Domino C?S/C?N Bond Formation Using Well-Defined Copper-Phosphine Complex Catalyst: Divergent Approach to 3-Sulfenylated Indoles

Article abstract of DOI:10.1002/adsc.201900612

A protocol was developed for the synthesis of 3-thioindoles in good-to-excellent yields involving sulfenylation between 2-nitrocinnamaldehydes and various thiols using a well-defined copper(I)-phosphine complex catalyst. This unconventional divergent approach involves in situ generation of indoles via domino C?S/C?N bond formation initiated by sulfa-Michael addition followed by intramolecular N-heteroannulation. This protocol shows good chemoselectivity and broad substrate scope. To briefly demonstrate the value of this approach, 2-benzoyl-3-sulfenylated indoles were prepared from commercially available 2-nitrochalcones and thiols. (Figure presented.).

Full text of DOI:10.1002/adsc.201900612

Title: Domino C-S/C-N Bond Formation using Well-Defined Copper-
Phosphine Complex Catalyst: Divergent Approach to 3-
Sulfenylated Indoles
Authors: Ramuel John Tamargo, Sung Hong Kim, and Yong Rok Lee
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900612
Link to VoR: http://dx.doi.org/10.1002/adsc.201900612

10.1002/adsc.201900612
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Domino C-S/C-N Bond Formation using Well-Defined Copper-
Phosphine Complex Catalyst: Divergent Approach to 3-
Sulfenylated Indoles
Ramuel John Inductivo Tamargo,a Sung Hong Kim,b and Yong Rok Leea*
a School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Republic of Kore. E-mail: yrlee@yu.ac.kr;
Fax: +82-53-810-4631; Tel: +82-53-810-2529
b Analysis Research Division, Daegu Center, Korea Basic Science Institute, Daegu 41566, Republic of Korea.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: A protocol was developed for the synthesis of 3- chemoselectivity and broad substrate scope. To briefly
thioindoles
in
good-to-excellent
yields
involving demonstrate the value of this approach, 2-benzoyl-3-
sulfenylation between 2-nitrocinnamaldehydes and various sulfenylated indoles were prepared from commercially
thiols using a well-defined copper(I)-phosphine complex available 2-nitrochalcones and thiols.
catalyst. This unconventional divergent approach involves in
situ generation of indoles via domino C-S/C-N bond
formation initiated by sulfa-Michael addition followed by
intramolecular N-heteroannulation. This protocol shows
good
Keywords: Annulation; Copper catalyst; Domino
reactions; Nitrogen heterocycles; Sulfa-Michael addition
sulfenylation with arenethiols,[15] it has been reported
that most of these complexes are ineffective for
sulfenylation with alkanethiols.[16]
Introduction
Indoles are widely considered a significant key
scaffold in biologically active molecules and
In addition, although numerous advances have been
made for C-S bond formation using well-defined
complexes, limited success has been achieved with
Au, Ag, and Cu metals.[17] Recently, we reported on
the construction of heterocycles through a base- or
CuI/base-promoted cascade reaction of 2-
nitrocinnamaldehydes with β-ketoesters or benzyl
pharmaceuticals.[1]
Consequently,
considerable
attention has been paid to the construction of highly
functionalized indoles.[2] Among these, 3-sulfenylated
indoles exhibit a variety of biological properties,
including anti-HIV,[3] anticancer,[4] antiallergy,[5]
antiobesity,[6]
anti-inflammatory,[7]
and
cyanides.[18a-c]
While
intramolecular
N-
cardiovascular activities.[8] They have also been used
as building blocks in the syntheses of natural
products[9] and potent drugs.[10]
heteroannulation has been employed as a powerful
arsenal to construct indoles,[19] one-pot tandem
sulfenylation/indolization which exploits readily
available 2-nitrocinnamaldehydes has not yet been
achieved.[20] As part of our pursuit of effective
methodologies to access these privileged scaffolds,
herein, we describe the direct construction of aryl-,
heteroaryl-, and alkylthioindoles through Cu(I)-
phosphine complex-catalyzed heteroannulation of 2-
nitrocinnamaldehydes with the corresponding thiols
via domino C-N/C-S bond formation (Scheme 1c).
Owing to the fascinating and important biological
activities of 3-sulfenylated indoles, a number of
methods for their preparation have been reported.[11–
14]
Typical approaches are based on transition-metal-
or metal-catalyzed sulfenylation of indoles in the
presence of Ru, Pd, V, Cu, Co, Ni, or Mg using a
variety of sulfenylating reagents, such as sulfonyl
chlorides,[11a]
disulfides,[12a]
thiols,[13a]
and
thiophthalimides[14a] (Scheme 1a). Transition-metal-
free synthetic approaches have also been developed,
including iodine-[12b,13e,14e] or organophosphorus-
catalyzed,[11b] base-promoted,[12d,13f] and electro-
catalytic sulfenylation of indoles with sulfenylating
reagents.[13g] (Scheme 1b). Although many methods
for the construction of 3-sulfenylindoles have been
developed, more facile and efficient protocols remain
highly desirable. Synthetic approaches for 3-
alkylsulfenylindoles in particular are only reported
sporadically.[11b,13b,14a] While a number of transition
metal complexes, such as Wilkinson’s catalyst
[ClRh(PPh3)3], have been utilized for catalytic
Scheme 1. Synthetic strategies for 3-sulfenylated indoles.
1
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10.1002/adsc.201900612
Advanced Synthesis & Catalysis
Results and Discussion
entry 16). However, with 20 mol % Pd(PPh3)4 as the
catalyst, 3a was not produced at all (entry 17). The
structure of 3a was determined through the analysis
To obtain the optimal conditions, reactions between
2-nitrocinnamaldehyde (1a) and thiophenol (2a) were
carried out under N2 using various bases, catalysts,
and solvents (Table 1). Initial attempts using
inorganic base Cs2CO3 (1 equiv.) in polar
dimethylformamide (DMF) and dimethyl sulfoxide
(DMSO) at 110 °C for 6 h provided thioether product
4 in 88% and 91% yields, respectively (entries 1 and
2, Table 1). In nonpolar toluene and 1,4-dioxane, 3a
was produced via deformylation in 5% and 7% yields,
respectively (entries 3 and 4). Encouraged by these
results, other bases were screened. When we used
stronger inorganic base t-BuOK (1 equiv.), the yield
of 3a increased to 10% (entry 5). However, with
organic bases 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) and 1,4-diazabicyclo[2.2.2]octane (DABCO),
no products were isolated (entries 6 and 7). To
increase the yield of 3a, additional reactions using
several catalysts were attempted. The reactions
featuring 20 mol % I2 or FeCl2 together with t-BuOK
did not result in any desired product (entries 8 and 9).
