Multicomponent Synthesis of Benzothiophen-2-acetic Esters by a Palladium Iodide Catalyzed S-cyclization – Alkoxycarbonylation Sequence

Article abstract of DOI:10.1002/adsc.202100782

A catalytic carbonylative approach to the multicomponent synthesis of benzothiophene derivatives from simple building blocks [1-(2-(methylthio)phenyl)prop-2-yn-1-ols, carbon monoxide, and an alcohol)] is presented. It is based on an S-cyclization-demethylation-alkoxycarbonylation-reduction sequence promoted by the PdI₂/KI catalytic system, occurring under relatively mild conditions (40 atm, 80 °C, 15 h). Benzothiophene-2-acetic esters are obtained in moderate to good yields (35–70%) starting from variously substituted substrates in combination with different alcohols as external nucleophiles (17 examples). (Figure presented.).

Full text of DOI:10.1002/adsc.202100782

RESEARCH ARTICLE
doi.org/10.1002/adsc.202100782
Multicomponent Synthesis of Benzothiophen-2-acetic Esters by a
Palladium Iodide Catalyzed S-cyclization – Alkoxycarbonylation
Sequence
Raffaella Mancuso,a,* Melania Lettieri,a Ida Ziccarelli,a Patrizio Russo,a
Antonio Palumbo Piccionello,b and Bartolo Gabrielea,*
a
Laboratory of Industrial and Synthetic Organic Chemistry (LISOC), Department of Chemistry and Chemical Technologies,
University of Calabria, Via Pietro Bucci 12/C, 87036 Arcavacata di Rende (CS), Italy
E-mail: raffaella.mancuso@unical.it; bartolo.gabriele@unical.it
Department of Biological, Chemical and Pharmaceutical Science and Technology-STEBICEF, University of Palermo, Viale delle
b
Scienze Ed.17, Palermo 90128, Italy
Manuscript received: June 23, 2021; Revised manuscript received: August 16, 2021;
Version of record online: August 27, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100782
© 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the
terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Abstract: A catalytic carbonylative approach to the multicomponent synthesis of benzothiophene derivatives
from simple building blocks [1-(2-(methylthio)phenyl)prop-2-yn-1-ols, carbon monoxide, and an alcohol)] is
presented. It is based on an S-cyclization-demethylation-alkoxycarbonylation-reduction sequence promoted by
°
the PdI2/KI catalytic system, occurring under relatively mild conditions (40 atm, 80 C, 15 h). Benzothiophene-
2-acetic esters are obtained in moderate to good yields (35–70%) starting from variously substituted substrates
in combination with different alcohols as external nucleophiles (17 examples).
Keywords: benzothiophenes; carbonylation; S-cyclization; multicomponent reaction; palladium
Introduction
cycles. In this contest, metal-catalyzed carbonylative
heterocyclization processes have been playing a major
Benzothiophenes are among the most important hetero- role. With these reactions it is possible to simulta-
cyclic derivatives. The benzothiophene nucleus is neously activate the organic substrate and carbon
present in many natural products and pharmaceuticals. monoxide to give the final carbonylated derivative in
These molecules have shown important bioactivities, one step.[4]
including anti-cancer, antifungal, anti-diabetic, estro-
Compared to the huge number of examples of
gen receptor modulation, and leukotriene synthesis carbonylative O- and N-heterocyclizations known so
inhibition activities.[1] Benzothiophene derivatives are far,[5,6] carbonylative S-heterocyclizations have been
also very useful substrates in organic synthesis. In fact, reported in a limited number of cases.[4] This is mainly
they can be employed for the preparation of new due to the well-known “poisoning” effect that the
compounds that find application in the pharmaceutical sulfur atom may exert on the metal catalyst.[7] In
field as well as in materials science.[2] Accordingly, the addition, sulfur-containing substrates can be unstable
development of novel strategies for the synthesis of when the reaction is carried out in the presence of an
benzothiophenes (based, in particular, on catalytic external oxidant (as in oxidative carbonylations).[8]
reactions) is of particular importance and interest.[3]
Nevertheless, some important carbonylative S-cycliza-
Catalytic processes are known to convert simple tion processes have been reported in the literature.
and readily available starting materials into high value These include: the synthesis of benzothiophene-3-
added functionalized molecules, including hetero- carboxylic esters from MOM-protected 2-alkynylthio-
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phenols (Scheme 1a);[9] the preparation of benzothio-
phene-2-carboxylic derivatives from 2-(2,2-dihalovin-
Results and Discussion
yl)thiophenols (Scheme 1b);[10] and the synthesis of Our work hypothesis for the carbonylative synthesis of
thiophene-3-carboxylic esters from 1-(methylthio)-3- benzothiophene-2-acetates 2 from 1-(2-(methylthio)-
yn-2-ols.[8]
phenyl)prop-2-yn-1-ols 1 (Scheme 1c) was based on
To the best of our knowledge, no approach has the use of the catalytic system PdI2/KI. This catalyst
been reported to date for the direct carbonylative has been successfully employed by our group for
synthesis of benzothiophene-2-acetic esters from an promoting
acyclic precursor,[11] in spite of the importance of these heterocyclizations.[4]
derivatives.[12] In this work, we wish to fill this gap, by
As shown in Scheme 2, in the present case, an
a
variety
of
carbonylative
reporting the palladium iodide-catalyzed synthesis of initial S-cyclization would lead to sulfonium intermedi-
alkyl benzothiophene-2-acetates 2 starting from 1-(2- ate I. S-demethylation by the iodide anion would give
(methylthio)phenyl)prop-2-yn-1-ols 1, CO, and an complex II together with methyl iodide. Alkoxycarbo-
alcohol (Scheme 1c).
nylation of II then affords 2-(3-hydroxybenzo[b]
thiophen-2(3H)-ylidene)acetate intermediate III and a
palladium hydride species (HÀ PdÀ I). The allylalco-
holic moiety of III undergoes reduction by HÀ PdÀ I to
give π-allylpalladium complex IV with elimination of
water.[13] Protonolysis of IV by HI eventually affords
the desired product 2. HI is formed by the reaction of
MeI (previously obtained by iodide attack to I) with
water (Scheme 2; anionic iodide ligands are omitted
for clarity).
