Generation of diverse 2-pyrones via palladium-catalyzed site-selective Suzuki-Miyaura couplings of 3-bromo-4-tosyloxy-2-pyrone

Article abstract of DOI:10.1039/c1ob05783a

Based on different reactivity of the (pseudo)halide substituents in the 2-pyrone (3-Br and 4-OTs), palladium-catalyzed sequential site-selective Suzuki-Miyaura cross-coupling reactions of 3-bromo-6-methyl-4-tosyloxy-2-pyrone are described, which afford the diverse 2-pyrones in good yields.

Full text of DOI:10.1039/c1ob05783a

View Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 6265
www.rsc.org/obc
PAPER
Generation of diverse 2-pyrones via palladium-catalyzed site-selective
Suzuki-Miyaura couplings of 3-bromo-4-tosyloxy-2-pyrone†
Xiaoli Lei,a Liang Gao,a Qiuping Ding,a Yiyuan Peng*a and Jie Wu*b
Received 19th May 2011, Accepted 8th June 2011
DOI: 10.1039/c1ob05783a
Based on different reactivity of the (pseudo)halide substituents in the 2-pyrone (3-Br and 4-OTs),
palladium-catalyzed sequential site-selective Suzuki–Miyaura cross-coupling reactions of
3-bromo-6-methyl-4-tosyloxy-2-pyrone are described, which afford the diverse 2-pyrones in good yields.
site-selective cross-coupling reactions for the synthesis of 3,4-
Introduction
disubstituted coumarins, which include 3,4-diaryl-coumarins,
3-aryl-4-aminocoumarins.16f
2-Pyrone is the structural unit in various biologically active
natural products.1 Compounds with different substitutions on
the 2-pyrone scaffold show diverse biological activities (such as
anticancer and antimicrobial agents, HIV-protease inhibitor and
selective cyclooxygenase-2 inhibitor).2 Meanwhile, 2-pyrone is a
versatile building block in organic synthesis.3 For example, it has
been utilized as a diene component in Diels–Alder reactions,4 and
as a precursor for the synthesis of other heterocyclic systems.5
So far, various methods have been developed for the synthesis
of substituted 2-pyrones. However, the formation of substituted
2-pyrones usually suffered from multi-steps, harsh reaction con-
ditions and generally low yields.6 Alternatively, halogenated 2-
pyrones have been used for direct couplings.7–10 Additionally, they
can be converted into organometallic reagents (such as tin,11
boron,12 zinc,13 and copper-based reagents14) for couplings with
electrophilic partners. Although the above research has focused
on the use of palladium-catalyzed C–C bond formation for
introduction of substituent 2-pyrones, most of these methods
are centered on mono-substituted 2-pyrones. Applications of
transition metal-catalyzed reactions for the synthesis of 3,4-
disubstituted 2-pyrones are limited, which is due to the restrictions
of regioselectivity problems. Therefore, the development of an
effective strategy for the synthesis of diverse 2-pyrones, especially
for 3,4-disubstituted 2-pyrones is highly desirable.
3-amino-4-arylcoumarins,
and
Prompted by these results, we conceived that the generation of
differentially 3,4-disubstituted 2-pyrones could be accessed by
using the similar strategy. Thus, the key step in our program
is to introduce leaving groups with different reactivities to the
electronically different C-3 and C-4 positions of 2-pyrones. We
envisioned that based on the controllable chemoselectivity of two
leaving groups, substituents would be expected to be successively
installed into the 2-pyrone moiety. Herein, we would like to
describe our recent efforts for the synthesis of 3,4-disubstituted
2-pyrones through palladium-catalyzed site-selective couplings of
3-bromo-4-tosyloxy-2-pyrone.
Results and discussion
As mentioned above, our strategy is based on the elaboration of
the readily available 2-pyrone core structure using site-selective
cross-coupling reactions. Thus, 4-hydroxy-2-pyrone 1 was selected
as the target for further development due to its easy availablility.
After halogenation and sulfonylation of 4-hydroxy-2-pyrone, 3-
bromo-6-methyl-4-tosyloxy-2-pyrone 3 could be prepared easily
with a total yield of 86% (Scheme 1).
Recently,
transition-metal-catalyzed
site-selective
cross-coupling reactions have been developed for the
compounds bearing two or more leaving groups, especially
dihaloheteroarenes.15,16 We also applied the palladium-catalyzed
Scheme 1 Synthesis of 3-bromo-4-tosyloxy-2-pyrone 3 from 4-hy-
droxy-2-pyrone 1.
aKey Laboratory of Functional Small Organic Molecules, Ministry of
Education and College of Chemistry and Chemical Engineering, Jiangxi
Normal University, Nanchang, Jiangxi, 330022, China. E-mail: yypeng@
jxnu.edu.cn; Fax: +86 791 812 0396; Tel: +86 791 812 0396
Due to the great functional group tolerance of Suzuki-Miyaura
cross-coupling reaction,17 initial studies were performed for the
palladium-catalyzed reaction of 3-bromo-6-methyl-4-tosyloxy-2-
pyrone 3 with phenylboronic acid (Table 1). To test the C3 and
C4 selectivity, the reaction was carried out in the presence of
Pd2(dba)3, JohnPhos, and KF in toluene. A mixture of mono-
coupled product 4a and di-coupled product 5a were obtained
bDepartment of Chemistry, Fudan University, 220 Handan Road, Shanghai,
200433, China. E-mail: jie_wu@fudan.edu.cn; Fax: +86 21 6564 1740;
Tel: 86 21 6510 2412
† Electronic supplementary information (ESI) available: General experi-
1
mental information, characterization data, H and 13C NMR spectra of
compounds 4–6. See DOI: 10.1039/c1ob05783a
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6265–6270 | 6265
©

View Online
Table 1 Initial studies for palladium-catalyzed reaction of 3-bromo-6-methyl-4-tosyloxy-2-pyrone 3 with phenylboronic acid
Entry
Pd2(dba)3 (mol%)
JohnPhos (mol%)
PhB(OH)2 (equiv.)
