Synthesis of: N -alkyl-3-sulfonylindoles and N -alkyl-3-sulfanylindoles by cascade annulation of 2-alkynyl- N, N -dialkylanilines

Article abstract of DOI:10.1039/c7ob00366h

An efficient and metal-free approach to N-alkyl-3-sulfonylindoles and N-alkyl-3-sulfanylindoles from 2-alkynyl-N,N-dialkylanilines has been developed. In the presence of iodine and tert-butylhydroperoxide (TBHP), a variety of 2-alkynyl-N,N-dialkylanilines underwent a cascade radical annulation to yield 3-arylsulfonylindoles. In contrast, 3-arylsulfanylindoles were conveniently prepared by iodine mediated electrophilic annulation reactions. The present protocol uses the economical and environmentally friendly I₂-TBHP or I₂ system, and potentially bioactive N-alkyl-3-sulfonylindoles and N-alkyl-3-sulfanylindoles with various functional groups were successfully synthesized in moderate to good yields.

Full text of DOI:10.1039/c7ob00366h

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DOI: 10.1039/C7OB00366H
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ARTICLE
Synthesis of N-alkyl-3-sulfonylindoles and N-alkyl-3-
sulfanylindoles by cascade annulation of 2-alkynyl-N,N-
dialkylanilines
Received 00th January 20xx,
Accepted 00th January 20xx
Jatuporn Meesin, Manat Pohmakotr, Vichai Reutrakul, Darunee Soorukram, Pawaret Leowanawat,
and Chutima Kuhakarn*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient and metal-free approach to N-alkyl-3-sulfonylindoles and N-alkyl-3-sulfanylindoles from 2-alkynyl-N,N-
dialkylanilines has been developed. In the presence of iodine and tert-butylhydroperoxide (TBHP), a variety of 2-alkynyl-
N,N-dialkylanilines underwent a cascade radical annulation to yield 3-arylsulfonylindoles. In contrast, 3-arylsulfanylindoles
were conveniently prepared by iodine mediated electrophilic annulation reactions. The present protocol uses the
economical and environmentally friendly I2–TBHP or I2 system, and the potentially bioactive N-alkyl-3-sulfonylindoles and
N-alkyl-3-sulfanylindoles with various functional groups were successfully synthesized in moderate to good yields.
indole motifs. Several sulfenylating agents such as disulfides,8
thiols,9 sulfinic acids,10 sulfinate salts,11 sulfonyl chlorides,12
sulfenyl chlorides,13 N-thioimides,14 quinone mono-O,S-
Introduction
acetals,15 arylsulfonyl cyanides,16 sulfonyl hydrazides,17
The indole scaffold is omnipresent in wide range of naturally
derived molecules as well as biologically active compounds.1
Among the numerous indole derivatives, those bearing
sulfonyl and sulfanyl moieties at the C2-, C3- and N-positions
exist in many pharmacologically important agents (Fig. 1).
Indolyl aryl sulfones were found to exhibit interesting
biological activities and therapeutic values. For example, 1-
sulfoxides,18
thiosulfonium
salts,19
and
arylboronic
acids/element sulfur20 have been reported to effect the C3
sulfenylation. Similarly, methods for direct C3 sulfonylation of
the preexisting indole ring were also reported albeit with less
number of approaches.21 Undoubtedly, 3-sulfonylindoles can
also be prepared by oxidation of the corresponding 3-
sulfanylindoles. Noteworthy, 2-alkynylanilines and derivatives
are well-known synthetically versatile substrates employed for
the preparation of substituted indoles.22 Several research
groups reported synthetic approaches to 3-arylsulfanylindoles
employing 2-alkynylaniline derivatives as the substrates to
react with sulfenyl chlorides, disulfides, and thiols.23 Although
a few methods were available for the preparation of 3-
arylsulfonylindoles by annulation of appropriate acyclic
substrates, none of these methods dealt with sulfonylating
reagents.24 Most recently, Han and coworkers disclosed an
elegant synthesis of 3-sulfonylindoles from 2-alkynylazide
employing sulfinic acids as the sulfonylating reagents.25
aminoalkyl-3-arylsulfonyl-1H-indoles
I
are human 5-HT6
receptor ligands.2 L-737,126 (II) is a selective non-nucleoside
reverse transcriptase inhibitor.3 4-Dialkylaminoethyl-3-
(phenylsulfonyl)-1H-indoles III serve as dual acting
norepinephrine reuptake inhibitors (NRIs) and 5-HT2A receptor
antagonists.4 N-Sulfonyl-C2-sulfonylindole derivatives IV are
cannabinoid CB2 receptor ligands.5 The 3-sulfanylindoles also
attracted considerable attention due to their potential uses in
several disease areas. For instance, MK-886 (
inhibitory activity against 5-lipoxygenase as well as anti-cancer
activity in human colorectal cancer and 3-(arylsulfanyl)indole
VI7 is capable of inhibiting tubulin polymerization and human
breast cancer growth.
