Highly efficient and practical syntheses of lavendamycin methyl ester and related novel quinolindiones

Article abstract of DOI:10.1021/jo960794t

The novel 7-(N-formyl-, 7-(N-acetyl-, and 7-(N-isobutyrylamino)-2-methylquinoline-5,8-diones were synthesized in excellent overall yields in three steps via the nitration of the commercially available 8-hydroxy-2-methylquinoline followed by a reduction-acylation step and then oxidation. Acid hydrolysis of 7-(N-acetylamino)-2-methylquinoline-5,8-dione (14a) afforded the novel 7-aminoquinoline-5,8-dione 7 in excellent yields. Due to our efficient preparation of dione 14a, we now report a short and practical method for the total synthesis of the potent antitumor agent lavendamycin methyl ester (1b) with an excellent overall yield.

Full text of DOI:10.1021/jo960794t

6552
J . Org. Chem. 1996, 61, 6552-6555
High ly Efficien t a n d P r a ctica l Syn th eses of La ven d a m ycin Meth yl
Ester a n d Rela ted Novel Qu in olin d ion es
Mohammad Behforouz,* J alal Haddad, Wen Cai, Macklin B. Arnold, Farahnaz Mohammadi,
Aron C. Sousa, and Mark A. Horn
Department of Chemistry, Ball State University, Muncie, Indiana 47306
Received April 30, 1996X
The novel 7-(N-formyl-, 7-(N-acetyl-, and 7-(N-isobutyrylamino)-2-methylquinoline-5,8-diones were
synthesized in excellent overall yields in three steps via the nitration of the commercially available
8-hydroxy-2-methylquinoline followed by a reduction-acylation step and then oxidation. Acid
hydrolysis of 7-(N-acetylamino)-2-methylquinoline-5,8-dione (14a ) afforded the novel 7-amino-
quinoline-5,8-dione 7 in excellent yields. Due to our efficient preparation of dione 14a , we now
report a short and practical method for the total synthesis of the potent antitumor agent
lavendamycin methyl ester (1b) with an excellent overall yield.
In tr od u ction
No short and efficient methods for the preparation of
7-aminoquinoline-5,8-diones (2) have been reported. This
is mainly due to the fact that direct nucleophilic substi-
tution-reoxidation reactions of quinolinediones cannot
be used because they give mixtures of the C-6 and C-7
substituted products with the predominance of the
undesired C-6 isomer.11-13 Consequently, the current
literature methods involve many steps such as halogena-
tion, oxidation, azidation, and reduction. Serious draw-
backs of these methods are that they are all lengthy and
involve unstable intermediates such as halo- and azi-
doquinones (3, 4).
Quinoline-5,8-diones are an important class of com-
pounds because of their wide spectrum of biological
activities as anitfungal,1a,2,6 antibacterial,1-3 anti-
tumor,1b,2,4,5 antiasthmatic,1b and antiparasitic1-3,6 agents.
It has been proposed that the 7-aminoquinolinedione
segment of the more complex anticancer agents strep-
tonigrin,7 streptonigrone,8 and lavendamycin (1a )9 is
For example, 7-amino-6-methoxy-2-methylquinolinedi-
one (5; streptonigrin A-B ring system) was synthesized
by Liao and co-workers14b from the commercially avail-
able 2-nitroanisidine in six steps with an overall yield of
about 10%, and the preparation of 7-aminoquinoline-5,8-
dione (6; A-B ring system of lavendamycin) from 8-hy-
droxy-2-nitroquinoline has been reported in six steps with
an overall yield of 25%.14a
In our own laboratory, quinone 7 was synthesized in
eight steps16 with an overall yield of 10% from the
commercially available 8-hydroxy-2-methylquinoline (11)
using the existing literature methods for similar systems
(Scheme 1).14a,15
7-Bromo-2-methylquinoline-5,8-dione (8) was prepared
according to the method of Petrow and Sturgeon15 and
then converted to 7, following Boger’s method of prepara-
tion of 7-aminoquinoline-5,8-dione (6).14a
most critical in determining the antitumor activity of
these compounds.10
X Abstract published in Advance ACS Abstracts, August 15, 1996.
