Copper-catalyzed domino synthesis of multi-substituted benzo[: B] thiophene through radical cyclization using xanthate as a sulfur surrogate

Article abstract of DOI:10.1039/d0cc08429h

The Cu-catalyzed domino synthesis of multi-substituted benzo[b]thiophene through radical cyclization of 2-iodophenyl ketones was developed using xanthate as a sulfur surrogate. This method was extended to obtain tetracyclic Lupinalbin analogues through do

Full text of DOI:10.1039/d0cc08429h

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Copper-catalyzed domino synthesis of multi-
substituted benzo[b]thiophene through radical
cyclization using xanthate as a sulfur surrogate†
Cite this: Chem. Commun., 2021,
57, 4512
Received 31st December 2020,
Accepted 23rd March 2021
Nallappan Sundaravelu, Tushar Singha, Anuradha Nandy and
Govindasamy Sekar
*
DOI: 10.1039/d0cc08429h
rsc.li/chemcomm
The Cu-catalyzed domino synthesis of multi-substituted benzo[b]thio- carbonyl compounds via SN2 displacement of a halogen atom
phene through radical cyclization of 2-iodophenyl ketones was develo- by nucleophiles (Scheme 1b).7 In contrast, the incorporation of
ped using xanthate as a sulfur surrogate. This method was extended to heteroatom functional groups into the b(sp3)-C–H bonds of
obtain tetracyclic Lupinalbin analogues through double C–S/C–O bond simple ketones is sparsely reported due to their less acidic
formation by changing the substituents. The products were converted to nature. Conventional methods involve Michael addition8 to
a HTI photoswitch, benzothiophene-fused flavone.
in situ synthesized a,b-unsaturated compounds via the oxida-
tion of the corresponding saturated carbonyl compounds in
Benzo[b]thiophenes are a promising class of organosulfur com- one or a few steps (Scheme 1b).9
pounds. In particular, multi-substituted 3-hydroxybenzo[b]thio-
Su and co-workers reported the first Cu-catalyzed direct
phene is considered essential, as it is used in a broad range b-functionalization of saturated ketones involving a tandem
of research fields, including medicinal sciences and materials ketone dehydrogenation-conjugate addition sequence.10 Such
chemistry. 3-Hydroxybenzo[b]thiophene is known to exhibit inhi- protocols that involve direct functionalization of unactivated car-
bitor activity against human monoamine oxidase (hMAO).1 It also bonyl compounds appear more attractive; however, there is a dearth
works as an anti-inflammatory agent,2 a selective estrogen receptor of these direct methodologies. Additionally, a,b-sulfenylation reac-
downregulator (SERD) and a selective estrogen receptor modulator tions are also sparsely reported since sulfur causes catalyst poison-
(SERM).3 Additionally, the 3-hydroxybenzo[b]thiophene core is a ing to the metal catalyst.
precursor for the synthesis of hemithioindigo (HTI), which is a
chromophore that demonstrates proficient photoswitching proper-
ties under visible light irradiation.4 Benzothiophene synthesis
from o-silylaryl triflates and acyl-substituted ketene dithioacetals
was developed by Singh and co-workers (Scheme 1a).5a Very recently,
Yoshida and co-workers reported the synthesis of 3-substi-
tuted benzothiophenes by reacting aryne with alkynyl sulfides
(Scheme 1a).5b In spite of their significance, the domino synthesis
of multi-substituted benzothiophenes remains difficult in terms of
the applicable functional groups and substitution patterns.
On the other hand, copper-catalyzed radical cyclization has
been established as a powerful tool for synthesizing complex
molecules.6 In particular, much focus has been placed on the
functionalization of carbonyl compounds and their derivatives,
due to its importance in organic synthesis. To date, many
reports are available on the a-functionalization of saturated
Department of Chemistry, Indian Institute of Technology Madras, Chennai-600036,
Tamil Nadu, India. E-mail: gsekar@iitm.ac.in
† Electronic supplementary information (ESI) available. CCDC 2031230, 2031231
Scheme 1 Transition metal-catalyzed Csp3–H functionalization of
and 2043956. For ESI and crystallographic data in CIF or other electronic format
carbonyl compounds.
see DOI: 10.1039/d0cc08429h
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Table
1
Cu-catalyzed synthesis of 2-thioaroyl-3-hydroxybenzo[b]-
thiophenea
Scheme 2 Optimized reaction conditions for 2-thioaroyl-3-hydroxy-
benzo[b]thiophene.
