Antitumor agents 287. Substituted 4-amino-2H-pyran-2-one (APO) analogs reveal a new scaffold from neo-tanshinlactone with in vitro anticancer activity

Article abstract of DOI:10.1016/j.bmcl.2011.02.084

4-Amino-2H-benzo[h]chromen-2-one (ABO) and 4-amino-7,8,9,10-tetrahydro-2H- benzo[h]chromen-2-one (ATBO) analogs were found to be significant in vitro anticancer agents in our previous research. Our continuing study has now discovered a new simplified (monocyclic rather than tricyclic) class of cytotoxic agents, 4-amino-2H-pyran-2-one (APO) analogs. By incorporating various substituents on the pyranone ring, we have established preliminary structure-activity relationships (SAR). Analogs 19, 20, 23, and 26-30 displayed significant tumor cell growth inhibitory activity in vitro. The most active compound 27 exhibited ED₅₀ values of 0.059-0.090 μM.

Full text of DOI:10.1016/j.bmcl.2011.02.084

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2341–2344
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Antitumor agents 287. Substituted 4-amino-2H-pyran-2-one (APO) analogs
reveal a new scaffold from neo-tanshinlactone with in vitro anticancer activity
Yizhou Dong a, Kyoko Nakagawa-Goto a, Chin-Yu Lai a, Susan L. Morris-Natschke a,
Kenneth F. Bastow b, Kuo-Hsiung Lee a,c,
⇑
a Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA
b Division of Medicinal Chemistry and Natural Products, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA
c Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Amino-2H-benzo[h]chromen-2-one (ABO) and 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-
one (ATBO) analogs were found to be significant in vitro anticancer agents in our previous research.
Our continuing study has now discovered a new simplified (monocyclic rather than tricyclic) class of
cytotoxic agents, 4-amino-2H-pyran-2-one (APO) analogs. By incorporating various substituents on the
pyranone ring, we have established preliminary structure–activity relationships (SAR). Analogs 19, 20,
23, and 26–30 displayed significant tumor cell growth inhibitory activity in vitro. The most active com-
Received 9 December 2010
Revised 18 February 2011
Accepted 22 February 2011
Available online 21 March 2011
Keywords:
pound 27 exhibited ED50 values of 0.059–0.090 lM.
4-Amino-2H-pyran-2-one (APO) analogs
Neo-tanshinlactone
Cytotoxicity
Ó 2011 Elsevier Ltd. All rights reserved.
In 2004, our group first isolated and synthesized neo-tanshin-
lactone (1).1 Compound 1 was 10-fold more potent and 20-fold
more selective as compared with tamoxifen citrate against the
ER+ human breast cancer cell lines MCF-7 and ZR-75-1. Further
structural optimization led to its 4-ethyl analog 2, which displayed
significant and selective anti-breast cancer activity both in vitro
and in vivo.2,3 Moreover, 2 was selective for a subset of breast can-
cer-derived cell lines and significantly less active against normal
breast-derived tissue. In order to explore the effect of individual
rings on the anticancer activity, identify new lead compounds,
and discover new chemical entities, we designed and reported five
classes of new anticancer agents, including 2-(furan-2-yl) naphtha-
len-1-ol (FNO),4 6-phenyl-4H-furo[3,2-c]pyran-4-one (AFPO),5
tetrahydronaphthalene-1-ol (TNO),6 4-amino-2H-benzo[h]chro-
men-2-one (ABO, 3, Fig. 1),7 and 4-amino-7,8,9,10-tetrahydro-2H-
benzo[h]chromen-2-one (ATBO, 4, Fig. 1)8 analogs. Interestingly,
the neo-tanshinlactone-inspired synthesis of a breast cancer selec-
tive ABO series was reported independently by others.9
Importantly, ABO and ATBO compounds displayed much higher
potency than 1-analogs, which encouraged us to further investi-
gate these scaffolds. Structure–activity relationship (SAR) studies
on 3 and 4 indicated that (1) a secondary amine (R2 or R3 = H) is
preferred over tertiary amine (R2 and R3 – H), (2) bulky groups
are favored at the R2/R3 position, (3) a 30-bromophenyl group can
cause a dramatic loss of potency, and (4) a non-aromatic ring-A
can increase potency and cancer cell line selectivity for certain
O
C
O
O
O
O
B
O
B
O
B
C
C
D
O
4
2
4
NR2R3
NR2R3
O
n
A
A
A
4
R'
6
R
R1
7
4
R1
R
ABO (3): R1, R2= H,
APO (5)
ATBO (4)
R = Me: Neo-tanshinlatone (1)
R = Et: 4-Ethyl neo-tanshinlatone ( )
R3= 4-OMePh
2
Figure 1. Structures of neo-tanshinlactone (1), 4-ethyl neo-tanshinlactone (2), previously reported ABO (3) and ATBO (4) scaffolds, and newly designed APO scaffold (5).
