), 116 (11.7), 115 (4.9). Anal.
calcd for C12H9N3O (211.2): C, 68.24; H, 4.30; N, 19.90.
Found: C, 68.53; H, 4.14; N, 19.65.
2-Benzylideneamino/p-nitrobenzylideneamino-4-methyl-
quinoline-3-carbonitrile (6a and 6b). A mixture of 2
(10 mmol) and benzaldehyde or p-nitrobenzaldehyde
(10 mmol) was refluxed in ethanol (20 mL) containing a
few drops of piperidine for 3 h. After cooling, the solid
product thus formed was collected by filtration and
recrystallized from ethanol to give the corresponding
Shiff bases 6a and 6b.
4-Amino-5-methyl-3-phenyl-2-thioxo-4-deoxo-5-deazafla-
vin (9). A mixture of 2 (10 mmol) and phenyl iso-
thiocyanate (12 mmol) was refluxed in pyridine (20 mL)
for 7 h. The reaction mixture was cooled and diluted
with ethanol, and the precipitate thus formed was col-
lected by filtration and dried by suction. The crude
product was recrystallized from a 4:1 mixture ethanol
and DMF to give 9 as yellow crystals in 90% yield, mp
235–237 ꢁC. IR (KBr): n 3400, 3300 (NH2), 1640
(C¼N), 1580 (C¼C), 1140 cmꢀ1 (C¼S). 1H NMR
(DMSO-d6): d 3.0 (s, 3H, CH3), 4.1 (br, 2H, NH2,
exchangeable with D2O), 7.5–8.3 ppm (m, 9H, Ar–H).
MS m/z (%) 320 [M++2] (6.3), 319 [M++1] (23.9),
318 [M+] (100), 317 (33.8), 285 (31.7), 260 (6.9), 259
(7.1), 258 (14.3), 242 (5.5), 241 (39.5), 231 (9.4), 183
(4), 167 (4), 155 (7.1), 141 (29.8), 140 (21.8), 129
(7.3), 128 (10), 102 (3.7), 77 (18), 51 (7.8). Anal.
calcd for C18H14N4S (318.4): C, 67.90; H, 4.43; N,
17.60; S, 10.06; Found: C, 67.66; H, 4.30; N, 17.99;
S, 10.17.
2-Benzylidenamino-4-methylquinoline-3-carbonitrile (6a).
The derivative 6a was obtained in 60% yield, mp260–
261 ꢁC. IR (KBr): n 2200 (CꢂN), 1640 (N¼CH), 1600
(C=N), 1580 cmꢀ1 (C¼C). H NMR (CDC13): d 3.3 (s,
1
3H, CH3), 7.0–8.2 (m, 9H, Ar–H), 8.6 ppm (s, 1H,
N¼CH). Anal. calcd for C18H13N3 (271.3): C, 79.68; H,
4.83; N, 15.49. Found: C, 79.77; H, 5.11; N, 15.11.
2-(p-Nitrobenzylidenamino)-4-methylquinoline-3-carboni-
trile (6b). The compound 6b was obtained in 78%
yield, mp318–319 ꢁC. IR (KBr): n 2200 (C ꢂ N), 1610
(N¼CH), 1590 (C¼N), 1570 cmꢀ1 (C¼C). 1H NMR
(CDC13): d 3.0 (s, 3H, CH3), 7.3–8.0 (m, 8H, Ar–H),
8.6 ppm (s, 1H, N¼CH). Anal. calcd for C18H12N4O2
(316.3): C, 68.35; H, 3.83; N, 17.72. Found: C, 68.13; H,
3.78; N, 17.40.