Our group has delved into metal-catalyzed C–S bond for-
mation using xanthate as a sulfur surrogate.11 Building upon
this work, we wanted to develop a methodology to afford 2,
3-disubstituted benzo[b]thiophene from unactivated ketones in
the presence of copper as a catalyst, through the radical
cyclization of the carbonyl compound using xanthate as a
sulfur source. It was hypothesized that 2-thioaroyl-3-hydroxy-
benzo[b]thiophenes could be synthesized from 2-halophenyl
ketones via Cu-catalyzed C–S bond formation through cross-
coupling, followed by metal–enolate complex formation and
homolytic cleavage of the complex, to eventually provide the
cyclized benzo[b]thiophene with an active methylene group. It
was further expected to undergo oxidation in the presence of
DMSO and acetic acid to generate a 2-thioaroylbenzothiophene.
Thus, keeping the above points in mind, a trial reaction was
performed with 2-iodophenyl ketone 1a, and potassium ethyl
xanthate (3 equiv.), in the presence of Cu(OAc)2 (10 mol%) and
acetic acid (2 equiv.) as additives in DMSO as a solvent at
110 1C. To our delight, the desired product 2a was isolated in
60% yield within a short time span of 1 h. Encouraged by this, a
thorough optimization of the reaction conditions was carried
out (see the ESI† for details). The resultant optimized condi-
tions utilize potassium ethyl xanthate (3 equiv.), Cu(OAc)2
(20 mol%) as a catalyst and acetic acid (2 equiv.) as an additive
in DMSO (2 mL) solvent at 120 1C to yield 85% of 2a in 1 h
(Scheme 2).
a
Reaction conditions: 1 (0.5 mmol), xanthate (1.5 mmol), Cu(OAc)2
(20 mol%), AcOH (1 mmol) in DMSO (2 mL) at 120 1C. All yields are
isolated yields.
ketones were subjected to the optimized reaction conditions to
With the optimized reaction conditions in hand, the scope produce 2y and 2z in 79% and 71% yield, respectively. The reaction
for this domino synthesis of 3-hydroxybenzo[b]thiophene was was even suitable for the biphenyl-substituted ketone, giving the
desired product 2aa in good yield. However, the reaction was not
explored with various 2-iodophenyl ketones and the results
are summarized in Table 1. The reaction worked well for successful when it was performed with an aliphatic substrate, such
2-iodophenyl ketone, with electron-donating substituents on as 2-iodophenyl pentyl ketone 2ab. This result suggests that the
the arene attached to the aliphatic chain, providing the desired benzylic position is necessary for thioketone formation.
products in good to excellent yields (Table 1, 2a–2j). The
The protocol was examined for less reactive bromo sub-
structures of 2b and 2i were confirmed by single crystal XRD strates, such as 20-bromophenylketone 4 (Table 2). On subject-
analysis (CCDC 2031230 and 2031231†). Even sterically ing 20-bromophenylketone 4a to the optimized reaction
crowded di- and tri-substituted saturated ketones gave the conditions, the desired cyclized product 2a was obtained
in 74% yield in 1.5 h. Further, 20-bromophenylketones with
desired products 2k–2m in moderate to good yields. The
protocol was further employed for 2-iodophenyl ketone sub- various substituents (4-Me, 4-Cl, 4-CN) underwent the cycliza-
stituted with halogen groups and electron withdrawing groups tion successfully irrespective of the electronic nature of the
on the arenes. Moderate to good yields of the resultant substituent, to provide the desired products 2b, 2n, and 2t in
3-hydroxybenzo[b]thiophene were obtained, irrespective of the moderate to good yields. Even 20-bromophenylketone bearing
position of the halogen substitution (2n–2u).
thiophene also furnished the corresponding product 2v in
Intriguingly, the reaction proceeded smoothly with 2-iodophenyl 70% yield.
ketone containing heterocyclic thiophene to give the cyclized
product 2v in 82% yield within 30 min. Sterically demanding
When the optimized reaction conditions were applied to
iodophenyl ketone 1z with a methoxy group at the ortho-
naphthalene and biphenyl-derived ketones underwent the domino position on the arene ring attached to the aliphatic chain, a
reaction successfully to afford 2w and 2x in moderate yields. Next, tetracyclic ring 3a was obtained in 12 h in 92% yield (Table 3).
the methodology was applied to 2-iodophenyl ketones bearing The tetracyclic ring possesses benzothiophene-fused thiofla-
substitution on the iodo-attached aryl ring. Bromo- and dioxolanyl vones, which are analogues of Lupinalbin that are known to be
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Table 2 Domino synthesis of 3-hydroxybenzo[b]thiophene from 20-bromo-
phenylketonea
a
Reaction conditions: 4 (0.5 mmol), xanthate (1.5 mmol), Cu(OAc)2
Scheme 3 Gram scale and synthetic applications of current protocol
through post synthetic modifications.
(20 mol%), AcOH (1 mmol) in DMSO (2 mL) at 120 1C. All yields are
isolated yields.