⇑
Corresponding author. Tel.: +1 919 962 0066; fax: +1 919 966 3893.
E-mail address: khlee@unc.edu (K.-H. Lee).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.02.084

2342
Y. Dong et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2341–2344
Table 1
analogs. Our studies also indicated that the lactone ring-C is critical
to the cytotoxic activity.3,7,8 Therefore, we designed a structurally
simplified monocyclic scaffold (5, Fig. 1) and incorporated various
substituents at the R and R0 positions to explore the contributions
of ring-A and -B, develop new chemical entities and new leads, and
establish the SAR. Herein, we report the design, synthesis, and bio-
logical activity of 4-amino-2H-pyran-2-one (APO) analogs.
As a first step in the current work, we designed two model com-
pounds 12 and 13 by eliminating the fused ring-A/B system and
incorporating pendant phenyl and styryl groups, respectively, on
the remaining pyranone C-ring. 6-Substituted 4-hydroxy-2H-pyr-
an-2-one 10 was synthesized according to the method reported
by Bach and Kirsch.10 The appropriate aldehyde (6) and an acetoac-
etate equivalent (7) underwent a vinylogous Mukaiyama aldol
addition to give 8, which was oxidized to 9 using the Dess–Martin
method. A thermal cyclization of 9 yielded 4-hydroxy-2H-pyra-
none 10. Chlorination followed by amination of 10 provided model
compounds 12 and 13.7,11
Cytotoxicity of 12–30 against human tumor cell line panel
a
Compd
ED50
(l
M)
KB
KB-VIN
A549
DU145
SKBR-3
3
0.11
9.69
1.25
>30
0.13
9.15
1.24
>30
0.17
16.02
2.02
>30
0.11
7.47
1.23
>30
0.13
10.91
1.53
>30
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
>30
>30
>30
>30
>30
4.42
5.42
4.62
0.093
0.11
1.62
1.91
0.15
>30
4.84
4.98
4.39
0.098
0.10
1.30
1.46
0.13
>30
10.06
8.38
8.32
0.16
0.15
2.42
2.66
0.18
>30
5.94
5.42
8.61
0.12
0.11
1.60
1.95
0.15
>30
4.93
4.73
5.29
0.079
0.083
1.34
1.76
0.13
>30
>30
>30
>30
>30
>30
0.12
0.067
0.31
0.44
0.63
0.15
0.059
0.24
0.49
0.55
0.13
0.064
0.32
0.35
0.49
0.098
0.073
0.34
0.37
0.66
0.13
0.090
0.40
0.54
0.74
Analogs 12 and 13 were tested for in vitro cytotoxic
activity against a panel of human tumor cell lines according to pre-
viously published methods (Table 1).3 Cell lines included A549
(non-small cell lung cancer), DU145 (prostate cancer cell line),
a
Mean from three or more independent tests.