4-Amino-5-methylpyrimido[4,5-b]quinoline (7). A mix-
ture of 2 (10 mmol) and formamide (20 mL) was
refluxed for 20 h. The reaction mixture was cooled,
poured onto ice/water, and the solid product that
appeared was collected by filtration and recrystallized
from ethanol to give brown crystals of 7 in 43% yield,
mp263–266 ꢁC. IR (KBr): n 3400, 3300 (NH2), 1600
(C¼N), 1580 cmꢀ1 (C¼C). 1H NMR (CDCl3): d 3.10 (s,
3H, CH3), 4.75 (br, 2H, NH2), 6.90 (m, 4H, Ar–H), 8.00
ppm (s, 1H, CH-2). MS m/z (%) 212 [M++2] (19.1),
211 [M++1] (1.2), 210 [M+] (0.4), 198 (30.9), 197 (100),
180 (9), 171 (9.17), 170 (34.3), 169 (7.4), 159 (5.6), 153
(25.9), 142 (10.2), 126 (5.4), 115 (6.3), 77 (2.4). Anal.
calcd for C12H10N4 (210.2): C, 68.57; H, 4.80; N, 26.66.
Found: C, 68.35; H, 4.52; N, 26.71.
5-methyl-2-phenyl-2-deoxo-5-deazaalloxazine (10) and 5-
methyl-2-phenyl-1,3-oxazino[4,5-b]quinoline-4-one (11).
A mixture of 2 (10 mmol) and benzoyl chloride
(80 mmol) was refluxed in pyridine (20 mL) for 6 h. The
excess of the benzoyl chloride was removed by distilla-
tion under vacuum, and the residue was cooled and
added to ice/water. The orange precipitate thus
obtained was collected and dried. Thin layer-chromato-
graphy (TLC) of the product using ethanol/ether (1:4)
as an eluent showed two spots. The mixture was found
to be partially soluble in acetic acid, and the above pre-
cipitate that had been filtered off, was washed with ace-
tic acid (ꢃ2) and recrystallized from pyridine to give 11
in 34% yield, mp210–213 ꢁC. IR (KBr): n 1690 (C¼O),
1590 (C¼N), 1580 (C¼C), 1110 cmꢀ1 (C–O–C). 1H
NMR (CDCl3): d 3.00 (s, 3H, CH3), 7.20–8.10 ppm (m,
9H, Ar–H). Anal. calcd for C18H12N2O2 (288.3): C,
74.98; H, 4.20; N, 9.72; Found: C, 75.00; H, 4.65; N,
10.00.
5-methyl-3H-2-deoxo-5-deazaalloxazine (8).
Method A. A solution of 7 (10 mmol) in ethanol
(10 mL) was added dropwise with stirring to a mixture
of acetic acid (3 mL) and 5% aqueous sodium nitrite
solution (7 mL) in the presence of HCl (5 mL) at 0 ꢁC
for 1 h. The precipitate that resulted was collected by
filtration, washed with cold water several times, and
recrystallized from ethanol to give 8 as white needles
(61% yield).
The filtrate was diluted with water, and the yellow
crystals that resulted was recrystallized from dilute ace-
ꢁ
tic acid to give 10 in 63% yield, mp200 C. IR (KBr): n
3300 (NH), 1680 (C¼O), 1620 (C¼N), 1580 cmꢀ1
1
(C¼C). H NMR (CDCl3): d 3.10 (s, 3H, CH3), 7.00–
8.20 ppm [m, 10H (9H, Ar–H and 1H, NH exchange-
able on deuteration)]. MS m/z (%) 287 [M+] (7.9), 286
(35.9), 270 (7.7), 105 (100), 77 (53.8). Elemental anal.
calcd for C18H13N3O (287.3): C, 75.25; H, 4.56; N,
14.63. Found: C, 75.60; H, 4.84; N, 14.50.
Method B. A mixture of 13 (10 mmol), formamide or
formic acid (20 mL) was gently heated for 2 h. After
cooling, the reaction mixture was poured onto ice/

A. A. O. Sarhan et al. / Bioorg. Med. Chem. 9 (2001) 2993–2998
2997
3-Ethyl-5-methyl-2-phenyl-2-deoxo-5-deazaalloxazine (12).