T/◦C
Yield (%)a (4a/5a)
1
2
3
4
5
6
7
8
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
5.0
7.5
5
5
5
5
5
5
5
5
1.5
1.5
1.5
1.5
1.5
1.1
2.0
3.0
1.5
1.5
85
75
60
40
rt
60
60
60
60
60
38/10
35/6
49/0
15/0
5/0
40/0
45/0
46/0
40/0
50/0
9
10
10
15
a Isolated yield based on 3-bromo-6-methyl-4-tosyloxy-2-pyrone 3.
in 38% and 10% yield, respectively (Table 1, entry 1) when the
reaction occurred at 85 ◦C catalyzed by 2.5 mol% of Pd2(dba)3 and
5 mol% of JohnPhos. The amount of compound 5a was reduced
when the temperature decreased (Table 1, entry 2). Only product
4a was generated when the reaction was performed at 60 ◦C with
a 49% isolated yield (Table 1, entry 3). However, the reaction
was retarded when the temperature was lower (Table 1, entries 4
and 5). No obvious influence was observed when the amount of
phenylboronic acid or palladium catalyst was changed (Table 1,
entries 6–10).
To further improve the reaction, we investigated other reaction
parameters, such as palladium catalyst, ligand, base, and solvent
(Table 2). To our delight, screeing of solvents (Table 2, entries
1–13) revealed that mono-coupled product 4a was generated in
92% yield when toluene/water (v/v: 2/1) was used as the co-
solvent in the presence of Pd2(dba)3, JohnPhos, and KF (Table 2,
entries 13), and no formation of 4-position coupled product was
observed. Reactions employing other palladium catalysts such as
Pd(OAc)2, Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd/C gave rise to the
corresponding product 4a in lower yields (Table 2, 14–17). Inferior
results were displayed when other ligands such as PPh3, Josiphos,
Xantphos, DPPF, and DIPF were examined (Table 2, entries 18–
23). No better results were obtained when different bases (Na2CO3,
K2CO3, Cs2CO3, NaHCO3, K3PO4·3H2O, K2HPO4·3H2O, and
Et3N) were used in the reaction (Table 2, entries 24–30).
Scheme 2 Synthesis of 3-aryl-4-tosyloxy-2-pyrone 4.
position. Our investigation began with the reaction of 6-methyl-
3-phenyl-4-tosyloxy-2-pyrone 4a with phenylboronic acid under
the above optimized reaction conditions. The expected product
5a was generated only in 28% yield. After screening of different
conditions, the best result (89% yield) was obtained when the
reaction was catalyzed by 5 mol% of Pd(OAc)2 and 10 mol% of
PCy3 in the presence of 3.0 equiv. of K2HPO4·3H2O in MeOH at
◦
90 C. To test the effectiveness of the 4-position couplings of 6-
methyl-3-aryl-4-tosyloxy-2-pyrone 4, a range of arylboronic acids
were examined under the optimized reaction conditions (Table 3).
As shown, various arylboronic acids bearing electron-withdrawing
as well as electron-donating substituents underwent the 4-position
cross-coupling reactions, providing 3,4-diarlyated 2-pyrones in fair
to excellent yields. For example, 6-methyl-3-phenyl-4-tosyloxy-
2-pyrone 4a coupled with 4-tolylboronic acid gave the desired
product 5b in 95% yield (Table 3, entry 2). Reaction of compound
4c with 4-chlorophenylboronic acid afforded the corresponding
product 5k in 80% yield (Table 3, entry 11). Various symmetrical
or unsymmetrical 3,4-diarylated 2-pyrones 5 could be generated as
well under the standard conditions. Again, when ester-substituted
phenylboronic acid was used in the reaction of 6-methyl-3-phenyl-
4-tosyloxy-2-pyrone 4a, the desired product 5l could be formed
with a 66% yield (Table 3, entry 12). However, only a trace
With this promising result in hands, we investigated the
cross-coupling reactions between 3-bromo-6-methyl-4-tosyloxy-2-
pyrone 3 and various arylboronic acids under optimized reaction
conditions [Pd2(dba)3 (2.5 mol%), JohnPhos (5 mol%), KF (3.0
equiv.), toluene/H2O = 2/1, 60 ◦C]. The results indicated that
arylboronic acids containing electron-donating or -withdrawing
groups could be successfully employed in the reaction, leading
to the corresponding 2-pyrone derivatives in good to excellent
isolated yields (Scheme 2). For instance, 4-methylphenyl-boronic
acid reacted with compound 3, giving rise to the desired product
4b in 83% yield. It is noteworthy that the ester group could be
tolerated under the standard conditions, and compound 4g was
isolated in 95% yield.
