Re-cyclization of 3-(E)-methyl 3-(4-oxo-4H-chromen-3-yl)acrylate with amines and their potential mechanism

Article abstract of DOI:10.1016/j.tet.2013.08.032

The synthesis of 2-pyridone derivatives from different substituted amines and various 3-(E)-methyl 3-(4-oxo-4H-chromen-3-yl)acrylate derivatives was proposed and described. The optimized reaction conditions and the generality of the reaction were investig

Full text of DOI:10.1016/j.tet.2013.08.032

Tetrahedron 69 (2013) 8839e8846
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Tetrahedron
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Re-cyclization of 3-(E)-methyl 3-(4-oxo-4H-chromen-3-yl)acrylate
with amines and their potential mechanism
*
Yikai Zhang, Zhiliang Lv, Mingfeng Zhang, Ke Li
Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 June 2013
Received in revised form 29 July 2013
Accepted 15 August 2013
Available online 22 August 2013
The synthesis of 2-pyridone derivatives from different substituted amines and various 3-(E)-methyl 3-(4-
oxo-4H-chromen-3-yl)acrylate derivatives was proposed and described. The optimized reaction condi-
tions and the generality of the reaction were investigated, respectively. Moreover, less side products
could be formed than the traditional method. Finally, based on the fact that (E)-methyl 2-(7-methoxy-4-
oxo-3-((phenylamino)methylene)chroman-2-yl)acetate was separated and determined via X-ray single
crystal diffraction, we could propose an interesting and reasonable reaction mechanism for the first time.
The reaction could render this method particularly attractive for the efficient preparation of biologically
and medicinally interesting molecules.
Keywords:
Re-cyclization
Benzopyran-4-one
2-Pyridone
Ó 2013 Elsevier Ltd. All rights reserved.
Mechanism
1. Introduction
2-Pyridone analogues have been widely found in nature and
have a broad range of applications in the medical research.9,16e23
As known to all, the benzopyran-4-one derivatives, also known
as chromone, have shown promising a wide range of valuable
physiological activities.1e3 However, the useful application of
chromone as starting material affording drug-like aromatic com-
pounds was less known.4e9 Among them, 3-formylchromone
(Fig. 1) derivatives are the most attractive substrates, which were
widely used to prepare a variety of heterocyclic compounds.10e13
The chemical structure of 3-formylchromone has been surveyed
previously and the most interesting feature of this molecule is that
it contains three potential sites, which could be attacked by nu-
cleophilic species: the C-4 atom, unsaturated keto function; the C-2
atom, a hidden aldehyde function (Fig. 1), which is very reactive
electrophilic center; the C-10 atom, conjugated second carbonyl
group at C-3. In addition, the nucleophilic reactivity of C-2 and C-10
is similar, whereas, the unsaturated keto function is much
lower.5,10e15
The synthesis of 2-pyridone derivatives from 3-formylchromone
was first proposed by Nohara.24 However, this method had its
own disadvantages, such as low yield, complex products, and in-
complete understanding of the reaction mechanism, largely due to
the similar reactivity of C-2 and C-10 mentioned above.24e29 As
shown in Scheme 1, generally, the reaction involved an initial
Knoevenagel condensation between aldehyde group and simple
nucleophiles (Path A, compound 4). However, 3-formylchromone
could be assumed as the synthetic equivalent of the unknown (2-
hydroxyphenyl)malonic dialdehyde (Fig. 1). Thus, it is often diffi-
cult to tell, which electrophilic center was attacked firstly because
of the ‘chemical symmetry’ of the two centers. Thereby, at the same
time, the Michael addition could also occur at position C-2 and
subsequent opening of the pyrone moiety (Path B, compound
5).10,26 For better understanding of the reaction, we had some al-
teration on the compound 4 to generate compound 6, which could
be easily obtained by Heck reaction.30 There are two reasons for this
change: one is that we kept the basic methyl acrylate side chain at
C-3, which is a necessary moiety for 2-pyridone ring cyclization;
the other is that C-2 now is the most reactive electrophilic center in
this molecule, which is easier and clearer for us to study the next
rearrangement step.
Fig. 1. Chemical structures of 3-formylchromone.
2. Results and discussion
In initial investigations, we examined the rearrangement re-
action of the model substrate (E)-methyl 3-(7-methoxy-4-oxo-4H-
* Corresponding author. Tel.: þ86 21 81871237; e-mail address: proflike@sina.-
com (K. Li).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.032

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Y. Zhang et al. / Tetrahedron 69 (2013) 8839e8846
(Table 1, entry 12). Finally, reaction time was adjusted to 4, 6, and
8 h, respectively. The results showed that 6 h was exactly the best
reaction time for the main product yield (Table 1, entries 14e16).
Thereby, the optimal reaction conditions were using K2CO3
(3.0 equiv) as the base and ethanol (25 mL) as the solvent at reflux
for 6 h.
Under the optimized reaction conditions, the generality of the
reaction was investigated by using substituted (E)-methyl 3-(4-
oxo-4H-chromen-3-yl)acrylate and a variety of substituted amine
to produce re-cyclization derivatives. The results are summarized
in Tables 2 and 3. The findings showed that these reactions led to
production of the corresponding products in moderate to good
yields. Notably, although electron-withdrawing group or electron-
donating groups with amines were applied and the reaction
could be smoothly performed, an electron-donating group was
more favorable than an electron-withdrawing group (Table 2, en-
tries 1e3). Furthermore, the presence of hydroxy group on the
Scheme 1. Design of the compound 6.
Table 2
Synthesis of compounds 9e12a
chromen-3-yl)acrylate (6) with aniline (7), using triethylamine as
base, and methanol as solvent at reflux for 10 h (Table 1, entry 1). A
series of different bases, solvents, temperatures, and reaction time
were screened. As can be seen from Table 1, of the bases screened,
triethylamine, and K2CO3 showed the best results and the corre-
sponding products were obtained in 76% and 80% yield, re-
spectively (Table 1, entries 1 and 8). The results above indicate that
either the inorganic base or the organic base could help to have
a good yield. There were indications that the choice of solvent had
distinct impact. Thereby, solvents, such as methanol, ethanol, ace-
tonitrile, and THF were used, respectively. Considering the nucle-
ophilic reaction, the results reasonably showed that polar protic
solvent, such as ethanol and methanol could drastically boost the
yields of desired compound because of the solvent effect. Moreover,
the higher boiling point made ethanol to be the better selection
(Table 1, entries 8 and 11). Likewise, acetonitrile (strong polar
aprotic solvent) have moderate solvent effect and the correspond-
ing product yield was not satisfactory (Table 1, entry 13). On the
contrary, THF is a moderately polar aprotic solvent and was sup-
posed to be negative for this reaction due to its weak solvent effect
Entry R1
R2
R3
H
R4
Product Yieldb (%)
1
2
H
H
OCH3
9a
9b
91
35
OCH3
H
3
4
H
H
OCH3
OH
H
H
9c
89
66
10a
Table 1
5
H
OH
H
10b
53
Synthesis of compound 8a
6
7
H
H
OH
OH
H
H
10c
10d
55
68
Entry
Solvent
Base
Temp (ꢀC)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
EtOH
THF
MeCN
EtOH
EtOH
Et3N
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
reflux
Reflux
Reflux
Reflux
Reflux
Reflux
10
10
10
10
10
10
10
10
10
10
10
10
10
8
76
71
0
DMAP
Pyridine
NaOH
KOH
8
9
H
H
OH
OH
H
H
10e
10f
69
34
69
75
66
23
80
68
82
86
Trace
73
85
88
58
DBU
KOAc
K2CO3
t-BuOK
EtN3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
9
10
11
12
13
14
15
16
10
11
12
OCH3
OCH3
OCH3
H
H
11a
11b
11c
55
33
62
6
4
EtOH
a
Unless otherwise specified, all reactions were performed with compound 6
(2 mmol), compound 7 (2.4 mmol), and base (6 mmol) in solvent (25 mL) via oil
heating.
