A new protocol for synthesis of 3-hydroxymethyl-4-methoxy-2H-pyrone derivatives

Article abstract of DOI:10.1016/S0040-4020(01)00347-7

The title compounds have been prepared by treatment of 4-methoxy-3-phenylsulfinylmethyl-2H-pyrone derivatives with trifluoroacetic anhydride, followed by basic work-up.

Full text of DOI:10.1016/S0040-4020(01)00347-7

TETRAHEDRON
Pergamon
Tetrahedron 57 72001) 5039±5043
A new protocol for synthesis of
3-hydroxymethyl-4-methoxy-2H-pyrone derivatives
Hisahiro Hagiwara,a,p Katsuhiro Kobayashi,a Takashi Hoshi,a Toshio Suzukia and
Masayoshi Andob
aGraduate School of Science and Technology, Niigata University, 8050, 2-nocho, Ikarashi, Niigata 950-2181, Japan
bFaculty of Engineering, Niigata University, 8050, 2-nocho, Ikarashi, Niigata 950-2181, Japan
Dedicated to Professor Barry M. Trost on the occasion of his 60th birthday
Received 2 January 2001; revised 21 February 2001; accepted 22 February 2001
AbstractÐThe title compounds have been prepared by treatment of 4-methoxy-3-phenylsul®nylmethyl-2H-pyrone derivatives with
tri¯uoroacetic anhydride, followed by basic work-up. q 2001 Elsevier Science Ltd. All rights reserved.
Among polyketide natural products, there exist many
4-alkoxy-2H-pyrone derivatives, some of which have
3-alkoxy or 3-formyl substituents. Solanapyrones A 1 and
B 2 were isolated by Oikawa and Ichihara1 from phytogenic
fungi Altenaria solani and Ascochyta rabiei as unique
phytotoxic polyketides which possess decaline frameworks
with a 3-formyl- or a 3-hydroxymethyl-4-methoxy-2H-
pyrone moiety, respectively 7Fig. 1). In the course of our
independent synthetic study of solanapyrones, one major
issue was the construction of the 3-hydroxymethyl-4-meth-
oxy-2H-pyrone moiety at the later stage of the synthetic
sequence according to our synthetic design 7Scheme 1).
Introduction of the 4-alkoxy-2H-pyrone moiety to the
decaline framework would be feasible by cyclization of
b,d-diketo-ester 3 installed by Claisen condensation.
However, to our knowledge, procedures for introduction
of a hydroxymethyl or formyl group at C-3 of the
4-alkoxy-2H-pyrone derivatives 4 or 5 7R0ˆH or Me) are
quite limited.
Only one known example to date for our purpose is the
reaction of 4-methoxy-2H-pyrone derivatives with
dichloromethylmethyl ether in the presence of titanium tetra-
chloride leading to 3-formyl-4-methoxy-2H-pyrone deriva-
tives 8 7Scheme 2),2 although we found that the application
of this procedure to solanapyrone synthesis was dif®cult.
5
Consequently, we started our investigation on this issue and
delineate a new protocol to introduce a hydroxymethyl unit
at C-3 of the 4-hydroxy-2H-pyrone derivatives 4 or 5. Our
initial attempts of direct condensation of 4-hydroxy-2H-
pyrones 4 with formaldehyde provided dimeric compounds
under either acidic or basic conditions.3 Our attempts to
Scheme 1.
Figure 1.
Keywords: hydroxymethylation; 2H-pyrones; solanapyrones; sul®nyl
compounds.
p
Corresponding author. Fax: 181-25-262-7368;
e-mail: hagiwara@gs.niigata-u.ac.jp
Scheme 2.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020701)00 347-7

5040
H. Hagiwara et al. / Tetrahedron 57 -2001) 5039±5043
Scheme 3. Reagents and conditions: 7i) 7HCHO)n, PhSH, AcOH, piperidine, EtOH, 558C; 7ii) Me2SO4, K2CO3, acetone; 7iii) MCPBA, CH2Cl2;
7iv) 7CF3CO)2O, CH2Cl2, 08C then 1 N NaOH, THF.
generate a carbanion at C-34 of 5 and react it with formalde-
hyde did not produce the desired product 7.
