Direct, Metal-free C(sp2)?H Chalcogenation of Indoles and Imidazopyridines with Dichalcogenides Catalysed by KIO3

Article abstract of DOI:10.1002/chem.201705404

Herein, we report a greener protocol for the synthesis of 3-Se/S-indoles and imidazo[1,2-a]pyridines through direct C(sp²)?H bond chalcogenation of heteroarenes with half molar equivalents of different dichalcogenides, using KIO₃ as a non-toxic, easy-to-handle catalyst and a stoichiometric amount of glycerol. The reaction features are high yields, based on atom economy, easy performance on gram-scale, metal- and solvent-free conditions as well as applicability to different types of N-heteroarenes.

Full text of DOI:10.1002/chem.201705404

A Journal of
Accepted Article
Title: Direct, metal-free C(sp2)-H chalcogenation of indoles and
imidazopyridines with dichalcogenides, catalysed by KIO3
Authors: Jamal Rafique, Sumbal Saba, Marcelo S. Franco, Luana
Bettanin, Alex R Schneider, Lais T. Silva, and Antonio Luiz
Braga
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To be cited as: Chem. Eur. J. 10.1002/chem.201705404
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Direct, metal-free C(sp2)-H chalcogenation of indoles and
imidazopyridines with dichalcogenides, catalysed by KIO3
Jamal Rafique,† Sumbal Saba,† Marcelo S. Franco,† Luana Bettanin, Alex R. Schneider, Lais T. Silva,
Antonio L. Braga*[a]
Abstract: Herein, we report a greener protocol for the synthesis of
3-Se/S-indoles and imidazo[1,2-a]pyridines through direct C(sp2)-H
bond chalcogenation of heteroarenes with half molar equiv. of
single molecule, 3-Se/S-indoles/IPs, have been reported.[9]
Several methods described in the literature offer interesting
features,[10,11] but some have drawbacks which include the use of
non-green solvents, pre-functionalized coupling partners, low
atom economy, narrow substrate scope, transition-metal
catalysts, malodorous reagents and elaborate multi-stepped
processes.
In recent years, reactions catalysed by molecular iodine
and iodine salts have emerged a versatile tool in the cross-
coupling reaction for C-C and C-X bond formation.[12] Iodine
catalysis represents a promising powerful approach to organic
synthesis since it offers advantages over transition-metal
catalysis including: greater atom economy; greener and milder
reaction conditions; and broader substrate compatibility.[13]
Furthermore, metal- and solvent-free reaction conditions have
gained considerable attention from research groups and are
widely applied in the functionalization of the C-H bond, which
represents an important contribution to the development and
prdogress of sustainable chemistry.[14]
different dichalcogenides, using KIO3 as
a non-toxic, easily
handleable catalyst and stoichiometric amount of glycerol. The
reaction features are high yields, based on atom economy, ease to
gram scale, metal- and solvent-free approach as well as applicable
to different types of N-heteroarenes.
Introduction
Functionalization of the indole and imidazo[1,2-a]pyridine (IP)
cores are an important synthetic task, since they are well
established as privileged scaffolds[1,2] and are widely used for
pharmaceutical, biological and material applications.[3,4] These
nuclei are frequently found in several commercially available
pharmaceutical drugs,[5] e.g., alpidem 1a, zolpidem 1b,
miroprofen 1c, zolimidine 1d, naratriptan 1e, delavidine 1f
(Figure 1).
Recently, we developed an I2 catalysed C(sp2)-H bond
selenylation/sulfenylation of IPs using DMSO as oxidant under
solvent free conditions.[11h] Now, considering our continuous
interest in designing and developing eco-friendly processes as
well as in the chalcogenation of biologically-relevant
heterocycles,[11h,12b-c,15] we disclose
environmentally-benign protocol for the synthesis of 3-Se/S-
Indoles and imidazo[1,2-a]pyridines through
C(sp2)-H
a
new alternative
functionalization using a KIO3/glycerol catalytic system (Scheme
1). This new alternative and more sustainable approach uses
KIO3 as stable, non-toxic,easily handleable catalyst, allowing the
use of glycerol in stiochimetric amount. Using this broader,
regioselective, metal- and solvent-free approach worked
effectively using indole/IP with a half-molar equivalent of
diorganyl dichalcogenides (Se, S) as a non-malodorous source
of chalcogens.
Figure 1. Indole and IP-based drugs and chalcogenated hybrids.
Similarly, the construction of C–S/Se bonds is becoming
increasingly appreciated, due to their biological properties.[6,7]
Reports in recent decades of antioxidant, anti-inflammatory,
antitumor, and antiviral activities have led to increased interest in
these compounds.[8]
Despite the wide spectrum of therapeutic properties
associated with indole/IPs and the biological relevance of
organochalcogen compounds, few synthetic methods for the
construction of these hybrid structures, 1g-k (Figure 1) in a
Scheme 1. KIO3-catalysed 3-chalcogenyl-indole/IP.
Results and Discussion
To identify the best reaction conditions, we begin our studies
using indole 2a and diphenyl diselenide 3a as model substrates
(Table 1). Based on our previous experience of solvent-free
systems,[11h,12a-c] the reactions were carried out under solvent-
free conditions. The reaction in the absence of a catalyst was
ineffective (entry 1). Transition metals and KI afforded the
selenylated product in trace amounts only (entries 2,3,5), while
