Regioselective synthesis of thieno[3,2-c][1]benzopyran-4-ones by thio-Claisen rearrangement

Article abstract of DOI:10.1007/s00706-003-0164-4

A number of thieno[3,2-c][1]benzopyran-4-ones, potential antiinflamatory, antipyretic, and antiallergic drugs, are synthesized in 65-80% yield by thermal thio-Claisen rearrangement of 4-allylthio[1]benzopyran-2-ones in refluxing quinoline for 0.5-8.0 h. T

Full text of DOI:10.1007/s00706-003-0164-4

Monatshefte f€ur Chemie 135, 1001–1007 (2004)
DOI 10.1007/s00706-003-0164-4
Regioselective Synthesis of Thieno[3,2-
c][1]benzopyran-4-ones by Thio-Claisen
Rearrangement
ꢀ
Krishna C. Majumdar and Anindita Biswas
Department of Chemistry, University of Kalyani, Kalyani 741 235, West Bengal, India
Received November 4, 2003; accepted (revised) November 29, 2003
Published online May 21, 2004 # Springer-Verlag 2004
Summary. A number of thieno[3,2-c][1]benzopyran-4-ones, potential antiinflamatory, antipyretic, and
antiallergic drugs, are synthesized in 65–80% yield by thermal thio-Claisen rearrangement of 4-
allylthio[1]benzopyran-2-ones in refluxing quinoline for 0.5–8.0 h. The 4-allylthio[1]benzopyran-2-
ones are in turn prepared in 75–85% yield from 4-mercaptocoumarin and different allylic halides by
phase-transfer-catalysed alkylation with TBAB or BTEAC catalyst in chloroform-aq. NaOH at room
temperature.
Keywords. Allylic halides; 4-Mercaptocoumarin; Phase-transfer-catalysed alkylation; [3,3]-Sigma-
tropic rearrangement; Thio-Claisen rearrangement.
Introduction
Coumarin [1] and its derivatives [2] are important for their physiological activities.
In continuation of our work on the synthesis of potential bioactive heterocycles [3]
containing a coumarin nucleus by means of [3,3]-sigmatropic rearrangement [4]
we ended up in the study of the related thio-Claisen rearrangement [5]. As com-
pared to oxygen [6] and aza-Claisen rearrangements [7] not much work has been
carried out on the corresponding thio-Claisen rearrangement [8]. Our recent find-
ing [9] on the regioselective synthesis of 2H-thiopyrano[3,2-c]coumarins by ther-
mal [3,3]-sigmatropic rearrangement prompted us to undertake a study on the
thio-Claisen rearrangement of 4-allylmercaptocoumarin. Here we report the results.
Results and Discussion
4-Mercaptocoumarin (1) was reacted with different allylic halides (2a–2f) under
phase-transfer-catalysis condition [10] using tetrabutylammoniumbromide (TBAB)
or benzyltriethylammoniumchloride (BTEAC) in chloroform-aqueous sodium
ꢀ
Corresponding author. E-mail: kcm@klyuniv.ernet.in

1002
K. C. Majumdar and A. Biswas
Scheme 1
hydroxide (1%) at room temperature for 4 h to give a number of 4-allylthiocou-
marin derivatives (3a–3e) in 75–85% yield, which served as the starting materials
(Scheme 1). Halides 2b and 2f gave the same sulfide 3b because of a SN dis-
0
2
placement in case of 2f. Compounds 3a–3e were characterised from elemental
analyses and spectroscopic data.
No change was observed when 3a was subjected to heating in chlorobenzene.
This was then heated in 1,2-dichlorobenzene. The reaction was monitored by TLC.
No change was recorded. Although the ꢀ-pyrone ring of coumarin does not involve
a ꢁ-sextet and was thus expected to undergo thio-Claisen rearrangement at lower
temperature [11], substrate 3a did not show any conversion in TLCs when heated
in chlorobenzene, 1,2-dichlorobenzene, and even in N,N-diethylaniline (216ꢁC).
However, when refluxed in quinoline (238ꢁC) for 8 h, 3a gave 5a, a white crystal-
1
line solid (yield 80%). The H NMR spectrum of 5a exhibited a singlet at
ꢂ ¼ 2.59 ppm due to –CH3 and a multiplet at ꢂ ¼ 7.28–7.63 ppm due to four ArH
and one ¼CH. The 13C spectrum of 5a also strongly supported its structure. The
13C chemical shifts and multiplicity of compound 5a were assigned by a DEPT
experiment. The mass spectrum of 5a showed a moleculer ion peak at m=z ¼ 216
(Mþ). It was also characterized from its elemental analysis and spectral data.
Substrates 3b and 3c were similarly heated in quinoline to afford products 5b
and 5c in 76 and 70% yield. However, 3d on similar treatment in quinoline for
2.5 h gave unlike 3a–3c, the dihydro compound 4d (65%) (Scheme 2).
Scheme 2

