Synthesis of 6-substituted 3-(alkoxycarbonyl)-5-aryl-α-pyrones

Article abstract of DOI:10.1055/s-0033-1338575

An efficient synthesis of 6-substituted 3-(alkoxycarbonyl)-5-aryl-α- pyrones is reported. This methodology consists of the successive manipulation of an addition-elimination reaction between benzyl ketone derivatives and dimethyl methoxymethylenemalonate,

Full text of DOI:10.1055/s-0033-1338575

496▌
PAPER
paper
Synthesis of 6-Substituted 3-(Alkoxycarbonyl)-5-aryl-α-pyrones
6-Substituted 3-(Alkoxycarbonyl)-5-aryl-α-pyrones
Takuya Miura, Saki Fujioka, Naoto Takemura, Hiroki Iwasaki, Minoru Ozeki, Naoto Kojima, Masayuki Yamashita*
Kyoto Pharmaceutical University, 1 Misasagi-Shichono, Yamashina, Kyoto 607-8412, Japan
Fax +81(75)5954775; E-mail: yamasita@mb.kyoto-phu.ac.jp
Received: 22.10.2013; Accepted after revision: 18.11.2013
aromatic compound 2 (Scheme 1).4 Moreover, we have
Abstract: An efficient synthesis of 6-substituted 3-(alkoxycarbon-
recently reported the skeleton transformation reaction of
yl)-5-aryl-α-pyrones is reported. This methodology consists of the
α-pyrone 1 into bicyclo[3.1.0]hexane derivative 3 using
successive manipulation of an addition–elimination reaction be-
tween benzyl ketone derivatives and dimethyl methoxymethylene-
dimethyl sulfoxonium methylide [H2C=S(O)Me2].5 In the
malonate, and an acid-catalyzed condensation reaction. The course of our study, we were interested in the reactivity of
synthesis is applicable to various 5-p-substituted-aryl 6-substituted
α-pyrones and good to excellent yields were obtained over two steps
from benzyl ketone derivatives that were easily prepared from
several methods for the synthesis of α-pyrones with an
phenylacetic acid by the Negishi coupling or the Claisen decarbox-
ylation reaction.
5-aryl-α-pyrone derivative as the reaction substrate under
skeleton transformation reaction conditions. Although
electron-withdrawing group in the 3-position have been
reported,6 as far as we know, there are few reports of the
Key words: α-pyrone, heterocycles, 1,4-addition, condensation,
synthesis of 5-aryl-α-pyrone derivatives with an electron-
ketones
withdrawing group in the 3-position.6b,7 Herein, we report
an efficient synthesis of 6-substituted 3-(alkoxycarbonyl)-
5-aryl-α-pyrones through successive manipulations.
The α-pyrone (2H-pyran-2-one) ring system is found in
various natural products1 and pharmacologically active
O
O
compounds, such as non-peptidic HIV-1 protease inhibi-
MeO
OMe
OMe
tors.2 Furthermore, α-pyrones that contain conjugated di-
enes and ester groups have found use as reliable building
blocks.3
base
THF
OMe
O
O
O
O
4
5
1
OR
O
O
O
OMe
OMe
1,4-addition–
elimination
condensation
cyclization
OR
OMe
(A) Diels–Alder reaction
OR
O
2
6
O
5
6
Scheme 2 Synthesis of α-pyrone via 1,4-addition–elimination and
condensation–cyclization
OMe
3
O
O
O
O
1
One of the most convenient and reliable methods for the
synthesis of α-pyrone 1 is the condensation–cyclization
reaction between cyclic ketone 4 and dimethyl methoxy-
methylenemalonate (5)8 under basic conditions (Scheme
2).4,9 In this case, the enolate of cyclic ketone 4 displaces
the terminal methoxy group of 5 by a 1,4-addition–elimi-
nation reaction to yield adduct 6. Then, 6 is subjected to
lactonization to form α-pyrone 1 in one step. We applied
Boger and Mullican’s method9 to cyclic ketones to obtain
the desired compounds in good yields.5 Next, we applied
this method to the synthesis of 5-aryl-α-pyrones. Instead
of cyclic ketone 4, acyclic benzyl ketone derivative 7a
was treated with dimethyl methoxymethylenemalonate
(5)8 using lithium diisopropylamide or lithium hexameth-
yldisilazanide in tetrahydrofuran. Unfortunately, desired
product 8a was obtained in 28% and 32% yields, respec-
tively (Table 1, entries 1 and 2). The addition of 5 Å mo-
lecular sieves enhanced the product yield to 60% (entry
3). However, when the reaction conditions used in Table
H
OMe
CH2=S(O)Me2
H
(B) skeleton transformation
reaction (our group)
O
3
Scheme 1 Reactivity of α-pyrone with an electron-withdrawing
group at the 3-position
The introduction of an electron-withdrawing group at the
3-position of α-pyrone plays an important role in the reac-
tivity of α-pyrone. α-Pyrone 1 with an electron-withdraw-
ing group at the 3-position is a good substrate for the
inverse-electron-demand Diels–Alder reaction, forming
SYNTHESIS 2014, 46, 0496–0502
Advanced online publication: 16.12.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338575; Art ID: SS-2013-F0692-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
6-Substituted 3-(Alkoxycarbonyl)-5-aryl-α-pyrones
497
1, entry 3 were applied to the synthesis of 5-p-substituted-
aryl α-pyrones 8b–f, either no product was obtained or
product was obtained in low yield (Scheme 3). From this
disappointing outcome, we assumed that further condition
optimization was necessary to obtain useful methodology
for the synthesis of α-pyrones 8b–f. To obtain the desired
products 8a–f in good yields, the reaction must proceed
via thermodynamically controlled enolates of 7a–f, which
are formed by deprotonation at the α-position between the
phenyl group and the carbonyl group in 7a–f with a base.