H
b
Isolated yield.

Y. Zhang et al. / Tetrahedron 69 (2013) 8839e8846
8841
Table 2 (continued )
Table 3
Synthesis of compounds 14e15a
Entry R1
R2
R3
R4
Product Yieldb (%)
13
14
H
H
OCH3
11d
11e
61
71
Entry
R1
H
R2
Product
Yieldb (%)
OCH3
1
14a
48
15
16
17
H
H
OCH3
OCH3
11f
56
54
2
3
4
H
H
H
14b
14c
14d
47
46
35
11g
H
H
OH
OH
NO2
NO2
12a
12b
42
50
18
a
Unless otherwise specified, all reactions were performed with substituted (E)-
methyl 3-(4-oxo-4H-chromen-3-yl)acrylate (2 mmol), substituted amine
(2.4 mmol), and K2CO3 (6 mmol) in EtOH (25 mL) via oil heating.
5
6
7
H
H
H
14e
14f
14g
45
48
44
b
Isolated yield.
position-7 of the (E)-methyl 3-(4-oxo-4H-chromen-3-yl)acrylate
led to decreased yields (Table 2, entries 4e9) as a consequence of
weak acidic of the phenol. Moreover, when position-6 of the (E)-
methyl 3-(4-oxo-4H-chromen-3-yl)acrylate was substituted with
acetamide, the final yield could also drop to 33e55% (Table 2, en-
tries 10, 11). Likewise, different substituted amide at position-8
would also be unfavorable to the re-cyclization and electronic ef-
fects of substituents amide affected the reactions and it is clear that
an electron-withdrawing group would decrease the reactivity of
the reaction (Table 2, entries 12e16). Interestingly, the existence of
strong electron-withdrawing group, such as nitro-group on the
postion-8 of the benzopyrone did not retard the reaction and
the yields were similar to the amide substitutions (Table 2, entries
17, 18).
Oxazolyl group at position-7 and position-8 were explored to
further probe the scope of the process (Table 3). Clearly, the het-
erocycle on the benzene ring also strongly contributed to the yield
decrease of the re-cyclization. Both steric hindrance effect and
electron deficiency of the oxazolyl ring might be the key reasons of
the low yields.
8
9
H
14h
15a
39
61
CH3
10
11
CH3
15b
57
CH3
CH3
15c
15d
56
64
12
a
Unless otherwise specified, all reactions were performed with compound 13
(2 mmol), substituted amine (2.4 mmol), and K2CO3 (6 mmol) in EtOH (25 mL) via oil
heating.
b
Isolated yield.
Aliphatic amine (Table 2, entries 3, 8, 15, 16, and 18; Table 3,
entries 6e8) substations could also be applied for re-cyclization
and the yield is similar to the aniline.
In order to further confirm the structure of the 2-pyridone de-
rivative, the crystal structure of compound 9c was determined.
Fig. 2 showed the ORTEP drawing of compound 9c, indicating that
the re-cyclization reaction was successful. Moreover, a key in-
termediate (17) during the re-cyclization was obtained and the
crystal structure was also determined. The ORTEP drawing of 17
was shown in Fig. 3.
Based on the fact that intermediates 17 was successfully sepa-
rated and determined via X-ray single crystal diffraction (Fig. 3), we
could propose a tentative reaction mechanism (Scheme 2). There
are several proton transfers that have to occur. We have shown
a base ‘B’: carrying out these proton transfers: this might be
a molecule of base we used, or it might be a molecule of the solvent.
These details do not matter. First of all, amines are good nucleo-
philes for conjugate addition reactions and the polarization of
conjugated C]C bond of compound 6 led to C2 atom was easily
Fig. 2. ORTEP drawing of 9c (CCDC 705282).

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Y. Zhang et al. / Tetrahedron 69 (2013) 8839e8846
cyclization. As expected, compound 18 was also successfully ob-
tained and determined (Scheme 3).
3. Conclusion
In summary, we have developed an efficient and mild procedure
for the synthesis of 2-pyridone derivatives with different benzo-
pyran-4-one derivatives and substituted amines. Our reaction
condition was as follows: cheap and readily available potassium
carbonate and ethanol were used as base and solvent, respectively.
The short reaction times and simple reaction conditions render this
method particularly attractive for the efficient preparation of bi-
ologically and medicinally interesting molecules. Furthermore, the
mechanism of this interesting re-cyclization reaction could be ob-
tained according to the key intermediate determination. All these
factors contribute to the importance of the described chemistry.
This simple method circumvents chemical complexity of the 2-
pyridone synthesis reported before and this is also likely to be of
value in medicinal chemistry applications.
4. Experimental section
4.1. General
All reactions were carried out in oven-dried glassware. Unless
otherwise stated, all chemicals were obtained from commercial
sources and used without further purification. Analytical thin
layer chromatography (TLC) was performed on precoated silica
gel GF-254 plates with visualization by ultraviolet (UV) irradia-
Fig. 3. ORTEP drawing of 17 (CCDC 943099).
attacked by aniline under alkaline condition. Intermediate B was
then generated by the CeN bond-forming reactions in the next
step. Ether linkage cleavage promoted via base resulted in the
formation of enamine (intermediate C). Transformation among
intermediates C, D, and E was evoked by CeC single bond rotation
and imineeenamine tautomerism. Moreover, intermediate E could
undergo another conjugate addition reaction to produce in-
termediate 17. However, the ester linkage of 17 was unstable under
alkaline condition. As the time went on, the final product 8 could be
formed because of the acylation reaction.
tion at
l
¼254 nm or staining with I2. Purifications were per-
formed by silica gel chromatography (230e400 mesh or
200e300 mesh). Melting points reported are of chromatograph-
ically purified materials and are uncorrected. NMR experiments
were performed on 300 or 600 MHz spectrometer and samples
were obtained in CDCl3 (referenced to residual CHCl3 at 7.26 ppm
for 1H and 77.0 ppm for 13C) or DMSO-d6 (referenced to residual
DMSO at 2.50 ppm for 1H and 39.5 ppm for 13C). Chemical shifts
(d) are reported in parts per million (ppm) and coupling constants
Scheme 2. Putative reaction mechanism.
