Preparation of 2-pyridone-containing tricyclic alkaloid derivatives as potential inhibitors of tumor cell proliferation by regioselective intramolecular N- and C-acylation of 2-pyridone

Article abstract of DOI:10.1248/cpb.53.67

A novel and practical preparation of 2-pyridone-containing tricyclic alkaloid derivatives was developed. By regioselective intramolecular N- and C-acylation of 2-(4-aryl-2-pyridon-6-yl)benzoic acid, a pair of structural isomers 2-aryl pyrido[2,1-a]isoindo

Full text of DOI:10.1248/cpb.53.67

January 2005
Chem. Pharm. Bull. 53(1) 67—71 (2005)
67
Preparation of 2-Pyridone-Containing Tricyclic Alkaloid Derivatives as
Potential Inhibitors of Tumor Cell Proliferation by Regioselective
Intramolecular N- and C-Acylation of 2-Pyridone
a
a
a
a
a
,b
*
Shaozhong WANG, Liya CAO, Haijian SHI, Yanmei DONG, Jianwei SUN, and Yuefei HU
a Department of Chemistry, Nanjing University; Nanjing 210093, P. R. China: and b Department of Chemistry, Tsinghua
University; Beijing 100084, P. R. China. Received August 16, 2004; accepted October 7, 2004
A novel and practical preparation of 2-pyridone-containing tricyclic alkaloid derivatives was developed. By
regioselective intramolecular N- and C-acylation of 2-(4-aryl-2-pyridon-6-yl)benzoic acid, a pair of structural
isomers 2-aryl pyrido[2,1-a]isoindole-4,6-diones and 4-aryl 1-methyl-1H-indeno[1,2-b]-pyridine-2,5-diones, as
potential inhibitors of tumor cell proliferation, were prepared respectively.
Key words synthesis; tricyclic alkaloid; 2-pyridone; intramolecular N-acylation; intramolecular C-acylation
Recently, A-ring alkoxyl subsitituted b-carbolin-1-ones (1, Results and Discussion
Chart 1) were reported to inhibit colon and lung tumors in a
Preparation of 2-Aryl Pyrido[2,1-a]isoindole-4,6-diones
patent literature.1) Subsequently, we found that 3-aryl b-car- (9a—j) Following the known procedure,38) the mixtures of
bolin-1-ones (2) inhibit the proliferation of HeLa cells with 2-acetylbenzoic acid (5) and aryl aldehydes 6a—j were
IC50 values in the low micromolar range and that the aro- treated respectively with NaOH in aqueous EtOH at room
matic substitution on C3 in 2 proved to be essential for their temperature for 20 h. As shown in Table 1, the corresponding
biological activity.2,3) To broaden the scope of previous stud- products 2-(3-aryl acryloyl)benzoic acids (7a—j) were
ies, aryl-substituted 2-pyridone-containing derivatives, such yielded conveniently in high yields. However, the aryl alde-
as pyrido[2,1-a]isoindole-4-one (3) and 1H-indeno[1,2- hydes bearing an electron-withdrawing group, such as o-, m-,
b]pyridine-2-one (4), were designed as our synthetic targets
to make it possible to probe their structure–activity relation-
ships.
Some alkaloids having frameworks of 3 and 4 occur in na-
ture,4—7) whose analogues were synthesized more often in
laboratories for their potent bioactivities as receptor lig-
ands,8—10) enzyme inhibitors11) or anti-tumor agents.12,13)
Since 3 and 4 are a pair of structural isomers, it is reasonable
to expect that they could be prepared from a common precur-
sor, which should have a structure of 6-substituted 2-pyri-
done allowing a disconnection between methylene and C-
ring in 3 and 4 (Chart 1). However, neither such precur-
sor nor procedure has been employed for this purpose so
far.14—26) Since the methods for preparation of 3-unsub-
stituted 2-pyridone have been well established in recent
years,27—37) herein we report a novel synthetic route to 3
and 4 as shown in Chart 2. The route starts from an aldol
condensation between 2-acetylbenzoic acid (5) and aryl alde-
hyde (6) to yield chalcone (7), which subsequently undergoes
a [3ꢀ3] annulation to give 2-(2-pyridon-6-yl)benzoic acid
(8). Serving as a common precursor, 8 goes through an in-
tramolecular N-acylation to produce 2-aryl pyrido[2,1-
Chart 2
a]isoindole-4,6-diones (9), or carries out an intramolecular
C-acylation to yield 4-aryl 1-methyl-1H-indeno[1,2-b]pyri-
Table 1. The Yields and Physical Properties of Compounds 7a—j
dine-2,5-diones (11) regioselectively.
7
Ar
Yield (%)
mp (°C)
IR (cmꢁ1
)
a
b
c
d
e
f
g
h
i
C6H5
90
90
92
90
88
88
90
88
95
90
151—152
165—166
152—153
135—137
165—166
134—135
132—133
128—129
135—136
134—135
1696, 1648
1693, 1637
1669, 1604
1692, 1644
1689, 1666
1689, 1666
1690, 1649
1713, 1610
1711, 1611
1691, 1658
4-CH3C6H4
4-i-PrC6H4
4-FC6H4
4-ClC6H4
2-ClC6H4
4-MeOC6H4
3-MeOC6H4
2-Furyl
j
2-Thienyl
Chart 1
∗ To whom correspondence should be addressed. e-mail: yfh@mail.tsinghua.edu.cn
© 2005 Pharmaceutical Society of Japan

68
Vol. 53, No. 1
Table 2. The Yields of Compounds 8—11
Yield (%)
10
Yield (%)
8—11
Ar
8—11
Ar
8
9
11
8
9
10
11
a
b
c
d
e
C6H5
63
65
60
70
68
98
96
90
92
90
83
80
81
87
85
92
90
92
90
90
f
g
h
i
2-ClC6H4
4-MeOC6H4
3-MeOC6H4
2-Furyl
68
75
73
60
62
90
95
91
89
90
75
80
78
80
81
85
90
88
85
86
4-CH3C6H4
4-i-PrC6H4
4-FC6H4
4-ClC6H4
j
2-Thienyl
p-nitrobenzaldehydes, failed to afford the expected chal-
cones.