6
V
)
exhibits
Due to the special pharmacological properties, there has
been growing interest in developing a general and efficient
route to access indole-based sulfones and sulfides. In
particular, 3-arylsulfanylindoles and 3-arylsulfonylindoles can
be prepared by two strategies including direct C3
functionalization of the indole core structures, and cascade
annulation of the acyclic precursors toward construction of the
Department of Chemistry and Center of Excellence for Innovation in Chemistry
(PERCH-CIC), Faculty of Science, Mahidol University, Rama 6 Road, Bangkok
10400, Thailand. E-mail: chutima.kon@mahidol.ac.th
†Electronic Supplementary Information (ESI) available: Full experimental
information, compound characterization and copies of NMR spectra. See
DOI: 10.1039/x0xx00000x
Fig.
1
Examples of biologically active sulfonyl- and
sulfanylindole derivatives.
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During the past few years, sulfonyl hydrazides
Journal Name
The study was first examined using N,N-dVimieweAtrhticylle-O2n-(lipne-
tolylethynyl)aniline (1a) and p-toluenes lf zi
,
economical
D
u
O
I
o
:
n
10
y
.
l
10
h
3
y
9
d
/C
r
7
a
O
B
d
0
e
03
(2a)
6
6
H
and shelf-stable reagents, received considerable attention in
organic synthesis. Depending on the reaction conditions, they
can serve as sulfonylating,26 sulfenylating,27 and arylating
reagents.28 With our continuing interest in the synthesis of
organosulfur compounds via sulfonylation and sulfenylation of
olefins,29 unsaturated carboxylic acids,30 and heterocyclic
scaffolds,31 we reported herein the synthesis of N-alkyl-3-
sulfonylindoles and N-alkyl-3-sulfanylindoles using 2-alkynyl-
as benchmarking substrates to screen for the optimal reaction
conditions (Table 1). In the beginning, when 1a (0.25 mmol)
and 2a (2 equiv.) were treated with molecular iodine (I2, 1.5
equiv.) and TBHP (70% in water, 3 equiv.) and the reaction
mixture was stirred in ethyl acetate (EtOAc, 2 mL, 0.125 M) at
o
80 C for 4 h, the reaction readily took place and provided the
corresponding 3-sulfonylindole 3aa in 14% yield (Table 1, entry
1). Attempt to increase the amount of TBHP employed (from 3
equiv. to 5 equiv.) did not give satisfactory results (Table 1,
entry 2). An increase in the quantity of 2a (from 2 equiv. to 3
equiv.) gave 3aa in moderate yield (47% yield; Table 1, entry
3). No appreciable results were obtained when the reaction
time was extended (from 4 h to 24 h) (Table 1, entry 4). The
reaction time can be shortened (from 4 h to 2 h) without
lowering the product yield (Table 1, entry 5). Various solvents,
including dichloroethane (DCE), methanol (MeOH), ethanol
(EtOH), acetonitrile (MeCN), tetrahydrofuran (THF), 1,4-
dioxane and toluene, were next screened (Table 1, entries 6‒
12). Among those, EtOAc was chosen as the solvent of choice
to further study other reaction parameters due to the ease of
handling and the reaction in general was much cleaner.
