Synergistic Dual Role of [hmim]Br-ArSO2Cl in Cascade Sulfenylation-Halogenation of Indole: Mechanistic Insight into Regioselective C-S and C-S/C-X (X = Cl and Br) Bond Formation in One Pot

Article abstract of DOI:10.1021/acs.joc.8b03097

Bifunctionalized indoles are an important class of biologically active heterocyclic compounds and potential drug candidates. Because of the lack of efficient synthetic methods, one pot cascade synthesis of these compounds is rare and remains a challenge.

Full text of DOI:10.1021/acs.joc.8b03097

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Article
Synergistic Dual Role of [hmim]Br-ArSO2Cl in Cascade Sulfenylation-
Halogenation of Indole: Mechanistic Insight into Regioselective
C-S and C-S/C-X (X= Cl & Br) Bonds Formation in One-Pot
Danish Equbal, Richa Singh, SAIMA Malik, ADITYA GANDHIDAS LAVEKAR, and Arun K Sinha
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03097 • Publication Date (Web): 08 Feb 2019
Downloaded from http://pubs.acs.org on February 11, 2019
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Synergistic Dual Role of [hmim]Br-ArSO2Cl in
Cascade Sulfenylation-Halogenation of Indole:
Mechanistic Insight into Regioselective C-S and C-
S/C-X (X= Cl & Br) Bonds Formation in One-Pot
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a
a
a,b
a,b
Danish Equbal, Richa Singh, Saima, Aditya G. Lavekar, Arun K Sinha
*,a,b
a
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10,
Jankipuram Extension, Sitapur Road, Lucknow 226031(India).
b
Academy of Scientific and Innovative Research (AcSIR), New Delhi (India)
*E-mail: aksinha08@rediffmail.com, ak.sinha@cdri.res.in
KEYWORDS: Cascade Reaction, Cooperative Catalysis, Functionalized Indole, Halogenation,
Ionic Liquid, Sulfenylation, Water
ABSRTACT: Bifunctionalized indoles are an important class of biologically active heterocyclic
compounds and potential drug candidates. Because of the lack of efficient synthetic methods, one
pot cascade synthesis of these compounds is rare and remains a challenge. To expand this field,
we herein disclose a step-economical and temperature tunable strategy wherein the synergistic
effect between [hmim]Br-ArSO2Cl leads exclusively to the formation of 3-arylthio indole via
sulfenylation of indole at room temperature while heating the reaction mixture at 50 ºC provided
an unexpected 2-halo-3-arylthio indole with construction of C-S and C-S/C-X (X= Cl & Br) bonds
without addition of any external halogenating agent via cascade sulfenylation-halogenation
reactions under metal-oxidant-base-free condition. Further, insight into the reaction mechanism
provides an unprecedented observation wherein the synergistic interaction between [hmim]Br-
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ArSO2X in the presence of catalytic amount of water generates arylsulfonic anhydride (ArSO2)2O
in-situ as a new sulfur source along with the formation of [hmim]PTS as probed by NMR, ESI-
MS, DART-MS and HPLC studies. Notably, the mixture of bifunctionalized 2-halo(Br/Cl)-3-
arylthio indole was smoothly diversified with privileged heterocycle triazole to provide 2-(1H-
triazole-1-yl)-3-arylthio indole which is an analogue of the potent indole-based anticancer agent.
INTRODUCTION
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From the standpoint of green chemistry,1-3 cascade reactions2-3,4-8 have emerged as a powerful tool
for the construction of a wide range of carbon-carbon7-8 or carbon-heteroatom5-6 bonds in one pot
which is generally accomplished by using various catalytic systems including transition-metal
catalysts,8 organocatalysts,7 synergistic cooperative catalysis5-6 etc. In recent years, there has been
significant interest in cooperative catalysis since they enable access to many multistep chemical
transformations including synthesis and functionalization of heterocyclic compounds in a shorter
step which otherwise is not obtainable or tedious by the use of a single catalyst.
Heterocyclic compounds9-10 have always attracted substantial attention due to their broad
biological and therapeutic applications. Among various heterocyclic compounds, functionalized
indoles such as 3-arylthio indoles and 2-halo-3-arylthio indoles bearing C-S and C-S/C-X (X= Cl,
Br & I) bonds respectively occupy upmost position due to their potent biological and
pharmaceutical activities11-16 including anti-cancer, anti-bacterial, heart diseases and HIV inhibitor
besides their use as an important intermediate for the synthesis of various functional organic
materials.17-18 Moreover, bifunctionalized indole including 2-iodo-3-arylthio indole is of particular
interest as this moiety can be further diversified with appropriate boronic acid13 or bioisosteric
five-membered heterocyclic nucleus14 including triazole leading to biologically potent active
molecules with improved metabolic stability (Figure 1).
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Figure 1: Some biologically active 2,3-bifunctionalized arylthio indole
In this regard, considerable efforts have been devoted towards the synthesis of 3-arylthio
indoles19-24 where a variety of sulfenylating agents25-32 such as aryl sulfonylhydrazides,25-26
thiols,20,27-28 disulfides,29-30 aryl sulfonium salts31 and aryl sulfenyl halides32 have been employed
for 3-sulfenylation of indole in the presence of either a metal catalyst,20-22 strong base,21-22 lewis
acid23-24 or oxidant.20,25 Very recently, aryl sulfonylhydrazide (ArSO2NHNH2) has emerged as an
effective and versatile sulfur electrophile for the sulfenylation25 of indoles and related electron rich
hetero(aromatic)arenes in catalytic amount of iodine. However, the synthesis of aryl
sulfonylhydrazides itself requires additional step by reaction of ArSO2Cl with hydrazine.33-34
On the other hand, arylsulfonyl chloride35-39 (ArSO2Cl) has also been employed as one of
the cheaper and easily available source for sulfenylation reaction. Zheng and co-workers36 have
described a photocatalyzed sulfenylation of indole with arylsulfonyl chloride in the presence of
ruthenium catalyst. Also, some alternative protocols have been reported in the literature which
requires either metal catalyst,37 oxidants,38-39 additive,35 acid/base,37,39 high temperature,37,39 for
sulfenylation of indole with ArSO2Cl. However, one pot sulfenylation-halogenation of indoles40-
are very sparsely reported and requires either t-BuOLi/I2/DMSO40 or NBS/DMF41 with the
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maintenance of temperature (up to -10 ºC) for simultaneous sulfenylation-halogenation of indole
(C-S and C-X (X= Cl & Br) bonds). Hence, the development of a practical and highly efficient
green one-pot synthetic protocol for the targeted molecules (3-arylthio indoles and 2-halo-3-
arylthio indoles) under the metal-base-oxidant-free condition is highly desirable.
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Ionic liquids (ILs)42-43 have received growing attention as solvent cum catalyst due to their
versatility for a number of organic transformations,44-47 besides being compatible with a wide
range of solvents46-47 including water. Water as a cosolvent with ionic liquid has been reported to
enhance the reaction yield and selectivity besides exhibiting cooperative effect7,48 towards multiple
bond formation. We herein report an unprecedented synergistic interaction between 1-hexyl-3-
methylimidazolium bromide ([hmim]Br) and ArSO2X (X= Cl & Br) towards the synthesis of 3-
arylthio indoles as well as 2-halo-3-arylthio indoles under tunable reaction temperature (rt & 50
°C) (Scheme 1). Moreover, the reaction mechanistic pathways probed by NMR, ESI-MS, DART-
MS and HPLC depicts the in-situ generation of arylsulfonic anhydride (ArSO2)2O and
bromide/chloride as a sulfur and halogen source along with the formation of 1-hexyl-3-
methylimidazolium p-toluene sulfonate ([hmim]PTS) in the presence of catalytic amount of water.
