Cascade Synthesis of Benzothieno[3,2- b]indoles under Oxidative Conditions Mediated by CuBr and tert-Butyl Hydroperoxide

Article abstract of DOI:10.1021/acs.orglett.8b02614

A series of biologically relevant compounds of benzothieno[3,2-b]indole derivatives were conveniently synthesized from reactions of N-protected 2-((2-bromophenyl)ethynyl)anilines and potassium ethylxanthate, mediated by cuprous bromide/tert-butyl hydroper

Full text of DOI:10.1021/acs.orglett.8b02614

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cascade Synthesis of Benzothieno[3,2‑b]indoles under Oxidative
Conditions Mediated by CuBr and tert-Butyl Hydroperoxide
Xiaoyuan Zhao,† Qiao Li,† Jun Xu,† Donghua Wang,† Daisy Zhang-Negrerie,† and Yunfei Du*,†,‡
†Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin 300072, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
S
* Supporting Information
ABSTRACT: A series of biologically relevant compounds of
benzothieno[3,2-b]indole derivatives were conveniently synthe-
sized from reactions of N-protected 2-((2-bromophenyl)ethynyl)-
anilines and potassium ethylxanthate, mediated by cuprous
bromide/tert-butyl hydroperoxide. The method features the
construction of the pyrrole and thiophene rings in a cascade
sequence with the pyrrole ring being formed prior to the
thiophene ring via a possible reactive Cu(III)-pyrrole inter-
mediate.
enzothieno[3,2-b]indoles are important objectives for
synthesis. Their skeleton has not only been adopted in
the engineering of pharmaceutical agents exhibiting useful
biological activities but also in polymeric materials possessing
promising electronic properties.1−4 Listed in Figure 1 are a few
quantitate amyloid deposits in human diseases, including
Alzheimer’s disease and Down Syndrome.4
B
Owing to the diverse therapeutic applications of compounds
comprising the benzothieno[3,2-b]indole structural element,
much effort has been directed at the problem of constructing
this special type of heterocyclic skeleton. Existing methods
mainly consist of two fundamentally distinct approaches: in
one approach, the indole nucleus is annulated onto substrates
already containing the benzothiophene moiety;5−7 in the
other, the benzothiophene ring is built onto a preexisting
indole derivative.8 As illustrated in Scheme 1, method 1 starts
from substituted benzothiophenes and forms the correspond-
ing benzothieno[3,2-b]indoles via a Pd-catalyzed intramolec-
ular cyclization of diarylamines (Scheme 1, method a),5a,b or
by subjecting N-containing 2-phenybenzo[b]thiophenes to
PPh3,6a Cu,6b,c or microwave6d (Scheme 1, method b), or
through coupling reactions between 3-N-aryl benzothiophene
and dibromobenzenes through Pd-mediated C−N and C−C
bond formations (Scheme 1, method c).7 Method 2, however,
uses substituted indole substrates as the starting material and
achieves the synthesis of the desired benzothieno[3,2-b]indoles
over the course of a tandem cross-coupling reaction of K2S and
2-(2-iodophenyl)-1H-indoles mediated by CuI and I2 and
involves a sulfur insertion, as well as C−H and C−I bond
cleavages.8 Herein, we describe a third strategy, not resembling
either of the mainstream approaches, featuring a spontaneous
construction of both N- and S-heterocycles in a copper-
promoted transformation of a readily available diaryl alkyne.
The discovery of this method was a result of our ongoing
effort to directly introduce sulfur into organic compounds by
the action of readily accessible sulfur reagents and without
Figure 1. Representative benzothieno[3,2-b]indole compounds of
application values.