A mixture of 2 (10 mmol) and ethyl iodide (20 mmol)
was stirred in DMF (20 mL) in the presence of anhy-
drous potassium carbonate (5 mmol) for 4 h. The solid
product, obtained on dilution with water, was collected
and recrystallized from ethanol to give the correspond-
ing 12 as pale yellow crystals in 55% yield, mp 343–
345 ꢁC. IR (KBr): n 1690 (C¼O), 1620 (C¼N),
(CF3COOD): d 3.10 (s, 3H, CH3), 7.00–7.90 ppm (m,
9H, Ar–H). MS m/z (%) 319 [M+] (0.1), 202 (9.2), 201
(53.7), 185 (13.2), 184 (86.1), 183 (4), 166 (7.3), 157
(43.9), 156 (12.5), 155 (29.1), 130 (12.3), 129 (19.6), 128
(17.6), 114 (6.1), 102 (9.3), 101 (11.1), 77 (4). Anal. calcd
for C18H13N3OS (319.4): C, 67.68; H, 4.10; N, 13.16; S,
10.04. Found: C, 68.00; H, 4.13; N, 13.06; S, 10.00.
1
1580 cmꢀ1 (C¼C). H NMR (DMSO-d6) d 1.35 (t, 3H,
3-Amino-5-methyl-2-deoxo-5-deazaalloxazine (17).
A
CH2CH3), 3.10 (s, 3H, CH3), 3.30 (q, 2H, CH2CH3),
7.00-8.10 ppm (m, 9H, Ar-H). Anal. calcd for
C20H17N3O (315.4): C, 76.16; H, 5.43; N, 13.32. Found:
C, 76.33; H, 5.40; N, 13.38.
mixture of 8 (10 mmol) and 80% hydrazine hydrate
(40 mmol) was refluxed in ethanol (10 mL) for 3 h. After
cooling, the solid product thus obtained was collected
and recrystallized from ethanol/DMF to give 17 as pale
yellow crystals in 43% yield, mp >300 ꢁC. IR (KBr): n
3420, 3320 (NH2), 1660 (C¼O), 1610 (C¼N), 1590 cmꢀ1
(C¼C). 1H NMR (DMSO-d6): d 3.10 (s, 3H, CH3), 6.8–
7.7 (m, 4H, Ar–H), 7.80 (br, 2H, NH2), 8.3 ppm (s, 1H,
CH-2). MS m/z (%): 226 [M+] (0.1), 184 (26), 183 (100),
182 (12.2), 168 (2.3), 167 (2.8), 166 (8), 156 (11.3), 155
(34.4), 141 (5), 140 (5.7), 139 (7), 129 (7.9), 128 (13.5),
114 (6), 102 (5.4), 101 (6.3), 77 (8.1), 76 (4.3), 51 (7.8).
Anal. calcd for C12H10N4O (226.2): C, 63.71; H, 4.46;
N, 24.77. Found: C, 63.58; H, 4.45; N, 24.80.
2-Amino-4-methylquinoline-3-carboxamide (13). A sam-
ple of 2 (10 mmol) was warmed in 60% aqueous H2SO4
(10 mL) with stirring for 30 min. The reaction mixture
was cooled, diluted with cold water, and then neu-
tralized (pH 8) by addition of aqueous sodium hydrox-
ide solution (10%). The resulting precipitate was
recrystallized from ethanol to give the carboxamide
derivative 13 as white crystals, in 90% yield, mp200–
203 ꢁC. IR (KBr): n 3400, 3300 (NH2), 3250, 3150
(NH2CO), 1660 (C¼O), 1620 (C¼qN), 1580 cmꢀ1
(C¼C). 1H NMR (CDCl3): d 2.80 (s, 3H, CH3), 3.40 (br,
2H, NH2), 5.80 (s, 2H, CONH2), 7.20–8.20 ppm (m, 4H,
Ar–H). Anal. calcd for C11H11N3O (201.2): C, 65.66; H,
5.51; N, 20.89. Found: C, 65.65; H, 5.30; N, 21.05.