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RESULT and DISCUSSION
Reaction Evaluation on Sulfenylation and Cascade Sulfenylation-Halogenation of Indole via
C-S and C-S/C-X (X= Br/Cl) Bond Formation. Inspired by our previous report on oxidative
coupling of thiophenol into S-S bond47 and thiol-ene click reaction for C-S bond45 formation in
neutral [hmim]Br, we herein further got interested for metal-base-oxidant-free C-3 sulfenylation
of indole with thiophenol in neutral [hmim]Br ionic liquid. To verify our proposed strategy, a
mixture of 5-bromoindole (1a) and thiophenol was stirred in neutral [hmim]Br at room temperature
(rt) for 12 h or more, but no desired 3-sulfenylated indole product (3a) was observed (Table 1,
entry 1) although diphenyldisulfide was detected due to oxidative coupling of thiophenol in IL47
along with unreacted 1a.
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Scheme 1: Sulfenylation and unprecedented cascade sulfenylation-halogenation of indole in
[hmim]Br-ArSO2X in one pot.
In the same way, the use of PhSO2NHNH225-26 or PhSO2Na31 as sulfenylating agents (up to 1.5
equiv.) could not provide 3a (Table 1, entries 2-3) even after 18 h of reaction time. However, to
our delight benzene sulfonyl chloride (PhSO2Cl) provided the product 3a in 55% yield using
[hmim]Br (0.5 g, 2 mmol) in 5h (Table 1, entry 4). It is worth mentioning that NMR and HRMS
analysis confirmed the product 3a as 3-sulfenylated indole under metal or oxidant free condition
instead of 3-sulfonylated indole as aryl sulfonyl chloride is generally known to act as a
sulfonylating reagent.49 To further increase the yield of 3a, the reaction was screened with respect
to the amount of PhSO2Cl (up to 2.5 equiv.) and reaction time (Table 1, entries 4d and 4e). Thus it
was concluded that 2.0 equiv. of PhSO2Cl (2a) provided the improved yield of 3a (69%) when the
reaction was stirred at rt (Table 2, entry 4d) for 5 h.
Subsequent studies on the impact of nature of ionic liquids as solvent cum catalyst45 were
studied (Table 2, entries 1-5) wherein it was realized that counter anion (bromide, chloride and
iodide) of neutral ionic liquid (Table 2, entries 1-3) played a crucial role towards the formation
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Table 1: Effect of different thiolating agent for sulfenylation of indole in [hmim]Br.[a]
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of 3a. In contrary to [hmim]Br which provided 3a in 69% (Table 2, entry 1), 1-hexyl-3-
methylimidazolium iodide ([hmim]I) offered lower yield (61%) of 3a (Table 2, entry 3) while no
reaction occurred in 1-hexyl-3-methylimidazolium chloride ([hmim]Cl) (Table 2, entry 2). Also,
variation in chain length did not affect the overall yield of the sulfenylation reaction (Table 2,
entries 4-5). Next, we shifted our attention to evaluate the reliance of the above reaction with
respect to acidic ionic liquids such as [hmim]PTS and 1-hexyl-3-methylimidazolium hexafluoro
phosphate ([hmim]PF6), where the yield dropped drastically and in some cases, no product was
observed (Table 2, entries 6-7). Further, C-2 methylated ionic liquid 1-hexyl-2,3-
dimethylimidazolium bromide ([hmmim]Br), resulted in a drastic decrease in the yield of 3a upto
49% (Table 2, entry 8) thus emphasizing the importance of C-2 proton of [hmim]Br. As reported
ILs being viscous and hygroscopic tends to absorb air and moisture, and in some cases, the
presence of moisture in ionic liquid tends to increase the reaction yield and selectivity besides
exhibiting cooperative role towards multiple bond formation.7,50 Hence, the effect of co-solvent
(Table 2, entry 9) with [hmim]Br was taken into consideration during sulfenylation of indole (1a)
with 2a. To our delight, addition of catalytic amount of water (50 μl, 2.78 mmol) in reaction
mixture was found to play a crucial role in increasing the yield of 3a up to 75% with simultaneous
reduction of reaction time to 3h (Table 2, entry 9) from 5h (Table 2, entry 1).
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Table 2: Screening for optimal reaction conditions for sulfenylation and cascade sulfenylation-
halogenation of indole with ArSO2Cl in [hmim]Br under metal-oxidant-base-free condition.[a]
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Further decrease or increase in the amount of water (25 μl, 1.39 mmol & 100 μl, 5.56 mmol)) did
not improve the yield of the product 3a (Table 2, entries 10d & 10e). Moreover, when the reaction
was carried out in lyophilized [hmim]Br, 3a was formed in only 9% yield (Table 2, entry 11),
whereas the use of sole water (Table 2, entry 12) and other organic solvents (Table 2, entries 13-
15) failed to afford the desired product (3a).
To further enhance the yield of 3a, the effect of temperature was taken into account. Thus, a
mixture of 1a and 2a in [hmim]Br and 50 μl water was heated at 50 °C (Table 2) wherein TLC
analysis of reaction mixture after 1 h depicted the formation of an unknown product (Table 2, entry
16g) having different Rf from the expected product (3a) obtained at rt. Column purification
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followed by HRMS and H NMR analysis of the unknown product (4a) was compared with
product 3a and it was found that the product 4a is a mixture of 2,5-dibromo-3-phenylthio indole
(4a’) and 5-bromo-2-chloro-3-phenylthio indole (4a’’) in the ratio of 6:4 (see S.I, page S3-S9),
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wherein [hmim]Br and aryl sulfonyl chloride act as sylfenylating as well as halogenating
agent.24,51-54
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Substrate Scope and Limitation for 3-Sulfenylated Indole/Azaindole (C-S Bond Formation)
at rt. Having established the structure of both products 3a and 4a as well as with optimized
sulfenylation and sulfenylation-halogenation reaction conditions in our hand (Table 2), we first
Table 3: Substrate scope for sulfenylation of indoles with [hmim]Br-ArSO2Cl at rt.[a]
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extended the developed sulfenylation protocol for the synthesis of 3-arylthio indoles (Table 3, 3a-
3p & 3r-3t) and azaindoles (Table 3, 3u-3w). From Table 3, it was observed that both electron
donating as well as electron withdrawing groups present either on indole (1) or on benzene sulfonyl
chloride (2) had no adverse effect on the yield of products (Table 3, 3a-3p). Further, the reaction
was found to be highly regioselective as no sulfenylated product 3q was obtained by using C-3
methyl indole as a starting material (Table 3) while C-2 substituted indole provided the desired
products 3r-3t (Table 3) in good yield. Interestingly, the protocol successfully allowed the
synthesis of 3-arylthio azaindoles (Table 3, 3u-3w) by reaction of azaindole with arylsulfonyl
chloride (2) in [hmim]Br at rt. Unfortunately, aliphatic and heterocyclic sulfonyl chlorides such as
methyl sulfonyl chloride and thiophene-2-sulfonyl chloride as well as electron rich arene i.e. 1-
naphthyl amine did not provide the sulfenylated product (Table 3, 3x-3z and 3aa) even at higher
temperature (ranging from 50 °C to 100 °C).