Gratifyingly, with the increase of the stoichiometric amount of
2a (from 3 equiv. to 5 equiv.) and TBHP (from 5 equiv. to 6
equiv.), the yield of 3aa was significantly increased to 85%
yield (Table 1, entry 13). Although the requirement of excess
amount of TBHP cannot be explained, similar need was
reported in the literature.32 The amount of I2 employed can be
lower (from 1.5 equiv. to 1.2 equiv.) providing 3aa in
comparable yield (87% yield) (Table 1, entry 14). The effects of
oxidants, including 5.5 M TBHP in decane, di-tert-butyl
peroxide (DTBP), 30% aqueous hydrogen peroxide, and
benzoyl peroxide, were also examined, but the results
obtained were less satisfactory.
N,N-dialkylanilines
1
and sulfonyl hydrazides
2 as the sulfur
source (Scheme 1)
. The present work is metal-free, generates
eco-friendly by-products, presents a simple experimental
procedure and short reaction time, and can accommodate
wide range of substrate scopes to access both 3-
sulfonylindoles and 3-sulfanylindoles by tuning the
combinations of molecular iodine and tert-butylhydroperoxide
(TBHP).
Scheme 1 Synthesis of N-alkyl-3-sulfonylindoles
3-sulfanylindoles from 2-alkynyl-N,N-dialkylanilines
sulfonyl hydrazides
3
and N-alkyl-
4
1
and
2
Table 1. Synthesis of 3-sulfonylindoles 3: Screening for optimal
reaction conditionsa
With the optimized reaction conditions (Table 1, entry 14),
the substrate scope and limitation of the reaction were
evaluated. First, we sought to examine the scope of the
reaction of N,N-dimethyl-2-(p-tolylethynyl)aniline (1a) with
various types of sulfonyl hydrazides under the established
reaction conditions and the results are summarized in Scheme
2. Although benzenesulfonyl hydrazide delivered the product
3ab in lower efficiency (53% yield), arenesulfonyl hydrazides
bearing electronically different substituents on the phenyl ring
(p-Cl, p-Br, p-NO2, m-F) gave the corresponding 3-
entry
2a
(equiv)
I2
(equiv)
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
aq TBHP
(equiv)
solvent
time
(h)
4
4
4
24
2
2
2
2
2
2
2
2
2
2
yieldb
(%)
14
15
47
46
48
35
52
51
44
41
28
36
85
87
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2
2
3
3
3
3
3
3
3
3
3
3
5
5
3
5
5
5
5
5
5
5
5
5
5
5
6
6
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
DCE
MeOH
EtOH
MeCN
THF
1,4-dioxane
toluene
EtOAc
EtOAc
sulfonylindoles 3ac‒af in good to excellent yields (74‒97%
yields). 2,4-Dimethylbenzenesulfonyl hydrazide (2g) reacted
with 1a to yield 3ag in low yield (11% yield), while 1a was
completely consumed, implying that the present reaction was
significantly
influenced
by
steric
effect.
Finally,
methanesulfonyl hydrazide failed to provide the desired 3-
sulfonylindole product.
aReaction conditions: 1a (0.25 mmol) in solvent (2 mL) at 80 C, open
o
air. bIsolated yields after column chromatography (SiO2).
Results and discussion
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7OB00366H
3ba (39%)b
3ad (97%)
3ca (43%)b
3ga (48%)
3ka (81%)
3da (72%)
3ea (36%)b
3ia (50%)
3aa (87%)
3ab (53%)
3ac (86%)
3fa (70%)b
3ha (55%)c
3ae (74%)
3af (79%)
3ag (11%)
aConditions: 1a (0.25 mmol),
2 (5 equiv.), I2 (1.2 equiv.), 70% TBHP in
o
3ja (53%)
3la (53%)
3ma (37%)
H2O (6 equiv.) in EtOAc (2 mL) at 80 C, open air, 2 h. In parentheses:
isolated yields after chromatographic purification (SiO2, column
chromatography).