O
O
O
O
N
H
N
H
13
12
O
O
O
O
O
O
a
OH
O
O
b
rt
+
R
H
O
OTMS
d
R
O
R
O
8
9
7
6
O
O
O
c
e or f
O
O
O
R
OH
R
Cl
R
R'
10
11
12-30
R= Me
R'=
HN
17
16
18
15
14
OMe
O
22
21
23
20
19
R'=
HN
HN
Me
N
HN
R=
27
26
25
24
28
HN
HN
HN
Br
MeO
29
OMe
30
Scheme 1. Reagents and conditions: (a) TiCl4, CH2Cl2, ꢀ78 °C; (b) Dess–Martin reagent, rt; (c) toluene, reflux; (d) POCl3, Et3N, reflux, 1 h; (e) aliphatic amines, EtOH, reflux,
2 h; (f) aromatic amines, ethylene glycol, 160 °C, 1 h.

Y. Dong et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2341–2344
2343
KB (nasopharyngeal carcinoma), and KB-VIN (vincristine-resistant
Supplementary data
MDR KB subline), SK-BR-3 (estrogen receptor negative, HER2
over-expressing breast cancer). Importantly, 13 showed significant
inhibition of all human cancer cell lines tested with ED50 values
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.02.084.
from 1.23 to 2.02 lM, while 12 displayed moderate activity.
Encouraged by these promising results, analogs 14–30 were de-
signed to establish SAR correlations as well as to optimize struc-
ture and identify more active derivatives with the desired
biological properties11. Firstly, we installed various groups at the
pyranone 6-position (R group) to explore the effect of group size,
ring size, and aromaticity. Secondly, different substituents at the
pyranone 4-position (R0 group) were investigated while retaining
the best R group. As shown in Scheme 1, new analogs 14–30 were
obtained through the five-step procedure similarly to 12 and 13,
and then evaluated against five human tumor cell lines from differ-
ent tissues.
Compounds 14 and 15 with methyl and isopropyl R groups
were not active, and 16–18 with pentyl, cyclopentyl, and cyclo-
hexyl groups showed moderate activity. These results suggested
that long alkyl chains and cyclic alkyl groups were favored at the
pyranone 6-position. Compounds 19–23, which contain different
aromatic R groups, including phenyl, styryl, benzyl, furanyl, and
naphthyl, displayed significant activity. Especially, 19 and 20 with
phenyl and styryl groups, respectively, were the most potent ana-
References and notes
1. Wang, X.; Bastow, K. F.; Sun, C. M.; Lin, Y. L.; Yu, H. J.; Don, M. J.; Wu, T. S.;
Nakamura, S.; Lee, K. H. J. Med. Chem. 2004, 47, 5816.
2. Wang, X.; Nakagawa-Goto, K.; Bastow, K. F.; Don, M. J.; Lin, Y. L.; Wu, T. S.; Lee,
K. H. J. Med. Chem. 2006, 49, 5631.
3. Dong, Y.; Shi, Q.; Pai, H. C.; Peng, C. Y.; Pan, S. L.; Teng, C. M.; Nakagawa-Goto,
K.; Yu, D.; Liu, Y. N.; Wu, P. C.; Bastow, K. F.; Morris-Natschke, S. L.; Brossi, A.;
Lang, J. Y.; Hsu, J. L.; Hung, M. C.; Lee, E. Y.; Lee, K. H. J. Med. Chem. 2010, 53,
2299.
4. Dong, Y.; Shi, Q.; Liu, Y.-N.; Wang, X.; Bastow, K. F.; Lee, K.-H. J. Med. Chem.
2009, 52, 3586.
5. Dong, Y.; Shi, Q.; Nakagawa-Goto, K.; Wu, P. C.; Morris-Natschke, S. L.; Brossi,
A.; Bastow, K. F.; Lang, J. Y.; Hung, M. C.; Lee, K. H. Bioorg. Med. Chem. 2010, 8,
803.
6. Dong, Y.; Shi, Q.; Nakagawa-Goto, K.; Wu, P. C.; Bastow, K. F.; Morris-Natschke,
S. L.; Lee, K. H. Bioorg. Med. Chem. Lett. 2009, 19, 6289.
7. Dong, Y.; Nakagawa-Goto, K.; Lai, C. Y.; Morris-Natschke, S. L.; Bastow, K. F.;
Lee, K. H. Bioorg. Med. Chem. Lett. 2010, 20, 4085.
