Titanium reagents for the synthesis of 2-substituted benzo[b]thiophenes on the solid phase

Article abstract of DOI:10.1021/jo049344o

Titanium(IV) benzylidenes (Schrock carbenes) bearing a masked sulfur nucleophile in the ortho position were generated from thioacetals with use of low-valent titanocene complex Cp₂Ti[P(OEt)₃]₂ and alkylidenated Merrifield resin-bound esters to give enol ethers. Treatment of the resin-bound enol ethers with a 5:5:90 mixture of TFA, TFAA, and dichloromethane led to cleavage from resin, removal of the tert- butyldimethylsilyl (TBDMS) protecting group, and concomitant cyclization to complete the traceless solid-phase synthesis (SPS) of benzothiophenes. Switching the nature of the linker from acid-stable to acid-sensitive ensured good purity.

Full text of DOI:10.1021/jo049344o

Tita n iu m Rea gen ts for th e Syn th esis of
2-Su bstitu ted Ben zo[b]th iop h en es on th e
Solid P h a se
Christine F. Roberts and Richard C. Hartley*
Department of Chemistry, University of Glasgow,
Glasgow G12 8QQ, United Kingdom
F IGURE 1. Examples of 2-substituted benzo[b]thiophene
drugs
richh@chem.gla.ac.uk
Received April 19, 2004
Abstr a ct: Titanium(IV) benzylidenes (Schrock carbenes)
bearing a masked sulfur nucleophile in the ortho position
were generated from thioacetals with use of low-valent
titanocene complex Cp2Ti[P(OEt)3]2 and alkylidenated Mer-
rifield resin-bound esters to give enol ethers. Treatment of
the resin-bound enol ethers with a 5:5:90 mixture of TFA,
TFAA, and dichloromethane led to cleavage from resin,
removal of the tert-butyldimethylsilyl (TBDMS) protecting
group, and concomitant cyclization to complete the traceless
solid-phase synthesis (SPS) of benzothiophenes. Switching
the nature of the linker from acid-stable to acid-sensitive
ensured good purity.
F IGURE 2.
We have recently shown that titanium benzylidene
reagents13-16 3 and 4 (Figure 2) bearing a protected
oxygen or nitrogen nucleophile in the ortho position are
easy to generate from thioacetals using low-valent tita-
nium species, Cp2Ti[P(OEt)3]2 5, and benzylidenate esters
to give enol ethers.17 A range of functionality is tolerated,
including boronate, acetal, fluoro, and some amino and
carbamate groups, and the reagents have been used for
the solid-phase synthesis of benzofurans13,15,16 and in-
doles14,15 in high purity. The reagents work better on the
solid phase because of the ease of purification following
alkylidenation reaction and also ensure the high purity
of products by switching the nature of the linker from
acid-stable to acid-sensitive.
The synthesis of 2-substituted benzo[b]thiophenes is
important as such compounds have a range of useful
pharmaceutical properties. Zileuton 1, for example, is a
potent and selective inhibitor of 5-lipoxygenase,1 while
many 2-substituted benzothiophenes are selective estro-
gen receptor modulators and one such compound, raloxi-
fene 2 (Figure 1), is used to treat osteoporosis.2 Some
inhibit serine proteases, such as thrombin3,4 and factor
Xa,5 and so have potential as anticoagulants, or inhibit
the cysteine protease cathepsin K providing a potential
alternative route for the treatment of osteoporosis.6
Others may be anticancer agents reversing multidrug
resistance,7 or binding tubulin.8,9 There are also examples
of 2-substituted benzothiophenes acting as dopamine D3
receptor antagonists,10 inhibiting cell adhesion11 and
showing promise as antiallergy agents.12
We here describe adaptation of this approach to the
synthesis of 2-substituted benzo[b]thiophenes.18 We in-
tended to generate novel thio-functionalized titanium
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10.1021/jo049344o CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/30/2004
J . Org. Chem. 2004, 69, 6145-6148
6145

