Some new routes for the preparation of 3-amino-2-phenyl-4(1H)-quinolinones from anthranilamides

Article abstract of DOI:10.1021/jo051303k

Several new routes for the preparation of 3-amino-2-phenyl-4-1(H)- quinolinone 7a are compared. The most efficient is based on the cyclization of phenacyl anthranilamide 2a in the presence of (poly)phosphoric acid. The mechanisms of the rearrangements inv

Full text of DOI:10.1021/jo051303k

Scheme 1 outlines the reaction conditions and final products.
The key intermediate 2a (and analogues) has been proposed
several times in the literature8,9 but has not been previously
isolated. These compounds were prepared by reaction of the
commercially available 2-aminoacetophenones 1a-k with isa-
toic anhydride, following a method similar to that employed
for the synthesis of a chloro analogue.10 Diazepinone 4a has
been prepared, and its melting point is reported in the literature,8
but we have found that, in contrast to the previous report, use
of piperidine as a catalyst led to a less clean reaction.
When anthranilamide 2a was heated with polyphosphoric acid
at 150 °C, we observed the formation of some diazepinone 4a
in TLC and another compound which was identified as
aminoquinolone 7a by NMR, MS, and X-ray diffraction. This
compound (7a) is known in the literature11 and was prepared,
albeit in very low yield, from 2-phenyl-3-acetyl-4(1H)-quinolone
in a multistep synthesis. In contrast, the yield of cyclization
described here is very high (97%) and 7a generated by this
method is unusually pure (98% purity was determined for the
crude product by HPLC). Furthermore, starting materials are
readily available. Formation of compound 7a was also observed
after heating of anthranilamide 2a with phosphoric acid.
The cyclization of anthranilamides 2 in acid conditions is
interesting not only from a preparative point of view, but also
for mechanistic reasons. Formation of diazepinone 4a as an
intermediate during the reaction was followed by TLC and
HPLC. Its concentration remained approximately stable as
long as compound 2a was present in the reaction mixture,
being gradually replaced by 7a when 2a disappeared. At the
end of the reaction, only quinolinone 7a was present. Heating
diazepinone 4a with phosphoric or polyphosphoric acid also
afforded compound 7a.
Some New Routes for the Preparation of
3-Amino-2-phenyl-4(1H)-quinolinones from
Anthranilamides
Pavel Hradil,*,†,‡ Martin Grepl,‡ Jan Hlava´cˇ,†
Miroslav Soural,† Michal Malonˇ,§ and Valerio Bertolasi|
Department of Organic Chemistry, Palacky´ UniVersity,
Trˇ. SVobody 8, 771 46 Olomouc, Czech Republic,
Farmak a.s., 771 17 Olomouc, Czech Republic,
Laboratory of Growth Regulators, Palacky´ UniVersity,
Sˇlechtitelo˚ 11, 783 71 Olomouc, Czech Republic, and
Dipartimento di Chimica and Centro di Strutturistica
Diffrattometrica, UniVersity of Ferrara, Via L. Borsari, 46,
44100 Ferrara, Italy
hradil@farmak.cz
ReceiVed June 25, 2005
Several new routes for the preparation of 3-amino-2-phenyl-
4-1(H)-quinolinone 7a are compared. The most efficient is
based on the cyclization of phenacyl anthranilamide 2a in
the presence of (poly)phosphoric acid. The mechanisms of
the rearrangements involved are discussed on the basis of
the structures of isolated heterocyclic intermediates. The best
methodology for the preparation of the title compound 7a
was verified, and 10 other quinolinones 7 were prepared.
The reactivity of anthranilamide 2a and diazepinone 4a with
different acids and reagents under various conditions was tested
(Scheme 1). When 4a was heated in concentrated hydrochloric
acid, anthranilamide 2a was formed with only traces of amino-
quinolinone 7a. When diazepinone 4a was heated in sulfuric
acid, anthranilamide 2a was formed and several other com-
pounds appeared in TLC. The main product was the same as
that resulting from the reaction of anthranilamide 2a with
sulfuric acid9,13 and was subsequently identified as the oxazole
derivative 3a, arising from intramolecular dehydration of 2a.
Heating the compound 3a with polyphosphoric acid at 170 °C
caused aminoquinolone 7a to be formed in very high yield.