It was considered that lithium hexamethyldisilazanide, a
relatively bulky base, was unsuitable for this reaction.
Thus, we selected conditions that used sodium hydride at
room temperature so that the reaction would proceed via
thermodynamically controlled enolates of 7a–f. Although
a complex mixture was obtained under the conditions in
which sodium hydride was employed instead of lithium
hexamethyldisilazanide (Table 1, entry 4), changing the
solvent from tetrahydrofuran to dimethyl sulfoxide in-
creased the yield of the reaction intermediates 9 and 10
(Figure 1), and 8a was obtained in 7% yield after purifica-
tion (entry 5). Reaction intermediates 9 and 10 were sug-
gested to be formed by the addition reaction between 7a
and 5 without further condensation–cyclization reaction
under basic conditions. The flexibility of intermediates 9
and 10, which were produced from acyclic ketone 7a,
would be disadvantageous for the cyclization compared
with the case using cyclic ketone 4. Thus, we explored the
optimum conditions in which reaction intermediates 9 and
10 would be converted into the desired product 8a.
O
O
MeO
OMe
OMe
OMe
OMe
O
O
Et
O
Et
O
9
10
Figure 1 Noncyclized intermediates 9 and 10
O
MeO
OMe
OMe
R
O
O
5
O
R
O
OMe
LHMDS, 5 Å MS
Et THF, r.t., 21 h
Et
O
7b R = F
8b R = F, 29%
8c R = CF3, 23%
8d R = NO2, 26%
8e R = OMe, –
8f R = Ph, –
7c R = CF3
7d R = NO2
7e R = OMe
7f R = Ph
Scheme 3 Disappointing results of 5-p-substituted aryl-α-pyrone
synthesis under conditions specified in Table 1, entry 3
The acid-catalyzed condensation cyclization is a classic
strategy for the construction of an α-pyrone ring system.
In 1902, Buchner and Schroder reported the acid-cata-
lyzed condensation cyclization of a synthetic intermediate
using hydrochloric acid that furnished 5-alkyl-α-pyrone-
6-carboxylic acid.10 Other groups reported the synthesis
of α-pyrone derivatives under acidic conditions.11 Our
preliminary study revealed the applicability of acid-cata-
lyzed condensation cyclization using acetic acid (Scheme
4).12,13 A mixture of reaction intermediates 9 and 10 was
heated under reflux in acetic acid for 19 hours, and the two
spots of 9 and 10 on a TLC plate converged to form an al-
most single spot of α-pyrone 8a. To summarize the re-
sults, after the formation of a thermodynamically
controlled enolate in the reaction of benzyl ketone deriva-
tive 7a with sodium hydroxide in dimethyl sulfoxide at
room temperature, malonate 5 was added in the presence
of 5 Å molecular sieves, and the resulting crude mixture
was refluxed in acetic acid. This was followed by purifi-
cation by silica gel column chromatography to give the
desired α-pyrone 8a in 80% yield in two steps through
successive manipulations with one purification (entry 6).
Table 1 Optimization of Conditions
O
MeO
OMe
OMe
O
O
5
O
Ph
Et
O
OMe
base, additive
r.t.
Et
O
7a
8a
Entry
Base
Additive
Solvent Time (h) Yielda (%)
1
2
3
4
5
6
LDAb
–
–
THF
22
24
21
21
22
22
28
LHMDSc
THF
32
LHMDSc 5 Å MS
THF
60
O
O
NaHd
NaHd
NaHd
5 Å MS
5 Å MS
5 Å MS
THF
complex
7e,f
MeO
OMe
OMe
OMe
OMe
AcOH
8a
DMSO
DMSO
reflux
19 h
81%
O
O
80g
Et
O
Et
O
9
10
a Isolated yield unless otherwise indicated.
b The enolate was prepared from 7a with LDA at –78 °C to –5 °C.
c The enolate was prepared from 7a with LHMDS at 0 °C.
d The enolate was prepared from 7a with NaH at r.t.
e Determined by 1H NMR.
9/10 = 5:1
Scheme 4 Preliminary study of acid-catalyzed condensation cycliza-
tion
f Compounds 9 and 10, which are noncyclized intermediates, were
also obtained in 70% and 3% yields, respectively.
g The crude mixture was refluxed with AcOH for 16 h.
In order to establish the generality of the synthesis of α-
pyrone, benzyl ketone derivatives 7b–f, 12, 13, and 15 as
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 496–502

498
T. Miura et al.
PAPER
substrates were prepared from commercially available
phenylacetic acids 11, as shown in Scheme 5. Benzyl eth-
yl ketone derivatives 7b–f containing such substituents as
F, CF3, NO2, OMe, and Ph at the para position of the ben-
zene ring were prepared by Negishi coupling.14 In the cas-
es of aryl benzyl ketone derivatives 12 and 13, the Claisen
decarboxylation reaction15 was employed. With the
Claisen decarboxylation reaction, thiophene-2-acetic acid
(14) could be also converted into the corresponding ke-
tone derivative 15.