For further confirming the generality of the reaction mechanism
we proposed, (E)-methyl 3-(7-methoxy-8-nitro-4-oxo-4H-chro-
men-3-yl)acrylate and aliphatic amine were utilized for this re-
(J) are in hertz (Hz). HRMS analyses were performed using
a TOF analyzer, the ionization methods are provided in the
compound characterization. Crystal structure was determined on

Y. Zhang et al. / Tetrahedron 69 (2013) 8839e8846
8843
Scheme 3. Synthesis of intermediate 18.
a diffractometer equipped with Cu radiation. Yields refer to
quantities obtained after chromatography.
4.2.1.5. 5-(2,4-Dihydroxybenzoyl)-1-(4-ethoxyphenyl)pyridin-
2(1H)-one (10a). Yellow solid (0.46 g, 66%); mp: 231.0e231.9 ꢀC; 1H
NMR: (300 MHz, DMSO-d6) d: 1.31e1.36 (t, 3H), 4.01e4.10 (t, 2H),
6.31e6.37 (m, 2H), 6.52 (d, 1H, J¼9.6 Hz), 6.99e7.03 (m, 2H),
7.36e7.39 (m, 2H), 7.46 (d, 1H, J¼8.4 Hz), 7.79e7.83 (dd, 1H,
J1¼9.6 Hz, J2¼2.4 Hz), 7.93 (d, 1H, J¼2.4 Hz), 10.41 (s, 1H), 11.29 ppm
4.2. General experimental procedure
4.2.1. Target compounds. A solution of substituted (E)-methyl 3-(4-
oxo-4H-chromen-3-yl)acrylate (2 mmol), substituted amine
(2.4 mmol), and K2CO3 (6 mmol) in EtOH (25 mL) was stirred under
reflux for 6 h. After the mixture was cooled to room temperature
and the solvent removed, the crude product was purified by chro-
matography over silica gel (eluent petroleum ether/acetic ether, 9:1
to 3:1 v/v) to give target compounds.
(s,1H); 13C NMR (75 MHz, DMSO-d6)
d: 14.5, 63.4, 102.7, 107.8,113.8,
114.6, 116.8, 119.4, 127.8, 132.9, 133.6, 139.3, 144.5, 158.3, 161.1, 161.6,
163.5, 192.0 ppm; HRMS (ESI) calculated for C20H17NO5 [MþH]þ
352.1140, found 352.1119.
4.2.1.6. 5-(2,4-Dihydroxybenzoyl)-1-p-tolylpyridin-2(1H)-one
(10b). Yellow solid (0.34 g, 53%); mp: 264.4e265.2 ꢀC; 1H NMR:
(300 MHz, DMSO-d6) d: 2.35 (s, 3H), 6.31e6.37 (m, 2H), 6.55 (d, 1H,
4.2.1.1. 5-(2-Hydroxy-4-methoxybenzoyl)-1-phenylpyridin-
2(1H)-one (8). Yellow solid (0.56 g, 88%); mp: 179.0e179.7 ꢀC; 1H
J¼9.6 Hz), 7.29e7.36 (m, 4H), 7.46 (d, 1H, J¼8.4 Hz), 7.80e7.84 (dd,
1H, J1¼9.6 Hz, J2¼2.4 Hz), 7.93 (d, 1H, J¼2.4 Hz), 10.40 (s, 1H), 11.28
NMR: (300 MHz, CDCl3)
d
: 3.86 (s, 3H), 6.45e6.49 (dd, 1H, J1¼9 Hz,
(s, 1H); 13C NMR (75 MHz, DMSO-d6)
d: 20.6, 102.7, 107.9, 113.9,
J2¼2.7 Hz), 6.51 (d, 1H, J¼2.7 Hz), 6.70 (d, 1H, J¼9.3 Hz), 7.41e7.52
116.9, 119.3, 126.4, 129.5, 133.6, 137.8, 138.2, 139.4, 144.4, 161.0,
161.6, 163.6, 192.0 ppm; HRMS (ESI) calculated for C19H15NO4
[MþH]þ 322.1035, found 322.1032.
(m, 2H), 7.53e7.54 (m, 2H), 7.55e7.56 (m, 2H), 7.78e7.82 (dd, 1H,
J1¼9.3 Hz, J2¼2.7 Hz), 7.93 (d, 1H, J¼2.7 Hz), 12.23 ppm (s, 1H); 13
C
NMR (75 MHz, CDCl3) d: 55.7, 102.6, 108.7, 113.8, 114.9, 116.9, 119.4,
127.5, 128.0, 132.6, 139.3, 143.8, 158.5, 161.0, 161.4, 163.5, 192.0 ppm;
HRMS (ESI) calculated for C19H15NO4 [MþH]þ 322.1035, found
322.1031.
4.2.1.7. 5-(2,4-Dihydroxybenzoyl)-1-m-tolylpyridin-2(1H)-one
(10c). Yellow solid (0.35 g, 55%); mp: 155.5e156.8 ꢀC; 1H NMR:
(300 MHz, DMSO-d6) d: 2.53 (s, 3H), 6.31e6.37 (m, 2H), 6.64e6.70
(m, 2H), 6.55 (d, 1H, J¼9.6 Hz), 7.29e7.37 (m, 4H), 7.46 (d, 1H,
J¼8.7 Hz), 7.80e7.84 (dd, 1H, J1¼2.7 Hz, J2¼2.7 Hz), 7.93 (d, 1H,
J¼2.1 Hz),10.40 (s,1H),11.28 ppm (s,1H); 13C NMR (75 MHz, DMSO-
4.2.1.2. 5-(2-Hydroxy-4-methoxybenzoyl)-1-(4-methoxyphenyl)
pyridin-2(1H)-one (9a). Yellow solid (0.64 g, 91%); mp:
152.2e152.6 ꢀC; 1H NMR: (300 MHz, CDCl3)
d: 3.86 (s, 3H), 3.87 (s,
d6) d: 20.6, 102.7, 107.9, 113.9, 116.9, 119.5, 126.4, 129.5, 133.6, 137.8,
3H), 6.45 (dd, 1H, J1¼9 Hz, J2¼2.7 Hz), 6.52 (d, 1H, J¼2.7 Hz), 6.69 (d,
1H, J¼9.6 Hz), 7.01e7.04 (m, 2H), 7.32e7.35 (m, 2H), 7.53 (d, 1H,
J¼9 Hz), 7.77e7.81 (dd, 1H, J1¼9.6 Hz, J2¼2.7 Hz), 7.93 (d, 1H,
138.2, 139.4, 144.3, 161.0, 161.6, 163.5, 192.0 ppm; HRMS (ESI) cal-
culated for C19H15NO4 [MþH]þ 322.1035, found 322.1031.
J¼2.7 Hz), 12.24 ppm (s, 1H); 13C NMR (75 MHz, CDCl3)
d: 55.6, 55.7,
4.2.1.8. 5-(2,4-Dihydroxybenzoyl)-1-(2-methoxyphenyl)pyridin-
76.9, 77.0, 77.4, 101.5, 107.2, 112.6, 114.8, 117.6, 120.7, 127.5, 133.3,
139.4, 143.1, 165.7, 166.3 ppm; HRMS (ESI) calculated for C20H17NO5
[MþH]þ 352.1140, found 352.1135.
