Lewis acid/Broensted acid mediated benz-annulation of thiophenes and electron-rich arenes

Article abstract of DOI:10.1021/ol501006t

A facile preparation of benz-annulated heterocycles were achieved at rt involving a Lewis acid/Broensted acid mediated annulation of heterocycles using 2,5-dimethoxytetrahydrofuran as a four-carbon synthon. The benz-/naphth-annulation was found to be successful with electron-rich arenes as well.

Full text of DOI:10.1021/ol501006t

Letter
pubs.acs.org/OrgLett
̈
Lewis Acid/Bronsted Acid Mediated Benz-Annulation of Thiophenes
and Electron-Rich Arenes
Settu Muhamad Rafiq, Ramakrishnan Sivasakthikumaran, and Arasambattu K Mohanakrishnan*
Department of Organic Chemistry, School of Chemical Sciences, University of Madras, Guindy Campus, Chennai 600 025, Tamil
Nadu, India
S
* Supporting Information
ABSTRACT: A facile preparation of benz-annulated heterocycles were
achieved at rt involving a Lewis acid/Bronsted acid mediated annulation
̈
of heterocycles using 2,5-dimethoxytetrahydrofuran as a four-carbon
synthon. The benz-/naphth-annulation was found to be successful with
electron-rich arenes as well.
enzo[b]thiophene and its analogues 11 are traditionally
prepared involving an intramolecular cyclization of the
at 0 °C for 15 min followed by 2 h at rt afforded
dibenzothiophene 5a in 84% yield (Scheme 2).
B
respective arylthioalkyl derivatives. The optical and medicinal
applications of annulated thienyl oligomers added further stimuli
to the development of the plethora of synthetic protocols for
benzo[b]thiophene and its derivatives.2 The synthesis of
benzo[b]thiophene-5,6-dicarboxaldehyde3 has been achieved in
good yield by the reaction of thiophene-2,3-dicarboxaldehyde
with 2,5-dimethoxytetrahydrofuran (DMTHF) in acetic acid
under reflux conditions. A direct access to 2,3-dimethoxynaph-
thalene4 was realized in low yield via the interaction of 1,2-
dimethoxybenzene with DMTHF in the presence of sulfuric acid.
Recently, DMTHF has been widely employed as a four-carbon
synthon for the syntheses of heterocycles such as pyrrole,5
indole,6 and carbazole.7
Scheme 2. LA-Mediated Benz-Annulation of Thiophene,
Fuuran, and Selenophene Analogues
A similar type of benz-annulation of thiophene using DMTHF
4 as a four-carbon synthon is unexplored (Scheme 1). The
Scheme 1. Synthesis of Benzo[b]thiophenes
Under identical conditions, selenophene 3b also underwent
consecutive benz-annulations to afford dibenzoselenophene 5b.
However, the expected benz-annulation was found to be
unsuccessful with furan 3c, affording only a black polymeric
material. The benz-annulation was then successfully performed
with benzo fused heterocycles 6a−c to furnish the respective
dibenzo heterocycles 5a−c in excellent yields. Controlled benz-
annulation of the thiophene 3a/selenophene 3b using 1 equiv of
the four-carbon synthon and ZnBr2 led to the isolation of
benzo[b]thiophene 5a/benzo[b]selenophene 5b in 82% and
79% yields, respectively.
promising optical applications of benz-annelated thienyl hetero-
cycles8 prompted us to carry out a systematic study on the benz-
annulation of thiophene and its analogues. Further, in
continuation of our interest in the synthesis of π-conjugated
heterocycles,9 we report herein our preliminary results on the
benz-annulation of thiophene and its analogues using a Lewis
As a representative case, bis-benz-annulation of thiophene 3a
with 4.4 equiv of DMTHF 4 was then carried out using different
Lewis acids/Bronsted acids, and the results obtained are
̈
presented in Table 1. In general, the reaction was found to be
successful with Lewis and Bronsted acids (entries 1−10). The
̈
bis-benz-annulation of 3a with DMTHF 4 using 1 equiv of ZnBr2
in DCM at rt led to the isolation of dibenzothiophene 5a in low
acid/Bronsted acid as a catalyst.
̈
Based on our previous study on Lewis acid (LA)-mediated
domino reactions,9 the benz-annulation of thiophene 3a was first
initiated using ZnBr2 as a catalyst. As expected, the reaction of
thiophene 3a with 4 equiv of DMTHF 4 in the presence of ZnBr2
Received: April 5, 2014
Published: April 28, 2014
© 2014 American Chemical Society
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Letter
benzo[c]furan 5c′ in 35% yield. Under identical conditions, the
naphth-annulation of 6c using 4.4 equiv of DMTHF afforded 5c′
in 76% yield (entry 3). The naphtho[2,1-b]thiophene 6g10/
naphtho[1,2-b]thiophene 6h10 underwent smooth benz-annula-
tion to afford 5g/5h in excellent yield. The benz-annualtion of
4,7-dimethoxybenzo[b]thiophene 6i with DMTHF 4 using
ZnBr2/triflic acid in DCM at rt followed by column chromato-
graphic purification led to the isolation of respective quinone 5i′
as a yellow solid (entry 5).
