Catalyst-free synthesis of 3-(1-arylsulfonylalkyl)indoles via three-component reaction of indoles, carbonyls, and arenesulfinic acids

Article abstract of DOI:10.1080/10426507.2015.1100182

A catalyst-free three-component reaction of indoles, carbonyls, and arenesulfinic acids performed at room temperature provides direct access to biologically important 3-(1-arylsulfonylalkyl)indoles. This process features mild conditions, low cost, broad s

Full text of DOI:10.1080/10426507.2015.1100182

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Catalyst-Free Synthesis of 3-(1-
Arylsulfonylalkyl)indoles via Three-Component
Reaction of Indoles, Carbonyls, and Arenesulfinic
Acids
Wenzhong Huang, Juan Yang, Xiangguang Li, Lin Yuan, Yinhai Ma, Qinglong
Zhou & Deqiang Liang
To cite this article: Wenzhong Huang, Juan Yang, Xiangguang Li, Lin Yuan, Yinhai Ma, Qinglong
Zhou & Deqiang Liang (2016): Catalyst-Free Synthesis of 3-(1-Arylsulfonylalkyl)indoles via
Three-Component Reaction of Indoles, Carbonyls, and Arenesulfinic Acids, Phosphorus, Sulfur,
and Silicon and the Related Elements, DOI: 10.1080/10426507.2015.1100182
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1100182
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Date: 21 March 2016, At: 17:35

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Catalyst-Free Synthesis of 3-(1-Arylsulfonylalkyl)indoles via Three-Component Reaction of
Indoles, Carbonyls, and Arenesulfinic Acids
Wenzhong Huang,1 Juan Yang,1 Xiangguang Li,1 Lin Yuan,1 Yinhai Ma,1 Qinglong Zhou,1,2 and
Deqiang Liang*,1
1Department of Chemistry, Kunming University, Kunming 650214, China
2Ruichang No.1 Middle School, Ruichang 332200, China
*Address correspondence to Deqiang Liang, Department of Chemistry, Kunming University,
Kunming 650214, China. E-mail: ldq5871@126.com
Abstract
A catalyst-free three-component reaction of indoles, carbonyls, and arenesulfinic acids
performed at room temperature provides direct access to biologically important
3-(1-arylsulfonylalkyl)indoles. This process features mild conditions, low cost, broad substrate
scope, and high yields, and mechanistically bis(indolyl)methanes were identified as the key
intermediates.
Keywords
Multicomponent reaction; indole functionalization; sulfinic acids
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INTRODUCTION
The indole nucleus is a privileged structural motif that has been found in a vast number of
alkaloid natural products and of synthetic molecules with significant biological activities,1-4 and
is therefore addressed as “The Lord of the Rings” of aromatic compounds.5 On the other hand,
sulfones are well known for their ability to inhibit various types of enzymatic processes and for
their broad spectrum of medicinal applications.6,7 As a consequence, the introduction of a
sulfonyl functionality in the indole system to form, say, 3-(1-arylsulfonylalkyl)indole derivatives,
is a common practice in drug design.8-12 Moreover, they are versatile synthons in organic
synthesis and have further scope for a wide range of synthetic transformations.13-16,19-21,23-25
3-(1-Arylsulfonylalkyl)indoles are generally synthesized through acid-promoted/catalyzed
Friedel-Crafts reaction of indoles with α-amido sulfones, which are, in advance, prepared from
carbamates, aldehydes, and sodium sulfinates.17-20 A complementary indirect entry to these
sulfonyl heterocycles is nucleophilic substitution reaction of pre-functionalized 3-alkyl indoles
with sodium sulfinates, of which the substrate scope is rather limited.21,22 Not long ago, Petrini et
al. disclosed an elegant and straightforward synthesis of 3-(1-arylsulfonylalkyl)indoles via
multicomponent reaction (MCR) from simple starting materials, yet in his condensation 50 mol%
of Brønsted acid was needed as promoter.23-25 Given the proven importance of sulfonyl indoles,
there is still an urgent need for mild and economic protocols for their preparation.