4-Chloro-5-methyl-2,4-deoxo-5-deazaalloxazine (18). A
sample of 8 (10 mmol) was refluxed in a mixture of
phosphorus pentachloride (12 mmol) and phosphorus
oxychloride (7 mL) for 4 h. The reaction mixture was
cooled and carefully poured onto ice/ammonia mixture.
The solid product thus formed was filtered off and
recrystallized from benzene to give 18 as pale yellow
crystals in 60% yield, mp173–175 ꢁC; IR (KBr): n 1600
(C¼N), 1580 cmꢀ1 (C¼C). 1H NMR (CDC13): d 3.00 (s,
3H, CH3), 7.00–8.10 (m, 4H, Ar–H), 8.30 ppm (s, 1H,
CH-2). MS m/z (%) 231 [M++2] (28.3), 229 [M+] (0.4),
219 (11.1), 218 (87), 217 (37.3), 216 (100), 180 (5.3), 154
(27.6), 153 (28), 142 (6.1), 140 (9.5), 128 (15.7), 127
(17.4), 126 (12), 115(8), 108 (6.4), 101 (6.6), 90 (13.9), 77
(6.1). Anal. calcd for C12H8ClN3 (229.7): C, 62.75; H,
3.51; N, 18.30; Cl, 15.44. Found: C, 62.78; H, 3.60; N,
18.20; Cl, 15.90.
2,5-Dimethyl-2-deoxo-5-deazaalloxazine (14) and 2-
Acetylamino-4-methylquinoline-3-carboxylic acid (15). A
mixture of 13 (10 mmol) and glacial acetic acid (20 mL)
was refluxed for 40 h. The reaction mixture was cooled
and poured onto ice/water. The resulting precipitate
was collected and washed several times with hot aqu-
eous Na2CO3 (10%), and recrystallized from ethanol/
water to give 14 as white crystals in 63% yield, mp178–
180 ꢁC. IR (KBr): n 3400 (OH), 3250 (NH), 1650
(C¼O), 1600 (C¼N), 1580 cmꢀ1 (C¼C). 1H NMR
(DMSO-d6): d 2.30 (s, 3H, CH3), 3.00 (s, 3H, CH3),
6.90–7.80 (m, 4H, Ar–H), 8.10 ppm (s, 1H, NH). Ele-
mental anal. calcd for C13H11N3O (225.2): C, 69.33; H,
4.93; N, 18.66. Found: C, 69.29; H, 5.00; N, 18.50.
5-Methyl-4-thioxo-2-deoxo-5-deazaalloxazine (19)
Method A. A mixture of 18 (10 mmol) and thiourea
(2.5 mmol) was refluxed in dry methanol (20 mL) for
1 h. The reaction mixture was cooled, and the yellow
crystalline product that appeared was collected by fil-
tration, washed with methanol, and then heated with
10% aqueous sodium hydroxide (20 mL). The resulting
solution was acidified (pH 5.6–5.8) with dilute acetic
acid. The precipitate thus formed was recrystallized
from acetic acid to give 19 in 74% yield, mp205 ꢁC. IR
(KBr): n 2700–2550 (SH), 1620 (C¼N), 1580 cmꢀ1
(C¼C). 1H NMR (DMSO-d6): d 3.10 (s, 3H, CH3),
7.10–7.50 [m, 5H, (4H, Ar–H and 1H, SH)], 8.35 ppm
(s, 1H, CH-2). Anal. calcd for C12H9N3S (227.3): C,
63.40; H, 3.90; N, 18.50; S, 14.10. Found: C, 63.11; H,
3.68; N, 18.30; S, 14.30.
The above filtrate was acidified with acetic acid to
afford a solid product, which was recystallized from
acetic acid to yield 15 in 35% yield, mp200 ꢁC. IR
(KBr): n 3220 (NHCO), 1700 (COOH), 1640 (NHCO),
1
1600 (C¼N), 1580 cmꢀ1 (C¼C). H NMR (CDCl3): d
2.20 (s, 3H, COCH3), 3.00 (s, 3H, CH3), 6.90–7.90 [m,
5H, (4H, Ar–H and 1H, NH exchangeable on deutera-
tion)], 9.80 (s, 1H, OH, exchangeable on deuteration).
