A new concise strategy for synthesis of dibenzo[b,f]thiepins and related fused symmetrical thiepin derivatives

Article abstract of DOI:10.1021/jo701627g

(Chemical Equation Presented) A new strategy for preparation of dibenzo[b,f]thiepins and related fused systems in good overall yields is described, featuring ortho-metalation of aromatic or heterocyclic aldehyde acetals followed by treatment with bis(phen

Full text of DOI:10.1021/jo701627g

A New Concise Strategy for Synthesis of
Dibenzo[b,f]thiepins and Related Fused
Symmetrical Thiepin Derivatives
Hamid Shirani and Tomasz Janosik*
Unit for Organic Chemistry, Department of Biosciences and
Nutrition, Karolinska Institute, NoVum Research Park, SE-141
FIGURE 1. Structures of the parent dibenzo[b,f]thiepin (1) and some
biologically active derivatives (2 and 3).
5
7 Huddinge, Sweden
toja@biosci.ki.se
5
thioxanthene p-toluenesulfonate, Friedel-Crafts-type cycliza-
tion of 2-(2-arythiophenyl)acetic acids, followed by further
elaboration of the resulting 10,11-dihydrodibenzo[b,f]thiepin-
0-one derivatives, or treatment of bis(aryl) sulfides with
chloroacetyl chloride in the presence of AlCl3.
ReceiVed July 25, 2007
6
1
7
Since the existing routes to dibenzo[b,f]thiepins either require
preparation of elaborate starting materials, or proceed in low
overall yields, we embarked upon development of an alternative
concise approach starting from readily available 2-bromoben-
zaldehyde acetals. It is well-established that treatment of
metalated aromatics or heteroaromatics with bis(phenylsulfonyl)
8
9
sulfide provides good yields of bis(aryl) sulfides or bis-
(
8
,10
heteroaryl) sulfides,
respectively. Hence, it was envisaged
A new strategy for preparation of dibenzo[b,f]thiepins and
related fused systems in good overall yields is described,
featuring ortho-metalation of aromatic or heterocyclic alde-
hyde acetals followed by treatment with bis(phenylsulfonyl)
sulfide for construction of the required bis(aryl)- or bis-
that utilization of lithiated benzenes incorporating masked
1
1
reactive functional groups ortho to the metal in a similar
fashion may give bis(aryl) sulfide intermediates suitable for
synthesis of new fused thiepin derivatives. Accordingly, the
1
2
13
benzaldehyde acetals 4 and 5 were subjected to halogen-
lithium exchange, followed by treatment of the resulting
organolithium species with bis(phenylsulfonyl) sulfide to afford
the desired bis(aryl) sulfides 6 and 7 (Scheme 1). These
compounds were thereafter subjected to acid induced deacetal-
(heteroaryl) sulfide precursors, which were thereafter sub-
jected to deacetalization, and finally McMurry coupling as
the ring-forming step.
1
4
ization providing the known dialdehyde 8 and its derivative
9, which served as substrates in intramolecular McMurry
1
The thiepins, including the condensed ring system dibenzo-
1
c
15
[
b,f]thiepin (1), have attracted considerable attention over the
coupling reactions, eventually giving the known parent diben-
5
years, for instance, in connection with theoretical studies
concerning aromaticity. More importantly, it has also been
demonstrated that several dibenzo[b,f]thiepin derivatives display
potent biological activities, as illustrated, for example, by the
molecule zotepine (2), which has psychosedative and antipsy-
zo[b,f]thiepin (1), as well as the electron-rich substituted system
10.
(
5) Bergmann, E. D.; Rabinovitz, M. J. Org. Chem. 1960, 25, 828-
829.
(6) See for example: Protiva, M.; Sˇ ediv y´ , Z.; Pomyk a´ cˇ ek, J.; Sv a´ tek,
E.; Holubek, J. Collect. Czech. Chem. Commun. 1981, 46, 1199-1209.
7) J ´ı lek, J.; Pomyk a´ cˇ ek, J.; Holubek, J.; Sv a´ tek, E.; Ryska, M.; Protiva,
2
3
chotic properties, or the prostaglandin antagonist 3 (Figure 1).
A series of compounds based on this ring system has also been
(
4
evaluated for antiestrogenic affects. The interest for dibenzo-
M.; Protiva, M. Collect. Czech. Chem. Commun. 1984, 49, 603-620.
[b,f]thiepins in pharmacological applications has exerted con-
(8) De Jong, F.; Janssen, M. J. J. Org. Chem. 1971, 36, 1645-1648.