3-acetoxymethyl-4-methoxy-6-nonyl-2H-pyrone even at
1608C along with recovery of a large amount of the starting
sulfoxide 11b. More reactive reagents such as trimethylsilyl
tri¯uoromethanesulfonate gave complex mixtures.
We then turned our attention to an alternative strategy utili-
zing a phenylthiomethyl group as a synthetic equivalent of a
hydroxymethyl group 7Scheme 3). The starting 4-hydroxy-
2H-pyrone derivatives 4 were procured or prepared via 1,8-
diazabicyclo[2.2.2]undec-7-ene 7DBU)5 promoted cycli-
zation of b,d-diketoesters.6 A phenylthiomethyl group was
introduced to the 4-hydroxy-2H-pyrone derivatives 4
according to the procedure by Moreno-Manas et al.7 to
give 4-hydroxy-3-phenylthiomethyl-2H-pyrone derivatives
9. After conventional O-methylation with dimethyl sulfate,
the resulting 4-methoxy-3-phenylthiomethyl-2H-pyrone
derivatives 10 were oxidized with m-chloroperoxybenzoic
acid 7MCPBA) to give 4-methoxy-3-phenylsul®nylmethyl-
2H-pyrone derivatives 11. Treatment of the sulfoxides 11
with tri¯uoroacetic anhydride followed by quenching with 1
N aq. NaOH and THF furnished 3-hydroxymethyl-4-meth-
oxy-2H-pyrone derivatives 7 in good yields. Addition of
THF was crucial to make the solution homogeneous during
hydrolysis. These results are summarized in Table 1. The
yield of 10e was low due to repeated chromatography.
Under the reaction conditions, no Pummerer reaction
occurred8 and no 3-formyl-4-methoxy-2H-pyrone deriva-
tives 8 were produced. It is important to use dichloro-
methane 7CH2Cl2) without ethanol 7EtOH) contamination
in the last experiment. Also important is the use of apparatus
without a rubber septum and balloon. Reaction with acetic
anhydride was very sluggish and provided only 16% of
Our proposed mechanism of the substitution reaction is
shown in Scheme 4. One possibility is SN2 substitution of
the sulfonium ion 12 by a tri¯uoroacetoxy anion. Another
possibility is SN1 substitution in which acylation of the
phenylsul®nyl group of 11 into sulfonium ions 12 followed
by elimination led to oxonium ions 13. Addition of a
tri¯uoroacetoxy anion to the oxonium ion 13 afforded
4-methoxy-3-tri¯uoroacetoxymethyl-2H-pyrone derivatives
14. The tri¯uoroacetates 14 were readily hydrolyzed by
weakly basic work-up to give the desired products 7. An
attempt at direct substitution of 4-methoxy-6-nonyl-3-
phenylsul®nylmethyl-2H-pyrone 11b with aqueous sodium
hydroxide resulted in complete recovery. 4-Methoxy-6-
nonyl-3-phenylsulfonylmethyl-2H-pyrone gave the same
result. Steric hindrance of the methoxy group at C-4 might
prevent abstraction of a proton a to the sulfonium ion 12 by
tri¯uoroacetoxy anion 7Pummerer reaction pathway)8 and
its electron-donating character might enable rapid elimi-
nation to the oxonium ion 13. Addition of triethylamine
resulted in decrease of yield. The reaction was quite fast
even at 278 to 2408C and 3-hydroxymethyl-4-methoxy-5-
nonyl-2H-pyrone derivative 7b was obtained in 69% yield
after basic work-up. Intermediary 4-methoxy-6-nonyl-3-
tri¯uoroacetoxymethyl-2H-pyrone 14b [Rˆ7CH2)8CH3] was
isolated when the reaction was quenched only with aq.
Table 1. Synthesis of 3-hydroxymethyl-2H-pyrone derivatives 7
4-Hydroxy-2H-pyrone 4
Sul®de 9 7%)
Methyl ether 10 7%)
Sulfoxide 11 7%)
Alcohol 7 7%)
a RˆMe
a 96
b 99
c 71
d 67
e 75
a 69
b 70
c 76
d 86
e 36
a 96
b 86
c 93
d 90
e 58
a 68
b 82
c 98
d 93
e 78
b Rˆ7CH2)8CH3
c Rˆ7CH2)2Ph
d Rˆcyclohexyl
e Rˆ5,6-benzo
Scheme 4.