SCHEME 1
SCHEME 2
2-yl)carboxylates have been prepared by intramolecular
Claisen reaction,12,30 and intramolecular Wittig reactions
with thioesters have been used to make a range of
2-substituted benzo[b]thiophenes.1,31 Dihydrothiophenes
have been prepared by titanium alkylidenes reacting
intramolecularly with thioesters,32 but the method has
not been applied to benzothiophenes. Although a few
solid-phase syntheses of compounds33 bearing a benzo-
thiophene ring are known,4,6,34 none have involved the
construction of the benzothiophene moiety.35
Our proposed approach to 2-substituted benzothiophenes
raised a number of questions. Could the 1,3-dithiane
moiety be reduced to form the titanium benzylidene
without affecting other sulfide functionality? How could
problems of chemoselectivity between different sulfur-
containing functionality be avoided during the synthesis
of the thioacetal substrates? Could we find mild condi-
tions for the final cyclization that would give only volatile
side products so that no further purification was neces-
sary? The choice of protecting group would be the key to
answering these questions. We postulated that reaction
between 2-aryl-1,3-dithianes 11 with titanium(II) com-
plex 5 occurs stepwise giving first intermediate 12 and
then bimetallic 13, which is the reagent added into the
flask containing the resin-bound esters (Scheme 2). Rate-
determining generation36 of the Schrock carbene37 14 is
then followed by rapid alkylidenation38 of the ester. We
decided to make alkyl-protected thiols since they would
be easy to prepare, and this functionality would be less
reactive toward complex 5 than the dithiane group
because the benzylic carbanion in organotitanium inter-
mediate 12 is stabilized both by conjugation with the
aromatic ring and by the R-sulfur atom.
benzylidenes 7 from 1,3-dithianes 6 and use them to
convert Merrifield resin-bound esters 8 into enol ethers
9 (Scheme 1). Treatment with mild acid would then
cleave the enol ethers but would leave any residual esters
unaffected so ensuring the purity of the released com-
pounds. Finally, cyclization would give benzothiophenes
10. This solid-phase synthesis of 2-substituted benzo[b]-
thiophenes would be traceless19 in that, theoretically,
substituents would be allowed at any site, and would be
classified as using an Ssp2-Csp2 (benzothiophene) linker.20
There are many methods for the synthesis of 2-sub-
stituted benzo[b]thiophenes.21 Recent approaches include
construction of the thiophene moiety by 5-endo-dig elec-
trophilic9,22 or radical23 cyclizations, by intramolecular
aldol condensation24 or other cyclocondensation,25 and by
cyclization of 2-arylthio-ketones,26 or benzoannelation by
electrocyclization-oxidation27 and by cyclocondensation.28
However, there is only one method where the heterocyclic
ring is formed by nucleophilic attack by the sulfur on a
ketone or an oxonium ion derived from an acetal or enol
ether and that involves using an N,N,N′,N′-tetrameth-
ylphosphorodiamidothio group as a masked thiol.29 Meth-
ods that employ alkylidenation of carboxylic acid deriva-
tives are also rare: methyl (3-hydroxybenzo[b]thiophen-
(19) Blaney, P.; Grigg, R.; Sridaran, V. Chem. Rev. 2002, 102, 2607-
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6146 J . Org. Chem., Vol. 69, No. 18, 2004