Among the methods for preparation of 3-unsubstituted 2-
pyridone,27—37) [3ꢀ3] annulation between chalcone and
C–C–N fragment connected with a leaving group displayed
high convenience and efficiency, such as N-(2-carbamoyl-
methyl)-pyridinium ylide,29—33) 2-acetamidoacetamide34) or
2-(benzotriazol-1-yl)acetamide.35—37) By scanning the condi-
tions, the best yield (63%) of desired 2-pyridone 8a was ob-
tained when chalcone 7a was refluxed with 2-(benzotriazol-
1-yl)acetamide35) in the presence of NaOH for 6 h. Under
similar conditions, other compounds 7b—j were annulated to
give the corresponding products 8b—j in 60—75% yields. It
is worthy to note that the heterocycles 8i—j showed good
toleration of the conditions (Table 2).
Fig. 1. Structure of Compound 9d
Usually, intramolecular N-acylation of amides can be well
accomplished in refluxing acetic anhydride for several
hours.39,40) But it failed in our case largely due to the poor
solubility of both substrates and products in refluxing acetic
anhydride. Fortunately, the intramolecular N-acylation of 8a
was achieved successfully in almost quantitative yield by re-
fluxing it in xylene for 8 h with a Dean–Stark trap. Similarly,
the N-acylation of 8b—j yielded the corresponding 9b—j in
85—96% yields (Chart 2, Table 2). Since the products 9a—j
have much less solubility in xylene at room temperature, they
were collected cleanly by filtration in the work-up procedure.
The structure of compound 9d was confirmed by its single
crystal X-ray diffraction analysis (Fig. 1).41)
Preparation of 4-Aryl 1-Methyl-1H-indeno[1,2-b]pyri-
dine-2,5-diones (11a—j) To the best of our knowledge, no
successful intramolecular C-acylation of 2-pyridone has been
reported in literature. In a few samples of intermolecular C-
acylation of N-alkylated 2-pyridones, very harsh conditions
were employed.42—44) Therefore, it was not surprising that
our attempts to C-acylate 8a under Friedel–Crafts conditions
catalyzed by PPA, H2SO4, CH3SO3H, TFA, ZnCl2, AlCl3 or
SnCl4 failed. We hypothesized that those undesired results
might be caused by the presence of the active proton on ni-
trogen in 8a and N-alkylation of 8a was required.
Fig. 2. Structure of Compound 11g
PPA at 120 °C for 0.5 h to give the desired product 11a in
high yield (92%). Under the similar conditions, intramolecu-
lar C-acylation of 10b—j yielded the corresponding 11b—j
in 85—92% yields. As the long-range coupling of protons on
C3 and C5 in 10a—j displays two doublet signals at d
1
6.75—6.60 ppm and d 6.40—6.06 ppm in their H-NMR
spectra respectively, the singlet signals appearing at d 6.94—
6.41 ppm in 1H-NMR spectra of 11a—j are in full agreement
with their structural assignments. In addition, the structure of
11g was confirmed by its single crystal X-ray diffraction
analysis (Fig. 2).51)
In summary, a novel synthetic route was developed for
the preparation of 2-aryl pyrido[2,1-a]isoindole-4,6-dione
(9) and 4-aryl 1-methyl-1H-indeno[1,2-b]pyridine-2,5-dione
(11) by using 2-(4-aryl-2-pyridon-6-yl)benzoic acid (8) as a
common precursor. By refluxing compound 8 in xylene for
8 h, an intramolecular N-acylation was accomplished to yield
alkaloid 9 in high yield. While, alkaloid 11 was achieved sat-
isfactorily by an intramolecular C-acylation when N-meth-
ylated 8 was heated with PPA for 0.5 h.
2-Pyridone has two tautomeric forms (hydroxy and oxo
forms) under basic conditions and it normally yields O-
or/and N-alkylated products mainly depending upon the
media used.45—50) It is interesting to observe that N-methyl-
ated product 10a was obtained regioselectively in 83% yield
when 8a was treated by Me2SO4 in 2.0 M aqueous solution of
NaOH at 0 °C for 2 h. Under the same conditions, 8b—j
were also N-methylated to give the corresponding products
10b—j in 75—87% yields smoothly.
Experimental
The IR spectra were recorded on a Nicolet FT-IR 5DX spectrometer as
KBr pellets. The NMR spectra were recorded on a Bruker ACF-300 spec-
trometer in CDCl3 with TMS as internal reference. The J values are given in
Hz. MS spectra were obtained on a VG-ZAB-HS mass spectrometer with
70 eV. The elemental analyses were performed on a Perkin-Elmer 240C in-
In agreement with our expectation, compound 10a took
place an intramolecuar C-acylation smoothly catalyzed by strument. PE is petroleum ether (60—90 °C).

January 2005
69
A General Procedure for the Preparation of 2-(3-Aryl acryloyl)ben- H, 3.73; N, 4.71. Found: C, 64.67; H, 3.99; N, 4.63.
zoic Acids (7a—j) To a stirred cold solution (ice-bath) of 2-acetylbenzoic
acid (5, 3.28 g, 20 mmol) and aryl aldehyde (6, 20 mmol) in EtOH (10 ml)
was added an aqueous solution of NaOH (1.5 M, 20 ml). After stirred at
A General Procedure for the Preparation of 2-Aryl Pyrido[2,1-
a]isoindole-4,6-dione (9a—j) The solution of compound 8 (3 mmol) in
xylene (60 ml) was heated to reflux to move continuously out the water with
room temperature for another 20 h, the resultant mixture was poured into a Dean–Stark equipment. After 8 h (monitored by TLC), it was cooled to
ice-water and neutralized by aqueous HCl (6.0 M). The crude product as
solid was collected by filtration and recrystallized from EtOAc to give com-
pound 7. Some properties of 7a—j were showed in Table 1.
room temperature. The precipitated yellowish crystals were collected to get
pure compound 9 (Table 2).