H. Hagiwara et al. / Tetrahedron 57 -2001) 5039±5043
5041
NaOH, though it decomposed soon after NMR measurement.
When CH2Cl2 was contaminated with EtOH, a more nucleo-
philic ethoxy group was introduced to give only 3-ethoxy-
methyl-4-methoxy-6-nonyl-2H-pyrone derivative in low
yields.
181±1838C; nmax/cm21 7KBr pellet) 3464, 3036, 2928,
1660, 1636, 1590, 1556, 1436, 1414 and 1262,; H-NMR
7200 MHz) d 7ppm) 2.65±2.77 7m, 2H), 2.87±2.99 7m, 2H),
4.14 7s, 2H), 5.70 7s, 1H) and 7.07±7.42 7m, 10H).
1
1.1.4. 6-Cyclohexyl-4-hydroxy-3-phenylthiomethyl-2H-
pyran-2-one *9d). 67%; amorphous solid; m.p. 157±
1598C; nmax/cm21 7KBr pellet) 3428, 3084, 2936, 1672,
In conclusion, we have newly developed a synthetic pro-
cedure for the 3-hydroxymethyl-4-methoxy-2H-pyrone
derivatives 7 via 4 steps starting from the 4-hydroxy-2H-
pyrone derivatives 4 in acceptable and reproducible yields.
Active manganese dioxide oxidation9 of 7 afforded 3-formyl-
2H-pyrone 8 in good yield. Application of the present proto-
col to solanapyrone synthesis will be reported in due
course.10
1
1630, 1576, 1434, 1422, and 1262; H-NMR 7200 MHz) d
7ppm) 1.17±1.48 7m, 5H), 1.63±1.98 7m, 5H), 2.32 7m, 1H),
4.16 7s, 2H), 5.75 7s, 1H), 7.20±7.42 7m, 5H) and 8.32 7s,
1H).
1.1.5. 5,6-Benzo-4-hydroxy-3-phenylthiomethyl-2H-pyran-
2-one *9e). 75%; amorphous solid; nmax/cm21 7KBr pellet)
3480, 3088, 3008, 2930, 1654, 1632, 1566, 1500, 1482,
1456, 1396, 1260and 1176; 1H-NMR 7200 MHz) d 7ppm)
4.31 7s, 2H), 7.20±7.65 7m, 7H), 7.84 7dd, 1H, J 8.2, 1.6 Hz)
and 8.01 7m, 1H).
1.Experimental
1.1. General
Representative procedure of methylation is as follows:
M.p.s were determined with a Yanaco MP hot-stage appa-
ratus and are uncorrected. IR spectra were recorded on a
Shimadzu FT/IR-4200 spectrophotometer for solutions in
chloroform or Hitachi IR 270-30 spectrophotometer for
1.1.6. 4-Methoxy-6-methyl-3-phenylthiomethyl-2H-pyran-
2-one *10a). A suspension of 4-hydroxy-2H-pyrone 9a
71.70g, 6.9 mmol), dimethyl sulfate 73.3 ml, 34 mmol)
and potassium carbonate 74.74 g, 34 mmol) in acetone
750ml) was stirred at room temperature for 4 h. H 2O
73 ml) was added and the resulting solution was stirred at
room temperature for 2 h. After addition of aqueous ammo-
nium chloride, the reaction mixture was extracted with
CH2Cl2 twice. The combined organic extracts were washed
with water and brine. Evaporation of the solvent followed
by column chromatography of the residue provided 4-meth-
1
KBr pellets. H-NMR spectra were obtained for solutions
in deuteriochloroform with a Varian Gemini 200H 7200
MHz) instrument with tetramethylsilane as internal stan-
dard. 13C-NMR spectra were measured with a Varian
Gemini 200H 750 MHz) instrument. Mass spectral data
were run on a JEOL GC-Mate spectrometer. Medium-
pressure liquid chromatographies 7MPLC) were carried
out on a GL Science PU 612 instrument with a silica gel
packed column. Microanalyses were carried out in the
microanalytical laboratory of the Instrumental Analysis
Center for Chemistry, Tohoku University. Compounds
10b, 11c and 11d did not give satisfactory analytical data
after repeated analyses.
oxy-6-methyl-3-phenylthiomethyl-2H-pyran-2-one
71.24 g, 69%) as crystals.
