Synthesis of functionalized benzo[b]thiophenes by the intramolecular copper-catalyzed carbomagnesiation of alkynyl(aryl)thioethers

Article abstract of DOI:10.1002/anie.201106734

Highly functional: A copper(I)-catalyzed intramolecular carbomagnesiation under mild conditions transforms readily available alkynyl(aryl)thioethers into magnesiated benzothiophenes. Subsequent reaction with various electrophiles (acid chlorides, allyl bromides, aryl halides) provides polyfunctional benzo[b]thiophenes (see scheme). Further modification of the cyclization products affords highly diversified benzothiophene derivatives and new heterocyclic scaffolds.

Full text of DOI:10.1002/anie.201106734

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DOI: 10.1002/anie.201106734
Heterocycle Synthesis
Synthesis of Functionalized Benzo[b]thiophenes by the Intramolecular
Copper-Catalyzed Carbomagnesiation of Alkynyl(aryl)thioethers**
Thomas Kunz and Paul Knochel*
The synthesis of novel functionalized heterocycles is an
important topic in synthetic organic chemistry.[1] Several
methodologies for the construction of indoles, benzofurans,
benzothiophenes, and other fused-ring compounds by cycli-
zation reactions have been reported.[2] These ring-closing
procedures include metalative cyclizations,[2b,3] gold-catalyzed
reactions,[2a,4] copper-promoted halocyclizations,[5] and palla-
dium-mediated iodocyclizations.[2d,6,7]
Herein, we report a mild and general method for the
preparation of functionalized benzo[b]thiophenes and
benzo[b]thieno[2,3-d]thiophenes by means of an intramolec-
ular catalytic carbocupration[16,17] reaction starting from
alkynyl(aryl)thioethers. The treatment of the thioether 1a
with iPrMgCl·LiCl[18] provided the corresponding magnesium
reagent 2a (258C, 4 h, > 95% conversion; Scheme 2). In the
Among these heterocyclic scaffolds, benzo[b]thiophenes[8]
are of particular interest, as they are often found in
biologically active molecules such as raloxifene[9] and poten-
tial drug candidates[10] and are also widespread in material
chemistry.[11] Recently, Larock and co-workers applied a Pd-
catalyzed iodocyclization for the elaboration of oligomeric
benzo[b]thiophenes.[12] Also, a novel tandem reaction con-
sisting of an intramolecular S-vinylation and a subsequent
À
intermolecular C C bond formation has been reported by
Lautens and co-workers.[13] Since ortho-alkynyl benzenethiols
are not accessible by Sonogashira coupling,[14] we envisioned a
metalative cyclization involving alkynyl(aryl)thioethers,
which are readily available in three straightforward steps
starting from the corresponding 1,2-bromoiodoarenes
(Scheme 1).[15]
Scheme 2. Preparation of benzo[b]thiophenes by a copper-catalyzed
carbomagnesiation of alkynyl(aryl)thioethers of type 1.
presence of a catalytic amount of CuCN·2 LiCl[19] (30 mol%)
a smooth cyclization occurred (258C, 24 h)[20] producing the
magnesiated compound 3a. A subsequent acylation reaction
with thiophene-2-carbonyl chloride (0.9 equiv) afforded the
polyfunctional benzothiophene 4a in 72% yield. Similarly,
the reaction with 4-chlorobenzoyl chloride provided the
acylated benzothiophene 4b in 80% yield (Table 1, entry 1).
Various functionalized alkynyl(aryl)thioethers (1b–e) bear-
ing a protected hydroxy group (1b) or a chloro (1c), cyano
(1d), or ester substituent (1e) underwent cyclization under
similar conditions. The intermediate Mg reagents were either
acylated or allylated providing diverse polyfunctional benzo-
thiophenes (4b–j) in 71–91% yield (Table 1, entries 2–9).
In the case of the cyano-substituted thioether (1d), the Br/
Mg exchange with iPrMgCl·LiCl was performed at 08C (1 h).