2-Phenylpyrido[2,1-a]isoindole-4,6-dione (9a): mp 266—268 °C (xy-
A General Procedure for the Preparation of 2-(4-Aryl 2-pyridon-6- lene); IR cmꢁ1: 3053, 1783, 1751, 1675, 1616; 1H-NMR d: 8.02 (1H, d,
yl)benzoic Acid (8a—j) The mixture of compound
7 (10 mmol), Jꢂ7.6), 7.82—7.74 (2H, m), 7.68—7.62 (3H, m), 7.57—7.51 (3H, m), 6.94
BtCH2CONH2 (1.76 g, 10 mmol) and NaOH (1.4 g, 35 mmol) in EtOH
(60 ml) was heated to reflux for 6 h. After compound 7 was exhausted com-
pletely (monitored by TLC), most of the solvent was evaporated. The
residue then was poured into ice-water and neutralized by aqueous HCl
(6.0 M). The crude product as solid was collected and was recrystallized
from MeOH to give compound 8 (Table 2).
(1H, d, Jꢂ1.4), 6.80 (1H, d, Jꢂ1.4); 13C-NMR d: 165.4, 160.6, 151.9,
141.0, 136.8, 135.4, 134.9, 131.6, 130.7, 129.6, 127.7, 127.0, 126.3, 121.7,
121.2, 102.5; MS m/z: 275 (Mꢀ2, 1.5%), 274 (Mꢀ1, 12.6), 273 (Mꢀ, 60.5),
245 (100). Anal. Calcd for C18H11NO2: C, 79.11; H, 4.06; N, 5.13. Found: C,
79.00; H, 4.12; N, 5.13.
2-(4-Methylphenyl)-pyrido[2,1-a]isoindole-4,6-dione (9b): mp 264—
2-(4-Phenyl-2-pyridon-6-yl)benzoic Acid (8a): mp 260—262 °C (MeOH); 266 °C (xylene); IR cmꢁ1: 3061, 1782, 1754, 1674, 1617; H-NMR d: 8.03
IR cmꢁ1: 3038, 1661, 1634, 1595; 1H-NMR (DMSO-d6) d: 7.93 (1H, d, (1H, d, Jꢂ7.5), 7.82—7.74 (2H, m), 7.64—7.56 (3H, m), 7.33 (2H, d,
Jꢂ7.5), 7.75—7.72 (2H, m), 7.69—7.54 (3H, m), 7.51—7.46 (3H, m), 6.60 Jꢂ8.0), 6.94 (1H, d, Jꢂ1.2), 6.79 (1H, d, Jꢂ1.1), 2.45 (3H, s); MS m/z: 289
(1H, s), 6.48 (1H, s); MS-FAB m/z: 291 (Mꢀ, 0.3%), 273 (100). Anal. Calcd (Mꢀ2, 2.5%), 288 (Mꢀ1, 22.7), 287 (Mꢀ, 100). Anal. Calcd for
for C18H13NO3: C, 74.22; H, 4.50; N, 4.81. Found: C, 74.30; H, 4.66; N, C19H13NO2: C, 79.43; H, 4.56; N, 4.88. Found: C, 79.32; H, 4.59; N, 4.72.
1
4.83.
2-(4-Isoproylphenyl)-pyrido[2,1-a]isoindole-4,6-dione (9c): mp 237—
1
2-[4-(4-Methylphenyl)-2-pyridon-6-yl]benzoic Acid (8b): mp 267—
239 °C (xylene); IR cmꢁ1: 3068, 1782, 1755, 1674, 1617; H-NMR d: 8.04
268 °C (MeOH); IR cmꢁ1: 3028, 1664, 1627, 1595; 1H-NMR (DMSO-d6) d: (1H, d, Jꢂ7.3), 7.82—7.74 (2H, m), 7.63—7.60 (3H, m), 7.39 (2H, d,
7.92 (1H, d, Jꢂ7.6), 7.69—7.53 (5H, m), 7.27 (2H, d, Jꢂ8.2), 6.57 (1H, s), Jꢂ7.7), 6.95 (1H, s), 6.80 (1H, s), 3.06—2.96 (1H, m), 1.32 (6H, d, Jꢂ6.9);
6.46 (1H, s), 2.35 (3H, s); MS-FAB m/z: 306 (Mꢀ1, 3.6%), 91 (100). Anal.
Calcd for C19H15NO3: C, 74.74; H, 4.95; N, 4.59. Found: C, 74.65; H, 5.00; for C21H19NO2: C, 79.98; H, 5.43; N, 4.44. Found: C, 79.98; H, 5.29; N,
N, 4.41. 4.56.
2-[4-(4-Isoproylphenyl)-2-pyridon-6-yl]benzoic Acid (8c): mp 222— 2-(4-Fluorophenyl)-pyrido[2,1-a]isoindole-4,6-dione (9d): mp 276—
MS m/z: 317 (Mꢀ2, 3.4%), 316 (Mꢀ1, 25.4), 315 (Mꢀ, 100). Anal. Calcd
223 °C (MeOH); IR cmꢁ1: 3025, 1660, 1629; H-NMR (DMSO-d6) d: 7.92 278 °C (xylene); IR cmꢁ1: 3061, 1784, 1758, 1673, 1616; H-NMR d: 8.03
(1H, dd, Jꢂ7.6, 1.1), 7.68—7.64 (3H, m), 7.61—7.53 (2H, m), 7.34 (2H, d, (1H, d, Jꢂ7.6), 7.82—7.74 (2H, m), 7.69—7.60 (3H, m), 7.26—7.18 (2H,
Jꢂ8.2), 6.58 (1H, d, Jꢂ1.3), 6.46 (1H, s), 2.95—2.91 (1H, m), 1.22 (6H, d, m), 6.89 (1H, d, Jꢂ1.5), 6.75 (1H, d, Jꢂ1.5); MS m/z: 292 (Mꢀ1, 20.7%),
Jꢂ6.9); MS-FAB m/z: 334 (Mꢀ1, 10.2%), 59 (100). Anal. Calcd for 291 (Mꢀ, 100). Anal. Calcd for C18H10FNO2: C, 74.22; H, 3.46; N, 4.81.
1
1
C19H15NO4: C, 75.66; H, 5.74; N, 4.20. Found: C, 75.60; H, 5.80; N, 4.21.
Found: C, 74.16; H, 3.52; N, 4.76.