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In a step- and atom-economical manner, MCR is a powerful tool for rapid construction of
molecular complexity.26,27 As the electron-rich indole nucleus exhibits an enhanced reactivity
toward electrophiles, we speculated that arenesulfinic acids, though a kind of weak acid, might
serve dual roles as nucleophile and acid promoter in MCRs of indoles. Herein, we report the
successful execution of this scheme, and present
a
catalyst-free synthesis of
3-(1-arylsulfonylalkyl)indoles via three-component reaction of indoles, carbonyls, and
arenesulfinic acids, which is mild, efficient, and cost-effective.
RESULTS AND DISCUSSION
At the outset of the present study, 1H-indole 1a, benzaldehyde 2a, and p-toluenesulfinic acid
3a were employed as model substrates to screen reaction conditions (Table 1). <Table 1> When
the MCR was conducted with CH2Cl2 as solvent and without any catalyst, target
3-(phenyl(tosyl)methyl)indole 4a was produced in 76% yield within 1 h (entry 1, note c).
Though the yield did not increase appreciably with prolonged reaction time, heating, or addition
of 10 mol% of H2SO4, an excellent yield of 91% was achieved by using higher loading of 3a
(entry 1). These could be rationalized by the instability of sulfinic acids.28,29 A series of control
experiments confirmed that it made little difference that various Brønsted acids (entry 2),
including H2SO4, p-toluenesulfonic acid (TsOH),23-25 trifluoromethanesulfonic acid (TfOH), and
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trifluoroacetic acid (TFA), or Lewis acids (entry 3), such as BF3·Et2O, FeCl3, SnCl4, and Br2,30
were additionally added at the loading of 10 mol%. It should be noted that p-toluenesulfinic acid
3a used in these transformations was freshly prepared and carefully washed with water to ensure
complete removal of H2SO4.29 Next, we evaluated several solvents in comparison with CH2Cl2
and found that with CH3CN as solvent, product 4a was delivered in 86% yield after a longer
reaction time of 4 h (entry 4), whereas the use of ethyl acetate (entry 5), tetrahydrofuran (THF,
entry 6), N,N-dimethylformamide (DMF, entry 7), ethanol (entry 8) or toluene (entry 9) led to
incomplete MCRs even after 24 h, in which only moderate yields of 4a were furnished. During
all these reactions, noticeable amounts of bis(indolyl)methane derivative Ia were always
observed.
<Table 2>
Having developed optimized reaction conditions (Table 1, entry 1), we subsequently explored
the scope of this MCR with respect to the three components, and the results are summarized in
Table 2. It proved that while indoles 1 bearing a phenyl (entry 2) or alkyl group (entry 3) at
2-position reacted with benzaldehyde 2a and p-toluenesulfinic acid 3a smoothly to provide the
corresponding sulfones 4b,c in excellent yields, ethyl indole-2-carboxylate gave product 4d in
only 33% yield even when the reaction was run with 3 equivalents of 3a at reflux temperature for
12 h (entry 4). A range of electron-rich and electron-deficient indoles substituted at C(5)-C(7) all
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worked well in the MCR, giving expected products 4e,f,h,i in high to excellent yields (entries 5,
6, 8, and 9), except in the case concerning 5-nitroindole, which gave product 4g only in a
moderate yield even after the temperature was elevated to 82 °C and 3 equivalents of 3a were
employed (entry 7). Target sulfonyl indole 4j was delivered in 93% yield from N-methylindole
(entry 10), whereas the MCR carried out with N-phenylsulfonylindole did not proceed even
under those enhanced conditions (entry 11). The poor or non-reactivity of indole-2-carboxylate
(entry 4), 5-nitroindole (entry 7), and N-phenylsulfonylindole (entry 11) was readily rationalized
by their far more electron-deficient characteristic. Then, other carbonyls 2 were tested. It was
found that both selected aromatic aldehydes bearing either electron-donating (entries 12-14) or
-withdrawing substituents (entries 15-18) at para, meta, or ortho positions, and a heteroaromatic
one (entry 19) reacted efficiently with 1a and 3a to provide desired products 4k-r in high to
excellent yields. Aliphatic paraformaldehyde also underwent the same reaction to give product
4s in 85% yield (entry 20). Notably, electrophile 2 could be cyclohexanone as well, and the
corresponding sulfone 4t was obtained in a high yield (entry 21). Finally, the scope of
arenesulfinic acids 3 was investigated, and it proved that 3 having either a phenyl (entry 22) or
an electron-deficient aromatic group (entry 23) were good substrates too, giving desired sulfonyl
derivatives 4u,v in high to excellent yields. The irregular and often enough relatively much
longer reaction times in many cases (entries 6, 8-10, 14, and 18, for instance), reflected the poor
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solubility of related intermediate bis(indolyl)methanes I generated during reactions.