(1) (a) Babu, B. H.; Rao, N. V. S. Proc. Ind. Acad. Sci. 1968, 31, and
references cited therein. (b) Hibino, S. Heterocycles 1977, 6, 1485.
(2) Chung-Kyu, R.; Hee-J eong, K. Arch. Pharmacol. Res. 1994, 17,
139, and refences therein.
(3) Wan, Y. P.; Porte, T. H.; Folkers, K. J . Heterocycl. Chem. 1974,
11, 519.
(4) Boger, D. L.; Yasuda, M.; Mitscher, L. A.; Drake, S. D.; Kitos, P.
A., Thompson, S. C. J . Med. Chem. 1987, 30, 1918.
(5) Behforouz, M.; Merriman, R. L. PCT Int. Appl. WO 94 29308,
1994; Chem. Abstr. 122, 239454a.
(6) J eschke, P.; Linder, W.; Mueller, N.; Harder, A.; Mencke, N. Eur.
Patent Appl. EP 519290, 1992; Chem. Abstr. 118, 233893.
(7) (a) Rao, K. V.; Cullen, W. P. Antibiot. Annu. 1959-1960, 950.
(b) Rao, K. V.; Biemann, K.; Woodward, R. B. J . Am. Chem. Soc. 1963,
85, 2532.
(8) Herlt, A. J .; Rickards, R. W., Wu, J .-P. J . Anitbiot. 1985, 38, 516.
(9) (a) Doyle, T. W.; Balitz, D. M.; Grulich, R. E.; Nettleton, D. E.;
Gould, S. J .; Tann, C.; Moews, A. E. Tetrahedron Lett. 1981, 22, 4595.
(b) Balitz, D. M.; Bush, J . A.; Bradner, W. T.; Doyle, T. W.; O’Herron,
F. A.; Nettleton, D. E. J . Antibiot. 1982, 35, 259.
(11) Pratt,y.T.; Drake, N. L J . Am. Chem. Soc. 1959, 82, 1155.
(12) Klimovich,O. S.; Boldyrev, B. G.; Kolesnikov, V. T. Khim.
Geterosikl. Soedine 1975, 11, 1539; Chem. Abstr. 1976, 84, 74064e.
(13) Yoshida, K.; Ishiguro, M.; Honda, H.; Yamamoto, M.; Kubo, Y.
Bull. Chem. Soc. J pn. 1988, 61, 4335 (Eng).
(14) (a) Boger, D. L.; Duff, S. R.; Panek, J . S.; Yasuda, M. J . Org.
Chem. 1985, 50, 5782. (b) Liao, T. K.; Nyberg, W. H.; Cheng, C. C. J .
Heterocycl. Chem. 1976, 13, 1063. (c) Hibino, S.; Weinreb, S. M. J . Org.
Chem. 1977, 42, 232.
(15) Petrow, V.; Sturgeon, B. J . Chem. Soc. 1954, 570.
(16) Azidoquinone 9 was purified by column chromotography (silica
gel, ethyl acetate-hexane 30-70) as a red-orange solid (91%, mp 105-
106°). 1H NMR (CDCl3) δ 8.29 (d, J ) 8 Hz, 1H), 7.56 (d, J ) 8Hz,
1H), 6.49 (s, 1H), 2.78 (s, 3H); HRMS calcd for C10H6N4O2 214.0491,
found 214.0484. Triphenylphosphine amino compound 10 was purified
by column chromotography (silica gel, ethyl acetate-hexane, 3:5, then
7:5) to give purple crystals (62%, mp 215-216°). 1H NMR (CDCl3) δ
8.23 (d, J ) 8 Hz, 1H), 7.75-7.9 (m, 5H), 7.4-7.6 (m, 10H), 7.38 (d, J
) 8 Hz, 1H), 6.52 (s, 1H), 2.64 (s, 3H); HRMS calcd for C22 H21 N2 O2P
448.1341, found 448.1332. Aminoquinone 7 was purified by column
chromotography (silica gel, ethyl acetate-hexane 1:2, then 1:1) as a
red solid (87%).