Scheme 2 Synthesis of 3-sulfonylindoles
hydrazides 2a
3: Scope of sulfonyl
3na (53%)c
3oa (11%)c
3pa (0%)
3qa (73%)
Next, the reactions between p-toluenesulfonyl hydrazide
2a) and various types of 2-alkynylanilines were evaluated
(
1
and the results are summarized in Scheme 3. First, various
substituents (R2) on the phenyl ring of 2-alkynylanilines were
evaluated. The reaction proceeded smoothly to provide the
3ra (59%)
3sa (36%)
3ta (25%)c
corresponding 3-sulfonylindoles 3ba
yields (36‒72% yields). 2-Alkynylanilines
electronically different groups (p-F, m-F, m-Br, p-Br, p-NO2, p-
CF3, p-OMe) on the phenyl ring of the arylethynyl moiety were
well tolerated and yielded the corresponding 3-sulfonylindoles
‒
fa in moderate to good
bearing a series of
aConditions:
1 (0.25 mmol), 2a (5 equiv.), I2 (1.2 equiv.), 70% TBHP in
o b
1
H2O (6 equiv.) in EtOAc (2 mL) at 80 C, open air, 2 h. Reactions were
carried out for 4 h. cReactions were carried out for 6 h. In parentheses:
isolated yields after chromatographic purification (SiO2, column
chromatography).
3ga‒na in variable yields (37‒81% yields). The influence of the
steric effect was also emphasized and was found to disfavor
the reactions. Thus, 3oa was obtained in low yield (11% yield)
and 3pa was not observed. Other arylalkynyl group such as 2-
naphthylethynyl also delivered the corresponding product 3qa
in good yield (73% yield). Gratifyingly, aliphatic alkynyl 1r (R1 =
n-hexyl) readily reacted with 2a to yielded 3ra in 59% yield. In
addition, N,N-diethyl-2-(p-tolylethynyl)aniline 1s containing
diethyl groups on the aniline nitrogen was also employed in
this study. As expected, N-ethyl-3-sulfonylindole 3sa was
produced despite in low yield (36% yield). Finally, when 1-(2-
(p-tolylethynyl)phenyl)pyrrolidine 1t was used as a starting
compound, 3ta was isolated in 25% yield. This observation
highlighted the involvement of iodide ion (I-) in the
mechanistic pathway leading to the obtained 2-sulfonylindoles
Scheme 3 Synthesis of 3-sulfonylindoles
alkynylanilines 1a
3: Scope of 2-
Notably, sulfonyl hydrazides were extensively used as
sulfenylating reagents as having been reported by several
research groups.27 However, to the best of our knowledge, the
formation of 3-sulfanylindoles from the reaction of 2-
alkynylanilines
1 and sulfonyl hydrazides 2 has not been
explored so far. Therefore, the synthetic utility of the current
protocol was further extended to the synthesis of N-alkyl-3-
sulfanylindoles from 2-alkynyl-N,N-dialkylanilines. To our
delight, when 1a (0.25 mmol) was treated with 2a (3 equiv.) in
the presence of molecular iodine (I2, 1.1 equiv.), without the
o
3.
addition of TBHP in EtOAc at 80 C for 2 h, the expected 3-
sulfanylindole 4aa was isolated in 94% yield (Scheme 4). Our
initial result has proved that the present protocol was a facile
and convenient route to access 3-sulfanylindoles 4.
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DOI: 10.1039/C7OB00366H
Scheme 4 Synthesis of 3-sulfanylindoles
4
Having the optimized reaction conditions in hand (Scheme
4), we next demonstrated the generality of the present
protocol by exploring the scope of sulfonyl hydrazides
alkynylanilines as shown in Schemes 5 and 6, respectively.
The results suggested that the reaction can accommodate a
variety of 2-alkynylanilines and sulfonyl hydrazides under
the optimal reaction conditions. Initially, a collection of
sulfonyl hydrazides were explored (Scheme 5). Arenesulfonyl
hydrazides bearing electronically different substituents on
the phenyl ring smoothly reacted with N,N-dimethyl-2-(p-
tolylethynyl)aniline (1a), producing the corresponding 3-
sulfanylindoles 4aa‒ah in excellent yields (83‒97% yields).
Pleasingly, methanesulfonyl hydrazide also reacted readily to
yield 4ai in moderate yield (58% yield).
2 and 2-
4aa (94%)
4ab (93%)
4ac (97%)
4ad (95%)
1
1
2
2
2
4ae (93%)
4ai (58%)
4af (95%)
4ag (96%)
4ah (86%)
Subsequently, the reactions between a variety of 2-
alkynylanilines
1 and p-toluenesulfonyl hydrazide (2a) were
aConditions: 1a (0.25 mmol),
at 80 oC, open air,
h. In parentheses: isolated yields after
chromatographic purification (SiO2, column chromatography).