(9) See, for example: (a) Yamazaki, D.; Nishinaga T.; Komatsu, K. Org.
siderable impact on the development of their chemistry, resulting
in hundreds of papers and patents.1 However, despite the
numerous publications on the subject, there are only a few
synthetic routes to dibenzo[b,f]thiepin derivatives available,
namely acid-induced rearrangement of 9-(hydroxymethyl)-
Lett. 2004, 6, 4179-4182. (b) D o¨ tze, M.; Klar, G. Phosphorus Sulfur Silicon
c
1
993, 84, 95-106.
(10) For some recent examples, see: (a) Rajca, A.; Wang, H.; Pink, M.;
Rajca, S. Angew. Chem., Int. Ed. 2000, 39, 4481-4483. (b) Miyasaka, M.;
Rajca, A.; Pink, M.; Rajca, S. J. Am. Chem. Soc. 2005, 127, 13806-13807.
(
c) Miyasaka, M.; Rajca, A. J. Org. Chem. 2006, 71, 3264-3266. (d)
Shirani, H.; Stensland, B.; Bergman J.; Janosik, T. Synlett 2006, 2459-
2463.
(
1) For reviews, see: (a) Yamamoto, K.; Yamazaki, S. In ComprehensiVe
Heterocyclic Chemistry II; Katritzky, A. R., Rees C. W., Scriven, E. F. V.,
Eds.; Elsevier: Amsterdam, 1996; Vol. 9, pp 67-111. (b) Schwan, A. L.
In Science of Synthesis; Weinreb, S. M., Ed.; Thieme: Stuttgart, 2004; Vol.
(11) For reviews, see: (a) Snieckus, V. Chem. ReV. 1990, 90, 879-933.
(b) Schlosser, M. Angew. Chem., Int. Ed. 2005, 44, 376-393.
(12) (a) Watanabe, T.; Soma, N. Chem. Pharm. Bull. 1971, 19, 2215-
2221. (b) Newman, M. S.; Lee, L.-F. J. Org. Chem. 1975, 40, 2650-2652.
(13) Charlton, J. L.; Alauddin, M. M. J. Org. Chem. 1986, 51, 3490-
3493.
(14) (a) Jiang, J.-J.; Chang, T.-C.; Hsu, W.; Hwang, J.-M.; Hsu, L.-Y.
Chem. Pharm. Bull. 2003, 51, 1307-1310. (b) Britovsek, G. J. P.; Gibson,
V. C.; Hoarau, O. D.; Spitzmesser, S. K.; White, A. J. P.; Williams, D. J.
Inorg. Chem. 2003, 42, 3454-3465.
1
7, pp 717-748. (c) Protiva, M. J. Heterocycl. Chem. 1996, 33, 497-521.
2) Ueda, I.; Sato, Y.; Maeno, S.; Umio, S. Chem. Pharm. Bull. 1978,
6, 3058-3070.
3) (a) U.S. Patent 4237160, 1980; Chem. Abstr. 1981, 94, 208728. (b)
(
2
(
Hands, D.; Marley, H.; Skittrall, S. J.; Wright, S. H. B.; Verhoeven, T. R.
J. Heterocycl. Chem. 1986, 23, 1333-1337.
(4) Acton, D.; Hill, G.; Tait, B. S. J. Med. Chem. 1983, 26, 1131-1137.
10.1021/jo701627g CCC: $37.00 © 2007 American Chemical Society
8
984
J. Org. Chem. 2007, 72, 8984-8986
Published on Web 10/12/2007

SCHEME 1a
SCHEME 3a
a
Reagents and conditions: (i) n-BuLi, THF, -78 °C, 0.5 h; then
a
(PhSO2)2S, -78 °C to rt, 16 h, 74%; (ii) aq HClO4, H2O, acetone, rt, 24 h,
4%; (iii) TiCl4, Zn, pyridine, THF, reflux, 2.5 h; then 17, rt, 16 h; reflux,
h; then K2CO3, rt, 18 h, 86%.
Reagents and conditions: (i) n-BuLi, THF, -78 °C, 0.5 h; then
9
4
(
PhSO2)2S, -78 °C to rt, 16 h; (ii) aq HClO4, acetone, rt, 1-2 h; (iii) TiCl4,
Zn, pyridine, THF, reflux, 2.5 h; then 8/9, rt, 16 h; reflux, 4 h; then K2CO3,
rt, 18 h.