10a
69%; blocks; m.p. 54±558C; nmax/cm21 7CHCl3) 2998,
1703, 1647, 1566, 1466, 1441, 1247 and 1022; H-NMR
1
7200 MHz) d 7ppm) 2.27 7s, 3H), 3.72 7s, 3H), 3.98 7s,
2H), 5.96 7s, 1H), 7.12±7.31 7m, 3H) and 7.40±7.50 7m,
2H); 13C-NMR 750MHz) d 7ppm) 20.5, 28.1, 56.3, 94.8,
101.4, 126.3, 128.5, 130.9, 136.5, 162.7, 164.1 and 167.0;
7Found: C, 63.92, H, 5.38, S, 12.23; C14H14O3S requires: C,
64.1, H, 5.58, S, 12.22%).
4-Hydroxy-3-phenylthiomethyl-2H-pyrones 9 were pre-
pared according to the modi®ed procedure by Moreno-
Manas et al.7 including non-aqueous work-up by column
chromatography and used without puri®cation for further
reaction because of stubborn nature towards recrystalli-
zation. 4-Hydroxy-6-methyl-2H-pyrone 4a and 5,6-benzo-
4-hydroxy-2H-pyrone 4e were procured from Tokyo Kasei
Co.
1.1.7. 4-Methoxy-6-nonyl-3-phenylthiomethyl-2H-pyran-
2-one *10b). 70%; amorphous solid; m.p. 48±508C; nmax
/
cm21 7CHCl3) 2930, 2857, 1699, 1564, 1469, 1265 and
1028; H-NMR 7200 MHz) d 7ppm) 0.88 7t, 3H, J 6.4 Hz),
1.1.1. 4-Hydroxy-6-methyl-3-phenylthiomethyl-2H-pyran-
2-one *9a).7 96%; amorphous solid; nmax/cm21 7KBr pellet)
3480, 3000, 2932, 1660, 1636, 1576, 1430, 1408, 1384 and
1
1.21±1.38 7m, 12H), 1.55±1.72 7m, 2H), 2.807t, 2H,
J
1
7.5 Hz), 3.73 7s, 3H), 3.98 7s, 2H), 5.93 7s, 1H), 7.17±7.31
7m, 3H) and 7.40±7.49 7m, 2H); 13C-NMR 750MHz) d
7ppm) 13.9, 22.4, 26.7, 28.0, 28.8, 29.0, 29.2, 31.6, 34.1,
56.2, 93.9, 101.0, 126.1, 128.3, 130.7, 136.3, 164.0, 166.3
and 166.9.
1258; H-NMR 7200 MHz, CDCl3) d 7ppm) 2.17 7s, 3H),
4.14 7s, 2H), 5.78 7s, 1H) and 7.17±7.45 7m, 5H).
1.1.2. 4-Hydroxy-6-nonyl-3-phenylthiomethyl-2H-pyran-
2-one *9b). .99%; amorphous solid; m.p. 74±768C; nmax/
cm21 7KBr pellet) 3480, 2932, 1666, 1632, 1588, 1558,
1436, 1416 and 1258; H-NMR 7200 MHz) d 7ppm) 0.88
1
1.1.8. 4-Methoxy-6-*2-phenylethyl)-3-phenylthiomethyl-
2H-pyran-2-one *10c). 76%; blocks; m.p. 101±1028C;
7t, 3H, J 6.3 Hz), 1.19±1.38 7m, 12H), 1.46±1.71 7m, 2H),
2.407t, 2H, J 7.5 Hz), 4.13 7s, 3H), 5.807s, 1H) and 7.19±
7.42 7m, 5H).
n
max/cm21 7CHCl3) 2949, 1703, 1645, 1566, 1466, 1264,
1127, 1030 and 1012; 1H-NMR 7200 MHz) d 7ppm)
2.73±2.85 7m, 2H), 2.92±3.07 7m, 2H), 3.62 7s, 3H),
3.97 7s, 2H), 5.87 7s, 1H) and 7.10±7.48 7m, 10H); 13C
NMR 750MHz) d 7ppm) 28.2, 33.1, 36.2, 56.3, 94.8,
1.1.3. 4-Hydroxy-6-*2-phenylethyl)-3-phenylthiomethyl-
2H-pyran-2-one *9c). 71%; amorphous solid; m.p.

