A cascade deprotonation/intramolecular aldol reaction of α-carbonyl sulfonium ylides with 2-mercaptoindole-3-carbaldehydes and 2-mercaptobenzaldehydes to access thieno[2,3-b]indoles and benzothiophenes

Article abstract of DOI:10.1039/d1ob00349f

The first catalyst-free cascade deprotonation/intramolecular aldol reaction of α-carbonyl sulfonium ylides with 2-mercaptoindole-3-carbaldehydes and 2-mercaptobenzaldehydes was developed. A series of thieno[2,3-b]indoles and benzothiophenes were smoothly obtained in high to excellent yields. The salient features of the protocol include catalyst-free conditions, an environment-friendly solvent, broad substrate scope, and large-scale synthesis.

Full text of DOI:10.1039/d1ob00349f

Organic &
Biomolecular Chemistry
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PAPER
A cascade deprotonation/intramolecular aldol
reaction of α-carbonyl sulfonium ylides with
2-mercaptoindole-3-carbaldehydes and
2-mercaptobenzaldehydes to access thieno[2,3-b]
indoles and benzothiophenes†
Cite this: Org. Biomol. Chem., 2021,
19, 3678
b
Lei Yang,a,b,c Shun Zhou,a,b,c Jian-Qiang Zhao, b Yong You,
Zhen-Hua Wang, b Ming-Qiang Zhoua and Wei-Cheng Yuan
*
b
The first catalyst-free cascade deprotonation/intramolecular aldol reaction of α-carbonyl sulfonium ylides
with 2-mercaptoindole-3-carbaldehydes and 2-mercaptobenzaldehydes was developed. A series of
thieno[2,3-b]indoles and benzothiophenes were smoothly obtained in high to excellent yields. The salient
features of the protocol include catalyst-free conditions, an environment-friendly solvent, broad substrate
scope, and large-scale synthesis.
Received 24th February 2021,
Accepted 23rd March 2021
DOI: 10.1039/d1ob00349f
rsc.li/obc
heterocyclic compounds.5 In this scenario, the vast majority of
the methods developed to date proceed through a common
Introduction
Thieno[2,3-b]indoles are important fused heterocycles that are sequential addition–cyclization–elimination process to access
widely found in numerous natural products, biologically active diverse cyclic compounds, mainly including epoxides, aziri-
agents and pharmaceutical molecules,1 and they show poten- dines, cyclopropanes, and five- and six-membered rings
tial applications in organic optoelectronic materials (Fig. 1).2 (Scheme 1a).5 Yet, only two reports related to the application
The development of efficient methods for the preparation of of α-carbonyl sulfonium ylides for the unconventional X–H
these compounds has attracted significant attention in organic (X = C, N, O, S) bond insertion have been documented.6–8 In
synthesis. Among them, the traditional methods for the syn- 1999, Müller and coworkers reported only one case concerning
thesis of thieno[2,3-b]indoles are mainly based on multi-step Rh-catalyzed intramolecular C–H bond insertion of α-carbonyl
reaction approaches using functionalized heterocyclic starting sulfonium ylides (Scheme 1b).7 Recently, an elegant work
materials, such as thiophenes, indoles, isatins, etc.3 involving chiral phosphoric acid catalyzed N–H bond insertion
Alternatively, there are also reports focusing on the use of of α-carbonyl sulfonium ylides was reported by Sun and Li
elemental sulfur as the sulfur source via a cascade reaction.4 et al. (Scheme 1c).8 It is conceivable that there is great research
Considering the high value of thieno[2,3-b]indole compounds, potential in the development of a creative methodology for
exploring facile methods for readily accessing the structural organic synthesis by taking advantage of the reaction of
skeletons is still in high demand.
α-carbonyl sulfonium ylides with X–H bonds.
α-Carbonyl sulfonium ylides have been recognized as versa-
Considering the relative basicity of α-carbonyl sulfonium
tile synthons in organic synthesis. A great number of reactions ylides and the relative acidity of thiophenols, we envisioned
involving α-carbonyl sulfonium ylides have been reported for that the deprotonation of the –SH group of thiophenols by
the synthesis of various kinds of important carbocyclic and α-carbonyl sulfonium ylides would result in a type of di-sulfur
ion pair (Scheme 1, bottom). Then, the presence of the
aNational Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China
bInstitute for Advanced Study, Chengdu University, Chengdu 610106, China.
E-mail: yuanwc@cioc.ac.cn
cUniversity of Chinese Academy of Sciences, Beijing, 100049, China
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, spectral data of new compounds, and crystallographic data. CCDC
2048940. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d1ob00349f
Fig. 1 Selected valuable molecules of thieno[2,3-b]indoles.
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Table 1 Optimization of reaction conditionsa
Entry
Solvent
t (h)
Yieldb (%)
1c
2
3
4
5
Toluene
Toluene
CH2Cl2
MTBE
EtOAc
CH3CN
EtOH
3
6
3
5
5
5
5
5
5
89
90
97
90
90
97
97
94
97
6
7
8d
9e
EtOH
EtOH
a Unless otherwise noted, the reactions were carried out with 1a
(0.1 mmol) and 2a (0.15 mmol) in 1.0 mL of solvent under catalyst-free
conditions at room temperature for the specified reaction time.
b Isolated yields. c 20 mol% Et3N was used. d Performed at 50 °C. e The
ratio of 1a : 2a = 1.0 : 1.2. MTBE = methyl tert-butyl ether.
from an environment-friendly point of view, we selected EtOH
as the best solvent. Afterwards, increasing the temperature to
50 °C in EtOH led to a slightly reduced yield for 3a (entry 8).
The yield of 3a could remain constant even upon slightly
decreasing the ratio of 1a : 2a from 1.0 : 1.5 to 1.0 : 1.2 (entry 9).
As a result, the conditions used in entry 9 were selected as the
optimal reaction conditions for further study.
Scheme 1 Profile of reaction pathways involving α-carbonyl sulfonium
ylides and the reaction design in this work.
With the optimal conditions established, we further
explored the substrate scope of the reaction between 2-mercap-
toindole-3-carbaldehydes and α-carbonyl sulfonium ylides
(Scheme 2). Each reaction could proceed to completion within
5 h under the standard conditions. The 2-mercaptoindole-3-
carbaldehydes bearing an electron-withdrawing substituent on
the indole unit were suitable substrates for reacting with 2a,
furnishing the corresponding products 3b–e in 94–99% yields.
Similarly, the substrates bearing an electron-donating group
also could give the expected products in excellent yields (pro-
ducts 3f and 3g). On the other hand, with regard to the
α-carbonyl sulfonium ylide substrates, different substituents
(Me–, MeO–, Cl–, Br–, NO2–) incorporated on the phenyl ring,
regardless of their electronic properties and substitution
pattern, could be well tolerated in the reaction with 1a to gene-
rate thieno[2,3-b]indole derivatives 3h–o in high to excellent
yields. In addition, the β-naphthyl substrate was also suitable
strongly nucleophilic thiolate and good leaving group dimethyl
sulfide in the ion pairs would readily lead to thioether com-
pounds via a substitution–elimination pathway. Then, if a suit-
able electrophilic functional group was present in the struc-
ture, an intramolecular nucleophilic addition would be poss-
ible for constructing sulfur-containing heterocycles. Along this
line and in continuation of our studies on sulfonium ylide
chemistry,9 herein we report the first cascade deprotonation/
intramolecular aldol reaction of α-carbonyl sulfonium ylides
with 2-mercaptoindole-3-carbaldehydes and 2-mercaptobenzal-
dehydes, enabling an efficient synthesis of thieno[2,3-b]indole
and benzothiophene derivatives in high to excellent yields
under catalyst-free conditions (Scheme 1, bottom).