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Substrate Scope for Sulfenylated Hydroxyaryls (C-S Bond Formation) at 50 ºC. The above
optimized reaction condition (Table 3) was further extended for the sulfenylation of hydroxyaryls
such as 2-naphthol and 4-hydroxycoumarin derivatives at 50 °C (Table 4). Thus,
Table 4: Substrate scope for sulfenylation of 2-naphthol and 4-hydroxy coumarin with [hmim]Br-
ArSO2Cl at 50 °C.[a]
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the reaction of 2-naphthol or 4-hydroxycoumarin with different arylsulfonyl chlorides in [hmim]Br
provided the corresponding 1-sulfenyl-2-hydroxynaphthalenes (Table 4, 7a-7c) and 3-sulfanyl-4-
hydroxycoumarins (Table 4, 8a-8c) respectively in moderate to good yields under metal, additive
and acid-free condition when compared to the reported multi step synthesis requiring expensive
reagents.27,55-57
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Substrate Scope for Unexpected 2-Halo-3-sulfenylated Indole/Azaindole (Cascade C-S/C-X
(X= Cl/Br) Bond Formation) at 50 °C. We next decided to extend the above protocol for cascade
sulfenylation-halogenation of various indole and azaindole via C-S and C-X bond formations in
IL at 50 °C (Table 5). Both indole and benzenesulfonyl chloride having electron donating or
electron-withdrawing groups present at aromatic ring yielded a mixture of 2-bromo-3-arylthio
indole and 2-chloro-3-arylthio indole in varying ratio of 80:20 to 25:75 based upon NMR
spectroscopy (Table 5, entries 4a-4o). However, among the screened substrates none of them
exclusively provided either 2-bromo-3-arylthio indole (4’) or 2-chloro-3-arylthio indole (4’’). It is
worth mentioning that aryl sulfonyl chloride (ArSO2Cl)53 has been reported as either
Table 5: Substrate scope for cascade sulfenylation-halogenation of indole in [hmim]Br-ArSO2Cl
with a catalytic amount of water at 50 °C.[a]
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sulfonylating or chlorinating agent depending upon use of reaction condition and transition metal
catalyst, however our protocol for the first time provided cascade sulfenylation and halogenation
with ArSO2Cl in [hmim]Br in one-pot under metal-free condition.
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Selective Synthesis of 2-Bromo-3-sulfenylated Indole/Azaindole with ArSO2Br. We next
investigated ArSO2Br (instead of ArSO2Cl) for sulfenylation-bromination of 1a in [hmim]Br with
catalytic amount of water towards the selective synthesis of 4a’(Table 6). To validate our
hypothesis, sulfenylation-bromination of 5-bromoindole (1a) was carried out with
benzenesulfonyl bromide (PhSO2Br) (9a) in [hmim]Br and catalytic amount of water at 50 °C
which exclusively provided 2,5-dibromo-3-phenylthioindole 4a’ (Table 6). To our satisfaction,
ArSO2Br bearing electron rich or electron withdrawing group at aromatic ring successfully
provided the desired 2-bromo-3-arylthioindole/azaindole derivatives in moderate to good yield
(Table 6, entries 4a’-4f’).
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Table 6: Substrate scope for cascade sulfenylation-bromination of indole with ArSO2Br in
[hmim]Br with a catalytic amount of water at 50 °C towards exclusive synthesis of 2-bromo-3-
sulfenylated indole.[a]
Effect of Different PhSO2X (X= F, Cl, Br & I) and [hmim]X (X= Cl, Br & I) with Indole at
50 °C. Thus, various permutation and combination of benzene sulfonyl halides (PhSO2X) and
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ionic liquid [hmim]X such as PhSO2Cl-[hmim]Cl (Method A), PhSO2Cl-[hmim]I (Method B),
PhSO2Cl-[hmim]Br (Method C), PhSO2I-[hmim]Br (Method D), PhSO2F-[hmim]Br (Method E)
and PhSO2Br-[hmim]Br (Method F) were investigated (Scheme 2, Methods A-F). Unfortunately,
sulfenylation of 1a with PhSO2Cl in [hmim]Cl at 50 °C (or up to100 °C) even with extended
reaction time (up to 5 h) could not allow the formation of either 4a’’ or 3a (Scheme 2, Method A).
Interestingly, when the sulfenylation-halogenation of 1a was carried out with PhSO2Cl in [hmim]I
or PhSO2I in [hmim]Br at 50 °C for 1 h, only product 3a was formed in both the cases (Method B
and D) while PhSO2F in [hmim]Br or PhSO2Cl in [hmim]Cl did not provide either 3a or 4a’’
(Method E and A). From the comparison results shown in Scheme 2, it was concluded that
PhSO2Br-[hmim]Br for the first time is being used as a source of cascade sulfenylating-
brominating agent for synthesis of 2,3-bifunctionalized indole whereas the previous report has
utilized [hmim]Br3 as a brominating agent for 2-aminopyrimidine.58
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Scheme 2: Comparison study in sulfenylation and halogenation of indole with different benzene
sulfonyl halide (PhSO2X) in different ionic liquid [hmim]X at 50 °C (Method A-F).
Gram Scale Synthesis of 3a and 4a. Next, the temperature tunable synthetic protocol for the
synthesis of 2-halo-3-phenylthioindole 4a at 50 °C and 3-phenylthioindole 3a at rt (Table 5 and 3)
was successfully applied to the gram scale operations. For instance, the sulfenylation and cascade
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sulfenylation-halogenation of indole 1a (6 mmol, 1.18 g) with PhSO2Cl (2a) (2 equiv.) in
[hmim]Br (1.5 g) and catalytic amount of water provided the desired product 4a at 50 °C (2.5 h)
and 3a at rt (5 h) in 72% and 74% respectively (Scheme 3).
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Scheme 3: Gram-scale synthesis of 5-bromo-3-phenylthioindole (3a) and 5-bromoo-2-halo-3-
phenylthioindole (4a).
Diversification of 2-Halo-3-sulfenylated Indole into Privileged 2-(1H-triazole/ pyrazole-1-yl)-
3-arylthio indole. With the optimized reaction condition for the synthesis of 4a bearing
bromo/chloro atom at 2-position of 3-sulfenylated indole, an opportunity for further synthetic
elaboration into more potent bifunctionalized59-61 indoles including 2-(1H-triazole-1-yl)-3-arylthio
indole as an analogue of anti-cancer agent14 was explored. Notably, the bifunctionalized 2-halo-3-
arylthio indole derivatives (4a or 4k) react with excess of privileged heterocycles like triazole or
pyrazole (10 equiv.) in sealed tube62 and thus provided the desired products (10a-10c) with C-N
bond formation (Table 7) in good yield without discrimination of substitution of bromo/chloro
atom at 2-position of indole. As expected 2-bromo substituted arylthio indole (4a’)
Table 7: Functionalization of 2-halo-3-arylthio indoles with privileged heterocycles towards the
synthesis of bioactive 2-(1H-triazole-1-yl)-3-arylthioindole derivatives.[a]
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provided the desired product 10a in little higher yield (75%). Encouraged by excellent selective
functionalization of indole with C-S (Table 3), C-S/C-X (Table 5-6) and C-S/C-N (Table 7) bond
formation under milder reaction conditions, we now turned our attention towards establishing the
reaction mechanism.