Anal. calcd for C13H12N2O3 (244.3): C, 63.91; H, 4.95;
N, 11.47. Found: C, 64.02; H, 4.83; N, 11.50.
5-Methyl-3-phenyl-2-thioxo-5-deazaalloxazine (16).
A
mixture of 13 (10 mmol) and phenylisothiocyanate
(12 mmol) was refluxed in pyridine (20 mL) for 5 h. The
reaction mixture was cooled and diluted with ethanol,
and the resulting precipitate was collected by filtration
and recrystallized from DMF to give 16 in 86% yield,
mp263–266 ꢁC. IR (KBr): n 3350 (NH), 1640 (C¼O),
Method B. A mixture of 8 (10 mmol) and P2S5 (3.0 g)
was refluxed in pyridine (15 mL) for 5 h. The reaction
mixture was cooled, and the precipitate thus formed was
1
1600 (C¼N), 1550 (C¼C), 1130 cmꢀ1 (C¼S). H NMR

2998
A. A. O. Sarhan et al. / Bioorg. Med. Chem. 9 (2001) 2993–2998
collected and triturated with acetic acid. The resulting
precipitate was collected by filtration and recrystallized
from acetic acid to give 19 in 70% yield.
References and Notes
1. Yoneda, F.; Tanaka, K. Med. Res. Rev. 1987, 7, 477 and
references cited therein.
4-Methoxy-5-methyl-2,4-deoxo-5-deazaalloxazine (20).
A methanolic solution of sodium methoxide (10 mL),
prepared from sodium metal (0.23 g and methanol
(10 mL) was added dropwise to a solution of 18
(10 mmol) in methanol (10 mL). The reaction mixture
was cooled in ice bath for 10 min, then allowed to warm
to room temperature, and finally heated gently on a
steam bath for 30 min. The resulting product was col-
lected and recrystallized from methanol to give 20 in
44% yield, mp248–249 ꢁC. IR (KBr): n 1600 (C¼N),
2. Shinkai, S.; Kawase, A.; Yamaguchi, T.; Manabe, O. J.
Chem. Soc., Chem. Commun. 1988, 457.
3. Ikeuchi, Y.; Tanaka, K.; Chen, X.; Yoneda, F. Chem.
Pharm. Bull. 1992, 40, 282.
4. Blythin, D. J.; Domalski, M. S.; Kim, Y. C.; Kuo, J.; Liu,
J.-H. Heterocycles 1981, 16, 203.
5. (a) Eker, A. P. M.; Dekker, R. H.; Berends, W. Photochem.
Photobiol. 1981, 33, 65. (b) Eikyu, Y.; Nakamura, Y.;
Akiyama, T.; Yoneda, F.; Tanaka, K.; Fujii, K. Chem. Pharm.
Bull. 1992, 40, 291.
6. (a) Kimachi, T.; Yoneda, F.; Sasaki, T. J. Heterocycl.
Chem. 1992, 29, 763. (b) Hirayama, R.; Kawase, M.; Kimachi,
T.; Tanaka, K.; Yoneda, F. J. Heterocycl. Chem. 1989, 26,
1255. (c) Yoneda, F.; Sakuma, Y. Tetrahedron Lett. 1981, 22,
3977.
7. (a) Coatney, G. R. Am. J. Trop. Hyg. 1963, 12, 121. (b)
Burckhalter, J. H.; Tendick, F. H. J. Am. Chem. Soc. 1948, 70,
1363.
8. Keepyrung, N.; Won Sup, K.; Kwang Yul, M. Bioorg.
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Chem. Soc. 1996, 73, 623.
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mizu, K.; Tomishima, M.; Bessho, K.; Yoneda, F.; Mikata, Y.
Bioorg. Med. Chem. Lett. 1995, 5, 2109.
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cycl. Chem. 1970, 7, 99.
14. Senga, K.; Shimizu, K.; Nishigaki, S.; Yoneda, F. Het-
erocycles 1977, 6, 1361.