<Scheme 1>
In an effort to ascertain the role of the key bisindole derivatives I, the reaction of indole 1a,
cyclohexanone, and p-toluenesulfinic acid 3a under optimized conditions was quenched after 1 h,
affording bisindole Ib in 78% yield, along with sulfonyl product 4t in 13% yield (Scheme 1a).
Then, 3,3'-(phenylmethylene)bisindole Ia was prepared and utilized to reacted with sulfinic acid
3a (Scheme 1b). As might be expected, the reaction proceeded rapidly and within 1 h compound
4a, the same product obtained in corresponding MCR, was delivered in 94% yield.
<Scheme 2>
On the basis of the above results, a plausible mechanism is outlined in Scheme 2. Initially,
well-established condensation of indole 1 with carbonyl compound 2 took place under the acidic
conditions and bis(indolyl)methane I was first generated,30 which was known to undergo
acid-promoted elimination of a molecule of indole 1 to give vinylogous iminium ion III via
protonated intermediate II.23,31 At last, III was captured by arenesulfinic acid 3 through
conjugate addition and sufone 4 was produced.
CONCLUSION
In conclusion, we have developed a catalyst-free and efficient method for the synthesis of
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3-(1-arylsulfonylalkyl)indoles via MCR of indoles, carbonyls, and arenesulfinic acids, and a
mechanism is proposed in which bis(indolyl)methanes were identified as the key intermediates.
This reaction is associated with low cost, mild conditions, flexible substitution patterns, and
potential synthetic and biomedical utility of the products.
EXPERIMENTAL
General
All chemicals were purchased from commercial sources and used without treatment, unless
otherwise indicated. Sulfinic acids 329 and 3,3'-(phenylmethylene)bisindole Ia30 were prepared
by reported methods. 1H NMR and 13C NMR spectra were recorded at 25 °C on a Bruker Avance
II-400 spectrometer. High-resolution mass spectra (HRMS) were obtained using a Bruker
MicroTOF II Focus spectrometer (electrospray ionization, ESI). Thin-layer chromatography
(TLC) was carried out using silica gel GF254 plates. 4a,17-20 4b,32 4c,18-20,23 4e,k,l,o,p,19 4j,17-19
and 4q20 are known compounds and their spectral data can be found in literatures. The
1
Supplemental Materials contains sample H and 13C NMR spectra for the novel products
(Figures S 1 – S 24)
General Procedure for Synthesis of Sulfones 4 (4f as Example)
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A 25-mL flask was charged with a magnetic stirring bar and p-toluenesulfinic acid 3a (312 mg,
2.0 mmol), followed by addition of CH2Cl2 (5.0 mL). After the mixture had been stirred for 1
min to fully dissolve 3a, 5-bromoindole (196 mg, 1.0 mmol) and benzaldehyde 2a (0.112 mL,
1.1 mmol) were added, and the resulting solution was stirred at room temperature for 1 h. After
5-bromoindole was consumed, as indicated by TLC, the reaction mixture was quenched with
saturated aqueous K2CO3 solution (20.0 mL), and extracted with CH2Cl2 four times. The solvent
of the extract was removed, and the residue was purified by column chromatography (silica gel,
petroleum ether–dichloromethane–ethyl acetate = 8:1:1, v/v) to afford sulfone 4f as a pink crystal
(379 mg, 86% yield).