8. Dong, Y.; Nakagawa-Goto, K.; Lai, C. Y.; Morris-Natschke, S. L.; Bastow, K. F.;
Lee, K. H. Bioorg. Med. Chem. Lett. 2011, 21, 545.
9. Sashidhara, K. V.; Rosaiah, J. N.; Kumar, M.; Gara, R. K.; Nayak, L. V.; Srivastava,
K.; Bid, H. K.; Konwar, R. Bioorg. Med. Chem. Lett. 2010, 20, 7127.
10. Bach, T.; Kirsch, S. Synlett 2001, 1974–1976.
11. Spectroscopic data: 4-(Cyclohexylamino)-6-phenyl-2H-pyran-2-one (12): 1H
NMR (400 MHz, DMSO-d6): d 7.75 (m, 2H, Ar-H), 7.39 (m, 3H, Ar-H), 6.21 (d,
1H, J = 2.0 Hz,), 5.11 (d, 1H, J = 1.6 Hz, 3-H), 4.94 (d, 1H, J = 7.2 Hz, NH), 3.29 (m,
1H, NCH), 2.05 (m, 2H, NCHCH2), 1.78 (m, 2H, NCHCH2), 1.26 (m, 6H,
cyclohexyl-H). MS m/z 270 (M++1). (E)-4-(Cyclohexylamino)-6-styryl-2H-
pyran-2-one (13): 1H NMR (400 MHz, DMSO-d6): d 7.47 (m, 3H, Ar & olefin-
H), 7.32 (m, 3H, Ar-H), 6.53 (d, 1H, J = 13.6 Hz, olefin-H), 5.71 (s, 1H, 3-H), 5.08
(d, 1H, J = 1.6 Hz,), 4.73 (d, 1H, J = 7.2 Hz, NH), 3.27 (m, 1H, NCH), 2.05 (m, 2H,
NCHCH2), 1.78 (m, 2H, NCHCH2), 1.26 (m, 6H, cyclohexyl-H). MS m/z 296
(M++1). 4-[(4-Methoxyphenyl)amino]-6-methyl-2H-pyran-2-one (14): 1H NMR
(400 MHz, CD3OD): d 7.14 (d, 2H, J = 8.8 Hz, Ar-H), 6.97 (d, 2H, J = 8.8 Hz, Ar-H),
5.97 (d, 1H, J = 2.0 Hz, 5-H), 5.14 (d, 1H, J = 1.6 Hz, 3-H), 3.82 (s, 1H, 40-OCH3),
2.20 (d, 3H, J = 0.8 Hz, 6-CH3). MS m/z 230 (M+ꢀ1). 6-Isopropyl-4-[(4-
logs with ED50 values of 0.079–0.163 lM, and were equally or
slightly more potent than ABO analog 3. The results indicated that
an aromatic ring at the pyranone 6-position may be critical to the
cytotoxic activity.
Based on structural simplicity and chemical availability as well
as the above results, we designed analogs 24–30, which have var-
ious substituents at the pyranone 4-position and a phenyl group
fixed at the 6-position. Among them, 26–30 with substituted ani-
line groups displayed significant activity against all tested tumor
cell lines compared with analogs containing cycloalkyl groups,
including cyclohexylamine (12), cyclopropylamine (24), and piper-
idine (25). The latter two compounds totally lost cytotoxic activity.