Results and discussion
We began the study with the reaction of 2-mercaptoindole-3-car- for the formation of 3p in 99% yield. Moreover, heteroaromatic
baldehyde 1a 10 and sulfonium ylide 2a as the model reaction substrates, including 2-furyl, 2-thienyl and 2-pyridyl substi-
for condition screening. As shown in Table 1, with the presence tuted sulfonium ylides, also worked efficiently in the cascade
of 20 mol% Et3N in toluene, a cascade deprotonation/intra- reaction with 1a, delivering the expected products 3q–s in high
molecular aldol reaction could give thieno[2,3-b]indole 3a in yields. However, when the reaction of 2-mercaptoindole-3-car-
89% yield (entry 1). To our delight, 3a was also obtained in 90% baldehyde 1a with diphenyl(2,2,2-trifluoroethyl)sulfonium
yield even without using any catalyst (entry 2). Under catalyst- ylide was tested, it was found that the reaction only furnished
free conditions, a series of solvents were further tested, and it the corresponding thioether product, but further intra-
was found that solvents have no significant influence on the molecular aldol reaction did not occur (see the Experimental
reactivity and yield (entries 3–6). Moreover, with EtOH as the section and the ESI†). Notably, the structure of the product 3d
solvent, 3a could be obtained in 97% yield (entry 7). Therefore, was confirmed by single crystal X-ray diffraction analysis.11
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substrate, such as 2-naphthyl sulfonium ylide, was also evalu-
ated, affording 5j in a high yield. Furthermore, the heteroaro-
matic substrates were also suitable for reacting with 4, deliver-
ing products 5k and 5l in 99% and 97% yields, respectively.
Upon replacing 2-mercaptobenzaldehyde
4
with either
2-hydroxybenzaldehyde or N-(2-formylphenyl)-4-methyl-
benzenesulfonamide for the reaction with 2a, unfortunately,
the reaction did not occur under the standard conditions.
However, when 1-(2-mercaptophenyl)ethan-1-one was used for
reacting with 2a, the desired cascade reaction could proceed in
refluxing EtOH to give the expected product (3-hydroxy-3-
methyl-2,3-dihydrobenzo[b]thiophen-2-yl)(phenyl)methanone
in 95% yield (see the Experimental section and the ESI†).
In order to evaluate the practicability and synthetic value of
this cascade reaction, a gram-scale experiment of 1a and 2a
was carried out under the standard conditions, which was 40
times larger than the scale of the model reaction in Table 1,
entry 9. The gram-scale reaction proceeded well and afforded
3a in 92% yield (Scheme 4). It is worth noting that 3a could be
isolated by direct filtration without using silica gel column
chromatography. This indicates that this cascade reaction pro-
tocol has a promising prospect for large-scale production.
Meanwhile, some representative transformations of 3a were
also explored (Scheme 4). On treating 3a with KOH in the
mixture solvents of MeOH and DMSO for 10 min, the Boc-
group was removed to afford product 6 in a quantitative yield.
Reduction of the carbonyl group of 3a with NaBH4 in MeOH/
CH2Cl2 led to the formation of compound 7 in 99% yield. 3a
could readily react with ethynylmagnesium bromide in THF at
room temperature, giving compound 8 in 65% yield. The car-
bonyl group could also be easily transformed to the CvC
bond with the Wittig reaction, delivering compound 9 in 82%
yield.12
Scheme 2 Substrate scope for the cascade reaction of 2-mercaptoin-
dole-3-carbaldehydes and α-carbonyl sulfonium ylides. The reactions
were carried out with 1 (0.2 mmol) and 2 (0.24 mmol) in 2.0 mL of EtOH
at room temperature for
compounds.
5 h. Yields refer to the isolated pure
Encouraged by the success of the above cascade reaction,
we attempted to investigate the cascade deprotonation/intra-
molecular aldol reaction of 2-mercaptobenzaldehyde and
various α-carbonyl sulfonium ylides (Scheme 3). Under the
standard conditions, the reaction of 2-mercaptobenzaldehyde
4 with 2a proceeded smoothly to give the desired product 5a in
96% yield. Besides, for the sulfonium ylides, regardless of an
electron-donating or electron-withdrawing substituent on the
phenyl ring, the reactions could proceed smoothly to furnish
the corresponding 5b–i in 90–98% yields. The fused aromatic
To shed some light on the reaction mechanism, several
control experiments were carried out (Scheme 5).12 Under the
standard conditions, the reaction of 10 and 2a did not work
(Scheme 5a). Likewise, 2-chloroindole-3-carbaldehyde 11 also
Scheme 3 Substrate scope for the cascade reaction of 2-mercapto-
benzaldehyde and α-carbonyl sulfonium ylides. The reactions were
carried out with 4 (0.2 mmol) and 2 (0.24 mmol) in 2.0 mL of EtOH at
room temperature for 5 h. Yields refer to the isolated pure compounds.
Scheme 4 Gram-scale experiments and diverse transformations of 3a.
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Scheme 6 Proposed mechanism for the cascade deprotonation/intra-
molecular aldol reaction.
the reaction proceeds through a cascade deprotonation and
the following intramolecular aldol condensation pathway.
Based on our experimental results and previous literature
reports,6,8 we proposed a reaction mechanism for this cascade
deprotonation/intramolecular aldol reaction. As shown in
Scheme 6, due to the relative basicity of sulfonium ylide, 2a
can capture the hydrogen proton from the –SH group of sub-
strate 1a, leading to the formation of the di-sulfur ion pair
intermediate I. Then, owing to the presence of the strongly
nucleophilic thiolate and good leaving group dimethyl sulfide
in the ion pair, the thiolate will participate in a nucleophilic
substitution reaction while simultaneously releasing the
dimethyl sulfide to generate intermediate II, which is liable to
be tautomerized to enolate intermediate II′. Subsequently, an
intramolecular aldol reaction in enolate intermediate II′ gives
rise to intermediate III, which is apt to undergo dehydration
for the formation of the thieno[2,3-b]indole product 3a.