Ethyl 3-(phenyl(tosyl)methyl)-1H-indole-2-carboxylate (4d): White crystal; mp 187–188 °C
(dec); 1H NMR (400 MHz, DMSO-d6)δ 1.30 (t, J = 7.2 Hz, 3H), 2.29 (s, 3H), 4.22-4.34 (m, 2H),
7.15-7.24 (m, 4H), 7.29-7.41 (m, 6H), 7.50 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 7.2 Hz, 2H), 8.23 (d,
13
J = 8.4 Hz, 1H), 11.98 (s, 1H); C NMR (100 MHz, DMSO-d6) δ 161.5 (CO2Et), 144.8 (ArC),
136.9 (ArC), 135.9 (ArC), 133.7 (ArC), 130.1 (2ArC), 129.7 (2ArC), 129.0 (2ArC), 128.7 (ArC),
128.5 (2ArC), 125.9 (ArC), 125.7 (ArC), 125.6 (ArC), 124.2 (ArC), 121.2 (ArC), 114.1 (ArC),
113.4 (ArC), 67.6 (CH), 61.4 (CH2), 21.4 (CH3), 14.6 (CH2CH3); HRMS (ESI-TOF) Calcd for
C25H24NO4S+ ([M+H]+) 434.1421. Found 434.1422.
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1
5-Bromo-3-(phenyl(tosyl)methyl)-1H-indole (4f): Pink crystal; mp 169–170 °C (dec); H
NMR (400 MHz, DMSO-d6)δ 2.30 (s, 3H), 6.28 (s, 1H), 7.17 (dd, J = 1.6, 8.4 Hz, 1H), 7.25 (d,
J = 8.0 Hz, 2H), 7.28-7.34 (m, 4H), 7.56-7.61 (m, 4H), 7.75 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 2.0
Hz, 1H), 11.54 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 144.5 (ArC), 135.9 (ArC), 134.5
(ArC), 134.3 (ArC), 130.6 (2ArC), 129.7 (2ArC), 129.3 (ArC), 129.0 (2ArC), 128.7 (2ArC),
127.5 (ArC), 124.5 (ArC), 121.5 (ArC), 114.0 (ArC), 112.3 (ArC), 106.8 (ArC), 66.4 (CH), 21.5
(CH3); HRMS (ESI-TOF) Calcd for C22H19BrNO2S+ ([M+H]+) 440.0314. Found 440.0312.
5-Nitro-3-(phenyl(tosyl)methyl)-1H-indole (4g): Light yellow solid; mp 200–201 °C (dec); 1H
NMR (400 MHz, DMSO-d6)δ 2.27 (s, 3H), 6.53 (s, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.30-7.35 (m,
3H), 7.52 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.65 (dd, J = 6.0, 7.6 Hz, 2H), 7.94-7.97
(m, 2H), 8.71 (d, J = 2.0 Hz, 1H), 12.04 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 144.5 (ArC),
141.4 (ArC), 139.0 (ArC), 135.8 (ArC), 134.1 (ArC), 130.6 (2ArC), 130.0 (ArC), 129.9 (2ArC),
129.6 (2ArC), 129.0 (2ArC), 128.8 (ArC), 126.9 (ArC), 117.3 (ArC), 116.9 (ArC), 112.6 (ArC),
110.0 (ArC), 66.1 (CH), 21.4 (CH3); HRMS (ESI-TOF) Calcd for C22H19N2O4S+ ([M+H]+)
407.1060. Found 407.1042.
1
6-Chloro-3-(phenyl(tosyl)methyl)-1H-indole (4h): Pink crystal; mp 176–177 °C (dec); H
NMR (400 MHz, DMSO-d6)δ 2.27 (s, 3H), 6.27 (s, 1H), 7.00 (dd, J = 8.4, 1.6 Hz, 1H), 7.23 (d,
J = 8.0 Hz, 2H), 7.28-7.32 (m, 3H), 7.42 (d, J = 1.6 Hz, 1H), 7.59-7.63 (m, 4H), 7.71 (d, J = 8.4
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Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 11.45 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 144.3 (ArC),
136.3 (ArC), 136.1 (ArC), 134.3 (ArC), 130.6 (2ArC), 129.6 (2ArC), 128.9 (2ArC), 128.7
(2ArC), 127.1 (ArC), 126.7 (ArC), 126.3 (ArC), 120.7 (ArC), 119.8 (ArC), 111.6 (ArC), 107.4
(ArC), 66.8 (CH), 21.4 (CH3); HRMS (ESI-TOF) Calcd for C22H19ClNO2S+ ([M+H]+) 396.0820.
