Alkanethiol-Mediated Cyclization of o-Alkynylisocyanobenzenes: Synthesis of Bis-Thiolated Indole Derivatives

Article abstract of DOI:10.1021/acs.joc.0c00003

Reactions of o-alkynylisocyanobenzenes with a variety of alkanethiols (Alk-SH) provide the corresponding bis-thiolated indole derivatives. The advantages of the reaction include metal-free, room-temperature, mild reaction conditions and broad functional group compatibility. The reaction proceeds via nucleophilic addition of an alkanethiol to an isonitrile moiety, 5-exo cyclization, followed by nucleophilic addition of an alkanethiol to a 3-alkylidene indole intermediate. Density functional calculations on the electronic structures and relative free energies of 5-exo and 6-endo cyclization pathways support that the 5-exo cyclization is preferable.

Full text of DOI:10.1021/acs.joc.0c00003

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Article
Alkanethiols Mediated Cyclization of o-Alkynylisocyanobenzenes:
Synthesis of bis-Thiolated Indole Derivatives
Kannika La-ongthong, Phiphop Naweephattana, Onnicha Khaikate, Panida Surawatanawong, Darunee
Soorukram, Manat Pohmakotr, Vichai Reutrakul, Pawaret Leowanawat, and Chutima Kuhakarn
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00003 • Publication Date (Web): 01 Apr 2020
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Alkanethiols Mediated Cyclization of o-Alkynylisocyanobenzenes:
Synthesis of bis-Thiolated Indole Derivatives
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Kannika La-ongthong, Phiphop Naweephattana, Onnicha Khaikate, Panida Surawatanawong,
Darunee Soorukram, Manat Pohmakotr, Vichai Reutrakul, Pawaret Leowanawat, and
Chutima Kuhakarn*
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Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-
CIC), Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
chutima.kon@mahidol.ac.th
Reactions of o-alkynylisocyanobenzenes with a variety of alkanethiols (Alk-SH) provide the
corresponding bis-thiolated indole derivatives. The merits of the reaction include metal-free,
room temperature, mild reaction conditions, and broad functional group compatibility. The
reaction proceeds via nucleophilic addition of the alkanethiol to an isonitrile moiety, 5-exo
cyclization, followed by nucleophilic addition of alkanethiol to a 3-alkylideneindole
intermediate. Density functional calculations on the electronic structures and relative free
energies of 5-exo and 6-endo cyclization pathways support that the 5-exo cyclization is
preferable.
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INTRODUCTION
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Indoles are a group of ubiquitous heterocycles found in nature and possess diverse
biological activities.1 Not surprisingly, the indole scaffolds constitute an important class of
compounds in many pharmaceuticals. As a result, the synthesis of indole core2 and
functionalization of indoles3,4 have become a major focus of synthetic organic chemists and
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numerous synthetic ปmethods have been continually reported. Among the indole derivatives,
those bearing organosulfur moieties both the sulfonyl and the sulfanyl synthons also display
vast applications in various fields.5
o-Alkenyl- and o-alkynylisocyanobenzenes are versatile functional group which could
directly serve as important synthetic synthons for the synthesis of nitrogen-containing
heterocyclic compounds via anionic cyclization in the presence of nucleophiles,6 Lewis acid
mediated cyclization reactions7 and radical mediated cyclization reactions.8 Along these lines,
we have recently reported that o-alkynylisocyanobenzenes 2 can undergo nucleophilic addition
by water, sodium sulfinates, and ammonium thiocyanate to provide the respective quinolin-
2(1H)-ones, 2-sulfonyl- and 2-thiocyanatoquinolines (Scheme 1, a).9 Therefore, we envisioned
the strategy would apply to the synthesis of 2-sulfanylquinolines from the reaction of o-
alkynylisocyanobenzenes 2 and thiol derivatives (Scheme 1, b). Unexpectedly, upon treatment
of
o-(phenylethynyl)isocyanobenzene
(2a),
freshly
prepared
from
N-(2-
(phenylethynyl)phenyl)formamide (1a),9 with 1-propanethiol (3a, 2 equiv.) in DMF, the
reaction readily took place at room temperature (2 h) and gave 3-(phenyl(propylthio)methyl)-
2-(propylthio)-1H-indole (4aa) in 70% yield via 5-exo cyclization (Table 1, entry 1). It is worth
to note that the corresponding 3-phenyl-2-(propylthio)quinoline derived from 6-endo
cyclization was not observed. To the best of our knowledge, previously reported works on the
addition of thiols to isonitrile were proposed to proceed via thiyl radicals derived from thiol or
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disulfide precursors in the presence of radical initiators or under photochemical conditions.10
The methodology was also applied to the synthesis of bis-thiolated indoles.8a, 8d These results
prompted us to examine the synthesis of the bis-thiolated indoles by the reaction of o-
alkynylisocyanobenzenes 2 with alkanethiols 3. Also described here are our density functional
calculations showing that the reaction of o-alkynylisocyanobenzenes 2 with alkanethiols 3
results in an unprecedented ionic approach beginning with addition of the alkanethiol to an
isonitrile moiety, 5-exo cyclization and consecutive protonation, followed by the addition of a
second molecule of alkanethiol to the transient 3-alkylidene-3H-indole intermediate, to yield
bis-thiolated indoles 4 (Scheme 2).
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Scheme 1. Nucleophilic Addition to Isonitrile Followed by Intramolecular Trapping
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RESULTS AND DISCUSSION
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Taking the proposed pathway in mind (Scheme 2), we further examined the optimized
reaction conditions employing o-(phenylethynyl)isocyanobenzene (2a) and 1-propanethiol
(3a) as model substrates and the results are summarized in Table 1. As previously mentioned,
the reaction of 2a and 3a in DMF at room temperature for 2 h gave 4aa in 70% yield (Table 1,
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o
entry 1). The reaction performed at higher temperature (80 C) did not provide better yield
(Table 1, entry 2); 4aa was obtained in comparable yield (69% yield). The reactions carried
out at room temperature with extended reaction time gave inferior results (Table 1, entries 3
and 4). These results implied the instability of 4aa with prolonged reaction time. Slightly better
yield of 4aa was observed when 3a was employed in excess amount (Table 1, entries 5 and 6).
External bases including organic bases (DBU, Et3N, and pyridine) and inorganic base (K2CO3
and Cs2CO3) as well as AgNO3 were also employed but they failed to improve the reaction
efficiency (Table 1, entries 7−12). The effect of solvents (DMSO, toluene and dry DMF) was
also evaluated and they all gave inferior results (Table 1, entries 13−15).
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Table 1. Optimization of Reaction Conditionsa
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entry
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3a (equiv)
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5
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solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
Toluene
Dry DMF
additive
−
−
−
−
−
−
DBU
Et3N
Pyridine
K2CO3
Cs2CO3
AgNO3
−
temp. (oC) time (h) yieldb (%)
rt
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−
aReaction conditions: Step A: 1a (0.1106 g, 0.5 mmol, 1.0 equiv), POCl3 (0.07 mL, 0.75
mmol, 1.5 equiv), (i-Pr)2NEt (0.70 mL, 4.0 mmol, 8.0 equiv), CH2Cl2 (4 mL, 0.125 M), 0 oC
1 h; followed by aqueous work-up, concentrated, diluted with EtOAc and filtered through a
short-path column chromatography (aluminium oxide, Type E) eluted with EtOAc, and
concentrated. Step B: A crude mixture from Step A was treated with 1-propanethiol (3a)
b
under various reaction conditions. Isolated yields (2 steps) after column chromatography
(SiO2).