The cyclization of esters of anthranilic acids and 2-hydroxy-
ketones has been studied for some time. Originally, the for-
mation of a seven-membered ring was described in the litera-
ture.1,2 It was proved later that rearrangement to a six-membered
ring takes place leading to a general, simple, and efficient
synthetic entry into 2-substituted-3-hydroxy-4(1H)-quino-
linones.3-5 These compounds are interesting because they can
be considered as isosteres of flavonols, which are well-known
for their applications in medicine6 and for the various kinds of
biological activity they exhibit.7 For this reason, and in an effort
to improve the synthesis, the course of the cyclization of an-
thranilamides 2 under various conditions was studied.
(5) Hradil, P.; Krejcˇ´ı, P.; Hlava´cˇ, J.; Wiedermannova´, I.; Lycˇka, A.;
Bertolasi, V. J. Heterocycl. Chem. 2004, 41, 375.
(6) Middleton, E. J.; Kadaswami, C. The FlaVonoids: AdVances in
Research since 1986; Harborne, J. B., Ed.; Chapman and Hall: London,
1993.
(7) Leung, L. K.; Po, L. S.; Lau, T. Y.; Yuen, Y. M. Br. J. Nutr. 2004,
91, 831.
(8) Weber, K. H. Arch. Pharm. Ber. Dtsch. Pharm. Ges. 1969, 302, 584.
(9) Zhu, Q.; Yoon, H. S.; Parikh, P. B.; Chang, Y. T.; Yao, S. Q.
Tetrahedron Lett. 2002, 43, 5083.
(10) Santilli, A. A.; Del, A.; Osdene T. S. U.S. Patent 3,336,300, 1967.
(11) Staskun, B. J. Org. Chem. 1966, 31, 2674.
(12) Hradil, P. Second doctorate thesis, Palacky´ University, Olomouc,
Czech Republic, 1999.
† Department of Organic Chemistry, Palacky´ University.
‡ Farmak a.s.
§ Laboratory of Growth Regulators, Palacky´ University.
| University of Ferrara.
(1) Sicker, D. J. Prakt. Chem. 1990, 332, 336.
(2) Gandhi, S. S.; Bell, K. L.; Gibson, M. S. Tetrahedron 1995, 51,
13301.
(3) Hradil, P.; Jirman, J. Collect. Czech. Chem. Commun. 1995, 60, 1357.
(4) Hradil, P.; Hlava´cˇ, J.; Lemr, K. J. Heterocycl. Chem. 1999, 36, 141.
(13) Schiketanz, I.; Istrati, D.; Deleanu, C.; Draghici, C.; Balaban, A.
T. Collect. Czech. Chem. Commun. 1997, 62, 769.
(14) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna,
R. J. Appl. Crystallogr. 1999, 32, 115.
10.1021/jo051303k CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/24/2005
J. Org. Chem. 2006, 71, 819-822
819

SCHEME 1
SCHEME 2
Formation of anthranilamide 2a or diazepinone 4a was not
observed during the reaction, but this is not surprising, as
reaction temperatures were very high and these compounds are
known to be unstable under such conditions. Other attempted
cyclization conditions (POCl3, SOCl2) led to complex mixtures.
The most successful method of cyclization of anthranilamide
2a in polyphosphoric acid was also tested on phenacyl anthra-
nilamide derivatives 2b-k. The aminoquinolones 7b-k resulted
in high yield and purity.
These data suggest that formation of a seven-membered ring
occurs initially and is then followed by rearrangement, as shown
in Scheme 2. A similar type of rearrangement in the reactions
of phenacyl anthranilate was anticipated, but the formation of
an intermediate analogous to 4a was not observed.3,12
The behavior of the isomeric anthranilamide 6 with poly-
phosphoric acid under similar conditions was tested. This
reaction provided quinolinone 7a as the sole identifiable product
in 43% isolated yield (Scheme 3).
SCHEME 3
The formation of compound 7a from compound 6 is
tentatively explained in Scheme 4, involving formation of an
aziridine intermediate.
In conclusion, the cyclization of anthranilamides 2 constitutes
an efficient and straightforward pathway toward derivatives of
3-amino-2-phenyl-4-1(H)-quinolinone (7a), compounds with a
prospective application in medicine. Starting anthranilamides
2 were prepared from simply available 2-aminoacetophenones
and isatoic anhydride. The mechanism of transformation an-
thranilamide 2a and to rearrange intermediate 4a with a seven-
membered ring to the final 3-amino-2-phenyl-4-1(H)-quinoli-
none 7a was proposed.
