Studies on triacetic acid lactone-annulated heterocycles: Synthesis of 3-aryloxyacetyl-6-methyl-2,3-dihydrothieno[3,2-c]pyran-4-ones by tandem cyclization

Article abstract of DOI:10.1016/S0040-4020(02)01418-7

The hitherto unreported 3-aryloxyacetyl-6-methyl-2,3-dihydrothieno[3,2-c]pyran-4-ones were synthesized in 62-71% yield by the sulfoxide rearrangement of 4-(4′-aryloxybut-2′-ynylthio)-6-methyl-2-pyrone. The substrates were synthesized by phase-transfer-catalysed alkylation of the hitherto unreported 4-mercapto-6-methylpyran-2-one.

Full text of DOI:10.1016/S0040-4020(02)01418-7

Tetrahedron 58 (2002) 10309–10313
Studies on triacetic acid lactone-annulated heterocycles:
synthesis of 3-aryloxyacetyl-6-methyl-2,3-dihydrothieno-
[3,2-c]pyran-4-ones by tandem cyclization
*
K. C. Majumdar, U. K. Kundu and S. Ghosh
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
Received 20 August 2002; revised 8 October 2002; accepted 31 October 2002
Abstract—The hitherto unreported 3-aryloxyacetyl-06-methyl-2,3-dihydrothieno[3,2-c]pyran-4-ones were synthesized in 62–71% yield by
the sulfoxide rearrangement of 4-(40-aryloxybut-2 -ynylthio)-6-methyl-2-pyrone. The substrates were synthesized by phase-transfer-
catalysed alkylation of the hitherto unreported 4-mercapto-6-methylpyran-2-one. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
ation of our work on the synthesis of bioactive heterocycles
by the application of [2,3] sigmatropic rearrangements6–10
we became interested in incorporating the 4-hydroxy-6-
methyl-2-pyrone system in the substrates in order to achieve
the synthesis of new heterocycles.
4-Hydroxy-6-methyl-2-pyrone (triacetic acid lactone) 1 is a
natural product of polyketide origin.1 It may also be
obtained by deacetylation of dehydroacetic acid.2 Many
natural products containing the basic structures of
4-hydroxy or (methoxy)-6-methyl-2-pyrone have been
isolated, some of them carrying biogenetically plausible
groups at C3 or C5 or both. Elasnin, isolated from
Streptomyces sp., for example, is a specific inhibitor of
human leucocyte elastase, an enzyme involved in inflam-
matory processes such as pulmonary emphysema.3 As a
logical extension, many more simple pyrones structurally
related to elasnin have been synthesized and evaluated as
inhibitors of several elastases.4 Some 4-hydroxy-2-pyrones
have also been tested as anticoagulant agents.5 In continu-
2. Results and discussion
The starting materials for this investigation, 4-(40-aryloxy-
but-20-ynylthio)-6-methylpyran-2-ones 5a–f were synthe-
sized in 50–55% yields by the treatment of 4-mercapto-6-
methylpyran-2-one 3 with 1-aryloxy-4-chlorobut-2-yne
4a–f at room temperature under phase-transfer catalysis
condition using benzyl triethyl ammonium chloride
(BTEAC). Compound 3, in turn, was prepared by the
Scheme 1.
Keywords: [2,3] sigmatropic rearrangement; regioselective synthesis; Claisen rearrangement; phase-transfer catalysis.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01418-7

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K. C. Majumdar et al. / Tetrahedron 58 (2002) 10309–10313
Scheme 2.
reaction of 6-methyl-4-tosyloxypyran-2-one11 2 with NaSH
in dry ethanol at room temperature under a nitrogen
atmosphere (Scheme 1).
one-proton doublet of doublets at d 3.55 (J¼9, 12 Hz) and d
3.70 (J¼6, 12 Hz) indicating the presence of two C2–H.
The C3–H appeared as another one-proton double doublet at
d 4.59 (J¼6, 9 Hz). Two one-proton doublets at d 4.87
(J¼17 Hz) and 4.91 (J¼17 Hz) showed the presence of the
aryloxymethylene protons adjacent to ketonic carbonyl
group at C3.