examples of such compounds that bear the benzothieno[3,2-
b]indole structure. BTCN, an unsymmetrically substituted
dicyanovinyl heterotetracene compound with extra low-lying
LUMO (lowest unoccupied molecular orbital), can be adopted
in the design of n-type or bipolar organic semiconductors as
organic electronics.1 Compound A, which displays high
binding affinities to ERα and ERβ proteins, has been used to
mimic the effects of estrogen and can thus be useful in
medicinal chemistry for developing new treatments of
menopausal symptoms and postmenopausal osteoporosis.2
Compound B has potential to be a surrogate for zoxazolamine,
which causes paralysis in young rats by stimulating zoxazol-
amine hydroxylase synthesis.3 Compound C possesses
amyloid-binding properties and may be used to detect and
Received: August 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02614
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Mainstream Strategies for the Synthesis of
Benzothieno[3,2-b]indoles and the Method Reported
Herein
Table 1. Reaction Conditions Study
b
temp ( yield
entry
1
oxidant
catalyst
none
S reagent degC)
(%)
Cu(OTf)2
KSC(S)
80
80
80
80
80
80
80
80
80
80
80
80
NR
OEt
2
Cu(CF3COO)2
CuBr
none
KSC(S)
OEt
KSC(S)
OEt
KSC(S)
OEt
17
11
31
35
50
52
78
65
ND
24
40
3
none
4
TBHP
Cu(OTf)2
5
TBHP
Cu(CF3COO)2 KSC(S)
OEt
CuI
6
TBHP
KSC(S)
OEt
KSC(S)
OEt
KSC(S)
OEt
KSC(S)
OEt
KSC(S)
OEt
KSC(S)
OEt
KSC(S)
OEt
7
TBHP
CuSCN
CuBr
CuBr
CuBr
CuBr
CuBr
8
TBHP
9
PIDA
10
11
12
PIFA
m-CPBA
DTBP
13
14
15
16
17
TBHP
TBHP
TBHP
TBHP
TBHP
CuBr
CuBr
CuBr
CuBr
CuBr
KSCN
S8
K2S
KSAc
KSC(S)
OEt
KSC(S)
OEt
KSC(S)
OEt
KSC(S)
OEt
80
80
80
80
rt
NR
ND
ND
18
recourse to stepwise functionalizations of sulfur-containing
substrates.9 Sulfur-containing compounds, in addition to their
wide applications in biology,10 material science,11 and food
chemistry,12 are key constituents of proteins and, therefore,
essential to living organisms. Research efforts aimed at
developing new synthetic methods to incorporate sulfur
atoms into organic compounds are easily justified, especially
nowadays with all of the advances in genetic engineering and
material science.13
NR
18
19
20
TBHP
TBHP
TBHP
CuBr
CuBr
CuBr
40
60
trace
70
100
56
1,2-Diarylethynes have been widely applied for cascaded
synthesis of heterocycles.14 Thus, our study commenced with
the reaction of N-(2-((2-bromophenyl)ethynyl)phenyl)-4-
methylbenzenesulfonamide (1a)15 with potassium ethylxan-
thate in the presence of Cu(OTf)2, in which the Cu(II) was
thought to initially act as an oxidant and, subsequently, in the
form of Cu(I), as a catalyst. However, to our disappointment,
no reaction occurred when the reaction mixture was conducted
at 80 °C for 24 h (Table 1, entry 1). To our delight, however,
when Cu(CF3COO)2 was employed, the desired benzothieno-
[3,2-b]indole, 2a, was formed in 17% yield (Table 1, entry
2).16 The yield of 2a decreased when CuBr was employed
(Table 1, entry 3). At this stage, we sought an alternative and
more effective oxidative system composed of organic oxidants
and copper catalysts. Cu(OTf)2, Cu(CF3COO)2, CuI,
CuSCN, and CuBr were tested17 with TBHP as the oxidant.
Our results showed that CuBr gave the best yield of 2a (Table
1, entries 4−8). With CuBr as the catalyst, several oxidants,
such as phenyliodine(III) diacetate (PIDA), phenyliodine(III)
bis(trifluoroacetate) (PIFA), m-chloroperbenzoic acid (m-
CPBA), and 2,6-di-tert-butylpyridine (DTBP) were screened;
however, none of these reagents outcompeted TBHP (Table 1,
entries 9−11). When potassium ethylxanthate was replaced by
KSCN, S8, K2S, or KSAc, no product formation or low yields
were observed (Table 1, entries 12−16). Temperature-
a
Reaction conditions: 1a (1 mmol), oxidant (3 equiv), catalyst (0.2
equiv) and S reagent (2 equiv) in DMSO (4 mL). Isolated yield.
b
optimization studies identified the ideal temperature to be 80
°C (Table1, entries 17−20). On the basis of all of the
screening results, the optimal reaction conditions were
concluded to be 1 mmol of substrate, 3 equiv of THBP, 0.2
equiv of CuBr, and 2 equiv KSC(S)OEt with DMSO as solvent
at 80 °C.