To assess our work hypothesis, we synthesized 1-
(2-(methylthio)phenyl)-3-phenylprop-2-yn-1-ol
1a
(R1 =R2 =H, R3 =Ph) by alkynylation of 2-(meth-
ylthio)benzaldehyde, and used it as model substrate to
optimize reaction conditions.
The first experiment was carried out in MeOH as
the solvent (1a concentration, 0.10 mmol per mL of
Scheme 1. (a, b) Previuosly reported[9,10] carbonylative S-cycli-
zation reactions to benzothiophene derivatives and (c) This
work: Synthesis of benzothiophene-2-acetic esters 2 by palla-
dium iodide-catalyzed carbonylative S-cyclization of 1-(2-
(methylthio)phenyl)prop-2-yn-1-ols 1.
°
MeOH), at 100 C for 15 h, under 30 atm of CO, and
in the presence of PdI2 (10 mol%) and an excess of KI
(2 equiv., to promote sulfur demethylation). However,
under these conditions, mainly substrate decomposition
was observed, and the desired product, methyl 2-
(benzo[b]thiophen-2-yl)-2-phenylacetate
2a,
was
formed only in traces (Table 1, entry 1). A detectable
yield of 2a (8%) could be observed when using a
larger excess of KI (3 equiv.) (Table 1, entry 2). The
yield improved to 26% with 15 equiv. of KI (Table 1,
entry 3) and to 40% with 30 equiv. of KI (Table 1,
entry 4). Under the last conditions, small amounts of 2-
(methoxy(phenyl)methyl)benzo[b]thiophene 3a,[14] de-
riving from annulative methoxylation without CO
incorporation, were also detected (2% and 5%,
respectively). With 30 equiv. of KI, the yield of 2a
dropped to ca. 25% when the process was performed
under more concentrated or diluted conditions (Ta-
ble 1, entries 5 and 6, respectively). On the other hand,
the 2a yield increased to 50–55% when performing the
process under higher CO pressures (Table 1, entries 7
and 8) or at a lower temperature (Table 1, entry 9). The
final optimized conditions therefore corresponded to
an 1a concentration=0.10 mmol/mL of MeOH, at
Scheme 2. Mechanistic hypothesis for the formation of benzo-
thiophene-2-acetic esters 2 by PdI2/KI-catalyzed carbonylation
of 1-(2-(methylthio)phenyl)prop-2-yn-1-ols 1.
°
80 C for 15 h under 40 atm of CO and in the presence
of 10 mol% PdI2 and 30 equiv. of KI. Under these
conditions, 2a was isolated with an acceptable yield of
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Table 1. PdI2/KI-catalyzed carbonylation of 1-(2-(methylthio)phenyl)-3-phenylprop-2-yn-1-ol 1a under different conditions.[a]
°
Entry
KI/1a/PdI2
molar ratio
T [ C]
Substrate
PCO
[atm]
Substrate
Yield of 2a
Yield of 3a
concentration[b]
conversion[c]
[%][d]
[%][d]
1
2
3
4
5
6
7
8
20:10:1
50:10:1
100
100
100
100
100
100
100
100
80
0.10
0.10
0.10
0.10
0.22
0.05
0.10
0.10
0.10
0.10
0.10
0.10
30
30
30
30
30
30
40
60
30
40
40
40
30
42
75
91
91
90
92
98
92
100
41
100
traces
8
0
0
2
5
1
4
4
5
150:10:1
300:10:1
300:10:1
300:10:1
300:10:1
300:10:1
300:10:1
300:10:1
300:20:1
300:10:1
26
40
25
24
50
52
55
70
23
0
9
traces
10
11
12[e]
80
80
80
0
0
0
[a] Unless otherwise noted, all reactions were carried out in MeOH as the solvent for 15 h.
[b] Mmol of 1a per mL of MeOH.
[c] Determined by isolation of unreacted 1a from the reaction mixture.
[d] Isolated yield based on starting 1a.
[e] The reaction was carried out with PdCl2 and KCl in place of PdI2 and KI, and led to the formation of (2-(1-methoxy-3-
phenylprop-2-yn-1-yl)phenyl)(methyl)sulfane 4a in 54% isolated yield.
70%, with formation of traces of byproduct 3a group. This is exemplified by the reaction of 2-(2-
(Table 1, entry 10). With a lower catalyst loading (methylthio)phenyl)-4-phenylbut-3-yn-2-ol 1k (R1 =
(5 mol%), the process was significantly less efficient, H, R2 =Me, R3 =Ph), which was converted into a
as shown in Table 1, entry 11. Interestingly, the use of mixture of methyl 2-(3-methylbenzo[b]thiophen-2-yl)-
PdCl2/KCl in place of PdI2/KI did not lead to the 2-phenylacetate 2k and 2-(methoxy(phenyl)methyl)-3-
formation of 2a, and the substrate was converted into methylbenzo[b]thiophene 3k[14] (45% and 18% yields,
its methyl ether 4a in 54% yield, (Table 1, entry 12). respectively; Table 2, entry 11). This is likely due to
This latter result clearly shows the importance of the the steric effect exerted by the R2 substituent, which
iodide anions for the success of the carbonylative tends to make less efficient the CO insertion into
process leading to 2a, according to the mechanistic intermediate II (see Scheme 2). With 1-(2-(methylthio)
hypothesis shown in Scheme 2.