2(1H)-one (10d). Yellow solid (0.46 g, 68%); mp: 251.3.2e252.4 ꢀC;
1H NMR: (300 MHz, DMSO-d6)
d: 3.78 (s, 3H), 6.31e6.37 (m, 2H),
6.51 (d, 1H, J¼9.6 Hz), 7.04e7.09 (m, 1H), 7.21 (d, 1H, J¼7.8 Hz),
7.35e7.49 (m, 3H), 7.79e7.87 (m, 2H), 10.46 (s, 1H), 11.66 ppm (s,
4.2.1.3. 5-(2-Hydroxy-4-methoxybenzoyl)-1-(4-nitrophenyl)pyr-
1H); 13C NMR (75 MHz, DMSO-d6)
d: 55.9, 102.8, 107.9, 112.7, 113.8,
idin-2(1H)-one (9b). Yellow solid (0.26 g, 35%); mp: 158.6e161.1 ꢀC;
1H NMR: (300 MHz, CDCl3)
d
: 3.88 (s, 1H), 6.47 (dd, 1H, J1¼9 Hz,
116.7, 119.6, 120.6, 128.6, 130.6, 133.6, 139.6, 145.2, 153.8, 160.8,
161.9, 163.7, 192.2 ppm; HRMS (ESI) calculated for C19H15NO5
[MþH]þ 338.0984, found 338.0981.
J2¼2.4 Hz), 6.62 (d, 1H, J¼2.4 Hz), 6.73 (d, 1H, J¼9.3 Hz), 7.51 (d,
1H, J¼9 Hz), 7.65e7.69 (m, 2H), 7.81e7.85 (dd, 1H, J1¼9.6 Hz,
J2¼2.7 Hz), 7.91 (d, 1H, J¼2.4 Hz), 8.40e8.41 ppm (m, 2H); 13C NMR
4.2.1.9. 1-Butyl-5-(2,4-dihydroxybenzoyl)pyridin-2(1H)-one
(75 MHz, CDCl3) d: 55.7, 101.5, 107.8, 112.5, 118.0, 120.9, 127.8, 129.8,
(10e). Yellow solid (0.4 g, 69%); mp: 172.4e173.3 ꢀC; 1H NMR:
133.2, 135.2, 138.5, 139.8, 142.3, 161.5, 165.9, 166.4, 193.6 ppm;
HRMS (ESI) calculated for C19H14N2O6 [MþH]þ 367.0885, found
367.0873.
(300 MHz, DMSO-d6)
d: 0.89e0.90 (t, 3H), 1.19e1.34 (m, 2H),
1.56e1.66 (m, 2H), 3.92e4.03 (m, 2H), 6.34e6.39 (m, 2H), 6.42 (d,
1H, J¼9.3 Hz), 7.39 (d, 1H, J¼9.6 Hz), 7.68e7.72 (dd, 1H, J1¼2.4 Hz,
J2¼2.4 Hz), 8.19 (d,1H, J¼2.7 Hz),10.38 (s,1H), 11.33 ppm (s,1H); 13
C
4.2.1.4. 1-Allyl-5-(2-hydroxy-4-methoxybenzoyl)pyridin-2(1H)-
one (9c). Yellow solid (0.51 g, 89%); mp: 131.7e132.6 ꢀC; 1H NMR:
NMR (75 MHz, DMSO-d6) d: 13.5,19.1,102.7,107.8,113.8,116.7,118.5,
133.4, 139.0, 144.4, 161.2, 161.9, 165.6, 192.3 ppm; HRMS (ESI) cal-
(300 MHz, CDCl3) d: 3.87 (s, 1H), 4.63e4.66 (m, 2H), 5.25e5.38 (m,
culated for C16H17NO4 [MþH]þ 288.1191, found 288.1188.
2H), 5.92e6.06 (m, 1H), 6.45e6.49 (dd, 1H, J1¼9 Hz, J2¼2.7 Hz), 6.52
(d, 1H, J¼2.7 Hz), 6.62 (d, 1H, J¼9.6 Hz), 7.46 (d, 1H, J¼9 Hz),
7.71e7.75 (dd, 1H, J1¼9.6 Hz, J2¼2.7 Hz), 7.86 (d, 1H, J¼2.7 Hz),
4.2.1.10. 5-(2,4-Dihydroxybenzoyl)-1-(3-nitrophenyl)pyridin-
2(1H)-one (10f). Yellow solid (0.24 g, 34%); mp: 269.6e270.9 ꢀC; 1H
12.24 ppm (s,1H); 13C NMR (75 MHz, CDCl3)
d: 30.9, 51.6, 55.7,101.5,
NMR: (300 MHz, DMSO-d6) d: 6.32e6.37 (m, 2H), 6.51 (d, 1H,
107.6, 112.6, 117.7, 119.8, 112.0, 131.7, 133.3, 139.1, 142.0, 161.8, 165.9,
166.2, 193.8 ppm; HRMS (ESI) calculated for C16H15NO4 [MþH]þ
286.1035, found 286.1052.
J¼2.7 Hz), 6.61 (d, 1H, J¼9.6 Hz), 7.54 (d, 1H, J¼8.4 Hz), 7.81e7.86
(m, 2H), 7.98e8.01 (m, 1H), 8.13 (d,1H, J¼2.4 Hz), 8.31e8.34 (dd,1H,

8844
Y. Zhang et al. / Tetrahedron 69 (2013) 8839e8846
J1¼8.4 Hz, J2¼2.4 Hz), 8.43e8.44 (m, 1H), 10.47 (s, 1H), 11.45 ppm (s,
1H); 13C NMR (75 MHz, DMSO-d6)
: 102.7, 107.9, 113.9, 116.9, 119.5,
126.4, 129.5, 133.6, 137.8, 138.2, 139.4, 144.3, 161.0, 161.6, 163.5,
192.0 ppm; HRMS (ESI) calculated for C18H12N2O6 [MþH]þ
353.0771, found 353.0792.
(11f). Yellow solid (0.51 g, 56%); mp: 197.4e198.6 ꢀC; 1H NMR:
(300 MHz, DMSO-d6)
d
d
: 1.04e1.06 (t, 3H), 1.30 (d, 6H, J¼6.6 Hz),
2.32e2.39 (m, 2H), 3.84 (s, 3H), 4.99e5.03 (t, 1H), 6.45 (d, 1H,
J¼9.6 Hz), 6.71 (d, 1H, J¼9.0 Hz), 7.69 (dd, 1H, J1¼9.6 Hz, J2¼2.4 Hz),
8.11 (d, 1H, J¼2.4 Hz), 9.17 (s, 1H), 10.72 ppm (s, 1H); 13C NMR
(75 MHz, DMSO-d6) d: 9.8, 21.0, 23.4, 47.4, 56.0, 103.2, 114.5, 116.6,
4.2.1.11. N-(4-Hydroxy-2-methoxy-5-(1-(4-methoxyphenyl)-6-
oxo-1,6-dihydropyridine-3-carbonyl)phenyl)acetamide (11a). Yellow
solid (0.45 g, 55%); mp: 198.6e199.3 ꢀC; 1H NMR: (300 MHz,
118.6, 130.2, 138.1, 140.2, 154.0, 158.7, 160.0, 173.1, 192.1 ppm; HRMS
(ESI) calculated for C19H22N2O5 [MþH]þ 459.1562, found 359.1533.