Further attempts with 20 mol % copper(II) triflate
(Cu(OTf)2) and CuCl afforded 3a in 43% and 46%
yields, respectively (entries 10 and 11). The best
yield (87%) was achieved when 20 mol %
CuCl(PPh3)3 (C1) was used with t-BuOK (1 equiv.)
in refluxing 1,4-dioxane for 9 h (entry 12). Carrying
out the reaction in open air resulted to a significant
decrease in yield of 3a (entry 13). Moreover, neither
decreasing the t-BuOK loading to 0.5 equiv. (entry
14) nor increasing it to 2 equiv.
1
of its spectral data. The H NMR spectrum showed
the characteristic signal of the NH proton at δ 8.39
ppm as a broad singlet and the vinyl proton on the
indole ring at δ 7.47 ppm as a doublet with a coupling
constant of 1.8 Hz.
With the optimized conditions in hand, reactions of
2-nitrocinnamaldehydes with various thiophenols
were examined next to explore the generality of this
protocol (Table 2). The reactions of 1a with arylthiols
2b–2f bearing electron-donating groups, namely 2-
Me, 3-Me, 4-Me, 4-OH, and 4-OMe, on their benzene
ring for 9–10 h provided products 3b–3f in 76–86%
yields, while substrates containing electron-
withdrawing substituents afforded desired products
3g–3i in slightly lower yields (67–82%). The scope of
this reaction was explored further using 2-
nitrocinnamaldehydes 1b and 1c bearing an electron-
donating and -withdrawing group, namely 6-OMe
and 4-Cl, on the benzene ring, which afforded the
desired products, 3j and 3k, in good yields. In
addition, the reaction of 1a with naphthalene-2-thiol
(2j) afforded 3-(naphthalen-2-ylthio)indole (3l) in
83% yield. In addition, we also explored the reaction
of (E)-3-(1-nitronaphthalen-2-yl)acrylaldehyde (1d)
with 2a, which provided 3m in 91% yield. These
results suggest that this reaction protocol tolerates a
wide range of functionalities on both 2-
nitrocinnamaldehydes and thiols.
Table 2. Results of reactions of 1a–1d with 2a–2j for 3-
arylthioindoles 3b–3m.[a,b]
Table 1. Optimization of the reaction conditions.[a]
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), and
solvent (5 mL) under N2. [b] In open air.
[c] Isolated yields.
[a]
Reaction conditions: 1a-1d (0.5 mmol), 2a-2j (0.75
mmol), and solvent (5 mL) under N2.
(entry 15) improved the yield of 3a. In addition,
decreasing the C1 catalyst loading to 10 mol % led to
3a being provided in a somewhat lower yield (83%,
[b] Isolated yields.
2
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10.1002/adsc.201900612
Advanced Synthesis & Catalysis
Table 3. Results of reactions of 1a with 2k–2q for 3-
alkylthioindoles 5a–5g.[a,b]
Table 4. Results of reactions of 8 with 2a, 2d, 2f, 2l, and
2s for 2-benzoyl-3-thioindoles 9a–9e.[a,b]
[a] Reaction conditions: 1a (0.5 mmol), 2k-2q (0.75 mmol),
and solvent (5 mL) under N2.
[b] Isolated yields.
[a] Reaction conditions: 8 (1 mmol), 2a, 2d, 2f, 2l, or 2s
(1.5 mmol), and solvent (10 mL) under N2.
[b] Isolated yields.
The scope of this protocol was further demonstrated
by using alkyl thiols with various functionalities and
degrees of bulkiness (Table 3). The reactions of 1a
with primary alkyl thiols, butane-1-thiol (2k),
phenylmethanethiol (2l), and 2-furfurylthiol (2m),
successfully furnished desired products 5a–5c in 91%,
85%, and 81% yields, respectively. Moreover,
secondary alkyl thiols 2-butanethiol (2n) and
cyclohexanethiol (2o) were also able to afford their
corresponding products, 5d and 5e, in 82% and 86%
Scheme 3. Gram-scale synthesis of 9a.
yields,
respectively.
Notably,
2-methyl-2-
propanethiol (2p) provided the desired product, 5f, in
70% yield. Thiol 2q bearing a hydroxyl group was
also an efficient substrate in this transformation,
giving 5g chemoselectively in 71% yield.
To elucidate the reaction mechanism, we
conducted the control experiment shown in Scheme 4.
To eliminate the possibility of a radical sulfenylation
pathway, 1a was reacted with 2a under the standard
reaction conditions in the presence of (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO) in one
equivalent. Product 3a was formed in 81% yield,
while TEMPO adduct 10 was not observed. Based on
this result, this transformation does not directly
involve a radical pathway.[15c]
Having seen the generality for the construction of
3-aryl- and 3-alkylthioindoles, we employed
heteroaryl thiols as substrates (Scheme 2). When 2-
pyridinethiol (2r) and 1-methyl-2-imidazolethiol (2s)
were used, the desired products, 6 and 7, were
isolated in 61% and 78% yields, respectively.
To demonstrate the utility of this protocol, we
applied
2-nitrochalcone
instead
of
2-
nitrocinnamaldehydes as the starting material to
provide 2-benzoyl-3-sulfenylated indoles (Table 4).
The reaction of 2-nitrochalcone (8) with 2a provided
product 9a in 94% yield. In the cases of arylthiols 2d
and 2e, desired products 9b and 9c were obtained in
91% and 93% yields, respectively. Moreover, with
phenylmethanethiol
(2l)
and
1-methyl-2-
Scheme 4. Control experiment.
imidazolethiol (2s), compounds 9d and 9e were
produced in 88% and 71% yields. The applicability of
this protocol was further demonstrated with the gram-
scale synthesis of 9a (Scheme 3).