R1
R1
a or b
O
O
OH
R2
11
7b R1 = F, R2 = Et, 70%
7c R1 = CF3, R2 = Et, 74%
7d R1 = NO2, R2 = Et, 55%
7e R1 = OMe, R2 = Et, 99%
7f R1 = Ph, R2 = Et, 79%
12 R1 = CF3, R2 = Ph, 64%
13 R1 = CF3, R2 = 2-furyl, 83%
The scope and limitations of α-pyrone synthesis are sum-
marized in Table 2. The introduction of an electron-with-
drawing (F, CF3, NO2) or an electron-donating (Ph, OMe)
group to the para position of the phenyl group was accept-
able, giving the corresponding α-pyrones 8b–f in moder-
ate yields (entries 1–5). α-Pyrones 8g and 8h having
isopropyl and butyl groups at the 6-position were also
synthesized in good yields, 90% and 79%, respectively
(entries 6 and 7). In the cases of α-pyrones having aryl
groups at the 6-position (entries 8–11), the lithium hexa-
methyldisilazanide and tetrahydrofuran system was used
instead of the sodium hydride and dimethyl sulfoxide sys-
tem to furnish the corresponding α-pyrones 8i–l in moder-
ate to good yields, because the substrates contained only
one deprotonation position at the α-position of carbonyl
groups and there was no problem about selectivity for the
formation of enolates. In fact, the lithium hexamethyldis-
ilazanide and tetrahydrofuran system was favorable for
S
O
S
O
c
70%
OH
Ph
15
14
Scheme 5 Synthesis of benzyl ketone derivatives. Reagents and con-
ditions: (a) 1. (COCl)2, DMF (cat.), CH2Cl2, r.t., 1 h; 2. Pd(PPh3)4,
Et2Zn, benzene, r.t., 14–20 h for 7b–f; (b) R2CO2Me, NaHMDS,
THF, DMF, –10 °C, 3.5 h for 12 and 13; (c) PhCO2Me, NaHMDS,
THF, DMF, –10 °C, 3.5 h.
the synthesis of α-pyrone 8j, which was obtained in higher
yield using this system (77%) than using sodium hydride
and dimethyl sulfoxide (58%) (entry 9). In this synthesis
method, heterocycles were accommodated at the 5- or 6-
position. Benzyl furyl ketone 13 was converted into α-py-
rone 8k in 75% yield, which contained a furan moiety at
Table 2 Scope and Limitations
O
MeO
OMe
OMe
i)
5
O
O
O
O
Ar
base, 5 Å MS
solvent, r.t.
OMe
Ar
R
ii) AcOH, reflux
R
O
Entry
Substrate
Ar
R
Base, solvent
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
7b
7c
7d
7e
7f
4-FC6H4
4-F3CC6H4
4-O2NC6H4
4-MeOC6H4
4-PhC6H4
Ph
Et
NaH, DMSO
NaH, DMSO
NaH, DMSO
NaH, DMSO
NaH, DMSO
NaH, DMSO
NaH, DMSO
LHMDS, THF
8b
8c
8d
8e
8f
68
65
66
73
57
90
79
85
Et
Et
Et
Et
7g
7h
7i
i-Pr
Bu
Ph
Ph
8g
8h
8i
Ph
Ph
12
4-F3CC6H4
LHMDS, THF
NaH, DMSO
8j
77
58
10
11
13
15
4-F3CC6H4
2-thienyl
2-furyl
Ph
LHMDS, THF
LHMDS, THF
8k
8l
75
57
a Isolated yield.
Synthesis 2014, 46, 496–502
© Georg Thieme Verlag Stuttgart · New York

PAPER
6-Substituted 3-(Alkoxycarbonyl)-5-aryl-α-pyrones
499
IR (CHCl3): 1714 cm–1.
the 6-position (entry 10). 5-(2-Thienyl)-α-pyrone 8l was
1H NMR (400 MHz, CDCl3): δ = 1.06 (t, J = 7.2 Hz, 3 H), 2.51 (q,
J = 7.2 Hz, 2 H), 3.76 (s, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.59 (d,
J = 8.0 Hz, 2 H).
also accessible in moderate yield (entry 11).
In conclusion, we have developed an efficient procedure
for the synthesis of 6-substituted 3-(alkoxycarbonyl)-5-
aryl-α-pyrones. Our method produced α-pyrone deriva-
tives in moderate to good yields in two steps through suc-
cessive manipulations of the addition–elimination
reaction by using the sodium hydride and dimethyl sulfox-
ide or lithium hexamethyldisilazanide and tetrahydrofu-
ran systems and acid-catalyzed condensation–cyclization
in acetic acid. This method allowed the easy incorporation
of a range of substituents into the benzene ring in the 5-
position and 6-position of the α-pyrone. Benzyl ketone de-
rivatives, substrates of the α-pyrone synthesis, were easily
prepared from the corresponding phenylacetic acid deriv-
atives via the Negishi coupling reaction or the Claisen de-
carboxylation reaction. The reactivities of these 3-
(alkoxycarbonyl)-5-aryl-α-pyrones will be reported in
due course.
13C NMR (100 MHz, CDCl3): δ = 7.7, 35.7, 49.1, 124.1 (q,
3
1JC,F = 270.6 Hz), 125.5 (q, JC,F = 3.8 Hz, 2 C), 129.3 (q,
2JC,F = 23.3 Hz), 129.8 (2 C), 138.3, 207.7.
MS (EI): m/z (%) = 216 (M+, 5.0), 159 (52.5), 109 (27.7), 57
(100.0).
