Solvent-controlled highly regio-selective thieno[2,3-: B] indole formation under metal-free conditions

Article abstract of DOI:10.1039/c7gc02818k

An efficient three-component thieno[2,3-b]indole formation method was developed under metal-free conditions. The cascade cyclization was enabled by acid-promoted annulation of indoles, ketones and sulfur powder, which enabled modular synthesis of 2-substituted and 3-substituted thieno[2,3-b]indoles with excellent regioselectivity and broad functional group tolerance. DMF solvent played an important role in the regioselectivity control.

Full text of DOI:10.1039/c7gc02818k

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Solvent-controlled highly regio-selective thieno[2,3-b]indole
formation under metal-free conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Penghui Ni,a Bin Li,a Huawen Huang,a Fuhong Xiaoa* and GuoꢀJun Denga*
DOI: 10.1039/x0xx00000x
www.rsc.org/chemcomm
An efficient three-component thieno[2,3-b]indole formation
has been developed under metal-free conditions. The
cascade cyclization was enabled by the acid-promoted
annulation of indoles, ketones and sulfur powder, which
provided modular synthesis of 2-substituted and 3-
substituted
thieno[2,3-
b
]indoles
with
excellent
regioselectivity and broad functional group tolerance. DMF
solvent played an important role in the regioselectivity
control.
Thienoindole derivatives are important fused heterocycles because
they have potential biological activities with applications in
agricultural chemistry and pharmaceutical industries.1 Such as
thienoindolin (Figure 1, A) isolated from the culture broth of
Streptomyces albogriseolus (MJ 286ꢀ76F7) displays both growth
promoting and inhibiting activities in rice seedlings.2 Thienoindoles
are also widely used in organic electronics as novel
electroluminescence materials for designing lightꢀemitting devices.
For example, thieno[2,3ꢀb]indole dyes (Figure 1, BꢀD) having a Dꢀ
π−A (DonorꢀpꢀbridgeꢀAcceptor) structure, which have been
evaluated in DSSCs and OSCs.3 Accordingly, the development of
efficient methods for the synthesis of thieno[2,3ꢀb]indoles has
attracted considerable interest. The current reported synthetic
methods are mainly based on using functionalized indoles,4 furans,5
isatins6 and thiophenes,7 which require several steps to prepare.
Therefore, the development of oneꢀpot thieno[2,3ꢀb]indoles
fromation from readily available starting materials under simple
conditions is highly desirable.
Figure 1 Valuable thieno[2,3ꢀb]indoleꢀcontaining molecules.
high efficiency and chemical selectivity.9 However, in view of the
concerns about the influences of trace metals on human consumption
drugs and the efficiency of organic electronic devices, the
development of envionmentally benign synthetic methods with high
selectivity under metalꢀfree conditions is critical in modern organic
synthesis, especially in the process of multicomponent reactions
which selectivity control is always very challenging.
Multicomponent reactions (MCRs) constitutes one of the most
efficient tools in modern synthetic organic chemistry. These
reactions present a straightforward and atomꢀeconomic synthetic
approach that offers highlighted advantages over conventional multiꢀ
step reaction sequences.8 The transitionꢀmetalꢀcatalyzed MCRs is
one of the most popular research topics in organic chemistry since its
a
Key Laboratory for Green Organic Synthesis and Application of Hunan Province, Key
Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education,
College of Chemistry, Xiangtan University, Xiangtan 411105, China. E-mail:
fhxiao@xtu.edu.cn; gjdeng@xtu.edu.cn
Scheme 1 New strategy for the synthesis of benzothieno[2,3ꢀ.
b]indole.