(15) Sheldrick, G. M. SHELXL-97, Program for Crystal Structures
Refinement; University of Go¨ttingen: Go¨ttingen, Germany, 1997.
(16) Burnett, M. N.; Johnson, C. K. ORTEPIII, Report ORNL-6895; Oak
Ridge National Laboratory: Oak Ridge, TN, 1996.
(17) Bertolasi, V.; Gilli, P.; Ferretti, V.; Gilli, G. Acta Crystallogr., Sect.
B 1995, 51, 1004.
Experimental Section
MS characterization was carried out using the direct exposure
probe-chemical ionization-tandem mass spectrometry (DEP-CI-MS-
(18) Bertolasi, V.; Gilli, P.; Ferretti, V.; Gilli, G. Acta Crystallogr., Sect.
B 1998, 54, 50.
820 J. Org. Chem., Vol. 71, No. 2, 2006

SCHEME 4
131.3, 129.8, 128.8, 127.8, 126.6, 126.5, 125.6, 38.5. IR (KBr,
cm-1): 3436, 1658, 1596, 1466. CI(methane)-MS; full MS, m/z
(relative intensity) 237 (100) [M + H]+, 265 [M + C2H5]+, 277
[M + C3H5]+; MS2(237,w5,EV1.5), m/z 235, 220, 208, 194, 179,
167, 134, 105. Anal. Calcd for C15H12N2O: C, 76.25; H, 5.12; N,
11.86. Found: C, 76.31; H, 5.14; N, 11.90.
2-(2-Oxo-2-phenylethylamino)benzamide (6). Anthranilamide
(5) (1 g, 7.3 mmol) was dissolved in dimethylformamide (10 mL),
and potassium carbonate (1 g, 7.14 mmol) was added. The reaction
mixture was heated to 90 °C and stirred for 2 h. Then the solution
was cooled to 20 °C, and phenacyl bromide (1.45 g, 7.3 mmol)
was added. After being stirred for 180 min, the solution was poured
into cold water. The precipitated solid was collected by filtration,
washed with water, and dried, yielding 1 g (54%) of 6. The product
was crystallized from ethanol for analytical purposes: mp 175-
MS) technique with quadrupole ion trap mass analyzer and methane
as the CI reagent gas. Thin-layer chromatography was performed
on Sil G/UV254 plates with UV detection at 254 nm. NMR spectra
were measured with a spectrometer operating at 300.13 MHz (1H)
and 75.47 MHz (13C). The compounds were dissolved in DMSO-
d6 and measured at 300 K. Melting points were determined on a
Boetius stage and were not corrected.
1
177 °C. H NMR (DMSO-d6, 300 MHz) δ 8.73 (1H, bs), 8.12-
8.07 (2H, m), 7.81 (1H, bs), 7.69 (1H, tt, J ) 7.3, 1.3 Hz), 7.63
(1H, dd, J ) 7.9, 1.5 Hz), 7.57 (2H, t, J ) 7.5 Hz), 7.32-7.25
(1H, m), 7.15 (1H, bs), 6.76 (1H, d, J ) 8.4 Hz), 6.58 (1H, t,
J ) 7.5 Hz), 4.80 (2H, s); 13C NMR (DMSO-d6, 75 MHz) δ
195.5, 171.3, 148.7, 135.0, 133.6, 132.4, 128.9, 128.8, 127.8, 114.5,
114.3, 112.0, 49.7. IR (KBr, cm-1): 3367, 3236, 1731, 1643, 1632,
1618, 1513. CI(methane)-MS; full MS, m/z (relative intensity)
255 (40) [M + H]+, 283 [M + C2H5]+, 295 [M + C3H5]+,
238 (100) [M + H - NH3]+, 194 [C6H5NHCHCH C6H5]+; MS2-
(255,w5,EV1), m/z 238, 220, 212, 194, 149, 132, 120. Anal. Calcd
for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C, 70.61;
H, 5.55; N, 10.98.
3-Amino-2-phenyl-4(1H)-quinolinone (7a). Method A: An-
thranilamide 2a (2 g, 7.87 mmol) was mixed with polyphos-
phoric acid (20 g), and the reaction mixture was heated to 150 °C.