Found 396.0823.
1
7-Methyl-3-(phenyl(tosyl)methyl)-1H-indole (4i): Pink crystal; mp 195–196 °C (dec); H
NMR (400 MHz, DMSO-d6)δ 2.27 (s, 3H), 2.42 (s, 3H), 6.21 (s, 1H), 6.86 (s, 2H), 7.25-7.28 (m,
13
5H), 7.47-7.70 (m, 6H), 11.29 (s, 1H); C NMR (100 MHz, DMSO-d6) δ 144.2 (ArC), 136.4
(ArC), 135.4 (ArC), 134.6 (ArC), 130.7 (2ArC), 129.7 (2ArC), 128.9 (2ArC), 128.6 (2ArC),
127.1 (ArC), 125.3 (ArC), 122.5 (ArC), 121.1 (ArC), 119.6 (ArC), 116.7 (ArC), 107.5 (ArC),
67.1 (CH), 21.4 (SO2Ph-CH3), 17.1 (C7-CH3); HRMS (ESI-TOF) Calcd for C23H22NO2S+
([M+H]+) 376.1366. Found 376.1366.
3-((3,4-Dimethoxyphenyl)(tosyl)methyl)-1H-indole (4m): Light yellow solid; mp 180–181 °C
(dec); 1H NMR (400 MHz, CDCl3)δ 2.24 (s, 3H), 3.65 (s, 3H), 3.74 (s, 3H), 5.56 (s, 1H), 6.65 (d,
J = 8.4 Hz, 1H), 6.86-7.05 (m, 6H), 7.19 (dd, J = 6.0, 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.45
13
(d, J = 7.6 Hz, 2H), 7.59 (s, 1H), 8.57 (s, 1H); C NMR (100 MHz, CDCl3) δ 149.2 (ArC),
148.6 (ArC), 144.3 (ArC), 135.6 (ArC), 135.4 (ArC), 129.3 (2ArC), 129.0 (2ArC), 127.0 (ArC),
125.8 (ArC), 124.8 (ArC), 122.9 (ArC), 122.4 (ArC), 119.9 (ArC), 118.4 (ArC), 113.2 (ArC),
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111.5 (ArC), 110.9 (ArC), 107.4 (ArC), 68.9 (CH), 55.9 (OCH3), 55.8 (OCH3), 21.6 (CH3);
HRMS (ESI-TOF) Calcd for C24H24NO4S+ ([M+H]+) 422.1421. Found 422.1425.
3-((4-Bromophenyl)(tosyl)methyl)-1H-indole (4n): Light pink crystal; mp 170–171 °C (dec);
1H NMR (400 MHz, CDCl3)δ 2.29 (s, 3H), 6.30 (s, 1H), 6.95-7.08 (m, 2H), 7.25-7.36 (m, 3H),
7.54-7.70 (m, 8H), 11.33 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 144.5 (ArC), 136.1 (ArC),
135.9 (ArC), 134.0 (ArC), 132.8 (2ArC), 131.6 (2ArC), 129.7 (2ArC), 128.9 (2ArC), 127.3
(ArC), 125.8 (ArC), 122.1 (ArC), 122.0 (ArC), 119.5 (ArC), 119.1 (ArC), 112.0 (ArC), 106.6
(ArC), 66.2 (CH), 21.5 (CH3); HRMS (ESI-TOF) Calcd for C22H19BrNO2S+ ([M+H]+) 440.0314.
Found 440.0317.