Table 1. Effect of Catalyst on Benz-Annulation of 3a
a
b
entry
LA/Bronsted acid
conditions
yield (%)
̈
1
2
3
4
5
6
7
8
9
10
1 equiv of ZnBr2
2 equiv of ZnBr2
1 equiv of SnCl4
DCM, rt, 2 h
DCM, rt, 2 h
DCM, rt, 2.5 h
DCM, rt, 2.5 h
DCE, ref, 36 h
DCE, ref, 24 h
DCE, ref, 24 h
DCE, ref, 24 h
DCM, rt, 2 h
DCM, rt, 3 h
20
84
81
78
53
62
56
10
92
83
1 equiv of BF3·OEt2
1 equiv of CuBr2
20 mol % InBr3
20 mol % FeCl3
The benz-annulation could be successfully performed with
naphtho[b]thiophenes 6j−m11 to afford the respective hetero-
cycles 5j−m in good yields (entries 6, 7). The benz-annulation of
2-aryl substituted thiophenes 6n−t12 and naphtho[b]thiophenes
6v and 6w proceeded in good yields (entries 8−14). As in the
case of N-hexylindole 6d′, the preferential protonation at the 6-
position of N-hexylcarbazole 6u may disfavor the benz-
annulation (entry 11). In the case of naphtho[b]thiophene
6x13 depending upon the equivalents of DMTHF, mono-/bis-
benz-annulation could be achieved in a selective manner to afford
respective heterocycles 5x and 5n in excellent yields (entry 14).
The controlled mono-benz-annulation of benzodithiophene
6y14 using 1 equiv of DMTHF 4 furnished heterocycle 5y in 86%
yield. The bis-benz-annulation of thienyl heterocycle 7a15 and
dithienylanthracene 7b16 using 4.4 equiv of DMTHF 4 led to the
isolation of respective annulated products 8a and 8b in excellent
yields (entries 16 and 17). All attempts to perform the mono-/
bis-benz-annualtion of 1,3-dithienylbenzo[c]thiophene 7c17
were unsuccessful and led to the formation of an intractable
black material. Finally, the benz-annulation reaction was then
achieved with electron-rich arenes 9a−f to afford corresponding
benz-annulated compounds 10a−f (entries 19 and 20). As a
representative case, the structure of naphthodibenzothiophene
5t was confirmed by a single crystal X-ray diffraction analysis.18
A facile benz-annulation of a wide variety of arenes and
heteroarenes, at rt, prompted us to explore a naphth-annulation
reaction using 1,3-dimethoxy-1,3-dihydroisobenzofuran 11.19
The expected naphth-annulation of 9a/9b with isobenzofuran 11
in the presence of triflic acid at rt for 2 h followed by workup and
column chromatographic purification led to the isolation of
anthracenes 12a,b and anthraquinones 13a,b. The formation of
13a,b can be visualized through the aerial oxidation of respective
9-hydroxyanthracene.
To our delight, when the naphth-annulation of 9a/9b was
performed in the presence of ethanol as a reducing agent, the
anthracene 12a/12b was obtained as a sole product in excellent
yield. Using similar conditions, naphth-annulation of 2,3-
disubstituted naphthalene 10a/10c also afforded annulated
compound 14a/14c, avoiding the formation of respective
quinones (Scheme 3).
A plausible mechanism for annulation of 1,2-dimethoxyben-
zene 9a with furan 4/11 is presented in Scheme 4. The benz-
annulation of 9a in the presence of ZnBr2 may proceed through
the formation of the intermediate 15 and/or 16. Successive
eliminations of water/MeOH from these intermediates may give
product 10a. In the case of a five-member heterocycle such as
thiophene 3a, the benz-annulation is expected to occur via
bicyclic intermediate 17. Obviously, the corresponding inter-
mediate 18 formed during naphth-annulation of 9a underwent
ethanol-mediated reductive cleavage followed by dehydration to
furnish 2,3-dimethoxyanthracene 12a as a sole product. In the
absence of ethanol, the methanol produced during the reaction
led to a reductive cleavage as well as ring-opening of the furan
unit to give respective intermediates 19 and 20. The intermediate
1 equiv of CH3CO2H
1 equiv of CF3SO3H
1 equiv of CH3SO3H
a
Reaction was performed using 1 equiv of 3a and 4.4 equiv of 4.
Isolated yield of dibenzothiophene 5a.
b
yield (entry 1). However, the successive benz-annulation of 3a
could be performed in excellent yield using 2 equiv of ZnBr2
(entry 2).
