An intramolecular Diels-Alder route to novel tetracyclic benzo[b]thiophene derivatives

Article abstract of DOI:10.1016/S0040-4039(02)00565-8

A one-pot route to 3-benzo[b]thiophen-2-yl-acrylates (2) from the corresponding thiophenols (1) is reported. Ester reduction and subsequent hydroxyl esterification deliver psuedo trienoates (II) which undergo an intramolecular Diels-Alder (IMDA) reaction to give two 2-oxa-9-thiacyclopenta[b]fluoren-3-one products (I) - the major Diels-Alder product rearomatizes to 7.

Full text of DOI:10.1016/S0040-4039(02)00565-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3963–3966
An intramolecular Diels–Alder route to novel tetracyclic
benzo[b]thiophene derivatives
Pilho Kim,a Jennifer M. Tsuruda,a Marilyn M. Olmstead,a Shawn Eisenbergb and Mark J. Kurtha,*
aDepartment of Chemistry, One Shields Avenue, University of California, Davis, CA 95616, USA
bAmgen, One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
Received 11 January 2002; revised 15 March 2002; accepted 20 March 2002
Abstract—A one-pot route to 3-benzo[b]thiophen-2-yl-acrylates (2) from the corresponding thiophenols (1) is reported. Ester
reduction and subsequent hydroxyl esterification deliver psuedo trienoates (II) which undergo an intramolecular Diels–Alder
(IMDA) reaction to give two 2-oxa-9-thiacyclopenta[b]fluoren-3-one products (I)—the major Diels–Alder product rearomatizes to
7. © 2002 Elsevier Science Ltd. All rights reserved.
Benzo[b]thiophene derivatives present interesting syn-
thetic targets and encompass numerous biological activ-
ities.1 While they have been synthesized through various
methods,2 the intramolecular Diels–Alder (IMDA) reac-
tions of benzo[b]thiophene derivatives have not been
studied extensively.3 We have investigated this IMDA
reaction with the objective of producing novel ben-
zo[b]thiophene-containing tetracyclic structures (I;
Scheme 1) and present here (i) a one-pot preparation of
2-substituted benzo[b]thiophene derivative 2 from thio-
phenol 1,4 (ii) the reactivity and stereoselectivity of
IMDA reactions of benzo[b]thiophene derivatives (II),
and (iii) observations regarding rearomatization of I
subsequent to the IMDA reaction.
with nBuLi and TMEDA in cyclohexane5 followed by
treatment of the ortho-lithiated phenylthioate with
DMF in THF. Subsequent addition of methyl 4-bro-
mocrotonate gave esters 2—the consequence of ortho
formylation, S-alkylation, and intramolecular aldol con-
densation. When ortho formylation was accomplished
with DMF diluted in cyclohexane, the reaction mixture
was difficult to stir, resulting in low product yield
(15–20%). Substituting THF for cyclohexane largely
solved this problem and formation of 2 followed by
DIBAL-H reduction of the crude dienoate delivered
2-Substituted benzo[b]thiophene derivative 2 was pre-
pared from thiophenol 1 (Scheme 2) by ortho lithiation
Scheme 2. Preparation of benzo[b]thiophene-based pseudo
trienoates. (a) (i) nBuLi, TMEDA, cyclohexane, rt, 24 h, (ii)
DMF, THF, rt, 12 h, (iii) methyl 4-bromocrotonate, rt, 6 h; (b)
DIBAL-H, 0°C, 2 h; (c) R2CO2H, DCC, DMAP, CH2Cl2, rt,
2 h.
Scheme 1. An intramolecular Diels–Alder approach to tetra-
cyclic benzo[b]thiophenes.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00565-8

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P. Kim et al. / Tetrahedron Letters 43 (2002) 3963–3966
1
hydroxy diene 36 in 37–41% overall yield from thiophe-
nol 1. DCC-mediated esterification of 3 with various
acrylic acid derivatives gave esters 4 in good yield
(84–98%). Unfortunately, these pseudo trienoates failed
as IMDA substrates—even under harsh, sealed tube
reaction conditions (e.g. 255°C, 7 days). These disap-
pointing results clearly indicate that (2-vinyl)-
benzo[b]thiophene derivatives afford poor diene reac-
tivity for the IMDA reaction. Attempts at Lewis acid
catalyzed IMDA with these substrates were equally
ineffective, leading to extensive starting material
decomposition.