To further diversify the monocoupled 2-pyrones, we then
explored the reactivity of the remaining tosyloxy group at the C4
6266 | Org. Biomol. Chem., 2011, 9, 6265–6270
This journal is
The Royal Society of Chemistry 2011
©

View Online
Table 2 Condition screening for palladium-catalyzed reaction of 3-bromo-6-methyl-4-tosyloxy-2-pyrone 3 with phenylboronic acid
Entry
[Pd]
Ligand
Base
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd/C
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
—
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
Toluene
THF
MeCN
Dioxane
DCE
DMF
NMP
DMSO
49
5
27
Trace
41
nr
nr
nr
19
21
Trace
nr
92
49
58
64
24
44
45
52
33
42
51
43
33
45
66
38
49
56
9
Acetone
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
MeOH
tBuOH
H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
Toluene/H2O
PPh3
Josiphos
Xantphos
DPPF
DIPF
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
Na2CO3
K2CO3
Cs2CO3
NaHCO3
K3PO4·3H2O
K2HPO4·3H2O
Et3N
a Isolated yield based on 3-bromo-6-methyl-4-tosyloxy-2-pyrone 3.
amount of product was observed when compound 4 with electron-
withdrawing group attached to the aromatic ring in the 3-position
was used (Table 3, entries 13–15).
We also tried the one-pot synthesis of symmetrical
3,4-diarylated 2-pyrone derivatives from 3-bromo-6-methyl-4-
tosyloxy-2-pyrone 3 under the conditions shown in Table 2
(Scheme 3). Good yields were observed for the transformation
when arylboronic acids bearing eletron-donating or -withdrawing
substituents were used, by increasing the amount of arylboronic
acid to 3.0 equiv. compared to substrate 3. For instance, reaction of
compound 3 with 4-methylphenylboronic acid led to 2-pyrone 5e
in 73% yield. Trifluoromethyl- or ester-substituted phenylboronic
acid was a good partner as well in the conversion.
Conclusions
In summary, we have developed an efficient synthetic method
for the synthesis of 3,4-disubstituted 2-pyrones via a sequential
site-selective Pd-catalyzed Suzuki cross-coupling reactions of
3-bromo-6-methyl-4-tosyloxy-2-pyrone. This approach has the
potential for the rapid synthesis of bioactive substituted 2-pyrone
derivatives. Further studies for generation of diverse 2-pyrones are
currently underway in our laboratory.
Scheme 3 One-pot synthesis of symmetrical 3,4-diarylated 2-pyrones 5.
Experimental Section
Unless otherwise stated, all commercial reagents and solvents
were used without additional purification. All solvents were dried
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6265–6270 | 6267
©

View Online
Table 3 Palladium-catalyzed cross-coupling reactions of compound 4
126.0, 116.2, 102.4, 21.74, 21.34, 20.09; HRMS (ESI) Calcd for
C20H18O5SH (M+H+) 371.0953; Found, 371.0951.
with arylboronic acidsa
3-(4-Methoxylphenyl)-6-methyl-4-(4-methylbenzenesulfonyl-
1
oxy)-2-pyrone 4c. Yellow oil (62% yield). H NMR (400 MHz,
CDCl3) d 7.35 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 7.04
(d, J = 8.4 Hz, 2H), 6.74 (d, J = 8.4 Hz, 2H), 6.43 (s, 1H), 3.81
(s, 3H), 2.39 (s, 3H), 2.33 (s, 3H); 13C NMR (400 MHz, CDCl3) d
163.2, 161.2, 159.4, 155.9, 145.7, 131.3, 129.6, 127.9, 121.1, 115.1,
113.2, 102.5, 55.2, 21.7, 20.0; HRMS (ESI) Calcd for C20H18O6SNa
(M+Na+) 409.0722; Found, 409.0714.
Entry 4/Ar1
Ar2
Product 5 Yield (%)b
1
2
3
4
5
6
7
8
4a/C6H5
C6H5
5a
5b
5c
5d
5e
5f
5g
5h
5i
89
95
94
73
82
70
64
55
67
80
80
66
4a/C6H5
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-MeC6H5
4-MeOC6H4
4-ClC6H4
C6H5
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-MeO2CC6H4
4-MeOC6H4
4-ClC6H4
3-(4-Chlorophenyl)-6-methyl-4-(4-methylbenzenesulfonyloxy)-
4a/C6H5
4a/C6H5
◦
1
2-pyrone 4d. Yellow solid (59% yield), mp: 108.1–109.3 C. H
NMR (400 MHz, CDCl3) d 7.34 (d, J = 8.4 Hz, 2H), 7.16 (d, J =
8.4 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.43
(s, 1H), 2.34 (s, 3H), 2.23 (s, 3H); 13C NMR (400 MHz, CDCl3) d
163.0, 162.3, 156.8, 146.2, 134.3, 131.5, 129.7, 127.9, 127.8, 127.5,
114.9, 102.7, 21.7, 20.2; HRMS (ESI) Calcd for C19H15ClO5Na
(M+Na), 413.0226; Found, 413.0219.
4b/4-MeC6H4
4b/4-MeC6H4
4b/4-MeC6H4
4c/4-MeOC6H4
4c/4-MeOC6H4
4c/4-MeOC6H4
4c/4-MeOC6H4
4a/C6H5
9
10
11
12
13
14
15
5j
5k
5l
3-(2-Methoxyphenyl)-6-methyl-2-oxo-2H-pyran-4-yl 4-methyl-
benzenesulfonate 4e. Yellow solid (66% yield), mp: 134.9–136.2 ◦C.
1H NMR (400 MHz, CDCl3) d 7.37 (d, J = 8.0 Hz, 2H), 7.27 (d,
J = 12.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H),
6.77 (d, J = 8.0 Hz, 2H), 6.44 (s, 1H), 3.65 (s, 3H), 2.42 (s, 3H),
2.34 (s, 3H); 13C NMR (400 MHz, CDCl3) d 162.8, 161.8, 157.1,
157.0, 145.5, 132.0, 131.3, 130.3, 130.0, 129.7, 128.4, 127.9, 120.1,
118.3, 113.5, 110.8, 101.8, 55.4, 21.7, 20.1; HRMS (ESI) Calcd for
C20H18NaO6S (M+Na), 409.0722; Found, 409.0710.