A comparable yield of the product 5a was obtained using 1
equiv of SnCl4 (entry 3). It should be noted that the bis-benz-
annulation was smoothly performed at rt using Lewis acids such
as ZnBr2, SnCl4, and BF3·OEt2 (entries 2−4). CuBr2 required
refluxing conditions and a longer reaction time (entry 5). The
bis-benz-annulation was successfully performed using 20 mol %
InBr3 in 1,2-DCE at reflux for 24 h (entry 6). In the presence of 1
equiv of FeCl3, the annulation was found to be complicated
possibly due to the polymer formation. However, the annulation
was achieved in moderate yield using 20 mol % FeCl3 in 1,2-DCE
at reflux for 24 h (entry 7). The bis-benz-annulation of 3a was
found to be slow with acetic acid, even under refluxing conditions
affording only a poor yield (10%) of 5a (entry 8). Among the
Bronsted acids employed for the bis-benz-annulation of 3a, triflic
̈
acid gave the maximum yield (entry 9). The reaction was also
found to be successful with methanesulfonic acid affording the 5a
in an excellent yield (entry 10).
A comprehensive study on the benz-annulation of thiophene
3a confirmed 2 equiv of ZnBr2 or 1 equiv of triflic acid at rt as the
most suitable conditions. To further understand the substrate
scope and limitations, the benz-annulation reaction was explored
with substituted thiophenes, benzo[b]heterocycles, and elec-
tron-rich arenes (Table 2). The reaction was found to be
successful for 2-bromo-3-methylthiophene 3d affording the
expected benzo[b]thiophene 6d in 89% yield. The 3-methyl-
thiophene 3e failed to give the expected product 3-methyl-
benzo[b]thiophene 6e possibly due to a competing reaction at
the 2-position of thiophene. In the case of 3-hexylthiophene 3f,
the preferential reaction at the 5-position gave the annulation
product 6f. Surprisingly, the reaction was found to be complex
with bithiophene 3h and failed to give any characterizable
product. The benz-annulation of 2-thienyl lactone 3i was
unsuccessful probably due to the reduced nucleophilicity of the
thiophene unit. The reaction was found to be successful with a
wide variety of benzo[b]heterocycles 6a−f with the exception of
N-hexylindole 6d′ (entries 3−5). It should be noted that even
though the benz-annulation of N-hexylindole 6d′ failed to
produce the N-hexylcarbazole (entry 3), under identical
conditions, N-phenylsulfonylindole underwent benz-annulation
to furnish N-phenylsulfonyl carbazole in excellent yield.7b This
clearly confirms that the LA/triflic acid reacts at the 3-position of
N-hexylindole 6d′ to deter the benz-annulation. To our surprise,
the benz-annulation of 6c with 2.2 equiv of DMTHF in the
presence of triflic led to the formation of naphth-annulated
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Letter
Table 2. Scope and Limitation of Triflic Acid/LA-Mediated Benz-Annulation of Thiophenes/Electron-Rich Arenes (NR: No
Reaction)
a
b
Reaction conditions: Substrate (0.5 mmol), DMTHF 4 (1.1 mmol), and CF3SO3H (0.5 mmol) in DCM. Substrate (0.5 mmol), DMTHF 4 (2.2
c
d
mmol), and CF3SO3H (1 mmol) in DCM. Substrate (0.5 mmol), DMTHF 4 (1.1 mmol), and ZnBr2 (0.5 mmol) in DCM. Substrate (0.5 mmol),
DMTHF 4 (0.5 mmol), and CF3SO3H (0.5 mmol) in DCM.
20 upon elimination of methanol followed by aerial oxidation
afforded anthraquinone 13a.
In summary, for the first time, a facile benz-annulation of
substituted thiophenes and electron-rich arenes was achieved
under mild conditions. For some selected heterocycles, depend-
ing upon the equivalents of DMTHF and LA/triflic acid, mono-
and bis-benz-annulation were performed in acceptable yields.
The reaction could be successfully extended for the naphth-
annulation of electron-rich arenes. However, the benz-
annulation was found to be unsuccessful with electron-rich
heterocycles such as furan, indole, and carbazole. Reasonable
mechanisms for benz-/naphth-annulation were proposed.
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Scheme 4. Mechanism of Annulation for Arene 9a and
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Further studies on similar types of annulations with analogues of
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedure, copies of NMR spectra (for new
compounds), and X-ray crystallographic data of 5t (CIF). This
material is available for free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
(14) He, M.; Zhang, F. J. Org. Chem. 2007, 72, 442.
(15) Takimiya, K.; Konda, Y.; Ebata, H.; Niihara, N.; Otsubo, T. J. Org.
Chem. 2004, 69, 5568.
*E-mail: mohanakrishnan@unom.ac.in; mohan_67@hotmail.
com.
(16) Ghosh, A. K.; Kotha, S. Synlett 2002, 3, 451.
(17) Mohanakrishnan, A. K.; Lakshmikantham, M. V.; Mc Dougal, C.;
Cava, M. P.; Baldwin, J. W.; Metzger, R. M. J. Org. Chem. 1998, 63, 3105.
(18) Structure was confirmed by single-crystal X-ray data. CCDC
number for compound 5t: 994367 (see SI).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(19) Mirsadeghi, S.; Rickborn, B. J. Org. Chem. 1987, 52, 787.
Financial assistance from DST New Delhi is acknowledged. The
authors thank DST-FIST for the high-resolution NMR facility.
S.M.R. thanks DST, New Delhi for a DST-INSPIRE fellowship.
R.S. thanks UGC for a fellowship.
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