Substrates 5a–f contain a suitably placed alkynyl segment
so as to allow the occurrence of a [2,3] sigmatropic
rearrangement in the corresponding sulfoxides. With this
end in view, compound 5a was treated with m-chloro-
peroxybenzoic (m-CPBA) acid at 0–58C in chloroform
solution. A spot corresponding to a highly polar compound
appeared on TLC as soon as the addition of m-CPBA to
compound 5a was started. Compound 5a was completely
converted to this newly developed spot in 0.5 h. During
hydrolytic work up, another new spot appeared on TLC but
the conversion was only partial. The solvent was removed
from this mixture of compounds and the reaction was
refluxed in dry carbon tetrachloride. Complete conversion
required 1.5 h (Scheme 2).
The formation of 6 from 5 may be mechanistically
interpreted as depicted in Scheme 3. [2,3] Sigmatropic
rearrangement in the sulfoxide 8 may give the allenyl
derivative 9. Occurrence of [3,3] sigmatropic rearrangement
in 9 may generate the intermediate 10 which may undergo
tautomerization to 11. Intermediate 11 has a nucleophilic
–SH functionality favourably juxtaposed to an a,b-enone
moiety so as to allow a Michael-type addition to produce
compound 6. (pathway a, Scheme 3).
Another mode of cyclization9,12,13 (pathway b) may also be
operative in the intermediate 11. Thus, –SH can deliver its
nucleophilic attack to the carbonyl carbon of 0 the enone
moiety leading to the allylic alcohol 13. SN2 attack of
A compound corresponding to this new spot was isolated
and shown to be 6a from its elemental analysis and spectral
data. The 1H NMR spectrum of compound 6a displayed two
Scheme 3.

K. C. Majumdar et al. / Tetrahedron 58 (2002) 10309–10313
10311
water12 or m-chlorobenzoate9,13 ion on 13 may give rise to
compound 14. However, we did not obtain compound 14 in
any case.
stirred at room temperature for 4 h. The reaction mixture
was then diluted with water (50 mL). Chloroform layer was
separated and washed with 2N HCl (20 mL), brine (20 mL),
water (20 mL) and dried (Na2SO4). Evaporation of chloro-
form left a gummy residue which was subjected to column
chromatography. Elution of the column with benzene–ethyl
acetate (9:1) afforded compounds 5a–f. All the compounds
5a–f were recrystallised from chloroform–petroleum ether.
The yields were calculated with respect to the quantity of
compound 2 used for the preparation of compound 3.
Substrates 5a–d gave compounds 6a–d. Surprisingly the
corresponding oxidized compounds 7e and f were achieved
from substrates 5e and f. These were also characterized from
1
their elemental analysis and spectral data. The H NMR
spectrum of compound 7e revealed two one-proton singlets
at d 7.73 and d 6.54 assignable to C2–H and C7–H,
respectively, a two-proton singlet at d 5.32 due to
aryloxymethylene protons, a three-proton singlet at d 2.35
owing to C6–Me and a four-proton complex multiplet at d
6.86–7.31 assignable to four aromatic protons. However,
the reason for the tendency of compounds 6e and f to get
oxidized is not clear.
3.2.1. 4-(4-Phenoxybut-2-ynylthio)-6-methyl-2-pyrone
(5a). 1.48 g, 52%. Pale brown solid, mp 78–808C.
[Found: C, 67.32; H, 4.98. C16H14O3S requires C, 67.13;
H, 4.89%]; Rf (10% ethyl acetate/benzene) 0.39; lmax 220,
269, 302 nm; nmax (KBr) 1700, 1610, 1475, 1220 cm21; dH
(300 MHz, CDCl3) 2.19 (s, 3H, C6–CH3), 3.67 (s, 2H,
–SCH2), 4.69 (s, 2H, –OCH2), 5.82 (s, 1H, C3–H), 5.94 (s,
1H, C5–H), 6.91–7.31 (m, 5H, ArH); m/z 286 (Mþ).
The reaction displayed appreciable generality and regio-
selectivity. This can be treated as a mild and direct method
for synthesizing fused thienopyrone polyheterocycles.
3.2.2. 4-[4-(20-Methylphenoxybut-2-ynylthio)]-6-methyl-
2-pyrone (5b). 1.62 g, 54%. Pale brown solid, mp 77–798C.