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Elemental sulfur is widely distribute in nature, nontoxic and stable increased when the amount of HOAc increased (entries 10ꢀ11). The
under normal conditions. Therefore, direct use of elemental sulfur as ratio of 1ꢀmethylꢀ1Hꢀindole (1a) to acetophenone (2a) also affected
the sulfur source for the construction of sulfurꢀcontaining the reaction yield profoundly and the reaction yield could be
heterocycles is a direct, simple, and atomꢀeconomical approach.10 improved to 83% when the ratio of 1a: 2a was changed to 1: 2 (entry
Various methods have been developed to use elemental sulfur for the 11).
synthesis of sulfurꢀcontaining heterocycles.11 Very recently, we
With the optimized conditions established, the scope and
reported
various
methods
for
benzothieno[2,3ꢀb]indoles,
generality of the cyclization reaction were probed (Table 2).
Various substituted acetophenones were examined under the
optimized reaction conditions, as summarized in Table 2. The
model reaction of 1a and 2a in the presence of sulfur powder
afforded 3aa in 81% isolated yield. Similar yields were
obtained for substrates with various functional groups (both
electronꢀdonating and electronꢀwithdrawing groups) in the para
position of the phenyl ring (3abꢀ3ai). The desired product 3ad
was obtained in 83 % yield when a methoxy substituent was
present. Halogen substituents on the benzene ring, including F,
phenothiazines, 1,2,4ꢀthiadiazoles, and 2ꢀarylbenzothiazoles
formation from elemental sulfur base on multicomponent reactions.12
Our previous research showed that palladium catalyst is necessary
for the threeꢀcomponent benzothieno[2,3ꢀb]indole formation
(Scheme 1). As our continuing efforts on using readily available
elemental sulfur to selective construct sulfurꢀcontaining heterocycles,
herein we describe
a general multicomponent reaction for
thieno[2,3ꢀb]indole formation from readily available indoles, ketones
and sulfur powder. The reaction could be realized under metalꢀfree
conditions and the regioselectivity was well controlled by solvent
and additive.
Cl, Br and I, were compatible for this kind of cyclization (3ae
3ah). The steric effect of the substituent was obvious since 1ꢀ
(3ꢀbromophenyl)ethanone (2n) and 1ꢀ( ꢀtolyl)ethanone (2q
ꢀ
Table 1 Screening the reaction conditionsa
o
)
gave 3an and 3aq in only 47% and 37% yield, respectively.
Acetophenones 2t, 2u and 2v with two functional groups were
also suitable substrates and gave the desired products in good
yields (3at
used, the desired product 3aw was observed, albeit in 31%
yield. To our surprise, 2,8ꢀdimethylꢀ3ꢀphenylꢀ8 ꢀthieno[2,3ꢀ
]indole 3ax was obtained in 91% yield when propiophenone
ꢀ3av). When 1ꢀ(naphthalenꢀ2ꢀyl)ethanone (2w) was
H
b
(
(
2x) was used as the substrate. However, 1,2ꢀdiphenylethanone
2y) was proved to be a less efficient coupling partner, which
resulted in the desired product 3ay in only 33% yield.
Table 2 Substrate scope with respect to the ketones a
R
O
HI (50 mol%)
L-phenylalanine
R1
R1
+
S8 +
air, 130 oC, 4 h
N
R
S
N
1a
2
3
R = H, 3aa, 81%
R = CH3, 3ab, 82%
R = i-Bu, 3ac, 61%
R = OCH3, 3ad, 83%
R = F, 3ae, 65%
R = Cl, 3af, 63%
R = Br, 3ag, 61%
R = I, 3ah, 70%
R = 3-CH3, 3aj, 83%
3ak, 74%
R
R
R = 3-OCH3,
R = 3-F, 3al, 81%
3am, 71%
a Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), S (1.0 mmol), 130 oC, 4
h, under air. b GC yield based on 2a. c LꢀPhenylalanine (0.5 mmol). d 150 oC,
16 h. e 1a (0.2 mmol), 2a (0.4 mmol), S (1.0 mmol), GC yield based on 1a.