Regioselective Synthesis of Thieno[3,2-c][1]benzopyran-4-ones
1003
Scheme 3
Substrates 3a and 3e afforded the same product 5a. Compound 4d was dehy-
drogenated to the corresponding aromatic product 5d by reaction with palladised
charcoal in refluxing diphenylether for 2 h (Scheme 3).
The formation of products 5a–5c and 4d from 3a–3e may be explained by an
initial [3,3]-sigmatropic rearrangement followed by enolization to give allylene-
thiol 7. Quinoline base may bring about the cyclization of allylene-thiols 7a, 7b,
7d, and 7e to 4a, 4b, 4d, and 4e. Intermediates 4a and 4b undergo oxidation to 5a
Scheme 4

1004
K. C. Majumdar and A. Biswas
and 5b under these reaction conditions. Intermediate 4e eliminates one molecule of
HCl to give 5a. Allylene-thiol 7c undergoes cyclization to 9c, which after two 1,3-
prototropic shifts furnishes 5c (Scheme 4).
Thieno[3,2-c]coumarins reported earlier by Makisumi et al. have been shown to
be antiinflamatory, antipyretic, and antiallergic drugs [12]. In conclusion it was
seen that all the cases studied so far involve thio-Claisen rearrangement and no
[1,3]-radical shift [13] was observed. Thus, this reaction provides a simple regio-
selective synthesis of thieno[3,2-c]coumarins.
Experimental
Melting points were measured on a sulfuric acid bath and are uncorrected. UV=Vis absorption spectra
were recorded on a UV-VIS Spectrophotometer Shimadzu UV-2401PC (absolute ethanol). IR spectra
were run on KBr discs on a Perkin-Elmer 1330 apparatus and FTIR spectrophotometer Perkin-Elmer
L120-000A. 1H NMR spectra were recorded in CDCl3 with TMS as internal standard on Bruker DPX-
300 (300MHz) and Bruker DPX-500 (500MHz) spectrometers. The 13C NMR (125MHz) spectra
were recorded on a Bruker DPX-500 spectrometer. Elemental analyses results agreed favourably with
the calculated values and mass spectra were recorded at RSIC (CDRI) Lacknow on a JEOL D-300 (EI)
instrument. Silica gel (60–120) was obtained from Spectrochem. Extracts were dried over anhydrous
Na2SO4. Compound 1 was prepared according to Ref. [14].
Alkylation of 4-Mercaptocoumarin
To a mixture of 4 mmol of 4-mercaptocoumarin and 6 mmol of allylic halide in 50cm3 of CHCl3 was
added a solution of 0.9 mmol of BTEAC (0.25 g) in 50cm3 1% aq. NaOH and the mixture was stirred
for a period of 4 h. This was then diluted with 125 cm3 of H2O and extracted with 2ꢂ50cm3 of CHCl3.
The CHCl3 extract was washed successively with 2ꢂ50cm3 of 2 N HCl, 2ꢂ50cm3 of brine, 50cm3 of
H2O, and dried (Na2SO4). Chloroform was removed and the residual mass was purified by column
chromatography over silica gel. The product was obtained by eluting the column with benzene.
4-(Prop-2-enylthio)[1]benzopyran-2-one (3a, C12H10O2S)
Yield 80% (0.7g); white solid; mp 106ꢁC; 1H NMR (CDCl3, 500 MHz): ꢂ ¼ 3.70 (d, J ¼ 6 Hz, SCH2),
5.32–5.47 (m, ¼CH2), 5.89–5.97 (m, SCH2CH), 6.18 (s, COCH), 7.28–7.76 (m, 4ArH) ppm; IR
(KBr): ꢃꢀ¼ 1710, 1590, 1180 cmꢃ1; UV=Vis (EtOH): ꢄmax ð log "Þ ¼ 213 (4.27), 274 (3.97), 298 (4.02)
nm; MS: m=z ¼ 218 (Mþ).
4-(3-Methylprop-2-enylthio)[1]benzopyran-2-one (3b, C13H12O2S)
1
Yield 85% (0.79 g); white solid; mp 92ꢁC; H NMR (CDCl3, 300 MHz): ꢂ ¼ 1.74 (d, J ¼ 6.6 Hz,
¼CHCH3), 3.65 (d, J ¼ 6 Hz, SCH2), 5.51–5.61 (m, SCH2CH¼), 5.83–5.94 (m, ¼CHCH3), 6.18
(s, COCH), 7.24–7.75 (m, 4ArH) ppm; IR (KBr): ꢃꢀ¼ 1700, 1590, 1170 cmꢃ1; UV=Vis (EtOH): ꢄmax
ð log "Þ ¼ 212 (4.25), 274 (3.97), 299 (4.02) nm; MS: m=z ¼ 232 (Mþ).
4-(4-Chlorobut-2-enylthio)[1]benzopyran-2-one (3c, C13H11ClO2S)
Yield 85% (0.91 g); white solid; mp 91ꢁC; 1H NMR (CDCl3, 300MHz): ꢂ ¼ 3.71–4.19 (m, SCH2 and
CH2Cl), 5.8–6.06 (m, CH¼CH), 6.16 (s, COCH), 7.28–7.74 (m, 4ArH) ppm; IR (KBr): ꢃꢀ¼ 1700,
1595, 1180 cmꢃ1; UV=Vis (EtOH): ꢄmax ð log "Þ ¼ 212 (4.3), 274 (3.98), 297 (4.01) nm; MS:
m=z ¼ 266, 268 (Mþ).