1
4, which was finally annulated under McMurry conditions
SCHEME 2a
providing the novel ring system 11. However, all attempts to
remove the phenylsulfonyl groups by exposure to bases failed,
leading to degradation. This observation could be attributed to
the fact that the two electron rich indole units cannot provide
enough stabilization for the central thiepin ring. It should be
emphasized in this context that many simple thiepins, as well
as several fused derivatives, are unstable molecules which
undergo decomposition even at moderate temperatures.1a
Likewise, protection of the easily available 3-bromobenzo-
1
7
[b]thiophene-2-carboxaldehyde afforded the known acetal
1
7a
1
5,
which was subjected to metalation and subsequent
treatment with bis(phenylsulfonyl) sulfide rendering the diacetal
6 (Scheme 3). This product underwent deacetalization provid-
1
ing the dialdehyde 17, which could eventually be converted to
the fused thiepin 18 by intramolecular McMurry coupling. It
should also be noted that some related symmetrical thiepins
containing two fused thiophene units have previously been
prepared in four steps from 2-bromo-3-iodothiophene or 3-bromo-
a
Reagents and conditions: (i) LDA, THF, -78 °C, 0.5 h; then
(
8
PhSO2)2S, -78 °C to rt, 16 h, 78%; (ii) aq HClO4, H2O, 1,4-dioxane, rt,
h, 98%; (iii) TiCl4, Zn, pyridine, THF, reflux 2.5 h; then 14, rt, 16 h;
reflux 4 h; then K2CO3, rt, 18 h, 79%.
1
8
4
-iodothiophene in low overall yields.
In conclusion, a new concise route to fused thiepins has been
devised, providing convenient access to the parent dibenzo[b,f]-
thiepin, as well as some novel similar condensed systems which
are not easily available using the previously published methods.
In addition, the use of relatively mild conditions may allow
preparation of new pharmacologically relevant fused thiepins
bearing sensitive functional groups. It can also be envisaged
that variations of this strategy may find applications in syntheses
of other closely related fused 7-membered heterocycles.
The successful preparation of the dibenzo[b,f]thiepins 1 and
0 encouraged us to implement this new strategy in a route to
1
the diindolothiepin 11 (Scheme 2). Metalation of the protected
indole-3-carboxaldehyde 12,16 and subsequent treatment of the
resulting lithioindole with bis(phenylsulfonyl) sulfide gave the
bis(indolyl) sulfide 13. Treatment of this material with aqueous
perchloric acid in 1,4-dioxane furnished the dicarboxaldehyde
(
15) For reviews, see: (a) McMurry, J. E. Acc. Chem. Res. 1983, 16,
4
05-411. (b) McMurry, J. E. Chem. ReV. 1989, 89, 1513-1524. For some
Experimental Section
applications of McMurry coupling to preparation of fused aromatics and
related structures, see, for example: (c) Yamamoto, K.; Harada, T.;
Nakazaki, M.; Naka, T.; Kai, Y.; Harada, S.; Kasai, N. J. Am. Chem. Soc.
Bis(aryl) Sulfide 6. To a solution of the acetal 4 (1.40 g, 6.1
mmol) in THF (40 mL) was added n-BuLi (2.5 M in hexanes, 3.0
mL, 7.5 mmol) dropwise at -78 °C. The resulting mixture was
1
983, 105, 7171-7172. (d) Yamamoto, K.; Harada, T.; Okamoto, Y.;
Chikamatsu, H.; Nakazaki, M.; Kai, Y.; Nakao, T.; Tanaka, M.; Harada,
S.; Kasai, N. J. Am. Chem. Soc. 1988, 110, 3578-3584. (e) Gies, A.-E.;
Pfeffer, M. J. Org. Chem. 1999, 64, 3650-3654. (f) Kirsch, G.; Deprets,
S. Z. Naturforsch. 2006, 61b, 427-430. (g) Some, S.; Dutta, B.; Ray, J. K.
Tetrahedron Lett. 2006, 47, 1221-1224.
(17) (a) Dore, G.; Bonhomme, M.; Robba, M. Tetrahedron 1972, 28,
2553-2573. (b) Bj o¨ rk, M.; Grivas, S. J. Heterocycl. Chem. 2006, 43, 101-
109.
(18) Yasuike, S.; Nakashima, F.; Kurita, J.; Tsuchiya, T. Heterocycles
1997, 45, 1899-1902.
(16) Gribble, G. W.; Jiang, J.; Liu, Y. J. Org. Chem. 2002, 67, 1001-
1
003.