phenyl)-1,3-diphenylprop-2-yn-1-ol 1l (R1 =H, R2 =
To verify the generality of the process, we then R3 =Ph), the yield of the corresponding methyl
applied the optimized conditions to differently sub- benzothiophene-2-acetate 2l was 50% (Table 2, en-
stituted substrates; the results obtained are shown in try 12). Unfortunately, when the triple bond was
Table 2. The presence of an electron-donating group at substituted with an alkyl group, such as butyl (sub-
the para position of the phenyl group bonded to the strate 1m), the product yield was modest (yield of 2m,
triple bond (Me, t-Bu, or OMe) led to the correspond- 35%; Table 2, entry 13). On the other hand, a hetero-
ing methyl benzothiophene-2-acetic esters 2b–d in 66– aromatic ring, such as 3-thienyl (substrate 1n), led to a
68% yields (Table 2, entries 2–4). A halogen atom good yield of the corresponding product 2n (68%;
such as bromine or chlorine on the phenyl substituent Table 2, entry 14).
was compatible as well, the corresponding benzothio-
The reaction also worked nicely when a higher
phene derivatives being formed in 64–65% yields alcohol was employed as solvent and external nucleo-
(Table 2, entries 5–7). The reaction of substrates 1h–j, phile. The results obtained with 1a in EtOH, PrOH,
bearing a methyl or methoxy substituent on the and i-PrOH are shown in Table 2, entries 15-17. With
aromatic ring in different positions with respect to the these alcohols, the substrate conversion rate was
methylthio group, was also successful (Table 2, en- slower with respect to MeOH, so the reaction time was
tries 8–10).
increased to 24 h. As can be seen from entries 15–17,
The yields tended to be lower when the substrate the product yield depended on the nucleophilicy of the
presented a tertiary rather than secondary alcoholic alcohol, the lowest yield (51%) being obtained with
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Table 2. Synthesis of benzothiophene-2-acetic esters 2 by PdI2/KI-catalyzed carbonylation of 1-(2-(methylthio)phenyl)prop-2-yn-1-
ols 1.[a]
Entry
1
ROH
2
Yield of 2 [%][b]
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Table 2. continued
Entry
1
ROH
2
Yield of 2 [%][b]
[a]
°
Unless otherwise noted, all reactions were carried out in ROH as the solvent (0.10 mmol of 1 per mL of ROH) at 80 C for 15 h
under 40 atm of CO, in the presence of PdI2 (10 mol%) and KI (30 equiv.). Substrate conversion was quantitative in all cases.
[b] Isolated yield based on starting 1.
[c] The reaction also led to the formation of 2-(methoxy(phenyl)methyl)-3-methylbenzo[b]thiophene 3k (18%).
[d] The reaction was carried out for 24 h.
the most sterically hindered isopropanol (Table 2, group to the triple bond coordinated to the Pd(II)
entry 17).[15]
center) followed by iodide-promoted demethylation
and alkoxycarbonylation. This leads to a 2-(3-hydrox-
ybenzo[b]thiophen-2(3H)-ylidene)acetate intermediate
and an HÀ PdÀ I complex. The formation of a π-
Conclusion
In conclusion, we have reported a carbonylative allylpalladium complex then takes place, from which
approach to the synthesis of benzothiophene-2-acetic the final product is formed by protonolysis.
esters starting from readily available 1-(2-(methylthio)
Our method therefore represents a direct carbon-
phenyl)prop-2-yn-1-ols, under the catalysis of palla- ylative approach to benzothiophene-2-acetic esters (an
dium iodide in the presence of an excess of potassium important class of heterocycles, with several applica-
iodide.
The catalytic process takes place through an
tions) from acyclic precursors.
ordered sequence of steps, involving S-cyclization (by
intramolecular nucleophilic attack by the thiomethyl
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Experimental Section
Synthesis of Methyl 2-(Benzo[b]Thiophen-2-yl)-
2-Phenylacetate 2a in Larger Scale
General Experimental Methods
A 50 mL stainless-steel autoclave was charged in the presence
of air with PdI2 (42.5 mg, 0.118 mmol), KI (5.9 g, 35.4 mmol),
1
Melting points are uncorrected. H NMR and 13C NMR spectra
°
were recorded at 25 C in CDCl3 at 300 MHz or 500 MHz and
and
1-(2-(methylthio)phenyl)-3-phenylprop-2-yn-1-ol
1a
75 MHz or 125 MHz, respectively, with Me4Si as internal
standard. Chemical shifts (δ) and coupling constants (J) are
given in ppm and in Hz, respectively. IR spectra were taken
with an FT-IR spectrometer. Mass spectra were obtained using a
GC-MS apparatus at 70 eV ionization voltage (normal reso-
lution) and by electrospray ionization mass spectrometry (ESI-
MS) (high resolution) with a UHD accurate-mass Q-TOF
spectrometer equipped with a Dual AJS ESI source working in
positive mode or negative mode, and were recorded in the 150–
1000 m/z range. The flow-rate was 0.4 mL/min and the column
(300 mg, 1.18 mmol;) in MeOH (11.8 mL). The autoclave was
sealed, purged at room temperature several times with CO with
stirring (5 atm), and finally pressurized with CO (40 atm). After
°
being stirred at 80 C for 15 h, the autoclave was cooled,
degassed and opened. The solvent was evaporated and the
products were purified by column chromatography on silica gel
using as eluent 99:1 hexane-AcOEt (Yield: 230 mg, 69% based
on starting 1a).