5042
H. Hagiwara et al. / Tetrahedron 57 -2001) 5039±5043
101.8, 126.4, 126.5, 128.3, 128.5, 128.6, 131.1, 136.4,
139.7, 164.1, 164.8 and 166.8; 7Found: C, 71.28, H, 5.87;
C21H20O3S requires: C, 71.56, H, 5.72%).
cm21 7CHCl3) 2951, 1709, 1643, 1564, 1466, 1264, 1040
and 1036; 1H-NMR 7200 MHz) d 7ppm) 2.78±2.89 7m, 2H),
2.95±3.06 7m, 2H), 3.60 7s, 3H), 3.87 7d, 1H, J 12.1 Hz),
4.09 7d, 1H, J 12.1Hz), 5.84 7s, 1H), 7.13±7.36 7m, 5H),
7.37±7.52 7m, 3H) and 7.57±7.69 7m, 2H); 13C-NMR
750MHz) 32.9, 36.1, 53.2, 56.5, 94.6, 94.7, 124.3, 126.5,
128.2, 128.5, 128.6, 131.0, 139.4, 144.2, 163.9, 166.0 and
168.6.
1.1.9. 6-Cyclohexyl-4-methoxy-3-phenylthiomethyl-2H-
pyran-2-one *10d). 86%; needles; m.p. 145±1468C; nmax
/
cm21 7CHCl3) 2938, 1697, 1564, 1464, 1127 and 1033;
1H-NMR 7200 MHz) d 7ppm) 1.18±1.53 7m, 5H), 1.65±
2.02 7m, 5H), 2.42 7m, 1H), 3.74 7s, 3H), 3.99 7s, 2H),
5.91 7s, 1H) and 7.12±7.48 7m, 5H); 13C-NMR 750MHz)
d 7ppm) 25.6, 25.8, 28.1, 30.5, 42.8, 56.3, 92.0, 101.5, 126.2,
128.5, 130.7, 136.7, 164.2, 167.2 and 170.4; 7Found: C,
68.79, H, 6.69, S, 9.78; C19H22O3S requires: C, 69.06, H,
6.71, S, 9.7%).
1.1.14. 6-Cyclohexyl-4-methoxy-3-phenylsul®nylmethyl-
2H-pyran-2-one *11d). 90%; blocks; m.p. 139±1418C;
n
max/cm21 7CHCl3) 2859, 1703, 1640, 1563, 1466, 1260,
1
1031 and 1024; H-NMR 7200 MHz) d 7ppm) 1.22±1.35
7m, 5H), 1.78±2.03 7m, 5H), 2.43 7m, 1H), 3.76 7s, 3H),
3.84 7d, 1H, J 12.2 Hz), 4.11 7d, 1H, J 12.2 Hz), 5.94 7s,
1H), 7.43±7.52 7m, 3H) and 7.62±7.71 7m, 5H); 13C-NMR
750 MHz) 25.6, 25.7, 30.4, 42.9, 53.5, 56.5, 92.0, 94.9,
124.3, 128.7, 130.9, 144.5, 164.1, 169.1 and 171.5.