Based on literature precedence and our previous
studies,[15–25] we propose
a plausible reaction
pathway, which is shown in Scheme 5. The reaction
is initiated by the CuCl(PPh3)3 complex (C1) and t-
BuOK through salt metathesis to afford Cu-O-tBu
complex C2, which is readily attacked by the thiol,
affording copper-thiolate species C3.[21] Then, 1a is
activated by the coordination of resulting active
species C3 to form transition intermediate I, which
Scheme 2. Reactions of 1a with 2r and 2s for
heteroarylthioindoles 6 and 7.
3
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10.1002/adsc.201900612
Advanced Synthesis & Catalysis
Conclusion
directs the sulfa- Michael addition of a thiolate anion
via migratory insertion, resulting in II.[22] Next,
intramolecular nucleophilic addition occurs to furnish
intermediate III and copper specie C2 thru
protonation by t-BuOH. Intermediate III undergoes
dehydroxylation leading to nitroso intermediate IV.
Previously, the intramolecular cyclization of 2-
alkenyl nitroarenes via nitroso intermediate was
reported by Grignard reagents-, TiCl3- and base-
promoted reactions without external reducing
agent.[23] Oxidation of C2 to C4 enables the
conversion of nitroso intermediate IV to V. The
highly reactive hydroperoxide copper intermediate
C4 subsequently coordinates with the aldehyde
carbonyl of intermediate VI obtained from the
isomerization of intermediate V. Nucleophilic attack
by the hydroperoxide and subsequent dehydration
afford carboxylic acid intermediate VII,[24] which
forms intermediate VIII upon direct insertion of C2
into the aryl carboxylate bond.[25] Finally,
decarboxylation of VIII gives 3a and regenerates C2,
which reacts with 2a, regenerating C3 to complete
the catalytic cycle. In the case of 2-nitrcochalcone, no
further oxidation and decarboxylation for the
formation of 9a-9e occur while C4 and t-BuOH
possibly recombines to regenerate C2 by the removal
of H2O2 to complete the catalytic cycle.
In summary, we have described a highly divergent
protocol to access diverse 3-thioindoles from 2-
nitrocinnamaldehydes and various thiols via sulfa-
Michael addition followed by intramolecular
reductive N-heteroannulation using a well-defined
complex, chloro-tris(triphenylphosphine)-copper(I)
(C1), as the catalyst. The reaction shows good
tolerance towards various 2-nitrocinnamaldehydes as
well as several substituted aryl, alkyl, heteroaryl,
bulky secondary, and tertiary thiol systems with good
to excellent yields. The present protocol is likely to
attract the interest of synthetic chemists because of its
efficiency and broad utility. The applicability of this
protocol was briefly demonstrated in the synthesis of
3-thiobenzoylindoles using commercially available 2-
nitrochalcones. 2-vinyl nitroarenes
Experimental Section
General procedure for the synthesis of 3-thioindoles 3,
5, 6 and 7: A general procedure for the copper-phosphine
complex-catalyzed synthesis of 3-thioindoles is as follows:
An oven-dried 25 mL two necked round bottom flask was
charged with 2-nitrocinnamaldehyde (0.5 mmol), thiol
(0.75 mmol, 1.5 equiv.) and 20 mol % of CuCl(PPh3)3 in 5
mL anhydrous 1,4-dioxane and t-BuOK (0.5 mmol, 1
equiv.) was finally added. The reaction was then kept
under nitrogen atmosphere with continuous stirring. Then,
the reaction mixture was refluxed for about 9-12 h until the
completion of the reaction as indicated by TLC. The
resulting mixture was then dried in rotary evaporator under
reduced pressure to obtain the residue. The residue was
purified by column chromatography using silica gel as the
stationary phase and Hex/EtOAc (20:1) as the eluent to
isolate the pure product.
3-(Phenylthio)-1H-indole (3a): Prepared according to the
general procedure and obtained as white solid (98 mg, 87%
yield). Melting point: 153-155 °C. 1H NMR (600 MHz,
CDCl3)  8.39 (1H, br s), 7.60 (1H, d, J = 8.4 Hz), 7.47
(1H, d, J = 1.8 Hz), 7.42 (1H, d, J = 8.4 Hz), 7.26-7.24
(1H, m), 7.16-7.12 (3H, m), 7.09-7.08 (2H, m), 7.04-7.02
(1H, m); 13C NMR (150 MHz, CDCl3)  139.2, 136.4,
130.6, 129.1, 128.6, 125.8, 124.7, 123.0, 120.9, 119.6,
111.5, 102.9. IR (neat): 3404.8, 1739.7, 1577.8, 1475.9,
1454.7, 1406.1, 1236.3, 1087.3, 739.3 cm-1; HRMS m/z
(M+) calculated for C14H11NS: 225.0612. Found: 225.0611.
E)-3-(2-(Phenylthio)phenyl)acrylaldehyde (4): Obtained
during the screening of reaction conditions – Please see
1
Table 1. Melting point: 86-88 °C. H NMR (600 MHz,
CDCl3)  9.61 (1H, d, J = 7.8 Hz), 8.05 (1H, d, J = 15.6
Hz), 7.64-7.62 (1H, m), 7.36-7.35 (1H, m), 7.31-7.30 (2H,
m), 7.24 (2H, t, J = 7.8 Hz), 7.20-7.18 (3H, m), 6.60 (1H,
dd, J = 15.6, 7.8 Hz); 13C NMR (150 MHz, CDCl3) 
193.8, 149.7, 136.4, 135.5, 135.4, 133.9, 131.4, 130.2,
130.2, 129.39, 128.3, 127.5, 127.1; IR (neat): 3056.3,
2813.5, 1678.1, 1620.2, 1579.7, 1474.9, 1437.5, 1110.8,
735.1, 688.0 cm-1; HRMS m/z (M+) calculated for
C15H12OS: 240.0609. Found: 240.0609.
3-(o-Tolylthio)-1H-indole (3b): Prepared according to the
general procedure and obtained as dark brown solid (101
1
mg, 84% yield). Melting point: 114-116 °C. H NMR (600
MHz, CDCl3)  8.29 (1H, br s), 7.62 (1H, d, J = 7.8 Hz),
7.42-7.41 (2H, m), 7.29 (1H, t, J = 7.8 Hz), 7.20-7.16 (2H,
m), 7.01 (1H, t, J = 7.8 Hz), 6.92 (1H, t, J = 7.8 Hz), 6.76
(1H, d, J = 7.8 Hz), 2.53 (3H, s); 13C NMR (150 MHz,
Scheme 5. Plausible reaction pathway.