DMSO-d6)
d: 2.01 (s, 3H), 3.71 (s, 3H), 3.85 (s, 3H), 6.61e6.68 (m,
4.2.1.17. N-(3-(1-Butyl-6-oxo-1,6-dihydropyridine-3-carbonyl)-2-
2H), 6.90 (s, 1H), 7.01 (d, 1H, J¼9.6 Hz), 7.44 (d, 2H, J¼9.6 Hz), 7.82
hydroxy-6-methoxyphenyl)propionamide (11g). Yellow solid (0.4 g,
(d, 1H, J¼9 Hz), 8.10 (s, 1H), 9.17 (s, 1H), 11.16 ppm (s, 1H); 13C NMR
54%); mp: 185.9e186.8 ꢀC; 1H NMR: (300 MHz, DMSO-d6)
d:
(75 MHz, DMSO-d6)
d: 24.2, 55.6, 101.5, 112.6, 115.7, 117.7, 119.8,
0.85e0.91 (t, 3H), 1.02e1.11 (t, 3H),1.22e1.39 (m, 2H), 1.59e1.64 (m,
2H), 2.34e1.37 (m, 2H), 3.84 (s, 3H), 3.92e3.97 (m, 2H), 6.44 (d, 1H,
J¼9.6 Hz), 6.70 (d, 1H, J¼8.7 Hz), 7.42 (d, 1H, J¼8.79 Hz), 7.71e7.75
(dd, 1H, J1¼2.4 Hz, J2¼2.7 Hz), 8.22 (d, 1H, J¼2.7 Hz), 9.18 (s, 1H),
120.0, 120.8, 130.3, 133.0, 139.1, 139.5, 142.0, 161.8, 165.6, 166.2,
193.4 ppm; HRMS (ESI) calculated for C22H20N2O6 [MþH]þ
409.1355, found 409.1376.
10.74 ppm (s, 1H); 13C NMR (75 MHz, DMSO-d6)
d: 9.7, 13.8, 21.7,
4.2.1.12. N-(5-(1-(4-Fluorobenzyl)-6-oxo-1,6-dihydropyridine-3-
28.1, 28.3, 49.2, 56.1, 103.1, 114.6, 116.7, 117.2, 118.6, 130.2, 138.8,
145.1, 154.1, 154.9, 158.6, 161.3, 173.1, 192.1 ppm; HRMS (ESI) cal-
culated for C20H24N2O5 [MþH]þ 373.1719, found 373.1744.
carbonyl)-4-hydroxy-2-methoxyphenyl)acetamide
(11b). Yellow
solid (0.27 g, 33%); mp: 197.3e198.9 ꢀC; 1H NMR: (300 MHz, DMSO-
d6)
d
: 2.04 (s, 3H), 3.86 (s, 3H), 5.14 (s, 2H), 6.46 (d, 1H, J¼9.3 Hz),
8.45 (d, 1H, J¼2.4 Hz), 9.17 ppm (s, 1H); 13C NMR (75 MHz, DMSO-
4.2.1.18. 5-(2,4-Dihydroxy-3-nitrobenzoyl)-1-(4-methoxyphenyl)
d6)
d
: 21.2, 56.9, 102.7, 113.7, 116.5, 121.0, 126.0, 130.2, 131.1, 134.4,
pyridin-2(1H)-one (12a). Yellow solid (0.32 g, 42%); mp:
137.3, 138.76, 139.6, 143.9, 156.0, 156.6, 161.7, 193.5 ppm; HRMS
264.1e265.2 ꢀC; 1H NMR: (300 MHz, DMSO-d6)
d: 3.80 (s, 3H), 6.59
(ESI) calculated for C22H19FN2O5 [MþH]þ 411.1352, found 411.1385.
(d, 1H, J¼9.6 Hz), 6.60 (d, 1H, J¼9.0 Hz), 7.04 (d, 2H, J¼9.0 Hz), 7.39
(d, 2H, J¼9.0 Hz), 7.71 (d, 1H, J¼9.0 Hz), 7.78 (dd, 1H, J1¼9.6 Hz,
J2¼2.4 Hz), 8.05 (d, 1H, J¼3.0 Hz), 12.00 (s, 1H), 12.01 ppm (s, 1H);
4.2.1.13. N-(2-Hydroxy-6-methoxy-3-(1-(4-methoxyphenyl)-6-
oxo-1,6-dihydropyridine-3-carbonyl)phenyl)benzamide
(11c). Yellow solid (0.58 g, 62%); mp: 197.5e198.3 ꢀC; 1H
13C NMR (75 MHz, DMSO-d6)
d: 21.2, 56.9, 102.7, 113.7, 116.5, 121.0,
126.0, 130.2, 131.2, 134.34, 137.3, 138.8, 139.6, 143.9, 156.0, 156.6,
161.7, 193.5 ppm; HRMS (ESI) calculated for C19H14N2O7 [MþH]þ
383.0835, found 383.0833.
NMR: (300 MHz, DMSO-d6) d: 3.81 (s, 3H), 3.83 (s, 3H), 6.60 (d,
1H, J¼9.6 Hz), 6.73 (d, 1H, J¼9 Hz), 7.08 (d, 2H, J¼8.7 Hz), 7.43
(d, 2H, J¼8.7 Hz), 7.51e7.66 (m, 3H), 7.87e7.92 (dd, 1H,
J1¼9.6 Hz, J2¼2.7 Hz), 7.90e8.23 (m, 3H), 9.54 (s, 1H), 11.06 ppm
4.2.1.19. 1-Butyl-5-(2,4-dihydroxy-3-nitrobenzoyl)pyridin-2(1H)-
(s, 1H); 13C NMR (75 MHz, DMSO-d6)
d
: 55.6, 56.1, 103.1, 112.0,
one (12b). Yellow solid (0.32 g, 50%); mp: 256.1e257.1 ꢀC; 1H NMR:
113.5, 114.8, 116.1, 116.7, 119.0, 123.2, 128.0, 128.2, 132.7, 133.3,
134.9, 139.1, 139.5, 156.9, 161.8, 163.5, 165.2, 166.4, 192.2 ppm;
HRMS (ESI) calculated for C27H22N2O6 [MþH]þ 471.1562, found
471.1536.
