Application of directed metalation in synthesis. Part 7: Synthesis of suitably functionalised benzo[b]thiophenes as key intermediates in the synthesis of benzothienopyranones

Article abstract of DOI:10.1016/j.tetlet.2005.01.038

One-pot syntheses of (3-hydroxybenzo[b]thiophen-2-yl) aryl methanones from ortho-methylsulfanylaryl N,N-diethyl amides and of 1-(3-hydroxybenzo[b]thiophen- 2-yl)ethanone and 1-(3-hydroxybenzo[b]thiophen-2-yl)propan-1-one via an anionic ortho-Fries rearrangement are described. The hydroxy ketones were used as key intermediates in the synthesis of benzothienopyranones.

Full text of DOI:10.1016/j.tetlet.2005.01.038

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1493–1495
Application of directed metalation in synthesis. Part 7: Synthesis
of suitably functionalised benzo[b]thiophenes as key intermediates
in the synthesis of benzothienopyranonesq
Tarun Kanti Pradhan and Asish De*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 2 September 2004; revised 20 December 2004; accepted 7 January 2005
Available online 25 January 2005
Abstract—One-pot syntheses of (3-hydroxybenzo[b]thiophen-2-yl) aryl methanones from ortho-methylsulfanylaryl N,N-diethyl
amides and of 1-(3-hydroxybenzo[b]thiophen-2-yl)ethanone and 1-(3-hydroxybenzo[b]thiophen-2-yl)propan-1-one via an anionic
ortho-Fries rearrangement are described. The hydroxy ketones were used as key intermediates in the synthesis of
benzothienopyranones.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Benzothienopyranones, sulfur analogs of furanochro-
manones and furanocoumarins1 are interesting synthetic
targets because of their potentialto show bioolgical
activity.2 In this class of compounds, examples in which
the oxygenated ring is fused to the benzene ring of the
benzo[b]thiophene, are known in greater number than
those in which the pyranone ring is annulated to the thio-
phene moiety, despite the pronounced biological activi-
ties shown by some members of the latter group. For
example 4-oxo-4H-benzo[b]thieno[3,2-b]pyran-3-carb-
oxylic acid 1 has pronounced antiasthmatic activity2
(Fig. 1). It may be presumed that suitably functionalised
benzo[b]thiophenes, which could be intermediates in the
synthesis of this class of benzothienopyranones, are less
easily accessible. In this communication we present two
expedient routes to benzo[b]thiophenes possessing ke-
tone and hydroxy functions at the 2- and 3-positions,
respectively, and utilisation of the functionalised mole-
cules in the annulation of a pyranone ring. The synthe-
ses also constitute a novel application of directed
metalation.3
carboxamides by treatment with LDA and an appropri-
ate arylaldehyde, earlier reported by us, 5 it was observed
that the desired thioaurones were always accompanied
by varying amounts of other compounds and by careful
controlof the experimentalconditions it was possibel to
achieve the exclusive formation of either of the two
types of product. In a typicalexperiment, the ortho-
methylsulfanyl tertiary aryl amides were treated with
LDA followed by addition of the aryl aldehydes at
0 ꢁC. Acidic work up after 1 h at that temperature gave
the thioaurones. On the other hand, if the reaction mix-
ture was allowed to attain room temperature and stirred
for 5–6 h before acidic work up, (3-hydroxy-
benzo[b]thiophen-2-yl) aryl methanones were obtained.
The IR spectrum of the latter showed peaks dueÀt1o hy-
droxyland carbonylfunctions at 3440–3450 cm
and
at 1590 cmÀ1, respectively, suggesting intramolecular
hydrogen bonding between the two functionalities. The
existence of hydrogen bonding was further corroborated
1
by the H NMR spectra, which displayed signals due to
a hydrogen bonded OH as a one proton singlet at
around 13.5 ppm. From analytical and spectroscopic
data these compounds were assigned the (3-hydroxy
benzo[b]thiophen-2-yl) aryl ketone6 structures 5a–f
(Table 1). A plausible reaction mechanism requires
formation of the thioindoxyl 2 (Scheme 1) as the com-
mon intermediate for both the thioaurones and the
hydroxyketones. Deprotonation at the 2-position of 2
and subsequent attack by the incipient carbanion on
the carbonylcarbon of the aryladlehyde affords the
While examining the scope of the one-pot synthesis of
thioaurones,4 from ortho-methylsulfanyl N,N-diethyl
Keywords: Directed metalation; Chemoselectivity; Benzothieno-
pyranone; Thioaurone; Thioindoxyl.
q Part 6: See Ref. 12.