4d/4-ClC6H4
4d/4-ClC6H4
4g/4-MeO2CC6H4 4-MeOC6H4
—
—
—
Trace
Trace
Trace
a Reaction conditions: substrate 4 (0.30 mmol), arylboronic acid (1.5
equiv.), Pd(OAc)2 (5 mol%), PCy3 (10 mol%), K2HPO4·3H2O (3.0 equiv.),
methanol (2.0 mL), 60 ◦C, 12 h, Ar. b Isolated yield based on compound
4.
and distilled according to standard procedures. All reactions
were performed in reaction tubes under Ar. The flash column
chromatography was performed using silica gel (60-A pore size,
6-Methyl-2-oxo-3-m-tolyl-2H-pyran-4-yl 4-methylbenzenesul-
1
˚
fonate 4f. Yellow oil (85% yield). H NMR (400 MHz, CDCl3)
32–63 mm, standard grade). Analytical thin–layer chromatography
was performed using glass plates pre-coated with 0.25 mm 230–400
mesh silica gel impregnated with a fluorescent indicator (254 nm).
Thin layer chromatography plates were visualized by exposure to
ultraviolet light. Organic solutions were concentrated on rotary
evaporators at ~20 Torr (house vacuum) at 25–35 ◦C. Nuclear
magnetic resonance (NMR) spectra are recorded in parts per
million from internal tetramethylsilane (TMS) on the d scale.
General procedure for the synthesis of compound 4 through
palladium-catalyzed reaction of compound 3 with arylboronic
acids: A mixture of compound 3 (0.3 mmol), arylboronic acid
(1.5 equiv.), Pd2(dba)3 (2.5 mol%), JohnPhos (5 mol%), and KF
(3.0 equiv.) in 3.0 mL of toluene/H2O (v/v:2/1) was stirred at
d 7.32 (d, J = 8.0 Hz, 2H), 7.12–7.04 (m, 4H), 6.91 (d, J = 4.0 Hz,
1H), 6.81 (s, 1H), 6.45 (s, 1H), 2.39 (s, 3H), 2.33 (s, 3H), 2.24 (s,
3H); 13C NMR (400 MHz, CDCl3) d 163.3, 161.7, 156.3, 145.7,
137.3, 131.6, 130.4, 129.6, 128.9, 128.5, 127.9, 127.7, 127.2, 116.3,
102.4, 21.7, 21.3, 20.1; HRMS (ESI) Calcd for C20H19O5S (M+H),
371.0953; Found, 371.0958.
Methyl 4-(6-methyl-2-oxo-4-(tosyloxy)-2H-pyran-3-yl)benzo-
◦
1
ate 4g. Yellow solid (95% yield), mp: 152.1–153.8 C. H NMR
(400 MHz, CDCl3) d 7.86 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0
Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.47
(s, 1H), 3.94 (s, 3H), 2.39 (s, 3H), 2.35 (s, 3H); 13C NMR (400
MHz, CDCl3) d 166.6, 162.8, 162.7, 157.1, 146.2, 133.9, 131.3,
130.1, 129.8, 129.6, 128.8, 127.8, 115.0, 102.5, 52.2, 21.6, 20.2;
HRMS (ESI) Calcd for C21H18NaO7S (M+Na), 437.0671; Found,
437.0678.
◦
60 C for 24 h. After completion of the reaction as indicated by
TLC, the solvent was evaporated under reduced pressure and the
residue was purified by column chromatography on silica gel to
produce the corresponding product 4.
General procedure for the generation of 3,4-disubstituted 2-
pyrones 5 through palladium-catalyzed reaction of compound
4 with arylboronic acids: A mixture of substrate 4 (0.3 mmol),
arylboronic acid (1.5 equiv.), Pd(OAc)2 (5 mol%), PCy3 (10 mol%),
and K2HPO4·3H2O (3.0 equiv.) in methanol (2.0 mL) was stirred
6-Methyl-4-(4-methylbenzenesulfonyloxy)-3-phenyl-2-pyrone
◦
1
4a. White solid (92% yield), mp: 125.7–127.0 C. H NMR (400
MHz, CDCl3) d 7.30 (d, J = 7.2 Hz, 2H), 7.26–7.18 (m, 3H), 7.08–
7.05 (m, J = 8 Hz, 4 Hz, 4H), 6.45 (s, 1H), 2.39 (s, 3H), 2.34 (s,
3H); 13C NMR (400 MHz, CDCl3) d 163.2, 161.8, 156.4, 145.8,
131.5, 130.0, 129.7, 128.5, 128.1, 127.9, 127.7, 116.1, 102.3, 21.69,
20.1; HRMS (ESI) Calcd for C19H16O5SNa (M+Na+), 379.0616;
Found, 379.0622.
◦
at 60 C for 12 h. After completion of the reaction as indicated
by TLC, the solvent was evaporated under reduced pressure and
the residue was purified by column chromatography on silica gel
to produce the corresponding product 5.