(10) Rao, K. V. Cancer Chemother. Rep., Part 2 1974, 4(2), 1.
S0022-3263(96)00794-3 CCC: $12.00 © 1996 American Chemical Society

Syntheses of Novel Quinolindiones
J . Org. Chem., Vol. 61, No. 19, 1996 6553
Sch em e 1
Nitration of 8-hydroxy-2-methylquinoline (11) with a
70-30 (v/v) mixture of HNO3-H2SO4 at ice-bath tem-
perature afforded the known dinitro 12 in 73% yield.21
Compound 12 was reduced with hydrogen in the presence
of 5%Pd/C in 10% HCl solution at room temperature for
15 h. The catalyst was filtered off and the red solution
was treated with excess amounts of acetic or isobutyric
anhydrides in the presence of large amounts of sodium
acetate and sodium sulfite.22 The yellowish white solids
(76-85%) were filtered off. The resulting products were
either 5,7-bis(acylamino)-8-(acyloxy)-2-methylquinolines
and/or their 8-hydroxy derivatives. Treatment of the
products with MeOH-H2O under reflux caused the
acyloxy groups to hydrolyze and produce pure samples
of 13a and13b (eq 1).
Sch em e 2
To prepare 13c, the hydrochloride salt 15 had to be
isolated (98%) in the hydrogenation step and then treated
with the mixed anhydride 18 in the presence of sodium
sulfite and sodium formate. Formic trimethylacetic
anhydride (18) was prepared according to Fife’s method23
with a slight modification (eq 2).
Resu lts a n d Discu ssion
We now report short and practical syntheses of the
novel 7-amino-2-methylquinoline-5,8-dione (7) and three
of its N-acyl derivatives (14a -c). Except for our previous
report,17a which describes the preparation of dione 14a
via an azadiene Diels-Alder reaction (Scheme 3), to our
knowledge no 7-(N-acylamino)-2-methylquinoline-5,8-di-
one has ever been reported. Even for similar systems
there are only two reports in which the isolation of a
small amount of 7-acetamidoquinoline-5,8-dione as a
minor product18 or its 6-chloro derivative as an interme-
diate19 have been described.
Acyl chloride 16 was treated with 4 equiv (literature
method23 requires 1 equiv) of sodium formate (17) in the
presence of catalyst poly(4-vinylpyridine 1-oxide) to give
the pure 18 in 78% yield (lit. 48%).23
Compounds 13a -c were oxidized with potassium
dichromate in a solution of H2O-acetic acid at room
temperature to give the (acylamino)quinones 14a -c in
71-94% yields. Hydrolysis of 14a in the presence of
concentrated H2SO4 gave the aminoquinolinedione 7 in
88% yield. As expected the formamido group was sensi-
tive to acid hydrolysis and caused low yields of 14c. To
avoid this, 13c was oxidized on small scale, using less
acetic acid and shorter reaction times.
Our preliminary biological activity studies have shown
that these novel diones are potent antitumor agents.20
Diones 7 and 14a -c were synthesized from the com-
mercially available 8-hydroxy-2-methylquinoline (11) ac-
cording to Scheme 2.
The advantages of the method of Scheme 2 are that
(a) it introduces the C-7 nitrogen atom in the early stage
of the synthesis, and consequently, the use of unstable
intermediates such as 3 and 4 is avoided; (b) it produces
the diones in three to four steps with high overall yields;24
(c) none of the steps require chromotography or even
recrystallization for product purification; (d) as our data
indicate, stable diones 14, specifically 14a and 14b, can
(17) (a) Behforouz, M.; Gu, Z.; Cai, W.; Horn, M. A.; Ahmadian, M.
J . Org. Chem. 1993, 58, 7089. (b) Kende, A. S; Ebetino, F. H.;
Tetrahedron Lett. 1984, 25, 923. (c) Boger, D. L.; Duff, S. R.; Panek, J .