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Mechanistic Study and Synergistic Cooperative Effect:
To gain insights into the reaction mechanism of sulfenylation (Table 3) and cascade sulfenylation-
halogenation reaction (Table 5-6), several control experiments were conducted with model
substrate indole (1e) and p-tolylsufonyl chloride (2b) in ionic liquid. To understand the synergistic
effect of water, initially sulfenylation of indole (1e) was conducted with 2b in [hmim]Br which
provided the product 3f in 72% yield at rt in 5 h whereas the yield of product 3f drastically
decreased upto 10% when anhydrous [hmim]Br (lyophilised or vacuum dried to remove traces of
water from IL) was used. When 50 µl of water was charged during the sulfenylation of 1e, the
product 3f was achieved in 82% yield at rt while product 4n was obtained in 78% yield at 50 °C
(Scheme 4), which confirms the synergistic63-64 cooperative role of water63 during sulfenylation
and sulfenylation-halogenation of indole with [hmim]Br-ArSO2Cl.
Scheme 4: Synergistic Cooperative effect of water with [hmim]Br-ArSO2Cl
Based upon above control experiments, it was presumed that reaction may proceed via two
pathway viz. (i) firstly water reacts with 2b which in situ generates PTSA (p-toluene sulfonic acid)
that undergoes bromide exchange with neutral [hmim]Br to afford [hmim]PTS, an acidic ionic
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liquid (see S.I, Figure S11-S12), as a source of sulfenylating agent which would result in the
formation of 3f at rt with overall release of HCl and HBr during sulfenylation reaction of 1e, or
(ii) water reacts with 2b which in situ generates PTSA (p-toluene sulfonic acid) that undergoes
further reaction with second molecule of 2b leading to in situ formation of p-tolylsufonic
anhydride (4-MePhSO2)2O and release of HCl, which indeed interacts with [hmim]Br to afford
[hmim]PTS, an acidic ionic liquid and p-tolyl sulfenyl halide as a source of sulfenylating agent
which would result in the formation of 3f at rt.
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To confirm our hypothesis, a set of control reactions with 1e were conducted and it was
found that when the reaction of 1e was performed with either pre-synthesized [hmim]PTS or PTSA
in [hmim]Br, product 3f was not observed while 1e reacted with either p-tolyl sulfenyl chloride
(MePhSCl) or p-tolyl sulfonic anhydride in [hmim]Br afforded the desired product 3f.
Scheme 5: Control reaction.
ESI-MS and DART-MS Studies. To establish the reaction mechanism pathway, ESI-MS and
DART-MS were used as soft MS ionization techniques which are known to promote only a few
fragmentation products. ESI-MS analysis of [hmim]Br gives two peaks with m/z signals at 167.1
and 412.8 (see S.I, Figure S11), whereas direct analysis of an aliquot of reaction of [hmim]Br with
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4-MePhSO2Cl (2b) by ESI-MS in positive ion mode provides three peaks with m/z signals at
167.1, 412.8 and 504.8 (see S.I, Figure S12). The appearance of m/z signal at 504.8 confirms the
formation of [hmim]PTS as we postulated during sulfenylation-halogenation reaction. Similarly
in the DART-MS analysis of the aliquot withdrawn after 15 min of reaction between 1e and 2b,
peaks at m/z 296.05 (m5) (marked as C) and 362.0 (m7) (marked as E) were observed which
confirms that the sulfenylation reaction proceeds through anhydride pathway while the mass peaks
at m/z value of 274.04 (m4) (marked as B) and 317.9 (m6) (marked as D) confirms
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Figure 2: DART-MS analysis for the reaction of 1e and 2b at 50 °C in [hmim]Br with water (cat.)
after 15 min.
the formation of product (4n) as a mixture of 2-bromo-3-tolylthio indole and 2-chloro-3-tolylthio
indole. Moreover, the mass peak present at m/z value of 240.08 (m3) (marked as A) further
confirms the formation of sulfenylated indole (3f) followed by halogenation at 2-position leading
to 4n via cascade sulfenylation-halogenation rather via halogenation-sulfenylation reaction. To
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our extreme delight, HPLC (see S.I, Figure S14-S29) revealed the clean formation of 3f and 4n
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via Path A (Scheme 6).
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Scheme 6: Possible pathways A or B for cascade sulfenylation-halogenation reaction.
Proposed Mechanism. Based on ESI-MS, DART-MS and HPLC studies along with control
reactions, a reaction pathway for the sulfenylation and cascade sulfenylation-halogenation reaction
is proposed (Scheme 7).23-24,39,51-52 Firstly the two molecules of p-tolylsulfonyl chloride reacts in
presence of catalytic amount of water and [hmim]Br resulting in the formation of sulfonic
anhydride (intermediate II) via intermediate I. The intermediate II transforms into intermediate III
via reduction process in presence of [hmim]Br. This intermediate III interacts with [hmim]Br
leading to the generation of sulfenylating agent IV along with acidic ionic liquid [hmim]PTS. The
sulfenylating agent IV undergoes chloride exchange resulting into sulfenylating agent V at
equilibrium. The in-situ generated sulfenylating agent IV as well as V reacts with 1e generating
product 3f at rt. The product 3f at 50 °C undergoes cascade halogenation with in-situ liberated
halide ion followed by air oxidation resulting into the product 4n.
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Scheme 7: Proposed reaction mechanism for the sulfenylation and cascade sulfenylation-
halogenation reaction.
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CONCLUSION
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In conclusion, we have developed an efficient protocol that allowed for a more step-economical
synthesis of 3-arylthio indoles via C-S bond formation at rt and 2-halo-3-arylthioindoles via
cascade C-S and C-X (X= Cl & Br) bond formation at 50 °C from cheap and readily available
sulfenylating agent arylsulfonyl chloride (ArSO2Cl) with indole derivatives in [hmim]Br and
catalytic amount of water under metal-base-oxidant free condition. This temperature tunable
protocol is mild, safe, efficient and regioselective besides having a broad scope in terms of mono-
or bi-functionalization of indole, azaindole and hydroxyaryl derivatives with different
sulfenylating agents (ArSO2X where X= Cl, Br, I & F) at room temperature or 50 °C. Moreover,
ESI-MS, DART-MS, NMR and HPLC analysis probes the beneficial and synergistic cooperative
effect of water (cat.) with ArSO2Cl in [hmim]Br wherein in situ generation of aryl sulfonic
anhydride is found responsible for sulfenylation and halogenation of indole and other related
compounds. Diversification of bifunctionalized 2-halo(Bromo/Chloro)-3-arylthio indole with
privileged heterocycles such as triazole or pyrazole to obtain 2-(1H-triazole/pyrazole-1-yl)-3-
arylthioindoles, a potent analogue of the indole-based anticancer agent is an added merit of our
protocol. Thus the reported work presents an efficient protocol for sulfenylation and cascade
sulfenylation-halogenation, which could be of immense importance to academia and industry.