These data indicate that an aromatic amino R0 group is favored at
the 4-position. In addition, the position and type of substituent
on the aniline ring played an important role in the cytotoxic activ-
ity. The rank order of potency for all aromatic analogs against KB
was 27 (40-Me) > 19 (40-OMe) > 26 (H) > 28 (40-Br) ꢁ 29 (20-
OMe) ꢁ 30 (30-OMe). 4-Methylaniline-substituted 27 was the most
methoxyphenyl)amino]-2H-pyran-2-one (15): 1H NMR (400 MHz, CD3OD):
d
7.15 (d, 2H, J = 8.8 Hz, Ar-H), 6.97 (d, 2H, J = 8.8 Hz, Ar-H), 5.97 (d, 1H, J = 2.0 Hz,
5-H), 5.15 (d, 1H, J = 1.6 Hz, 3-H), 3.81 (d, 3H, J = 1.2 Hz, 40-OCH3), 2.72 (h, 1H,
J = 6.8 Hz, isopropyl-H), 1.24 (d, 6H, J = 6.8 Hz, isopropyl-H). MS m/z 258
(M+ꢀ1). 4-[(4-Methoxyphenyl)amino]-6-pentyl-2H-pyran-2-one (16): 1H NMR
(400 MHz, CD3OD): d 7.15 (d, 2H, J = 9.2 Hz, Ar-H), 6.97 (d, 2H, J = 8.8 Hz, Ar-H),
5.97 (d, 1H, J = 2.4 Hz, 5-H), 5.15 (d, 1H, J = 2.4 Hz, 3-H), 3.81 (s, 3H, 40-OCH3),
2.46 (t, 2H, J = 7.6 Hz, pentyl-H), 1.66 (p, 2H, J = 7.6 Hz, pentyl-H), 1.34–1.38 (m,
4H, pentyl-H), 0.93 (t, 3H, J = 7.2 Hz, pentyl-H). MS m/z 286 (M+ꢀ1). 6-
Cyclopentyl-4-[(4-methoxyphenyl)amino]-2H-pyran-2-one (17): 1H NMR
(400 MHz, CD3OD): d 7.14 (d, 2H, J = 8.8 Hz, Ar-H), 6.97 (d, 2H, J = 8.8 Hz, Ar-
H), 5.99 (d, 1H, J = 2.4 Hz, 5-H), 5.14 (d, 1H, J = 2.0 Hz, 3-H), 3.81 (s, 3H, 40-
OCH3), 2.40 (m, 1H, cyclopentyl-H), 2.89 (p, 1H, J = 8.0 Hz, cyclopentyl-H),
1.96–2.01 (m, 2H, cyclopentyl-H), 1.66–1.82 (m, 6H, cyclopentyl-H). MS m/z
284 (M+ꢀ1). 6-Cyclohexyl-4-[(4-methoxyphenyl)amino]-2H-pyran-2-one (18):
1H NMR (400 MHz, CD3OD): d 7.14 (d, 2H, J = 8.8 Hz, Ar-H), 6.97 (d, 2H,
J = 8.8 Hz, Ar-H), 5.95 (s, 1H, 5-H), 5.15 (s, 1H, 3-H), 3.81 (s, 1H, 40-OCH3), 2.40
(m, 1H, cyclohexyl-H), 1.72–1.94 (m, 5H, cyclohexyl-H), 1.25–1.47 (m, 5H,
cyclohexyl-H). MS m/z 298 (M+ꢀ1). 4-[(4-Methoxyphenyl)amino]-6-phenyl-2H-
pyran-2-one (19): 1H NMR (400 MHz, CDCl3): d 7.82–7.85 m, 2H, Ar-H, 7.48–
7.51 m, 3H, Ar-H, 7.20 (d, 2H, J = 8.8 Hz, Ar-H), 7.00 (d, 2H, J = 8.8 Hz, Ar-H),
6.66 (d, 1H, J = 2.0 Hz,5-H), 5.29 (d, 1H, J = 2.0 Hz, 3-H), 3.83 (s, 3H, 40-OCH3).