S.; Yasuda. M. J . Org. Chem. 1985, 50, 5790. (d) Hibino, S.; Okazaki,
M.; Ichikawa,M.; Sato, K.; Ishizu,T. Heterocycles 1985, 23, 261. (e) Rao,
A. V. R.; Chavan, S. P.; Sivadasan, L. Tetrahedron 1986, 42, 5065. (f)
Godard, A.; Rocca, P.; Fourquez, J -M.; Rovera, J .-C.; Marsais, F.;
Queguiner, G. Tetrahedron Lett. 1993, 34, 7919. (g) Ciufolini, M. A.;
Bishop, M. J .J . Chem. Soc., Chem. Commun. 1993, 18, 1463. (h)
Molina, P.; Murica, F.; Fresneda. P. M. Tetrahedron Lett. 1994, 35,
1453.
(21) Rose, D.; Weinrich, E. Ger. Offen. 2 441 598 (Cl. CO7D), 1976;
Chem. Abstr. 1976, 85, 7289q.
(22) Kelly, T. R.; Echavarren, A.; Behforouz, M. J . Org. Chem. 1983,
48, 3849.
(23) Fife, W. K.; Zhang, Z-d. J . Org. Chem. 1986, 51, 3744.
(24) Dione 7 was obtained in four steps with an overall yield of 35%
from the commercially available 11.
(18) Kaiya, t.; Kawazoe, Y.; Ono, M.; Tamura, S. Heterocycles 1988,
27, 645.
(19) Yanni, A. S. Collect. Czech. Chem. Commun. 1991, 56, 1919.
(20) Behforouz, M.; Merriman, R. L. unpublished results.

6554 J . Org. Chem., Vol. 61, No. 19, 1996
Behforouz et al.
mmol), and the reaction mixture was allowed to stir at 25 °C
under Ar for 3 h. The resulting mixture was filtered, and the
filtrate was evaporated in vacuo to give 5.11 g (78%) of a light
yellow liquid: 1H NMR (CDCl3) δ 9.49 (s, 1H), 1.27 (s, 9H).
Sch em e 3
8-Hyd r oxy-2-m eth yl-5,7-d in itr oqu in olin e (12).21 To an
ice-bath cooled and stirred solution of 70% (v-v) HNO3-H2-
SO4 (300 mL) was added 8-hydroxy-2-methylquinoline (11,
40.60 g, 0.25 mol) portionwise. The mixture was allowed to
stir in the ice bath for 2 h and then poured into a 2 L beaker
containing 1 L of ice-water (1:1) with vigorous stirring. The
bright yellow precipitate was filtered, washed with ice-water
(500 mL), washed with diethyl ether (300 mL), and air-dried
to give 45.5 g (72%) of 12: mp 296-300 °C; 1H NMR (DMSO-
d6) δ 9.67 (d, J ) 8.9 Hz, 1H), 9.21 (s, 1H), 8.15 (d, J ) 8.9
Hz), 2.95 (s, 3H).
5,7-Bis(acylam in o)-8-h ydr oxy-2-m eth ylqu in olin es (13a-
c). To a suspension of finely powdered 8-hydroxy-2-methyl-
5,7-dinitroquinoline (12, 5.98 g, 24 mmol) and 100 mL of 10%
hydrochloric acid solution (10 mL conc. HCl + 90 mL H2O) in
a 500 mL hydrogenation bottle was added 2.0 g of 5% Pd-C.
This mixture was hydrogenated (30 psi initial pressure) for
15 h using a Parr hydrogenator. The reaction mixture was
filtered, the filter cake was washed with 10 mL H2O, and the
filtrate containing the ammonium salt 15 was used for the
preparation of 13a -c as follows.
Sch em e 4
5,7-Dia ceta m id o-8-h yd r oxy-2-m eth ylqu in olin e (13a ).
The ammonium salt solution of 15 was treated with 20.0 g of
sodium acetate and 10.0 g of sodium sulfite. To this gently
stirred red solution was added 67 mL of acetic anhydride
(excess) dropwise over 1 h. The warm mixture was allowed
to stir for 1 h and then for an additional 30 min in an ice bath.