Further application of this protocol for the synthesis of biologically active heterocyclic compounds
is under progress.
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EXPERIMENTAL SECTION
General Information. All the substrates (reagent, catalyst etc.) used for the synthesis of
compounds were obtained from Sigma or Alfa or TCI. The ionic liquids and some indole standards
were obtained either commercially (from Merck or Alfa Aesar) or synthesized using earlier
reported methods.65-67,72-75 The purity of ILs was ascertained by NMR before use. The solvent used
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for isolation/purification of compounds were obtained from commercial sources (Merck, Qualigen
& Sd fine) and were used without further purification. The organic extracts were dried over
anhydrous sodium sulfate (Merck grade). Evaporation of solvent was performed at reduced
pressure using Buchi Rota vapor (Switzerland). 1H (400 MHz) and 13C (100 MHz) NMR spectra
were recorded on a Bruker Avance-400 spectrometers. TMS was used as an internal reference for
NMR. The following abbreviations were used to designate chemical shift multiplicities: s= singlet,
d= doublet, t= triplet, q= quartet, br= broad. Splitting patterns that could not be interpreted or easily
visualized are designated as multiple (m). The 13C NMR spectra are proton decoupled. The
Column chromatography was done on silica gel (100-200 mesh). TLC was performed on silica
TLC plates and compounds visualized in iodine or under UV lamp. The temperature of the reaction
mixture was monitored by the thermometer. HRMS spectra were recorded as ESI-HRMS on a Q-
TOF LC-MS/MS mass spectrometer. Melting points were obtained manually by capillary methods
and are uncorrected. HPLC was performed on Waters 2998 Photodiode Array Detector (waters
515 HPLC pump). The separation was performed on an XBRIDGE column (C18- 250 x 4.6 mm
id, 5 µm; Thermo). The mobile phase consisted of 0.01% TFA (Trifluoroacetic acid) in Mille pure
H2O and methanol/acetonitrile (in 70:30, v/v) with gradient elution (0-5 min, 60% A and 40% B;
6-11 min, 30% A and 70% B; 12-26 min, 0% A and 100% B; 27-29 min, 30% A and 70% B; 30
min. 60% A and 40% B with a flow rate of 0.8 ml/min. and analysis wavelength was set at 254
and 280 nm.
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Experimental procedure for the preparation of 3-Arylthio Indole at rt (Table 3, entries 3a-
3w). In a 25 ml RBF, 5-bromo indole (1a, 0.25 mmol) with benzenesulfonyl chloride (2a, 0.50
mmol) was stirred in neutral ionic liquid [hmim]Br (0.5 g, 2 mmol) in the presence of catalytic
amount of water (50 µL, 2.78 mmol) at room temperature for 3 h. After completion of the reaction,
the crude product was extracted with ethyl acetate (10 mL, three times), washed with water (3 x
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10 mL) and the combined organic was dried over anhydrous Na2SO4 and conc. under vacuum.
Column purification of the crude product was performed on silica gel (100-200 mesh) on glass
column with ethyl acetate/hexane (5:95) as eluent to afford the 5-bromo-3-phenylthio indole
(Table 3, entry 3a). Following the above procedure, various 3-arylthio indoles were synthesized
by using different indole/azaindole or aryl sulfonyl chloride (Table 3, entries 3b-3w).
5-Bromo-3-(phenylthio)-1H-indole (3a).68 Compound 3a was obtained as white solid (57 mg,
75% yield); mp 119-121 °C (Lit.[68] 120-121 °C); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.46 (s,
1H), 7.78 (d, J = 4 Hz, 1H), 7.50 (d, J = 4 Hz, 1H), 7.39–7.37 (m, 1H), 7.33 (d, J = 8 Hz, 1H),
7.23–7.19 (m, 2H), 7.12-7.09 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 138.7, 135.1,
131.9, 131.0, 128.8, 126.1, 125.9, 125.0, 122.2, 114.5, 113.1, 102.7; HRMS (ESI) m/z: [M+H]+
calculated for C14H11NSBr 303.9795; Found 303.9793. For gram scale reaction (Scheme 3), 3a
was obtained in 74% yield (1.35 g).
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5-Chloro-3-(phenylthio)-1H-indole (3b).31 Compound 3b was obtained as white solid (47 mg,
73% yield); mp 111-112 °C (Lit.[31] 112.5-113.5 °C); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.50
(s, 1H), 7.62 (d, J = 4.0 Hz, 1H), 7.52 (d, J = 4.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.25–7.10 (m,
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3H), 7.13-7.09 (m, 3H); C{1H} NMR (100 MHz, CDCl3): δ (ppm) 138.8, 134.8 132.0, 130.4,
128.8, 126.9, 125.9, 125.0, 123.5, 123.5, 119.1, 112.6, 102.9; HRMS (ESI) m/z: [M+H]+
calculated for C14H11NSCl 260.0301; Found 260.0288.
5-Nitro-3-(phenylthio)-1H-indole (3c).68 Compound 3c was obtained as yellow solid (48 mg,
71% yield); mp 157-160 °C (Lit.[68] 156-158 °C); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.86 (s,
1H), 8.60 (d, J = 4.0 Hz, 1H), 8.20 (dd, J = 8.0 Hz, 1H), 7.69 (d, J = 4.0 Hz, 1H), 7.52 (d, J = 12.0
Hz, 1H), 7.24-7.20 (m, 2H), 7.16-7.13 (m, 3H).; 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 142.9,
139.4, 137.7, 133.5, 128.9, 126.4, 125.5, 118.7, 116.9, 111.8, 106.7; HRMS (ESI) m/z: [M+H]+
calculated for C14H11N2SO2 271.0541; Found 271.0534.
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5-Methoxy-3-(phenylthio)-1H-indole (3d).68 Compound 3d was obtained as white solid (49 mg,
77% yield); mp 78-79 °C (Lit.[68] 77-78 °C); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.37 (s, 1H),
7.46 (d, J = 4.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.22–7.19 (m, 2H), 7.15-7.07 (m, 4H), 6.97-
6.94 (m, 1H), 3.82 (s 3H); 13C{1H} NMR (100MHz, CDCl3): δ (ppm) 155.1, 139.3, 131.3, 130.0,
128.7, 125.7, 124.7, 113.6, 112.4, 102.2, 100.8, 55.8. HRMS (ESI) m/z: [M]+ calculated for
C15H13NSO 255.0718; Found 255.0706.
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3-(Phenylthio)-1H-indole (3e).68 Compound 3e was obtained as colorless solid (52 mg, 81%
yield); mp 150-152 °C (Lit.[68] 150-152 °C); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.41 (s, 1H),
7.66 (dd, J = 4.0, 8.0 Hz, 1H), 7.50-7.46 (m, 2H), 7.33-7.29 (m, 1H), 7.23–7.18 (m, 3H), 7.17–
7.14 (m, 2H), 7.12–7.08 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 139.2, 136.5, 130.7,
129.1, 128.7, 125.9, 124.8, 123.0, 120.9, 119.6, 111.6, 102.8; HRMS (ESI) m/z: [M+H]+
calculated for C14H12NS 226.0690; Found 226.0684.