*
Corresponding author. Tel.: +91 33 2473 4971x120; fax: +91 33 2473
2805; e-mail: ocad@mahendra.iacs.res.in
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.038

1494
T. K. Pradhan, A. De / Tetrahedron Letters 46 (2005) 1493–1495
CO2H
O
O
_
O
O
O
R
R1
R
R1
O
S
S
S
H
2a
2b
1
Figure 1.
Table 1. (3-Hydroxybenzo[b]thiophen-2-yl) alkyl or aryl ketone
We also synthesised two (3-hydroxybenzo[b]thiophen-2-
yl) alkyl ketones 5g–h through a hitherto unreported anion-
ic ortho-Fries rearrangement. The anionic ortho-Fries
rearrangement8 first reported by Snieckus consists of di-
rected lithiation ortho to an O-carbamate and intramo-
lecular rearrangement in the absence of an electrophile
quench, leading to the salicylamide. We have shown
for the first time that a similar rearrangement is
possible with ortho-lithio derivatives of aryl acetates
and propionates. Thus benzo[b]thiophen-3-ylacetate
4a and benzo[b]thiophen-3-ylpropionate 4b,9 which
were prepared by treating the thioindoxylwith acetyl
chloride and propionyl chloride, respectively, in the
presence of sodium hydride or LDA in tetrahydrofuran,
were lithiated at the 2-position with LDA. The deproto-
nated species upon stirring at room temperature for
8–10 h underwent intramolecular rearrangement to
afford 1-(3-hydroxybenzo[b]thiophen-2-yl)ethanone 5g
and 1-(3-hydroxybenzo[b]thiophen-2-yl)propan-1-one
5h, respectively.
Entry
R
R1
Mp (ꢁC)
Yield (%)
5a
5b
5c
5d
5e
5f
H
Ph
102
139–141
88
93
89
H
PhCH@CH
2-Thienyl118
Ph
H
4-OMe
4-OMe
4-OMe
H
138
91
89
PhCH@CH
2-Thienyl174–176
Me
164–166
90
53
5g
5h
67
73
H
Et
69
ionic intermediate 2a (Fig. 1). Acidic work up after 1 h
results in dehydration leading to the thioaurones. When
the reaction mixture was stirred at room temperature in
the presence of an aryladl ehyde for 5–6 h it had suffi-
cient time to undergo Cannizzaro type hydride transfer
affording the 1,3-dicarbonylproduct 2b (Fig. 1) which
enolises to the hydroxyketone. It was difficult to isolate
the resulting reduced alcohol after work up. However,
from GC analysis of the crude reaction product ob-
tained from compound 2 (R = H) and benzaldehyde
we observed the formation of benzylacloholconfirming
the occurrence of the Cannizzaro type reaction.7 An
interesting switch of chemoselectivity is thus observed
between the elimination products 3 and the enolic 1,3-
dicarbonylderivatives 5a–f depending upon the reaction
conditions.