MS m/z 292 (M+ꢀ1). (E)-4-[(4-Methoxyphenyl)amino]-6-styryl-2H-pyran-2-one
(20): 1H NMR (400 MHz, CD3OD): d 7.60 d, 2H, J = 7.2 Hz, Ar-H, 7.33ꢀ7.44 m,
4Y, Ar & olefin-H, 7.17–7.20 (m, 2H, Ar-H), 6.98–7.00 (m, 2H, Ar-H), 6.85 (d, 1H,
J = 16.0 Hz, olefin-H), 6.20 (d, 1H, J = 2.0 Hz, 5-H), 5.25 (d, 1H, J = 1.6 Hz, 3-H),
3.82 (s, 1H, 40-OCH3). MS m/z 318 (M+ꢀ1). 6-Benzyl-4-[(4-methoxyphenyl)-
amino]-2H-pyran-2-one (21): 1H NMR (400 MHz, CD3OD): d 7.30–7.36 m, 5H,
Ar-H, 7.11 (d, 2H, J = 8.8 Hz, Ar-H), 6.95 (d, 2H, J = 9.2 Hz, Ar-H), 5.89 (s, 1H, 5-
H), 5.14 (d, 1H, J = 1.6 Hz, 3-H), 3.80 (s, 3H, 40-OCH3), 3.79 (s, 2H, 6-CH2). MS m/
potent analog with ED50 values of 0.059–0.090 lM. It was about
twofold more potent than ABO analog 3.
Overall, 19 and 27 showed greater in vitro antitumor activity
than other analogs, suggesting that the combination of a phenyl
group at the 6-position and a 40-methyl- or 40-methoxy-aniline at
the 4-position is favored for the APO analogs.
In summary, we designed and developed a new class (APO) of
in vitro anticancer agents, through structural simplification and
optimization. Lead compounds displayed potent antitumor activity
with ED50 values in the low micromolar range. SAR studies
indicated that: (1) an aromatic ring such as phenyl and styryl at
the pyranone 6-position is critical to the antitumor activity, (2) a
secondary amine at the 4-position is preferred over a tertiary
amine, (3) aromatic amine groups at the 4-position are crucial,
and (4) substituents on the aromatic amine group can increase
potency. Compounds 19 and 27 were the most potent analogs
z
306 (M+ꢀ1). 6-(Furan-2-yl)-4-[(4-methoxyphenyl)amino]-2H-pyran-2-one
(22): 1H NMR (400 MHz, CDCl3): d 7.68 s, 1H, Ar-H), 7.18 (d, 2H, J = 8.8 Hz,
Ar-H), 6.98–7.00 (m, 3H, Ar-H), 6.61–6.63 (m, 1H, Ar-H), 6.49 (d, 1H, J = 1.6 Hz,
5-H), 5.22 (d, 1H, J = 2.0 Hz, 3-H), 3.82 (s, 3H, 40-OCH3). MS m/z 282 (M+ꢀ1). 4-
[(4-Methoxyphenyl)amino]-6-(naphthalen-2-yl)-2H-pyran-2-one (23): 1H NMR
(400 MHz, CD3OD): d 8.42 s, 1H, Ar-H, 7.86–7.99 m, 4H, Ar-H, 7.57–5.59 m, 2Y,
Ar-H, 7.23 (d, 2H, J = 8.8 Hz, Ar-H), 7.02 (d, 2H, J = 9.2 Hz, Ar-H), 6.81 (d, 1H,
J = 2.0 Hz,5-H), 5.33 (d, 1H, J = 2.0 Hz, 3-H), 3.84 (s, 3H, 40-OCH3). MS m/z 342
(M+ꢀ1). 4-(Cyclopropylamino)-6-phenyl-2H-pyran-2-one (24): 1H NMR
(400 MHz, CD3OD): d 7.80 m, 2H, Ar-H, 7.46 m, 3H, Ar-H, 6.46 (s, 1H, 5-H),
5.41 (s, 1H, 3-H), 2.52 (s, 1H, 10-H), 0.85 (d, 2H, J = 6.4 Hz, 20 & 30-H), 0.58 (m,
2H, 20 & 30-H). MS m/z 226 (M+ꢀ1). 6-Phenyl-4-(piperidin-1-yl)-2H-pyran-2-one
(ED50 values of 0.059–0.163 lM) among all derivatives, and thus,
are new lead compounds that are promising for further
development of potential clinical trials candidates.