2-[4-(4-Fluorophenyl)-2-pyridon-6-yl]benzoic Acid (8d): mp 276—
2-(4-Chlorophenyl)-pyrido[2,1-a]isoindole-4,6-dione (9e): mp 306—
1
278 °C (MeOH); IR cmꢁ1: 3090, 1691, 1632, 1599; 1H-NMR (DMSO-d6) d: 308 °C (xylene); IR cmꢁ1: 3062, 1784, 1758, 1673, 1609; H-NMR d: 8.04
7.94 (1H, d, Jꢂ7.5), 7.83—7.79 (2H, m), 7.68—7.54 (3H, m), 7.30 (2H, t, (1H, d, Jꢂ7.5), 7.83—7.75 (2H, m), 7.66—7.60 (3H, m), 7.51 (2H, d,
Jꢂ8.7), 6.60 (1H, s), 6.49 (1H, s); MS-FAB m/z: 310 (Mꢀ1, 15.4%), 91 Jꢂ8.2), 6.88 (1H, s), 6.77 (1H, s); MS m/z: 310 (Mꢀ3, 3.5%), 309 (Mꢀ2,
(100). Anal. Calcd for C18H12FNO3: C, 69.90; H, 3.91; N, 4.53. Found: C, 27.5), 308 (Mꢀ1, 18.1), 307 (Mꢀ, 100). Anal. Calcd for C18H10ClNO2: C,
69.83; H, 4.06; N, 4.35.
70.25; H, 3.28; N, 4.55. Found: C, 70.29; H, 3.36; N, 4.51.
2-[4-(4-Chlorophenyl)-2-pyridon-6-yl]benzoic Acid (8e): mp 306—
2-(2-Chlorophenyl)-pyrido[2,1-a]isoindole-4,6-dione (9f): mp 270—
1
308 °C (MeOH); IR cmꢁ1: 3043, 1662, 1627, 1594; 1H-NMR (DMSO-d6) d: 271 °C (xylene); IR cmꢁ1: 3062, 1784, 1760, 1677, 1620; H-NMR d: 8.04
7.94 (1H, d, Jꢂ7.5), 7.78 (2H, d, Jꢂ8.5), 7.68—7.51 (5H, m), 6.62 (1H, s), (1H, d, Jꢂ7.5), 7.75 (2H, d, Jꢂ3.9), 7.66—7.59 (1H, m), 7.54—7.52 (1H,
6.49 (1H, s); MS-FAB m/z: 328 (Mꢀ3, 0.8%), 326 (Mꢀ1, 2.5), 91 (100). m), 7.45—7.39 (3H, m), 6.80 (1H, d, Jꢂ1.1), 6.63 (1H, d, Jꢂ1.1); MS m/z:
Anal. Calcd for C18H12ClNO3: C, 66.37; H, 3.71; N, 4.30. Found: C, 66.35; 310 (Mꢀ3, 5.9%), 309 (Mꢀ2, 35.8), 308 (Mꢀ1, 19.7), 307 (Mꢀ, 100).
H, 3.76; N, 4.24.
Anal. Calcd for C18H10ClNO2: C, 70.25; H, 3.28; N, 4.55. Found: C, 70.19;
H, 3.53; N, 4.40.
2-[4-(2-Chlorophenyl)-2-pyridon-6-yl]benzoic Acid (8f): mp 267—
269 °C (MeOH); IR cmꢁ1: 3097, 1718, 1619; H-NMR (DMSO-d6) d: 7.90
2-(4-Methoxyphenyl)-pyrido[2,1-a]isoindole-4,6-dione (9g): mp 260—
1
1
(1H, d, Jꢂ7.5), 7.74—7.43 (7H, m), 6.35 (1H, s), 6.21 (1H, s); MS-FAB
m/z: 328 (Mꢀ3, 1.6%), 326 (Mꢀ1, 1.9), 55 (100). Anal. Calcd for
C18H12ClNO3: C, 66.37; H, 3.71; N, 4.30. Found: C, 66.35; H, 3.79; N, 4.28.
2-[4-(4-Methoxyphenyl)-2-pyridon-6-yl]benzoic Acid (8g): mp 254—
262 °C (xylene); IR cmꢁ1: 3066, 1784, 1751, 1673, 1617; H-NMR d: 8.02
(1H, d, Jꢂ7.5), 7.82—7.73 (2H, m), 7.65—7.58 (3H, m), 7.03 (2H, d,
Jꢂ8.7), 6.93 (1H, d, Jꢂ1.4), 6.74 (1H, d, Jꢂ1.5), 3.90 (3H, s); MS m/z: 305
(Mꢀ2, 2.6%), 304 (Mꢀ1, 20.9), 303 (Mꢀ, 100). Anal. Calcd for
256 °C (MeOH); IR cmꢁ1: 3010, 1668, 1630, 1604; 1H-NMR (DMSO-d6) d: C19H13NO3: C, 75.24; H, 4.32; N, 4.62. Found: C, 75.23; H, 4.48; N, 4.57.
7.92 (1H, d, Jꢂ7.5), 7.73—7.53 (5H, m), 7.02 (2H, d, Jꢂ8.5), 6.55 (1H, s),
6.46 (1H, s), 3.81 (3H, s); MS-FAB m/z: 322 (Mꢀ1, 0.5%), 91 (100). Anal.
2-(3-Methoxyphenyl)-pyrido[2,1-a]isoindole-4,6-dione (9h): mp 206—
1
208 °C (xylene); IR cmꢁ1: 3060, 1763, 1677, 1620, 1597; H-NMR d: 8.02
Calcd for C19H15NO4: C, 71.02; H, 4.71; N, 4.36. Found: C, 71.08; H, 4.83; (1H, d, Jꢂ7.6), 7.78 (dd, 2H, Jꢂ16.9, 7.7), 7.62 (1H, t, Jꢂ7.3), 7.44 (1H, t,
N, 4.37.