Scheme 5 Control experiments.
did not react with 2a (Scheme 5b). These two experiments
reveal that sulfonium ylides are not able to directly react with
the aldehyde group, and the –SH group of substrates 1 and 4 is
vital for the occurrence of the cascade reaction. The reaction of
thiophenol 12 and 2a provides the product 13 in 97% yield
(Scheme 5c). This experiment indicates that the deprotonation
of the –SH group by α-carbonyl sulfonium ylides is highly feas-
ible. We also conducted a three component reaction including
10, 1a, and 2a under the standard conditions and obtained
only 3a in 95% yield, and compound 10 could be recovered in
an almost quantitative yield from the reaction mixture
(Scheme 5d). This reveals that the cascade deprotonation/intra-
molecular aldol reaction readily takes place under catalyst-free
conditions. On the other hand, the reaction of N-benzyl-2-mer-
captoindole-3-carbaldehyde 14 and 2 was carried out under
the standard conditions. The thioether compound 15 could be
obtained in 92% yield, but the desired product 16 was
observed in a trace amount (Scheme 5e). This suggests that the
deprotonation of the –SH group by α-carbonyl sulfonium
ylides is easy for the N-benzyl substrate, but the following
intramolecular aldol condensation process under the standard
conditions is difficult. However, when the reaction of 14 and 2
was performed in EtOH at 100 °C in a sealed tube, compounds
15 and 16 could be obtained in 63% and 30% yields, respect-
ively (Scheme 5f). Furthermore, stirring compound 15 in EtOH
Conclusions
In conclusion, we have developed an efficient cascade deproto-
nation/intramolecular aldol reaction of α-carbonyl sulfonium
ylides with 2-mercaptoindole-3-carbaldehydes and 2-mercapto-
benzaldehydes under catalyst-free conditions. With the devel-
oped protocol, a series of thieno[2,3-b]indole compounds and
benzothiophene derivatives could be smoothly obtained in
high to excellent yields (up to 99%). This new cascade reaction
protocol is characterized by catalyst-free conditions, an
environment-friendly solvent, broad functional group toler-
ance, and large-scale synthesis. With the help of several
control experiments, it was confirmed that the reaction pro-
ceeds through a deprotonation of the –SH group of thiophenol
compounds by α-carbonyl sulfonium ylides and a sequential
intramolecular aldol condensation pathway, and thereby, a
plausible reaction mechanism for the reaction is proposed.
Experimental section
General methods
at 100 °C in a sealed tube led to the intramolecular aldol con- The reagents were purchased from commercial sources and
densation product 16 with 54% yield (Scheme 5g). These three were used as received unless mentioned otherwise. The reac-
1
control experiments (Scheme 5e–g) further demonstrated that tions were monitored by TLC. H NMR and 13C NMR spectra
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1
were recorded in CDCl3 and DMSO-d6. 1H NMR chemical 15 : 1 as the eluent), m.p. 169.3–170.6 °C; H NMR (300 MHz,
shifts are reported in ppm relative to tetramethylsilane (TMS) CDCl3) δ 8.17 (s, 1H), 7.89 (d, J = 1.3 Hz, 1H), 7.86 (d, J =
with the solvent resonance employed as the internal standard 1.7 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.79 (s, 1H), 7.67–7.58 (m,
(CDCl3 at 7.26 ppm, DMSO-d6 at 2.50 ppm). The data are 1H), 7.54 (dd, J = 8.2, 6.6 Hz, 2H), 7.46 (dd, J = 8.9, 2.0 Hz, 1H),
reported as follows: chemical shift, multiplicity (s = singlet, br 1.77 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 189.3, 148.4, 146.9,
s = broad singlet, d = doublet, t = triplet, q = quartet, m = mul- 140.6, 139.2, 138.2, 132.2, 129.1(2C), 128.6(2C), 128.0, 126.1,
tiplet), coupling constants (Hz) and integration. 13C NMR 126.0, 122.4, 117.3, 117.2, 86.6, 28.4(3C); HRMS (ESI) calcd for
chemical shifts are reported in ppm from tetramethylsilane C22H18BrNNaO3S [M + Na]+: 478.0083; found: 478.0069.
(TMS) with the solvent resonance as the internal standard
tert-Butyl
2-benzoyl-6-chloro-8H-thieno[2,3-b]indole-8-car-
(CDCl3 at 77.16 ppm, DMSO-d6 at 39.52 ppm). The melting boxylate (3e). Light yellow solid, 38.4 mg, 94% yield (PE/EA =
1
points of the products were recorded on a Büchi Melting Point 15 : 1 as the eluent), m.p. 166.5–167.4 °C; H NMR (300 MHz,
B-545 system. HRMS spectra were recorded using a Bruker CDCl3) δ 8.35 (s, 1H), 7.88 (dt, J = 6.9, 1.5 Hz, 2H), 7.80 (s, 1H),
microTOF-Q II mass spectrometer (Bremen, Germany).
7.67–7.57 (m, 2H), 7.58–7.50 (m, 2H), 7.29 (dd, J = 8.3, 2.0 Hz,
General experimental procedures for the synthesis of com- 1H), 1.77 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 189.2, 148.4,
pounds 3. 2-Mercaptoindole-3-carbaldehydes 1 (0.1 mmol, 146.5, 140.6, 138.2, 132.2, 131.2, 129.1(2C), 128.6(2C), 126.6,
1.0 equiv.), sulfonium ylides 2 (0.12 mmol, 1.2 equiv.) and 125.9, 124.2, 122.9, 120.1, 116.3, 86.7, 28.3(3C); HRMS (ESI)
EtOH (1.0 mL) were added to a reaction tube. The reaction calcd for C22H19ClNO3S [M + H]+: 412.0774; found: 412.0768.
mixture was stirred at room temperature for 5 h. After complete
tert-Butyl 2-benzoyl-5-methoxy-8H-thieno[2,3-b]indole-8-car-
conversion of the starting material monitored by TLC, the reac- boxylate (3f). Light yellow solid, 40.3 mg, 99% yield (PE/EA =
1
tion mixture was concentrated by rotary evaporation and then 15 : 1 as the eluent), m.p. 136.3–137.4 °C; H NMR (300 MHz,
the residue was directly purified by flash chromatography on CDCl3) δ 8.16 (s, 1H), 7.95–7.84 (m, 2H), 7.81 (s, 1H), 7.66–7.57
silica gel (petroleum ether/ethyl acetate = 15 : 1 ∼ 10 : 1).
tert-Butyl
(m, 1H), 7.57–7.49 (m, 2H), 7.18 (d, J = 2.6 Hz, 1H), 6.96 (dd,
2-benzoyl-8H-thieno[2,3-b]indole-8-carboxylate J = 9.1, 2.6 Hz, 1H), 3.86 (s, 3H), 1.76 (s, 9H); 13C NMR
(3a). White solid, 36.6 mg, 97% yield (PE/EA = 15 : 1 as the (75 MHz, CDCl3) δ 189.3, 156.7, 148.8, 146.8, 139.9, 138.5,
eluent), m.p. 166.4–167.2 °C; 1H NMR (300 MHz, CDCl3) δ 8.27 134.7, 132.0, 129.1(2C), 128.6(2C), 127.1, 126.2, 125.4, 116.6,
(s, 1H), 7.95–7.87 (m, 2H), 7.85 (d, J = 1.8 Hz, 1H), 7.71 (dd, J = 113.0, 103.3, 85.9, 55.9, 28.4(3C); HRMS (ESI) calcd for
7.4, 1.7 Hz, 1H), 7.66–7.58 (m, 1H), 7.56–7.51 (m, 2H), C23H21NNaO4S [M + Na]+: 430.1083; found: 430.1067.