To gain mechanistic insight, a series of controlled experi-
ments were performed. In the presence of the radical scavenger
BHT, a drastic decline in the yield to 23% was observed, while
in the presence of TEMPO, not even a trace amount of the
desired product was formed (Scheme 4a). When the expected
intermediate xanthate ester 10 was used under the optimized
conditions, the reaction proceeded to give 70% of 2a, indicating
that 10 forms in the due course of reaction (Scheme 4b).
Next, thioflavone 11 was subjected to the optimized condi-
tions with iodine, since it is known that thioflavone rearranges
to a benzothiophene moiety in the presence of molecular
iodine. However, only the dehydrogenated thioflavone 12 was
isolated in 68% yield, which shows that benzothiophene is not
generated via the rearrangement of thioflavone 11 (Scheme 4c).
When chalcone 13 was used under the standard reaction
conditions, only 15% of the desired product 2a was isolated,
which might be due to the corresponding in situ generated
saturated ketone (Scheme 4d). The chalcone can become
reduced by xanthate and acetic acid through PCET,13 thus,
giving rise to the saturated ketone. This result suggests that
chalcone 13 may not play any role in the reaction mechanism.
Further, a reaction was performed using iodophenyl ketone
1h with DMF as the solvent, keeping the other reaction para-
meters constant (Scheme 4e). Although the reaction took a
longer time (6 h) to complete during the optimization in DMF,
here the reaction was quenched after 1 h, and 2-benzyl ben-
zothiophenone 14 was isolated in 58% yield. When the inter-
mediate 14 was subjected to the optimized reaction conditions,
87% of the desired 2-thioaroyl-3-hydroxybenzo[b]thiophenone
a potent estrogen receptor.12 Considering the importance of
this privileged scaffold, the scope of the tetracyclic moiety was
examined.
The reaction worked well with the iodophenyl ketone bearing
ethoxy and hydroxy groups at the ortho-position on the arene
group attached to the aliphatic chain, to furnish 3a in 78% and
85% yield, respectively. The reaction also gave good yields of 3a
with 2-bromophenylketone. When the reaction was carried out
with iodophenyl ketone containing a 2,4-dimethoxy substituent
on the arene ring attached to the aliphatic chain, the desired
product 3b was isolated in 14 h in 76% yield by the selective
cleavage of the ortho-methoxy groups.
Iodophenyl ketone with 2,5-dimethoxy and 2,3,4-trimethoxy
substituents on the arene ring attached to the aliphatic chain
were also found to be compatible under the reaction conditions
and gave 3c and 3d in moderate yields. The structure of the
tetracyclic benzothiophene-fused thioflavone was confirmed by
single crystal XRD analysis of 3c (CCDC 2043956†).
Furthermore, the synthetic utility of 2-thioaroyl-3-hydroxy-
benzothiophene 2b was demonstrated when it was derivatized
to produce hemithioindigo 6 with a 4-fold-substituted double
bond, which is known to function as an efficient photoswitch
(Scheme 3b). In addition, the hydroxy group in 2b was benzoy-
lated to give the ester-bearing benzothiophene 7 along with the
thioacylated by-product 8 (Scheme 3c). Also, the thioketone
moiety in the tetracyclic Lupinalbin analogue 3a was converted
to ketone 9 in 78% yield using iodine and DMSO (Scheme 3d).
Table 3 Synthesis of tetracyclic thiophene-fused thioflavonea
a
Reaction conditions: 1z (0.5 mmol), xanthate (1.5 mmol), Cu(OAc)2
(20 mol%), AcOH (1 mmol) in DMSO (2 mL) at 120 1C. All yields are
isolated yields.
Scheme 4 Controlled reactions.
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cyclization using xanthate as an odorless sulfur source. This
methodology was extended to less reactive 2-bromophenylketones
without changing any parameters. The reaction also resulted in
the formation of a tetracyclic Lupinalbin analogues by intro-
ducing the ortho-methoxy substituent in the iodophenyl ketones.
Also, 2-thioaroyl-3-hydroxybenzo[b]thiophene was derivatized to
produce hemithioindigo, which is known to function as an
efficient photoswitch, and a dethionated Lupinalbin analogue
using the I2/DMSO system.
G. S. thanks IIT Madras (No. CHY/17-18/847/RFIR/GSEK) for
financial support, N. S. thanks CSIR, A. N. thanks IIT Madras
for senior research fellowship. We thank DST and Department
of Chemistry, IIT Madras for instrumentation facilities.
Conflicts of interest
Scheme 5 Plausible mechanism.
There are no conflicts to declare.
Notes and references
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of the desired product 2a was obtained (Scheme 4h).
A plausible reaction mechanism for the synthesis of 3-hydroxy-
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In conclusion, an efficient copper-catalyzed domino proto-
col has been developed for the synthesis of 2-thioaroyl-3-
hydroxybenzothiophene from saturated ketones via radical
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