2-[4-(3-Methoxyphenyl)-2-pyridon-6-yl]benzoic Acid (8h): mp 178—
180 °C (MeOH); IR cmꢁ1: 3241, 1685, 1612, 1602; 1H-NMR (DMSO-d6) d:
Jꢂ7.9), 7.25 (1H, t, Jꢂ6.2), 7.16 (1H, t, Jꢂ2.0), 7.05 (1H, dd, Jꢂ8.2, 1.9),
6.92 (1H, d, Jꢂ1.3), 6.79 (1H, d, Jꢂ1.3), 3.89 (3H, s); MS m/z: 305 (Mꢀ2,
2.6%), 304 (Mꢀ1, 21.6), 303 (Mꢀ, 100). Anal. Calcd for C19H13NO3: C,
7.93 (1H, dd, Jꢂ7.4, 1.0), 7.69—7.54 (3H, m), 7.39 (1H, t, Jꢂ7.8), 7.30— 75.24; H, 4.32; N, 4.62. Found: C, 75.24; H, 4.33; N, 4.50.
7.23 (2H, m), 7.03—7.00 (1H, m), 6.62 (1H, d, Jꢂ1.6), 6.50 (1H, s), 3.82
(3H, s); MS-FAB m/z: 322 (Mꢀ1, 25.0%), 91 (100). Anal. Calcd for
C19H15NO4: C, 71.02; H, 4.71; N, 4.36. Found: C, 71.08; H, 4.64; N, 4.34.
2-(2-Furyl)-pyrido[2,1-a]isoindole-4,6-dione (9i): mp 267—268 °C (xy-
lene); IR cmꢁ1: 3120, 1764, 1744, 1689, 1634, 1610, 1593; 1H-NMR d: 8.02
(1H, d, Jꢂ7.5), 7.83—7.74 (2H, m), 7.64—7.59 (2H, m), 6.99 (1H, d,
2-[4-(2-Furyl)-2-pyridon-6-yl]benzoic Acid (8i): mp 256—258 °C Jꢂ3.3), 6.95 (1H, s), 6.84 (1H, s), 6.62 (1H, t, Jꢂ1.5); MS m/z: 264 (Mꢀ1,
1
(MeOH); IR cmꢁ1: 3110, 1670, 1633, 1576; H-NMR (DMSO-d6) d: 7.95 16.6%), 263 (Mꢀ, 100). Anal. Calcd for C16H9NO3: C, 73.00; H, 3.45; N,
(1H, d, Jꢂ7.6), 7.87 (1H, s), 7.69—7.57 (2H, m), 7.50 (1H, d, Jꢂ7.3), 7.25 5.34. Found: C, 73.13; H, 3.49; N, 5.29.
(1H, d, Jꢂ3.4), 6.65 (1H, t, Jꢂ1.6), 6.56 (1H, s), 6.49 (1H, s); MS-FAB m/z:
282 (Mꢀ1, 3.7%), 91 (100). Anal. Calcd for C16H11NO4: C, 68.32; H, 3.94; (xylene); IR cmꢁ1: 3085, 1781, 1757, 1673, 1619; H-NMR d: 8.0 (1H, d,
N, 4.98. Found: C, 68.28; H, 4.02; N, 4.94. Jꢂ7.5), 7.85—7.75 (2H, m), 7.65—7.53 (3H, m), 7.22—7.19 (1H, m), 6.92
2-(2-Thienyl)-pyrido[2,1-a]isoindole-4,6-dione (9j): mp 268—270 °C
1
2-[4-(2-Thienyl)-2-pyridon-6-yl]benzoic Acid (8j): mp 250—252 °C (1H, d, Jꢂ1.0), 6.79 (1H, d, Jꢂ1.0); MS m/z: 281 (Mꢀ2, 5.5%), 280 (Mꢀ1,
1
(MeOH); IR cmꢁ1: 3109, 1668, 1628, 1573; H-NMR (DMSO-d6) d: 7.95 17.1), 279 (Mꢀ, 100). Anal. Calcd for C16H9NO2S: C, 68.80; H, 3.25; N,
(1H, d, Jꢂ7.4), 7.75—7.71 (2H, m), 7.69—7.57 (2H, m), 7.52 (1H, d, 5.01. Found: C, 68.84; H, 3.30; N, 4.96.
Jꢂ7.4), 7.20—7.17 (1H, m), 6.54 (1H, d, Jꢂ1.3), 6.48 (1H, s); MS-FAB
A General Procedure for the Preparation of 2-(4-Aryl 1-methyl-2-
m/z: 298 (Mꢀ1, 12.2%), 91 (100). Anal. Calcd for C16H11NO3S: C, 64.63; pyridon-6-yl)benzoic Acid (10a—j) To a stirred solution of 8 (5 mmol) in

70
Vol. 53, No. 1
aqueous solution of NaOH (2.0 N, 20 ml) was added Me2SO4 (10 mmol) and
aqueous solution of NaOH (2.0 N, 80 ml) simultaneously at 0 °C. Then the
mixture was stirred for another 2 h at the same temperature and neutralized
by aqueous HCl (2.0 N). The precipitated solid was collected and the crude
product was purified by recrystallization to give compound 10 (Table 2).
deno[1,2-b]pyridine-2,5-dione (11a—j) Under the N2, a mixture of com-
pound 10 (3 mmol) in PPA (10 ml) was heated to 120 °C for 0.5 h. Then the
resultant mixture was cooled to room temperature and poured into ice-water.
After neutralization by solid NaHCO3, the mixture was extracted with
CH2Cl2. The combined organic layers were washed with water and dried
over Na2SO4. The solvent was removed to yield a residue, which was puri-
2-(1-Methyl-4-phenyl-2-pyridon-6-yl)benzoic Acid (10a): mp 258—
1
260 °C (EtOH); IR cmꢁ1: 1698, 1636, 1574; H-NMR (DMSO-d6) d: 8.04 fied by recrystalliation to give compound 11 (Table 3).