7.42–7.29 (m, 2H), 1.78 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
tert-Butyl 2-benzoyl-6-methoxy-8H-thieno[2,3-b]indole-8-car-
189.4, 148.6, 146.3, 140.1, 138.4, 132.1, 129.1(2C), 128.6(2C), boxylate (3g). Light yellow solid, 38.7 mg, 95% yield (PE/EA =
1
127.2, 126.3, 125.3, 124.5, 123.8, 119.6, 117.5, 115.9, 86.1, 28.4 15 : 1 as the eluent), m.p. 137.3–138.5 °C; H NMR (300 MHz,
(3C); HRMS (ESI) calcd for C22H20NO3S [M + H]+: 378.1158; CDCl3) δ 8.02–7.79 (m, 3H), 7.77 (s, 1H), 7.66–7.47 (m, 4H),
found: 378.1175.
tert-Butyl 2-benzoyl-5-fluoro-8H-thieno[2,3-b]indole-8-car- NMR (101 MHz, CDCl3) δ 189.4, 158.4, 148.7, 145.3, 139.9,
6.92 (dd, J = 8.6, 2.4 Hz, 1H), 3.90 (s, 3H), 1.77 (s, 9H); 13C
boxylate (3b). Light yellow solid, 37.1 mg, 94% yield (PE/EA = 138.5, 132.0, 129.1(2C), 128.6(2C), 127.3, 126.3, 126.0, 120.0,
1
15 : 1 as the eluent), m.p. 162.3–163.4 °C; H NMR (300 MHz, 118.0, 112.3, 100.8, 86.0, 55.8, 28.4(3C); HRMS (ESI) calcd for
CDCl3) δ 8.26 (s, 1H), 7.90–7.87 (m, 2H), 7.80 (s, 1H), 7.68–7.59 C23H22NO4S [M + H]+: 408.1264; found: 408.1263.
(m, 1H), 7.54 (dd, J = 8.2, 6.5 Hz, 2H), 7.37 (dd, J = 8.4, 2.6 Hz,
tert-Butyl 2-(2-methylbenzoyl)-8H-thieno[2,3-b]indole-8-car-
1H), 7.12–7.06 (m, 1H), 1.77 (s, 9H); 13C NMR (75 MHz, CDCl3) boxylate (3h). Light yellow solid, 38.9 mg, 99% yield (PE/EA =
1
δ 189.3, δ 159.7 (d, J = 241.6 Hz), 148.5, 147.4, 140.3, 138.2, 15 : 1 as the eluent), m.p. 133.3–134.5 °C; H NMR (300 MHz,
136.7, 132.2, 129.1(2C), 128.6(2C), 126.5, 126.2, 125.3, 116.9 (d, CDCl3) δ 8.27 (s, 1H), 7.92–7.77 (m, 3H), 7.71 (dt, J = 7.4, 0.9
J = 9.2 Hz), 112.7 (d, J = 24.6 Hz), 105.9 (d, J = 24.8 Hz), 86.4, Hz, 1H), 7.45–7.28 (m, 4H), 2.47 (s, 3H), 1.77 (s, 9H); 13C NMR
28.3(3C) 19F NMR (376 MHz, CDCl3) δ −118.66; HRMS (ESI) (75 MHz, CDCl3) δ 189.1, 148.8, 146.2, 142.8, 140.3, 135.7,
calcd for C22H18FNNaO3S [M
+
Na]+: 418.0884; found: 129.33(2C), 129.26(2C), 127.2, 125.9, 125.2, 124.5, 123.8, 119.5,
115.9, 86.0, 28.4(3C), 21.8; HRMS (ESI) calcd for
418.0874.
tert-Butyl
boxylate (3c). Light yellow solid, 40.1 mg, 97% yield (PE/EA =
2-benzoyl-5-chloro-8H-thieno[2,3-b]indole-8-car- C23H21NNaO3S [M + Na]+: 414.1134; found: 414.1123.
tert-Butyl 2-(3-methylbenzoyl)-8H-thieno[2,3-b]indole-8-car-
1
15 : 1 as the eluent), m.p. 168.3–169.6 °C; H NMR (300 MHz, boxylate (3i). Light yellow solid, 37.5 mg, 96% yield (PE/EA =
CDCl3) δ 8.22 (s, 1H), 7.89 (t, J = 1.4 Hz, 1H), 7.87 (d, J = 15 : 1 as the eluent), m.p. 131.4–132.5 °C; H NMR (300 MHz,
1
1.7 Hz, 1H), 7.80 (s, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.66–7.59 (m, CDCl3) δ 8.28 (s, 1H), 7.85 (s, 1H), 7.79–7.64 (m, 3H), 7.50–7.29
1H), 7.58–7.50 (m, 2H), 7.33 (dd, J = 8.9, 2.1 Hz, 1H), 1.77 (s, (m, 4H), 2.47 (s, 3H), 1.78 (s, 9H); 13C NMR (101 MHz, CDCl3)
9H); 13C NMR (75 MHz, CDCl3) δ 189.3, 140.5, 138.1, 132.3, δ 189.6, 146.3, 140.3, 138.52, 138.49 132.9, 129.6, 128.4, 127.2,
129.6, 129.1(2C), 128.7(2C), 126.1, 125.6, 125.3, 119.4, 116.9, 126.4, 126.2, 125.3, 124.5, 123.8, 119.6, 115.9, 86.1, 28.4(3C),
86.5, 28.4(3C); HRMS (ESI) calcd for C22H18ClNNaO3S 21.6; HRMS (ESI) calcd for C23H22NO3S [M + H]+: 392.1315;
[M + Na]+: 434.0588; found: 434.0589.
tert-Butyl 2-benzoyl-5-bromo-8H-thieno[2,3-b]indole-8-car-
found: 392.1306.
tert-Butyl 2-(3-methoxybenzoyl)-8H-thieno[2,3-b]indole-8-
boxylate (3d). Light yellow solid, 45.2 mg, 99% yield (PE/EA = carboxylate (3j). Light yellow solid, 39.5 mg, 97% yield
3682 | Org. Biomol. Chem., 2021, 19, 3678–3686
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(PE/EA = 15 : 1 as the eluent), m.p. 112.4–113.6 °C; 1H NMR
tert-Butyl 2-(2-naphthoyl)-8H-thieno[2,3-b]indole-8-carboxy-
(300 MHz, CDCl3) δ 8.27 (s, 1H), 7.88 (s, 1H), 7.77–7.67 (m, late (3p). Light yellow solid, 42.3 mg, 99% yield (PE/EA = 15 : 1
1H), 7.50–7.47 (m, 1H), 7.46–7.40 (m, 2H), 7.40–7.28 (m, 2H), as the eluent), m.p. 136.5–137.3 °C; 1H NMR (400 MHz, CDCl3)
7.17–7.13 (m, 1H), 3.89 (s, 3H), 1.78 (s, 9H); 13C NMR δ 8.42 (s, 1H), 8.30 (s, 1H), 8.05–7.85 (m, 5H), 7.72 (d, J =
(101 MHz, CDCl3) δ 189.0, 159.7, 139.9, 139.6, 129.5(2C), 127.1, 7.6 Hz, 1H), 7.64–7.57 (m, 2H), 7.42–7.38 (m, 1H), 7.35–7.31
126.2, 125.2, 124.4, 123.7, 121.6(2C), 119.5, 118.1, 115.8, 113.8, (m, 1H), 1.79 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 189.3,
86.0, 55.5, 28.3(3C); HRMS (ESI) calcd for C23H22NO4S 148.7, 146.4, 140.3, 135.7, 135.1, 132.5, 130.1, 129.4, 128.6,
[M + H]+: 408.1264; found: 408.1261.
128.2, 128.0, 127.3, 127.0, 126.4, 125.5, 125.3, 124.5, 123.8,
tert-Butyl 2-(4-methylbenzoyl)-8H-thieno[2,3-b]indole-8-car- 119.6, 115.9, 86.1, 28.4(3C); HRMS (ESI) calcd for C26H22NO3S
boxylate (3k). Light yellow solid, 38.0 mg, 97% yield (PE/EA = [M + H]+: 428.1315; found: 428.1303.