Regioselective Synthesis of Thieno[3,2-c][1]benzopyran-4-ones
1005
4-(3-Phenylprop-2-enylthio)[1]benzopyran-2-one (3d, C18H14O2S)
1
Yield 80% (0.94 g); white solid; mp 140ꢁC; H NMR (CDCl3, 300 MHz): ꢂ ¼ 3.88 (d, J ¼ 6 Hz,
SCH2), 6.23–6.33 (m, SCH2CH and COCH), 6.74 (d, J ¼ 15Hz, PhCH), 7.28–7.77 (m, 9ArH)
ppm; IR (KBr): ꢃꢀ¼ 1717, 1593, 1193 cmꢃ1; UV=Vis (EtOH): ꢄmax ð log "Þ ¼ 210 (4.47), 258
(4.22), 285 (4.03), 294 (4.03) nm; MS: m=z ¼ 294 (Mþ).
4-(2-Chloroprop-2-enylthio)[1]benzopyran-2-one (3e, C12H9ClO2S)
Yield 75% (0.76 g); white solid; mp 112ꢁC; 1H NMR (CDCl3, 300MHz): ꢂ ¼ 3.95 (s, SCH2), 5.52 (s,
CCl¼CH), 5.65 (s, CCl¼CH), 6.18 (s, COCH), 7.28–7.79 (m, 4ArH) ppm; IR (KBr): ꢃꢀ¼ 1700, 1590,
1185 cmꢃ1; UV=Vis (EtOH): ꢄmax ð log "Þ ¼ 212 (4.34), 273 (4.02), 295 (4.03) nm; MS: m=z ¼ 252,
254 (Mþ).
Thermal Rearrangement of 4-Allylthio[1]benzopyran-2-ones
Compounds 3a–3e (2mmol) were refluxed in 3 cm3 of quinoline for 0.5–8.0 h. The reaction mixture
was cooled and poured into ice-cold HCl (6N). This was then extracted with 3ꢂ25cm3 of CHCl3. The
CHCl3 extract was washed with 3ꢂ25 cm3 of 1:1 HCl, 3ꢂ25 cm3 of H2O, and dried (Na2SO4). The
CHCl3 was removed and the crude mass was purified by column chromatography over silica gel using
benzene:petroleum ether (1:1) as the eluent.
2-Methylthieno[3,2-c]benzopyran-4-one (5a, C12H8O2S)
Yield 80% (0.35 g); white solid; mp 140ꢁC; 1H NMR (CDCl3, 300 MHz): ꢂ ¼ 2.59 (s, CH3), 7.28–7.63
(m, 5ArH) ppm; 13C NMR (CDCl3, 125 MHz): ꢂ ¼ 16.08 (CH3), 117.79, 123.55, 124.52, 124.92,
130.21 (C-3, C-6, C-7, C-8, C-9), 117.62, 125.97, 141.61, 147.58, 151.48 (C-2, C-3a, C-5a, C-9a, C-
9b), 157.54 (C-4) ppm; IR (KBr): ꢃꢀ¼ 2910, 1720, 1605, 1460, 1190 cmꢃ1; UV=Vis (EtOH): ꢄmax
ð log "Þ ¼ 232 (4.3), 257 (3.62), 297 (3.73), 325 (4.07) nm; MS: m=z ¼ 216 (Mþ).
2,3-Dimethylthieno[3,2-c]benzopyran-4-one (5b, C13H10O2S)
1
Yield 76% (0.35 g); white solid; mp 130ꢁC; H NMR (CDCl3, 300 MHz): ꢂ ¼ 2.45 (s, CH3), 2.49 (s,
CH3), 7.22–7.62 (m, 4ArH) ppm; 13C NMR (CDCl3, 125 MHz): ꢂ ¼ 13.57, 13.71 (2CH3), 117.44,
123.25, 124.69, 129.88 (C-6, C-7, C-8, C-9), 117.74, 124.52, 134.17, 134.44, 146.02, 151.09 (C-2, C-3,
C-3a, C-5a, C-9a, C-9b), 157.54 (C-4) ppm; IR (KBr): ꢃꢀ¼ 2910, 1700, 1604, 1470, 1190 cmꢃ1
;
UV=Vis (EtOH): ꢄmax ( log ") ¼ 235 (4.25), 262 (3.73), 271 (3.61), 332 (4.09) nm; MS: m=z ¼ 230
(Mþ).
3-Ethylthieno[3,2-c]benzopyran-4-one (5c, C13H10O2S)
1
Yield 70% (0.32 g); white solid; mp 87ꢁC; H NMR (CDCl3, 300 MHz): ꢂ ¼ 1.30 (t, J ¼ 7.3 Hz,
CH2CH3), 3.03 (q, J ¼ 7.3 Hz, CH2CH3), 7.02 (s, SCH), 7.25–7.71 (m, 4ArH) ppm; IR (KBr):
ꢃꢀ¼ 2922, 1723, 1604, 1473, 1190cmꢃ1; UV=Vis (EtOH): ꢄmax ð log "Þ ¼ 231 (4.24), 262 (3.72),
272 (3.7), 325 (4.08) nm; MS: m=z ¼ 230 (Mþ).
2,3-Dihydro-2-methyl-3-phenylthieno[3,2-c]benzopyran-4-one (4d, C18H14O2S)
1
Yield 65% (0.38 g); white solid; mp 126ꢁC; H NMR (CDCl3, 300 MHz): ꢂ ¼ 1.63 (d, J ¼ 6.9 Hz,
CH3), 3.88–3.96 (m, SCH), 4.39 (d, J ¼ 2.7 Hz, PhCH), 7.07–7.73 (m, 9ArH) ppm; IR (KBr):