HRMS (EI): m/z [M]+ calcd for C11H11F3O: 216.0762; found:
216.0765.
1-(4-Nitrophenyl)butan-2-one (7d)
Following the typical procedure for 7b using 2-(4-nitrophenyl)ace-
tic acid (1.00 g, 5.52 mmol) gave 7d as yellowish prisms; yield: 584
mg (55%); mp 47–51 °C (n-hexane).
IR (CHCl3): 1716, 1607, 1348 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.08 (t, J = 7.4 Hz, 3 H), 2.55 (q,
J = 7.4 Hz, 2 H), 3.83 (s, 2 H), 7.37 (br d, J = 9.0 Hz, 2 H), 8.19 (br
d, J = 9.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 7.7, 36.0, 48.9, 123.7 (2 C), 130.4
(2 C), 141.7, 147.0, 206.9.
MS (EI): m/z (%) = 193 (M+, 3.4), 137 (23.6), 57 (100.0).
HRMS (EI): m/z [M]+ calcd for C10H11NO3: 193.0739; found:
193.0733.
All commercial reagents were used without further purification.
Melting points were measured with a Yanaco MP micro-melting
point apparatus and are uncorrected. NMR spectra were measured
on Jeol AL-270 (1H: 270 MHz) and Varian Inova 400NB (1H: 400
MHz; 13C: 100 MHz) spectrometers with TMS as internal standard.
IR spectra were recorded with a Shimadzu FTIR-8400. A JEOL
JMS-GC mate spectrometer was used for low-resolution and high-
resolution electron ionization MS (LR-EIMS and HR-EIMS). Silica
gel 60N (Kanto Chemical Co., Inc.) was used for column chroma-
tography.
1-(4-Methoxyphenyl)butan-2-one (7e)16
Following the typical procedure for 7b using 2-(4-methoxyphe-
nyl)acetic acid (3.00 g, 18.1 mmol) gave 7e as a yellowish liquid;
yield: 3.18 g (99%).
1H NMR (270 MHz, CDCl3): δ = 1.22 (t, J = 7.3 Hz, 3 H), 2.46 (q,
J = 7.3 Hz, 2 H), 3.62 (s, 2 H), 3.80 (s, 3 H), 6.84–6.89 (m, 2 H),
7.10–7.15 (m, 2 H).
1-(4-Fluorophenyl)butan-2-one (7b); Typical Procedure for the
Negishi Coupling Reaction14
1-(Biphenyl-4-yl)butan-2-one (7f)17
Following the typical procedure for 7b using 2-(biphenyl-4-yl)ace-
tic acid (1.00 g, 4.71 mmol) gave 7f as a yellowish solid; yield: 831
mg (79%).
1H NMR (270 MHz, CDCl3): δ = 1.06 (t, J = 7.3 Hz, 3 H), 2.52 (q,
J = 7.3 Hz, 2 H), 3.74 (s, 2 H), 7.22–7.60 (m, 9 H).
Oxalyl chloride (0.943 mL, 11.0 mmol) was added to a solution of
2-(4-fluorophenyl)acetic acid (1.00 g, 6.49 mmol) in CH2Cl2 (15
mL) at 0 °C. The reaction was initiated by the addition of 5 drops of
DMF. After 30 min at 0 °C, the mixture was allowed to warm to r.t.
and stirred for an additional hour. The solvents were evaporated and
the residue was dissolved in benzene (15 mL). Then, Pd(PPh3)4 (300
mg, 0.260 mmol) was added. After cooling to 0 °C, 1.06 M Et2Zn
in n-hexane (6.12 mL, 6.49 mmol) was added dropwise and the mix-
ture was stirred at r.t. for 15 h. After quenching by the addition of
water, the mixture was filtered over a Celite® pad and the filtrate
was extracted with EtOAc (3 ×). The combined organic layers were
washed with brine, dried (Na2SO4), filtered, and concentrated in
vacuo. The crude product was purified by column chromatography
(silica gel, n-hexane–EtOAc, 10:1) to give 7b (704 mg, 70%) as a
colorless liquid.
1-Phenyl-2-[4-(trifluoromethyl)phenyl]ethanone(12);18 Typical
Procedure for Claisen Decarboxylation Reaction15
To a solution of 2-[4-(trifluoromethyl)phenyl]acetic acid (200 mg,
0.980 mmol) and methyl benzoate (0.120 mL, 0.980 mmol) in DMF
was added 1.1 M NaHMDS in THF (3.60 mL, 3.96 mmol) at –10
°C over 1 min. The mixture was stirred at –10 °C for 3.5 h. To the
resulting mixture was added sat. aq NH4Cl and extraction was car-
ried out with EtOAc (3 ×). The combined organic layers were
washed with water, dried (Na2SO4), filtered, and concentrated in
vacuo. The crude product was purified by column chromatography
(silica gel, n-hexane–EtOAc, 10:1) to give 12 (165 mg, 64%) as a
white solid.
IR (CHCl3): 1717, 1510 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.04 (t, J = 7.2 Hz, 3 H), 2.48 (q,
J = 7.2 Hz, 2 H), 3.67 (s, 2 H), 6.98–7.04 (m, 2 H), 7.14–7.19 (m, 2
H).
13C NMR (100 MHz, CDCl3): δ = 7.7, 35.3, 48.7, 115.5 (d,
2JC,F = 21.2 Hz, 2 C), 130.1 (d, 4JC,F = 3.1 Hz), 130.9 (d, 3JC,F = 8.0
Hz, 2 C), 161.9 (d, 1JC,F = 244.0 Hz), 208.7.