Acknowledgment
This work was supported by NIH Grant CA-17625 from the
National Cancer Institute, awarded to K.H. Lee.

2344
Y. Dong et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2341–2344
(25) 1H NMR (400 MHz, CD3OD): d 7.89–7.92 m, 2H, Ar-H, 7.47–7.49 m, 3H, Ar-
1H, J = 8.4 Hz, Ar-H), 7.50–7.52 m, 3H, Ar-H, 7.23 (d, 1H, J = 8.8 Hz, Ar-H), 6.70
(d, 1H, J = 2.0 Hz, 5-H), 5.50 (d, 1H, J = 2.0 Hz, 3-H). MS m/z 340 (M+ꢀ1). 4-[(2-
Methoxyphenyl)amino]-6-phenyl-2H-pyran-2-one (29): 1H NMR (400 MHz,
H, 6.92 (d, 1H, J = 1.6 Hz, 5-H), 5.28 (d, 1H, J = 2.0 Hz, 3-H), 3.57 (t, 4H, J = 4.8 Hz,
20 & 60-H), 1.68–1.75 (m, 6H, 30, 40, & 50-H). MS m/z (M+ꢀ1). 6-Phenyl-4-
(phenylamino)-2H-pyran-2-one (26): 1H NMR (400 MHz, DMSO-d6): d 9.42 s,
1H, NH), 7.76–7.78 m, 2H, Ar-H, 7.53–7.56 m, 3H, Ar-H, 7.44 (t, 2H, J = 7.6 Hz,
Ar-H), 7.28 (d, 2H, J = 8.4 Hz, Ar-H), 7.21 (t, 1H, J = 7.2 Hz, Ar-H), 6.70 (d, 1H,
J = 1.6 Hz, 5-H), 5.34 (t, 1H, J = 1.2 Hz, 3-H). MS m/z 262 (M+ꢀ1). 6-Phenyl-4-(p-
tolylamino)-2H-pyran-2-one (27): 1H NMR (400 MHz, CD3OD): d 7.83–7.86 m,
2H, Ar-H, 7.50–7.52 m, 3H, Ar-H, 7.26 (d, 2H, J = 8.4 Hz, Ar-H), 7.17 (d, 2H,
J = 8.4 Hz, Ar-H), 6.69 (d, 1H, J = 2.0 Hz, 5-H), 5.41 (d, 1H, J = 2.0 Hz, 3-H), 2.37
(s, 3H, CH3). MS m/z 276 (M+ꢀ1). 4-[(4-Bromophenyl)amino]-6-phenyl-2H-
pyran-2-one (28): 1H NMR (400 MHz, CD3OD): d 7.84–7.87 m, 2H, Ar-H, 7.59 (d,
CD3OD):
d 7.83–7.86 m, 2H, Ar-H, 7.50–7.52 m, 3H, Ar-H, 7.34 (t, 1H,
J = 8.0 Hz, Ar-H), 6.81–6.89 (m, 3H, Ar-H), 6.71 (d, 1H, J = 2.0 Hz, 5-H), 5.53
(d, 1H, J = 2.0 Hz, 3-H), 3.82 (s, 3H, 40-OCH3). MS m/z 292 (M+ꢀ1). 4-[(3-
Methoxyphenyl)amino]-6-phenyl-2H-pyran-2-one (30): 1H NMR (400 MHz,
CD3OD):
d 7.83–7.86 m, 2H, Ar-H, 7.50–7.52 m, 3H, Ar-H, 7.34 (t, 1H,
J = 8.0 Hz, Ar-H), 6.81–6.89 (m, 3H, Ar-H), 6.71 (d, 1H, J = 2.0 Hz,5-H), 5.53 (d,
1H, J = 2.0 Hz, 3-H), 3.82 (s, 3H, 40-OCH3). MS m/z 292 (M+ꢀ1).