R = 3-Cl,
R = 3-Br, 3an, 47%
3ao
R = 3-CF3, , 75%
R = 3-NO2, 3ap, 65%
R = 2-CH3, 3aq, 37%
S
N
S
N
We commenced our investigation using 1ꢀmethylꢀ1Hꢀindole (1a),
acetophenone (2a) and sulfur powder as the model system (Table 1).
To our delight, the desired product 3aa was generated exclusively in
chlorobenzene at 130 oC when 50 mol% HI was used (entry 1). The
yield of 3aa could be slightly increased when other solvents such as
PhCF3, anisole and 1,4ꢀdioxane were used (entries 2ꢀ4). The reaction
yield could be slightly increased to 43% when a mixture of PhCF3
and 1,4ꢀdioxane were used (entry 5). The yield of 3aa could be
further improved to 80% when Lꢀphenylalanine (1 equiv.) was added
to the reaction (entry 6). Interestingly, a small amount of 4aa was
observed when DMF was used as the solvent (entry 7). The reaction
yield of 4aa and the ratio of 4aa:3aa both could be improved when
the reaction temperature was increased to 150 oC (entry 8). Further
optimization of the reaction conditions showed that the use of HOAc
was very effective (64% yield, 4aa:3aa = 60:1, entry 9). Delightedly,
the reaction yield and regioselectivity of the product 4aa both
R =CN, 3ai, 66%
R = 2-F,
3ar, 65%
R = 2-Cl, 3as, 63%
R
R
R
S
N
S
N
S
S
N
N
R1 = CH3, R = H, 3ax, 91%
R1 = Ph, R = H, 3ay, 33%
R = OCH3, 3at, 78%
R = Cl, 3au, 52%
3av, 61%
3aw, 31%
a
Conditions: 1a (0.6 mmol),
mol%), ꢀphenylalanine (1 equiv.), CF3Ph:1,4ꢀdioxane = 2:3 (1.0 mL),
130 oC, 4 h, under air atmosphere. Isolated yield based on 2a
2 (0.5 mmol), S (1.0 mmol), HI (50
L
.
The influence of the substituents on the indole moiety was
also evaluated and the results are presented in Table 3. The
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substituent position significantly affected the reaction yield and Table 4 Substrate scope with respect to the ketonesa
the reaction yields decreased dramatically when functional
groups were presented at the Cꢀ4 position in indole (3ba and
3ca). Better yields were obtained if the functional groups, such
as methyl (1d, 1i and 1l), methoxy (1e), fluoro (1f and 1j),
chloro (1g) and bromo (1h) were located at Cꢀ5, Cꢀ6 and Cꢀ7
position. When free NHꢀindole (1m) was used as the substrate
under the same conditions, 3ma was obtained in 57% yield. It
is noteworthy that other
Nꢀalkylindoles (1n, 1o and 1p) also
suitable coupling partners to give the corresponding products in
good yields.
Table 3 Substrate scope with respect to the indolesa
a
Reaction conditions: 1a (0.2 mmol),
2
(0.4 mmol), S (1.0 mmol),
HOAc (0.1 mL), DMF (0.3 mL), 150 C, 16 h, under air atmosphere.
Isolated yield based on 1a
o
.
To further examine the scope and limitations of the threeꢀ
component regioselective cyclization, we tested various indoles
for this kind of reaction (Table 5). Indoles bearing various
substituents could smoothly couple with acetophenone (2a).
When 5ꢀmethylindole was employed, the corresponding
product 4ba was obtained in 83% yield. Slightly lower yields
were obtained when the methyl group was located at Cꢀ6 and
Cꢀ7 position in the indole ring (4ha and 4ja). Indoles with
halogens were all accommodated well and furnished the desired
a
Conditions: 1 (0.6 mmol), 2a (0.5 mmol), S (1.0 mmol), HI (50 mol%), Lꢀ
phenylalanine (1 equiv.), CF3Ph:1,4ꢀdioxane = 2:3 (1.0 mL), 130 oC, 4 h,
under air atmosphere. Isolated yield based on 2a.