MS (EI): m/z (%) = 166 (M+, 10.3), 109 (38.5), 57 (100.0).
HRMS (EI): m/z [M]+ calcd for C10H11FO: 166.0794; found:
1H NMR (270 MHz, CDCl3): δ = 4.36 (s, 2 H), 7.37–7.63 (m, 7 H),
8.00–8.04 (m, 2 H).
1-(2-Furyl)-2-[4-(trifluoromethyl)phenyl]ethanone (13)
Following the typical procedure for 12 using 2-[4-(trifluorometh-
yl)phenyl]acetic acid (204 mg, 1.00 mmol) gave 13 as colorless
prisms; yield: 211 mg (83%); mp 120–122 °C (n-hexane).
166.0790.
IR (KBr): 1676, 1468 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.12 (s, 2 H), 6.57 (dd, J = 1.8, 3.6
Hz, 1 H), 7.26 (dd, J = 0.8, 3.6 Hz, 1 H), 7.43 (br d, J = 8.0 Hz, 2
H), 7.59 (br d, J = 8.0 Hz, 2 H), 7.62 (dd, J = 0.8, 1.8 Hz, 1 H).
1-[4-(Trifluoromethyl)phenyl]butan-2-one (7c)
Following the typical procedure for 7b using 2-[4-(trifluorometh-
yl)phenyl]acetic acid (1.00 g, 4.90 mmol) gave 7c as a white amor-
phous solid; yield: 787 mg (74%).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 496–502

500
T. Miura et al.
PAPER
13C NMR (100 MHz, CDCl3): δ = 44.9, 112.6, 118.0, 124.1 (q,
MS (EI): m/z (%) = 276 (M+, 100.0), 248 (46.7), 233 (42.0), 191
(92.5).
HRMS (EI): m/z [M]+ calcd for C15H13FO4: 276.0798; found:
276.0796.
3
1JC,F = 262.2 Hz), 125.5 (q, JC,F = 3.8 Hz, 2 C), 129.3 (q,
2JC,F = 32.2 Hz), 129.9 (2 C), 137.9, 146.8, 152.2, 185.6.
MS (EI): m/z (%) = 254 (M+, 5.3), 95 (100.0).
HRMS (EI): m/z [M]+ calcd for C13H9F3O2: 254.0554; found:
254.0559.
Methyl 6-Ethyl-2-oxo-5-[4-(trifluoromethyl)phenyl]-2H-pyran-
3-carboxylate (8c)
Following the typical procedure for 8a using 7c (521 mg, 2.41
mmol) gave 8c as a pale yellow amorphous solid; yield: 513 mg
(65%, 2 steps).
IR (CHCl3): 1765, 1742, 1713, 1545 cm–1.
1-Phenyl-2-(2-thienyl)ethanone (15)
Following the typical procedure for 12 using thiophene-2-acetic
acid (14, 1.00 g, 7.03 mmol) gave 15 as a white amorphous solid;
yield: 1.00 g (70%).
1H NMR (400 MHz, CDCl3): δ = 1.28 (t, J = 7.6 Hz, 3 H), 2.60 (q,
J = 7.6 Hz, 2 H), 3.92 (s, 3 H), 7.41 (dd, J = 0.6, 8.7 Hz, 2 H), 7.73
(dd, J = 0.6, 8.7 Hz, 2 H), 8.20 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 11.9, 25.6, 52.8, 114.2, 116.6,
123.8 (q, 1JC,F = 270.5 Hz), 126.0 (q, 3JC,F = 4.0 Hz, 2 C), 129.3 (2
C), 130.7 (q, 2JC,F = 32.6 Hz), 138.4, 151.8, 157.6, 163.8, 170.2.
MS (EI): m/z (%) = 326 (M+, 100.0), 298 (63.3), 283 (49.6), 241
(61.8).
HRMS (EI): m/z [M]+ calcd for C16H13F3O4: 326.0766; found:
326.0769.
IR (CHCl3): 1686, 1599 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.490 (br s, 1 H), 4.493 (br s, 1 H),
6.93–6.95 (m, 1 H), 6.97 (dd, J = 3.2, 5.0 Hz, 1 H), 7.23 (dd, J = 1.6,
5.0 Hz, 1 H), 7.46–7.50 (m, 2 H), 7.58 (tt, J = 1.4, 7.6 Hz, 1 H),
8.01–8.04 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 39.4, 125.1, 126.8, 126.9, 128.6
(2 C), 128.7 (2 C), 133.4, 135.5, 136.1, 196.0.
MS (EI): m/z (%) = 202 (M+, 27.8), 105 (100.0), 97 (20.5), 77
(70.9).
HRMS (EI): m/z [M]+ calcd for C12H10O4S: 202.0452; found:
202.0449.
Methyl 6-Ethyl-5-(4-nitrophenyl)-2-oxo-2H-pyran-3-carboxyl-
ate (8d)
Following the typical procedure for 8a using 7d (1.02 g, 5.29 mmol)
gave 8d as yellowish prisms; yield: 1.06 g (66%, 2 steps); mp 132–
135 °C (n-hexane–EtOAc).