3,4-Diphenyl-6-methyl-2-pyrone 5a. Yellow solid (89% yield),
mp: 130.1–130.7 ◦C. 1H NMR (400 MHz, CDCl3) d 7.24–7.20 (m,
6H), 7.14–7.12 (m, 2H), 7.09–7.07 (m, 2H), 6.17 (s, 1H), 2.33 (s,
3H); 13C NMR (400 MHz, CDCl3) d 160.1, 152.6, 137.5, 133.8,
130.8, 128.7, 128.6, 128.2, 127.9, 127.5, 122.0, 107.1, 19.9; HRMS
(ESI) Calcd for C18H14NaO2 (M+Na) 285.0891; Found, 285.0895.
6-Methyl-4-(4-methylbenzenesulfonyloxy)-3-(4-methylphenyl)-
2-pyrone 4b. Yellow oil (83% yield). 1H NMR (400 MHz, CDCl3)
d 7.32 (d, J = 8.0 Hz, 2H), 7.06–6.96 (m, 6H), 6.42 (s, 1H), 2.39
(s, 3H), 2.33 (s, 3H), 2.32 (s, 3H); 13C NMR (400 MHz, CDCl3) d
163.4, 161.5, 156.2, 145.8, 138.1, 131.6, 129.9, 129.5, 128.4, 127.9,
6268 | Org. Biomol. Chem., 2011, 9, 6265–6270
This journal is
The Royal Society of Chemistry 2011
©

View Online
6-Methyl-4-(4-methylphenyl)-3-phenyl-2-pyrone 5b. Yellow
solid (95% yield), mp: 109.2–110.7 ◦C. 1H NMR (400 MHz,
CDCl3) d 7.22–7.15 (m, 3H), 7.15–7.13 (m, 2H), 7.02–6.96 (m,
4H), 6.16 (s, 1H), 2.31 (s, 3H), 2.28 (s, 3H); 13C NMR (400 MHz,
CDCl3) d 163.7, 159.9, 152.7, 138.8, 134.5, 134.2, 130.8, 128.9,
128.7, 128.0, 127.4, 121.6, 107.2, 21.3, 19.9; HRMS (ESI) Calcd
for C19H16O2Na (M+Na+) 299.1048; Found, 299.1044.
J = 8.8 Hz, 2H) 6.30 (s, 1H), 3.77 (s, 6H), 2.30 (s, 3H); 13C NMR
(400 MHz, CDCl3) d 163.7, 161.8, 158.7, 151.70, 132.0, 130.3,
128.2, 126.4, 120.8, 114.6, 113.7, 107.1, 103.2, 55.5, 55.2, 19.9.
HRMS (ESI) Calcd for C20H18O4Na (M+Na+), 345.1103; Found,
345.1088.
4-(4-Chlorophenyl)-3-(4-methoxylphenyl)-6-methyl-2-pyrone
1
5k. Yellow oil (80% yield). H NMR (400 MHz, CDCl3) d 7.21
4-(4-Methoxylphenyl)-6-methyl-3-phenyl-2-pyrone 5c. Yellow
solid (94% yield), mp: 109.3–110.0 ◦C. 1H NMR (400 MHz,
CDCl3) d 7.24–7.22 (m, 3H), 7.16 (d, J = 8.8 Hz, 2H), 7.03 (d,
J = 8.8 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 6.17 (s, 1H), 3.75 (s,
3H), 2.31 (s, 3H); 13C NMR (400 MHz, CDCl3) d 163.7, 159.9,
152.2, 134.3, 130.9, 130.4, 129.5, 128.1, 127.5, 121.1, 113.7, 107.1,
55.2, 19.9; HRMS (ESI) Calcd for C19H16O3Na (M+Na) 315.0997;
Found, 315.0997.
4-(4-Chlorophenyl)-6-methyl-3-phenyl-2-pyrone 5d. Yellow
solid (73% yield), mp: 120.9–122.0 ◦C. 1H NMR (400 MHz,
CDCl3) d 7.26–7.11 (m, 8H), 7.03–7.01 (m, 1H), 6.13 (s, 1H),
2.33 (s, 3H); 13C NMR (400 MHz, CDCl3) d 163.1, 160.4, 151.4,
135.9, 134.8, 133.5, 130.8, 130.1, 128.6, 128.2, 127.8, 122.2, 106.7,
19.9; HRMS (ESI) Calcd for C18H13ClO2Na (M+Na+) 319.0502;
Found, 319.0495.
(d, J = 8.8 Hz, 2H), 7.06–7.03 (m, 4H), 6.78 (d, J = 8.8 Hz, 2H),
6.10 (s, 1H), 3.76 (s, 3H), 2.31 (s, 3H); 13C NMR (400 MHz,
CDCl3) d 163.6, 159.9, 159.0, 150.8, 136.2, 134.6, 132.0, 130.1,
128.6, 125.6, 121.8, 113.7, 106.7, 55.2, 19.9; HRMS (ESI) Calcd
for C19H15ClO3Na (M+Na+) 349.0607; Found, 349.0601.
Methyl 4-(6-methyl-2-oxo-3-phenyl-2H-pyran-4-yl)benzoate
◦
1
5l. Yellow solid (66% yield), mp: 195.0–196.1 C. H NMR (400
MHz, CDCl3) d 7.90 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 4.0 Hz,
2H), 7.17 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 4.0 Hz, 2H), 6.17 (s,
1H), 3.89 (s, 3H), 2.35 (s, 3H); 13C NMR (400 MHz, CDCl3) d
166.4, 163.2, 160.5, 151.5, 142.1, 133.3, 130.7, 130.1, 129.5, 128.7,
128.1, 127.8, 122.6, 106.5, 52.2, 19.9; HRMS (ESI) Calcd for
C20H16NaO4 (M+Na+) 343.0946; Found, 343.0931.