We next turned our attention to the development of the
corresponding regioselective cyclization, which the substituent was
located at Cꢀ2 position in the benzothieno[2,3ꢀb]indole ring. When
the reactions were performed in DMF, the regioselectivity of the
cyclization process was switched (Table S5ꢀS7). To further expand
the scope of this direct cyclization reaction, we next sought to
expand the scope of indoles and various substituted ketones, with the
Table 5 Substrate scope with respect to the indoles a
results shown in Table
4 and Table 5. Generally, aromatic
acetophenones smoothly reacted to give the corresponding
thieno[2,3ꢀb]indoles in moderate to good yields (Table 4, 4abꢀ4au,
41ꢀ85%), regardless of the functional groups at the paraꢀ, metaꢀ, or
orthoꢀposition. A large range of functional groups on the benzene
ring such as alkyl (2bꢀ2d, 2m, 2j and 2s), methoxy (2e, 2n and 2t),
fluoro (2f, 2o and 2k), chloro (2g, 2p and 2u), bromo (2h and 2q),
iodo (2i), and trifluoromethyl (2r) were all tolerated well under the
given reaction conditions. To our delight, 1ꢀ(naphthalenꢀ1ꢀ
yl)ethanone (2v) and 1ꢀ(naphthalenꢀ2ꢀyl)ꢀethanone (2w) also reacted
well to give the corresponding products 4av and 4aw in 51 and 47%
yield, respectively. Besides aromatic ketones, aliphatic ketones such
as 3ꢀmethylbutanꢀ2ꢀone (2x) and 1ꢀadamantyl methyl ketone (2y)
also could couple with indole and sulfur to give the desired product
in 37 and 43% yields, respectively.
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), S (1.0 mmol), HOAc
o
(0.1 mL), DMF (0.3 mL), 150 C, 16 h, under air atmosphere. Isolated yield
based on 1a.
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DMF and sulfur powder (WillgerodtꢀKindler reaction).14
Intermediate 4a can be resonated to intermediate A. Then, 1ꢀmethylꢀ
indole (1a) reacts with A to afford an intermediate B, which can be
further converted into the desired product 4aa under acidic
conditions.15 Solvent DMF plays an important role for the
regioselectivity control for this kind cyclization.
products in good yields. Notably, unprotected 1Hꢀindole (1k)
participated well in this protocol to provide the corresponding
product 4ka in 75% yield. We further tested this method with
N
ꢀethylindole (1l) and 1ꢀisopropylꢀ1
reaction proceeded smoothly to provide the desired products in
good yields (4la 4ma
Hꢀindole (1m), and the
ꢀ
)
The benzothieno[2,3ꢀb]indole product 4aa was obtained in 71%
yield in a gramꢀscale reaction. We further evaluated the oxidative
transformation of 4aa. When 4aa was treated with mꢀCPBA in
CHCl3 under an air atmosphere, the oxidized product 8ꢀmethylꢀ2ꢀ
phenylꢀ8Hꢀthieno[2,3ꢀb]indole 1,1ꢀdioxide (4aa’) was obtained in
87% yield (Scheme 2).
Ph
HI (50 mol%)
O
L-phenylalanine (1eq.)
+
Ph
air, 130 oC, 0.5 h
N
N
(a)
(b)
1a
0.6 mmol
2a
0.5 mmol
3a
, 21%
Ph
HI (50 mol%)
S (1.5 eq.)
m-CPBA (5 eq.)
3a
S
S
S
N
air, r.t., CHCl3
air, 130 oC, 4 h
O
N
N
O
3aa
, 95%
4aa, 71%, 3.73 g
(20 mmol scale)
HOAc (0.1 mL)
S8 (5.0 eq.)