(8). Moreover, the H NMR signal at ca. 5.5 ppm (Ha)
in 8 is clearly correlated with the 13C NMR signal at ca.
115 ppm. From these NMR experiments, it was clear
that the major product contains a rearomatized ben-
zo[b]thiophene structure, while the minor product does
not. That these two IMDA products are not in dynamic
equilibrium was established by exposing pure 7c and
pure 8c to IMDA reaction conditions for 10 h; neither
IMDA product isomerized to the other. Finally, the
structures of major (e.g. 7f) and minor (e.g. 8d) IMDA
products were confirmed by X-ray crystallographic
analysis (Fig. 1).
This lack of IMDA reactivity led us to investigate
doubly activating the dienophile moiety of pseudo
trienoate 4. Thus, alcohols 37 were esterified to 5 in
moderate yields (57–84%; Scheme 3) by treatment with
(E)-4-oxobut-2-enoic acid derivatives8 under DCC/
DMAP coupling conditions. We were pleased to find
that heating toluene solutions of these doubly activated
pseudo trienoates at 115–140°C in sealed tubes deliver
one major Diels–Alder product9 together with a minor
Diels–Alder product (Scheme 3) and a trace amount of
an aldehyde. Spectroscopic studies established this alde-
hyde to be (E)-3-(benzo[b]thiophen-2-yl)-2-propen-1-al,
which was apparently formed by a thermal ene reaction
of 5.
Clearly, the IMDA reaction of 5 can proceed via a
transition state in which the ketone carbonyl occupies
the endo position or via a transition state in which the
ester carbonyl occupies the endo position. The former
would lead to the unobserved IMDA adduct 6 while
the latter would deliver the observed product 8. The
endo-ketone cycloaddition (i.e. 5“6) followed by C,C-
double bond isomerization would deliver 7, which is in
fact the major product in each cycloaddition reaction.
In contrast, the minor endo–ester cycloadduct (8) does
not undergo C,C-double bond isomerization to the
benzo[b]thiophene substructure (i.e. to the unobserved
product 9). We were surprised at the apparent thermo-
dynamic energetics in the 6/7 versus 8/9 equilibration
processes and set out to establish computational energy
differences for these two C,C-double bond isomeriza-
tions. Using Wavefunction’s Spartan software with the
MMFF94 forcefield, we calculated that the lowest
energy conformer of isomerized 7c is 0.70 kcal/mol
more stable than the lowest energy conformer of
IMDA product 6c (see Scheme 4). While relative ener-
gies of such small magnitude must be viewed with
reservation, this result suggests that the observed iso-
merization of 6c to 7c is energetically favored. Since the
thermal [1,3] sigmatropic rearrangement 6c“7c would
be antarafacial, we assume this isomerization proceeds
by a stepwise process. However, cycloadduct 8c is
formed simultaneously with 6c (“7c) and could pre-
sumably avail itself to a similar stepwise isomerization
leading to 9c. Calculations show that this process is
energetically disfavored with the lowest energy con-
former of IMDA product 8c calculated to be 6.28
kcal/mol more stable than unobserved product 9c.
HMQC experiments identified two CH2 correlation
peaks for each major IMDA product (7), but only one
CH2 correlation peak for each minor IMDA product
The experimental results presented in Scheme 3 demon-
strate that both endo-ketone and endo-ester pathways
Scheme 3. IMDA of psuedo trienoate 5.
Figure 1. X-Ray structures of 7f and 8d.

P. Kim et al. / Tetrahedron Letters 43 (2002) 3963–3966
3965
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Scheme 4. C,C-double bond isomerization in 2-oxa-9-thia-
cyclopenta[b]-fluoren-3-ones.