(1H, dd, Jꢂ7.7, 1.3), 7.78—7.64 (4H, m), 7.55—7.52 (1H, m), 7.48—7.44
4-Phenyl-1-methyl-1H-indeno[1,2-b]pyridine-2,5-dione (11a): mp 188—
(3H, m), 6.73 (1H, d, Jꢂ2.0), 6.38 (1H, d, Jꢂ2.0), 3.10 (3H, s); MS m/z: 190 °C (CH2Cl2/PE); IR cmꢁ1: 1704, 1661; 1H-NMR d: 7.76 (1H, d, Jꢂ7.4),
307 (Mꢀ2, 3.3%), 306 (Mꢀ1, 19.7), 305 (Mꢀ, 100). Anal. Calcd for 7.64 (1H, dd, Jꢂ6.9, 1.3), 7.56—7.45 (7H, m), 6.41 (1H, s), 4.04 (3H, s);
C19H15NO3: C, 74.74; H, 4.95; N, 4.59. Found: C, 74.74; H, 5.03; N, 4.39.
MS m/z: 289 (Mꢀ2, 2.4%), 288 (Mꢀ1, 19.6), 287 (Mꢀ, 100). Anal. Calcd
2-[1-Methyl-4-(4-methylphenyl)-2-pyridon-6-yl]benzoic Acid (10b): mp for C19H13NO2: C, 79.43; H, 4.56; N, 4.88. Found: C, 79.41; H, 4.65; N,
223—225 °C (EtOH); IR cmꢁ1: 1694, 1631, 1574; H-NMR (DMSO-d6) d: 4.80.
1
8.05 (1H, d, Jꢂ7.6), 7.75 (1H, t, Jꢂ7.4), 7.68—7.56 (3H, m), 7.53 (1H, d,
4-(4-Methylphenyl)-1-methyl-1H-indeno[1,2-b]pyridine-2,5-dione (11b):
Jꢂ6.9), 7.26 (2H, d, Jꢂ7.9), 6.70 (1H, d, Jꢂ1.9), 6.37 (1H, d, Jꢂ1.9), 3.09 mp 204—206 °C (CH2Cl2/PE); IR cmꢁ1: 1712, 1661; 1H-NMR d: 7.76 (1H,
(3H, s), 2.34 (3H, s); MS m/z: 320 (Mꢀ1, 3.2%), 319 (Mꢀ, 13.9), 57 (100). d, Jꢂ7.2), 7.65 (1H, dd, Jꢂ7.5, 1.4), 7.56—7.45 (2H, m), 7.42 (2H, d,
Anal. Calcd for C20H17NO3: C, 75.22; H, 5.37; N, 4.39. Found: C, 75.20; H, Jꢂ8.0), 7.27 (2H, d, Jꢂ7.6), 6.41 (1H, s), 4.05 (3H, s), 2.44 (3H, s); MS
5.40; N, 4.40.
2-[1-Methyl-4-(4-isopropylphenyl)-2-pyridon-6-yl]benzoic Acid (10c): C20H15NO2: C, 79.72; H, 5.02; N, 4.65. Found: C, 79.79; H, 5.06; N, 4.63.
m/z: 303 (Mꢀ2, 2.7%), 302 (Mꢀ1, 20.6), 301 (Mꢀ, 100). Anal. Calcd for
mp 278—280 °C (EtOH); IR cmꢁ1: 1694, 1634, 1576; 1H-NMR (DMSO-d6)
4-(4-Isopropylphenyl)-1-methyl-1H-indeno[1,2-b]pyridine-2,5-dione
d: 8.05 (1H, dd, Jꢂ7.7, 1.1), 7.75 (1H, td, Jꢂ7.5, 1.4), 7.69—7.64 (3H, m), (11c): mp 140—142 °C (CH2Cl2/PE); IR cmꢁ1: 1716, 1698, 1656; 1H-NMR
7.52 (1H, dd, Jꢂ7.5, 1.0), 7.32 (2H, d, Jꢂ8.3), 6.71 (1H, d, Jꢂ2.0), 6.36 d: 7.76 (1H, d, Jꢂ6.9), 7.66 (1H, dd, Jꢂ6.6, 1.6), 7.57—7.45 (4H, m), 7.33
(1H, d, Jꢂ2.0), 3.09 (3H, s), 2.94—2.90 (1H, m), 1.20 (6H, d, Jꢂ6.9); MS
m/z: 349 (Mꢀ2, 3.7%), 348 (Mꢀ1, 24.7), 347 (Mꢀ, 100). Anal. Calcd for
C22H21NO3: C, 76.06; H, 6.09; N, 4.03. Found: C, 76.10; H, 6.03; N, 4.02.
(2H, d, Jꢂ8.1), 6.44 (1H, s), 4.06 (3H, s), 2.99 (1H, m), 1.32 (6H, d, Jꢂ6.9);
MS m/z: 331 (Mꢀ2, 2.8%), 330 (Mꢀ1, 22.1), 329 (Mꢀ, 100). Anal. Calcd
for C22H19NO2: C, 80.22; H, 5.81; N, 4.25. Found: C, 80.08; H, 5.90; N,
2-[1-Methyl-4-(4-fluorophenyl)-2-pyridon-6-yl]benzoic Acid (10d): mp 4.30.
1
164—166 °C (EtOH); IR cmꢁ1: 1704, 1636, 1551; H-NMR (DMSO-d6) d:
4-(4-Fluorophenyl)-1-methyl-1H-indeno[1,2-b]pyridine-2,5-dione (11d):
8.06 (1H, d, Jꢂ7.5), 7.84—7.79 (2H, m), 7.74 (1H, d, Jꢂ7.3), 7.66 (1H, t, mp 202—204 °C (CH2Cl2/PE); IR cmꢁ1: 1708, 1659; 1H-NMR d: 7.77 (1H,
Jꢂ6.8), 7.53 (1H, d, Jꢂ7.3), 7.28 (2H, t, Jꢂ8.8), 6.73 (1H, d, Jꢂ1.8), 6.39 d, Jꢂ6.9), 7.66 (1H, dd, Jꢂ6.8, 1.4), 7.55—7.48 (4H, m), 7.15 (2H, t,
(1H, d, Jꢂ1.9), 3.09 (3H, s); MS m/z: 325 (Mꢀ2, 3.9%), 324 (Mꢀ1, 18.5), Jꢂ8.6), 6.39 (1H, s), 4.05 (3H, s); MS m/z: 307 (Mꢀ2, 2.3%), 305 (Mꢀ,
323 (Mꢀ, 100). Anal. Calcd for C19H14FNO3: C, 70.58; H, 4.36; N, 4.33. 100). Anal. Calcd for C19H12FNO2: C, 74.75; H, 3.96; N, 4.59. Found: C,
Found: C, 70.51; H, 4.40; N, 4.32.