Methyl 6-Ethyl-2-oxo-5-phenyl-2H-pyran-3-carboxylate (8a);
Typical Procedure for 6-Substituted 3-(Alkoxycarbonyl)-5-
aryl-α-pyrones
To a stirred suspension of 1-phenylbutan-2-one (7a, 1.00 mL, 6.68
mmol) and 5 Å MS (508 mg) in DMSO (20 mL) was added NaH
(60% in oil, 294 mg, 7.35 mmol) in one portion at r.t. and the mix-
ture was stirred for 1 h. Dimethyl methoxymethylenemalonate (5,
1.40 g, 8.02 mmol) in DMSO (10 mL) was added at r.t. and the mix-
ture was stirred for 22 h. After acidification with aq 1 M HCl to pH
4 in an ice water bath, the mixture was filtered over Celite® pad and
the filtrate was extracted with Et2O (3 ×). The combined organic
layer was washed with H2O, dried (Na2SO4), filtered, and concen-
trated in vacuo to give the crude material as a yellow oil (2.27 g).
The crude material was dissolved in AcOH (40 mL) and the solution
was refluxed (oil bath temp: 135 °C). After 16 h, the mixture was
concentrated in vacuo to afford the crude product as an orange oil.
The crude product was purified by column chromatography (silica
gel, n-hexane–EtOAc, 3:1) to give 8a (1.38 g, 80%) as a pale yellow
oil.
IR (KBr): 1753, 1709, 1599, 1547, 1524 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.30 (t, J = 7.4 Hz, 3 H), 2.61 (q,
J = 7.4 Hz, 2 H), 3.92 (s, 3 H), 7.48 (dt, J = 2.2, 9.0 Hz, 2 H), 8.20
(s, 1 H), 8.33 (dt, J = 2.2, 9.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 11.9, 25.7, 52.8, 114.4, 115.9,
124.2 (2 C), 129.9 (2 C), 141.3, 147.7, 151.2, 157.2, 163.6, 170.4.
MS (EI): m/z (%) = 303 (M+, 100.0), 275 (84.0), 260 (39.7), 218
(62.4).
HRMS (EI): m/z [M]+ calcd for C15H13NO6: 303.0743; found:
303.0741.
Methyl 6-Ethyl-5-(4-methoxyphenyl)-2-oxo-2H-pyran-3-car-
boxylate (8e)
Following the typical procedure for 8a using 7e (1.03 g, 5.78 mmol)
gave 8e as a yellowish oil; yield: 1.21 g (73%, 2 steps).
IR (CHCl3): 1761, 1744, 1709, 1541 cm–1.
1H NMR (270 MHz, CDCl3): δ = 1.26 (t, J = 7.6 Hz, 3 H), 2.60 (q,
J = 7.6 Hz, 2 H), 3.91 (s, 3 H), 7.24–7.49 (m, 5 H), 8.23 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 11.9, 25.5, 52.6, 113.7, 117.9,
128.3, 128.8 (2 C), 129.0 (2 C), 134.7, 152.6, 158.0, 164.0, 169.9.
IR (CHCl3): 1759, 1740, 1709, 1611, 1541 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.25 (t, J = 7.6 Hz, 3 H), 2.60 (q,
J = 7.6 Hz, 2 H), 3.85 (s, 3 H), 3.90 (s, 3 H), 6.95–6.99 (m, 2 H),
7.16–7.20 (m, 2 H), 8.20 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 11.9, 25.5, 52.6, 55.3, 113.6,
114.3 (2 C), 117.5, 126.8, 130.0 (2 C), 152.9, 158.1, 159.6, 164.1,
169.7.
MS (EI): m/z (%) = 288 (M+, 85.5), 256 (35.5), 227 (100.0), 203
(57.1).
MS (EI): m/z (%) = 258 (M+, 100.0), 197 (79.4), 173 (90.2), 115
(52.3).
HRMS (EI): m/z [M]+ calcd for C15H14O4: 258.0892; found:
258.0901.
Methyl 6-Ethyl-5-(4-fluorophenyl)-2-oxo-2H-pyran-3-carbox-
ylate (8b)
Following the typical procedure for 8a using 7b (389 mg, 2.52
mmol) gave 8b as a yellowish oil; yield: 473 mg (68%, 2 steps).
HRMS (EI): m/z [M]+ calcd for C16H16O5: 288.0997; found:
288.0996.
Methyl 5-(Biphenyl-4-yl)-6-ethyl-2-oxo-2H-pyran-3-carboxyl-
ate (8f)
Following the typical procedure for 8a using 7f (1.09 g, 4.85 mmol)
gave 8f as a yellowish foam; yield: 920 mg (57%, 2 steps).
IR (CHCl3): 1763, 1742, 1711, 1541 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.26 (t, J = 7.6 Hz, 3 H), 2.56 (q,
J = 7.6 Hz, 2 H), 3.91 (s, 3 H), 7.12–7.18 (m, 2 H), 7.21–7.26 (m, 2
H), 8.18 (s, 1 H).
IR (CHCl3): 1761, 1740, 1709, 1541 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.29 (t, J = 7.6 Hz, 3 H), 2.66 (q,
J = 7.6 Hz, 2 H), 3.91 (s, 3 H), 7.32–7.50 (m, 5 H), 7.60–7.69 (m, 4
H), 8.27 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 11.9, 25.5, 52.7, 113.8, 116.1 (d,
3
2JC,F = 21.6 Hz, 2 C), 116.9, 130.6 (d, JC,F = 8.4 Hz, 2 C), 130.7,
152.4, 157.9, 162.6 (d, 1JC,F = 247.4 Hz), 164.0, 170.0.