The lemon yellow product was filtered and washed with 2 ×
10 mL of cold water. The filtrate was concentrated to about
one-quarter of its original volume, and then with stirring 13
mL of acetic anhydride was dropwise added over 15 min. The
mixture was allowed to stir for an additional 15 min at room
temperature and then for 15 min in an ice bath. The solid
was filtered off and carefully washed with 3 × 10 mL of cold
water to remove any inorganic salt. The two product samples
were added together and dried (6.42 g, 85%). This compound
was shown (by NMR) to be 5,7-diacetamido-8-acetoxy-2-
methylquinoline and decomposed at 260.5 °C. Treatment of
this product with 400 mL MeOH-H2O (10:1) under reflux for
30 min and then evaporation of the solution produced 5.57 g
(100%) of 5,7-diacetamido-8-hydroxy-2-methylquinoline (13a )
as a white solid. An analytical sample of 13a was obtained
by the recrystallization of the product with MeOH-H2O.
Melting point and spectral and elemental analyses are re-
ported in Table 1.
5,7-Diisob u t yr a m id o-8-h yd r oxy-2-m e t h ylq u in olin e
(13b). To the stirred ammonium salt solution of 15 were
added sodium acetate (17.0 g) and sodium sulfite (12.5 g), and
then 67.5 mL (64.4 g, 0.407 mol) of isobutyric anhydride was
added dropwise over a period of 1 h while the reaction mixture
was cooled in an ice bath. The mixture was vigorously stirred
for an additional hour. The white solid was filtered, washed
with 200 mL of H2O and 100 mL diethyl ether, and then air-
dried (7.5 g). NMR showed the product to be a mixture of 13b
and 5,7-diisobutyramido-8-isobutyroxy-2-methylquinoline. Treat-
ment of this mixture with 400 mL of MeOH-H2O (1:1) for 30
min under reflux, followed by the concentration of the resulting
solution to 200 mL and then cooling afforded 5.76 g (75%) of
white crystalline 13b. Melting point and spectral and elemen-
tal analyses are given in Table 1.
easily be functionalized to give other derivatives substi-
tuted at C-2, C-4, C-6, and C-7 positions.25
The synthesis of quinolinediones is part of our ongoing
research in the total synthesis of a series of lavendamycin
esters and analogs. Recently we reported a five-step
synthesis of lavendamycin methyl ester (1b) via the
Diels-Alder condensation of azadiene 20 with bromo-
quinone 19 and transformation of the resulting dione to
the final ester as shown in Scheme 3.17a
Although the method of Scheme 317a is much more
efficient than the previously reported syntheses,17b-h it
still involves a three-step preparation of bromoquinone
19 from the commercially available 2,4-dibromo-6-nitro-
phenol.22 Using our present method of synthesis of
7-acetamido-2-methylquinoline-5,8-dione (14a ; Scheme 2)
in place of our reported Diels-Alder method and follow-
ing our previously described transformations,17a we can
now prepare gram quantities of lavendamycin methyl
ester (1b) according to Scheme 4 in only five-steps from
the known dinitro compound 12 and â-methyltryptophan
methyl ester (22) in excellent overall yields of 37-43%
(Scheme 4).
Exp er im en ta l Section
Gen er a l P r oced u r es. See ref 17a.
F or m ic Tr im eth yla cetic An h yd r id e (18). For the prepa-
ration of anhydride 18, the method of Fife and Zhang23 was
modified as follows.
To a 500 mL round-bottomed flask equipped with a stirring
bar and containing dry sodium formate26 (13.60 g, 200 mmol)
and poly(4-vinylpyridine 1-oxide; 2.00 g) under Ar was added
dry acetonitrile (200 mL) with a syringe. To the vigorously
stirred mixture was added trimethylacetyl chloride (6.00 g, 50
5,7-Difor m a m id o-8-h yd r oxy-2-m eth ylqu in olin e (13c).