7. General experimental for 1b to 7d. Methyl (2E)-3-(5-
methylbenzo[b]thiophen-2-yl)prop-2-enoate (2b). A solution
of 4-methylbenzenethiol (1b, 3.0 g, 24 mmol) and TMEDA
(8.5 mL, 53 mmol) in distilled cyclohexane (200 mL) was
prepared in a 500 mL three-neck flask equipped with a
dropping funnel under a dry nitrogen atmosphere. n-BuLi
(1.6 M; 33 mL, 53 mmol) in hexanes was added dropwise
over 30 min at 0°C and the reaction mixture was stirred
for 24 h at rt. To the resulting slightly yellow, turbid
solution was added dropwise over 1 h DMF (4.6 mL, 60
mmol) in THF (30 mL) at 0°C. The reaction mixture was
stirred for 12 h at rt to give a white turbid solution to
which was added a solution of methyl 4-bromocrotonate
(4.3 mL, 31 mmol) in distilled cyclohexane (50 mL; drop-
wise at 0°C). After various color changes occurred (yellow
turbid“orange turbid“peach turbid) while stirring for 12
h at rt, a dark green turbid reaction mixture was obtained.
Aqueous 1N HCl was added dropwise to make a slightly
acidic solution and the organic layer was collected, dried
with anhydrous MgSO4, filtered, and concentrated.
Column chromatography (10% EtOAc/hex) afforded the
title compound as a slightly yellow solid (2.50 g, 10.8
mmol, 45%): Rf=0.53 (EtOAc/hex=1/2); mp 115.3–
are operative in the cycloaddition of 5. Moreover,
MMFF94 calculations indicate the final product distri-
bution (cf. Scheme 4) is determined by the relative
energetics of stepwise olefin isomerizations (6c“7c and
8c“9c).
Acknowledgements
We thank Mr. Hoyeong Sohn for performing initial
experiments in this study and we thank the National
Science Foundation and Cystic Fibrosis Foundation for
financial support of this research. The 400 and 300
MHz NMR spectrometers used in this study were
funded in part by a grant from NSF (CHE-9808183).
References
1. (a) Connor, D. T.; Cetenko, W. A.; Mullican, M. D.;
Sorenson, R. J.; Unangst, P. C.; Weikert, R. J.; Adolph-
son, R. L.; Kennedy, J. A.; Thueson, D. O.; Wright, C. D.
J. Med. Chem. 1992, 35, 958–965; (b) Graham, S. L.;
Shepard, K. L.; Anderson, P. S.; Baldwin, J. J.; Best, D.
B.; Christy, M. E.; Freedman, M. B.; Gautheron, P.;
Habecker, C. N.; Hoffman, J. M. J. Med. Chem. 1989, 32,
2548–2554; (c) Campaigne, E. In Comprehensive Hetero-
cyclic Chemistry; Bird, C. W.; Cheesemann, G. W. H.,
Eds.; Pergamon Press: Oxford, 1984; Vol. 4, pp. 863–934;
(d) Grese, T. A.; Dodge, J. A. In Annual Reports in
Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press:
New York, 1996; Vol. 31, pp. 181–190.
115.7°C; FTIR (KBr) 1711, 1629, 1431, 1321 cm−1 1H
;
NMR (400 MHz, CDCl3) l 2.45 (s, 3H), 3.81 (s, 3H), 6.28
(d, J=15.8 Hz, 1H), 7.20 (dm, J=8.2 Hz, 1H), 7.37 (s,
1H), 7.55 (s, br, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.86 (d,
J=15.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) l 21.4,
51.8, 118.5, 121.9, 124.2, 127.9, 128.4, 134.5, 137.3, 137.9,
139.4, 139.7, 166.8. Anal. calcd for C13H12O2S: C, 67.22;
H, 5.21. Found: C, 67.51; H, 5.35.
(2E)-3-(5-Methylbenzo[b]thiophen-2-yl)prop-2-en-1-ol (3b).