Synthesis 2014, 46, 496–502
© Georg Thieme Verlag Stuttgart · New York

PAPER
6-Substituted 3-(Alkoxycarbonyl)-5-aryl-α-pyrones
501
13C NMR (100 MHz, CDCl3): δ = 12.2, 25.8, 52.9, 114.0, 117.8,
127.3 (2 C), 127.9 (2 C), 128.0, 129.1 (2 C), 129.5 (2 C), 133.8,
140.3, 141.5, 152.8, 158.3, 164.3, 170.2.
13C NMR (100 MHz, CDCl3): δ = 52.7, 114.2, 117.9, 128.3 (2 C),
129.12 (2 C), 129.14 (3 C), 129.5 (2 C), 131.0, 131.1, 135.3, 153.6,
157.4, 162.7, 164.0.
MS (EI): m/z (%) = 334 (M+, 91.8), 273 (100.0), 249 (32.5).
MS (EI): m/z (%) = 306 (M+, 100.0), 278 (46.1), 105 (29.6).
HRMS (EI): m/z [M]+ calcd for C21H18O4: 334.1205; found:
334.1203.
HRMS (EI): m/z [M]+ calcd for C19H14O4: 306.0892; found:
306.0884.
Methyl 6-Isopropyl-2-oxo-5-phenyl-2H-pyran-3-carboxylate
(8g)
Following the typical procedure for 8a using 3-methyl-1-phenylbu-
tan-2-one (7g, 1.00 mL, 5.94 mmol) gave 8g as a pale yellow foam;
yield: 1.45 g (90%, 2 steps).
Methyl 2-Oxo-6-phenyl-5-[4-(trifluoromethyl)phenyl]-2H-py-
ran-3-carboxylate (8j)
Following the typical procedure for 8i using 12 (100 mg, 0.378
mmol) without column chromatography (silica gel) before refluxing
in AcOH gave 8j as a yellow amorphous solid; yield: 109 mg (77%,
2 steps).
IR (CHCl3): 1763, 1751, 1713, 1537, 1518 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.95 (s, 3 H), 7.28–7.44 (m, 7 H),
7.62 (br d, J = 8.0 Hz, 2 H), 8.33 (s, 1 H).
IR (CHCl3): 1763, 1740, 1709, 1526 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.25 (d, J = 6.8 Hz, 6 H), 2.95–
3.05 (m, 1 H), 3.90 (s, 3 H), 7.23–7.27 (m, 2 H), 7.39–7.48 (m, 3 H),
8.19 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 20.2 (2 C), 30.6, 52.6, 113.7,
116.9, 128.3, 128.8 (2 C), 129.0 (2 C), 134.8, 152.7, 158.0, 164.0,
172.8.
13C NMR (100 MHz, CDCl3): δ = 52.9, 114.6, 116.5, 123.8 (q,
1JC,F = 270.9 Hz), 126.1 (q, 3JC,F = 3.6 Hz, 2 C), 128.6 (2 C), 129.5
2
(2 C), 129.6 (2 C), 130.5 (q, JC,F = 32.6 Hz), 130.7, 131.5, 139.1,
152.8, 157.0, 163.5, 163.8.
MS (EI): m/z (%) = 374 (M+, 87.3), 346 (81.6), 315 (16.2), 259
MS (EI): m/z (%) = 272 (M+, 66.4), 229 (100.0), 197 (65.3), 173
(71.1).
(17.2), 105 (100.0).
HRMS (EI): m/z [M]+ calcd for C20H13F3O4: 374.0766; found:
HRMS (EI): m/z [M]+ calcd for C16H16O4: 272.1048; found:
272.1050.
374.0760.
Methyl 6-Butyl-2-oxo-5-phenyl-2H-pyran-3-carboxylate (8h)
Following the typical procedure for 8a using 1-phenylhexan-2-one
(7h, 1.00 mL, 5.45 mmol) gave 8h as a yellowish oil; yield: 1.23 g
(79%, 2 steps).
Methyl 6-(2-Furyl)-2-oxo-5-[4-(trifluoromethyl)phenyl]-2H-py-
ran-3-carboxylate (8k)
Following the typical procedure for 8i using 13 (150 mg, 0.589
mmol) without column chromatography (silica gel) before refluxing
in AcOH gave 8k as yellow prisms; yield: 161 mg (75%, 2 steps);
mp 163–166 °C (n-hexane–EtOAc).
IR (CHCl3): 1763, 1744, 1711, 1526 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.84 (t, J = 7.4 Hz, 3 H), 1.24–1.33
(m, 2 H), 1.64–1.72 (m, 2 H), 2.57 (t, J = 7.8 Hz, 2 H), 3.91 (s, 3 H),
7.23–7.27 (m, 2 H), 7.38–7.47 (m, 3 H), 8.21 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 13.6, 22.3, 29.6, 31.7, 52.7, 113.6,
118.4, 128.3, 128.9 (2 C), 129.0 (2 C), 134.8, 152.6, 158.1, 164.1,
169.3.
MS (EI): m/z (%) = 286 (M+, 100.0), 229 (42.3), 215 (63.3), 197
(59.3), 173 (63.8).
HRMS (EI): m/z [M]+ calcd for C17H18O4: 286.1205; found:
286.1207.