6-Methyl-3,4-dim-tolyl-2H-pyran-2-one 5m. Yellow oil (71%
1
yield). H NMR (400 MHz, CDCl3) d 7.07–7.00 (m, 5H), 6.93
3,4-Di(4-methylphenyl)-6-methyl-2-pyrone 5e. Yellow oil (82%
yield). 1H NMR (400 MHz, CDCl3) d 7.03–6.97 (m, 8H), 6.14 (s,
1H), 2.30 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H); 13C NMR (400 MHz,
CDCl3) d 163.8, 159.6, 152.3, 138.7, 137.2, 134.7, 131.1, 130.6,
128.9, 128.8, 128.6, 121.6, 107.2, 21.3, 19.9; HRMS (ESI) Calcd
for C20H18NO2Na (M+Na+) 313.1204; Found, 313.1204.
4-(4-Methoxylphenyl)-6-methyl-3-(4-methylphenyl)-2-pyrone
(s, 1H), 6.88–6.82 (m, 2H), 6.16 (s, 1H), 2.31 (s, 3H), 2.23 (s, 3H);
13C NMR (400 MHz, CDCl3) d 163.7, 159.8, 152.7, 137.8, 137.4,
137.3, 133.8, 131.3, 129.3, 129.2, 128.3, 128.0, 127.9, 127.8, 125.8,
122.0, 107.1, 21.4, 21.3, 19.9; HRMS (ESI) Calcd for C20H18NaO2
(M+Na+) 313.1204; Found, 313.1215.
6-Methyl-3,4-bis(4-(trifluoromethyl)phenyl)◦-2H-pyran-2-one
5n. White crystal (60% yield), mp: 125.8-126.8 C. 1H NMR (400
MHz, CDCl3) d 7.54–7.49 (m, 4H), 7.25 (d, J = 8.0 Hz, 2H), 7.22
(d, J = 8.0 Hz, 2H), 6.18 (s, 1H), 2.37 (s, 3H); 13C NMR (400
MHz, CDCl3) d 162.6, 161.6, 152.0, 140.6, 137.0, 131.5, 130.9,
129.7, 128.9, 125.6 (dd), 125.2 (dd), 122.5, 122.2, 121.2, 106.6,
20.0; HRMS (ESI) Calcd for C20H12F6NaO2 (M+Na+) 421.0639;
Found, 421.0651.
◦
1
5f. Yellow solid (70% yield), mp: 135.7–137.1 C. H NMR (400
MHz, CDCl3) d 7.05–7.29 (m, 6H), 6.72 (d, J = 8.8 Hz, 2H), 6.15 (s,
1H), 3.76 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H); 13C NMR (400 MHz,
CDCl3) d 163.9, 159.8, 159.6, 151.8, 137.1, 131.2, 130.7, 130.3,
129.8, 128.8, 121.2, 113.7, 107.1, 55.2, 21.3, 19.9; HRMS (ESI)
Calcd for C20H18O3Na (M+Na+) 329.1154; Found, 329.1160.
4-(4-Chlorophenyl)-6-methyl-3-(4-methylphenyl)-2-pyrone 5g.
White solid (64% yield), mp: 131.6–132.6 ◦C. 1H NMR (400 MHz,
CDCl3) d 7.20 (d, J = 8.4 Hz, 2H), 7.05–7.03 (m, 4H), 7.01(d, J =
8.0 Hz, 2H), 6.11 (s, 1H), 2.32 (s, 3H), 2.29 (s, 3H); 13C NMR (400
MHz, CDCl3) d 163.5, 160.1, 150.9, 137.6, 136.1, 134.7, 130.6,
130.4, 130.1, 128.9, 128.6, 122.2, 106.7, 21.3, 19.9; HRMS (ESI)
Calcd for C19H15ClO2Na (M+Na+) 333.0658; Found, 333.0664.
3-(4-Methoxylphenyl)-6-methyl-4-phenyl-2-pyrone 5h. Yellow
6-Methyl-2-pyrone 5o. Yellow solid (60% yield), mp: 54.9–
◦
1
55.9 C. H NMR (400 MHz, CDCl3) d 7.90–7.87 (m, 4H), 7.22
(d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 6.20 (s, 1H), 3.89
(s, 3H), 3.88 (s, 3H), 2.36 (s, 3H); 13C NMR (400 MHz, CDCl3) d
166.6, 166.2, 162.6, 161.3, 152.4, 141.5, 138.3, 130.9, 130.4, 129.6,
129.3, 129.2, 128.6, 121.5, 106.6, 52.2, 52.1, 20.0; HRMS (ESI)
Calcd for C22H18NaO6 (M+Na+) 401.1001; Found, 401.1012.
1
oil (55% yield). H NMR (400 MHz, CDCl3) d 7.24–7.22 (m,
Acknowledgements
3H), 7.11–7.05 (m, 4H), 6.75 (d, J = 8.8 Hz, 2H), 6.15 (s, 1H), 3.75
(s, 3H), 2.32 (s, 3H); 13C NMR (400 MHz, CDCl3) d 163.8, 159.6,
158.8, 152.1, 137.8, 132.0, 128.6, 128.5, 128.3, 125.9, 113.5, 107.1,
55.1, 19.8; HRMS (ESI) Calcd for C19H17O3 (M+H+) 293.1178;
Found, 293.1170.
Financial support from the National Natural Science Foundation
of China (Nos. 20862009 and 20962010) and the Natural Science
Foundation of Jiangxi Province (No. 2008GQH0026) is gratefully
acknowledged.