2 (3 equiv.), I2 (1.1 equiv.) in EtOAc (2 mL)
explored under the standard reaction conditions (Scheme 4)
and the results are summarized in Scheme 6. To our delight, a
range of substituents (R2) on the phenyl ring of 2-
alkynylanilines, including Br, Cl, F, Me, tolerated well and
delivered the corresponding products 4ba
yields (90‒98% yields). Similarly, 2-alkynylanilines
2
Scheme 5 Synthesis of 3-sulfanylindoles
hydrazides 2a
4
: Scope of sulfonyl
‒
fa in excellent
bearing
1
various electronically different groups on the phenyl ring of
the arylethynyl moiety, including p-F, m-F, m-Br, p-Br, p-NO2,
p-CF3, p-OMe, also underwent the reaction smoothly to yield
the corresponding products in decent yields (>90% yields).
Notably, the substituents on the phenyl ring of the arylethynyl
moiety exhibited a significant electronic effect. Moderate yield
(43% yield) of 4la was observed when N,N-dimethyl-2-((4-
nitrophenyl)ethynyl)aniline (1l) was employed as a starting
compound. In contrast to the respective sulfonylation
previously discussed in this work (Scheme 3), it turned out that
the sulfenylation is not particularly sensitive to steric effect.
4ba (97%)
4fa (97%)
4ca (93%)
4ga (95%)
4da (98%)
4ea (90%)
4ia (96%)
The
reactions
of
2-((2-bromophenyl)ethynyl)-N,N-
dimethylaniline (1o), 2-(mesitylethynyl)-N,N-dimethylaniline
(
1p
dimethylaniline
sulfanylindoles 4oa
)
and
2-((2,3-dimethoxyphenyl)ethynyl)-N,N-
produced the corresponding 3-
4pa, and 4ua in high yields. These
(
1u)
,
4ha (95%)
observations suggested that the present method tolerated
well towards the electronically and sterically demanding
substitution patterns on the phenyl rings of the aniline and
arylethynyl moieties. Again, N,N-dimethyl-2-(naphthalen-2-
ylethynyl)aniline (1q) and N,N-dimethyl-2-(oct-1-yn-1-yl)aniline
4ja (96%)
4na (87%)
4ka (98%)
4oa (99%)
4la (43%)
4pa (99%)
4ma (81%)
4qa (92%)
(
1r) also accommodated well under the reaction conditions,
leading to the respective products 4qa and 4ra in 92% and 46%
yields, respectively. The substituents on the aniline nitrogen
were also varied; N,N-diethyl-2-(p-tolylethynyl)aniline 1s gave
4sa in 96% yield. Finally, 4ta was obtained in 70% yield when
1-(2-(p-tolylethynyl)phenyl)pyrrolidine 1t was used as a
starting compound, implying the role of iodide ion (I-) in the
mechanistic pathway.
4ra (46%)
4sa (96%)
4ta (70%)
4ua (84%)
4 | J. Name., 2012, 00, 1-3
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aConditions:
at 80 oC, open air,
chromatographic purification (SiO2, column chromatography).
1
(0.25 mmol), 2a (3 equiv), I2 (1.1 equiv) in EtOAc (2 mL)
h. In parentheses: isolated yields after
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2
Scheme 6 Synthesis of 3-sulfanylindoles
alkynylanilines 1a
4: Scope of 2-
Finally, substrates
nitrogen atom were also investigated (Scheme 7). N-Benzyl-N-
methyl-2-(p-tolylethynyl)aniline 1v was employed to
1 bearing different alkyl groups at the
(
)
synthesize 3-sulfonylindoles and 3-sulfanylindoles under the
standard reaction conditions. To our delight, the dealkylation
step took place chemoselectively at the benzyl group to yield
3aa and 4aa in 42% and 76% yields, respectively.
Unfortunately, an inseparable mixture of products 4aa and 4sa
was obtained when N-ethyl-N-methyl-2-(p-tolylethynyl)aniline
(
1w) was used as a starting material. 1H-NMR integration
revealed that 4aa (R = Me) and 4sa (R = Et) were obtained in
31% and 51% yields, respectively. This observation suggested
that dealkylation preferably took place at the less steric site.