Methyl
(2E)-3-(5-methylbenzo[b]thiophen-2-yl)prop-2-
enoate (2b, 2.10 g, 9.0 mmol) was dissolved in toluene (30
mL) and DIBAL-H (1.0 M in hexanes; 20 mL, 20 mmol)
was added dropwise over 10 min at 0°C. After stirring 1 h

3966
P. Kim et al. / Tetrahedron Letters 43 (2002) 3963–3966
at 0°C, the reaction was quenched by addition of a tolu-
T.; Radulovic, S.; Juranic, I. J. Serb. Chem. Soc. 1999, 64,
505–512; (b) Stevovic, L. J. S.; Drakulic, B. J.; Juranic, I.
O.; Drmanic, S. Z.; Jovanovic, B. Z. J. Serb. Chem. Soc.
1998, 63, 359–365; (c) Obrecht, D.; Weiss, B. Helv. Chim.
Acta 1989, 72, 117–122; (d) Bolognese, A.; Scherillo, G. J.
Org. Chem. 1977, 42, 3867–3869.
ene/methanol (1:1; 20 mL) mixture and a saturated solu-
tion of Rochelle’s salt (aq.). Aqueous 1N HCl was added
to make a slightly acidic solution and the organic layer
was collected, dried with anhydrous MgSO4, filtered, and
concentrated. Column chromatography (20% EtOAc/hex)
afforded the title compound as a slightly yellow solid (1.65
g, 8.1 mmol, 90%): Rf=0.34 (EtOAc/hex=1/2); mp 115–
9. IMDA product 7a. Rf=0.33 (EtOAc/hex=1/2); mp 146–
1
147°C; FTIR (KBr) 1777, 1698, 1432 cm−1; H NMR (400
1
117°C; FTIR (KBr) 3277, 1492, 1443 cm−1; H NMR (400
MHz, CDCl3) l 2.62 (s, 3H), 2.69–2.89 (m, 2H), 2.97–3.06
(m, 1H), 3.14–3.21 (m, 1H), 4.15 (dd, J=10.5, 8.8 Hz,
1H), 4.26 (m, 1H), 4.63 (dd, J=8.6, 6.6 Hz, 1H), 7.28–7.35
(m, 2H), 7.37–7.42 (m, 1H), 7.74–7.79 (m, 1H); 13C NMR
(100 MHz, CDCl3) l 28.7, 31.2, 39.7, 46.2, 49.8, 71.4,
121.2, 122.7, 124.5, 124.7, 127.2, 137.3, 137.8, 138.9, 174.7,
208.7. Anal. calcd for C16H14O3S: C, 67.11; H, 4.93.
Found: C, 67.32; H, 5.05.
MHz, CDCl3) l 1.66 (s, br, 1H), 2.44 (s, 3H), 4.33 (dd,
J=5.5, 1.5 Hz, 2H), 6.28 (dt, J=15.8, 5.5 Hz, 1H), 6.84
(dm, J=15.8, 1H), 7.06 (s, 1H), 7.13 (dd, J=8.2, 1.6 Hz,
1H), 7.47 (s, br, 1H), 7.63 (d, J=8.1 Hz, 1H); 13C NMR
(100 MHz, CDCl3) l 21.3, 63.2, 121.8, 122.7, 123.5, 124.8,
126.4, 130.5, 134.1, 136.0, 140.3, 142.0.