For the more sensitive ester-substituted thioether (1e), this
exchange was carried out at À258C (1 h). As the cyclization at
this temperature is very slow and since higher temperatures
(> 08C) lead to side reactions, stoichiometric amounts of
CuCN·2LiCl were used in this case. In fact, with microwave
irradiation (508C, max. 100 W) the ring-closing reaction
reached completion within 1 h (Table 1, entries 8 and 9).
The tert-buyl ester is preferred, since for methyl and ethyl
esters a competitive addition of iPrMgCl·LiCl onto the ester
moiety was observed.
Scheme 1. Preparation of alkynyl(aryl)thioethers of types 1 and 11.
FG=functional group, TMS=trimethylsilyl, TIPS=triisopropylsilyl.
[*] M. Sc. T. Kunz, Prof. Dr. P. Knochel
Ludwig Maximilians-Universitꢀt Mꢁnchen, Department Chemie
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie and the European
Research Council (ERC) for financial support. We also thank BASF
AG (Ludwigshafen) and Chemetall GmbH (Frankfurt) for generous
gifts of chemicals.
The TMS-substituted benzothiophenes of type 4 were
readily converted to the desilylated compounds of type 5
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106734.
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Table 1: Functionalized benzothiophenes of type 4 obtained by the
copper-catalyzed carbomagnesiation of alkynyl(aryl)thioethers of type 1
and subsequent reaction with various electrophiles[a]
Scheme 3. Transformations of TMS-substituted benzo[b]thiophenes of
type 4. 1) Bu4NF, THF, 258C, 1 h; 2) ICl, CH2Cl2, 08C, 5 min. [a] All
compounds of types 5 and 6 are described in the Supporting
Information.
Entry
1
Substrate[b]
Product, yield [c]
2
3
4
5
1b
Scheme 4. Further functionalization of the benzo[b]thiophenes of types
5 and 6.
1c
piperidyl) followed by a reaction with ethyl cyanoformate
afforded the 2,3-disubstituted benzothiophene 7 in 78% yield
(method A, Scheme 4). Here, the carbonyl group acts as a
directing group[23] and the metalation occurs regioselectively
on position 3 of the benzo[b]thiophene ring. Alternatively,
the heterocyclic iodide 6a underwent a Pd-catalyzed[24]
Negishi cross-coupling reaction[25] with 4-acetoxybutylzinc
bromide[26] 8 (258C, 1 h) to provide the polyfunctional
benzothiophene 9 in 77% yield (method B). The third
transformation involves an
6
7
8
1d
I/Mg-exchange reaction on the iodide 6d using iPrMgCl·LiCl
(À788C, 5 min). After a subsequent copper(I)-catalyzed
acylation reaction with 2-furoyl chloride, the benzothiophene
10 was produced in 77% yield (method C, Scheme 4). This
magnesiation by means of I/Mg exchange is complementary
to the deprotonation with TMPMgCl·LiCl (method A), and is
relevant when direct deprotonation is not successful because
of chemo- and/or regioselectivity problems.
9
1e
[a] 0.9 equiv of electrophile was used. [b] See the Supporting Information
for the reaction conditions. [c] Yield of isolated, analytically pure product
based on the amount of electrophile used.
Interestingly, the activated triple bond of substrates
bearing a propargylic group is more susceptible to carbo-
metalation,[16,17] and the cyclization therefore occurs without
addition of a copper catalyst. Thus, treatment of the thioether
11a with iPrMgCl·LiCl (1.1 equiv, 258C, 5 h) provided the
magnesium reagent 12, which underwent ring closure (258C,
20 h) leading to the Mg intermediate 13a. After a carbox-
ylation with ethyl cyanoformate the benzothiophene 14a was
obtained in 76% yield (Scheme 5).
(Bu4NF (1.5 equiv), THF, 258C, 1 h) or to 3-iodobenzothio-
phenes of type 6 (ICl (1.1 equiv), CH2Cl2, 08C, 5 min)[21]
(Scheme 3). Heterocycles 5 and 6 are valuable intermediates
and can be further functionalized by three general types of
reactions: a direct magnesiation (method A), a Negishi cross-
coupling reaction (method B), or an I/Mg-exchange reaction
(method C, Scheme 4).