After heating for 1.5 h at this temperature, the starting material
was no longer observed in TLC (ethyl acetate). The reaction mix-
ture was poured onto sodium carbonate (20 g), and after foaming
had stopped, water (300 mL) was added. After 30 min of stirring,
a solid product was filtered off and washed with water. The
yield of the product 7a was 1.8 g (97%): mp 250-253 °C. Using
HPLC, we found its purity to be 98%. Crystallization was car-
ried out for analytical purposes: mp 256-259 °C (acetone) (lit:10
mp 243-245 °C, aqueous ethanol). 1H NMR (DMSO-d6, 300
MHz) δ 11.44 (1H, s), 8.12 (1H, d, J ) 8.2 Hz), 7.75-7.70 (2H,
m), 7.65-7.47 (5H, m), 7.24-7.17 (1H, m), 4.22 (2H, s); 13C NMR
(DMSO-d6, 75 MHz) δ 169.7, 137.6, 133.7, 129.8, 129.7, 129.1,
128.9, 128.8, 127.9, 124.6, 121.3, 120.6, 118.1. IR (KBr, cm-1):
3346, 1633, 1570, 1493. CI(methane)-MS; full MS, m/z (relative
intensity) 237 (100) [M + H]+, 265 [M + C2H5]+, 277 [M +
C3H5]+, 220 [M + H - NH3]+; MS2(237,w5,EV1.5), m/z 235, 220,
208, 206, 190, 180, 165, 152, 132, 104. Anal. Calcd for
C15H12N2O: C, 76.25; H, 5.12; N, 11.86. Found: C, 76.00; H, 5.14;
N, 11.80.
Method B: Diazepine 4a (250 mg, 1.058 mmol) was stirred with
polyphosphoric acid (5 g) at 150 °C. After an hour at this
temperature, the starting material could no longer be observed in
TLC (ethyl acetate). The reaction mixture was poured over solid
sodium carbonate (5 g). After foaming had stopped, water (60 mL)
was added. After 30 min of stirring, the solid product was filtered
off and washed with water. The yield of the product 7a was 225
mg (90%): mp 256-259 °C.
Method C: Oxazole derivative 3a (336 mg, 1.42 mmol) was
stirred with polyphosphoric acid (3.4 g), and the reaction mixture
was heated to 170 °C for 2 h. The reaction mixture was poured
onto sodium carbonate (5 g), and after foaming had stopped, water
(30 mL) was added. After 30 min of stirring, the solid product was
filtered off and washed with water. The yield of the product 7a
was 306 mg (91%). mp 254-258 °C (acetone).
2-Amino-N-(2-oxo-2-phenylethyl)benzamide (2a). 2-Amino-
acetophenone hydrochloride (1a) (1 g, 5.83 mmol) was dissolved
in water (20 mL). Isatoic anhydride (1.0 g, 6.14 mmol) and sodium
carbonate (0.38 g, 3.59 mmol) were added. After being stirred for
5 min, the reaction mixture was gradually heated to 80 °C over 30
min. At 30 °C the mixture began to foam. On reaching 80 °C it
was stirred for a further 10 min. After this, the solid phase was
filtered off and washed with a solution of sodium carbonate and
water to neutral pH. The solid was dried in vacuo to yield 1.38 g
(93%) of compound 2a. The product was used for the next synthetic
step without purification, but for analytical purposes it was
crystallized: mp 128-130 °C (acetone). 1H NMR (DMSO-d6, 300
MHz) δ 8.55 (1H, t, J ) 5.5 Hz), 8.06-8.01 (2H, m), 7.68 (1H, tt,
J ) 7.5, 1.3 Hz), 7.61-7.52 (3H, m), 7.20-7.13 (1H, m), 6.71
(1H, d, J ) 8.2 Hz), 6.58-6.51 (1H, m), 6.41 (2H, bs), 4.71
(2H, d, J ) 5.5 Hz); 13C NMR (DMSO-d6, 75 MHz) δ 195.6,
169.1, 149.7, 135.1, 133.4, 131.9, 128.8, 128.1, 127.8, 116.4, 114.6,
114.0, 46.1. IR (KBr, cm-1): 3449, 3344, 3331, 1697, 1633, 1534.