[Found: C, 68.25; H, 5.51. C17H16O3S requires C, 68.00; H,
5.33%]; Rf (10% ethyl acetate/benzene) 0.38; lmax 221, 270,
302 nm; nmax (KBr) 1700, 1620, 1470, 1215 cm21; dH
(300 MHz, CDCl3) 2.19 (s, 3H, –CH3), 2.22 (s, 3H, –CH3),
3.67 (s, 2H, –SCH2), 4.71 (s, 2H, –OCH2), 5.82 (s, 1H,
C3–H), 5.94 (s, 1H,C5–H), 6.86–7.16 (m, 4H, ArH); m/z
300 (Mþ).
3. Experimental
Melting points were measured on a sulphuric acid bath and
are uncorrected. UV absorption spectra were recorded in
EtOH on a Hitachi 200-20 Spectrophotometer. IR spectra
were run on KBr disks on a Perkin–Elmer 1330 apparatus.
1H NMR spectra were determined for solutions in CDCl3
with TMS as internal standard on a Bruker DPX-300
(300 MHz) instrument. Elemental analyses and recording of
mass spectra were carried out by RSIC(CDRI) Lucknow on
a [JEOL D-300 (El)] instrument. Silica gel (60–120 mesh),
Spectrochem, India, was used for chromatographic separa-
tion. Petroleum ether refers to the fraction boiling between
60 and 808C.
3.2.3. 4-[4-(40-Methylphenoxybut-2-ynylthio)]-6-methyl-
2-pyrone (5c). 1.50 g, 50%. Pale brown solid, mp 71–728C.
[Found: C, 68.21; H, 5.48. C17H16O3S requires C, 68.00; H,
5.33%]; Rf (10% ethyl acetate/benzene) 0.39; lmax 222, 270,
302 nm; nmax (KBr) 1700, 1620, 1485, 1220 cm21; dH
(300 MHz, CDCl3) 2.19 (s, 3H, –CH3), 2.28 (s, 3H, –CH3),
3.66 (s, 2H, –SCH2), 4.66 (s, 2H, –OCH2), 5.82 (s, 1H,
C3–H), 5.93 (s, 1H,C5–H), 6.81 (d, J¼9 Hz, 2H, ArH), 7.06
(d, J¼9 Hz, 2H, ArH); m/z 300 (Mþ).
3.1. Synthesis of 4-mercapto-6-methylpyran-2-one 3
To a magnetically stirred solution of NaSH (2.30 g,
40 mmol) in dry ethanol (50 mL), a solution of 6-methyl-
4-tosyloxypyran-2-one11 2 (2.8 g, 10 mmol) in dry ethanol
was added dropwise at room temperature under nitrogen
atmosphere over a period of 30 min. Stirring was continued
for additional 2 h after the completion of addition. Ethanol
was removed in vacuo at room temperature. The residue
was acidified with conc. HCl (20 mL). This was extracted
with chloroform (4£25 mL). The chloroform solution was
washed with water (2£20 mL) and dried (Na2SO4). Attempt
to evaporate chloroform led to considerable decompo-
sition of compound 3. So this chloroform solution was
directly used for the subsequent phase-transfer-catalysed
alkylations.
3.2.4. 4-[4-(40-Chlorophenoxybut-2-ynylthio)]-6-methyl-
2-pyrone (5d). 1.65 g, 52%. Pale brown solid, mp 76–788C.
[Found: C, 60.12; H, 4.26. C16H13ClO3S requires C, 59.90;
H, 4.05%]; Rf (10% ethyl acetate/benzene) 0.39; lmax 224,
271, 303 nm; nmax (KBr) 1700, 1620, 1480, 1215 cm21; dH
(300 MHz, CDCl3) 2.20 (s, 3H, C6–CH3), 3.66 (s, 2H,
–SCH2), 4.67 (s, 2H, –OCH2), 5.81 (s, 1H, C3–H), 5.91 (s,
1H,C5–H), 6.84 (d, J¼9 Hz, 2H, ArH), 7.21 (d, J¼9 Hz,
2H, ArH); m/z 320, 322 (Mþ).