Methyl 2-(benzo[b]thiophen-2-yl)-2-phenylacetate (2a):
Yield: 61.4 mg, starting from 79.0 mg of 1a (70%) (Table 2,
°
temperature was set to 30 C. The eluents were formic acid-
°
water (0.1:99.9, v/v) (phase A) and formic acid–acetonitrile
(0.1:99.9, v/v) (phase B). The following gradient was employed:
0–10 min, linear gradient from 5% to 95% B; 10–15 min,
washing and reconditioning of the column to 5% B. Injection
volume was 10 μL. The eluate was monitored through MS TIC.
The LCÀ MS experimental conditions were as follows: N2 was
entry 1). Yellow solid, mp=73–74 C. IR (KBr): v=1736 (s),
1458 (w), 1435 (m), 1296 (w), 1204 (m), 1157 (m), 1011 (w),
995 (w), 748 (m), 725 (w), 702 (w); 1H NMR (CDCl3,
500 MHz): δ=7.76–7.72 (m, 1H, aromatic), 7.70–7.67 (m, 1H,
aromatic), 7.45–7.25 (m, 2H, aromatic), 7.38–7.33 (m, 2H,
aromatic), 7.33–7.24 (m, 3H, aromatic), 7.21 (s, 1H at C-3),
5.27 (s, 1H, CHCO2Me), 3.78 (s, 3H, CO2Me); 13C NMR
(CDCl3, 125 MHz): δ=171.7, 141.9, 139.9, 139.4, 137.7,
128.8, 128.4, 128.0, 124.3, 124.2, 123.5, 123.0, 122.1, 52.9;
GC-MS (EI, 70 eV): m/z=282 (M+, 25), 223 (100), 221 (31),
178 (12); HRMS (ESI-TOF) m/z: [M+Na]+ calcd for
[C17H14NaO2S]+: 305.0607, found: 305.0621.
°
employed as desolvation gas at 300 C and a flow rate of 9 L/
min. The nebulizer was set to 45 psig. The Sheat gas temper-
ature was set at 350 C and a flow of 12 L/min. A potential of
°
3.5 kV was used on the capillary for positive ion mode or
2.6 kV for negative ion mode. The fragmentor was set to 175 V.
All reactions were analyzed by TLC on silica gel 60 F254 and by
GLC-MS using a gas chromatograph and capillary columns
with polymethylsilicone +5% phenylsilicone as the stationary
phase. Column chromatography was performed on silica gel 60
(70–230 mesh). Evaporation refers to the removal of solvent
under reduced pressure.
Ethyl 2-(benzo[b]thiophen-2-yl)-2-phenylacetate (2a’): Yield:
61.0 mg, starting from 79.1 mg of 1a (66%) (Table 2, entry 15).
°
Yellow solid, mp=59–60 C. IR (KBr): v=1736 (s), 1458 (w),
1435 (w), 1296 (w), 1150 (m), 1026 (m), 748 (w), 725 (w), 702
(w); 1H NMR (CDCl3, 300 MHz): δ=7.77–7.73 (m, 1H,
aromatic), 7.71–7.67 (m, 1H, aromatic), 7.46–7.42 (m, 2H,
aromatic), 7.38–7.24 (m, 5H, aromatic), 7.22 (s, 1H at C-3),
5.25 (s, 1H, CHCO2Et), 4.30–4.19 (m, 2H, CH2CH3), 1.28 (t,
J=7.1, 3H, Me); 13C NMR (CDCl3, 75 MHz): δ=171.2, 142.1,
139.9, 139.4, 137.9, 128.8, 128.3, 127.8, 124.24, 124.17, 123.4,
122.9, 122.1, 61.7, 53.1, 14.1; GC-MS (EI, 70 eV): m/z=296
(M+, 22), 223 (100), 221 (27), 178 (13); HRMS (ESI-TOF) m/
z: [MÀ H]À calcd for [C18H15O2S]À : 295.0798, found: 295.0796.
Preparation of Substrates 1
1-(2-(Methylthio)phenyl)prop-2-yn-1-ols 1a–n were prepared
by alkynylation of 2-(methylthio)benzaldehydes, 1-(2-(meth-
ylthio)phenyl)ethan-1-one, and (2-(methylthio)phenyl)(phenyl)
methanone, as described in the Supporting Information.
General Procedure for the Synthesis of Benzothio-
phen-2-Acetic Esters 2
Propyl 2-(benzo[b]thiophen-2-yl)-2-phenylacetate (2a’’):
Yield: 59.0 mg, starting from 79.0 mg of 1a (61%) (Table 2,
°
entry 16). Yellow solid, mp=72–74 C. IR (KBr): v=1736 (s),
A 50 mL stainless-steel autoclave was charged in the presence
of air with PdI2 (11.0 mg, 0.031 mmol), KI (1.54 g, 9.3 mmol),
and substrate 1 (0.31 mmol; 1a, 79.0 mg; 1b, 83.0 mg; 1c,
96.5 mg; 1d, 88.0 mg; 1e, 103.5 mg; 1f, 90.0 mg; 1g, 89.5 mg;
1h, 83.0 mg; 1i, 88.5 mg; 1j, 88.0 mg; 1k, 83.5 mg; 1l,
103.0 mg; 1m, 73.0 mg; 1n, 81.0 mg) in ROH (3.1 mL). The
autoclave was sealed, purged at room temperature several times
with CO with stirring (5 atm), and finally pressurized with CO
1596 (w), 1574 (w), 1458 (w), 1435 (m), 1319 (w), 1296 (w),
1
1204 (m), 1157 (s), 1011 (m), 748 (m), 725 (m); H NMR
(CDCl3, 500 MHz): δ=7.77–7.72 (m, 1 H, aromatic), 7.70–
7.66 (m, 1 H, aromatic), 7.46–7.41 (m, 2H, aromatic), 7.37–
7.23 (m, 5H, aromatic), 7.22 (s, 1H at C-3), 5.26 (s, 1H,
CHCO2Pr), 4.18–4.09 (m, 2 H, CH2CH2CH3), 1.67 (sextuplet,
J=7.3, 2H, CH2CH2CH3), 0.90 (t, J=7.3, 3 H, CH2CH2CH3);
13C NMR (CDCl3, 125 MHz): δ=171.3, 142.1, 140.0, 139.4,
138.0, 128.8, 128.4, 127.9, 124.3, 124.2, 123.5, 123.0, 122.1,
67.3, 53.2, 21.9, 10.3; GC-MS (EI, 70 eV): m/z=310 (M+, 10),
223 (100), 221 (27), 178 (12); HRMS (ESI-TOF) m/z: [M+
H]+calcd for [C19H19O2S]+: 311.1100, found: 311.1100.