4
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10.1002/adsc.201900612
Advanced Synthesis & Catalysis
CDCl3)  138.2, 136.4, 134.3, 130.7, 129.8, 129.1, 126.2,
125.2, 124.4, 122.9, 120.8, 119.5, 111.5, 102.1, 19.8; IR
(neat): 3418.8, 1735.1, 1585.0, 1451.8, 1400.7, 1233.1,
1090.2, 824.1, 734.7 cm-1; HRMS m/z (M+) calculated for
C15H13NS: 239.0769. Found: 239.0768.
Hz), 7.26 (1H, t, J = 7.8 Hz), 7.18-7.15 (1H, m), 7.10-7.07
(2H, m), 6.87-6.84 (2H, m); 13C NMR (150 MHz, CDCl3)
 160.8 (d, J = 242.7), 136.4, 133.9 (d, J = 3.4 Hz), 130.4,
128.8, 127.8 (d, J = 7.6 Hz), 123.1, 120.9, 119.5, 115.7 (d,
J = 21.9 Hz), 111.5, 103.4; IR (neat): 3403.2, 1589.7,
1486.1, 1407.8, 1215.8, 1092.9, 1009.8, 819.0, 745.9 cm-1;
HRMS m/z (M+) calculated for C14H10FNS: 243.0518.
Found: 243.0520.
3-(m-Tolylthio)-1H-indole (3c): Prepared according to the
general procedure and obtained as dark brown solid (101
mg, 84% yield). Melting point: 115-117 °C. 1H NMR (600
MHz, CDCl3)  8.35 (1H, br s), 7.62 (1H, d, J = 8.4 Hz),
7.44 (1H, s), 7.41 (1H, d, J = 7.8 Hz), 7.27-7.23 (1H, m),
7.16 (1H, t, J = 7.8 Hz), 7.03 (1H, t, J = 7.8 Hz), 6.98 (1H,
s), 6.87 (2H, t, J = 7.8 Hz) 2.22 (3H, s); 13C NMR (150
MHz, CDCl3)  138.9, 138.4, 136.4, 130.6, 129.1, 128.5,
126.4, 125.7, 122.9, 122.9, 120.8, 119.6, 111.5, 102.9,
21.3; IR (neat): 3411.0, 3107.6, 1588.8, 1453.5, 1404.9,
1336.8, 1236.9, 1093.2, 853.8, 769.7, 745.3 cm-1; HRMS
m/z (M+) calculated for C15H13NS: 239.0769. Found:
239.0770.
3-((4-(Trifluoromethyl)phenyl)thio)-1H-indole
(3i):
Prepared according to the general procedure and obtained
as black solid (98 mg, 67% yield). Melting point: 90-92 °C.
1H NMR (600 MHz, CDCl3)  8.47 (1H, br s), 7.54 (1H, d,
J = 8.4 Hz), 7.50 (1H, s), 7.45 (1H, d, J = 8.4 Hz), 7.36
(2H, d, J = 8.4 Hz), 7.28 (1H, t, J = 7.8 Hz), 7.17 (1H, t, J
= 7.8 Hz), 7.11 (2H, d, J = 7.8 Hz); 13C NMR (150 MHz,
CDCl3)  144.6, 136.5, 130.9, 128.7, 126.7 (q, J = 32.2
Hz), 125.4 (q, J = 3.7 Hz), 125.2, 124.4 (q, J = 273.7 Hz),
123.3, 121.2, 119.4, 111.7, 101.3; IR (neat): 3413.3,
2920.0, 1604.4, 1452.8, 1402.8, 1322.8, 1116.4, 1010.3,
824.0, 745.1 cm-1; HRMS m/z (M+) calculated for
C15H10F3NS: 293.0486. Found: 293.0487.
3-(p-Tolylthio)-1H-indole (3d): Prepared according to the
general procedure and obtained as black solid (102 mg,
85% yield). Melting point: 91-93 °C. 1H NMR (600 MHz,
CDCl3)  8.34 (1H, br s), 7.60 (1H, d, J = 7.8 Hz), 7.44
(1H, s), 7.41 (1H, d, J = 7.8 Hz), 7.25-7.23 (1H, m), 7.14
(1H, t, J = 7.8 Hz), 7.02 (2H, d, J = 8.4 Hz), 6.96 (2H, d, J
= 7.8 Hz), 2.23 (3H, s); 13C NMR (150 MHz, CDCl3) 
136.4, 135.4, 134.6, 130.3, 129.4, 129.0, 126.2, 122.9,
120.8, 119.6, 111.4, 103.5, 20.8; IR (neat): 3404.4, 2916.4,
1710.7, 1595.5, 1489.7, 1453.4, 1338.2, 1202.8, 1089.4,
1010.1, 802.9, 740.3 cm-1; HRMS m/z (M+) calculated for
C15H13NS: 239.0769. Found: 239.0771.
7-Methoxy-3-(phenylthio)-1H-indole (3j): Prepared
according to the general procedure and obtained as light
purple solid (105 mg, 82% yield). Melting point: 103-
105 °C. 1H NMR (600 MHz, CDCl3)  8.62 (1H, br s),
7.42 (1H, d, J = 3 Hz), 7.22 (1H, d, J = 7.8 Hz), 7.16-7.14
(2H, m), 7.11-7.09 (2H, m), 7.08-7.03 (2H, m), 6.70 (1H, d,
J = 7.8 Hz), 3.97 (3H, s); 13C NMR (150 MHz, CDCl3) 
146.2, 139.3, 130.5, 130.1, 128.6, 127.0, 125.7, 124.6,
121.2, 112.1, 103.0, 102.7, 55.3; IR (neat): 3404.0, 2963.0,
1742.9, 1579.5, 1413.8, 1250.9, 1084.4, 1009.2, 776.1,
730.5 cm-1; HRMS m/z (M+) calculated for C15H13NOS:
255.0718. Found: 255.0717.
4-((1H-Indol-3-yl)thio)phenol (3e): Prepared according to
the general procedure and obtained as dark brown oil (92
1
mg, 76% yield). H NMR (600 MHz, CDCl3)  8.46 (1H,
br s), 7.60 (1H, d, J = 7.8 Hz), 7.41 (1H, s), 7.38 (1H, d, J
= 8.4 Hz), 7.21 (1H, t, J = 8.4 Hz), 7.12 (1H, t, J = 7.8
Hz), 7.05 (2H, d, J = 9 Hz), 6.74 (1H, d, J = 9 Hz), 6.65
(2H, d, J = 9 Hz); 13C NMR (150 MHz, CDCl3)  154.1,
136.4, 133.0, 129.9, 128.9, 128.8, 122.8, 120.6, 119.5,
115.9, 111.4, 104.6; IR (neat): 3212.8, 1704.6, 1581.3,
1490.8, 1433.0, 1223.7, 983.9, 822.6, 742. 8 cm-1; HRMS
m/z (M+) calculated for C14H11NOS: 241.0561. Found:
241.0559.
5-Chloro-3-(phenylthio)-1H-indole
(3k):
Prepared
according to the general procedure and obtained as dark
green solid (104 mg, 80% yield). Melting point: 90-92 °C.
1H NMR (600 MHz, CDCl3)  8.49 (1H, br s), 7.56 (1H, s),
7.48 (1H, s), 7.33 (1H, d, J = 8.4 Hz), 7.19 (3H, m), 7.09-
7.04 (3H, m); 13C NMR (150 MHz, CDCl3)  138.6, 134.7,
131.9, 130.3, 128.7, 126.8, 125.87, 124.9, 123.5, 119.1,
112.6, 102.8; IR (neat): 3402.8, 2926.7, 1734.9, 1580.0,
1440.9, 1097.0, 1022.7, 801.0, 736.0 cm-1; HRMS m/z
(M+) calculated for C14H10ClNS: 259.0222. Found:
259.0224.
3-((4-Methoxyphenyl)thio)-1H-indole (3f): Prepared
according to the general procedure and obtained as dark
green solid (110 mg, 86% yield). Melting point: 75-77 °C.
1H NMR (600 MHz, CDCl3)  8.36 (1H, br s), 7.65 (1H, d,
J = 7.8 Hz), 7.39 (2H, m), 7.26 (1H, t, J = 7.8 Hz), 7.18
(1H, t, J = 7.8 Hz), 7.09 (1H, t, J = 8.4 Hz), 6.73 (1H, d, J
= 7.8 Hz), 6.70 (1H, s), 6.63 (1H, d, J = 8.4 Hz), 3.68 (3H,
s); 13C NMR (150 MHz, CDCl3)  159.7, 140.7, 136.3,
130.7, 129.5, 128.9, 122.9, 120.8, 119.4, 118.2, 111.5,
111.4, 110.26, 102.2, 55.0; IR (neat): 3412.0, 1795.7,
1588.2, 1473.9, 1280.7, 1229.2, 1144.8, 1040.5, 939.2,
837.0, 750.5 cm-1; HRMS m/z (M+) calculated for
C15H13NOS: 255.0718. Found: 255.0716.
3-(Naphthalen-2-ylthio)-1H-indole
(3l):
Prepared
according to the general procedure and obtained as black
solid (114 mg, 83% yield). Melting point: 155-157 °C. 1H
NMR (600 MHz, CDCl3)  8.41 (1H, br s), 7.70 (1H, d, J
= 7.8 Hz), 7.63-7.60 (2H, m), 7.55-7.53 (2H, m), 7.481
(1H, d, J = 1.2 Hz), 7.44 (1H, d, J = 7.8 Hz), 7.37-7.31
(2H, m), 7.27-7.25 (2H, m), 7.13 (1H, t, J = 7.8 Hz); 13C
NMR (150 MHz, CDCl3)  136.6, 136.5, 133.7, 131.3,
130.6, 129.1, 128.2, 127.6, 126.9, 126.3, 125.0, 124.7,
123.5, 123.0, 120.9, 119.7, 111.5, 102.9; IR (neat): 3410.9,
3052.9, 1801.8, 1586.4, 1499.7, 1337.9, 1088.5, 942.1,
813.0, 740.3 cm-1; HRMS m/z (M+) calculated for
C18H13NS: 275.0769. Found: 275.0765.
3-((4-Chlorophenyl)thio)-1H-indole
(3g):
Prepared
according to the general procedure and obtained as white
1
solid (105 mg, 81% yield). Melting point: 123-125 °C. H
3-(Phenylthio)-1H-benzo[g]indole
(3m):
Prepared
NMR (600 MHz, CDCl3)  8.41 (1H, br s), 7.55 (1H, d, J
= 7.8 Hz), 7.47 (1H, d, J = 1.8 Hz), 7.43 (1H, d, J = 7.8
Hz), 7.26 (1H, t, J = 7.8 Hz), 7.15 (1H, t, J = 7.8 Hz), 7.1
(2H, d, J = 7.8 Hz), 7.00 (2H, d, J = 8.4 Hz); 13C NMR
(150 MHz, CDCl3)  137.8, 136.5, 130.6, 130.5, 128.7,
128.7, 127.1, 123.2, 121.0, 119.5, 111.6, 102.5; IR (neat):
3401.5, 2972.7, 1738.7, 1471.7, 1385.7, 1232.0, 1088.4,
1006.8, 809.9, 745.5 cm-1; HRMS m/z (M+) calculated for
C14H10ClNS: 259.0222. Found: 259.0225.