With the suitably functionalised benzo[b]thiophenes in
hand we proceeded with the annulation reactions, repre-
sentative examples of which are given below. Thus 5c
and 5f were cyclised in ethanol by bubbling in dry
hydrogen chloride gas to afford 6a and 6b in 90% and
87% yields, respectively.10 Compounds 5g and 5h were
formylated with ethyl formate in the presence of sodium
When R1 = Alkyl
R1
CONEt2
SMe
O
(vii)
O
O
H
R2
H
O
R
R
R
R
R1
(ii)
(iii)
R1
O
S
S
S
5a-h
3
6a, R,R2=H, R1=Ph, 90%
(viii)
(iv)
(v)
6b, R=4-OMe, R2=H, R1=Ph, 87%
6c, R,R2=H, R1=OH, 85%
(i)
When R1 = CH=CHPh
OCOR1
(i)
O
6d, R=H, R1=OH, R2=Me, 89%
(vi)
R
R
(ix)
S
R2
S
4a, R1=Me, 89%
4b, R1= Et, 93%
2
O
R3
R
O
S
7a, R, R2, R3=H, 93%
7b, R, R2=H, R3=Me, 95%
Scheme 1. Reagents and conditions: (i) LDA (1.5 equiv)/THF/À78 ꢁC to rt; (ii) LDA (2.5 equiv)/THF/R1CHO/À10–0 ꢁC; (iii) LDA (2.5 equiv)/
THF/R1CHO/À10 ꢁC to rt; (iv) LDA (1.5 equiv)/THF/R1CHO/À10–0 ꢁC; (v) LDA (1.5 equiv)/THF/R1CHO/À10 ꢁC to rt; (vi) NaH/THF/R1COCl/
rt; (vii) NaH/THF/HCO2Et; (viii) ethanol/dry HCl (gas); (ix) PTSA/benzene.

T. K. Pradhan, A. De / Tetrahedron Letters 46 (2005) 1493–1495
1495
(2.2 mmol) in anhydrous THF (7 mL) ortho-methylsulfa-
nylbenzamide (0.223 g, 1 mmo)l in anhydrous THF
(4 mL) was added at À10 ꢁC using a syringe. After stirring
for 1 h at that temperature, benzaldehyde (0.1 g, 1 mmol)
in THF (2 mL) was added, the mixture was warmed to
room temperature and kept for 6 h at that temperature.
Next, water (25 mL) was added to the reaction mixture
and the pH was maintained at 4–5 by dropwise addition of
2 N HCl. The reaction mixture was extracted with
chloroform (3 · 20 mL) and the organic layer was washed
with water (3 · 25 mL) and dried over Na2SO4. Removal
of solvent left the crude material, which was purified by
column chromatography [eluant: ethyl acetate–petroleum
ether (1:19)]. Crystallisation from ethyl acetate–petroleum
ether gave a bright yellow solid (0.23 g, 93%). Mp 102 ꢁC.
hydride and the formylderivatives were cycilsed in situ
to afford 6c in 85% and 6d in 89% as mixtures of dia-
stereomers. Dehydration of 6c and 6d with p-toluene-
sulfonic acid (PTSA) in dry benzene afforded 7a and
7b,11 respectively, in almost quantitative yields. Pathways
leading to the formation of compounds 3–7 are summar-
ised in Scheme 1.
We have presented above a convenient method for the
synthesis of the benzo4,5thieno[3,2-b]pyranone system.
The synthesis of other members of this series, in order
to examine the scope of the reaction, is underway and
will be reported latter in due course.
IR mmax (KBr) 3445, 1595 cmÀ1 1H NMR (300 MHz,
;
CDCl3) d: 13.44 (1H, s, OH), 8.04–7.89 (3H, m), 7.72–7.62
(1H, m), 7.57–7.42 (4H, m), 7.36–7.23 (1H, m); 13C NMR
(75 MHz, CDCl3) d: 191.7, 165.3, 140.7, 138.1, 132.5,
130.1, 130.0, 128.6, 128.6, 128.3, 124.6, 123.8, 112.8, 109.4.
MS (EI) (m/z) 254.6, (M+); Anal. Calcd for C15H10O2S:
M (254.30) C, 70.84; H, 3.96. Found: C, 70.93; H,
3.85.
Acknowledgements
A.D. thanks the RoyalSociety of Chemistry (UK) and
the Councilof Scientific and IndustrialResearch (CSIR,
New Delhi) for financial help. T.K.P. thanks CSIR for
Junior and Senior Research Fellowships. Thanks are
also due to Professor L. M. Harwood for helpful
discussions.
7. We thank the referee for his valuable suggestion.
8. Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935–
1937.
9. Representative example: benzo[b]thiophen-3-yl propionate
4b. Liquid compound (0.57 g, 93%). IR mmax (neat)
References and notes
1764 cmÀ1 1H NMR (300 MHz, CDCl3): d 7.85–7.79
;
1. Mustafa, A. In Furopyrans and Furopyrones, The Chem-
istry of Heterocyclic Compounds; Weissberger, A., Ed.;
Wiley Interscience, 1967.