With the optimal reaction conditions established, we
investigated the substituent scope of this reaction. Substrates
bearing various R1 substituents (Me, F, Cl, Br) were all
converted to the corresponding product in good yields (Table
2, 2a−e) except for 2b, the only substrate carrying an electron-
donating group among the series, which was formed in a
noticeably lower yield in comparison to the other four
products. Concerning R2, both the electron-donating (Me,
OMe) and electron-withdrawing (F, Cl, Br, CF3) groups were
well tolerated, with the corresponding products in most cases
all obtained in high yields (2f−k). Lastly, the impact of the
substituent on the nitrogen atom (R3) was also evaluated,
which involved the use of substrates containing methanesul-
fonyl (Ms), benzenesulfonyl, and p-OMe, p-Cl-, and p-Br-
B
DOI: 10.1021/acs.orglett.8b02614
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
bond in the reaction of study was not initiated by the sulfur
moiety, but the nitrogen moiety. A second control experiment,
which investigated the reaction of 1a with CuBr in DMSO at
80 °C for 20 min, revealed that Int-2 was formed in 98% yield
(Scheme 2, (ii)), providing further support for the postulate
that the nitrogen atom initiates the addition to the alkyne.
Furthermore, reacting Int-1 with potassium ethylxanthate
under the standard conditions led to no benzothieno[3,2-
b]indole product (Scheme 2, iii), suggesting that formation of
the pyrrole ring precedes the formation of the benzothiophene
ring. In addition, no benzothieno[3,2-b]indole product was
formed when Int-2 was exposed to potassium ethylxanthate
under the standard conditions (Scheme 2, iv), implying that
intermediate Int-2 is not on the pathway between the diaryl
alkyne starting materials and the bis-heterocyclic products in
this process. Lastly, inclusion of TEMPO in the reaction
mixture did not affect the outcome of the reaction in any
significant way (Scheme 2, v), an observation that rules out a
radical mechanism for the double annulation process
developed in this study.
Table 2. Scope of Substituents
Based on the above results as well as literature reports,9,18 we
propose a mechanistic pathway for this novel cascade process
for synthesizing benzothieno[3,2-b]indoles from diaryl alkynes.
As depicted in Scheme 3, in the presence of copper(I)
Scheme 3. Proposed Reaction Mechanism
a
Reaction conditions: 1 (1 mmol), TBHP (3 equiv), CuBr (0.2
equiv) and KSC(S)OEt (2 equiv) in DMSO (4 mL) at 80 °C.
b
Isolated yield.
substituted benzenesulfonyl as group R3. All substrates
afforded the corresponding benzothieno[3,2-b]indole products
in satisfactory yields (Table 2, 2l−p). However, when the Ts
group in 1a was replaced with a benzyl or methyl group, the
corresponding substrates failed to provide the desired cyclized
products in each case (not shown).
A series of control experiments were carried out to gain
insights on the reaction mechanism. When diaryalkyne 3 was
subjected to the standard reaction conditions, no formation of
2-phenylthiophene product was observed (Scheme 2, (i)),
indicating that the addition across the carbon−carbon triple
Scheme 2. Control Experiments for Mechanistic Studies
bromide, 1a undergoes an intramolecular, 5-endo-dig nucleo-
philic addition of the nitrogen atom to the proximate alkyne,
leading to the formation of an indole−copper(I) complex,
intermediate A. In the presence of TBHP and potassium
ethylxanthate, A may be oxidized to copper(III) intermediate
B, which could subsequently undergo reductive elimination of
CuBr to give the indole intermediate C.19 Next, the reaction of
intermediate C with the ethylxanthate anion could give rise to
intermediate D, with the release of bis(ethoxythiocarbonyl)-
sulfide.20 The reaction of intermediate D with CuBr, for the
second time, could then generate Cu(III)complex E via
oxidative addition and a simple ligand substitution. From
intermediate E, the final carbon−sulfur bond formation would
occur in the course of a final reductive elimination with
regeneration of cuprous bromide; this final transformation
would complete the construction of benzothieno[3,2-b]indole
2a.
It is worth mentioning that the p-toluenesulfonyl (Ts) group
in the products can be easily removed under basic conditions
to afford the unprotected benzothieno[3,2-b]indole, another
series of biologically significant compounds. As described in
C
DOI: 10.1021/acs.orglett.8b02614
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4, compound 1q could be converted to the biological
interesting compound B in a straightforward two-step reaction,
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02614.
Experimental procedures, data of compounds character-
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Accession Codes
CCDC 1851291 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*Tel: +86-22-27406121. E-mail: duyunfeier@tju.edu.cn.
ORCID
Yunfei Du: 0000-0002-0213-2854
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the National Natural Science Foundation of
China (No. 21472136) and the Tianjin Research Program of
Application Foundation and Advanced Technology (No.
15JCZDJC32900) for financial support. We also thank Prof.
Erik J. Sorensen (Princeton University and Tianjin University)
for the helpful suggestions.
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product 2a. However, there is no reported synthetic route to access
intermediate C, and our several attempted approaches also proved to
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E
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