1006
K. C. Majumdar and A. Biswas
ꢃꢀ¼ 1713, 1605, 1485, 1190cmꢃ1; UV=Vis (EtOH): ꢄmax ð log "Þ ¼ 232 (4.28), 268 (3.97), 312 (4.03),
329 (4.02), 343 (3.82) nm; MS: m=z ¼ 294 (Mþ).
Dehydrogenation of Compound 4d
Compound 4d (0.147g, 0.5 mmol) was refluxed with 10mg 10% Pd-C in 2 cm3 of diphenylether for
2 h. The product 5d was obtained by column chromatography over silica gel using benzene:petroleum
ether (1:3) as eluent.
2-Methyl-3-phenylthieno[3,2-c]benzopyran-4-one (5d, C18H12O2S)
Yield 80% (0.12 g); white solid; mp 142ꢁC; 1H NMR (CDCl3, 300 MHz): ꢂ ¼ 2.4 (s, CH3), 7.29–7.708
(m, 9ArH) ppm; IR (KBr): ꢃꢀ¼ 1737, 1605, 1477, 1220 cmꢃ1; UV=Vis (EtOH): ꢄmax ð log "Þ ¼ 206
(4.37), 232 (4.21), 331 (3.97) nm; MS: m=z ¼ 292 (Mþ).
Acknowledgement
We thank the CSIR (New Delhi) for financial assistance. One of us (A.B.) is grateful to CSIR (New
Delhi) for a Junior Research Fellowship.
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Regioselective Synthesis of Thieno[3,2-c][1]benzopyran-4-ones
1007
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