according to the general procedure and obtained as black
solid (125 mg, 91% yield). Melting point: 125-127 °C. 1H
NMR (600 MHz, CDCl3)  9.11 (1H, br s), 8.00 (1H, d, J
= 7.8 Hz), 7.93 (1H, d, J = 8.4 Hz), 7.66 (1H, d, J = 9 Hz),
7.56-7.52 (3H, m), 7.46 (1H, t, J = 7.8 Hz), 7.15-7.09 (4H,
m), 7.03 (1H, t, J = 7.2 Hz); 13C NMR (150 MHz, CDCl3)
 139.3, 131.3, 130.8, 129.0, 128.7, 128.5, 125.8, 125.7,
125.5, 124.7, 124.5, 121.8, 121.7, 119.1, 119.1, 104.6; IR:
3305.5, 2920.2, 1711.3, 1573.1, 1469.6, 1181.5, 1120.4,
695.1 cm-1; HRMS m/z (M+) calculated for C18H13NS:
275.0769. Found: 275.0770.
3-((4-Fluorophenyl)thio)-1H-indole
(3h):
Prepared
according to the general procedure and obtained as white
1
solid (100 mg, 82% yield). Melting point: 136-138 °C. H
3-(Butylthio)-1H-indole (5a): Prepared according to the
general procedure and obtained as dark red oil (93 mg,
91% yield). 1H NMR (600 MHz, CDCl3)  8.21 (1H, br s),
NMR (600 MHz, CDCl3)  8.35 (1H, br s), 7.59 (1H, d, J
= 8.4 Hz), 7.46 (1H, d, J = 3.0 Hz), 7.42 (1H, d, J = 8.4
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900612
Advanced Synthesis & Catalysis
7.77 (1H, d, J = 7.8 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.26
(1H, d, J = 2.4 Hz), 7.23-7.18 (2H, m), 2.69 (2H, t, J = 7.2
Hz), 1.54-1.48 (2H, m), 1.42-1.35 (2H, m). 0.87-0.84 (3H,
m); 13C NMR (150 MHz, CDCl3)  136.2, 129.3, 129.1,
122.5, 120.2, 119.3, 111.4, 106.0, 36.0, 31.9, 21.6, 13.6; IR
(neat): 3399.6, 2955.5, 2919.8, 2868.9, 1615.8, 1452.3,
1336.4, 1224.9, 1008.0, 740.0 cm-1; HRMS m/z (M+)
calculated for C12H15NS: 205.0925. Found: 205.0923.
2920.7, 2875.0, 1710.5, 1406.0, 1234.9, 1004.6, 741.2 cm-
1; HRMS m/z (M+) calculated for C10H11NOS: 193.0561.
Found: 193.0563.
3-(Pyridin-2-ylthio)-1H-indole (6): Prepared according to
the general procedure and obtained as yellow solid (69 mg,
61% yield). Melting point: 136–137°C. 1H NMR (600
MHz, CDCl3)  9.66 (1H, br s), 7.35 (1H, d, J = 5.4 Hz),
7.52 (1H, d, J = 7.8 Hz), 7.49 (1H, d, J = 2.4 Hz), 7.45
(1H, d, J = 8.4 Hz), 7.37 (1H, t, J = 7.8 Hz), 7.21 (1H, t, J
= 7.8 Hz), 7.12 (1H, t, J = 7.2 Hz), 6.97 (1H, t, J = 6.6
Hz), 6.78 (1H, d, J = 8.4 Hz); 13C NMR (150 MHz,
CDCl3)  162.4, 147.4, 137.9, 136.7, 131.8, 128.5, 123.0,
121.0, 120.6, 119.5, 119.0, 112.1, 99.1; IR (neat): 3092.2,
2503.3, 1721.9, 1603.8, 1448.5, 1234.9, 1128.2, 744.7 cm-
1; HRMS m/z (M+) calculated for C13H10N2S: 226.0565.
Found: 226.0563.
3-(Benzylthio)-1H-indole (5b): Prepared according to the
general procedure and obtained as dark reddish oil (102 mg,
85% yield). 1H NMR (600 MHz, CDCl3)  8.13 (1H, br s),
7.69 (1H, d, J = 7.8 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.22-
7.15 (5H, m), 7.07 (2H, d, J = 6.6 Hz), 6.99 (1H, d, J = 2.4
Hz), 3.85 (2H, s); 13C NMR (150 MHz, CDCl3)  139.0,
136.1, 129.8, 129.2, 128.9, 128.1, 126.7, 122.6, 120.4,
119.2, 111.4, 105.2, 40.9; IR (neat): 3403.8, 3027.4,
1735.4, 1616.4, 1452.0, 1232.8, 1008.2, 741.7, 696.7 cm-
1.HRMS m/z (M+) calculated for C15H13NS: 239.0769.
Found: 239.0770.
3-((1-Methyl-1H-imidazol-2-yl)thio)-1H-indole
(7):
Prepared according to the general procedure and obtained
as brown solid (90 mg, 78% yield). Melting point: 149-
151 °C. 1H NMR (600 MHz, CDCl3)  9.73 (1H, br s),
7.33 (1H, d, J = 7.2 Hz), 7.17 (2H, d, J = 10.2 Hz), 7.03-
6.99 (2H, m), 6.79 (2H, d, J = 16.8 Hz), 3.64 (3H, s); 13C
NMR (150 MHz, CDCl3)  134.4, 122.4, 122.3, 121.7,
120.1, 119.7, 118.4, 117.2, 114.0, 112.1, 109.8, 35.5; IR
(neat): 3288.3, 1566.5, 1455.4, 1380.7, 1240.7, 1152.5,
3-((Furan-2-ylmethyl)thio)-1H-indole (5c): Prepared
according to the general procedure and obtained as black
solid (93 mg, 81% yield). Melting point: 85-87 °C. 1H
NMR (600 MHz, CDCl3)  8.11 (1H, br s), 7.59 (1H, d, J
= 10.2 Hz), 7.26-7.24 (2H, m), 7.15-7.08 (2H, m), 7.02
(1H, s), 6.11 (1H, s), 5.76 (1H, s), 3.77 (2H, d, J = 3.6 Hz);
13C NMR (150 MHz, CDCl3)  151.8, 141.8, 136.0, 130.19, 925.4, 728.4 cm-1; HRMS m/z (M+) calculated for
129.1, 122.6, 120.4, 119.1, 111.4, 110.3, 107.6, 104.8,
33.4; IR (neat): 3405.8, 3127.0, 1501.0, 1501.0, 1405.2,
1234.3, 1146.1, 1007.4, 933.9, 739.0 cm-1; HRMS m/z
(M+) calculated for C13H11NOS: 229.0561. Found:
229.0564.
C12H11N3S: 229.0674. Found: 229.0673.