1.1.10.
pyran-2-one *10e). 36%; needles; m.p. 93±948C; nmax
5,6-Benzo-4-methoxy-3-phenylthiomethyl-2H-
/
cm21 7CHCl3) 1712, 1625, 1622, 1456, 1354, 1273, 1099
1
and 1057; H-NMR 7200 MHz) d 7ppm) 4.02 7s, 3H), 4.18
7s, 2H), 7.17±7.407m, 5H), 7.45±7.65 7m, 3H) and 7.67±
7.72 7m, 1H); 13C-NMR 750MHz) d 7ppm) 29.6, 62.4,
112.7, 116.7, 117.0, 123.5, 124.1, 126.9, 128.9, 130.9,
132.0, 136.0, 152.8, 162.8 and 164.7; 7Found: C, 68.31,
H, 4.77, S, 10.58; C17H14O3S requires: C, 68.44, H, 4.73,
S, 10.75%).
1.1.15. 5,6-Benzo-4-methoxy-3-phenylsul®nylmethyl-2H-
pyran-2-one *11e). 58%; needles; m.p. 121±1238C; nmax
/
cm21 7CHCl3) 1713, 1626, 1613, 1572, 1354, 1101, 1063
and 1043; H-NMR 7200 MHz) d 7ppm) 4.02 7d, 1H, J
1
12.5 Hz), 4.23 7d, 1H, J 12.5 Hz), 4.23 7s, 3H), 7.28±7.42
7m, 2H), 7.50±7.65 7m, 4H) and 7.71±7.80 7m, 3H); 13C-
NMR 750 MHz) 55.4, 64.0, 106.1, 116.6, 117.0, 123.8,
123.9, 124.3, 129.2, 131.2, 132.5, 144.1, 152.9, 162.9 and
167.2; 7Found: C, 64.76, H, 4.68, S, 10.26; C17H14O4S
requires: C, 64.95, H, 4.49, S, 10.20%).
Representative procedure of oxidation is as follows:
1.1.11. 4-Methoxy-6-methyl-3-phenylsul®nylmethyl-2H-
pyran-2-one *11a). To a stirred solution of the sul®de 10a
71.11 g, 4.2 mmol) in CH2Cl2 730ml) was added MCPBA
780%, 913 mg, 5.3 mmol) at 08C. After being stirred for
20min, aqueous sodium hydrogen carbonate was added
and the reaction mixture was extracted with CH2Cl2 twice.
The combined organic layer was washed with water and
brine and evaporated to dryness. The residue was puri®ed
by column chromatography to afford 4-methoxy-6-methyl-
3-phenylsul®nylmethyl-2H-pyran-2-one 11a 71.13 g, 96%).
Representative procedure of hydroxymethylation is as
follows:
1.1.16.
3-Hydroxymethyl-4-methoxy-6-methyl-2H-
pyran-2-one *7a). To a stirred solution of the sulfoxide
11a 727.7 mg, 0.1 mmol) in CH2Cl2 7EtOH free, 4 ml) was
added tri¯uoroacetic anhydride 756 ml, 0.4 mmol) at 08C.
After being stirred for 30min at 0 8C, 1N aqueous NaOH
71 ml) and THF 76 ml) were added and stirring was con-
tinued for 1.5 h at room temperature. The reaction mixture
was extracted with ethyl acetate twice and the combined
organic layer was washed with aqueous ammonium
chloride, water and brine. Evaporation of the solvent
followed by MPLC puri®cation furnished 3-hydroxy-
methyl-4-methoxy-6-methyl-2H-pyran-2-one 7a 711.5 mg,
68%). In this experiment, use of a rubber septum and
balloon provided a complex mixture of undesired products.
96%; blocks; m.p. 128±1308C; nmax/cm21 7CHCl3) 3050,
1705, 1645, 1566, 1468, 1264, 1038 and 1022; H-NMR
1
7200 MHz) d 7ppm) 2.29 7s, 3H), 3.68 7d, 1H, J 12.2 Hz),
3.73 7s, 3H), 4.11 7d, 1H, J 12.2 Hz), 5.99 7s, 1H), 7.44±7.53
7m, 3H) and 7.61±7.71 7m, 2H); 13C-NMR 750MHz) d
7ppm) 20.4, 53.1, 56.5, 94.1, 94.7, 124.2, 128.6, 130.9,
144.2, 163.9 and 168.8; 7Found: C, 60.3, H, 5.12, S,
11.46; C14H14O4S requires: C, 60.42, H, 5.07, S, 11.52%).