1
15 : 1 as the eluent), m.p. 134.2–134.8 °C; H NMR (300 MHz,
tert-Butyl 2-(furan-2-carbonyl)-8H-thieno[2,3-b]indole-8-car-
DMSO-d6) δ 8.12 (s, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.86 (s, 1H), boxylate (3q). Light yellow solid, 35.5 mg, 97% yield (PE/EA =
1
7.56–7.45 (m, 2H), 7.45–7.30 (m, 4H), 2.31 (s, 3H), 1.71 (s, 9H); 10 : 1 as the eluent), m.p. 112.4–113.3 °C; H NMR (400 MHz,
13C NMR (75 MHz, DMSO-d6) δ 190.7, 148.2, 145.6, 140.3, CDCl3) δ 8.48 (s, 1H), 8.26 (s, 1H), 7.83–7.74 (m, 1H), 7.72 (dd,
139.5, 138.1, 135.5, 131.0(2C), 130.4(2C), 127.85, 127.78, 127.0, J = 1.7, 0.8 Hz, 1H), 7.48–7.28 (m, 3H), 6.63 (dd, J = 3.6, 1.7 Hz,
125.6, 125.5, 123.9, 120.5, 115.3, 86.2, 27.7(3C), 19.2; HRMS 1H), 1.77 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 174.3, 152.9,
(ESI) calcd for C23H21NNaO3S [M + Na]+: 414.1134; found: 146.2(2C), 138.9, 127.7, 125.3, 124.6, 123.8, 119.7, 118.3(2C),
414.1121.
tert-Butyl
115.9, 112.5, 86.0, 28.4(3C); HRMS (ESI) calcd for C20H18NO4S
2-(4-methoxybenzoyl)-8H-thieno[2,3-b]indole-8- [M + H]+: 368.0957; found: 368.0952.
carboxylate (3l). Light yellow solid, 40.3 mg, 99% yield (PE/EA
tert-Butyl 2-(thiophene-2-carbonyl)-8H-thieno[2,3-b]indole-8-
= 15 : 1 as the eluent), m.p. 113.2–114.1 °C; 1H NMR (400 MHz, carboxylate (3r). Light yellow solid, 31.5 mg, 82% yield (PE/EA
CDCl3) δ 8.28 (s, 1H), 7.98–7.89 (m, 2H), 7.86 (s, 1H), 7.72 (d, = 10 : 1 as the eluent), m.p. 108.2–109.3 °C; 1H NMR (400 MHz,
J = 7.6 Hz, 1H), 7.41–7.36 (m, 1H), 7.34–7.30 (m, 1H), 7.06–6.98 CDCl3) δ 8.27 (s, 1H), 8.14 (s, 1H), 7.95 (dd, J = 3.8, 1.1 Hz, 1H),
(m, 2H), 3.91 (s, 3H), 1.77 (s, 9H); 13C NMR (101 MHz, CDCl3) 7.85–7.73 (m, 1H), 7.70 (dd, J = 5.0, 1.2 Hz, 1H), 7.42–7.32 (m,
δ 188.0, 163.0, 148.8, 145.8, 140.4, 131.5(2C), 130.9, 127.1, 2H), 7.21 (dd, J = 5.0, 3.7 Hz, 1H), 1.77 (s, 9H); 13C NMR
125.4, 125.2, 124.6, 123.8, 119.5, 115.9, 113.9(2C), 86.0, 55.6, (101 MHz, CDCl3) δ 179.7, 146.0, 142.8, 140.5, 139.5, 132.9,
28.4(3C); HRMS (ESI) calcd for C23H21NNaO4S [M + Na]+: 132.8, 132.7, 128.0, 127.2, 125.3, 124.4, 123.8, 119.6, 115.9,
430.1083; found: 430.1073.
tert-Butyl 2-(4-chlorobenzoyl)-8H-thieno[2,3-b]indole-8-car- 406.0452; found: 406.0455.
86.1, 28.4(3C); HRMS (ESI) calcd for C20H17NNaO3S [M + Na]+:
boxylate (3m). Light yellow solid, 40.8 mg, 99% yield (PE/EA =
15 : 1 as the eluent), m.p. 135.7–136.9 °C; H NMR (300 MHz, (3s). Light yellow solid, 36.3 mg, 96% yield (PE/EA = 15 : 1 as
tert-Butyl 2-picolinoyl-8H-thieno[2,3-b]indole-8-carboxylate
1
DMSO-d6) δ 8.12 (s, 1H), 7.99 (s, 1H), 7.85–7.79 (m, 3H), 7.54 the eluent), m.p. 114.3–115.6 °C; 1H NMR (400 MHz, CDCl3)
(d, J = 8.5 Hz, 2H), 7.38–7.27 (m, 2H), 1.72 (s, 9H); 13C NMR δ 8.77 (d, J = 4.7 Hz, 1H), 8.72 (s, 1H), 8.20 (d, J = 8.2 Hz, 2H),
(101 MHz, DMSO-d6) δ 186.8, 147.9, 145.3, 138.8, 137.2, 136.0, 7.91–7.87 (m, 1H), 7.84–7.73 (m, 1H), 7.51–7.48 (m, 1H),
130.2(2C), 128.4(2C), 126.8, 126.5, 124.9, 123.8, 123.4, 119.6, 7.40–7.31 (m, 2H), 1.79 (s, 9H); 13C NMR (101 MHz, CDCl3)
115.1, 85.5, 27.6(3C); HRMS (ESI) calcd for C22H18ClNNaO3S δ 184.0, 154.2, 148.2(C), 137.3(2C), 136.7, 127.9, 127.2, 126.7,
[M + Na]+: 434.0588; found: 434.0571.
125.2, 124.7, 123.8, 123.7, 119.9, 115.8, 85.8, 28.4(3C); HRMS
tert-Butyl 2-(4-bromobenzoyl)-8H-thieno[2,3-b]indole-8-car- (ESI) calcd for C21H18N2NaO3S [M + Na]+: 401.0930; found:
boxylate (3n). Light yellow solid, 41.3 mg, 91% yield (PE/EA = 401.0933.
1
15 : 1 as the eluent), m.p. 170.7–171.9 °C; H NMR (300 MHz,
General experimental procedures for the synthesis of com-
CDCl3) δ 8.26 (s, 1H), 7.85–7.73 (m, 3H), 7.73–7.62 (m, 3H), pounds 5. 2-Mercaptobenzaldehyde 4 (0.2 mmol, 1.0 equiv.),
7.42–7.37 (m, 1H), 7.36–7.30 (m, 1H), 1.77 (s, 9H); 13C NMR sulfonium ylides 2 (0.24 mmol, 1.2 equiv.) and EtOH (2.0 mL)
(75 MHz, CDCl3) δ 188.0, 148.8, 146.6, 140.5, 139.6, 137.2, were added sequentially to a reaction tube. The reaction
131.9(2C), 130.7(2C), 127.3, 126.9, 126.1, 125.4, 124.4, 123.9, mixture was stirred at room temperature for 5 h. After com-
119.6, 116.0, 86.2, 28.4(3C); HRMS (ESI) calcd for plete conversion of the starting material monitored by TLC,
C22H18BrNNaO3S [M + Na]+: 478.0069; found: 478.0083.
tert-Butyl 2-(4-nitrobenzoyl)-8H-thieno[2,3-b]indole-8-car- and then the residue was directly purified by flash chromato-
the reaction mixture was concentrated by rotary evaporation
boxylate (3o). Light yellow solid, 40.4 mg, 96% yield (PE/EA = graphy on silica gel (petroleum ether/ethyl acetate = 20 : 1 ∼
1
15 : 1 as the eluent), m.p. 175.7–176.4 °C; H NMR (400 MHz, 15 : 1).