3.2.5. 4-[4-(20-Chlorophenoxybut-2-ynylthio)]-6-methyl-
2-pyrone (5e). 1.75 g, 55%. Pale brown solid, mp 112–
1138C. [Found: C, 60.14; H, 4.21. C16H13ClO3S requires C,
59.90; H, 4.05%]; Rf (10% ethyl acetate/benzene) 0.38;
lmax 221, 271, 302 nm; nmax (KBr) 1700, 1630, 1475,
1220 cm21; dH (300 MHz, CDCl3) 2.19 (s, 3H, C6–CH3),
3.66 (s, 2H, –SCH2), 4.78 (s, 2H, –OCH2), 5.82 (s, 1H, C3–
H), 5.92 (s, 1H,C5–H), 6.91–7.38 (m, 4H, ArH); m/z 320,
322 (Mþ).
3.2. General procedure for the synthesis of compounds
5a–f
To a mixture of 4-mercapto-6-methylpyran-2-one (3)
(obtained from 2.8 g, 10 mmol of compound 2) and
1-aryloxy-4-chlorobut-2-yne (10 mmol) (4a–f) in chloro-
form (100 mL) was added a solution of benzyl triethyl
ammonium chloride (BTEAC, 0.5 g, 1.8 mmol) in 1%
aqueous NaOH (100 mL) and the mixture was magnetically
3.2.6. 4-[4-(20,40-Dichlorophenoxybut-2-ynylthio)]-6-
methyl-2-pyrone (5f). 1.95 g, 55%. Pale brown solid, mp
140–1418C. [Found: C, 54.32; H, 3.54. C16H12Cl2O3S

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K. C. Majumdar et al. / Tetrahedron 58 (2002) 10309–10313
requires C, 54.08; H, 3.38%]; Rf (10% ethyl acetate/
benzene) 0.39; lmax 222, 270, 301 nm; nmax (KBr) 1700,
1620, 1470, 1220 cm21; dH (300 MHz, CDCl3) 2.21 (s, 3H,
C6–CH3), 3.66 (s, 2H, –SCH2), 4.77 (s, 2H, –OCH2), 5.81
(s, 1H, C3–H), 5.90 (s, 1H,C5–H), 6.92 (d, J¼9 Hz, 1H,
ArH), 7.16 (dd, J¼9, 3 Hz, 1H, ArH), 7.36 (d, J¼3 Hz, 1H,
ArH); m/z 354, 356, 358 (Mþ).
(dd, J¼6, 12 Hz, 1H, C2–H), 4.53 (dd, J¼6, 9 Hz, 1H,
C3–H), 4.85 (d, J¼17 Hz, 1H, –OCH2), 4.98 (d, J¼17 Hz,
1H, –OCH2), 6.09 (s, 1H, C7–H), 6.84 (dd, J¼3, 9 Hz,
2H, ArH), 7.21 (dd, J¼3, 9 Hz, 2H, ArH); m/z 336, 338
(Mþ).
3.3.5. Compound 7e. 128 mg, 64%. White solid, mp
104–1058C. [Found: C, 57.19; H, 3.15. C16H11ClO4S
requires C, 57.39; H, 3.28%]; Rf (benzene) 0.42; lmax
220, 307 nm; nmax (KBr) 1260, 1485, 1610, 1710,
2910 cm21; dH (300 MHz, CDCl3) 2.35 (s, 3H, C6–CH3),
5.32 (s, 2H, –OCH2), 6.54 (s, 1H, C7–H), 6.86–7.31 (m,
4H, ArH), 7.73 (s, 1H, C2–H), m/z 334, 336 (Mþ).
3.3. General procedure for the preparation of
compounds 6a–d and 7e and f
m-Chloroperoxybenzoic acid (50%, 210 mg, 1.22 mmol) in
chloroform (20 mL) was slowly added to a well-stirred
solution of the sulfides 5a–f (0.6 mmol) in chloroform
(25 mL) at 0–58C over a period of 30 min. The reaction
mixture was stirred for additional 30 min. Then the
chloroform solution was washed with saturated sodium
carbonate solution (3£20 mL) to remove the organic acid
followed by brine (3£20 mL), H2O (3£20 mL) and dried
(Na2SO4). At this time, the solution assumed a pale yellow
colour. The solvent was removed and the residue was
refluxed in carbon tetrachloride (25 mL) for 1.5 h. Then
carbon tetrachloride was distilled off and a viscous liquid
was obtained. It was then chromatographed over silica gel
using benzene as eluent to give compounds 6a–d as viscous
oil and 7e and f as white solid.