°
(40 atm). After being stirred at 80 C for 15 h (ROH=MeOH)
or 24 h (ROH=EtOH, PrOH, i-PrOH), the autoclave was
cooled, degassed and opened. The solvent was evaporated and
the products 2a–n were purified by column chromatography on
silica gel using as eluent 99:1 hexane-AcOEt.
Isopropyl 2-(benzo[b]thiophen-2-yl)-2-phenylacetate (2a’’’):
Yield: 49.0 mg, starting from 78.9 mg of 1a (51%) (Table 2,
°
entry 17). Yellow solid, mp=67–68 C. IR (KBr): v=1728 (s),
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1
1458 (w), 1373 (w), 1296 (w), 1204 (m), 1103 (s), 748 (w); H
NMR (CDCl3, 300 MHz): δ=7.78–7.72 (m, 1H, aromatic),
7.72–7.65 (m, 1H, aromatic), 7.49–7.21 (m, 7H, aromatic), 7.20
131.9, 130.1, 124.4, 123.5, 123.1, 122.13, 122.08, 52.8, 52.3;
GC-MS (EI, 70 eV): m/z=362 [(M+2)+, 26], 360 (M+, 26),
303 (75), 301 (78), 221 (100), 111 (17); HRMS (ESI-TOF) m/z:
[MÀ H]À calcd for [C17H12BrO2S]À : 358.9747, found: 358.9749.
i
(s, 1 H at C-3), 5.21 (s, 1H, CHCO2 Pr), 5.16–5.03 (m, 1H,
CHMe2), 1.35–1.17 [m, 6H, CH(CH3)2]; 13C NMR (CDCl3,
75 MHz): δ=170.7, 142.3, 140.0, 139.4, 138.0, 128.7, 128.3,
127.8, 124.2, 124.1, 123.4, 122.9, 122.1, 69.3, 53.4, 21.7, 21.6;
GC-MS (EI, 70 eV): m/z=310 (M+, 17), 223 (100), 221 (24),
178 (11); HRMS (ESI-TOF) m/z: [MÀ H]À calcd for
[C19H17O2S]À : 309.0955, found: 309.0953.
Methyl 2-(benzo[b]thiophen-2-yl)-2-(4-chlorophenyl)acetate
(2f): Yield: 64.1 mg, starting from 90.0 mg of 1f (65%)
°
(Table 2, entry 6). Yellow solid, mp=40–42 C. IR (KBr): v=
1736 (s), 1489 (w), 1435 (w), 1204 (w), 1157 (m), 1096 (w),
1
1011 (w), 826 (w), 748 (m); H NMR (CDCl3, 500 MHz): δ=
7.75 (d, J=7.9, 1H, aromatic), 7.72–7.68 (m, 1H, aromatic),
7.39–7.34 (m, 2 H, aromatic), 7.34–7.26 (m, 4H, aromatic),
7.20 (s, 1 H at C-3), 5.22 (s, 1H, CHCO2Me), 3.79 (s, 3H,
CO2Me); 13C NMR (CDCl3, 125 MHz): δ=171.3, 141.3, 139.9,
139.3, 136.2, 133.9, 129.8, 129.0, 124.4, 123.5, 123.1, 122.2,
52.2; GC-MS (EI, 70 eV): m/z=318 [(M+2)+, 9], 316 (M+,
24), 257 (100), 221 (70), 111 (13); HRMS (ESI-TOF) m/z:
[MÀ H]À calcd for [C17H12ClO2S]À : 315.0252, found: 315.0254.
Methyl 2-(benzo[b]thiophen-2-yl)-2-(p–tolyl)acetate (2b):
Yield: 62.5 mg, starting from 83.0 mg of 1b (68%) (Table 2,
°
entry 2). Yellow solid, mp=56–57 C. IR (KBr): v=1736 (s),
1512 (w), 1458 (w), 1435 (w), 1304 (w), 1204 (w), 1157 (s),
1
995 (w), 826 (m), 748 (m); H NMR (CDCl3, 500 MHz): δ=
7.75–7.72 (m, 1H, aromatic), 7.69–7.66 (m, 1H, aromatic),
7.33–7.24 (m, 4H, aromatic), 7.20 (s, 1H at C-3), 7.18–7.14 (m,
2H, aromatic), 5.23 (s, 1H, CHCO2Me), 3.77 (s, 3H, CO2Me),
2.23 (s, 3H, p-Me); 13C NMR (CDCl3, 125 MHz): δ=171.9,
142.3, 140.0, 139.4, 137.7, 134.8, 129.5, 128.2, 124.3, 124.2,
123.5, 122.9, 122.1, 52.6, 52.5, 21.1; GC-MS (EI, 70 eV): m/
z=296 (M+, 25), 237 (100), 221 (39); HRMS (ESI-TOF) m/z:
[M+H]+ calcd for [C18H17O2S]+: 297.0944, found: 297.0990.