1
3-(Thiophen-2-yl(tosyl)methyl)-1H-indole (4r): Pinkish crystal; mp 196–197 °C (dec); H
NMR (400 MHz, DMSO-d6)δ 2.30 (s, 3H), 6.59 (s, 1H), 6.97-7.00 (m, 2H), 7.09 (dd, J = 7.6,
7.2 Hz, 1H), 7.21 (d, J = 3.2 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.51 (d,
J = 5.2 Hz, 1H), 7.57-7.59 (m, 3H), 7.74 (d, J = 8.0 Hz, 1H), 11.32 (s, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 144.4 (ArC), 136.5 (ArC), 135.9 (ArC), 135.5 (ArC), 130.1 (ArC), 129.6 (2ArC),
129.0 (2ArC), 127.8 (ArC), 127.14 (ArC), 127.12 (ArC), 126.6 (ArC), 122.0 (ArC), 119.6 (ArC),
119.5 (ArC), 112.0 (ArC), 107.0 (ArC), 63.1 (CH), 21.5 (CH3); HRMS (ESI-TOF) Calcd for
+
C20H18NO2S2 ([M+H]+) 368.0773. Found 368.0789.
3-(Tosylmethyl)-1H-indole (4s): Red crystal; mp 158–159 °C; 1H NMR (400 MHz,
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DMSO-d6)δ 2.35 (s, 3H), 4.73 (s, 2H), 6.95-7.11 (m, 3H), 7.34-7.62 (m, 6H), 11.15 (s, 1H); 13C
NMR (100 MHz, DMSO-d6) δ 144.4 (ArC), 136.5 (ArC), 136.3 (ArC), 129.9 (2ArC), 128.5
(2ArC), 127.6 (ArC), 127.4 (ArC), 121.8 (ArC), 119.44 (ArC), 119.37 (ArC), 112.0 (ArC), 102.0
(ArC), 53.7 (CH2), 21.5 (CH3); HRMS (ESI-TOF) Calcd for C16H16NO2S+ ([M+H]+) 286.0896.
Found 286.0887.
1
3-(1-Tosylcyclohexyl)-1H-indole (4t): White crystal; mp 184–185 °C (dec); H NMR (400
MHz, DMSO-d6)δ 0.85-2.09 (m, 10H), 2.31 (s, 3H), 6.93-7.18 (m, 7H), 7.37 (d, J = 7.2 Hz, 1H),
13
7.56 (d, J = 7.6 Hz, 1H), 11.26 (s, 1H); C NMR (100 MHz, DMSO-d6) δ 144.1 (ArC), 137.2
(ArC), 132.8 (ArC), 130.2 (2ArC), 129.2 (2ArC), 129.0 (ArC), 126.8 (ArC), 121.7 (ArC), 121.2
(ArC), 119.5 (ArC), 112.2 (ArC), 106.9 (ArC), 69.5 (CQ), 25.3 (CH2), 22.1 (CH2), 21.5 (CH3);
HRMS (ESI-TOF) Calcd for C21H24NO2S+ ([M+H]+) 354.1522. Found 354.1520.
3-(Phenyl(phenylsulfonyl)methyl)-1H-indole (4u): Light gray solid; mp 193–194 °C (dec); 1H
NMR (400 MHz, DMSO-d6)δ 6.26 (s, 1H), 6.94 (td, J = 8.0, 0.8 Hz, 1H), 7.05 (td, J = 8.0, 0.8
Hz, 1H), 7.28-7.35 (m, 4H), 7.43 (dd, J = 7.6, 8.0 Hz, 2H), 7.55 (dd, J = 7.6, 7.2 Hz, 1H),
13
7.60-7.65 (m, 3H), 7.70-7.72 (m, 3H), 11.32 (s, 1H); C NMR (100 MHz, DMSO-d6) δ 139.0
(ArC), 135.7 (ArC), 134.3 (ArC), 133.9 (ArC), 130.7 (2ArC), 129.2 (2ArC), 128.8 (2ArC), 128.6
(2ArC), 127.3 (ArC), 125.9 (ArC), 122.0 (ArC), 119.4 (ArC), 119.1 (ArC), 112.0 (ArC), 106.7
(ArC), 66.9 (CH); HRMS (ESI-TOF) Calcd for C21H18NO2S+ ([M+H]+) 348.1053. Found
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348.1049.