74.75; H, 4.02; N, 4.58.
2-[1-Methyl-4-(4-chlorophenyl)-2-pyridon-6-yl]benzoic Acid (10e): mp
4-(4-Chlorophenyl)-1-methyl-1H-indeno[1,2-b]pyridine-2,5-dione (11e):
1
250—251 °C (EtOH); IR cmꢁ1: 1701, 1635, 1575; H-NMR (DMSO-d6) d: mp 220—222 °C (CH2Cl2/PE); IR cmꢁ1: 1712, 1679, 1664; 1H-NMR d:
8.06 (1H, dd, Jꢂ7.7, 1.3), 7.80—7.73 (3H, m), 7.69—7.64 (1H, m), 7.54— 7.78 (1H, d, Jꢂ6.9), 7.67 (1H, d, Jꢂ6.9), 7.58—7.51 (2H, m), 7.48—7.41
7.49 (3H, m), 6.75 (1H, d, Jꢂ2.0), 6.40 (1H, d, Jꢂ2.0), 3.09 (3H, s); MS
m/z: 341 (Mꢀ2, 15.3%), 340 (Mꢀ1, 20.7), 339 (Mꢀ, 68.7), 294 (100). Anal.
(4H, m), 6.38 (1H, s), 4.06 (3H, s); MS m/z: 324 (Mꢀ3, 6.4%), 323 (Mꢀ2,
34.7), 322 (Mꢀ1, 27.9), 321 (Mꢀ, 100). Anal. Calcd for C19H12ClNO2: C,
Calcd for C19H14ClNO3: C, 67.16; H, 4.15; N, 4.12. Found: C, 67.00; H, 70.92; H, 3.76; N, 4.35. Found: C, 70.92; H, 3.81; N, 4.33.
4.21; N, 4.09.
4-(2-Chlorophenyl)-1-methyl-1H-indeno[1,2-b]pyridine-2,5-dione (11f):
2-[1-Methyl-4-(2-chlorophenyl)-2-pyridon-6-yl]benzoic Acid (10f): mp
mp 194—196 °C (CH2Cl2/PE); IR cmꢁ1: 1704, 1677, 1660; 1H-NMR d:
304—306 °C (EtOH); IR cmꢁ1: 1711, 1640, 1574; H-NMR (DMSO-d6) d: 7.76 (1H, d, Jꢂ7.1), 7.61 (1H, dd, Jꢂ6.9, 0.5), 7.53—7.46 (3H, m), 7.42—
1
8.03 (1H, d, Jꢂ7.5), 7.74 (1H, t, Jꢂ7.5), 7.65 (1H, t, Jꢂ7.6), 7.57—7.51 7.35 (2H, m), 7.28—7.25 (1H, m), 6.35 (1H, s), 4.06 (3H, s); MS m/z: 324
(2H, m), 7.44—7.42 (3H, m), 6.45 (1H, s), 6.06 (1H, s), 3.12 (3H, s); MS
m/z: 340 (Mꢀ1, 1.6%), 339 (Mꢀ, 2.8), 43 (100). Anal. Calcd for Anal. Calcd for C19H12ClNO2: C, 70.92; H, 3.76; N, 4.35. Found: C, 70.92;
(Mꢀ3, 0.7%), 323 (Mꢀ2, 2.3), 322 (Mꢀ1, 1.5), 321 (Mꢀ, 7.6), 286 (100).
C19H14ClNO3: C, 67.16; H, 4.15; N, 4.12. Found: C, 67.37; H, 4.36; N, 4.06.
H, 3.84; N, 4.31.
2-[1-Methyl-4-(4-methoxylphenyl)-2-pyridon-6-yl]benzoic Acid (10g):
4-(4-Methoxylphenyl)-1-methyl-1H-indeno[1,2-b]pyridine-2,5-dione
mp 218—220 °C (EtOH); IR cmꢁ1: 1697, 1634, 1608; 1H-NMR (DMSO-d6) (11g): mp 118—120 °C (CH2Cl2/PE); IR cmꢁ1: 1718, 1650, 1628, 1611; 1H-
d: 8.05 (1H, d, Jꢂ7.6), 7.77—7.63 (4H, m), 7.52 (1H, d, Jꢂ7.4), 6.99 (2H, NMR d: 7.76 (1H, d, Jꢂ7.2), 7.66 (1H, dd, Jꢂ6.7, 1.1), 7.56—7.46 (4H,
d, Jꢂ8.5), 6.68 (1H, d, Jꢂ1.4), 6.36 (1H, d, Jꢂ1.4), 3.79 (3H, s), 3.08 (3H, m), 6.99 (2H, d, Jꢂ8.7), 6.40 (1H, s), 4.05 (3H, s), 3.88 (3H, s); 13C-NMR
s); MS m/z: 337 (Mꢀ2, 3.2%), 336 (Mꢀ1, 20.4), 335 (Mꢀ, 100). Anal.
Calcd for C20H17NO4: C, 71.63; H, 5.11; N, 4.18. Found: C, 71.66; H, 5.17; 128.6, 124.2, 123.7, 115.1, 113.7, 55.7, 32.6; MS m/z: 319 (Mꢀ2, 3.3%),
d: 188.0, 163.5, 161.1, 160.9, 150.7, 136.9, 135.7, 133.7, 132.3, 130.5,
N, 4.13.
2-[1-Methyl-4-(3-methoxylphenyl)-2-pyridon-6-yl]benzoic Acid (10h):
mp 261—262 °C (EtOH); IR cmꢁ1: 1705, 1637, 1572; 1H-NMR (DMSO-d6)
318 (Mꢀ1, 23.3), 317 (Mꢀ, 100). Anal. Calcd for C20H15NO3: C, 75.70; H,
4.76; N, 4.41. Found: C, 75.69; H, 4.69; N, 4.39.