Evaporation of the solution of ammonium salt 15 in vacuo gave
6.2 g (98%) of 15 as bright orange crystals, mp 200 °C (dec). A
stirred solution of 15 (2.1 g, 8 mmol) in 80 mL of H2O sodium
sulfite (4.0 g) and sodium formate (4.08 g) was treated with
formic trimethylacetic anhydride (18, 5.2g, 40 mmol) at 25 °C
under Ar for 3 h. The white precipitate was filtered and
washed with ether to give 1.65 g (82%) of pure 13c. Recrys-
tallization from MeOH-H2O gave a white solid, mp 271-273
°C. The spectroscopic and elemental analyses are given in
Table 1.
(25) References 5 and 17a and unpublished results.
(26) Anhydrous sodium formate (Sigma Chemical Co.) was dried
overnight in a 130 °C oven and then on a vacuum pump for 12 h before
use.

Syntheses of Novel Quinolindiones
J . Org. Chem., Vol. 61, No. 19, 1996 6555
Ta ble 1. 5,7-Bis(a cyla m in o)-8-h yd r oxy-2-m eth ylqu in olin es
mass spectrum,c m/z
(relative intensity)
compd
R
% yield
85
mp,a °C
229 (dec)
(MeOH-H2O)
1H NMR, δb
elemental analysis
13a
CH3
2.12 (s, 3), 2.14 (s, 3), 2.7 (s, 3),
7.37 (d, 1, J ) 8.6 Hz),
8.03 (s, 1), 8.14 (d, 1,
273 (M+, 82),
189 (73),
188 (100)
Calcd for C14H15N3O3:
C, 61.53; H, 5.53;
N, 15.38. Found:
J ) 8.6 Hz), 9.57 (s,1), 9.79 (s, 1)
C, 61.43; H, 5.49; N, 15.33
Calcd for C18H23N3O3:
C, 65.63; H, 7.04;
N, 12.76. Found:
C, 65.67; H, 7.06; N, 12.6
13b
(CH3)2CH
76
82
242-243 (dec) 1.13 (d, 6, J )7.0 Hz), 1.16 (d, 6,
329 (M+, 100),
286 (82), 259 (95),
188 (92)
(MeOH-H2O)
J ) 7.0 Hz), 2.71 (s, 3), 2.86 (m, 2),
7.39 (d, 1, J ) 8.7 Hz), 7.99 (s, 1),
8.08 (d, 1, J ) 8.7 Hz), 9.45 (s, 1),
9.69 (s, 1)
2.70 (s, 3), 7.40 (d,1, J ) 8.5 Hz),
8.21 (d, 1, J ) 8.5 Hz), 8.34 (s, 1),
8.38 (s, 1), 8.60 (s, 1), 9.97 (s, 1),
10.11 (s, 1)
13c
H
271-273
(MeOH-H2O)
246 (M+ + 1, 85),
245 (M+, 15),
155 (100)
Calcd for C12H11N3O3:
C, 58.77; H, 4.52;
N, 17.14. Found:
C, 58.56; H, 4.64; N, 17.09
a
b
c
Uncorrected. 200 MHz, DMSO-d6. All EIMS except FAB for 13c.
Ta ble 2. 7-(Acyla m in o)-2-m eth ylqu in olin e-5,8-d ion es
MS,c m/z
(rel. intensity)
compd
R
% yield
mp,a °C
1H NMR,b d
elemental analysis
14a
14b
CH3
(CH3)2CH
71
73
for mp, NMR, MS, and elemental analysis see ref. 17a
189-190 (dec) 1.26 (d, 6, J ) 6.6 Hz), 2.70 (m, 1),
258 (M+, 100),
215 (26),
Calcd for C14H14N2O3:
C, 65.11; H, 5.46;
N, 10.85. Found: C,
64.99; H, 5.43; N, 10.85
Calcd for C11H8N2O3:
C, 61.11; H, 3.73;
(EtOAc)
2.75 (s, 3), 7.54 (d, 1, J ) 8.0 Hz),
7.90 (s, 1), 8.29 (d, 1, J ) 8.0 Hz),
8.42 (br s, 1)
2.72 (s, 3), 7.54 (d, 1, J ) 8.0 Hz),
7.86 (s, 1), 8.28 (d, 1, J ) 8.0 Hz),
8.50 (s, 1), 8.65 (s, 1)
189 (41)
14c
H
94
199-200
216 (M+, 0.2),
188 (M+ - 28, 100),
161 (30)
(CH2Cl2-
pet .ether)
N, 12.96. Found: C,
60.99; H, 3.69; N, 12.97
a
b
c
Uncorrected. 200 MHz, CDCl3. All CIMS except FAB for 14c.