(2E)-3-(5-methylbenzo[b]thiophen-2-yl)prop-2-enyl (2E)-4-
oxo-4-phenylbut-2-enoate (5d). A solution of (2E)-4-oxo-4-
phenyl-2-butenoic acid (0.15 g, 0.87 mmol), DCC (0.18 g,
0.87 mmol), (2E)-3-(5-methylbenzo[b]thiophen-2-yl)prop-
2-en-1-ol (3b, 0.12 g, 0.62 mmol) and DMAP (7 mg, 0.06
mmol) in dichloromethane (20 mL), was stirred for 2 h at
rt. The N,N-dicyclohexylurea ppt was removed by filtra-
tion and the filtrate was washed with water, dried
(MgSO4), filtered, and concentrated. Column chromato-
graphy (20% EtOAc/ hex) afforded the title compound as
a slightly yellow solid (0.18 g, 0.51 mmol, 81%): Rf=0.65
(EtOAc/hex=1/2); mp 98–99°C; FTIR (KBr) 1723, 1670,
IMDA product 7b. Rf=0.24 (EtOAc/hex=1/2); mp 198.8–
199.3°C; FTIR (KBr) 1773, 1718, 1601, 1448 cm−1 1H
;
NMR (400 MHz, CDCl3) l 2.43 (s, 3H), 2.61 (s, 3H),
2.67–2.87 (m, 2H), 2.95–3.05 (m, 1H), 3.10–3.19 (m, 1H),
4.14 (dd, J=10.4, 8.8 Hz, 1H), 4.22 (dm, J=10.8 Hz, 1H),
4.62 (dd, J=8.6, 6.6 Hz, 1H), 7.11–7.19 (m, 2H), 7.63 (d,
J=8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) l 21.6, 28.8,
31.0, 39.7, 46.2, 49.9, 71.4, 121.2, 122.3, 126.2, 126.8,
134.5, 136.1, 137.6, 137.9, 174.7, 208.8. Anal. calcd for
C17H16O3S: C, 67.98; H, 5.37. Found: C, 67.81; H, 5.30.
IMDA product 7c. Rf=0.30 (EtOAc/hex=1/2); mp 271.7–
272.4°C; FTIR (KBr) 1774, 1732, 1676, 1623 cm−1 1H
;
1
1593, 1445 cm−1; H NMR (400 MHz, CDCl3) l 2.44 (s,
NMR (400 MHz, CDCl3) l 2.78–2.92 (m, 1H), 3.03–3.26
(m, 3H), 4.16 (dd, J=10.6, 9.0 Hz, 1H), 4.63 (dd, J=8.8,
6.8, 1H), 5.19 (d, J=10.6 Hz, 1H), 7.00–7.12 (m, 2H),
7.17–7.25 (m, 1H), 7.51–7.62 (m, 2H), 7.63–7.76 (m, 2H),
8.22 (d, J=7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) l
28.7, 39.8, 43.6, 47.6, 71.5, 121.6, 122.6, 124.3, 124.4,
128.3, 128.9, 129.1, 133.8, 137.3, 137.90, 137.92, 138.9,
174.7, 201.0. Anal. calcd for C21H16O3S: C, 72.39; H, 4.63.
Found: C, 72.52; H, 4.72.
3H), 4.91 (dd, J=6.4, 1.3 Hz, 2H), 6.22 (dt, J=15.6, 6.4
Hz, 1H), 6.92 (d, br, J=15.6 Hz, 1H), 6.94 (d, J=15.6 Hz,
1H), 7.12–7.16 (m, 1H), 7.14 (s, br, 1H), 7.48–7.56 (m,
3H), 7.60–7.66 (m, 2H), 7.96 (d, J=15.6 Hz, 1H), 7.99–
8.03 (m, 2H); 13C NMR (100 MHz, CDCl3) l 21.3, 65.3,
121.8, 123.6, 123.8, 124.1, 126.7, 128.5, 128.83, 128.84,
132.0, 133.8, 134.2, 136.2, 136.4, 136.8, 140.1, 141.1, 165.2,
189.3.
IMDA of 5d. A solution of 5d (0.20 g, 0.55 mmol) in
toluene (5 mL) was stirred for 14 h at 140°C in a sealed
tube. The solvent was evaporated under vacuum. Column
chromatography (20% EtOAc/hex) afforded two white
solids: 7d (110 mg) [Rf=0.38 (EtOAc/hex=1/2); mp
IMDA product 7e. Rf=0.23 (EtOAc/hex=1/2); mp 166–
168°C; FTIR (KBr) 1774, 1690, 1626, 1586 cm−1 1H
;
NMR (400 MHz, CDCl3) l 2.74–2.87 (m, 1H), 3.00–3.09
(m, 1H), 3.14–3.27 (m, 2H), 4.17 (dd, J=10.9, 8.6 Hz,
1H), 4.62 (dd, J=8.6, 6.8 Hz, 1H), 5.12 (m, 1H), 7.14–7.20
(m, 1H), 7.24–7.29 (m, 2H), 7.42–7.47 (m, 1H), 7.48–7.51
(m, 2H), 7.73–7.77 (m, 1H), 8.12 (dd, J=7.7, 1.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) l 28.7, 39.8, 47.1, 47.4, 71.4,
121.8, 122.5, 124.4, 124.5, 126.9, 127.5, 130.7, 131.5, 132.9,
133.0, 137.2, 138.0, 138.1, 138.8, 174.8, 200.4. Anal. calcd
for C21H15ClO3S: C, 65.88; H, 3.95. Found: C, 65.79; H,
3.87.