CDCl3) δ 8.38 (d, J = 8.7 Hz, 2H), 8.24 (s, 1H), 8.02 (d, J =
Benzo[b]thiophen-2-yl(phenyl)methanone (5a). Colorless
1
8.7 Hz, 2H), 7.79 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.43–7.39 (m, oil, 45.8 mg, 96% yield (PE/EA = 20 : 1 as the eluent); H NMR
1H), 7.36–7.32 (m, 1H), 1.78 (s, 9H); 13C NMR (101 MHz, (300 MHz, DMSO-d6) δ 8.14–8.03 (m, 3H), 7.97–7.86 (m, 2H),
CDCl3) δ 187.3, 149.7, 147.3, 143.8, 140.5, 139.0, 129.9(2C), 7.76–7.67 (m, 1H), 7.67–7.43 (m, 4H); 13C NMR (75 MHz,
127.5, 126.9, 125.7, 124.2, 124.1, 123.8(2C), 119.7, 116.0, 86.5, DMSO-d6) δ 188.9, 142.1, 141.7, 139.1, 137.1, 133.2, 132.7,
28.4(3C); HRMS (ESI) calcd for C22H19N2O5S [M + H]+: 129.0(2C), 128.7(2C), 127.8, 126.7, 125.2, 122.9; HRMS (ESI)
423.1009; found: 423.1018.
calcd for C15H11OS [M + H]+: 239.0531; found: 239.0532.
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Benzo[b]thiophen-2-yl(o-tolyl)methanone (5b). Light yellow HRMS (ESI) calcd for C16H10NOS [M + H]+: 264.0483; found:
1
oil, 46.4 mg, 92% yield (PE/EA = 20 : 1 as the eluent); H NMR 264.0486.
(300 MHz, CDCl3) δ 7.95–7.86 (m, 2H), 7.86 (d, J = 0.8 Hz, 1H),
Benzo[b]thiophen-2-yl(4-(trifluoromethyl)phenyl)methanone
7.77–7.66 (m, 2H), 7.52–7.37 (m, 4H), 2.46 (s, 3H); 13C NMR (5i). Colorless solid, 60.1 mg, 98% yield (PE/EA = 20 : 1 as the
(101 MHz, CDCl3) δ 189.9, 143.3, 142.8, 139.2, 138.5, 138.0, eluent), m.p. 175.3–176.4 °C; 1H NMR (300 MHz, CDCl3) δ 8.00
133.4, 132.2, 129.8, 128.4, 127.5, 126.6, 126.1, 125.1, 123.0, (d, J = 8.0 Hz, 3H), 7.90 (t, J = 7.9 Hz, 3H), 7.86–7.76 (m, 5H),
21.5; HRMS (ESI) calcd for C16H12NaOS [M + Na]+: 275.0501; 7.53–7.40 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 188.6, 143.1,
found: 275.0497.
142.5, 141.0, 139.0, 133.93 (q, J = 32.7 Hz), 132.9, 129.5(2C),
Benzo[b]thiophen-2-yl(p-tolyl)methanone (5c). Light yellow 128.0, 126.4, 125.7 (q, J = 3.8 Hz, 2C), 125.4, 123.8 (q, J = 272.8
solid, 49.1 mg, 97% yield (PE/EA = 20 : 1 as the eluent), Hz) 123.1; 19F NMR (376 MHz, CDCl3) δ −63.0; HRMS (ESI)
m.p. 107.5–108.4 °C; 1H NMR (300 MHz, CDCl3) δ 7.94–7.79 calcd for C16H10F3OS [M + H]+: 307.0399; found: 307.0391.
(m, 5H), 7.50–7.45 (m, 1H), 7.43–7.38 (m, 1H), 7.37–7.28 (m,
Benzo[b]thiophen-2-yl(naphthalen-2-yl)methanone
(5j).
2H), 2.47 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 189.4, 143.4, Light yellow solid, 54.8 mg, 95% yield (PE/EA = 20 : 1 as the
142.7, 139.2, 135.2, 131.9, 129.6(2C), 129.3(2C), 127.4, 126.1, eluent), m.p. 153.2–154.3 °C; 1H NMR (300 MHz, CDCl3) δ 8.45
125.1, 123.0, 21.8; HRMS (ESI) calcd for C16H13OS [M + H]+: (s, 1H), 8.01–7.84 (m, 7H), 7.68–7.54 (m, 2H), 7.52–7.40 (m,
253.0687; found: 253.0689.
2H); 13C NMR (75 MHz, CDCl3) δ 189.6, 143.3, 142.8, 139.2,
Benzo[b]thiophen-2-yl(4-methoxyphenyl)methanone
(5d). 135.4, 135.2, 132.4, 132.3, 130.8, 129.5, 128.6, 128.4, 128.0,
Light yellow solid, 48.2 mg, 90% yield (PE/EA = 20 : 1 as the 127.5, 127.1, 126.2, 125.4, 125.2, 123.0; HRMS (ESI) calcd for
eluent), m.p. 132.1–132.9 °C; 1H NMR (300 MHz, CDCl3) δ C19H13OS [M + H]+: 289.0687; found: 289.0685.
8.01–7.93 (m, 2H), 7.93–7.80 (m, 3H), 7.53–7.36 (m, 2H),
Benzo[b]thiophen-2-yl(furan-2-yl)methanone (5k). Light
7.08–6.95 (m, 2H), 3.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ yellow solid, 45.0 mg, 99% yield (PE/EA = 20 : 1 as the eluent),
1
188.2, 163.4, 143.4, 142.5, 139.2, 131.8(2C), 131.3, 130.5, 127.3, m.p. 99.6–100.2 °C; H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H),
126.0, 125.1, 122.9, 113.9(2C), 55.6; HRMS (ESI) calcd for 7.97 (dd, J = 3.8, 1.2 Hz, 1H), 7.94–7.86 (m, 2H), 7.73 (dd, J =
C16H13O2S [M + H]+: 269.0636; found: 269.0639.
4.9, 1.2 Hz, 1H), 7.52–7.38 (m, 2H), 7.21 (dd, J = 5.0, 3.8 Hz,
Benzo[b]thiophen-2-yl(4-fluorophenyl)methanone (5e). Light 1H); 13C NMR (101 MHz, CDCl3) δ 180.2, 142.7, 142.5, 142.3,
yellow solid, 48.5 mg, 95% yield (PE/EA = 20 : 1 as the eluent), 139.0, 134.0, 133.7, 130.4, 128.2, 127.4, 126.1, 125.2, 122.9;
m.p. 101.3–102.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.99–7.97 HRMS (ESI) calcd for C13H9O2S [M + H]+: 229.0323; found:
(m, 2H), 7.93–7.86 (m, 2H), 7.84 (s, 1H), 7.51–7.47 (m, 1H), 229.0324.