Methyl 2-(benzo[b]thiophen-2-yl)-2-(3-chlorophenyl)acetate
(2g): Yield: 63.0 mg, starting from 89.5 mg of 1g (64%)
°
(Table 2, entry 7). Yellow solid, mp=67–69 C. IR (KBr): v=
1736 (s), 1597 (w), 1574 (w), 1435 (m), 1319 (w), 1296 (w),
1204 (m), 1157 (s), 1011 (w), 748 (m); 1H NMR (CDCl3,
500 MHz): δ=7.76 (d, J=7.7, 1H, aromatic), 7.73–7.69 (m, 1
H, aromatic), 7.43 (s, br, 1H, aromatic), 7.35–7.27 (m, 5H,
aromatic), 7.23 (s, 1 H at C-3), 5.23 (s, 1H, CHCO2Me), 3.79
(s, 3H, CO2Me); 13C NMR (CDCl3, 75 MHz): δ=171.1, 140.9,
139.9, 139.5, 139.3, 134.6, 130.0, 128.5, 128.2, 126.6, 124.4,
123.6, 123.2, 122.1, 52.8, 52.5; GC-MS (EI, 70 eV): m/z=318
[(M+2)+, 11], 316 (M+, 29), 257 (100), 221 (72), 189 (6), 110
(11); HRMS (ESI-TOF) m/z: [MÀ H]À calcd for
[C17H12ClO2S]À : 315.0252, found: 315.0256.
Methyl
2-(benzo[b]thiophen-2-yl)-2-4-(tert-butyl)phenyl)
acetate (2c): Yield: 70.5 mg, starting from 96.5 mg of 1c
°
(67%) (Table 2, entry 3). Yellow solid, mp=66–68 C. IR
(KBr): v=1744 (s), 1512 (w), 1458 (w), 1435 (w), 1204 (m),
1157 (s), 1018 (w), 841 (w), 748 (m); 1H NMR (CDCl3,
500 MHz): δ=7.75 (d, J=7.9, 1 H, aromatic), 7.71–7.67 (m, 1
H, aromatic), 7.39–7.33 (m, 4 H, aromatic), 7.33–7.24 (m, 2 H,
aromatic), 7.22 (s, 1 H at C-3) 5.25 (s, br, 1H, CHCO2Me), 3.78
(s, 3H, CO2Me), 1.30 (s, 9H, t-Bu); 13C NMR (CDCl3,
75 MHz): δ=171.9, 150.8, 142.1, 139.9, 139.4, 134.7, 127.9,
125.7, 124.24, 124.15, 123.4, 122.9, 122.1, 52.61, 52.54, 34.5,
31.3; GC-MS (EI, 70 eV): m/z=338 (M+, 32), 279 (100), 249
(18), 223 (27), 118 (11); HRMS (ESI-TOF) m/z: [MÀ H]À calcd
for [C21H21O2S]À : 337.1268, found: 337.1268.
Methyl 2-(5-methylbenzo[b]thiophen-2-yl)-2-phenylacetate
(2h): Yield: 59.0 mg, starting from 83.0 mg of 1h (64%)
°
(Table 2, entry 8). Yellow solid, mp=59–61 C. IR (KBr): v=
1736 (s), 1450 (m), 1211 (w), 1157 (m), 995 (w), 880 (w), 802
1
(w), 756 (m); H NMR (CDCl3, 500 MHz): δ=7.61 (d, J=8.1,
1H, aromatic), 7.48 (s, 1H, aromatic), 7.45–7.37 (m, 2H,
aromatic), 7.37–7.26 (m, 3H, aromatic), 7.13 (s, 1H, aromatic),
7.09 (d, J=8.2, 1H, aromatic), 5.24 (s, 1H, CHCO2Me), 3.77
(s, 3H, CO2Me), 2.42 (s, 3H, Me at C-5); 13C NMR (CDCl3,
125 MHz): δ=171.7, 141.9, 139.7, 137.8, 137.1, 134.0, 128.8,
128.4, 127.9, 126.0, 123.4, 122.7, 121.8, 53.0, 52.7, 21.4; GC-
MS (EI, 70 eV): m/z=296 (M+, 30), 237 (100), 222 (36), 221
(40), 202 (5), 189 (3), 111 (4); HRMS (ESI-TOF) m/z: [MÀ H]À
calcd for [C18H15O2S]À : 295.0798, found: 295.0801.
Methyl
2-(benzo[b]thiophen-2-yl)-2-(p-methoxyphenyl)
acetate (2d): Yield: 64.1 mg, starting from 88.0 mg of 1d
(66%) (Table 2, entry 4). Yellow solid, mp=69–70 C. IR
(KBr): v=1736 (s), 1612 (w), 1512 (m), 1458 (w), 1435 (m),
1304 (w), 1250 (s), 1157 (s), 1034 (m), 833 (m), 748 (m); H
NMR (CDCl3, 500 MHz): δ=7.75–7.72 (m, 1H, aromatic),
7.69–7.66 (m, 1H, aromatic), 7.37–7.23 (m, 4H, aromatic), 7.19
(s, 1H at C-3), 6.90–6.85 (m, 2H, aromatic), 5.21 (s, 1H,
CHCO2Me), 3.79 (s, 3H, OMe), 3.77 (s, 3H, OMe); 13C NMR
(CDCl3, 125 MHz): δ=171.9, 159.3, 142.5, 139.9, 139.4,
129.9, 129.5, 124.3, 124.2, 123.5, 122.8, 122.1, 114.2, 55.3,
52.6, 52.2; GC-MS (EI, 70 eV): m/z=312 (M+, 18), 253 (100),
221 (14); HRMS (ESI-TOF) m/z: [M+Na]+ calcd for
[C18H16NaO3S]+: 335.0712, found: 335.0732.