277.7–278.5°C; FTIR (KBr) 1771, 1681, 1592 cm−1 1H
;
NMR (400 MHz, CDCl3) l 2.09 (s, 3H), 2.78–2.91 (m,
1H), 3.04–3.29 (m, 3H), 4.16 (dd, J=10.8, 8.8 Hz, 1H),
4.63 (dd, J=8.8, 6.8 Hz, 1H), 5.14 (dm, J=10.6 Hz, 1H),
6.84 (s, br, 1H), 7.03 (d, br, J=7.5 Hz, 1H), 7.55–7.62 (m,
3H), 7.65–7.72 (m, 1H), 8.20 (d, br, J=7.2 Hz, 2 H); 13C
NMR (100 MHz, CDCl3) l 21.3, 28.8, 39.8, 43.9, 47.5,
71.6, 122.0, 122.1, 125.9, 127.8, 128.8, 128.9, 129.0, 133.7,
134.0, 137.6, 137.9, 138.3, 174.9, 201.2. Anal. calcd for
C22H18O3S: C, 72.91; H, 5.01. Found: C, 72.95; H, 5.14.]
and 8d (39 mg) [Rf=0.47 (EtOAc/hex=1/2); FTIR (KBr)
IMDA product 7f. Rf=0.27 (EtOAc/hex=1/2); mp 203–
205°C; FTIR (KBr) 1769, 1687, 1587, 1434 cm−1 1H
;
NMR (400 MHz, CDCl3) l 2.21 (s, 3H), 2.72–2.87 (m,
1H), 2.99–3.18 (m, 2H), 3.25–3.34 (m, 1H), 4.19 (dd,
J=11.2, 8.6 Hz, 1H), 4.62 (dd, J=8.6, 7.0, 1H), 5.05 (d,
J=10.4 Hz, 1H), 6.97 (s, 1H), 7.08 (d, J=8.1 Hz, 1H),
7.44–7.62 (m, 4H), 8.18 (dd, J=7.3, 1.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) l 21.3, 28.8, 39.7, 46.8, 47.5,
71.4, 122.03, 122.05, 125.9, 126.9, 127.1, 130.6, 131.3,
132.8, 133.0, 134.2, 135.8, 137.5, 138.1, 138.4, 175.0, 200.4.
Anal. calcd for C22H17ClO3S: C, 66.58; H, 4.32. Found: C,
66.24; H, 4.33.
1
1746, 1682, 1467, 1446 cm−1; H NMR (400 MHz, CDCl3)
l 1.99 (s, 3H), 3.23 (m, 1H), 3.32 (m, 1H), 4.09 (m, 1H),
4.24 (dd, J=9.2, 4.4 Hz, 1H), 4.49 (dd, J=9.0, 6.6 Hz,
1H), 4.63 (dm, J=10.4 Hz, 1H), 5.67 (dd, J=3.5, 2.6 Hz,
1H), 6.55 (s, 1H), 6.93 (d, J=8.2 Hz, 1H), 7.05 (d, J=8.1
Hz, 1H), 7.20–7.31 (m, 2H), 7.50 (m, 1H), 7.61 (m, 1H),
8.13 (dd, J=8.4, 1.3 Hz, 1H); see X-ray structure in Fig. 1]
in a combined total yield of 75% (149 mg, 0.41 mmol).
8. (a) Juranic, Z.; Stevovic, L. J.; Drakulic, B.; Stanokovic,