Scheme 2. Proposed mechanism
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After the optimized reaction conditions were identified (Table 1, entry 5), we next
evaluated the scope and limitation of the bis-thiolated indole synthesis from the reaction of a
collection of o-alkynylisocyanobenzenes and alkanethiols. We first sought to examine the
scope of the reaction of structurally different o-alkynylisocyanobenzenes 2 with 1-propanethiol
(3a) under the established reaction conditions and the results are summarized in Table 2. First
various substituents on R1 on the phenyl ring of o-alkynylisocyanobenzenes were evaluated. It
was found that the reactions proceeded smoothly, under the standard reaction conditions, to
provide the corresponding products 4ba–4ha in low to good yields (30–68% yields).
Electronically different substituents (R3) on the arylethynyl moiety at the para, meta and ortho
positions (including p-F, p-Cl, p-Br, p-NO2, p-CH3, p-OCH3, m-F, m-Cl, m-Br, m-CH3, o-F,
and o-Cl) gave products 4ia–4ta in low to good yields (27–70% yields). 2-((2-
Isocyanophenyl)ethynyl)naphthalene yielded product 4ua in low yields, even at extended
reaction time (from 2 h to 16 h). Unexpectedly, 4va bearing o, p-dimethyl substituents at the
arylethynyl moiety was obtained in high yield (73% yield). The reaction can accommodate the
substrate bearing a 2-thienyl substituent to yield 4wa in 60% yield. Finally, aliphatic alkynyl
substrates were good substrates and afforded the corresponding products 4xa–4za in moderate
yields (59–60% yields). It is worth to note that a scaling up experiment was also demonstrated.
The reaction of 2a [prepared from 1a (1.1063 g, 5 mmol, 1 equiv)] reacted with 3a (1.1 mL,
12.5 mmol, 2.5 equiv) to deliver 4aa (1.2444 g, 70% yield) (Table 2).
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Table 2. Synthesis of bis-Thiolated Indoles 4: Scope of o-Alkynylisocyanobenzenes 2a,b
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4aa, R1 = H (74%) [70%]c
4ba, R1 = CH3 (68%)
4ca, R1 = F (52%)
4ha (34%)
4ia, R3 = F (66%)
4ja, R3 = Cl (61%)
4ka, R3 = Br (48%)
4la, R3 = NO2 (43%)
4ma, R3 = CH3 (68%)
4na, R3 = OCH3 (62%)
4da, R1 = Cl (34%)
4ea, R1 = Br (52%) [68%]d
4fa, R1 = NO2 (18%) [30%]d
4ga, R1 = CF3 (43%)
4oa, R3 = F (35%)
4pa, R3 = Cl (35%)
4qa, R3 = Br (49%)
4ra, R3 = CH3 (70%)
4sa, R3 = F (33%)
4ta, R3 = Cl (27%)
4ua (15%) [18%]d
4va (73%)
4wa (60%)
4xa, R2 = (CH2)3CH3 (60%)
4ya, R2 = (CH2)5CH3 (60%)
4za, R2 = (CH2)2CH(CH3)2 (59%)
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aReaction conditions: Step A: 1 (0.5 mmol, 1.0 equiv), POCl3 (0.07 mL, 0.75 mmol, 1.5 equiv),
(i-Pr)2NEt (0.70 mL, 4.0 mmol, 8.0 equiv), CH2Cl2 (4 mL, 0.125 M), 0 C 1 h, followed by
o
aqueous work-up, concentrated, diluted with EtOAc and filtered through a short-path column
chromatography (aluminium oxide, Type E) eluted with EtOAc, and concentrated. Step B: A
crude mixture from Step A was treated with 3a (0.11 mL, 1.25 mmol, 2.5 equiv) in DMF (2
b
mL, 0.25 M), rt (30–32 °C), 2 h. In parenthesis: isolated yields (2 steps) after column
c
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chromatography (SiO2). 1a (1.1063 g, 5 mmol, 1.0 equiv) and 3a (1.1 mL, 12.5 mmol, 2.5
equiv) were employed. dThe reaction was carried out at room temperature for 16 h.
Next, the reaction of 2a with a collection of alkanethiols 3 was investigated and the
results are shown in Table 3. The reaction of 2a with primary alkanethiols 3a‒3e gave the
corresponding bis-thiolated indoles 4aa‒4ae in moderate to good yields (44‒74% yields). The
steric effect was also evidenced and was found harmful to the reaction. Secondary and tertiary
alkanethiols including sec-butanethiol and tert-butanethiol were not good substrates and the
corresponding products 4af and 4ag were obtained in 13% and 15% yields, respectively albeit
at prolonged reaction time (16 h). Although phenylmethanethiol (3h) gave product 4ah in low
yield (22% yield), 2-phenylethane-1-thiol (3i) delivered 4ai in 50% yield, upon carrying out
the reaction at room temperature for 16 h. To our surprise, cyclohexanethiol (3j) readily reacted
with 2a, after stirring at room temperature for 16 h, to yield 4aj in 60% yield. It is worth
mentioning that 2a was previously reported to react with 3j in boiling benzene in the presence
of AIBN as a radical initiator to afford 3-phenylquinoline and spiro products derived from 1,5-
hydrogen translocation followed by 5-endo-trig cyclization of the firstly formed thioimidoyl
radical.8b The reaction of heterocyclic thiol, furan-2-ylmethanethiol, readily proceeded to yield
4ak in 32% yield. It should be noted that under the standard reaction conditions, the reaction
of 2a with thiophenol gave 3-phenyl-2-(phenylthio)quinoline (5) in 20% yield while the
corresponding bis-thiolated indole was not observed (Scheme 3). The reaction carried out in
the presence of Et3N (2 equiv) gave 5 in slightly higher yield (37% yield).
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Table 3. Synthesis of bis-Thiolated Indoles 4: Scope of Alkanethiols 3a,b
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4aa (74%)
4ab (55%)
4ac (57%)
4ad (44%)
4ae (65%)
4af (13%)
4ag (15%)c
4ah (22%)c
4ai (50%)c
4aj (60%)c
4ak (32%)
aReaction conditions: Step A: 1a (0.1106 g, 0.5 mmol, 1.0 equiv), POCl3 (0.07 mL, 0.75
mmol, 1.5 equiv), (i-Pr)2NEt (0.70 mL, 4.0 mmol, 8.0 equiv), CH2Cl2 (4 mL, 0.125 M), 0 oC
1 h, followed by aqueous work-up, concentrated, diluted with EtOAc and filtered through a
short-path column chromatography (aluminium oxide, Type E) eluted with EtOAc, and
concentrated. Step B: A crude mixture from Step A was treated with 3 (1.25 mmol, 2.5 equiv)
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b
in DMF (2 mL, 0.25 M), rt (30–32 °C), 2 h. In parenthesis: isolated yields (2 steps) after
column chromatography (SiO2). cThe reaction was carried out at room temperature for 16 h.
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Scheme 3. Reaction of 2a with Thiophenol
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At this stage we were anticipated to trap the transient 2-alkylthio-3-alkylidene-3H-
indole intermediate with two different nucleophiles. Unfortunately, we have been unsuccessful
in our attempts. Thus, 2a (prepared from 1a, 1 equiv) was treated with ethanethiol (3b, 1 equiv,
DMF, rt, 1 h) followed by the addition of a second nucleophile (1 equiv, rt, 1 h). Neither 2-
ethylhexane-1-thiol (3e) nor KCN were able to trap the firstly formed 3-benzylidene-2-
(ethylthio)-3H-indole derived from the first addition of 1 equivalent of 3b to 2a. After
chromatographic purification, 4ab was solely isolated in low yields (23–31% yields).