1.1.12. 4-Methoxy-6-nonyl-3-phenylsul®nylmethyl-2H-
pyran-2-one *11b). 86%; needles; m.p. 85±868C; nmax
68%; blocks; m.p. 151±1538C; nmax/cm21 7CHCl3) 3472,
2951, 1694, 1645, 1568, 1389, 1260and 1022; 1H-NMR
7200 MHz) d 7ppm) 2.307s, 3H), 3.91 7s, 3H), 4.54 7s,
2H), and 6.08 7s, 1H); 13C-NMR 750MHz) d 7ppm) 20.4,
54.5, 56.4, 95.1, 103.6, 163.3, 165.3 and 166.8; 7Found: C,
56.36, H, 5.98; C8H10O4 requires: C, 56.47, H, 5.92%).
/
cm21 7CHCl3) 2930, 2857, 1703, 1642, 1564, 1466, 1267
and 1032; H-NMR 7200 MHz) d 7ppm) 0.89 7t, 3H, J
1
6.4 Hz), 1.22±1.38 7m, 12H), 1.60±1.74 7m, 2H), 2.51 7t,
2H, J 7.5 Hz), 3.74 7s, 3H), 3.86 7d, 1H, J 12.1 Hz), 4.11 7d,
1H, J 12.1 Hz), 5.96 7s, 1H), 7.44±7.52 7m, 3H) and 7.62±
7.71 7m, 2H); 13C-NMR 750MHz) d 7ppm) 14.0, 22.5, 26.8,
28.8, 29.1, 29.3, 31.7, 34.3, 53.3, 56.5, 93.9, 94.5, 124.2,
128.6, 130.9, 144.3, 164.0, 167.7 and 168.8; 7Found: C,
67.38, H, 7.80, S, 8.38; C22H30O4S requires: C, 67.66, H,
7.74, S, 8.21%).
1.1.17. 3-Hydroxymethyl-4-methoxy-6-nonyl-2H-pyran-
2-one *7b). 82%; needles; m.p. 67±688C; nmax/cm21
7CHCl3) 3504, 2930, 1692, 1640, 1566, 1402, 1264 and
1
1030; H-NMR 7200 MHz) d 7ppm) 0.88 7t, 3H, J 6.4 Hz),
1.20±1.42 7m, 12H), 1.52±1.76 7m, 2H), 2.51 7t, 2H, J
7.5 Hz), 2.93 7t, 1H, J 6.8 Hz), 3.91 7s, 3H), 4.54 7d, 2H, J
6.8 Hz) and 6.04 7s, 1H); 13C-NMR 750MHz) d 7ppm) 14.1,
22.6, 27.0, 29.0, 29.2, 29.4, 31.8, 34.4, 54.7, 56.5, 94.3,
1.1.13. 4-Methoxy-6-*2-phenylethyl)-3-phenylsul®nyl-
methyl-2H-pyran-2-one *11c). 93%; viscous oil; nmax
/

H. Hagiwara et al. / Tetrahedron 57 -2001) 5039±5043
5043
94.5, 103.8, 165.5, 166.7 and 167.2; 7Found: C, 68.09, H,
9.23; C16H26O4 requires: C, 68.06, H, 9.28%).
1.1.21. 3-Tri¯uoroacetoxymethyl-4-methoxy-6-nonyl-2H-
pyran-2-one *14b). H-NMR 7200 MHz) d 7ppm) 0.88 7t,
1
3H, J 6.4 Hz), 1.12±1.45 7m, 12H), 1.55±1.76 7m, 2H), 2.52
7t, 2H, J 7.6 Hz), 3.95 7s, 3H), 5.26 7s, 2H) and 6.05 7s, 1H).
1.1.18. 3-Hydroxymethyl-4-methoxy-6-*2-phenylethyl)-
2H-pyran-2-one *7c). 98%; amorphous solid; m.p. 69±
718C; nmax/cm21 7CHCl3) 3472, 2982, 1692, 1642, 1566,
This compound decomposed soon after NMR measurement.