General procedure for the synthesis of 3-
thiobenzoylindoles 9: A general procedure for the copper-
phosphine
complex-catalyzed
synthesis
of
3-
thiobenzoylindoles 9 is as follows: An oven-dried 25 mL
two necked round bottom flask was charged with 2-
nitrochalcone (1 mmol), thiols (1.5 mmol) and 20 mol %
of CuCl(PPh3)3 in 10 mL anhydrous 1,4-dioxane and t-
BuOK (1 equiv.) was finally added. The reaction was then
kept under nitrogen atmosphere with continuous stirring.
Then, the reaction mixture was refluxed for about 9-12 h
until the completion of the reaction as indicated by TLC.
The resulting mixture was then dried in rotary evaporator
under reduced pressure to obtain the residue.The residue
was purified by column chromatography using silica gel as
the stationary phase and Hex/EtOAc (15:1) as the eluent to
isolate the pure product except benzoylindole 9e which
was purified through EtOAc washing of the dried reaction
mixture.
3-(sec-Butylthio)-1H-indole (5d): Prepared according to
the general procedure and obtained as dark brown liquid
1
(84 mg, 82% yield). H NMR (600 MHz, CDCl3)  8.24
(1H, br s), 7.84 (1H, d, J = 7.2 Hz), 7.37 (1H ,d, J = 7.8
Hz), 7.29-7.25 (3H, m), 2.93 (1H, m), 1.70-1.63 (1H, m),
1.54-1.47 (1H, m), 1.25 (3H, d, J = 6.6 Hz), 1.06 (3H, t, J
= 7.8 Hz); 13C NMR (150 MHz, CDCl3)  136.0, 130.2,
130.1, 122.4, 120.3, 119.5, 111.3, 104.5, 45.7, 29.5, 20.7,
11.6; IR (neat): 3401.8, 2961.6, 2872.0, 1615.7, 1452.1,
1336.8, 1232.5, 1090.8, 1007.9, 740.8 cm-1; HRMS m/z
(M+) calculated for C12H15NS: 205.0925. Found: 205.0923.
3-(Cyclohexylthio)-1H-indole (5e): Prepared according to
the general procedure and obtained as brown solid (100 mg,
86% yield). Melting point: 82-84 °C. 1H NMR (600 MHz,
CDCl3)  8.31 (1H, br s), 7.81 (1H, d, J = 7.8 Hz), 7.35
(1H, d, J = 7.8 Hz), 7.27 (1H, d, J = 2.4 Hz), 7.25-7.20
(2H, m), 2.83-2.78 (1H, m), 1.97-1.94 (2H, m), 1.75-1.71
(2H, m), 1.57-1.54 (1H, m), 1.36-1.30 (2H, m), 1.25-1.13
(3H, m); 13C NMR (150 MHz, CDCl3)  136.1, 130.2,
122.4, 120.2, 119.6, 119.5, 111.3, 104.4, 47.4, 33.6, 26.1,
25.6; IR (neat): 3391.9, 2928.2, 2849.6, 1450.7, 1337.0,
1094.8, 996.4, 739.5 cm-1; HRMS m/z (M+) calculated for
C14H17NS: 231.1082. Found: 231.1078.
Representative gram-scale procedure for the synthesis
of 3-thiobenzoylindole 9a: An oven-dried 50 mL two-
necked round bottom flask was charged with 2-
nitrochalcone 8 (4.0 mmol, 1.012 g.), benzenethiol 2a (1.5
eq, 6.0 mmol, 660 mg) and CuCl(PPh3)3 (20 mol %, 708.7
mg) in 20 mL anhydrous 1,4-dioxane and t-BuOK (1
equiv.) was finally added. The reaction was then kept
under nitrogen atmosphere with continuous stirring. Then,
each reaction mixture was refluxed until the completion of
the reaction as indicated by TLC for about 12 h. The
resulting mixture was then dried in rotary evaporator under
reduced pressure to obtain the residue. The residue was
purified by column chromatography using silica gel as the
stationary phase and Hex/EtOAc (15:1) as the eluent to
isolate the pure product.
3-(tert-Butylthio)-1H-indole (5f): Prepared according to
the general procedure and obtained as reddish brown solid
1
(72 mg, 70% yield). Melting point: 66-68 °C. H NMR
(600 MHz, CDCl3)  8.25 (1H, br s), 7.72 (1H, d, J = 7.2
Hz), 7.26 (1H, d, J = 7.2 Hz), 7.19 (1H, d, J = 2.4 Hz),
7.14-7.09 (2H, m), 1.20 (9H, s); 13C NMR (150 MHz,
CDCl3)  136.0, 131.5, 130.8, 122.3, 120.4, 120.0, 111.2,
104.4, 45.9, 30.9; IR (neat): 3351.8, 2964.0, 1500.3,
1453.0, 1166.8, 1092.3, 739.8 cm-1; HRMS m/z (M+)
calculated for C12H15NS: 205.0925. Found: 205.0924.
Phenyl(3-(phenylthio)-1H-indol-2-yl)methanone (9a):
Prepared using the general procedure and obtained as
yellow solid (309 mg, 94% yield). Melting point: 118-
1
120 °C. H NMR (600 MHz, CDCl3)  9.63 (1H, br s),
7.75 (2H, dd, J = 8.4, 1.2 Hz), 7.58 (1H, d, J = 7.8 Hz),
7.52 (1H, t, J = 7.8 Hz), 7.49 (1H, d, J = 8.4 Hz), 7.38 (1H,
t, J = 7.8 Hz), 7.33 (2H, t, J = 7.8 Hz), 7.14 (1H, t, J = 7.8
Hz), 7.10 (2H, t, J = 7.8 Hz), 7.04 (1H, t, J = 7.2 Hz),
6.93 (2H, d, J = 7.8 Hz); 13C NMR (150 MHz, CDCl3) 
188.9, 138.0, 137.8, 136.4, 136.2, 132.6, 130.2, 129.5,
128.7, 127.9, 126.7, 125.2, 122.0, 121.7, 112.3, 110.5; IR
(neat): 3303.2, 1610.4, 1475.6, 1334.9, 1258.3, 951.4,
2-((1H-Indol-3-yl)thio)ethan-1-ol
(5g):
Prepared
according to the general procedure and obtained as brown
1
liquid (69 mg, 71% yield). H NMR (600 MHz, CDCl3) 
8.38 (1H, br s), 7.75 (1H, d, J = 7.8 Hz), 7.37 (1H, d, J =
7.8 Hz), 7.31 (1H, s), 7.25-7.19 (2H, m), 3.61 (2H, t, J =
6.0 Hz), 2.85 (2H, t, J = 6.0 Hz), 2.24 (1H, br s); 13C NMR
(150 MHz, CDCl3)  136.2, 129.9, 129.1, 122.8, 120.6,
119.0, 111.5, 103.8, 60.2, 39.1; IR (neat): 3392.9, 3275.1,
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900612
Advanced Synthesis & Catalysis
729.9 cm-1; HRMS m/z (M+) calculated for C21H15NOS:
329.0874. Found: 329.0875.
References
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PR283.