(300 MHz, DMSO-d6) d: 0.87e0.88 (t, 3H), 1.27e1.29 (t, 2H),
1.60e1.62 (t, 2H), 3.94e3.97 (t, 2H), 6.48 (d, 1H, J¼9.0 Hz), 6.62 (d,
1H, J¼9.0 Hz), 7.59 (d, 1H, J¼9.0 Hz), 7.74 (dd, 1H, J1¼9.6 Hz,
J2¼2.4 Hz), 8.29 (d, 1H, J¼3.0 Hz), 11.91 (s, 1H), 12.03 ppm (s, 1H);
13C NMR (75 MHz, DMSO-d6)
d: 13.5, 19.1, 30.6, 49.0, 107.8, 114.2,
4.2.1.14. N-(3-(1-(4-Ethoxyphenyl)-6-oxo-1,6-dihydropyridine-3-
carbonyl)-2-hydroxy-6-methoxyphenyl)-4-nitrobenzamide
(11d). Yellow solid (0.65 g, 61%); mp: 199.4e199.9 ꢀC; 1H NMR:
115.9, 118.9, 130.7, 134.3, 138.7, 145.5, 152.9, 154.6, 161.2, 191.8 ppm;
HRMS (ESI) calculated for C16H16N2O6 [MþH]þ 333.1042, found
333.1045.
(300 MHz, DMSO-d6) d: 1.32e1.37 (t, 3H), 3.83 (s, 3H), 4.07e4.09
(m, 2H), 6.59 (d, 1H, J¼9.3 Hz), 6.74 (d, 1H, J¼9.0 Hz), 7.02 (d, 2H,
J¼8.7 Hz), 7.40 (d, 2H, J¼8.7 Hz), 7.64 (d, 1H, J¼8.7 Hz), 7.86e7.90
(dd, 1H, J1¼9.6 Hz, J2¼2.4 Hz), 8.01 (d, 1H, J¼2.4 Hz), 8.20 (d, 2H,
J¼8.4 Hz), 8.35 (d, 2H, J¼8.4 Hz), 9.90 (s, 1H), 11.07 ppm (s, 1H); 13C
4.2.1.20. 5-(4-Hydroxybenzo[d]oxazole-5-carbonyl)-1-
phenylpyridin-2(1H)-one (14a). Yellow solid (0.29 g, 44%); mp:
198.9e200.1 ꢀC; 1H NMR: (300 MHz, DMSO-d6)
d: 6.59 (d, 1H,
J¼9.6 Hz), 7.29 (d, 1H, J¼8.4 Hz), 7.42e7.53 (m, 6H), 7.90e7.94 (dd,
NMR (75 MHz, DMSO-d6) d: 14.6, 56.1, 63.4, 103.1, 113.6, 114.6, 116.1,
1H, J1¼9.6 Hz, J2¼2.7 Hz), 7.99 (d, 1H, J¼2.7 Hz), 8.74 (s, 1H),
116.7, 119.7, 123.5, 127.9, 129.3, 131.4, 132.8, 139.2, 139.8, 145.2, 149.1,
156.4, 158.4, 160.0, 161.2, 163.9, 192.2 ppm; HRMS (ESI) calculated
for C28H24N2O6 [MþH]þ 530.1519, found 530.1517.
11.43 ppm (s, 1H); 13C NMR (75 MHz, DMSO-d6)
d: 104.6, 119.4,
121.9, 122.7, 129.0, 130.3, 131.95, 131.4, 131.8, 141.3, 142.4, 148.0,
151.5, 155.1, 155.6, 163.3, 193.4 ppm; HRMS (ESI) calculated for
C19H12N2O4 [MþH]þ 333.0831, found 333.0842.
4.2.1.15. N-(2-Hydroxy-6-methoxy-3-(1-(4-methoxyphenyl)-6-
oxo-1,6-dihydropyridine-3-carbonyl)phenyl)-3-methylbenzamide
(11e). Yellow solid (0.69 g, 71%); mp: 193.9e194.4 ꢀC; 1H NMR:
4.2.1.21. 5-(4-Hydroxybenzo[d]oxazole-5-carbonyl)-1-(4-
methoxybenzyl)pyridin-2(1H)-one (14b). Yellow solid (0.35 g, 47%);
(300 MHz, DMSO-d6)
d: 2.38 (s, 3H), 3.81e5.11 (m, 5H), 6.59 (d, 1H,
mp: 135.1e136.0 ꢀC; 1H NMR: (300 MHz, DMSO-d6)
d: 3.71 (s, 3H),
J¼9.6 Hz), 6.72 (d,1H,J¼9.0Hz), 7.03e7.21 (m, 2H), 7.38e7.57 (m, 4H),
5.07 (s, 2H), 6.45 (d, 1H, J¼9.6 Hz), 6.87 (d, 2H, J¼8.7 Hz), 7.25e7.31
7.63 (d,1H, J¼9.0 Hz), 7.79e7.82 (m, 2H), 7.86e7.95 (dd,1H, J1¼9.6 Hz,
(m, 3H), 7.37 (d, 1H, J¼8.7 Hz), 7.74e7.78 (dd, 1H, J1¼9.6 Hz,
J2¼2.7 Hz), 8.01 (d, 1H, J¼2.7 Hz), 9.47 (s, 1H), 11.07 ppm (s, 1H); 13
C
J2¼2.7 Hz), 8.37 (d, 1H, J¼2.7 Hz), 8.75 (s, 1H), 11.35 ppm (s, 1H); 13
C
NMR (75 MHz, DMSO-d6)
d: 20.9, 55.5, 56.1, 103.1, 114.2, 114.4, 116.0,
NMR (75 MHz, DMSO-d6) d: 51.5, 55.1, 102.5, 114.0, 117.4, 118.8,
116.7, 119.7, 125.0, 128.0, 128.1, 128.4, 131.2, 132.0, 133.0, 134.0, 137.5,
139.2, 145.1, 156.6, 159.1, 160.1, 161.2, 165.6, 192.4 ppm; HRMS (ESI)
calculated for C28H24N2O6 [MþH]þ 485.1668, found 485.1663.
120.7, 127.9, 128.4, 129.2, 129.7, 138.9, 145.6, 149.3, 152.8, 153.4,
158.9, 161.4, 191.5 ppm; HRMS (ESI) calculated for C21H16N2O5
[MþH]þ 377.1093, found 377.1092.
4 . 2 .1.16 . N - ( 2 -H y d ro x y- 3 - ( 1 - i s o p ro p yl - 6 - o x o - 1, 6 -
dihydropyridine-3-carbonyl)-6-methoxyphenyl)propionamide
4.2.1.22. 1-(4-Chlorobenzyl)-5-(4-hydroxybenzo[d]oxazole-5-
carbonyl)pyridin-2(1H)-one (14c). Yellow solid (0.35 g, 46%); mp:

Y. Zhang et al. / Tetrahedron 69 (2013) 8839e8846
8845
106.7e107.3 ꢀC; 1H NMR: (300 MHz, DMSO-d6)
d
: 5.14 (s, 2H), 6.46
(s, 3H), 6.57e6.61 (dd, 1H, J1¼9.0 Hz, J2¼1.2 Hz), 7.19 (d, 1H,
J¼8.4 Hz), 7.31 (s, 4H), 7.40 (d, 1H, J¼8.4 Hz), 7.88e7.93 (m, 2H),
(d, 1H, J¼6.3 Hz), 7.12e7.18 (m, 2H), 7.29e7.43 (m, 4H), 7.77e7.81
(dd, 1H, J1¼9.6 Hz, J2¼2.7 Hz), 8.44 (d, 1H, J¼2.4 Hz), 8.75 (s, 1H),
11.28 ppm (s, 1H); 13C NMR (75 MHz, DMSO-d6)
d: 14.0, 20.6, 102.1,
11.36 ppm (s, 1H); 13C NMR (75 MHz, DMSO-d6)
d
: 51.4, 102.6, 115.3,
117.1, 119.6, 120.3, 126.4, 127.0, 129.6, 130.2, 137.7, 138.4, 138.9, 145.9,
148.4, 153.8, 161.1, 163.1, 191.5 ppm; HRMS (ESI) calculated for
C21H16N2O4 [MþH]þ 361.1144, found 361.1159.