3-((4-Chlorophenylsulfonyl)(phenyl)methyl)-1H-indole (4v): Pale reddish-brown solid; mp
198–199 °C (dec); 1H NMR (400 MHz, DMSO-d6)δ 6.30 (s, 1H), 6.94-7.08 (m, 3H), 7.31-7.36
(m, 4H), 7.50 (d, J = 8.0 Hz, 2H), 7.64-7.71 (m, 5H), 11.31 (s, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 138.9 (ArC), 138.0 (ArC), 135.8 (ArC), 134.2 (ArC), 130.8 (2ArC), 130.7 (2ArC),
129.3 (2ArC), 128.7 (2ArC), 127.4 (ArC), 126.1 (ArC), 122.0 (ArC), 119.5 (ArC), 119.1 (ArC),
112.0 (ArC), 106.5 (ArC), 67.1 (CH); HRMS (ESI-TOF) Calcd for C21H17ClNO2S+ ([M+H]+)
382.0663. Found 382.0661.
FUNDING
Financial support of this research by the Applied Basic Research Programs of Yunnan Science
and Technology Department (2014FD039 and 2013FZ103), the General Projects of Yunnan
Education Department (2013Y252), and the Students Research Projects of Kunming University
(XJD15079) is gratefully acknowledged.
SUPPORTING INFORMATION
Supplementary data of this article can be accessed on the publisher’s website,
www.tandfonline.com/gpss
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Table 1. Optimization of reaction conditionsa
Yield of 4a (%)b
Entry Solvent Time (h)
1
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
1
1
1
4
91 (76)c
90-92
89-92
86
2d
3e
4
5
EtOAc 24
65
6
THF
24
24
24
55
7
DMF
EtOH
62
8
60
9
Toluene 24
66
aReaction conditions: 1a (1.0 mmol), 2a (1.1 mmol), 3a (2.0 mmol), solvent (5.0 mL), room
temperature.
bIsolated yields.
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c1.0 equivalent of 3a was used.
d10 mol% of H2SO4, TsOH, TfOH, or TFA was additionally added as catalyst.
e10 mol% of BF3·Et2O, FeCl3, SnCl4, or Br2 was additionally added as catalyst.
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Table 2. Synthesis of 3-(1-arylsulfonylalkyl)indoles 4a
Entry R1
R2
H
H
H
R3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R4 Ar
4-MePh 1
4-MePh 4
t (h)
Yield (%)b
4
1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
91
95
97
33
82
86
45
90
90
93
0
4a
4b
4c
4d
4e
4f
4g
4h
4i
2
2-Ph
2-Me
3
4-MePh 1
4-MePh 24
4-MePh 2
4-MePh 24
4-MePh 24
4-MePh 12
4-MePh 12
4-MePh 12
4-MePh 24
4-MePh 1
4-MePh 1
4c
5
2-CO2Et H
5-MeO
5-Br
5-NO2
6-Cl
7-Me
H
H
6
H
7c
8
H
H
9
H
10
11c
12
13
Me
4j
H
SO2Ph Ph
H
H
H
4-MePh
4-MeOPh
94
88
4k
4l
H
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14
15
16
17
18
19
20
21
22
23
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3,4-(MeO)2Ph H 4-MePh 24
88
92
90
91
84
82
85
81
86
95
4m
4n
4o
4p
4q
4r
4s
4-BrPh
4-ClPh
2-ClPh
4-NO2Ph
2-Thienyl
H
H
H
H
H
H
H
4-MePh 3
4-MePh 3
4-MePh 4
4-MePh 24
4-MePh 5
4-MePh 24
4-MePh 6
(CH2)5
Ph
4t
H
H
Ph
4
2
4u
4v
Ph
4-ClPh
aReaction conditions: 1 (1.0 mmol), 2 (1.1 mmol), 3 (2.0 mmol), CH2Cl2 (5.0 mL), room
temperature.
bIsolated yields.
cThe reaction was run at 82 °C with 3 equiv of p-toluenesulfinic acid 3a which was added in
three equal portions at one-hour intervals.
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Scheme 1. Mechanistic investigations.
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Scheme 2. Proposed mechanism.
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