7.44–7.40 (m, 1H), 7.25–7.17 (m, 2H); 13C NMR (101 MHz,
Benzo[b]thiophen-2-yl(thiophen-2-yl)methanone (5l). Light
CDCl3) δ 188.2, 165.5 (d, J = 254.2 Hz), 142.9, 142.8, 139.1, yellow solid, 47.4 mg, 97% yield (PE/EA = 20 : 1 as the eluent),
134.15 (d, J = 3.1 Hz), 132.1(2C), 131.94 (d, J = 9.1 Hz), 127.6, m.p. 107.3–108.4 °C; 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H),
126.2, 125.2, 123.0, 115.8 (d, J = 21.8 Hz, 2C); 19F NMR 7.90 (dd, J = 17.4, 8.0 Hz, 2H), 7.72 (dd, J = 1.7, 0.8 Hz, 1H),
(376 MHz, CDCl3) δ −105.8; HRMS (ESI) calcd for C15H10FOS 7.51–7.36 (m, 3H), 6.63 (dd, J = 3.6, 1.7 Hz, 1H); 13C NMR
[M + H]+: 257.0436; found: 257.0437.
(101 MHz, CDCl3) δ 174.7, 152.5, 146.8, 142.4, 142.0, 139.4,
Benzo[b]thiophen-2-yl(4-chlorophenyl)methanone
(5f). 131.2, 127.5, 126.3, 125.1, 122.8, 119.4, 112.7; HRMS (ESI)
Light yellow solid, 50.2 mg, 92% yield (PE/EA = 20 : 1 as the calcd for C13H9OS2 [M + H]+: 245.0095; found: 245.0096.
eluent), m.p. 145.7–146.3 °C; 1H NMR (400 MHz, CDCl3) δ
Scale-up experiment. 1a (4.0 mmol, 1.11 g) and 2a
7.94–7.84 (m, 4H), 7.83 (s, 1H), 7.54–7.45 (m, 3H); 13C NMR (4.8 mmol, 0.87 g) were added to a 100 mL round-bottom flask
(101 MHz, CDCl3) δ 188.4, 142.8, 142.7, 139.0, 139.0, 136.2, equipped with a magnetic stirring bar, and then the solvent
132.3(2C), 130.8(2C), 129.0, 127.7, 126.2, 125.3, 123.0; HRMS EtOH (40 mL) was added. The mixture was stirred at room
(ESI) calcd for C15H10ClOS [M
273.0141.
+
H]+: 273.0141; found: temperature until the reaction was completed as monitored by
TLC (24 h). When 1a was consumed, a part of the solvent was
Benzo[b]thiophen-2-yl(4-bromophenyl)methanone
(5g). removed under reduced pressure; then the residue was filtered
Light yellow solid, 60.7 mg, 96% yield (PE/EA = 20 : 1 as the and washed with PE/EA=(15 : 1). The white solid was collected
eluent), m.p. 156.2–157.4 °C; 1H NMR (300 MHz, CDCl3) δ (1.34 g, 92% yield).
7.92–7.86 (m, 2H), 7.83 (s, 1H), 7.81–7.74 (m, 2H), 7.72–7.62
Synthesis of compound 6. KOH (1 mmol, 56 mg) was added
(m, 2H), 7.54–7.37 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 188.5, in portions to a solution of 3a (0.2 mmol, 67.5 mg) in a
142.8, 142.7, 139.0, 136.6, 132.3, 131.9(2C), 130.9(2C), 127.7, mixture solvent (VMeOH/VDMSO = 1 : 1, 2 mL) at 0 °C. After short
127.6, 126.2, 125.3, 123.0; HRMS (ESI) calcd for C15H10BrOS stirring, the reaction temperature was allowed to increase to
[M + H]+: 316.9636; found: 316.9637.
room temperature and the stirring was continued at that temp-
4-(Benzo[b]thiophene-2-carbonyl)benzonitrile (5h). Light erature until 3a was consumed. Then H2O (3 mL) was added to
yellow solid, 50.6 mg, 96% yield (PE/EA = 20 : 1 as the eluent), the reaction tube. The aqueous phase was extracted with ethyl
m.p. 175.3–176.4 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.11–8.02 acetate. The combined organic layers were dried over Na2SO4,
(m, 7H), 7.60–7.54 (m, 1H), 7.51–7.45 (m, 1H); 13C NMR filtered and concentrated in vacuo. Then the residue was puri-
(75 MHz, DMSO-d6) δ 188.0, 142.0, 141.4, 140.9, 139.0, 134.3 fied by column chromatography to afford compound 6 as a
(2C), 132.7(2C), 129.5, 128.3, 126.9, 125.4, 123.1, 118.1, 114.6; yellow solid (54.9 mg, 99% yield).
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Phenyl(8H-thieno[2,3-b]indol-2-yl)methanone (6). Yellow tion tube. The aqueous phase was extracted with EA. The
solid, 54.9 mg, 99% yield (PE/EA = 2 : 1 as the eluent), combined organic layers were dried over Na2SO4, filtered and
1
m.p. 196.5–197.4 °C; H NMR (400 MHz, DMSO-d6) δ 12.16 (s, concentrated in vacuo. Then the residue was purified by
1H), 8.24–8.11 (m, 1H), 7.67–7.52 (m, 4H), 7.31–7.15 (m, 2H); column chromatography to afford compound 9 as a yellow
13C NMR (101 MHz, DMSO-d6) δ 187.7, 148.1, 142.6, 138.3, solid (65.6 mg, 82% yield, Z/E = 1 : 1, determined by
135.2, 131.6, 128.8, 128.6, 128.6, 128.6, 128.5, 125.4, 123.5, 1H NMR).
122.1, 120.3, 119.9, 112.1; HRMS (ESI) calcd for C17H12NOS
[M + H]+: 278.0640; found: 278.0637.
tert-Butyl 2-(2-cyano-1-phenylvinyl)-8H-thieno[2,3-b]indole-
8-carboxylate (9). Yellow solid, 65.6 mg, 82% yield (PE/EA =
Synthesis of compound 7. NaBH4 (0.3 mmol, 12 mg) was 10 : 1 as the eluent), 200.5–201.4 °C, Z : E = 1 : 1; 1H NMR
added in portions to a solution of 3a (0.2 mmol, 67.5 mg) in (300 MHz, CDCl3) δ 8.17 (s, 1H), 7.63 (d, J = 7.5 Hz, 1H),
MeOH (2 mL) at 0 °C. The mixture was stirred at 0 °C until the 7.57–7.51 (m, 5H), 7.43–7.33 (m, 1H), 7.40–7.27 (m, 1H), 7.18
reaction was completed as monitored by TLC (30 min). When (s, 1H), 5.74 (s, 1H), 1.76 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
3a was consumed, H2O (3 mL) was added to the reaction tube. 157.2, 136.4, 132.0, 130.3, 129.5(2C), 129.1, 128.8(2C), 128.7,
The aqueous phase was extracted with DCM. The combined 127.4, 125.1, 123.8(2C), 119.6, 118.1, 115.8, 90.7, 86.0, 28.4
organic layers were dried over Na2SO4, filtered and concen- (3C); HRMS (ESI) calcd for
C24H20N2NaO2S [M +
Na]+:
trated in vacuo. Then the residue was purified by column 423.1138; found: 423.1140.
chromatography to afford compound 7 as a colorless oil
The reaction of 1a with diphenyl(2,2,2-trifluoroethyl)sulfo-
(75.1 mg, 99% yield).