15. (a) Kumar, V.; Woode, K. A.; Bryan, R. F.; Averill, B. A.
Am. J. Chem. Soc. 1986, 108, 490. (b) Walsh, C. Acc. Chem.
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917.
1
1580 cmꢀ1 (C¼C). H NMR (DMSO-d6): d 3.00 (s, 3H,
CH3), 3.55 (s, 3H, OCH3), 6.80–7.40 (m, 4H, Ar–H),
8.40 ppm (s, 1H, CH-2). Anal. calcd for C13H11N3O
(225.2): C, 69.33; H, 4.95; N, 18.66. Found: C, 69.18; H,
4.80; N, 18.21.
4-Hydrazino-5-methyl-2,4-deoxo-5-deazalloxazine (21).
A sample of chloro compound 18 (10 mmol) and 80%
hydrazine hydrate (40 mmol) was refluxed in ethanol
(20 mL) for 1 h. The reaction mixture was cooled to 0 ꢁC
and the solid product thus obtained was collected and
recrystallized from dilute acetic acid to give 21 in 73%
yield, mp205 ꢁC. IR (KBr): n 3470, 3220 (NHNH2),
1
1600 (C¼N), 1560 cmꢀ1 (C¼C). H NMR (DMSO-d6):
d 3.30 (s, 3H, CH3), 4.20 (d, 2H, NH2), 6.80–7.30 (m,
4H, Ar–H), 8.40 (s, 1H, CH-2), 10.60 (br, 1H, NH,
exchangeable on deuteration). MS m/z (%) 225 [M+]
(0.1), 218 (8), 217 (25.9), 216 (100), 197 (18.1), 182
(22.1), 154 (21), 153 (24.5), 140 (8.1), 128 (13.7), 127
(14), 101 (5.7), 90 (13.4), 77 (5.9). Anal. calcd for
C12H11N5 (225.3): C, 63.97; H, 4.92; N, 31.09. Found:
C, 64.00; H, 5.00; N, 31.00.
12-Methyl-1,2,4-s-triazolo[30,40:6,1]pyrimido[4,5-b]quino-
line (22). The hydrazino derivative 21 (10 mmol) was
refluxed in formic acid (5 mL) for 3 h. The reaction
mixture was cooled and poured onto ice/water. The
solid product thus obtained was collected and recrys-
tallized from acetic acid to give 22 in 66% yield, mp
227–230 ꢁC. IR (KBr): n 1600 (C¼N), 1560 cmꢀ1
1
(C¼C). H NMR (CF3COOD): d 3.10 (s, 3H, CH3),
6.90–7.45 (m, 4H, Ar–H), 8.40 (s, 1H, CH-5), 9.40 (s,
1H, CH-3). Anal. calcd for C13H9N5 (235.2): C, 66.30;
H, 3.86; N, 29.78. Found: C, 66.50; H, 3.69; N, 30.00.
19. Gavrilov, M.Yu.; Konshin, M. E. Izu. Vyssh. Uchebn.
Zaved., Khim. Khim. Tekhnol 1991, 34, 57.
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musiak, H.; Konarski, J.; Koziol, J. J. Chem. Soc., Perkin
Trans. 2, 229. (d) Lacroix, A.; Schabat, D.; Clerin, D.; Fleury,
J. Bull. Soc. Chim. Fr. 1987, 1065. (e) Szczesna, V.; Kozio, J.
Tetrahedron Lett. 1982, 23, 475. (f) Fenner, H.; Roessler,
H. H.; Grauert, R. W. Arch. Pharm 1981, 314, 1023. (g)
Tul’chinskaya, L. S.; polyakova, N. A.; Zapesochnaya, L. G.;
Karlstedt, N. B.; Gyach, N. V. J. Org. Chem. USSR 1981, 17,
917 (in English).
Acknowledgements
Our grateful thanks go to Professor Hassan El-Sherief
and Professor Abdalla Mahmoud, Department of
Chemistry, Faculty of Science, Assiut University, Egypt
for their kind helpand discussion.