2. Wright, J. B.; Johnson, H. G. J. Med. Chem. 1973, 16,
861–862.
(1H, m), 7.75–7.69 (1H, m), 7.47–7.36 (3H, m), 2.74 (2H,
q, J 7.5 Hz, CH2), 1.37 (3H, t, J 7.5 Hz, CH3); 13C NMR
(75 MHz, CDCl3) d: 171.7, 140.7, 136.8, 132.2, 125.1,
124.3, 122.9, 120.4, 111.7, 27.7, 9.2. Anal. Calcd for
C11H10O2S: C, 64.05; H, 4.89. Found: C, 64.23; H, 4.73.
10. Representative example: 2-phenyl-2,3-dihydrobenzo[4,5]-
thieno[3,2-b]pyran-4-one 6a. Solid, Mp 146 ꢁC (0.25 g,
3. Snieckus, V. Chem. Rev. 1990, 90, 879–933.
4. (a) Cabbidu, M. G.; Cabbidu, S.; Cadoni, E.; de Montis,
S.; Fattuni, C.; Melis, S.; Usai, M. Synthesis 2002, 875–
878; (b) Taylor, A. W.; Dean, D. K. Tetrahedron Lett.
1988, 29, 1845–1848; (c) Wadsworth, D. H.; Detty, M. R.
J. Org. Chem. 1980, 45, 4611–4615; (d) Hoffman, H.;
Westarnacher, H.; Haberstroh, H. J. Chem. Ber. 1973,
106, 349–354; (e) Cagniant, P.; Kirsch, G.; Cagniant, D.
C. R. Acad. Sci. Ser. C. 1972, 274, 711–714; (f) Guha, S.
K.; Chatterjea, J. N.; Mitra, A. K. Chem. Ber. 1961, 94,
3297–3303; (g) Perold, G. W.; van Ligen, P. F. A. Chem.
Ber. 1959, 92, 293–298; For various uses of thioaurones,
cf. (h) Ahlheim, M.; Berzoukas, M.; Bedwarth, P. V.;
Blanchard-Desce, M.; Fort, A.; Hu, Z. Y.; Marder, S. R.;
Perry, J. W.; Runser, C.; Staehleim, M.; Zysset, B. Science
1996, 271, 335–336.
90%); IR mmax (KBr) 1668 cmÀ1 1H NMR (300 MHz,
;
CDCl3) d: 7.92 (1H, d, J 7.7 Hz), 7.82 (1H, d, J 8.1 Hz),
7.56–7.36 (7H, m), 5.80 (1H, dd,
J 3.3, 13.6 Hz,
OCHCH2), 3.24–2.90 (2H, m, COCH2CH); 13C NMR
(75 MHz, CDCl3) d: 186.6, 161.1, 141.3, 138.3, 130.4,
129.8, 129.4, 129.2, 126.6, 125.1, 124.1, 123.6, 115.5, 83.2,
44.3. Anal. Calcd for C17H12O2S: C, 72.83; H, 4.31.
Found: C, 72.74; H, 4.43.
11. Representative example: 3-methylbenzo[4,5]thieno[3,2-
b]pyran-4-one 7b. Solid, Mp 186 ꢁC (0.20 g, 95%); IR mmax
(KBr) 1635, 1620 cmÀ1 1H NMR (300 MHz, CDCl3) d:
;
8.03 (1H, d, J 7.7 Hz), 7.89–7.86 (2H, m), 7.58–7.46 (2H,
m), 2.1 (3H, s, CH3); 13C NMR (75 MHz, CDCl3) d: 190.3,
150.4, 140.3, 137.3, 129.7, 128.8 125.1, 123.8, 122.3, 121.8,
109.3, 11.0. Anal. Calcd C12H8O2S: C, 66.65; H, 3.73.
Found: C, 66.53; H, 3.61.
5. Kamila, S.; Mukherjee, C.; De, A. Synlett 2003, 1479–
1481.
6. Representative example: (3-hydroxybenzo[b]thiophen-2-yl)
phenyl methanone 5a. To a well stirred solution of LDA
12. Pradhan, T. K.; Mukherjee, C.; Kamila, S.; De, A.
Tetrahedron 2004, 60, 5215–5224.