J. Org. Chem, Vol. 72, No. 23, 2007 8985

stirred for 30 min followed by addition of a solution of (PhSO
0.97 g, 3.1 mmol) in THF (30 mL) during 15 min. The mixture
was allowed to warm slowly to room temperature over 16 h,
followed by addition of satd aq NH Cl (40 mL). The mixture was
extracted with Et
O (2 × 40 mL). The combined organic extracts
were washed with water (40 mL) and brine (40 mL) and dried (Na
SO ). Evaporation of the solvents in vacuo gave a residue which
2
)
2
S
dialdehyde 8 (121 mg, 0.50 mmol) was added slowly as a dilute
solution in THF (100 mL) over 4 h. After the addition was complete,
the reaction mixture was allowed to stir at room temperature for
16 h and was thereafter heated at reflux for an additional period of
4 h. After the mixture was cooled to room temperature, a 50%
(
4
2
2
-
2 3
aqueous solution of K CO (50 mL) was added. The resulting
4
mixture was stirred vigorously for 18 h and thereafter passed
through a pad of Celite, which was washed with EtOAc (40 mL).
The layers were separated, and the aqueous phase was extracted
with EtOAc (50 mL). The combined organic layers were washed
was subjected to column chromatography [n-hexane/EtOAc (3:1)]
to give 6 (850 mg, 84%) as a yellowish viscous oil: IR (neat) 2885,
1
7
7
8
589, 1568, 1468, 1440, 1380, 1208, 1119, 1082, 1051, 969, 940,
-
1 1
66, 749 cm ; H NMR (DMSO-d
.30 (m, 4H), 7.12-7.06 (m, 2H), 6.09 (s, 2H), 4.11-3.94 (m,
H); 13C NMR (DMSO-d
) δ 138.0 (s), 134.5 (s), 132.4 (d), 130.1
6
) δ 7.62-7.56 (m, 2H), 7.38-
with water (2 × 50 mL) and brine (50 mL) and dried (Na
2 4
SO ).
Evaporation of the solvents in vacuo, and purification of the residue
by column chromatography [n-hexane/EtOAc (3:1)], followed by
recrystallization from MeOH gave compound 1 (100 mg, 95%) as
6
(
d), 127.5 (d), 127.0 (d), 100.5 (d), 65.0 (t). Anal. Calcd for
S: C, 65.43; H, 5.49. Found: C, 65.55; H, 5.60.
Dialdehyde 8. A solution of aq HClO (70%, 0.25 mL) in H
4 mL) was added to a solution of the diacetal 6 (0.59 g, 1.8 mmol)
5
C
18
H O
18 4
colorless crystals: mp 86-88 °C (lit. mp 89-90 °C); IR (neat)
-
1 1
4
2
O
1471, 1425, 1263, 1059, 1032, 799, 783, 768, 751, 738 cm ; H
(
NMR (CDCl
2H); 13C NMR (CDCl
) δ 140.3 (s), 134.9 (s), 134.0 (d), 132.8
3
3
) δ 7.53-7.50 (m, 2H), 7.33-7.25 (m, 6H), 7.06 (s,
in acetone (8 mL) at room temperature. The mixture was stirred at
room temperature for 2 h and was thereafter treated with satd aq
(d), 129.5 (d), 129.4 (d), 128.4 (d).
NaHCO
(
(
3
(20 mL). The resulting mixture was extracted with Et
2 × 30 mL). The combined organic layers were washed with water
30 mL) and brine (30 mL) and dried (Na SO ), and the solvents
O to
2
O
Acknowledgment. Financial support from “Magn. Bergvalls
Stiftelse” is gratefully acknowledged.
2
4
were evaporated in vacuo. The residue was triturated with Et
2
provide the dialdehyde 8 (380 mg, 87%) as a white solid: mp 97-
Supporting Information Available: General information,
experimental procedures and spectral data for compounds 7, 9, 10,
9
9 °C (lit.14 mp 95-97 °C).
4
Dibenzo[b,f]thiepin (1). TiCl (2.7 mL, 25 mmol) was added
1
13
1
3, 14, 11, and 16-18 and H and C NMR spectra for all new
cautiously during 10 min to THF (100 mL) at -78 °C under argon
atmosphere, and the resulting solution was stirred for 5 min. This
slurry was allowed to warm to room temperature, followed by
addition of zinc powder (3.3 g, 50 mmol) and pyridine (0.5 mL).
The resulting suspension was heated at reflux for 2.5 h. The
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO701627G
8
986 J. Org. Chem., Vol. 72, No. 23, 2007