115.6,117.7, 118.9,120.8, 128.0, 129.2, 130.3, 132.8,139.1,145.9, 149.4,
152.9, 153.4, 161.5, 191.5 ppm; HRMS (ESI) calculated for
C20H13ClN2O4 [MþH]þ 382.0534, found 382.0530.
4.2.1.29. 5-(4-Hydroxy-2-methylbenzo[d]oxazole-5-carbonyl)-1-
4.2.1.23. 1-(3-Fluorobenzyl)-5-(4-hydroxybenzo[d]oxazole-5-
(4-methoxyphenyl)pyridin-2(1H)-one (15b). Yellow solid (0.43 g,
carbonyl)pyridin-2(1H)-one (14d). Yellow solid (0.25 g, 35%); mp:
57%); mp: 206.8e207.3 ꢀC; 1H NMR: (300 MHz, DMSO-d6)
d: 2.61 (s,
156.0e156.8 ꢀC; 1H NMR: (300 MHz, DMSO-d6)
d
: 5.17 (s, 2H),
3H), 3.79 (s, 3H), 6.57 (d, 1H, J¼9.3 Hz), 7.01e7.04 (m, 2H), 7.19 (d,
6.48 (d, 1H, J¼9.6 Hz), 7.10e7.22 (m, 3H), 7.29e7.51 (m, 3H),
1H, J¼8.4 Hz), 7.34e7.43 (m, 3H), 7.87e7.93 (m, 2H), 11.28 ppm (s,
7.79e7.90 (dd, 1H, J1¼9.6 Hz, J2¼2.4 Hz), 8.45 (d, 1H, J¼8.7 Hz),
1H); 13C NMR (75 MHz, DMSO-d6)
d: 14.0, 55.5, 102.1, 114.3, 117.1,
8.75 (s, 1H), 11.35 ppm (s, 1H); 13C NMR (75 MHz, DMSO-d6)
d
:
119.5, 120.3, 127.0, 127.9, 130.2, 133.0, 138.9, 146.0, 148.4, 153.8,
159.2, 161.3,163.1,191.3 ppm; HRMS (ESI) calculated for C21H16N2O5
[MþH]þ 377.1093, found 377.1084.
51.6, 102.4, 114.3, 117.6, 118.8, 120.8, 123.7, 127.9, 129.2, 130.6,
130.7, 139.1, 139.5, 146.0, 149.4, 152.8, 153.3, 160.5, 161.3,
191.4 ppm; HRMS (ESI) calculated for C20H13FN2O4 [MþH]þ
365.0859, found 365.0931.
4.2.1.30. 1-(3-Chlorophenyl)-5-(4-hydroxy-2-methylbenzo[d]ox-
azole-5-carbonyl)pyridin-2(1H)-one (15c). Yellow solid (0.42 g,
4.2.1.24. 1-(2-Fluorobenzyl)-5-(4-hydroxybenzo[d]oxazole-5-
56%); mp: 222.7e223.6 ꢀC; 1H NMR: (300 MHz, DMSO-d6)
d: 2.62
carbonyl)pyridin-2(1H)-one (14e). Yellow solid (0.33 g, 45%); mp:
(s, 3H), 6.60 (d, 1H, J¼9.6 Hz), 7.23 (d, 1H, J¼8.7 Hz), 7.43e7.47 (m,
2H), 7.54e7.60 (m, 2H), 7.63 (s, 1H), 7.89e7.98 (dd, 1H, J1¼9.6 Hz,
J2¼2.4 Hz), 8.03 (d, 1H, J¼2.4 Hz), 11.32 ppm (s, 1H); 13C NMR
142.9e143.7 ꢀC; 1H NMR: (300 MHz, DMSO-d6)
d: 5.20 (s, 2H), 6.48
(d, 1H, J¼9.3 Hz), 7.15e7.66 (m, 6H), 7.81e7.95 (dd, 1H, J1¼9.3 Hz,
J2¼2.4 Hz), 8.36 (d, J¼2.4 Hz), 8.75 (s, 1H), 11.35 ppm (s, 1H); 13C
(75 MHz, DMSO-d6) d: 14.0, 102.1, 117.4, 119.6, 120.1, 125.8, 127.1,
NMR (75 MHz, DMSO-d6)
d
: 47.0, 102.6, 115.4, 115.7, 117.6, 119.0,
127.2, 138.8, 130.3, 130.8, 133.2, 139.4, 141.2, 145.4, 148.8, 153.9,
160.9, 163.1, 191.4 ppm; HRMS (ESI) calculated for C20H13ClN2O4
[MþH]þ 380.0564, found 380.0569.
120.7, 123.2, 123.3, 124.8, 127.9, 129.3, 130.0, 139.2, 146.3, 149.4,
152.9, 153.4, 161.4, 191.6 ppm; HRMS (ESI) calculated for
C20H13FN2O4 [MþH]þ 365.0859, found 365.0931.
4.2.1.31. 5-(4-Hydroxy-2-methylbenzo[d]oxazole-5-carbonyl)-1-
4.2.1.25. 5-(4-Hydroxybenzo[d]oxazole-5-carbonyl)-1-
m-tolylpyridin-2(1H)-one (15d). Yellow solid (0.46 g, 64%); mp:
isopropylpyridin-2(1H)-one (14f). Yellow solid (0.29 g, 48%); mp:
216.6e217.5 ꢀC; 1H NMR: (300 MHz, DMSO-d6)
d
: 2.35 (s, 3H), 2.61 (s,
1H), 6.58 (d, 1H, J¼9.3 Hz), 7.19e7.29 (m, 5H), 7.40e7.42 (m, 2H),
7.82e7.94 (m, 2H),11.29 ppm (s, 1H); 13C NMR (75 MHz, DMSO-d6)
185.6e185.9 ꢀC; 1H NMR: (300 MHz, DMSO-d6)
d: 1.27 (d, 6H,
J¼6.6 Hz), 4.94e5.04 (m, 1H), 6.44 (d, 1H, J¼9.6 Hz), 7.31 (d, 1H,
d:
J¼8.4 Hz), 7.45 (d, 1H, J¼8.4 Hz), 7.71e7.75 (dd, 1H, J1¼9.6 Hz,
14.0, 21.3,102.1,117.3,119.6,120.1,127.1,128.8,129.1,138.8,130.3,132.3,
133.2, 138.8, 139.2, 145.5, 148.6, 153.8, 161.0, 163.1, 191.4 ppm; HRMS
(ESI) calculated for C21H16N2O4 [MþH]þ 360.1110, found 360.1121.