To obtain preliminary mechanistic insights, we performed a series of probing
experiments (Scheme 4). In Scheme 4a, fluorescent light (tube rod; 18 watt) as radical initiator
had little influence on the yield of product 4aa (69% vs 61% in the dark). The addition of either
3,5-di-tert-butyl-4-hydroxytoluene (BHT, 1 and 2.5 equiv) or hydroquinone (2.5 equiv) had
little influence on the yield of 4aa. Although 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO)
has been shown to serve as a thiyl radical trapping reagent,11 it was found that TEMPO (1
equiv) had negligible impact on the product yield. However, excessive amount of TEMPO (2.5
equiv) was found harmful and proved to be incompatible with this reaction. In the absence of
3a, 2a completely decomposed after stirring with TEMPO (2.5 equiv). Next, it was previously
reported that ((2-isocyanophenyl)ethynyl)trimethylsilane (6), in the presence of AIBN at
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refluxing toluene, reacted with thiols leading to bis-thiolated indoles.8a In our hands, 6 readily
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6
o
reacted with 1-propanethiol (3a) (AIBN, toluene, 110 C, 15 min) to yield 7 in 52% yield
7
8
9
(Scheme 4b). In contrast, under our reported reaction conditions, 6 did not react with 3a and 6
was recovered unchanged in 90% yield (Scheme 4b). Additionally, o-arylisocyanobenzenes
which were widely reported to react with a variety of radical species to access 6-substituted
phenanthridine derivatives failed to react with alkanethiol under our standard reaction
conditions (Scheme 4c).12 Upon treatment of 2-isocyano-1,1'-biphenyl (8) with 1-propanethiol
(3a) in DMF at either at room temperature or at 80 oC for 2 h led to the recovery of 8 (80–90%
yields) without the detection of 6-(propylthio)phenanthridine (9).13 On the contrary, under
radical conditions (DTBP, DMF, 120 oC, 24 h), 8 reacted with 3a to yield 9 in 71% yield.14
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Scheme 4. Control Experiments
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(b)
(c)
To obtain an insight into the exclusive formation of bis-thiolated indoles under our
established reaction conditions, we performed density functional calculations to investigate the
5-exo and 6-endo cyclization pathways of intermediate A, which is presumably formed from
the nucleophilic addition of ethanethiol (EtSH) to the isonitrile of o-
(phenylethynyl)isocyanobenzene) (2a) (Scheme 5). When the ethanethiol attacks the isonitrile,
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it is expected to be deprotonated under the reaction conditions to form the anionic intermediate
A.
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Our calculation showed that intermediate A preferably undergoes 5-exo cyclization.
The 5-exo cyclization via the transition state TS1-AB to form cyclized intermediate B proceeds
with a lower free energy barrier than the direct 6-endo cyclization via the transition state TS4-
AC to form C (6.6 and 15.0 kcal/mol, respectively) (Scheme 5). The nucleophilic addition to
alkyne generally favors the obtuse trajectory at the * of the alkyne.15 Here, the C1-C5-C6
angle in TS1-AB for 5-exo cyclization is 121.6o while the C1-C6-C5 angle in TS4-AC for 6-
endo cyclization is only 95.3o (Scheme 5). This corresponds with the stereoelectronic
preference for 5-exo cyclization. In addition, the developed anionic charge of the 5-exocyclic
can be stabilized by the terminal aryl substituent at the alkyne.16 The 5-membered intermediate
B and the 6-membered intermediate C are rather stable relative to A (-28.4 and -33.5 kcal/mol).
The indirect pathway to form the 6-membered intermediate from the ring expansion of
the 5-membered intermediate via 3-exo cyclization has been previously suggested.8e,17 Here,
we investigated the 3-exo cyclization of the 5-membered intermediate B via TS2-BD to form
the tricyclic intermediate D, which rearranges to the 6-membered intermediate C via TS3-DC
(Scheme 5). This indirect pathway to form the 6-membered intermediate C needs to overcome
a rather high energy barrier of 35.4 kcal/mol (Scheme 5). Therefore, the 5-membered
intermediate B, which is easily formed, is unlikely to rearrange to the 6-membered intermediate
C. This is in good agreement with the fact that only the 5-membered ring product was observed
in this work. The 5-exo cyclization was also found more favorable than 6-endo cyclization in
the related benzannelated enediynes.16, 18-20
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Scheme 5. Relative Free Energy Profiles for 5-exo (in blue) and 6-endo (in black) Cyclization
Pathways of Intermediate A (Presumably Formed from the Nucleophilic Addition of
Ethanethiol (EtSH) to 2a.
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Note that the 6-endo cyclization leads to the product with a higher aromatic stabilization
than the 5-exo cyclization. For the nucleophilic addition of thiophenol (PhSH) to the isonitrile
of 2a, the corresponding 6-membered ring product, 3-phenyl-2-(phenylthio)quinoline (5), was
solely observed in our experiment, although in low yield (20% yield) (Scheme 3). From our
calculation, the intermediate M, which is presumably formed from the nucleophilic addition of
thiophenol to the isonitrile 2a, can proceed to both 5-exo and the 6-endo cyclization pathways
with the energy barriers of 6.4 and 15.1 kcal/mol, respectively (Scheme 6). These are similar
to the 5-exo and the 6-endo cyclization pathways for the intermediate A (Scheme 5). However,
here the 5-exo cyclization intermediate N is more stable than intermediate M by only -22.9
kcal/mol. It is probable that N rearranges back to M with the energy barrier of 29.3 kcal/mol
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and M takes the 6-endo cyclization pathway leading to the thermodynamically stable 6-endo
intermediate O (-29.8 kcal/mol) as being observed in this work.
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Scheme 6. Relative Free Energy Profiles for 5-exo (in blue) and 6-endo (in black) Cyclization
Pathways of Intermediate M (Presumably Formed from the Nucleophilic Addition of
Thiophenol (PhSH) to 2a.
In our previous study,9b the nucleophilic addition of methanesulfinate sodium salt
(MeSO2Na) to isonitrile 2a also leads to the 6-endo cyclization product. Thus, we calculated
the 5-exo cyclization and the 6-endo cyclization of the intermediate I, which is formed from
the nucleophilic addition of MeSO2Na to isonitrile 2a (Scheme 7). The 5-exo cyclization of I
via TS1-IJ needs to overcome a higher energy barrier than the 5-exo cyclization of A via TS1-
AB (11.0 and 6.6 kcal/mol, respectively) (Scheme 7 and Scheme 5) while the energy barrier
for the 6-endo cyclization of I via TS4-IK is comparable to that for the 6-endo cyclization of
A via TS4-AC (15.8 and 15.0 kcal/mol, respectively). Thus, the energy barrier for the 6-endo
cyclization via TS4-IK to form K is only slightly higher than that for the 5-exo cyclization via
TS1-IJ to form J (15.8 and 11.0 kcal/mol, respectively) (Scheme 7). In addition, the
rearrangement of the 5-membered intermediate J to the 6-membered intermediate K through
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the 3-exo cyclization proceeds with the overall energy barrier of only 25.6 kcal/mol, which is
significantly lower than the rearrangement of B to C (35.4 kcal/mol).