7-Isobu tyr am ido-2-m eth ylqu in olin e-5,8-dion e (14b). To
yellow crystals of 14c (0.102 g, 94%). Melting point and
a
stirred suspension of 5,7-diisobutyramido-8-hydroxy-2-
spectral and elemental analyses are reported in Table 2.
methylquinoline (13b, 3.29 g, 10 mmol) in 122 mL of glacial
acetic acid was added a solution of potassium dichromate (8.8
g, 30 mmol) in 115 mL of water. The resulting dark mixture
was allowed to stir for 1.5 h and then extracted with CH2Cl2
(12 × 50 mL). The combined organic extracts were washed
with 3% sodium bicarbonate solution (2 × 100 mL). The
aqueous layer was extracted with 2 × 50 mL of CH2Cl2 , added
to the original extracts, and dried (MgSO4). Evaporation under
vacuum gave an orange yellow solid (14b, 1.89 g, 73%), which
was recrystallized from ethyl acetate. The melting point, and
spectral and elemental analyses are given in Table 2.
7-Aceta m id o-2-m eth ylqu in olin e-5,8-d ion e (14a ). This
was prepared according to the procedure used for 14b in 60
or 71% yield using 5,7-diacetamido-8-acetoxy-2-methylquino-
line or its hydroxy derivative 13a , respectively. The reaction
time for the former was 15 h.
7-Am in o-2-m eth ylqu in olin e-5,8-d ion e (7). A solution of
7-acetamido-2-methylquinoline-5,8-dione (14a , 0.23 g, 1 mmol)
in 15 mL of dry methanol was treated with 1 mL of concen-
trated H2SO4 at 25 °C under Ar for 1 h. The resulting red
solution was neutralized with 10 mL of 5% sodium bicarbonate
solution and extracted with 5 × 40 mL of CH2Cl2
. The
combined extracts were dried (Na2SO4) and evaporated in
vacuo to give 0.155 g (82%) of 7 as a red solid. Recrystalliza-
tion of this material from MeOH gave red needle-shaped
1
crystals: mp 240 °C; H NMR (CDCl3) δ 8.22 (d, J ) 7.9 Hz,
1H), 7.43 (d, J ) 7.9 Hz, 1H), 5.96 (s, 1H), 5.23 (br s, 2H), 2.67
(s, 3H); EIMS, m/e (rel intensity) 189 (M + 1, 62), 188 (M+,
100), 179 (44), 174 (20), 161 (65), 149 (22), 120 (28), 107 (36);
Anal. Calcd for C10H8N2O2: C, 63.82; H, 4.28; N, 14.89.
Found: C, 63.75; H, 4.37; N, 14.70.
7-F or m a m id o-2-m eth ylqu in olin e-5,8-d ion e (14c) was
prepared according to the method used for 14b, except that
the reaction was carried out on smaller amounts of 13c using
less acetic acid and shorter reaction times. Thus, a solution
of 0.446g (1.5 mmol) of potassium dichromate in 6 mL of H2O-
AcOH (1:5) was added to 0.123 g (0.5 mmol) of 13c and stirred
for 10 min at 25 °C. The reaction mixture was extracted with
5 × 10 mL of CH2Cl2 and then washed with 5% NaHCO3
solution to pH ∼8. The aqueous layer was extracted with 2 ×
10 mL of CH2Cl2 and the combined extracts were washed with
10 mL of brine, dried (Na2SO4), and evaporated to give light
Ack n ow led gm en t. We thank the National Institute
of Health (Grant Nos. GM37491, CA 54517), The
American Cancer Society (Grant No. DHP-110), the
donors of the Petroleum Research Fund, administered
by the American Chemical Society, Eli Lilly and Com-
pany, and Ball State University for financial support
of this work.
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