4aa', 87%
O
S
Ph
Ph
(c)
(d)
DMF, air, 150 o
C
N
Scheme 2 Derivation of resultant benzothieno[2,3ꢀb]indole.
4a
, 63%
2a
To understand the mechanism of the reaction, we performed
several control experiments (Scheme 3). When 1a reacted with 2a in
the absence of sulfur powder, an intermediate 3a was obtained in
21% yield after 0.5 h (Scheme 3, a). The intermediate 3a could
convert into the target benzothiophene 3aa with almost full
conversation (Scheme 3, b). This result indicates that the reaction
may proceed through [4+1] type synthetic route to 3ꢀphenyl
thieno[2,3ꢀb]indole.13 Treatment of 2a with sulfur powder under
standard conditions without 1ꢀmethylꢀindole (1a) gave the N,Nꢀ
dimethylꢀ2ꢀphenylethanethioamide (4a) in 63% yield (Scheme 3, c).
Trace amount of desired product was obtained when 1ꢀmethylꢀ3ꢀ
styrylꢀ1Hꢀindole (5a) was treated with sulfur powder (Scheme 3, d).
This observation implies that procedure of the product 4aa is
different to the product 3aa pathway. Further treatment of 4a with 1ꢀ
methylꢀindole (1a) afforded the desired product 4aa in 49% yield
(Scheme 3, e). The product 3aa could be gained in 81% yield when
using 2ꢀphenylthiirane (6a) as the substrate with 1ꢀmethylꢀindole (1a)
(Scheme 3, f).
Ph
HOAc (0.1 mL)
S8 (5.0 eq.)
Ph
S
DMF, air, 150 o
C
N
N
4aa
, trace
5a
HOAc (0.1 mL)
S8 (5.0 eq.)
Ph
1a
4a
+
S
(e)
(f)
DMF, air, 150 o
C
N
0.2 mmol
0.3 mmol
4aa
, 49%
HOAc (0.1 mL)
S8 (1.0 mmol)
Ph
S
1a
+
Ph
S
DMF, air, 150 o
C
N
6a
4aa
, 81%
0.2 mmol
0.3 mmol
Scheme 3 Control experiments under various conditions.
Figure 2 Xꢀray structure of 3ah and 4aa.
Scheme 4 Proposed mechanism of 4aa.
According to the above control experiments and related references,
a proposed mechanism for 4aa is illustrated in Scheme 4. N,Nꢀ
In summary, we have developed a simple, efficient and
solventꢀcontrolled regioꢀselective method for preparing
dimethylꢀ2ꢀphenylethanethioamide (4a) is generated from 2a with thieno[2,3ꢀ
b
]indole derivatives from indoles, ketones, and
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sulfur powder under metalꢀfree conditions. Cheap and readily 10
available sulfur powder was acted as the sulfur source to
selectively assemble the thienoꢀfused indole derivatives.
Functional groups such as halogen, trifluoromethyl and cyano
were well tolerated under the optimized reaction conditions.
This threeꢀcomponent approach affords a facile route for the
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rapid synthesis of thieno[2,3ꢀb]indoles. The detailed
mechanism and synthetic application of this reaction are
currently under investigation.
11
ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (21572194, 21502160, 21372187), the
Collaborative Innovation Center of New Chemical Technologies for
Environmental Benignity and Efficient Resource Utilization, the
Hunan Provincial Innovative Foundation for Postgraduate
(CX2017B301), Hunan Provincial Natural Science Foundation of
China (16JJ3112), the Scientific Research Fund of Hunan Provincial
Education Department (YB2016B024).
12
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DOI: 10.1039/C7GC02818K
Solvent-controlled
highly
regio-selective
thieno[2,3-b]indole
formation under metal-free conditions
Penghui Ni,a Bin Li,a Huawen Huang,a Fuhong Xiaoa* and Guo-Jun Denga*
Thieno[2,3-b]indole derivatives were selectively prepared from indoles, ketones and
sulfur powder under metal-free conditions.