3-(p-Tolylthio)-1H-indole (3f).68 Compound 3f was obtained as white solid (49 mg, 82% yield);
mp 130-132 °C (Lit.[68] 124-126 °C); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.39 (s, 1H), 7.66 (d,
J = 8.0 Hz, 1H), 7.49-7.44 (m, 2H), 7.31–7.28 (m, 1H), 7.21-7.17 (m, 1H), 7.07 (d, J = 12.0 Hz,
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2H), 7.01 (d, J = 8.0 Hz, 2H), 2.28 (s, 3H); C{1H} NMR (100 MHz, CDCl3): δ (ppm) 136.5,
135.5, 134.6, 130.4, 129.5, 129.1, 126.3, 122.9, 120.8, 119.7, 111.5, 103.5, 20.8; HRMS (ESI)
m/z: [M+H]+ calculated for C15H14NS 240.0847; Found 240.0840.
3-((4-Methoxyphenyl)thio)-1H-indole (3g).68 Compound 3g was obtained as pale yellow solid
(50 mg, 78% yield); mp 111-113 °C (Lit.[68] 111-112 °C); 1H NMR (400 MHz, CDCl3): δ (ppm)
8.36 (s, 1H), 7.70 (d, J = 4.0 Hz, 1H), 7.42–7.37 (m, 2H), 7.32-7.26 (m, 1H), 7.24-7.19 (m, 3H),
6.79 (d, J = 8.0 Hz, 2H), 3.77 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 158.2, 134.4,
129.5, 129.3, 129.2, 127.9, 123.2, 121.4, 119.3, 114.5, 110.7, 102.8, 55.3; HRMS (ESI) m/z:
[M+H]+ calculated for C15H14NSO 256.0796; Found 256.0783.
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3-((4-Fluorophenyl)thio)-1H-indole (3h).25 Compound 3h was obtained as white solid (46 mg,
75% yield); mp 134-136 °C (Lit.[25] 132-134 °C); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.44 (s,
1H), 7.62 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 4.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.31–7.28 (m,
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MHz, CDCl3): δ (ppm) 162.3, 159.8, 136.5, 130.4, 128.8, 127.9, 127.8, 123.1, 120.9, 119.5, 115.8,
115.6, 111.6, 103.5; HRMS (ESI) m/z: [M+H]+ calculated for C14H11NSF 244.0596; Found
244.0586.
3-((4-Chlorophenyl)thio)-1H-indole (3i).68 Compound 3i was obtained as white solid (50.6 mg,
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78% yield); mp 134-135 °C (Lit.[68] 129-131 °C); H NMR (400 MHz, CDCl3) δ (ppm) 8.49 (s,
1H), 7.60 (d, J = 4.0 Hz, 1H), 7.51 (d, J =4.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.33-7.28 (m, 1H),
7.22-7.13 (m, 1H), 7.15 (d, J = 12.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H);13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 137.8, 136.5, 130.7, 130.5, 128.7, 127.1, 123.2, 121.0, 119.5, 111.6, 102.5;
HRMS (ESI) m/z: [M+H]+ calculated for C14H11NSCl 260.0301; Found 260.0304.
3-((4-Bromophenyl)thio)-1H-indole (3j).68 Compound 3j was obtained as white solid (57.8 mg,
76% yield); mp 142-143 °C (Lit.[68] 141-143 °C); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.48 (s,
1H), 7.60 (d, J = 8.0Hz, 1H), 7.52–7.47 (m, 2H), 7.32-7.28 (m, 3H), 7.22-7.18 (m, 1H), 7.00–6.97
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(m, 2H); C{1H} NMR (100 MHz, CDCl3): δ (ppm) 138.5, 136.5, 131.6, 130.7, 128.8, 127.4,
123.2, 121.0, 119.5, 118.3, 111.6, 102.3; HRMS (ESI) m/z: [M+H]+ calculated for C14H11NSBr
303.9796; Found 303.9799.
3-((4-Iodophenyl)thio)-1H-indole (3k).68 Compound 3k was obtained as red solid (66.7 mg, 76%
yield); mp 134-135 °C (Lit.[68] 135-137 °C); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.45 (s, 1H),
7.56 (d, J = 12.0 Hz 1H), 7.48 (s, 1H), 7.44-7.43 (m, 3H), 7.27-7.25 (m, 1H), 7.17 (t, J = 8.0 Hz,
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1H), 6.83 (d, J = 12.0 Hz 2H); C{1H} NMR (100 MHz, CDCl3): δ (ppm) 139.5,137.5, 136.5,
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for C14H11NSI 351.9657; Found 351.9643.
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74% yield); mp 172-174 °C (Lit.[25]-174-175°C); H NMR (400MHz, CDCl3): δ (ppm) 8.62 (s,
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1H), 8.01 (d, J = 8.0 Hz, 2H), 7.58-7.52 (m, 3H), 7.35 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz,
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1H), 7.16 (d, J = 8.0 Hz, 2H); C{1H} NMR (100 MHz, CDCl3): δ (ppm) 149.7, 144.9, 136.5,
131.1, 128.4, 125.1, 123.8, 123.5, 121.4, 119.2, 111.9, 100.2; HRMS (ESI) m/z: [M]+ calculated
for C14H10N2SO2 270.0463; Found 270.0449.
3-((4-Cyanophenyl)thio)-1H-indole (3m).26 Compound 3m was obtained as white solid (47 mg,
75% yield); mp 183-184 °C (Lit.[26] 184-186 °C); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.63 (s,
1H), 7.57-7.54 (m, 2H), 7.52 (d, J = 4. 0Hz, 1H), 7.42 (d, J = 8. 0Hz, 2H), 7.34 (t, J = 8.0 Hz, 1H),
7.22 (d, J = 8.0 Hz, 1H), 7.25-7.13 (d, J = 8.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm)
147.1, 136.6, 132.1, 131.1, 128.5, 125.4, 123.5, 121.3, 119.3, 119.1, 111.9, 107.6, 100.3; HRMS
(ESI) m/z: [M]+ calculated for C15H10N2S 250.0565; Found 250.0550.
1-(4-((1H-indol-3-yl)thio)phenyl)ethanone (3n). Compound 3n was obtained as brown solid (50
mg, 75% yield); mp 115-116 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.75 (s, 1H), 7.77 (d, J =
8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 4.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.32 (t, J
= 8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H) 2.54 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ (ppm) 197.45, 147.0, 136.6, 133.6, 131.1, 129.3, 128.7, 125.0, 123.3, 121.2,
119.4, 111.8, 101.0, 26.4; HRMS (ESI) m/z: [M+H]+ calculated for C16H14NSO 268.0796; found
268.0794.