nium ylide. 2-Mercaptoindole-3-carbaldehyde 1a (0.1 mmol,
tert-butyl 2-(hydroxy(phenyl)methyl)-8H-thieno[2,3-b]indole- 1.0 equiv.), diphenyl(2,2,2-trifluoroethyl)sulfonium ylide 17
8-carboxylate (7). Colorless oil, 75.1 mg, 99% yield (PE/EA = (0.12 mmol, 1.2 equiv.), DABCO (0.15 mmol, 1.5 equiv.) and
5 : 1 as the eluent); 1H NMR (300 MHz, DMSO-d6) δ 8.12 (s, EtOH (1.0 mL) were added to a reaction tube. The reaction
1H), 7.77 (d, J = 7.3 Hz, 1H), 7.50 (d, J = 7.0 Hz, 2H), 7.40–7.25 mixture was stirred at room temperature. After complete con-
(m, 5H), 7.20 (s, 1H), 6.40 (d, J = 4.3 Hz, 1H), 6.02 (d, J = 4.3 version of the starting material monitored by TLC, the reaction
Hz, 1H), 1.66 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 148.4, mixture was concentrated by rotary evaporation, and then the
147.3, 144.7, 138.5, 138.3, 128.2(2C), 127.2, 126.2(2C), 125.1, residue was directly purified by flash chromatography on silica
124.3, 123.9, 123.2, 119.2, 115.1, 113.8, 84.8, 71.1, 27.7(3C); gel (petroleum ether/ethyl acetate = 20 : 1) to give tert-butyl
HRMS (ESI) calcd for C22H21NNaO3S [M + Na]+: 402.1134; 3-formyl-2-((2,2,2-trifluoroethyl)thio)-1H-indole-1-carboxylate.
found: 402.1121.
tert-Butyl 3-formyl-2-((2,2,2-trifluoroethyl)thio)-1H-indole-1-
White solid, 33.4 mg, 93% yield,
Synthesis of compound 8. Ethynyl magnesium bromide carboxylate.
(2.0 equiv.) was added drop by drop under an argon atmo- m.p. 87.8–88.2–167.2 °C; 1H NMR (300 MHz, CDCl3) δ 10.51 (s,
sphere with a syringe to a solution of 3a (0.2 mmol, 67.5 mg) 1H), 8.42–8.31 (m, 1H), 8.03–7.92 (m, 1H), 7.49–7.31 (m, 2H),
and anhydrous THF (2 mL) at 0 °C. The mixture was 3.64 (q, J = 9.7 Hz, 2H), 1.76 (s, 9H); 13C NMR (75 MHz, CDCl3)
stirred at 0 °C until the reaction was completed as moni- δ 188.5, 148.9, 138.1, 137.0, 127.0, 126.6, 125.3, 125.2 (q, J =
tored by TLC. When 3a was consumed, saturated NH4Cl 274.5 Hz) 124.9, 122.1, 115.1, 86.7, 39.2 (q, J = 32.3 Hz), 28.2;
aqueous solution (2 mL) was added to the reaction tube. The HRMS (ESI) calcd for C16H16F3NNaO3S [M + Na]+: 382.0695;
aqueous phase was extracted with EA. The combined found: 382.0677.
organic layers were dried over Na2SO4, filtered and concen-
The reaction of 1-(2-mercaptophenyl)ethan-1-one with 2a. 1-
trated in vacuo. Then the residue was purified by column (2-Mercaptophenyl)ethan-1-one (0.1 mmol, 1.0 equiv.), sulfo-
chromatography to afford compound 8 as a colorless oil nium ylide 2a (0.12 mmol, 1.2 equiv.) and EtOH (1.0 mL) were
(52.4 mg, 65% yield).
added to a reaction tube. The reaction was carried out in
tert-Butyl 2-(1-hydroxy-1-phenylprop-2-yn-1-yl)-8H-thieno refluxing EtOH for 5 h. After complete conversion of the start-
[2,3-b]indole-8-carboxylate (8). Colorless oil, 52.4 mg, 65% ing material monitored by TLC, the reaction mixture was con-
1
yield (PE/EA = 8 : 1 as the eluent); H NMR (300 MHz, DMSO- centrated by rotary evaporation and then the residue was
d6) δ 8.10 (s, 1H), 7.86 (d, J = 7.4 Hz, 1H), 7.72–7.60 (m, 2H), directly purified by flash chromatography on silica gel (pet-
7.44–7.26 (m, 7H), 3.98 (s, 1H), 1.66 (s, 9H); 13C NMR (75 MHz, roleum ether/ethyl acetate = 20 : 1) to give the expected product
DMSO-d6) δ 148.2, 145.2, 138.6, 128.1(2C), 127.7, 125.5(2C), (3-hydroxy-3-methyl-2,3-dihydrobenzo[b]thiophen-2-yl)(phenyl)
124.7, 124.3, 124.1, 123.3, 119.5, 115.1, 114.5, 86.5, 85.0, 77.0, methanone.
70.7, 27.7(3C); HRMS (ESI) calcd for C24H21NNaO3S [M + Na]+:
426.4852; found: 426.4854.
(3-Hydroxy-3-methyl-2,3-dihydrobenzo[b]thiophen-2-yl)
(phenyl)methanone. Yellow oil, 25.7 mg, 95% yield. H NMR
1
Synthesis of compound 9. NaH (0.3 mmol, 12 mg, 60% dis- (300 MHz, CDCl3) δ 7.92 (dt, J = 7.1, 1.4 Hz, 2H), 7.70–7.56 (m,
persion in mineral oil) was added in portions to a solution of 1H), 7.56–7.45 (m, 2H), 7.45–7.36 (m, 1H), 7.33–7.16 (m, 2H),
diethyl (cyanomethyl)phosphonate (0.24 mmol, 67.5 mg) in 7.15–7.05 (m, 1H), 4.82 (s, 1H), 4.75 (s, 1H), 1.75 (s, 3H); 13C
anhydrous THF (2 mL) at 0 °C. After 10 min, 3a (0.2 mmol, NMR (75 MHz, CDCl3) δ 195.1, 145.1, 135.1, 134.5, 133.9,
67.5 mg) was added in portions, and the reaction was com- 129.0, 128.9, 128.6, 126.3, 123.2, 123.0, 84.4, 56.8, 27.3.; HRMS
pleted as monitored by TLC. When 3a was consumed, satu- (ESI) calcd for C16H14NaO2S [M + Na]+: 293.0607; found:
rated NH4Cl aqueous solution (2 mL) was added to the reac- 293.0601.
This journal is © The Royal Society of Chemistry 2021
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Paper
Organic & Biomolecular Chemistry
W.-B. Sheng, P. Yin, C.-T. Zhang, C.-Y. Peng, D.-M. Peng,
D.-F. Liao and R.-G. Fu, Tetrahedron Lett., 2019, 60, 80;
(d) J. Liu, Y. Zhang, Y. Yue, Z. Wang, H. Shao, K. Zhuo,
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
We are grateful for the financial support from the National Key
R&D Program of China (2018YFC0807301-3), the NSFC (no.
21901024, 21871252, 21801024 and 21801026), and the
Material Evidence Identification Center of Ministry of Public
Security (2019CSEEKFKT06).
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3686 | Org. Biomol. Chem., 2021, 19, 3678–3686
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