°
1
Methyl 2-(5-methoxylbenzo[b]thiophen-2-yl)-2-phenylace-
tate (2i): Yield: 64.0 mg, starting from 88.5 mg of 1i (66%)
°
(Table 2, entry 9). Yellow solid, mp=87–89 C. IR (KBr): v=
1736 (s), 1605 (m), 1458 (m), 1435 (m), 1219 (m), 1157 (s),
1
1026 (w), 702 (w); H NMR (CDCl3, 300 MHz): δ=7.60 (d,
J=8.8, 1H, aromatic), 7.47–7.28 (m, 5H, aromatic), 7.17–7.11
(m, 2H, aromatic), 6.93 (dd, J=8.8, 2.0, 1H, aromatic), 5.24 (s,
1H, CHCO2Me), 3.83 (s, 3H, OMe), 3.78 (s, 3H, OMe); 13C
NMR (CDCl3, 75 MHz): δ=171.7, 157.5, 143.1, 140.4, 137.7,
132.3, 128.8, 128.3, 127.9, 122.9, 122.8, 114.4, 105.7, 55.5,
53.0, 52.7; GC-MS (EI, 70 eV): m/z=312 (M+, 35), 253 (100),
238 (8), 221 (26), 165 (10); HRMS (ESI-TOF) m/z: [MÀ H]À
calcd for [C18H15O3S]À : 311.0747, found: 311.0747.
Methyl 2-(benzo[b]thiophen-2-yl)-2-(4-bromophenyl)acetate
(2e): Yield: 73.0 mg, starting from 103.5 mg of 1e (65%)
(Table 2, entry 5). Yellow solid, mp=42–44 C. IR (KBr): v=
1736 (s), 1489 (w), 1435 (w), 1204 (w), 1157 (m), 1011 (w),
748 (m); H NMR (CDCl3, 300 MHz): δ=7.79–7.63 (m, 2H,
aromatic), 7.52–7.40 (m, 2H, aromatic), 7.36–7.15 (m, 5H,
aromatic), 5.22 (s, 1H, CHCO2Me), 3.78 (s, 3H, CO2Me); 13C
NMR (CDCl3, 75 MHz): δ=171.2, 141.1, 139.9, 139.3, 136.7,
°
1
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Methyl 2-(6-methoxylbenzo[b]thiophen-2-yl)-2-phenylace-
tate (2j): Yield: 63.0 mg, starting from 88.0 mg of 1j (65%)
(CDCl3, 300 MHz): δ=7.80–7.72 (m, 1H, aromatic), 7.72–7.65
(m, 1H, aromatic), 7.37–7.10 (m, 6H, aromatic), 5.37 (s, 1H,
CHCO2Me), 3.79 (s, 3H, CO2Me); 13C NMR (CDCl3, 75 MHz):
δ=171.4, 141.6, 139.9, 139.4, 137.6, 127.7, 126.1, 124.33,
124.29, 123.5, 123.3, 122.8, 122.2, 52.7, 48.5; GC-MS (EI,
70 eV): m/z=288 (M+, 24), 229 (100), 227 (11), 184 (19);
HRMS (ESI-TOF) m/z: [MÀ H]À calcd for [C15H11O2S]À :
287.0206, found: 287.0208.
°
(Table 2, entry 10). Yellow solid, mp=42–44 C. IR (KBr): v=
1736 (s), 1497 (w), 1458 (w), 1435 (m), 1319 (m), 1196 (m),
1
1157 (m), 1011 (m), 756 (m); H NMR (CDCl3, 300 MHz): δ=
7.60–7.53 (m, 1H, aromatic), 7.46–7.26 (m, 5 H, aromatic),
7.22 (d, J=2.4, 1H, aromatic), 7.10 (s, 1H at C-3), 6.93 (dd,
J=8.7, 2.4, 1H, aromatic), 5.23 (s, 1H, CHCO2Me), 3.83 (s,
3H, OMe), 3.78 (s, 3H, OMe); 13C NMR (CDCl3, 125 MHz):
δ=171.8, 157.4, 141.4, 139.1, 137.9, 133.4, 128.8, 128.4,
127.9, 124.1, 122.6, 114.4, 104.7, 65.9, 55.6, 52.9; GC-MS (EI,
70 eV): m/z=312 (M+, 25), 253 (100), 221 (18), 209 (24);
HRMS (ESI-TOF) m/z: [M+H]+ calcd for [C18H17O3S]+:
313.0893, found: 313.0891.
(2-(1-Methoxy-3-phenylprop-2-yn-1-yl)phenyl)(methyl)-
sulfane (4a): Yield: 45 mg, starting from 79.0 mg of 1a (54%)
(Table 1, entry 12). Yellow oil. IR (KBr): v=2222 (w), 1589
(m), 1443 (m), 1319 (m), 1273 (w), 1188 (m), 1080 (s), 988
1
(m), 756 (s); H NMR (CDCl3, 500 MHz): δ=7.79 (d, J=7.2,
1H, aromatic), 7.52–7.46 (m, 2H, aromatic), 7.37–7.27 (m, 5H,
aromatic), 7.26–7.21 (m, 1H, aromatic), 5.71 (s, 1H, CHOMe),
3.54 (s, 3H, OMe), 2.50 (s, 3 H, SMe); 13C NMR (CDCl3, 125
MHz): δ=137.7, 137.2, 131.8, 129.1, 128.5, 128.3, 127.9,
127.5, 125.7, 122.6, 87.7, 86.5, 70.8, 56.3, 17.0; GC-MS (EI,
70 eV): m/z=268 (M+, absent), 253 (100), 238 (28), 221 (35),
189 (8), 161 (15), 111 (16).