CI(methane)-MS; full MS, m/z (relative intensity) 255 (30) [M +
H]+, 283 [M + C2H5]+, 295 [M + C3H5]+, 237 [M + H - H2O]+,
120 (100) [C6H4CO(NH2)]+; MS2(255,w5,EV1), m/z 237, 235, 224,
194, 149, 120. Anal. Calcd for C15H14N2O2: C, 70.85; H, 5.55; N,
11.02. Found: C, 70.53; H, 5.53; N, 11.00.
2-(5-Phenyl-2-oxazolyl)phenylamine (3a). A mixture of an-
thranilamide 2a (280 mg, 1.1 mmol) and sulfuric acid (3 mL) was
heated to 50 °C for 3 h, and the reaction mixture was subsequently
poured into water and neutralized with sodium carbonate. The
precipitated product was filtered off, dried, and crystallized from
methanol: 230 mg (88%), mp 130-131.5 °C (lit:13 mp 128 °C).
1H NMR (DMSO-d6, 300 MHz) δ 7.91 (1H, dd, J ) 8.1, 1.5 Hz),
7.86-7.82 (3H, m), 7.54-7.47 (2H, m), 7.38 (1H, tt, J ) 7.3, 1.3
Hz), 7.24-7.17 (1H, m), 6.93-6.73 (2H, bs), 6.86 (1H, dd, J )
8.3, 0.8 Hz), 6.70-6.64 (1H, m); 13C NMR (DMSO-d6, 75 MHz)
δ 160.7, 148.6, 147.3, 131.3, 129.1, 128.4, 127.4, 127.0, 123.9,
123.1, 115.8, 115.4, 107.5. IR (KBr, cm-1): 3462, 3360, 3339,
1603, 1537, 1489, 1446. CI(methane)-MS; full MS, m/z (relative
intensity) 237 (100) [M + H]+, 265 [M + C2H5]+, 277 [M +
C3H5]+; MS2(237,w5,EV1.5), m/z 236, 219, 209, 180, 131. Anal.
Calcd for C15H12N2O: C, 76.25; H, 5.12; N, 11.86. Found: C,
76.20; H, 5.17; N, 11.95.
2-Phenyl-3H-benzo[e][1,4]diazepin-5-one (4a). Anthranilamide
2a (0.5 g, 1.97 mmol) was dissolved in xylene (5 mL), and the
reaction mixture was heated under reflux for 4 h. The organic
solution was evaporated to dryness, and the residue was purified
by column chromatography on silica gel with toluene as eluent.
One main product was isolated. This product was crystallized from
tetrahydrofuran to give compound 4a: 260 mg (56%), mp 132-
135 °C (lit:8 mp 173-175 °C). 1H NMR (DMSO-d6, 300 MHz) δ
8.56 (1H, t, J ) 5.9 Hz), 8.10-8.06 (2H, m), 7.89-7.84 (1H, m),
7.66-7.51 (4H, m), 7.40-7.32 (2H, m), 3.96 (2H, d, J ) 5.9 Hz);
13C NMR (DMSO-d6, 75 MHz) δ 167.9, 167.4, 146.4, 136.2, 131.6,
Method D: Anthranilamide 6 (250 mg, 0.983 mmol) was stirred
with polyphosphoric acid (5 g), and the reaction mixture was heated
to 140 °C for 2 h. After the starting material could no longer be
J. Org. Chem, Vol. 71, No. 2, 2006 821

observed in TLC (ethyl acetate), the reaction mixture was poured
over solid sodium carbonate (10 g), and after foaming had stopped,
water (150 mL) was added. The solution was subsequently extracted
using ethyl acetate. The organic solution was evaporated to dryness
and the residuum was separated by column chromatography on
silica gel with ethyl acetate as eluent. Three main products were
separated. Product 7a was isolated in yield of 100 mg (43%): mp
253-255 °C (acetone).
Method E: Anthranilamide 2a (500 mg, 1.97 mmol) was mixed
with 85% phosphoric acid (10 mL), and the reaction mixture was
heated to 140 °C (reflux). After 2 h of heating, the starting material
was no longer observed in TLC (ethyl acetate). The reaction mixture
was poured onto sodium carbonate (5 g), and after foaming had
stopped, water (75 mL) was added. After 30 min of stirring, a solid
product was filtered off and washed with water. The yield of the
product 7a was 440 mg (95%): mp 251-253 °C.
Acknowledgment. We are grateful to the Ministry of
Education, Youth and Sport of the Czech Republic, for Grant
MSM6198959216.
Supporting Information Available: HPLC procedure for
compounds 2a, 4a, and 7a and results of analysis of the reaction
mixture. Information about synthesis and analysis of compounds
2b-k and 7b-k. X-ray crystallographic data for compound 7a in
CIF format. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO051303K
822 J. Org. Chem., Vol. 71, No. 2, 2006