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The extended -system can facilitate the 3-exo cyclization of the 5-membered
intermediates. We investigated the frontier molecular orbitals (MOs) and MO energies of 5-
membered intermediates J, N, and B, which contain –SO2Me, –SPh, and –SEt substituent,
respectively (Scheme S4). The * LUMO energy is in the order of –SO2Me, –SPh, and –SEt
substituent (-1.77, -1.32, and -1.22 eV, respectively). The presence of electron withdrawing –
SO2Me group (in intermediate J) decreases the * LUMO energy, which promotes the 3-exo
cyclization to proceed with lower energy barrier than that of B bearing the –SEt group.
In place of the alkanethiol group (EtS- group), the presence of the electron withdrawing
sulfonyl group (MeSO2- group) does not only disfavor the 5-exo cyclization process but also
facilitates the indirect formation of the 6-membered ring product through the 3-exo cyclization.
Therefore, for the sulfonylation by methanesulfinate sodium salt, the thermodynamically more
stable 6-membered intermediate K can be formed from the direct 6-endo cyclization of I (in
close competition with 5-exo cyclization) and from the indirect rearrangement of the 5-exo
cyclization intermediate J via the 3-exo cyclization. On the other hand, for the thiolation by
ethanethiol, the 5-exo cyclization of A is much more kinetically favorable than the direct 6-
endo cyclization of A and the indirect rearrangement of the 5-exo cyclization intermediate B
to the 6-endo cyclization product C needs to overcome the prohibitively high energy barrier.
This corresponds with the fact that the 6-membered quinoline products were obtained when
sulfinate salts were employed as nucleophiles in our previous work9b and the 5-membered
indole products were observed when alkanethiols were used as nucleophiles in this work.
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Scheme 7. Relative Free Energy Profiles for 5-exo (in blue) and 6-endo (in black) Cyclization
Pathways of Intermediate I (Formed from the Nucleophilic Addition of Methanesulfinate
Sodium Salt (MeSO2Na) to 2a.
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Finally, the synthetic applications of some selected bis-thiolated indole derivatives
were demonstrated (Scheme 8). Upon treatment of the bis-thiolated indoles (including 4aa,
4ab, 4ac, 4ai and 4aj) with m-CPBA (4.1 equiv, CH2Cl2, 0 oC to rt, 16 h), the corresponding
bis-sulfonyl indoles 10 were obtained in moderate to good yields (52–88% yields). It should
also emphasize here that all of the bis-sulfonyl indoles derivatives were obtained as solids and
they are relatively more stable than their corresponding bis-thiolated indole derivatives. The
sulfonyl moiety at the benzylic position of 3-substituted indoles serves as a good leaving group
enabling the formation of vinylogous imine intermediates, which are able to react with several
nucleophiles.21 In this work, the reaction of selected bis-sulfonylated indoles 10 (including
10aa, 10ab and 10aj) with allyltrimethylsilane catalyzed by InCl3 were evaluated (Scheme
8).22 Pleasingly, the reaction readily proceeded to yield the corresponding allylated adducts 11
in moderate yields (Scheme 8).
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Scheme 8. Synthetic Applications of the bis-Thiolated and bis-Sulfonyl Indole Derivatives.
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CONCLUSIONS
In conclusion, we have prepared a collection of bis-thiolated indole derivatives via
facile cyclization of o-alkynylisocyanobenzenes employing alkanethiols as nucleophiles. The
range of alkanethiols was found to be synthetically useful. To the best of our knowledge, the
present work is the first report on nucleophilic addition of alkanethiols to o-
alkynylisocyanobenzenes to access bis-thiolated indole derivatives under mild conditions.
Efforts to perform density functional calculations on the electronic structures and relative free
energies of 5-exo and 6-endo cyclization pathways revealed that the 5-membered ring product
through 5-exo cyclization is preferable when the alkanethiols were employed as nucleophiles
while the sulfinate sodium salts and thiophenol preferentially led to the 6-membered ring
products.
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EXPERIMENTAL SECTION
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General: H NMR spectra were recorded with a Bruker AVANCE 400 spectrometer (400
MHz) and JEOL-400 spectrometer (400 MHz) in CDCl3 by using tetramethylsilane (δ = 0 ppm)
or residual non-deuterated solvent peak as an internal standard. 13C NMR spectra were recorded
with a Bruker AVANCE 400 (100 MHz) spectrometer and JEOL-400 spectrometer (400 MHz).
Infrared spectra were recorded with a Bruker ALPHA FT-IR spectrometer and only partial data
were listed. High-Resolution Mass Spectra (HRMS) were recorded with a Bruker micro TOF
spectrometer in the ESI mode. Reactions were monitored by Thin-Layer Chromatography and
visualized by UV and a solution of KMnO4. N-(2-Arylethynyl)phenyl)formamides and N-(2-
alkylethynyl)phenyl)formamides were synthesized according to literature procedures. The
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structures of known compounds were confirmed by comparing their H NMR and C NMR
data with those in the literature. All reagents and solvents were obtained from commercial
sources and used without further purification. Column chromatography was performed by
using Merck silica gel 60 (Art 7734).
All isolated compounds were characterized on the basis of H NMR, 13C NMR
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spectroscopic data, IR spectra and HRMS data. H NMR and C NMR chemical shifts are
reported in ppm using tetramethylsilane (TMS) as an internal standard or residual non-
deuterated solvent peak as an internal standard.
Computation details
All calculations were performed by Gaussian 09 program.23 The geometry
optimizations and frequency calculations were carried out by B3LYP24-26 functional with 6-
31G(d)27-29 basis set. The single point energy in solvent was calculated on the gas-phase
optimized geometries using M0630 functional with 6-31++G(d,p)27-29 basis set. The solvation
correction was performed by using the conductor-like polarizable continuum model (CPCM)31-
32 with solvent parameters corresponding to N,N-dimethylformamide (ε = 37.219).
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General Procedure for the Synthesis of N-(2-(Arylethynyl)phenyl)formamides and N-
(2-(Alkylethynyl)phenyl)formamides 1.9b To a round-bottom flask filled with formic acid (40
mmol, 4.0 equiv) was added Ac2O (20 mmol, 2.0 equiv) at room temperature, and the resulting
mixture was stirred for 10 minutes. To this mixture was added a solution of 2-iodoaniline
derivatives (10 mmol, 1.0 equiv) in CH2Cl2 (0.80 mL/mmol) then the reaction chamber was
stirred for 2 h at room temperature. After completion, the reaction was quenched with H2O (5
mL) and the resulting mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated (aspirator)
to yield the corresponding N-(2-iodoaryl)formamide which was used in the coupling reaction
without prior purification. To a two-neck flask containing N-(2-iodoaryl)formamide (10 mmol,
1.0 equiv), PdCl2(PPh3)2 (91.2 mg, 0.13 mmol, 0.013 equiv), and CuI (19.0 mg, 0.1 mmol, 0.01
equiv) was added THF (1 mL/mmol) and NEt3 (1 mL/mmol) under argon atmosphere. Then,
monosubstituted acetylene (11 mmol, 1.1 equiv) was added dropwise to the reaction mixture.
The reaction was allowed to stir at room temperature under argon atmosphere for overnight.
After completion, the reaction was quenched with diluted HCl solution (20 mL) and the
resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were
washed with brine (20 mL), dried (MgSO4), filtered, and concentrated (aspirator). Crude
product was purified by column chromatography on silica gel (EtOAc/hexane) to provide the
corresponding N-(2-(arylethynyl)phenyl)formamide or N-(2-(alkylethynyl)phenyl)formamide
1.