SCHEME 3
SCHEME 6
SCHEME 4
SCHEME 5
bonds would be cleaved easily under acidic conditions,
the functionality should be stable to low-valent titanium
complexes as the silicon atom would be resistant to
reduction. Initially, we synthesized TBDMS sulfide 32
from readily available 2-mercaptobenzoic acid 27 by
modifying the route of Kasmai and Mischke42 for the
preparation of 2-mercaptobenzaldehyde (Scheme 6). Thus,
reduction to the alcohol 28 was followed by oxidation with
version of the resulting 2-alkylthio-benzaldehydes 15-
17 into thioacetals 18-20 (Scheme 3). Resin-bound esters
21a -e contained within small porous polypropylene
reactors were prepared from Merrifield resin.40 Unsur-
prisingly, p-methoxybenzyl aryl sulfide 20 did not give
an effective benzylidenating agent. It is likely that the
benzylic sulfide reacts with the low-valent titanium
complex 5. However, a titanium reagent, presumably
titanium benzylidene 22, could be generated from thio-
acetal 18 and reacted with resin-bound ester 21a to give
ketone 24a following cleavage from resin under mild acid
conditions. This showed that chemoselectivity was pos-
sible (Scheme 4). More importantly, titanium benzylidene
23, generated from aryl tert-butyl sulfide 19, could be
used to make ketones 25b-e in moderate to good yield
based on resin loading, and ketones 25b and 25d could
be cyclized to give benzothiophenes 26b and 26d (Scheme
5). However, the cyclization conditions were harsh and
recrystallization of the benzothiophenes was required to
obtain pure samples.
42
a PCC silica gel homogenate43 or with MnO2 to give
disulfide 29 in 83% or 70% yield, respectively. Using
IBX44 in ethyl acetate45 gave disulfide 29 cleanly in higher
yield, but if heat spots were allowed to develop during
the addition of IBX, use of this reagent led to explosion
(CAUTION). Thioacetal formation gave disulfide 30 and
reduction then gave thiol 31, which was protected as the
TBDMS sulfide 32 by adaptation of a reported method
for protecting phenols.46 However, a more general route
began from readily available 2-nitrobenzaldehydes 33
and 34. Thioacetal formation and reduction by the
method we have previously described15 gave aniline
derivatives 35 and 36. Using the method of Hori et al.,47
diazonium ion formation and SNAr displacement of
nitrogen with potassium ethyl xanthate was followed by
reduction of the resulting S-aryl xanthates to give thiols
We realized that tert-butyldimethylsilyl protection41 of
the thiol might be more effective because although S-Si
(42) Kasmai, H. S.; Mischke, S. G. Synthesis 1989, 763-765.
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J . Org. Chem, Vol. 69, No. 18, 2004 6147

SCHEME 7
SCHEME 8
F IGURE 3.
and trifluoroacetic anhydride (as a dehydrating agent)
in dichloromethane. The benzothiophenes were isolated
in moderate to good yield (based on the original loading
of the Merrifield resin, see Figure 3) following solvent
31 and 37 in good yield. Silyl protection was accomplished
as before to give TBDMS sulfides 32 and 38.
1
removal without any need for purification (see H NMR
An amino substituent could be introduced by using
2-chloro-5-nitrobenzaldehyde 39 as the starting material
(Scheme 7). Conversion into thioacetal 40, followed by
nucleophilic displacement of the chloride with sodium
sulfide48 gave thiol 41. An intractable mixture of com-
pounds was formed when displacement of the chloride
by the sulfide dianion was attempted on the unprotected
aldehyde 39. Reduction of the nitro group gave aniline
derivative 42. Finally, N-methylation49 to give thiol 43
was followed by TBDMS protection to give the substrate
44 for titanium benzylidene formation.
Neither the disulfide 30 nor the free thiol 31 gave
effective alkylidenating agents when treated with 4 equiv
of low-valent titanium complex 5. However, titanium
reagents, presumably titanium benzylidenes 45, could be
generated from thioacetals 32, 38, and 44 and these
alkylidenated resin-bound esters 21a -d (Scheme 8). It
was necessary to retreat the resin to obtain good conver-
sion. Optimized conditions for release from resin with
concomitant cyclization to give benzothiophenes 26 and
46-48 employed a 50:50 mixture of trifluoroacetic acid
spectra of crude benzothiophenes in the Supporting
Information). As in our earlier work with benzofurans,15
lower yields arose from electron-rich p-methoxybenzoate
ester 21d . This would be expected to react more slowly
with the nucleophilic titanium benzylidene 45, allowing
alternative routes for the decomposition of the Schrock
carbene to compete in the product-determining step.
In conclusion, we have described novel titanium ben-
zylidene reagents that allow a new approach to the
synthesis 2-substituted benzothiophenes. We have used
these reagents to provide the first examples of the
construction of benzothiophenes by solid-phase synthe-
sis.35 Our method is traceless and ensures the purity of
the benzothiophenes by switching the nature of the linker
from acid-stable to acid-sensitive.
Ack n ow led gm en t. The authors thank the Univer-
sity of Glasgow Loudon Bequest for funding and Gordon
J . McKiernan for early synthetic studies.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of all compounds synthesized; 1H
NMR spectra of all compounds synthesized including benzo-
thiophenes 26, and 46-48 as released from resin following
solvent removal (with no further purification). This material
is available free of charge via the Internet at http://pubs.acs.org.
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1996, 39, 4608-4621.
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J O049344O
6148 J . Org. Chem., Vol. 69, No. 18, 2004