1
1466, 1402, 1260, 1037 and 1011; H-NMR 7200 MHz) d
7ppm) 2.77±3.05 7m, 5H), 3.82 7s, 3H), 4.53 7d, 2H, J
6.9 Hz), 5.92 7s, 1H) and 7.12±7.36 7m, 5H); 13C-NMR
750MHz) d 7ppm) 33.1, 36.2, 54.6, 56.5, 95.1, 104.0,
126.5, 128.3, 128.6, 139.6, 165.4, 165.5 and 166.6; m/z
2607M 1, 37%), 245 77), 242 715), 231 713), 152 728), 141
727), 91 7100), 77 711) and 69 716) 7Found: 260.10843;
C15H16O4 requires: 260.10484).
References
1. Oikawa, H.; Kobayashi, T.; Katayama, K.; Suzuki, Y.;
Ichihara, A. J. Org. Chem. 1998, 63, 8748±8756 and earlier
references cited therein.
2. Poulton, G. A.; Cyr, T. D. Can. J. Chem. 1982, 60, 2821±
2829.
3. 7a) Hagiwara, H.; Miya, S.; Suzuki, T.; Ando, M.; Yamamoto,
I.; Kato, M. Heterocycles 1999, 51, 493±496 and earlier
references cited therein. 7b) Hagiwara, H.; Fujimoto, N.;
Suzuki, T.; Ando, M. Heterocycles 2000, 53, 549±552.
4. Carpenter, T. A.; Jenner, P. J.; Leeper, F. J.; Staunton, J.
Chem. Commun. 1980, 1227.
1.1.19. 6-Cyclohexyl-3-hydroxymethyl-4-methoxy-2H-
pyran-2-one *7d). 93%; needles; m.p. 94±958C; nmax
/
cm21 7CHCl3) 3472, 2859, 1688, 1638, 1566, 1466, 1261,
1254 and 1037; 1H-NMR 7200 MHz) d 7ppm) 1.20±1.55 7m,
5H), 1.66±2.02 7m, 5H), 2.43 7m, 1H), 2.94 7t, 1H, J
6.9 Hz), 3.907s, 3H), 4.55 7d, 2H, J 6.9 Hz) and 6.01 7s,
1H); 13C-NMR 750MHz) d 7ppm) 25.6, 25.7, 30.5, 42.9,
54.7, 56.4, 92.3, 103.9, 165.4, 166.8 and 171.0; 7Found:
C, 65.38, H, 7.70; C13H18O4 requires: C, 65.53, H, 7.88%).
5. Ishibashi, Y.; Ohba, S.; Nishiyama, S.; Yamamura, S. Tetra.
Lett. 1996, 37, 2997±3000.
6. Lygo, D. Tetrahedron 1995, 51, 12850±12868.
7. 7a) de March, P.; Moreno-Manas, M.; Pi, R.; Trius, A. J.
Heterocyclic Chem. 1982, 19, 335±336. 7b) Moreno-Manas,
M. Synthesis 1984, 430±431.
1.1.20. 5,6-Benzo-3-hydroxymethyl-4-methoxy-2H-pyran-
2-one *7e). 78%; needles; m.p. 112±1138C; nmax/cm21
7CHCl3) 3202, 1698, 1622, 1616, 1358, 1070 and 1007;
1H-NMR 7200 MHz) d 7ppm) 2.89 7t, 1H, J 7.0Hz), 4.21
7s, 3H), 4.72 7d, 2H, J 7.0Hz), 7.31±7.40 7m, 2H), 7.54
7ddd, 1H, J 1.5, 7.2, 8.6 Hz) and 7.79 7dd, 1H, J 1.5,
7.8 Hz); 13C-NMR 750MHz) d 7ppm) 55.9, 63.1, 112.8,
116.8, 117.1, 123.9, 124.4, 132.3, 152.7, 164.5 and 164.8;
7Found: C, 63.85, H, 5.02; C11H10O4 requires: C, 64.07, H,
4.89%).
8. Sugihara, H.; Tanikaga, R.; Kaji, A. Synthesis 1978, 881.
9. Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama, K.; Anzai,
M.; Ando, A.; Shioiri, T. Synlett. 1998, 35±36.
10. Hagiwara, H.; Kobayashi, K.; Miya, S.; Hoshi, T.; Suzuki, T.;
Ando, M. Org. Lett. 2001, 3, in press.