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General Procedure for the Synthesis of o-Alkynylisocyanobenzenes 2. To a solution of
N-(2-(arylethynyl)phenyl)formamide or N-(2-(alkylethynyl)phenyl)formamide 1 (0.5 mmol,
1.0 equiv) and diisopropylethylamine (0.70 mL, 4.0 mmol, 8.0 equiv) in CH2Cl2 (4 mL, 0.125
o
M) was added dropwise POCl3 (0.07 mL, 0.75 mmol, 1.5 equiv) at 0 C under argon
atmosphere. The reaction mixture was stirred at 0 °C for 1 h. After completion, the reaction
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was quenched with NaHCO3 (5 mL) and the resulting mixture was extracted with CH2Cl2 (3 ×
10 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4),
filtered, and concentrated (aspirator). Crude product was filtered through a short-path layer of
aluminium oxide (Type E), eluted with 100% ethyl acetate to provide the corresponding o-
alkynylisocyanobenzene 2 which were subsequently used in the next step without prior
purification.
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General Procedure for the Synthesis of bis-Thiolated Indoles 4 and Quinoline 5. To a
round-bottomed flask filled with o-alkynylisocyanobenzene 2 {freshly prepared from the
corresponding N-(2-(arylethynyl)phenyl)formamide or N-(2-(alkynyl)phenyl)formamide 1
(0.5 mmol, 1.0 equiv)} was diluted with DMF (2 mL, 0.25 M). To this mixture was added thiol
nucleophiles (1.25 mmol, 2.5 equiv). The reaction mixture was stirred at room temperature for
2 h. After completion, the reaction mixture was diluted with H2O (5 mL) and the resulting
mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed
with brine (20 mL), dried (MgSO4), filtered, and concentrated (aspirator). Crude product was
purified by column chromatography on silica gel (EtOAc/hexane).
General Procedure for the Synthesis of bis-Sulfonyl Indoles 10. To a round-bottomed
flask filled with bis-thiolated indole 4 (1.0 mmol, 1.0 equiv) was diluted with CH2Cl2 (5 mL,
0.20 M). To this mixture was slowly added to m-CPBA (0.71 g, 4.1 mmol, 4.1 equiv) in CH2Cl2
(6 mL, 0.68 M) at 0 oC. The reaction mixture was stirred at room temperature for 16 h before
the reaction mixture was diluted with H2O (10 mL). The resulting mixture was extracted with
EtOAc (3 × 15 mL). The combined organic layers were washed with brine (20 mL), dried
(MgSO4), filtered, and concentrated (aspirator). Crude product was purified by column
chromatography on silica gel (EtOAc/hexane).
General Procedure for the Synthesis of Allylated Compounds 11. To a round-bottomed
flask filled with bis-sulfonyl indole 10 (0.25 mmol, 1.0 equiv), InCl3 (3 mg, 5 mol%) in CH2Cl2
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(2.5 mL, 0.10 M). To this mixture was slowly added allyltrimethylsilane (0.38 mmol, 1.5
equiv). The reaction mixture was stirred at room temperature for 11 h before the reaction
mixture was diluted with H2O (3 mL). The resulting mixture was extracted with EtOAc (3 ×
10 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4),
filtered, and concentrated (aspirator). Crude product was purified by column chromatography
on silica gel (EtOAc/CH2Cl2/hexane).
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3-(Phenyl(propylthio)methyl)-2-(propylthio)-1H-indole (4aa). Purification by column
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chromatography (EtOAc/hexane, 1:19 v/v) afforded 4aa (0.1316 g, 74%); red brown oil; H
NMR (CDCl3, 400 MHz): δ 8.05 (s, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 7.6 Hz, 2H),
7.26 (dd, J = 14.6, 7.6 Hz, 3H), 7.21–7.14 (m, 2H), 7.06 (t, J = 7.5 Hz, 1H), 5.81 (s, 1H), 2.66
(t, J = 7.3 Hz, 2H), 2.44–2.28 (m, 2H), 1.65–1.56 (m, 2H), 1.56–1.46 (m, 2H), 0.91 (dt, J =
10.1, 7.3 Hz, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 141.6, 136.7, 128.5, 128.2, 128.1,
126.6, 126.5, 123.0, 121.7, 120.9, 119.7, 110.6, 46.0, 39.0, 34.4, 23.4, 22.6, 13.6, 13.1 ppm;
IR (neat): 3463, 3062, 2966, 2874, 1493, 1445, 770, 670 cm-1; HRMS (ESI-TOF) m/z: [M - H]-
Calcd for C21H24NS2 354.1356; Found 354.1359.
5-Methyl-3-(phenyl(propylthio)methyl)-2-(propylthio)-1H-indole (4ba). Purification
by column chromatography (EtOAc/hexane, 1:19 v/v) afforded 4ba (0.1240 g, 68%); orange
viscous liquid; 1H NMR (CDCl3, 400 MHz): δ 7.97 (s, 1H), 7.75 (s, 1H), 7.56 (d, J = 7.6 Hz,
2H), 7.29–7.24 (m, 2H), 7.21–7.15 (m, 2H), 7.02 (dd, J = 8.3, 0.9 Hz, 1H), 5.78 (s, 1H), 2.64
(t, J = 7.3 Hz, 2H), 2.40 (s, 3H), 2.39–2.28 (m, 2H), 1.69–1.59 (m, 2H), 1.54–1.45 (m, 2H),
0.91 (dt, J = 19.2, 7.3 Hz, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 141.7, 135.1, 128.9, 128.2,
128.2, 127.6, 126.8, 126.6, 124.7, 121.2, 120.3, 110.3, 46.0, 39.1, 34.4, 23.4, 22.7, 21.6, 13.6,
13.1 ppm; IR (neat): 3392, 3058, 2960, 2870, 1599, 1448, 739, 697 cm-1; HRMS (ESI-TOF)
m/z: [M - H]- Calcd for C22H26NS2 368.1512; Found 368.1511.
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5-Fluoro-3-(phenyl(propylthio)methyl)-2-(propylthio)-1H-indole (4ca). Purification
by column chromatography (EtOAc/hexane, 1:9 v/v) afforded 4ca (0.0970 g, 52%); orange oil;
1H NMR (CDCl3, 400 MHz): δ 8.06 (s, 1H), 7.64 (dd, J = 10.1, 2.4 Hz, 1H), 7.53 (d, J = 7.5
Hz, 2H), 7.30–7.25 (m, 2H), 7.20 (dt, J = 9.2, 5.9 Hz, 2H), 6.94 (td, J = 9.0, 2.5 Hz, 1H), 5.77
(s, 1H), 2.68 (t, J = 7.3 Hz, 2H), 2.36 (dddd, J = 20.1, 14.7, 12.7, 7.5 Hz, 2H), 1.65–1.47 (m,
4H), 0.92 (dd, J = 15.7, 7.5 Hz, 6H);13C{1H} NMR (CDCl3, 100 MHz): δ 157.3 (d, JC,F = 235.4
Hz), 149.6, 141.3, 133.2, 128.5, 128.2 (d, JC,F = 29.2 Hz), 126.9, 126.8, 121.0 (d, JC,F = 4.8
Hz), 111.7, 111.4 (d, JC,F = 11.1 Hz), 111.3 (d, JC,F = 9.6 Hz), 106.7, 106.4, 45.9, 39.0, 34.3,
23.4, 22.6, 13.6, 13.1 ppm; IR (neat): 3408, 3059, 2960, 2870, 1577, 1440, 1063, 739, 697 cm-
1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C21H23FNS2 372.1261; Found 372.1263.