Scheme 8 Control experiments
On the basis of the above-mentioned control experiments
and the reported literature,17,23,26-27 we propose plausible
reaction mechanisms as shown in Scheme 9. For the formation
of N-alkyl-3-sulfonylindoles, a mechanism that involved a
sulfonyl radical was proposed [Scheme 9 (I)]. It is well known
that TBHP is thermally unstable and decomposes to the tert-
butoxyl and tert-butylperoxy radicals. The reaction of these
two radicals with iodine and sulfonyl hydrazide
2 produces
sulfonyl radical in situ through the elimination of nitrogen gas.
Next, the resulting sulfonyl radical then regioselectively adds
to the alkynyl moiety of 2-alkynyl-N,N-dialkylaniline
produce vinyl radical intermediate . Subsequent cascade
annulation followed by oxidation gives indolium intermediate
which upon dealkylation with the aid of iodide ion
nucleophile to finally produce the 3-sulfonylindole product
The sulfenylation reaction begins with the reaction of
1 to
A
Scheme 7 Effect of the alkyl groups on dealkylation Step
B
3.
To verify the reaction mechanisms, several control
experiments were conducted (Scheme 8). First, to understand
the role of molecular iodine, the reaction was carried out in
the absence of I2. Neither 3-sulfonylindole 3aa nor 3-
sulfanylindole 4aa was obtained when molecular iodine (I2)
was excluded from the reaction [Scheme 8 (a)]. This outcome
emphasized the important role of molecular iodine. Next, to
validate that the sulfonylation reaction undergoes through the
radical cascade process, the radical trapping experiments were
sulfonyl hydrazide
2
with iodine to yield sulfenyl iodide (R3SI),
possibly through two pathways (route A17a,26i,27j,27n and route
B17a,27d,27l) [Scheme 9 (II)]. Electrophilic addition of which to the
alkynyl moiety of 2-alkynyl-N,N-dialkylaniline
thiirenium ion intermediate C 23
Subsequent nucleophilic
attack by the nitrogen nucleophile of the aniline moiety
leading to indolium intermediate , followed by removal of
1
gives
.
D
the alkyl group by iodide ion to furnish the indole ring
construction.
also
conducted
by
employing
TEMPO
(2,2,6,6-
tetramethylpiperidin-1-yl)oxyl) and BHT (2,6-di-tert-butyl-4-
methylphenol) as radical scavengers. The reactions of 1a and
o
2a with I2, TBHP in EtOAc at 80 C for 2 h were suppressed
when TEMPO or BHT was added in the reaction [Scheme 8 (b)].
The observed results implied that the sulfonylation process is
likely to involve a radical pathway. Noteworthy, sulfonyl
hydrazides have been widely used as sulfonyl radical
precursors mediated by molecular iodine and TBHP.26c,h,n
Additionally, the reactions of 1a with freshly prepared p-
toluenesulfonyl iodide under the standard reaction conditions
(Table 1, entry 14 and Scheme 4) were examined [Scheme 8
(c)]. No desired product 3aa or 4aa was produced, attesting
that sulfonyl iodide is unlikely an intermediate in the present
reactions.
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(I)
Journal Name
for financial support. The Institute for the Promotion of
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Teaching Science and Technology andDSOcIi:e1n0.c1e039A/cCh7iOeBv0e0m36e6nHt
Scholarship of Thailand (SAST) for financial support through
student scholarship to J.M. are also gratefully acknowledged.
Notes and references
1
(a) K. Higuchi and T. Kawasaki, Nat. Prod. Rep., 2007, 24,
843; (b) M. Ishikura, T. Abe, T. Choshi and S. Hibino, Nat.
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S and
C
N bonds formation followed by dealkylation. Given that
various structurally different substrates can be employed for
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Acknowledgements
We thank the Thailand Research Fund (BRG5850012 and
IRN58W0005), the Center of Excellence for Innovation in
Chemistry (PERCH-CIC), the Office of the Higher Education
Commission, Mahidol University under the National Research
Universities Initiative, and PICS6663 ISMA (France/Thailand)
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