Thus, the metalation of benzothiophene 5e with
TMPMgCl·LiCl[22] (À308C, 3 h, TMP = 2,2,6,6-tetramethyl-
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quent microwave-assisted (758C, max. 150 W, 2 h) nucleo-
philic aromatic substitution led to the thieno[3,2-c]chromene
16a in 79% yield. Likewise, the deprotected benzylic alcohol
15b was oxidized to the aldehyde with Dess–Martin period-
inane (2 equiv, CH2Cl2, 08C, 12 h) and condensation with
hydrazine hydrate (3 equiv, EtOH, 258C, 12 h) furnished the
thieno[2,3-d]pyridazine 16b in 90% yield (Scheme 6).
Scheme 5. Preparation of benzo[b]thiophenes by cyclization of pro-
tected hydroxymethyl-substituted alkynyl(aryl)thioethers.
Likewise, copper(I)-catalyzed acylation or Pd-catalyzed
cross-coupling reactions afforded the derived benzothio-
phenes 14b–d in 74–87% yield (Table 2, entries 1–3). The
cyclization of the ester-substituted arene 11c was carried out
at lower temperatures (À5 to 08C, 52 h) to avoid decom-
position of this sensitive Mg intermediate. The ester-substi-
tuted benzothiophene 14e was obtained in 78% yield
(Table 2, entry 4).
Scheme 6. Intramolecular aromatic substitution reaction leading to
new heterocyclic scaffolds. TBAF=tetrabutylammonium fluoride,
DMP=Dess–Martin periodinane.
Table 2: Functionalized benzothiophenes of type 14 obtained by carbo-
magnesiation of alkynyl(aryl)thioethers of type 11 and subsequent
reaction with electrophiles[a]
The present methodology can be extended to the prep-
aration of benzothienothiophenes. Thus, ethynylbenzothio-
phene 1 f was conveniently metalated with TMPMgCl·LiCl
(258C, 2 h). The ring closure is more challenging, since it
involves the formation of a fused five-membered ring on an
existing five-membered ring. This is much less favored than
the formation of a six-membered ring. However, it was
achieved using catalytic CuCN·2LiCl (30 mol%) and micro-
wave irradiation (758C, max. 200 W, 3 h). A CuI-catalyzed
allylation with ethyl (2-bromomethyl)acrylate[27] produced
the benzo[b]thieno[3,2-d]thiophene 4k in 68% yield
(Scheme 7). As expected, the more activated substrate 11d
Entry
1
Substrate[b]
Product, yield[c]
2
11a
3
4
[a] 0.9 equiv of electrophile was used. [b] See the Supporting Information
for the reaction conditions. [c] Yield of isolated, analytically pure product
based on the amount of electrophile used. dba=dibenzylideneacetone,
tfp=tri(2-furyl)phosphine.
Scheme 7. Functionalized benzo[b]thieno[2,3-d]thiophenes obtained by
carbomagnesiation and subsequent reaction with electrophiles.
The benzylic hydroxy group of benzothiophenes of type
14 can be further used to prepare new heterocyclic scaffolds.
Desilylation of compound 14d (Bu4NF (1.5 equiv), THF,
258C, 2 h, 15a, 88%) followed by deprotonation of the free
alcohol (NaH (2 equiv), THF/DMF, 258C, 2 h) and subse-
cyclized in the absence of a copper catalyst under similar
conditions. After transmetalation to zinc and Pd-catalyzed
cross-coupling with ethyl 4-iodobenzoate, the functionalized
benzothienothiophene 14 f was obtained in 57% yield.
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b) K. G. Pinney, A. D. Bounds, K. M. Dingeman, V. P. Mocharla,
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b]thiophenes and benzo[b]thieno[2,3-d]thiophenes in excel-
lent yields. This method tolerates a wide range of functional
groups, and further modifications of the cyclization products
afford highly diversified benzothiophene derivatives as well
as new heterocyclic scaffolds. An extension of this method-
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Received: September 22, 2011
Revised: November 25, 2011
Published online: January 17, 2012
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Keywords: benzo[b]thiophenes · carbomagnesiation ·
copper catalysis · cyclization · heterocycle synthesis
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