5-Chloro-3-(phenyl(propylthio)methyl)-2-(propylthio)-1H-indole (4da). Purification
by column chromatography (EtOAc/hexane, 1:9 v/v) afforded 4da (0.0670 g, 34%); dark
orange oil; 1H NMR (CDCl3, 400 MHz): δ 8.11 (s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.52 (d, J =
7.6 Hz, 2H), 7.31–7.25 (m, 2H), 7.22–7.17 (m, 2H), 7.14 (dd, J = 8.6, 1.9 Hz, 1H), 5.76 (s,
1H), 2.67 (t, J = 7.3 Hz, 2H), 2.43–2.27 (m, 2H), 1.68–1.46 (m, 4H), 0.92 (dt, J = 12.3, 7.3 Hz,
6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 141.2, 135.0, 129.3, 128.4, 128.0, 127.5, 126.8,
125.4, 123.4, 120.9, 120.5, 111.7, 45.8, 38.9, 34.4, 23.4, 22.6, 13.6, 13.1 ppm; IR (neat): 3408,
3062, 2958, 2864, 1601, 1442, 798, 698 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for
C21H23ClNS2 388.0966; Found 388.0956.
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5-Bromo-3-(phenyl(propylthio)methyl)-2-(propylthio)-1H-indole (4ea). Purification by
column chromatography (EtOAc/hexane, 1:9 v/v) afforded 4ea (0.1131 g, 52%, reaction time:
2 h) (0.1290 g, 68%, reaction time: 16 h); pale orange oil; 1H NMR (CDCl3, 400 MHz): δ 8.14
(d, J = 1.7 Hz, 2H), 7.52 (d, J = 7.5 Hz, 2H), 7.28 (dd, J = 8.7, 7.2 Hz, 3H), 7.20 (d, J = 7.3
Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 5.75 (s, 1H), 2.66 (t, J = 7.3 Hz, 2H), 2.43–2.26 (m, 2H),
1.66–1.46 (m, 4H), 0.92 (dt, J = 13.7, 7.3 Hz, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 141.2,
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135.3, 128.4, 128.2, 128.2, 128.1, 126.9, 126.0, 124.0, 120.5, 113.1, 112.1, 45.9, 38.9, 34.4,
23.4, 22.6, 13.5, 13.1 ppm; IR (neat): 3406, 3058, 2959, 2869, 1598, 1448, 761, 696, 583 cm-
1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C21H23BrNS2 432.0461; Found 432.0460.
5-Nitro-3-(phenyl(propylthio)methyl)-2-(propylthio)-1H-indole (4fa). Purification by
column chromatography (EtOAc/hexane, 1:4 v/v) afforded 4fa (0.0360 g, 18%, reaction time:
2 h) (0.060 g, 30%, reaction time: 16 h); yellow oil; 1H NMR (CDCl3, 400 MHz): δ 8.95 (d, J
= 2.0 Hz, 1H), 8.53 (s, 1H), 8.10 (dd, J = 9.0, 2.2 Hz, 1H), 7.55 (d, J = 7.5 Hz, 2H), 7.34–7.28
(m, 3H), 7.21 (t, J = 7.3 Hz, 1H), 5.78 (s, 1H), 2.75 (t, J = 7.3 Hz, 2H), 2.46–2.31 (m, 2H),
1.68–1.51 (m, 4H), 0.94 (t, J = 7.3 Hz, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 141.6, 140.7,
139.5, 130.5, 128.6, 128.0, 127.1, 125.8, 123.5, 118.6, 118.5, 110.7, 45.7, 38.8, 34.5, 23.5,
22.5, 13.5, 13.1 ppm; IR (neat): 3373, 3059, 2962, 2854, 1619, 1522, 1445, 1336, 1321, 740,
698 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C21H23N2O2S2 399.1206; Found 399.1201.
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3-(Phenyl(propylthio)methyl)-2-(propylthio)-5-(trifluoromethyl)-1H-indole
(4ga).
Purification by column chromatography (EtOAc/hexane, 1:19 v/v) afforded 4ga (0.0910 g,
43%); dark orange oil; 1H NMR (CDCl3, 400 MHz): δ 8.30 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 7.5
Hz, 2H), 7.42 (dd, J = 8.6, 1.4 Hz, 2H), 7.36 (d, J = 8.6 Hz, 1H), 7.31–7.25 (m, 2H), 7.20 (t, J
= 7.3 Hz, 1H), 5.79 (s, 1H), 2.69 (t, J = 7.3 Hz, 2H), 2.47–2.27 (m, 2H), 1.67–1.47 (m, 4H),
13
0.96–0.87 (m, 6H); C{1H} NMR (CDCl3, 100 MHz): δ 141.5, 137.9, 129.3, 128.4, 128.1,
127.4 (d, JC,F = 289.1 Hz), 126.9, 122.2 (d, JC,F = 32.1 Hz), 122.0, 119.7 (d, JC,,F = 3.3 Hz),
119.3 (d, JC,F = 4.3 Hz), 111.0, 45.9, 38.9, 34.5, 23.4, 22.5, 13.5, 13.1 ppm; IR (neat): 3407,
3031, 2962, 2872, 1624, 1601, 1422, 1326, 1112, 744, 699 cm-1; HRMS (ESI-TOF) m/z: [M -
H]- Calcd for C22H23F3NS2 422.1229; Found 422.1228.
6-Chloro-3-(phenyl(propylthio)methyl)-2-(propylthio)-1H-indole (4ha). Purification
by column chromatography (EtOAc/hexane, 1:9 v/v) afforded 4ha (0.0660 g, 34%); dark
brown oil; 1H NMR (CDCl3, 400 MHz): δ 8.05 (s, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.52 (d, J =
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7.5 Hz, 2H), 7.31–7.24 (m, 4H), 7.19 (t, J = 7.3 Hz, 1H), 7.03 (dd, J = 8.6, 1.8 Hz, 1H), 5.76
(s, 1H), 2.67 (t, J = 7.3 Hz, 2H), 2.43–2.25 (m, 2H), 1.67–1.44 (m, 4H), 0.95–0.85 (m, 6H);
13C{1H} NMR (DMSO-d6, 100 MHz): δ 141.9, 137.9, 128.9, 128.6, 128.1, 127.4, 127.3, 124.9,
122.1, 119.8, 118.9, 111.1, 45.6, 37.7, 34.0, 23.1, 22.6, 13.8, 13.4 ppm; IR (neat): 3409, 3063,
2961, 2870, 1608, 1443, 1072 (SO2) cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for
C21H23ClNS2 388.0966; Found 388.0961.
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3-((4-Fluorophenyl)(propylthio)methyl)-2-(propylthio)-1H-indole (4ia). Purification
by column chromatography (EtOAc/hexane, 1:19 v/v) afforded 4ia (0.1230 g, 66%); dark
brown oil; 1H NMR (CDCl3, 400 MHz): δ 8.09 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.54–7.49 (m,
2H), 7.29 (d, J = 8.1 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.93 (t, J = 8.1
Hz, 2H), 5.78 (s, 1H), 2.71–2.59 (m, 2H), 2.43–2.26 (m, 2H), 1.64–1.45 (m, 4H), 0.95–0.85
(m, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 161.6 (d, JC,F = 245.0 Hz), 137.3 (d, JC,F = 2.9
Hz), 136.7, 129.7 (d, JC,F = 7.9 Hz), 126.7, 126.4, 123.2, 121.5, 120.6, 119.8, 115.0 (d, JC,F
=
21.3 Hz), 110.7, 45.3, 39.0, 34.4, 23.4, 22.6, 13.6, 13.1 ppm; IR (neat): 3391, 3056, 2959, 2869,
1503, 1444, 1015, 741, 674 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C21H23FNS2
372.1261; Found 372.1247.