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F. Piscitelli, A. Lavecchia, E. Novellino, A. Bergamini,
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Kambhampati, S. Vishwakarma, N. V. Kandikere, S.
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[8] N. Zhou, W. Zeller, M. Krohn, H. Anderson, J. Zhang,
E. Onua, A. S. Kiselyov, J. Ramirez, G. Halldorsdottir,
Þ. Andrésson, M. E. Gurney, J. Singh, J. Bioorg. Med.
Chem. Lett. 2009, 19, 123-126.
Phenyl(3-(p-tolylthio)-1H-indol-2-yl)methanone (9b):
Prepared using the general procedure and obtained as
yellow solid (312 mg, 91% yield). Melting point: 155-
1
157 °C. H NMR (600 MHz, CDCl3)  9.40 (1H, br s),
7.75 (2H, d, J = 7.2 Hz), 7.56 (1H, d, J = 7.8 Hz), 7.52
(1H, t, J = 7.2 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.38-7.33 (3H,
m), 7.12 (1H, t, J = 7.8 Hz), 6.91 (2H, d, J = 7.8 Hz), 6.85
(2H, d, J = 8.4 Hz) 2.22 (3H, s); 13C NMR (150 MHz,
CDCl3)  188.8, 138.1, 136.4, 136.0, 135.1, 134.0, 132.5,
130.2, 129.5, 129.5, 127.9, 127.1, 126.6, 122.2, 121.6,
112.2, 111.4, 20.8; IR (neat): 3314.2, 2920.1, 1606.8,
1486.2, 1329.2, 1255.7, 949.8, 728.7 cm-1; HRMS m/z
(M+) calculated for C22H17NOS: 343.1031. Found:
343.1031.
(3-((4-Methoxyphenyl)thio)-1H-indol-2-yl)(phenyl)
methanone (9c): Prepared using the general procedure and
obtained as yellow solid (334 mg, 93% yield). Melting
point: 167-169 °C. 1H NMR (600 MHz, CDCl3)  9.42 (1H,
br s), 7.77 (2H, d, J = 7.8 Hz), 7.57-7.53 (2H, m), 7.44 (1H,
d, J = 8.4 Hz), 7.40-7.34 (3H, m), 7.11 (1H, t, J = 7.8 Hz),
6.92 (2H, d, J = 9 Hz), 6.66 (2H, d, J = 8.4 Hz), 3.70 (3H,
s); 13C NMR (150 MHz, CDCl3)  188.8, 158.0, 138.1,
136.4, 135.5, 132.5, 130.0, 129.6, 129.5, 128.1, 128.0,
126.6, 122.1, 121.5, 114.4, 112.8, 112.2, 55.2; IR (neat):
3292.4, 2834.8, 1618.8, 1488.6, 1238.7, 1025.0, 951.5,
742.6 cm-1; HRMS m/z (M+) calculated for C22H17NO2S:
359.0980. Found: 359.0978.
(3-(Benzylthio)-1H-indol-2-yl)(phenyl)methanone (9d):
Prepared using the general procedure and obtained as
brown oil (343 mg, 88% yield). Melting point: 120-122 °C.
1H NMR (600 MHz, CDCl3)  9.21 (1H, br s), 7.85 (1H, d,
J = 8.4 Hz), 7.62 (2H, d, J = 7.8 Hz), 7.56 (1H, t, J = 7.2
Hz), 7.44-7.37 (4H, m), 7.24-7.22 (1H, m), 7.12 (1H, t, J =
7.2 Hz), 7.06 (2H, t, J = 7.8 Hz), 6.67 (2H, d, J = 7.2 Hz),
3.70 (2H, s); 13C NMR (150 MHz, CDCl3)  188.6, 138.0,
137.4, 136.9, 136.1, 132.3, 130.4, 129.8, 128.6, 128.1,
127.8, 126.9, 126.5, 121.6, 121.4, 112.6, 112.2, 41.1; IR
(neat): 3286.5, 3059.7, 1624.1, 1491.8, 1330.3, 1259.3,
732.8, 692.0 cm-1; HRMS m/z (M+) calculated for
C22H17NOS: 343.1031. Found: 343.1033.
[9] S. P. B. Ovenden, R. J. Capon, J. Nat. Prod. 1999, 62,
1246-1249.
[10]a) P. R. Reid, T. M. Bridges, D. J. Sheffler, H. P. Cho,
L. M. Lewis, E. Days, J. S. Daniels, C. K. Jones, C.
M. Niswender, C. D. Weaver, P. J. Conn, C. W.
Lindsley, M. R. Wood, Bioorg. Med. Chem. Lett. 2011,
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9.34 (1H, br s), 7.71 (2H, d, J = 7.8 Hz), 7.57 (1H, d, J =
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6.38 (1H, s), 6.34 (1H, s), 3.5 (3H, s); 13C NMR (150 MHz,
CDCl3)  187.0, 137.4, 135.1, 132.1, 132.0, 128.9, 128.8,
127.7, 127.1, 123.9, 121.9, 121.5, 119.2, 118.6, 117.8,
112.6, 35.3; IR (neat): 3290.4, 2916.5, 1724.4, 1618.0,
1469.5, 1336.5, 1258.9, 709.2 cm-1; HRMS m/z (M+)
calculated for C19H15N3OS: 333.0936. Found: 333.0938.
Acknowledgements
This work was supported by the National Research Foundation of
Korea (NRF) grant funded by the Korean government (MSIT)
(2018R1A2B2004432), the Priority Research Centers Program
(2014R1A6A1031189), and the Korean Ministry of Education,
Science and Technology (2012M3A7B4049675).
7
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FULL PAPER
Domino C-S/C-N Bond Formation using Well-
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