3-((2,3-Dichlorophenyl)thio)-1H-indole (3o). Compound 3o was obtained as off white solid (49
mg, 67% yield); mp 124-125 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.56 (s, 1H), 7.60 (d, J =
8.0 Hz, 1H), 7.55 (d, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz,
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1H), 7.17 (d, J = 8.0 Hz, 1H), 6.88 (t, J = 8.0 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3): δ (ppm) 141.3, 136.5, 133.0, 131.4, 128.7, 127.8, 127.0, 125.0, 124.3, 123.4,
121.3, 119.5, 111.7, 101.3; HRMS (ESI) m/z: [M]+ calculated for C14H9NSCl2 292.9833; Found
292.9818
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2-Phenyl-3-(phenylthio)-1H-indole (3p). Compound 3p was obtained as Brown viscous (50 mg,
64% yield); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.57 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.67 (d,
J = 8.0 Hz, 1H), 7.47 (t, J = 8.0, 3H), 7.42 (d, J = 8.0, 1H), 7.32-7.29 (m, 1H), 7.19 (t, J = 8.0,
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1H), 7.05-6.99 (m, 4H), 2.28 (s,3H); C{1H} NMR (100 MHz, CDCl3): δ (ppm) 141.8, 135.8,
135.6, 134.4, 131.5, 131.2, 129.6, 128.8, 128.6, 128.1, 125.7, 123.3, 121.1, 120.0, 111.1, 100.0,
20.8; HRMS (ESI) m/z: [M]+ calculated for C21H17NS 315.1082; Found 315.1080.
2-Methyl-3-(phenylthio)-1H-indole (3r).68 Compound 3r was obtained as white solid (46 mg,
77% yield); mp 109-110 °C (Lit.[68] 109-111 °C); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.26 (s,
1H), 7.58 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.25–7.18 (m, 4H), 7.09–7.07 (m, 3H),
2.54 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 141.1, 139.3, 135.4, 130.3, 128.7, 125.5,
124.5, 122.2, 120.7, 119.0, 110.6, 99.4, 12.1; HRMS (ESI) m/z: [M+H]+ calculated for C15H14NS
240.0847; Found 240.0837.
3-(Phenylthio)-1H-indole-2-carboxylic acid (3s).26 Compound 3s was obtained as brown solid
(44 mg, 65% yield); mp 160-161 °C (Lit.[26] 160-161 °C); 1H NMR (400 MHz, DMSO-d6): δ (ppm)
12.98 (s, 1H), 11.74 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.45-7.40 (m, 2H),
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7.38-7.30 (m, 2H), 7.29–7.05 (m, 3H); C{1H} NMR (100 MHz, DMSO-d6): δ (ppm) 163.2,
137.7, 130.6, 129.9, 129.3, 128.8, 127.6, 127.3, 126.7, 125.5, 124.7, 122.3, 120.4, 112.9, 107.7;
HRMS (ESI) m/z: [M+H]+ calculated for C15H12NSO2 270.0589; Found 270.0585.
Ethyl 3-(phenylthio)-1H-indole-2-carboxylate (3t).26 Compound 3t was obtained as creamish
solid (56 mg, 75% yield); mp 129-130 °C (Lit.[26] 130-132 °C); 1H NMR (400 MHz, DMSO-d6):
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δ (ppm) 12.38 (s, 1H), 7.56 (d, J = 4.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H),
7.22-7.20 (m, 2H), 7.12-7.07 (m, 4H), 4.3 (q, J = 7.0 Hz, 2H), 1.25 (t, J = 7.0 Hz, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6): δ (ppm) 160.8, 138.2, 136.7, 129.7, 129.6, 129.3, 126.9, 125.8,
125.7, 121.6, 120.7, 113.6, 107.8, 61.2, 14.5; HRMS (ESI) m/z: [M]+ calculated for C17H15NSO2
297.0823; Found 297.0796.
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3-(Phenylthio)-1H-pyrrolo[2,3-b]pyridine (3u). Compound 3u was obtained as white solid (51
mg, 76% yield); mp 186-188 °C; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 12.28 (s, 1H), 8.32 (dd,
J = 4.0 Hz, 1H), 7.93 (s, Hz, 1H), 7.80 (dd, J = 4.0 Hz, 1H), 7.22 (t, J = 8.0, 2H), 7.15-7.13 (m,
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1H), 7.12 (d, J = 4.0, 1H), 7.09-7.06 (m, 2H); C{1H} NMR (100 MHz, DMSO-d6): δ (ppm)
149.4, 144.2, 139.0, 133.7, 129.4, 127.1, 126.0, 125.6, 121.4, 117.0, 99.1; HRMS (ESI) m/z:
[M+H]+ calculated for C13H11N2S 227.0643; Found 227.0631.
3-(p-Polylthio)-1H-pyrrolo[2,3-b]pyridine (3v).69 Compound 3v was obtained as off white solid
(47 mg, 78% yield); mp 154-155 °C (Lit.[69] 162-165 °C); 1H NMR (400 MHz, DMSO-d6): δ (ppm)
8.37 (d, J = 4.0, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 4.0, 1H), 7.42
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(d, J = 8.0, 2H), 7.30 (dd, J = 4.0, 1H), 6.81 (d, J = 8.0, 1H), 2.34 (s, 3H); C{1H} NMR (100
MHz, DMSO-d6): δ (ppm) 147.1, 146.0, 145.1, 135.1, 130.6, 130.4, 128.0, 127.3, 122.9, 119.8,
106.4, 21.5; HRMS (ESI) m/z: [M+H]+ calculated for C14H13N2S 241.0799; Found 241.0804.
3-((4-Bromophenyl)thio)-1H-pyrrolo[2,3-b]pyridine (3w). Compound 3w was obtained as
white solid (56 mg, 74% yield); mp 209-210 °C; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 12.3
(s, 1H), 8.32 (dd, J = 4.0 Hz, 1H), 7.96 (d, J = 4.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.40 (d, J =
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8.0, 2H), 7.15 (dd, J = 4.0,1H), 6.98 (d, J = 8.0, 2H); C{1H} NMR (100 MHz, DMSO-d6): δ
(ppm) 149.4, 144.3, 138.9, 133.9, 132.2, 127.9, 127.1, 121.2, 118.3, 117.2, 98.4; HRMS (ESI)
m/z: [M+H]+ calculated for C13H10N2SBr 304.9748; Found 304.9743.
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Experimental procedure for the Synthesis of 1-Arylthio-2-naphthol at 50 °C (Table 4, entries
7a-7c). In a 25 ml RBF, 2-naphtol (5, 0.25 mmol) with benzenesulfonyl chloride (2a, 0.50 mmol)
was stirred in neutral ionic liquid [hmim]Br (0.5 g, 2 mmol) in the presence of catalytic amount of
water (50 µL, 2.78 mmol) at 50 °C for 4 h. After completion of the reaction, the crude product was
extracted with ethyl acetate (10 mL, three times), washed with water (3 x 10 mL) and the combined
organic layer was dried over anhydrous Na2SO4 and conc. under vacuum. Column purification of
the crude product was performed on silica gel (100-200 mesh) on glass column with ethyl
acetate/hexane (10:90) as eluent to afford the 1-phenylthio-2-naphthol (7a). Following the above
procedure, various 1-arylthio-2-naphthols were synthesized by using different aryl sulfonyl
chloride.
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1-(Phenylthio)naphthalen-2-ol (7a).70 Compound 7a was obtained as white solid (46 mg, 73%
yield); mp 57-58 °C (Lit.[70] 58-59 °C); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.23 (s, 1H), 7.94
(d, J = 12 Hz, 1H), 7.84 (d, J = 8 Hz, 1H), 7.54–7.50 (m, 1H), 7.39 (d, J = 8 Hz, 1H), 7.37 (d, J =
12 Hz, 1H), 7.22-7.18 (m, 3H), 7.15-7.13 (m, 1H), 7.07-7.04 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3): δ (ppm) 157.0, 134.6, 133.1, 132.2, 129.5, 128.6, 127.9, 124.4, 124.0, 119.6, 116.9;
HRMS (ESI) m/z: [M+Na]+ calculated for C16H12OSNa 275.0507; Found 275.0477.