3-((4-Chlorophenyl)(propylthio)methyl)-2-(propylthio)-1H-indole (4ja). Purification
by column chromatography (EtOAc/hexane, 1:9 v/v) afforded 4ja (0.1200 g, 61%); dark brown
oil; 1H NMR (CDCl3, 400 MHz) δ 8.08 (s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.4 Hz,
2H), 7.31 (d, J = 8.2 Hz, 1H), 7.25–7.17 (m, 3H), 7.07 (dd, J = 15.1, 0.8 Hz, 1H), 5.76 (s, 1H),
2.73–2.61 (m, 2H), 2.43–2.26 (m, 2H), 1.65–1.47 (m, 4H), 0.92 (td, J = 7.3, 2.8 Hz, 6H);
13C{1H} NMR (CDCl3, 100 MHz): δ 140.1, 136.7, 132.4, 129.6, 128.8, 128.4, 126.3, 123.2,
121.5, 120.4, 119.8, 110.7, 45.4, 39.1, 34.4, 23.4, 22.6, 13.6, 13.1 ppm; IR (neat): 3392, 3055,
2958, 2868, 1614, 1444, 742, 581 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C21H23ClNS2
388.0966; Found 388.0959.
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3-((4-Bromophenyl)(propylthio)methyl)-2-(propylthio)-1H-indole (4ka). Purification
by column chromatography (EtOAc/hexane, 1:9 v/v) afforded 4ka (0.1040 g, 48%); dark
brown oil; 1H NMR (CDCl3, 400 MHz): δ 8.09 (s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.44 (d, J =
8.3 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.1 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.07
(t, J = 7.5 Hz, 1H), 5.74 (s, 1H), 2.73–2.60 (m, 2H), 2.35 (dtd, J = 20.1, 13.0, 7.2 Hz, 2H), 1.65
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– 1.47 (m, 4H), 0.91 (td, J = 7.2, 2.1 Hz, 6H); C{1H} NMR (CDCl3, 100 MHz): δ 140.7,
136.8, 131.7, 131.3, 130.0, 126.8, 126.3, 123.8, 123.2, 121.5, 119.9, 110.8, 45.5, 39.1, 34.4,
23.4, 22.6, 13.6, 13.2 ppm; IR (neat): 3391, 3055, 2958, 2868, 1613, 1443, 744, 580 cm-1;
HRMS (ESI-TOF) m/z: [M - H]- Calcd for C21H23BrNS2 432.0461; Found 432.0452.
3-((4-Nitrophenyl)(propylthio)methyl)-2-(propylthio)-1H-indole (4la). Purification by
column chromatography (EtOAc/hexane, 1:4 v/v) afforded 4la (0.0860 g, 43%); brown oil; 1H
NMR (CDCl3, 400 MHz): δ 8.16 (s, 1H), 8.13 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.1 Hz, 1H),
7.74 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.6 Hz,
1H), 5.85 (s, 1H), 2.77–2.63 (m, 2H), 2.48–2.30 (m, 2H), 1.67–1.48 (m, 4H), 0.94 (td, J = 7.3,
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4.6 Hz, 6H); C{1H} NMR (CDCl3, 100 MHz): δ 139.1, 131.3, 130.8, 129.1, 128.5, 127.8,
127.7, 123.6, 123.4, 121.1, 120.1, 110.9, 45.7, 39.1, 34.6, 23.4, 22.6, 13.5, 13.0 ppm; IR (neat):
3389, 3058, 2960, 2870, 1597, 1516, 1444, 1341, 737, 695 cm-1; HRMS (ESI-TOF) m/z: [M -
H]- Calcd for C21H23N2O2S2 399.1206; Found 399.1200.
2-(Propylthio)-3-((propylthio)(p-tolyl)methyl)-1H-indole (4ma). Purification by
column chromatography (EtOAc/hexane, 1:19 v/v) afforded 4ma (0.1260 g, 68%); dark orange
oil; 1H NMR (CDCl3, 400 MHz): δ 8.04 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 7.6 Hz,
2H), 7.25 (d, J = 8.1 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 6.6 Hz, 3H), 5.78 (s, 1H),
2.65 (t, J = 7.2 Hz, 2H), 2.43–2.28 (m, 2H), 2.27 (s, 3H), 1.65–1.46 (m, 4H), 0.90 (dd, J = 13.3,
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6.6 Hz, 6H); C{1H} NMR (CDCl3, 100 MHz): δ 138.5, 136.7, 136.2, 128.9, 128.0, 126.5,
126.5, 122.9, 121.7, 121.0, 119.6, 110.6, 45.7, 39.0, 34.3, 23.4, 22.6, 21.0, 13.6, 13.1 ppm; IR
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(neat): 3390, 3050, 2959, 2869, 1619, 1443, 739, 671 cm-1; HRMS (ESI-TOF) m/z: [M - H]-
Calcd for C22H26NS2 368.1512; Found 368.1513.
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3-((4-Methoxyphenyl)(propylthio)methyl)-2-(propylthio)-1H-indole (4na). Purification
by column chromatography (EtOAc/hexane, 1:19 v/v) afforded 4na (0.1200 g, 62%); dark
orange oil; 1H NMR (CDCl3, 400 MHz): δ 8.06 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.47 (d, J =
8.4 Hz, 2H), 7.29 (d, J = 8.1 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.79 (d,
J = 8.4 Hz, 2H), 5.76 (s, 1H), 3.75 (s, 3H), 2.66 (t, J = 7.3 Hz, 2H), 2.43–2.25 (m, 2H), 1.64–
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1.45 (m, 4H), 0.95–0.87 (m, 6H); C{1H} NMR (CDCl3, 100 MHz): δ 158.2, 136.7, 133.7,
129.2, 126.5, 126.5, 123.0, 121.7, 121.1, 119.6, 113.6, 110.6, 55.2, 45.4, 39.0, 34.3, 23.4, 22.6,
13.6, 13.2 ppm; IR (neat): 3331, 3056, 2957, 2869, 1608, 1445, 1243, 826, 743 cm-1; HRMS
(ESI-TOF) m/z: [M - H]- Calcd for C22H26NOS2 384.1461; Found 384.1464.
3-((3-Fluorophenyl)(propylthio)methyl)-2-(propylthio)-1H-indole (4oa). Purification
by column chromatography (EtOAc/hexane, 1:19 v/v) afforded 4oa (0.0640 g, 35%); dark
yellow oil; 1H NMR (CDCl3, 400 MHz): δ 8.08 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.36–7.28 (m,
3H), 7.25–7.17 (m, 2H), 7.10–7.05 (m, 1H), 6.87 (td, J = 8.4, 2.4 Hz, 1H), 5.77 (s, 1H), 2.74–
2.63 (m, 2H), 2.46–2.28 (m, 2H), 1.64–1.51 (m, 4H), 0.93 (td, J = 7.3, 3.6 Hz, 6H); 13C{1H}
NMR (CDCl3, 100 MHz): δ 162.8 (d, JC,F = 245.1 Hz), 144.3, 136.7, 129.6 (d, JC,F = 8.3 Hz),
126.6 (d, JC,F = 46.7 Hz), 123.8 (d, JC,F = 2.6 Hz), 123.2, 121.5, 120.4, 119.9, 119.4, 115.2 (d,
JC,F = 22.3 Hz), 113.6 (d, JC,F = 21.2 Hz), 110.7 (d, JC,F = 4.7 Hz), 45.6, 39.1, 34.4, 23.4, 22.6,
13.6, 13.2 ppm; IR (neat): 3394, 3056, 2960, 2870, 1586, 1440, 1013, 740, 685 cm-1; HRMS
(ESI-TOF) m/z: [M - H]- Calcd for C21H23FNS2 372.1261; Found 372.1259.