3-(4-Methoxylphenyl)-6-methyl-4-(4-methylphenyl)-2-pyrone
1
5i. Yellow oil (67% yield). H NMR (400 MHz, CDCl3) d 7.08–
Notes and references
6.98 (m, 6H), 6.76 (d, J = 8.4 Hz, 2H), 6.13 (s, 1H), 3.76 (s, 3H),
2.30 (s, 3H), 2.29 (s, 3H); 13C NMR (400 MHz, CDCl3) d 163.9,
159.4, 158.8, 152.1, 138.6, 134.8, 132.0, 129.0, 128.6, 126.2, 121.2,
113.5, 107.2, 55.1, 21.2, 19.8; HRMS (ESI) Calcd for C20H19O3
(M+H+) 307.1334; Found, 307.1329.
1 (a) G. Schlingmann, L. Milne and G. T. Carter, Tetrahedron, 1998, 54,
13013; (b) X. Shi, W. S. Leal, Z. Liu, E. Schrader and J. Meinwald,
Tetrahedron Lett., 1995, 36, 71.
2 (a) R. W. Spencer, L. J. Copp and J. R. Pfister, J. Med. Chem., 1985, 28,
1828; (b) J. V. N. Vara Prasad, K. S. Para, E. A. Lunney, D. F. Ortwine,
J. B. Dunbar, D. Ferguson, P. J. Tummino, D. Hupe, B. D. Tait, J. M.
Domagala, C. Humblet, T. N. Bhat, B. Liu, D. A. M. Guerin, E. T.
Baldwin, J. W. Erickson and T. K. Sawyer, J. Am. Chem. Soc., 1994,
116, 6989; (c) P. N. P. Rao, M. J. Uddin and E. E. Knaus, J. Med. Chem.,
3,4-Di(4-methoxylphenyl)-6-methyl-2-pyrone 5j. Yellow oil
1
(80% yield). H NMR (400 MHz, CDCl3) d 7.09 (d, J = 8.4 Hz,
2H), 7.05 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 6.75 (d,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6265–6270 | 6269
©

View Online
2004, 47, 3972; (d) P. N. P. Rao, M. Amini, H. Li, A. G. Habeeb and
E. E. Knaus, J. Med. Chem., 2003, 46, 4872; (e) L. R. Marrison, J. M.
Dickinsona and I. J. S. Fairlamb, Bioorg. Med. Chem. Lett., 2002, 12,
3509.
12 (a) E. C. Gravett, P. J. Hilton, K. Jones and F. Romero, Tetrahedron
Lett., 2001, 42, 9081; (b) E. C. Gravett, P. J. Hilton, K. Jones and J. M.
Peron, Synlett, 2003, 253.
13 (a) F. Bellina, M. Biagetti, A. Carpita and R. Rossi, Tetrahedron
Lett., 2001, 42, 2859; (b) B. Danieli, G. Lesma, M. Martinelli,
D. Passarella, I. Peretto and A. Silvani, Tetrahedron, 1998, 54,
14081.
3 (a) G. H. Posner, C. G. Cho, T. E. N. Anjeh, N. Johnson, R. L. Horst, T.
Kobayashi, T. Okano and N. Tsugawa, J. Org. Chem., 1995, 60, 4617;
(b) L. Li, J. A. Bender and F. G. West, Tetrahedron Lett., 2009, 50, 1188;
(c) N. T. Tam and C. G. Cho, Org. Lett., 2008, 10, 601; (d) L. Li, C. E.
Chaseband and F. G. West, Chem. Commun., 2008, 4025; (e) R. Sagar,
J. Park, M. Koh and S. B. Park, J. Org. Chem., 2009, 74, 2171.
4 (a) N. H. Tam, E. J. Jung and C. G. Cho, Org. Lett., 2010, 12, 2012;
(b) N. H. Tam and C. G. Cho, Org. Lett., 2007, 9, 3391; (c) G. H. Posner,
T. D. Nelson, C. M. Kinter and J. N. Johnson, J. Org. Chem., 1992, 57,
4083; (d) C. J. Moody and K. F. Rahimtoola, J. Chem. Soc., Perkin
Trans. 1, 1990, 673.
5 (a) M. Rueping, E. Merino and A. Ugionoa, Adv. Synth. Catal., 2008,
350, 2127; (b) H. Miyauchia, C. Ikematsu, T. Shimazakib, S. Kato, T.
Shinmyozu, T. Shimo and K. Somekawa, Tetrahedron, 2008, 64, 4108.
6 (a) S. Mochida, K. Hirano, T. Satoh and M. Miura, J. Org. Chem.,
2009, 74, 6295; (b) Y. Kuninobu, A. Kawata, M. Nishi, H. Takata and
K. Takai, Chem. Commun., 2008, 6360; (c) T. Yao and R. C. Larock, J.
Org. Chem., 2003, 68, 5936; (d) S. Rousset, M. Abarbri, J. Thibonnet, J.
L. Parrainb and A. Duchenea, Tetrahedron Lett., 2003, 44, 7633; (e) R.
C. Larock, M. J. Doty and X. Han, J. Org. Chem., 1999, 64, 8770; (f) R.
C. Larock, X. Han and M. J. Doty, Tetrahedron Lett., 1998, 39, 5713;
(g) W. Henry and R. P. Hughes, J. Am. Chem. Soc., 1986, 108, 7862.
7 (a) L. R. Marrison, J. M. Dickinsona and I. J. S. Fairlamb, Bioorg.
Med. Chem. Lett., 2003, 13, 2667; (b) S. Cerezo, M. M. Manas and R.