4-(3-Methoxylphenyl)-1-methyl-1H-indeno[1,2-b]pyridine-2,5-dione
d: 8.05 (1H, d, Jꢂ7.7), 7.75 (1H, t, Jꢂ7.4) 7.66 (1H, t, Jꢂ7.6), 7.53 (1H, d, (11h): mp 168—170 °C (CH2Cl2/PE); IR cmꢁ1: 1709, 1664, 1604; 1H-NMR
Jꢂ7.5), 7.37 (1H, t, Jꢂ7.8), 7.28 (1H, d, Jꢂ7.9), 7.24 (1H, m), 7.02—6.99 d: 7.77 (1H, d, Jꢂ6.8), 7.66 (1H, dd, Jꢂ6.6, 1.5), 7.58—7.47 (2H, m), 7.38
(1H, m), 6.74 (1H, d, Jꢂ2.0), 6.40 (1H, d, Jꢂ2.0), 3.81 (s, 3H), 3.09 (s, 3H); (1H, t, Jꢂ7.8), 7.06—7.00 (3H, m), 6.46 (1H, s), 4.07 (3H, s), 3.87 (3H, s);
MS m/z: 336 (Mꢀ1, 24.6%), 335 (Mꢀ, 67.9), 44 (100). Anal. Calcd for
C20H17NO4: C, 71.63; H, 5.11; N, 4.18. Found: C, 71.63; H, 5.17; N, 4.10.
2-[1-Methyl-4-(2-furyl)-2-pyridon-6-yl]benzoic Acid (10i): mp 230—
MS m/z: 319 (Mꢀ2, 4.2%), 318 (Mꢀ1, 21.3), 317 (Mꢀ, 100). Anal. Calcd
for C20H15NO3: C, 75.70; H, 4.76; N, 4.41. Found: C, 75.78; H, 4.82; N,
4.33.
1
232 °C (EtOH); IR cmꢁ1: 1706, 1639, 1575; H-NMR (DMSO-d6) d: 8.05
4-(2-Furyl)-1-methyl-1H-indeno[1,2-b]pyridine-2,5-dione
(11i):
mp
(1H, dd, Jꢂ7.6, 1.0), 7.86 (1H, d, Jꢂ1.5), 7.75 (1H, td, Jꢂ7.4, 1.3), 7.66 232—234 °C (CH2Cl2/PE); IR cmꢁ1: 1699, 1647; H-NMR d: 8.10 (1H, d,
1
(1H, td, Jꢂ7.6, 1.3), 7.51 (1H, dd, Jꢂ7.5, 0.9), 7.24 (1H, d, Jꢂ3.4), 6.65— Jꢂ3.5), 7.73 (1H, d, Jꢂ6.9), 7.69 (1H, dd, Jꢂ6.0, 1.3), 7.57 (1H, s), 7.55—
6.63 (2H, m), 6.40 (1H, d, Jꢂ1.9), 3.06 (3H, s); MS m/z: 297 (Mꢀ2, 2.6%),
296 (Mꢀ1, 15.0), 295 (Mꢀ, 79.9), 250 (100). Anal. Calcd for C17H13NO4: C,
69.15; H, 4.44; N, 4.74. Found: C, 69.25; H, 4.30; N, 4.52.
7.46 (2H, m), 6.94 (1H, s), 6.60—6.58 (1H, m), 4.02 (3H, s); MS m/z: 278
(Mꢀ1, 18.2%), 277 (Mꢀ, 100). Anal. Calcd for C17H11NO3: C, 73.64; H,
4.00; N, 5.05. Found: C, 73.74; H, 3.95; N, 5.14.
2-[1-Methyl-4-(2-thienyl)-2-pyridon-6-yl]benzoic Acid (10j): mp 242—
4-(2-Thienyl)-1-methyl-1H-indeno[1,2-b]pyridine-2,5-dione (11j): mp
1
244 °C (EtOH); IR cmꢁ1: 1701, 1635, 1575; H-NMR (DMSO-d6) d: 8.06 178—180 °C (CH2Cl2/PE); IR cmꢁ1: 1703, 1655; 1H-NMR d: 7.89 (1H, dd,
(1H, dd, Jꢂ7.7, 1.1), 7.79—7.64 (4H, m), 7.52 (1H, dd, Jꢂ7.5, 1.1), 7.18— Jꢂ3.7, 0.9), 7.79—7.76 (1H, m), 7.72—7.69 (1H, m), 7.58—7.47 (3H, m),
7.15 (1H, m), 6.64 (1H, d, Jꢂ2.1), 6.39 (1H, d, Jꢂ2.1), 3.06 (3H, s); MS
m/z: 313 (Mꢀ2, 6.2%), 312 (Mꢀ1, 11.8), 311 (Mꢀ, 60.8), 279 (100). Anal.
7.19—7.16 (1H, m), 6.63 (1H, s), 4.05 (3H, s); MS m/z: 295 (Mꢀ2, 5.3%),
294 (Mꢀ1, 19.7), 293 (Mꢀ, 100). Anal. Calcd for C17H11SNO2: C, 69.61; H,
Calcd for C17H13NO3S: C, 65.58; H, 4.21; N, 4.50. Found: C, 65.63; H, 4.20; 3.78; N, 4.77. Found: C, 69.63; H, 3.68; N, 4.78.
N, 4.60.
A General Procedure for the Preparation of 4-Aryl 1-Methyl-1H-in-
Acknowledgment We are grateful to the National Natural Science

January 2005
71
Foundation of China and the Education Ministry of China for financial sup-
port.
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0.106 mmꢁ1, 3041 reflections measured, 2364 unique (Rintꢂ0.1411);
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51) Crystal data of compound 11g: (C20H15NO3)2(CH2Cl2)2, Mꢂ804.51,
Orthorhombic; aꢂ7.412(2) Å, bꢂ21.360(5) Å, cꢂ23.310(7) Å;
Vꢂ3690.4(17) Å3, Tꢂ298(2) K; space group: P212121; Zꢂ4, Absorp-
tion coefficient: 0.374 mmꢁ1, 4164 reflections measured, 3933 unique
(Rintꢂ0.0358); Final
R
indices [Iꢃ2sigma(I)]: R1ꢂ0.0563,
wR2ꢂ0.1482; R indices (all data): Rꢂ0.1983, wR2ꢂ0.1930. Crystallo-
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