3-((3-Chlorophenyl)(propylthio)methyl)-2-(propylthio)-1H-indole (4pa). Purification
by column chromatography (EtOAc/hexane, 1:19 v/v) afforded 4pa (0.0680 g, 35%); dark
brown oil; 1H NMR (CDCl3, 400 MHz): δ 8.10 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.58 (s, 1H),
7.44 (d, J = 7.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.22–7.13 (m, 3H), 7.08 (t, J = 7.6 Hz, 1H),
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= 7.3, 1.7 Hz, 6H); C{1H} NMR (CDCl3, 100 MHz): δ 143.7, 136.7, 134.0, 129.5, 128.3,
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126.8, 126.3, 123.1, 121.3, 120.2, 110.7, 45.6, 39.0, 34.4, 23.4, 22.6, 13.5, 13.1 ppm; IR (neat):
3395, 3059, 2960, 2869, 1590, 1444, 745, 682 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for
C21H23ClNS2 388.0966; Found 388.0952.
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3-((3-Bromophenyl)(propylthio)methyl)-2-(propylthio)-1H-indole (4qa). Purification
by column chromatography (EtOAc/hexane, 1:19 v/v) afforded 4qa (0.1070 g, 49%); dark
brown oil; 1H NMR (CDCl3, 400 MHz) δ 8.09 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.73 (s, 1H),
7.49 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.23–7.17 (m, 1H), 7.15–7.05 (m, 2H), 5.74
(s, 1H), 2.69 (td, J = 7.9, 2.0 Hz, 2H), 2.44–2.29 (m, 2H), 1.64–1.58 (m, 2H), 1.56–1.51 (m,
2H), 0.93 (t, J = 7.3 Hz, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 144.1, 136.7, 131.3, 130.5,
130.1, 129.8, 126.8, 126.3, 123.1, 122.3, 121.3, 120.2, 119.9, 110.7, 45.6, 39.1, 34.5, 23.4,
22.6, 13.5, 13.2 ppm; IR (neat): 3396, 3058, 2960, 2869, 1569, 1446, 744, 687, 600 cm-1;
HRMS (ESI-TOF) m/z: [M - H]- Calcd for C21H23BrNS2 432.0461; Found 432.0453.
2-(Propylthio)-3-((propylthio)(m-tolyl)methyl)-1H-indole (4ra). Purification by
column chromatography (EtOAc/hexane, 1:19 v/v) afforded 4ra (0.1250 g, 70%); red brown
oil; 1H NMR (CDCl3, 400 MHz): δ 8.04 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.40 (s, 1H), 7.35 (d,
J = 7.8 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.19 (t, J = 7.3 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.06
(t, J = 7.5 Hz, 1H), 6.99 (d, J = 7.5 Hz, 1H), 5.77 (s, 1H), 2.68 (t, J = 7.3 Hz, 2H), 2.43–2.31
(m, 2H), 2.30 (s, 3H), 1.64–1.51 (m, 4H), 0.92 (td, J = 7.3, 2.3 Hz, 6H); 13C{1H} NMR (CDCl3,
100 MHz): δ 141.5, 137.8, 136.7, 128.9, 128.1, 127.5, 126.6, 125.2, 123.0, 121.7, 121.1, 120.7,
119.7, 110.6, 46.0, 39.1, 34.4, 23.4, 22.6, 21.5, 13.6, 13.2 ppm; IR (neat): 3395, 3049, 2958,
2867, 1602, 1443, 740, 626 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C22H26NS2
368.1512; Found 368.1507.
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3-((2-Fluorophenyl)(propylthio)methyl)-2-(propylthio)-1H-indole (4sa). Purification
by column chromatography (EtOAc/hexane, 1:19 v/v) afforded 4sa (0.0620 g, 33%); dark
yellow oil; 1H NMR (CDCl3, 400 MHz): δ 8.07 (d, J = 8.3 Hz, 2H), 7.86 (t, J = 7.3 Hz, 1H),
7.30 (d, J = 8.1 Hz, 1H), 7.22–7.14 (m, 2H), 7.08 (dt, J = 11.3, 7.5 Hz, 2H), 7.02–6.95 (m, 1H),
6.07 (s, 1H), 2.67 (t, J = 7.3 Hz, 2H), 2.48–2.35 (m, 2H), 1.69–1.43 (m, 4H), 0.92 (dt, J = 16.2,
7.3 Hz, 6H); 13C{1H} NMR (CDCl3, 100 MHz): δ 161.4, 159.0 (d, JC,F = 247.2 Hz), 136.5,
130.0 (d, JC,F = 3.1 Hz), 129.1, 128.9 (d, JC,F = 13.4 Hz), 128.4 (d, JC,F = 8.3 Hz), 126.9 (d, JC,F
= 1.3 Hz), 124.0 (d, JC,F = 3.5 Hz), 122.9, 121.2, 119.8, 115.3 (d, JC,F = 22.3 Hz), 110.7, 39.0,
38.8, 34.5, 23.4, 22.5, 13.5, 13.1 ppm; IR (neat): 3395, 3055, 2960, 2870, 1584, 1443, 1013,
742, 673 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C21H23FNS2 372.1261; Found
372.1265.
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3-((2-Chlorophenyl)(propylthio)methyl)-2-(propylthio)-1H-indole (4ta). Purification
by column chromatography (EtOAc/hexane, 1:19 v/v) afforded 4ta (0.0510 g, 27%); yellow
oil; 1H NMR (CDCl3, 400 MHz): δ 8.18–8.12 (m, 2H), 7.91 (dd, J = 7.5, 1.9 Hz, 1H), 7.35–
7.27 (m, 2H), 7.22–7.16 (m, 2H), 7.15–7.09 (m, 2H), 6.14 (s, 1H), 2.60 (td, J = 7.7, 2.3 Hz,
2H), 2.47–2.34 (m, 2H), 1.67–1.57 (m, 2H), 1.51–1.37 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H), 0.84
13
(t, J = 7.3 Hz, 3H); C{1H} NMR (CDCl3, 100 MHz): δ 139.1, 136.5, 133.6, 130.3, 129.7,
128.1, 127.5, 127.3, 126.8, 122.8, 121.3, 119.8, 119.4, 110.7, 43.3, 38.6, 35.3, 23.3, 22.5, 13.5,
13.1 ppm; IR (neat): 3394, 3057, 2959, 2870, 1570, 1440, 743, 706 cm-1; HRMS (ESI-TOF)
m/z: [M - H]- Calcd for C21H23ClNS2 388.0966; Found 388.0969.
3-(Naphthalen-2-yl(propylthio)methyl)-2-(propylthio)-1H-indole (4ua). Purification
by column chromatography (EtOAc/hexane, 1:19 v/v) afforded 4ua (0.0305 g, 15%, reaction
time: 2 h) (0.0370 g, 18%, reaction time: 16 h); yellow oil; 1H NMR (CDCl3, 400 MHz): δ 8.48
(d, J = 8.5 Hz, 1H), 8.10 (d, J = 7.4 Hz, 2H), 8.02 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H),
7.72 (d, J = 8.2 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 7.7 Hz,
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