3.3.6. Compound 7f. 135 mg, 61%. White solid, mp122–
1238C. [Found: C, 52.21; H, 2.93 C16H10Cl2O4S requires
C, 52.03; H, 2.71%]; Rf (benzene) 0.43; lmax 221, 307 nm;
nmax (KBr) 1260, 1490, 1610, 1710, 2920 cm21
dH(300 MHz, CDCl3) 2.35 (s, 3H, C6–CH3), 5.33 (s, 2H,
;
–OCH2), 6.55 (s, 1H, C7–H), 6.92 (d, J¼9 Hz, 1H, ArH),
7.14 (dd, J¼3, 9 Hz, 1H, ArH), 7.31 (d, J¼3 Hz, 1H, ArH),
7.73 (s, 1H, C2–H), m/z 368, 370, 372 (Mþ).
Acknowledgements
We thank the CSIR (New Delhi) for financial assistance and
the University of Kalyani for providing laboratory facilities.
3.3.1. Compound 6a. 120 mg, 68%. Viscous oil. [Found: C,
63.41; H, 4.50. C16H14O4S requires C, 63.57; H, 4.63%]; Rf
(benzene) 0.39; lmax 220, 309 nm; nmax (neat) 1260, 1490,
1600, 1710, 2920 cm21; dH (300 MHz, CDCl3) 2.25 (s, 3H,
C6–CH3), 3.55 (dd, J¼9, 12 Hz, 1H, C2–H), 3.70 (dd, J¼6,
12 Hz, 1H, C2–H), 4.59 (dd, J¼6, 9 Hz, 1H, C3–H),
4.87 (d, J¼17 Hz, 1H, –OCH2), 4.91 (d, J¼17 Hz, 1H,
–OCH2), 6.09 (s, 1H, C7–H), 6.87–7.31 (m, 5H, ArH); m/z
302 (Mþ).
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3.3.2. Compound 6b. 135 mg, 71%. Viscous oil. [Found: C,
64.32; H, 4.89. C17H16O4S requires C, 64.55; H, 5.06%]; Rf
(benzene) 0.38; lmax 221, 316 nm; nmax (neat) 1250, 1485,
1610, 1710, 2920 cm21; dH (300 MHz, CDCl3) 2.25 (s, 3H,
–CH3), 2.29 (s, 3H, –CH3), 3.56 (dd, J¼9, 12 Hz, 1H,
C2–H), 3.68 (dd, J¼6, 12 Hz, 1H, C2–H), 4.65 (dd, J¼6,
9 Hz, 1H, C3–H), 4.86 (d, J¼17 Hz, 1H, –OCH2), 4.92 (d,
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3.3.3. Compound 6c. 125 mg, 66%. Viscous oil. [Found: C,
64.38; H, 5.06. C17H16O4S requires C, 64.55; H, 5.06%]; Rf
(benzene) 0.38; lmax 224, 310 nm; nmax (neat) 1250, 1500,
1610, 1710, 2920 cm21; dH (300 MHz, CDCl3) 2.25 (s, 3H,
–CH3), 2.27 (s, 3H, –CH3), 3.53 (dd, J¼9, 12 Hz, 1H,
C2–H), 3.68 (dd, J¼6, 12 Hz, 1H, C2–H), 4.58 (dd, J¼6,
9 Hz, 1H, C3–H), 4.83 (d, J¼17 Hz, 1H, –OCH2), 4.90
(d, J¼17 Hz, 1H, –OCH2), 6.07 (s, 1H, C7–H), 6.80 (d,
J¼9 Hz, 2H, ArH), 7.06 (d, J¼9 Hz, 2H, ArH); m/z 316
(Mþ).
3.3.4. Compound 6d. 125 mg, 62%. Viscous oil. [Found: C,
57.22; H, 3.98. C16H13ClO4S requires C, 57.05; H, 3.86%];
Rf (benzene) 0.38; lmax 220, 312 nm; nmax (neat) 1250,
1490, 1620, 1710, 2920 cm21; dH (300 MHz, CDCl3) 2.26
(s, 3H, C6-CH3), 3.55 (dd, J¼9, 12 Hz, 1H, C2–H), 3.73
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