IR (CHCl3): 1767, 1753, 1709, 1562, 1529, 1502 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.92 (s, 3 H), 6.50 (dd, J = 1.6, 3.6
Hz, 1 H), 6.94 (dd, J = 0.8, 3.6 Hz, 1 H), 7.38 (dd, J = 0.8, 1.6 Hz,
1 H), 7.46 (br d, J = 8.0 Hz, 2 H), 7.72 (br d, J = 8.0 Hz, 2 H), 8.21
(s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 52.8, 112.8, 113.2, 114.3, 117.8,
123.9 (q, 1JC,F = 230.9 Hz), 125.7 (q, 3JC,F = 3.8 Hz, 2 C), 129.7 (2
2
C), 130.7 (q, JC,F = 32.6 Hz), 138.5, 145.5, 146.6, 152.8, 153.1,
156.0, 163.7.
MS (EI): m/z (%) = 364 (M+, 100.0), 336 (73.4), 95 (84.5).
HRMS (EI): m/z [M]+ calcd for C18H11F3O5: 364.0558; found:
Methyl 2-Oxo-5,6-diphenyl-2H-pyran-3-carboxylate (8i); Typi-
cal Procedure
To a stirred suspension of 1,2-diphenylethanone (7i, 1.00 g, 5.10
mmol) and 5 Å MS (500 mg) in THF (5 mL) was added 1.0 M
LHMDS in THF (5.10 mL, 5.10 mmol) dropwise at 0 °C and the
mixture was stirred for 30 min at 0 °C. Dimethyl methoxymeth-
ylenemalonate (5, 977 mg, 5.61 mmol) in THF (3 mL) was added at
0 °C and the mixture was stirred for 19 h at r.t. After acidification
with aq 1 M HCl to pH 4 in an ice-water bath, the mixture was fil-
tered over Celite® pad and the filtrate was extracted with Et2O (3 ×).
The combined organic layer was washed with water, dried
(Na2SO4), filtered, and concentrated in vacuo. The crude material
was purified by column chromatography (silica gel, n-hexane–EtO-
Ac, 3:1) to give a mixture of 8i and reaction intermediates (1.80 g,
8i/reaction intermediate, 1.0:1.6).
364.0563.
Methyl 2-Oxo-6-phenyl-5-(2-thienyl)-2H-pyran-3-carboxylate
(8l)
Following the typical procedure for 8i using 15 (590 mg, 2.92
mmol) without column chromatography (silica gel) before refluxing
in AcOH gave 8l as pale yellow needles; yield: 515 mg (57%, 2
steps); mp 114–116 °C (n-hexane–EtOAc).
IR (CHCl3): 1761, 1744, 1713, 1541, 1526, 1489 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.94 (s, 3 H), 6.94 (dd, J = 1.2, 3.6
Hz, 1 H), 7.01 (dd, J = 3.6, 5.2 Hz, 1 H), 7.31–7.35 (m, 3 H), 7.42
(tt, J = 1.2, 7.6 Hz, 1 H), 7.51–7.54 (m, 2 H), 8.37 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 52.8, 111.4, 114.1, 127.2, 127.7,
128.0, 128.4 (2 C), 129.3 (2 C), 131.0, 131.4, 136.1, 153.5, 157.0,
163.4, 163.8.
MS (EI): m/z (%) = 312 (M+, 100.0), 284 (33.1), 105 (68.1), 77
(32.9).
HRMS (EI): m/z [M]+ calcd for C17H12O4S: 312.0456; found:
312.0453.
The mixture of 8i and reaction intermediates (1.44 g, 4.04 mmol)
was dissolved in AcOH (30 mL) and the solution was refluxed (oil
bath temp: 135 °C). After 24 h, the mixture was concentrated in vac-
uo. The crude product was purified by column chromatography (sil-
ica gel, n-hexane–EtOAc, 3:1) to give 8i (1.06 g, 85%, 2 steps) as
yellowish prisms; mp 167–170 °C (THF–n-hexane).
IR (KBr): 1786, 1744, 1703, 1541, 1489 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.94 (s, 3 H), 7.20–7.43 (m, 10 H),
8.35 (s, 1 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 496–502

502
T. Miura et al.
PAPER
Lee, H. S.; Kim, N. Tetrahedron Lett. 2007, 48, 1069.
Acknowledgment
(c) Ma, S.; Yin, S.; Li, L.; Tao, F. Org. Lett. 2002, 4, 505.
(7) Only one example of the synthesis of 3-(alkoxycarboxy)-5-
aryl-α-pyrone was shown in the following paper as an
undesired product: Ceglia, S. S.; Kress, M. H.; Nelson, T. D.;
McNamara, J. M. Tetrahedron Lett. 2005, 46, 1731.
(8) (a) For a procedure of preparation of dimethyl
methoxymethylenemalonate, see: Fuson, R. C.; Parham, W.
E.; Reed, L. S. J. Org. Chem. 1946, 11, 194. (b) For a review
of alkoxymethylenemalonate, see: Milata, V. Aldrichimica
Acta 2001, 34, 20. (c) In this study, dimethyl
This research was supported in part by a Strategic Research Foun-
dation Grant-Aided Project for Private Universities from the Mini-
stry of Education, Culture, Sports, Science, and Technology of
Japan (MEXT), and a Grant-in-Aid for Scientific Research (C)
(22590023) from Japan Society for the Promotion of Science
(JSPS).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
methoxymethylenemalonate was purchased from TCI
(Tokyo Chemical Industry Co., Ltd.) and used without
further purification
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Synthesis 2014, 46, 496–502
© Georg Thieme Verlag Stuttgart · New York