Methyl 2-(3-methylbenzo[b]thiophen-2-yl)-2-phenylacetate
(2k): Yield: 41.7 mg, starting from 83.5 mg of 1k (45%)
(Table 2, entry 11). Yellow oil. IR (film): v=1736 (s), 1458
(w), 1435 (m), 1319 (m), 1227 (w), 1196 (m), 1157 (m), 1011
1
(w), 756 (m), 725 (m), 702 (w); H NMR (CDCl3, 300 MHz):
δ=7.75 (dist d, J=7.4, 1H, aromatic), 7.64 (dist d, J=7.4, 1H,
aromatic), 7.46–7.19 (m, 7H, aromatic), 5.43 (s, 1H,
CHCO2Me), 3.77 (s, 3H, CO2Me), 2.35 (s, 3H, Me at C-3); 13C
NMR (CDCl3, 75 MHz): δ=172.0, 140.1, 139.0, 137.7, 135.2,
129.1, 128.8, 128.3, 127.7, 124.2, 123.9, 122.2, 121.6, 52.6,
51.0, 11.9; GC-MS (EI, 70 eV): m/z=296 (M+, 20), 237 (100),
147 (7), 115 (9); HRMS (ESI-TOF) m/z: [M+Na]+ calcd for
[C18H16NaO2S]+: 319.0763, found: 319.0765.
Acknowledgements
We thank AtenCenter, University of Palermo, for HRMS
measurements.
References
Methyl 2-phenyl-2-(3-phenylbenzo[b]thiophen-2-yl)acetate
(2l): Yield: 56.0 mg, starting from 103.0 mg of 1l (50%)
(Table 2, entry 12). Colorless oil. IR (film): v=1736 (s), 1597
(w), 1435 (m), 1312 (w), 1196 (m), 1157 (m), 1011 (m), 756
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(m), 702 (m); H NMR (CDCl3, 300 MHz): δ=7.84–7.81 (m,
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1H, aromatic), 7.81–7.77 (m, 1H, aromatic), 7.54–7.40 (m, 5H,
aromatic), 7.35–7.25 (m, 7H, aromatic), 5.34 (s, 1H,
CHCO2Me), 3.72 (s, 3H, CO2Me); 13C NMR (CDCl3, 75 MHz):
δ=172.1, 139.6, 139.3, 138.3, 137.4, 136.0, 134.8, 130.1,
128.7, 128.2, 127.9, 127.6, 124.6, 124.2, 123.2, 122.1, 52.6,
51.2; GC-MS (EI, 70 eV): m/z=358 (M+, 32), 299 (59), 221
(100); HRMS (ESI-TOF) m/z: [MÀ H]À calcd for [C23H17O2S]À :
357.0955, found: 357.0948.
Methyl 2-(benzo[b]thiophen-2-yl)hexanoate (2m): Yield:
28.5 mg, starting from 73.0 mg of 1m (35%) (Table 2,
entry 13). Yellow oil. IR (film): v=1736 (s), 1458 (w), 1435
(w), 1219 (m), 1165 (m), 1018 (w), 772 (m), 748 (m); 1H NMR
(CDCl3, 500 MHz): δ=7.77 (d, J=7.9, 1H, aromatic), 7.69 (d,
J=7.9, 1H, aromatic), 7.35–7.24 (m, 2H, aromatic), 3.90 (t, J=
7.7, 1H, CHCO2Me), 3.71 (s, 3H, CO2Me), 2.17–2.07 (m, 1H,
CHCHH), 1.97–1.87 (m, 1H, CHCHH), 1.42–1.25 (m, 4 H,
CH2CH2CH3), 0.89 (t, J=7.0, 3 H, CH2CH3); 13C NMR (CDCl3,
125 MHz): δ=173.3, 142.6, 139.5, 124.3, 124.1, 123.3, 122.2,
122.07, 122.06, 52.3, 47.7, 33.9, 29.6, 22.4, 13.8; GC-MS (EI,
70 eV): m/z=262 (M+, 21), 206 (15), 203 (19), 174 (9), 161
(10), 147 (100), 115 (12); HRMS (ESI-TOF) m/z: [M+H]+
calcd for [C15H19O2S]+: 263.1100, found: 263.1100.
Methyl 2-(benzo[b]thiophen-2-yl)-2-(thiophen-3-yl)acetate
(2n): Yield: 61.0 mg, starting from 81.0 mg of 1n (68%)
°
(Table 2, entry 14). Yellow solid, mp=144–146 C. IR (KBr):
v=1736 (s), 1458 (w), 1435 (m), 1319 (w), 1304 (w), 1196
1
(w), 1157 (m), 1080 (w), 1011 (w), 748 (m), 725 (w); H NMR
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allylalcoholic moieties was observed by us in other cases.
See references 11a-e and: a) B. Gabriele, G. Salerno, M.
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8286.
[11] The synthesis of benzofuran-2-acetic derivatives and [15] No reaction took place with highly hindered tert-butanol,
indol-2-acetic esters starting from 1-(2-allyloxyphenyl)-
2-yn-1-ols and 1-(2-aminoaryl)-2-yn-1-ols, respectively,
while a complex mixture of products was formed with a
high-boiling alcohol, such as phenethyl alcohol.
Adv. Synth. Catal. 2021, 363, 1–10
9
© 2021 The Authors. Advanced Synthesis & Catalysis
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RESEARCH ARTICLE
Multicomponent Synthesis of Benzothiophen-2-acetic Esters
by a Palladium Iodide Catalyzed S-cyclization – Alkoxycar-
bonylation Sequence
Adv. Synth. Catal. 2021, 363, 1–10
R. Mancuso*, M. Lettieri, I. Ziccarelli, P. Russo, A. P.
Piccionello, B. Gabriele*