1-(p-Tolylthio)naphthalen-2-ol (7b).70 Compound 7b was obtained as white solid (48 mg, 72%
yield); mp 71-74 °C (Lit.[70] 72.5-73.5 °C); 1H NMR (400 MHz, CDCl3): δ (ppm) 8.26 (d, J = 8.0
Hz, 1H), 7.92 (d, J = 8.0, Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.54-7.50 (m, 1H), 7.41-7.35 (m, 2H),
7.24 (s, 1H), 7.03–6.97 (m, 4H), 2.27 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 156.8,
135.9, 135.4, 132.6, 131.7, 129.9, 129.4, 128.5, 127.8, 126.7, 124.7, 123.7, 116.8, 108.7, 20.8;
HRMS (ESI) m/z: [M]+ calculated for C17H14OS 266.0765; Found 266.0756.
1-((4-Bromophenyl)thio)naphthalen-2-ol) (7c).70 Compound 7c was obtained as yellow solid
(57 mg, 69% yield); mp104-105 °C (Lit.[70] 103-105 °C); 1H NMR (400 MHz, CDCl3): δ (ppm)
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8.18 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.55-7.51 (m, 1H),
7.43–7.41 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.35-7.30 (m, 2H), 7.11 (s, 1H), 6.91 (d, J = 8.0 Hz,
2H); 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 157.0, 135.1, 134.6, 133.1, 132.2, 129.5, 128.6,
128.1, 127.9, 124.4, 124.0, 119.6, 116.9, 107.6; HRMS (ESI) m/z: [M+H]+ calculated for
C16H12OSBr 330.9792; Found 330.9787.
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Experimental procedure for the Synthesis of 3-Arylthio-4-hydroxy Coumarin at 50 °C
(Table 4, entries 8a-8c). 4-hydroxy coumarin (6, 0.25 mmol) with benzenesulfonyl chloride (2a,
0.50 mmol) was stirred in neutral ionic liquid [hmim]Br (0.5 g, 2 mmol) in the presence of catalytic
amount of water (50 µL, 2.78 mmol) at 50 °C for 8 h. After completion of the reaction, the crude
product was extracted with ethyl acetate (10 mL, 3 times), washed with water (3 x 10 mL) and the
combined organic layer was dried over anhydrous Na2SO4 and conc. under vacuum. The column
purification of the crude product was performed on silica gel (100-200 mesh) on glass column with
ethyl acetate/hexane (20:80) as eluent to afford the 3-phenylthio-4-hydroxy coumarin (Table 4,
entry 8a). Following the above procedure, various 3-phenylthio-4-hydroxy coumarins were
synthesized by using different aryl sulfonyl chloride (Table 4, entries 8b-8c).
4-Hydroxy-3-(phenylthio)-2H-chromen-2-one (8a).71 Compound 8a was obtained as white solid
(45 mg, 66% yield); mp 198-199 °C (Lit.[71] 200-202 °C);1H NMR (400 MHz, DMSO-d6): δ (ppm)
7.98-7.96 (m, 1H), 7.74–7.70 (m, 1H), 7.45-7.39 (m, 2H), 7.31-7.27 (m, 2H), 7.20-7.14 (m, 3H);
13C{1H} NMR (100M Hz, DMSO-d6): δ (ppm) 169.0, 161.4, 153.5, 136.5, 134.0, 129.5, 126.6,
125.9, 124.8, 124.6, 116.9, 116.3, 94.5; HRMS (ESI) m/z: [M+H]+ calculated for C15H11O3S
271.0429; Found 271.0429.
4-Hydroxy-3-(p-tolylthio)-2H-chromen-2-one (8b).71 Compound 8b was obtained as white solid
(49 mg, 69% yield); mp 160–161 °C (Lit.[71] 160–161 °C); 1H NMR (400 MHz, CDCl3): δ (ppm)
7.97–7.94 (m, 1H), 7.73–7.68 (m, 1H), 7.43–7.38 (m, 2H), 7.11-7.11 (m, 4H), 2.24 (s, 3H).13C{1H}
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NMR (100 MHz, CDCl3): δ (ppm) 167.1, 161.5, 153.5, 137.3, 133.7, 130.0, 128.8, 124.4, 124.2,
116.8, 114.3, 97.5, 20.9; HRMS (ESI) m/z: [M+H]+ calculated for C16H13O3S 285.0585; Found
285.0572.
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4-Hydroxy-3-((4-hydroxyphenyl)thio)-2H-chromen-2-one (8c).71 Compound 8c was obtained
as white solid (57 mg, 65% yield); mp 196-197 °C (Lit.[71] 197–198 °C); 1H NMR (400 MHz,
DMSO-d6): δ (ppm) 8.32 (s, 1H), 7.83-7.80 (m, 1H), 7.46-7.42 (m, 1H), 7.31–7.29 (m, 2H), 7.16–
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7.12 (m, 2H), 6.93–6.91 (m, 2H); C{1H} NMR(100 MHz, DMSO-d6): δ (ppm) 169.2, 161.3,
153.5, 136.3, 134.1, 132.2, 128.7, 124.9, 124.6, 118.6, 116.9, 116.4, 94.1; HRMS (ESI) m/z:
[M+H]+ calculated for C15H10O3SBr 348.9534; Found 348.9528.
Experimental procedure for the Preparation of mixture of 2-Halo(bromo/chloro)-3-arylthio
Indole at 50 °C (Table 5, entries 4a-4o). 5-bromo indole (1a, 0.25 mmol) with benzenesulfonyl
chloride (2a, 0.50 mmol) was stirred in neutral ionic liquid [hmim]Br (0.5 g, 2 mmol) in the
presence of catalytic amount of water (50 µL, 2.78 mmol) at 50 °C for 1 h. After completion of
the reaction, the crude product was extracted with ethyl acetate (10 mL, 3 times), washed with
water (3 x 10 mL) and the combined organic layer was dried over anhydrous Na2SO4 and conc.
under vacuum. Colum purification of the crude product was performed on silica gel (100-200
mesh) on glass column with ethyl acetate/hexane (5:95) as eluent to afford the 5-bromo-2-halo
(halo= Cl/Br)-3-phenylthio indole (Table 5 entry 4a) in 73% yield wherein yield was calculated
on the basis of molecular weight of 2-bromo-3-phenylthio indole derivative. Following the same
procedure different 2-halo-3-arylthio indoles were synthesized by using different indole/azaindole
or aryl sulfonyl chloride (Table 5, entries 4b-4o).
2,5-Dibromo-3-(phenylthio)-1H-indole and 5-Bromo-2-chloro-3-(phenylthio)-1H-indole
(4a). Compound 4a was obtained as white solid (70 mg, 73% yield); 1H NMR (400 MHz, CDCl3):
δ (ppm) 8.60 (s, 0.60H), 8.56 (s, 0.40H), 7.74-7.73 (m, 1H), 7.38-7.34 (m, 1H), 7.26–7.21 (m, 3H),
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