Pleixats, Tetrahedron, 1998, 54, 7813.
8 (a) I. J. S. Fairlamb, L. R. Marrison, J. M. Dickinson, F. J. Lua and I.
J. S. Schmidt, Bioorg. Med. Chem., 2004, 12, 4285; (b) I. J. S. Fairlamb,
A. F. Lee, F. E. M. Loe-Mie, E. H. Niemela, C. T. O’Brien and A.
C. Whitwood, Tetrahedron, 2005, 61, 9827; (c) J. H. Lee, J. S. Park
and C. G. Cho, Org. Lett., 2002, 4, 1171; (d) L. R. Marrison, J. M.
Dickinsona, R. Ahmeda and I. J. S. Fairlamb, Tetrahedron Lett., 2002,
43, 8853; (e) E. H. Niemela, A. F. Lee and I. J. S. Fairlamb, Tetrahedron
Lett., 2004, 45, 3593; (f) I. J. S. Fairlamb, C. T. O’Brien, Z. Linb and
K. C. Lam, Org. Biomol. Chem., 2006, 4, 1213.
9 W. S. Kim, H. J. Kim and C. G. Cho, J. Am. Chem. Soc., 2003, 125,
14288.
10 J. H. Lee and C. G. Cho, Tetrahedron Lett., 2003, 44, 65.
11 (a) J. H. Lee, W. S. Kim, Y. Y. Leeb and C. G. Cho, Tetrahedron Lett.,
2002, 43, 5779; (b) Z. Liu and J. Meinwald, J. Org. Chem., 1996, 61,
6693.
14 G. H. Posner, W. Harrison and D. G. Wettlaufer, J. Org. Chem., 1985,
50, 5041.
15 (a) S. Schro¨ter, C. Stock and T. Bach, Tetrahedron, 2005, 61, 2245;
(b) P. Zezschwitz, F. Petry and A. Meijere, Chem.–Eur. J., 2001, 7,
4035; (c) K. Voigt, P. Zezschwitz, K. Rosauer, A. Lansky, A. Adams, O.
Reiser and A. Meijere, Eur. J. Org. Chem., 1998, 1521; (d) S. T. Handy
and J. J. Sabatini, Org. Lett., 2006, 8, 1537; (e) X.-F. Duan, X.-H. Li,
F.-Y. Li and C.-H. Huang, Synthesis, 2004, 2614; (f) I. Kaswasaki,
M. Yamashita and S. Ohta, J. Chem. Soc., Chem. Commun., 1994,
2085; (g) F. Bellina, A. Anselmi, F. Martina and R. Rossi, Eur. J. Org.
Chem., 2003, 2290; (h) F. Bellina, E. Falchi and R. Rossi, Tetrahedron,
2003, 59, 9091; (i) I. C. Christoforou and P. A. Koutentis, Org. Biomol.
Chem., 2007, 5, 1381; (j) I. Cerna, R. Pohl, B. Klepetarova and M.
Hocek, Org. Lett., 2006, 8, 5389; (k) R. Pereira, A. Furst, B. Iglesias,
P. Germain, H. Gronemeyerb and A. R. Lera, Org. Biomol. Chem.,
2006, 4, 4514; (l) J. X. Araujo-Junior, M. Schmitt, P. Benderittera and
J. Bourguignon, Tetrahedron Lett., 2006, 47, 6125; (m) T. T. Dang,
N. Rasool, H. Reinkea and P. Langer, Tetrahedron Lett., 2007, 48,
845.
16 (a) I. J. S. Fairlamb, Chem. Soc. Rev., 2007, 36, 1036; (b) F. Bellinaa
and R. Rossi, Adv. Synth. Catal., 2010, 352, 1223; (c) N. T. Hung, M.
Hussain, I. Malik, A. Villinger and P. Langer, Tetrahedron Lett., 2010,
51, 2420; (d) J. H. Chang, H. U. Kang, I. K. Jung and C. G. Cho, Org.
Lett., 2010, 12, 2016; (e) X. Zhang, W. Xie and W. Chen, Tetrahedron,
2010, 66, 1188; (f) L. Zhang, T. Meng, R. Fan and J. Wu, J. Org.
Chem., 2007, 72, 7279; (g) D. Conreaux, E. Bossharth, N. Monteiro,
P. Desbordes, J. Vors and G. Balme, Org. Lett., 2007, 9, 271; (h) K.
Ryu, Y. S. Cho, S. I. Jung and C. G. Cho, Org. Lett., 2006, 8, 3343;
(i) W. S. Kim, H. J. Kim and C. G. Cho, J. Am. Chem. Soc., 2003, 125,
14288; (j) F. Bellina, C. Anselmi, S. Viel, L. Mannina and R. Rossi,
Tetrahedron, 2001, 57, 9997.
17 For selected examples, see: (a) D. Alonso, I. P. Beletskaya and M. Yus,
Tetrahedron, 2008, 64, 3047; (b) A. Suzuki, Proc. Jpn. Acad., Ser. B,
Phys. Biol. Sci., 2004, 80, 359; (c) S. Kotha, K. Lahiri and D. Kashinath,
Tetrahedron, 2002, 58, 9633; (d) Y. Peng, J. Liu, X. Lei and Z. Yin, Green
Chem., 2010, 12, 1072; (e) C. M. So, C. P. Lau, A. S. C. Chan and F. Y.
Kwong, J. Org. Chem., 2008, 73, 7731.
6270 | Org. Biomol. Chem., 2011, 9, 6265–6270
This journal is
The Royal Society of Chemistry 2011
©