J2¼2.4 Hz), 8.13 (d, 1H, J¼2.4 Hz), 8.77 (s,1H),11.44 ppm (s,1H); 13
C
NMR (75 MHz, DMSO-d6) d: 1.0, 47.6, 102.6, 117.2, 118.4, 120.5,
128.1, 129.2, 138.1, 141.4, 149.4, 152.9, 153.4, 161.0, 191.4 ppm;
HRMS (ESI) calculated for C16H14N2O4 [MþH]þ 298.0954, found
298.0967.
4.2.2. Intermediate 17 and 18. The reaction was monitored via TLC
every 20 min. The intermediate 17 (18) appeared firstly and then
the desired compound was formed after 2 h. The reaction was
stopped and the solvent was removed, the crude product was pu-
rified by chromatography over silica gel (eluent petroleum ether/
acetic ether, 9:1 to 3:1 v/v) to give compound 17 (18).
4.2.1.26. 5-(4-Hydroxybenzo[d]oxazole-5-carbonyl)-1-
isobutylpyridin-2(1H)-one (14g). Yellow solid (0.27 g, 44%); mp:
163.3e164.0 ꢀC; 1H NMR: (300 MHz, DMSO-d6)
d: 0.79 (d, 6H,
J¼6.6 Hz), 1.99e2.05 (m, 1H), 3.77 (d, 2H, J¼7.2 Hz), 6.46 (d, 1H,
J¼9.3 Hz), 7.31 (d, 1H, J¼8.4 Hz), 7.42 (d, 1H, J¼8.4 Hz), 7.78e7.82
(dd, 1H, J1¼9.3 Hz, J2¼2.7 Hz), 8.17 (d, 1H, J¼2.4 Hz), 8.77 (s, 1H),
4.2.2.1. (E)-Methyl 2-(7-methoxy-4-oxo-3-((phenylamino)methy-
lene)chroman-2-yl)acetate (17). Yellow solid (0.37 g, 53%); mp:
11.34 ppm (s, 1H); 13C NMR (75 MHz, DMSO-d6)
d
: 19.4, 27.3, 55.7,
116.5e116.9 ꢀC; 1H NMR: (600 MHz, DMSO-d6)
d: 2.81e2.90 (m,
102.4, 116.9, 118.6, 120.8, 127.8, 129.1, 138.5, 146.2, 149.3, 152.7,
253.3, 161.6, 191.5 ppm; HRMS (ESI) calculated for C17H16N2O4
[MþH]þ 312.1110, found 312.1113.
2H), 3.62 (s, 3H), 3.79 (s, 3H), 5.53e5.55 (dd, 1H, J1¼4.8 Hz,
J2¼4.8 Hz), 6.43 (d, 1H, J¼2.4 Hz), 6.65e6.67 (dd, 1H, J1¼2.4 Hz,
J2¼2.4 Hz), 7.04e7.06 (t, 1H), 7.28e7.30 (m, 2H), 7.32e7.36 (m,
2H), 7.72 (d, 1H, J¼8.4 Hz), 7.83 (d, 1H, J¼12.6 Hz), 11.60 ppm (d,
4.2.1.27. 5-(4-Hydroxybenzo[d]oxazole-5-carbonyl)-1-
1H, J¼12 Hz); 13C NMR (150 MHz, DMSO-d6)
d: 40.62, 51.54,
propylpyridin-2(1H)-one (14h). Yellow solid (0.23 g, 39%); mp:
55.62, 75.67, 101.51, 102.65, 109.39, 115.89, 116.12, 123.19, 127.62,
129.58, 140.03, 141.63, 158.98, 164.64, 170.05, 180.26 ppm; HRMS
(ESI) calculated for C20H19NO5 [MþH]þ 354.1297, found
354.1274.
163.2e163.9 ꢀC; 1H NMR: (300 MHz, DMSO-d6)
d: 0.81e0.86 (t,
3H), 1.58e1.65 (dd, 2H, J1¼7.5 Hz, J2¼7.5 Hz), 3.86e3.91 (t,
2H), 6.44 (d, 1H, J¼9.6 Hz), 7.30 (d, 1H, J¼8.4 Hz), 7.42 (d,
1H, J¼8.4 Hz), 7.76e7.80 (dd, 1H, J1¼9.6 Hz, J2¼2.7 Hz), 8.23
(d, 1H, J¼2.7 Hz), 8.76 (s, 1H), 11.32 ppm (s, 1H); 13C NMR
4.2.2.2. (E)-Methyl 2-(3-((butylamino)methylene)-7-methoxy-8-
(75 MHz, DMSO-d6)
d
: 10.7, 21.9, 50.6, 102.4, 117.0, 118.5, 120.7,
nitro-4-oxochroman-2-yl)acetate (18). Yellow solid (0.36 g, 48%);
127.9, 129.2, 138.5, 145.9, 149.3, 152.7, 153.3, 161.3, 191.4 ppm;
HRMS (ESI) calculated for C16H14N2O4 [MþH]þ 298.0954, found
298.0936.
mp: 102.1e102.8 ꢀC; 1H NMR: (300 MHz, CDCl3)
d: 0.95e0.97 (t,
3H), 1.35e1.42 (m, 2H), 1.53e1.61 (m, 2H), 2.61e2.68 (m, 1H),
2.91e2.98 (m, 1H), 3.26e3.32 (m, 2H), 3.69 (s, 3H), 3.94 (s, 3H),
5.41e5.46 (t, 3H), 6.69 (d, 1H, J¼9 Hz), 6.88 (d, 1H, J¼12.9 Hz),
6.94 (d, 1H, J¼9 Hz), 10.00e10.04 ppm (t, 1H); 13C NMR (75 MHz,
4.2.1.28. 5-(4-Hydroxy-2-methylbenzo[d]oxazole-5-carbonyl)-1-
p-tolylpyridin-2(1H)-one (15a). Yellow solid (0.44 g, 61%); mp:
CDCl3) d: 13.5, 19.6, 32.9, 41.4, 49.1, 51.8, 56.6, 76.6, 98.3, 105.0,
214.7e215.8 ꢀC; 1H NMR: (300 MHz, DMSO-d6)
d: 2.35 (s, 3H), 2.61
117.5, 128.7, 131.3, 149.5, 151.8, 155.0, 170.2, 178.0 ppm; HRMS

8846
Y. Zhang et al. / Tetrahedron 69 (2013) 8839e8846
(ESI) calculated for C18H22N2O7 [MþH]þ 379.1461, found
10. Plaskon, A. S.; Grygorenko, O. O.; Ryabukhin, S. V. Tetrahedron 2012, 68, 2743.
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13. Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.; Tolmachev, A. A. Synlett
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This work was supported by the National Natural Science
Foundation of China (Grant No. 21172259). We also thank the Key
Laboratory of Drug Research for Special Environments, PLA.
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Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.08.032.
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