[a]
Dr. J. Rafique, Dr. S. Saba, M. S. Franco, L. Bettanin, A. R.
Schneider, L. T. Silva,Prof. Dr. A. L. Braga
Departamento de Química,
Universidade Federal de Santa Catarina
Florianopolis, 88040-900, SC-Brazil. http://labselen.ufsc.com/
E-mail: braga.antonio@ufsc.br
Supporting information for this article is given via a link at the end of
the document
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molecular iodine resulted in 4a with 14% yield (entry 4). On
switching from KI (entry 5) to KIO3 (entry 6), the coupled product
was isolated with 49% yield while its sodium analogue gave 40%
yield (entry 7). Next, the type of additive was screened for this
transformation (entries 8-11) and best results were obtained in
glycerol (entry 9).
(4e-f vs 4b-c). In addition, there was a weaker influence of the
steric hindrance of the ortho-substituted diselenides as
compared to the respective para-derivatives (4b-c vs 4g-h). By
using a sterically bulkier substrate, the desired product 4i was
obtained in 65% yield. Furthermore, aliphatic diselenide 3j
afforded the respective product 4j in 65% yield.
With the best catalyst and additive in hand, we then
monitored the influence of the reaction temperature and time
(entries 12-15) and ideal values of 100 °C and 6h were obtained.
Subsequently, the catalyst loading and the stoichiometry of the
additive were screened (entries 13-18). On using 5 mol% of
KIO3, 4a was obtained in lower yield (entry 17). Increasing the
catalyst loading to 15 mol% did not provide further improvement
in the yield (entry 16). On decreasing the amount of glycerol
from 5 to 4 equiv., 4a was obtained in 87% yield (entry 18), while
a further decrease in glycerol afforded a lower yield of 4a
(entries 18-19). The use of glycerol (2 mL) as the solvent did not
provide any further positive influence on the yield of 4a (entry 20
vs 18).
We further extended the scope of diorganyl
dichalcogenides by using diorganyl disulfides 5a-i as coupling
partner (Scheme 1), affording the corresponding sulfenylated
products 4k-s in yields of 59% to 85%. The sulfenylation of
indole 2a showed similar electronic and steric effects to those
observed during the selenylation. There was a small decrease in
the yield of the sulfenylated product 4k-s as compared with the
corresponding selenylated indoles 4a-j. The stronger S–S bond
of the diaryl disulfides 5 in relation to the respective diselendies
3 offers a possible explanation in this regard.
Scheme 1. Scope of diorganyl dicalcogenides 3 and 5.[a]
Table 1. Optimization of reaction conditions.[a]
Entry catalyst [mol %] additive [eq.] T [°C]
t [h] Yield [%][b]
1
2
3
4
5
6
7
-
PEG-400 (5)
PEG-400 (5)
PEG-400 (5)
PEG-400 (5)
PEG-400 (5)
PEG-400 (5)
PEG-400 (5)
100
100
100
100
100
100
100
8
8
8
8
8
8
8
NR
traces
traces
14
traces
49
ZnI2 (10)
CuI (10)
I2 (10)
KI (10)
KIO3 (10)
NaIO3 (10)
40
8
9
KIO3 (10)
KIO3 (10)
KIO3 (10)
KIO3 (10)
KIO3 (10)
KIO3 (10)
KIO3 (10)
KIO3 (10)
KIO3 (15)
KIO3 (5)
KIO3 (10)
KIO3 (10)
KIO3 (10)
Et. lactate (5)
Glycerol (5)
DMSO (5)
100
100
100
100
90
110
100
100
100
100
100
100
100
8
8
8
8
8
8
6
4
8
8
6
6
6
71
87
11
traces
73
85
87
65
87
61
10
11
12
13
14
15
16
17
18
19
20 c
toluene (5)
Glycerol (5)
Glycerol (5)
Glycerol (5)
Glycerol (5)
Glycerol (5)
Glycerol (5)
Glycerol (4)
Glycerol (3)
Glycerol
87
70
86
[a] Reaction conditions: 1a (0.25 mmol), 2a (0.125 mmol), catalyst
(mol %), additive (equivalent). [b] Isolated yields. [c] 2 mL Glycerol.
After ascertaining the best reaction parameters (Table 1,
entry 16), the generality and scope of the C(sp2)-H
chalcogenylation of other indole 2 with various diorganyl
dichalcogenides 3 were investigated (Schemes 1-2).
The reaction worked efficiently for structurally diverse
diselenides 3. This was tested through the use of different
substituted diaryl diselenides with electron-donating (R = Me,
OMe) and electron-withdrawing (R = F, Cl, CF3) groups as well
as sterically bulky groups (R = naphthyl). The results verified
that the corresponding products were obtained in good to
excellent yields (65−92%; 4a−i). Notably, in general, good
results were obtained in the case of electron-withdrawing groups
[a] Isolated yields.
To further broaden the scope in relation to the substrate,
the influence of the indoles 2 moiety was evaluated with 3a and
5a (Scheme 2). The indole nucleus was tested with different
functionalities, e.g. halogen, ester, nitrile, and methyl groups,
attached at the aryl moiety.
The system tolerated the electronic effects of the
substituents on the phenyl group and both electron-withdrawing
and electron-donating groups were found to be suitable
substrates, affording the corresponding products 6a-f and 6aa-af
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in 65% to 88% yields. In this case, electron-donating groups
Scheme 3. Scope of diorganyl dicalcogenides 3 and 5.[a],[b]
showed
superiority
over
electron-withdrawing
groups.
Substituents at the 1- and 2-positions of the indole also
influenced the performance of this transformation. For example,
1-methyl and 1-phenyl derivatives gave the desired products 6g-
h and 6ag-ah in 78% to 89% yield, respectively. Interestingly, 2-
methyl substituted indoles resulted in the corresponding
products 6i-j and 6ai-aj in 80% to 99% (yields, respectively).
Scheme 2. Scope of Indoles 2.[a]
[a] Isolated yields.
[a] In the case of PhS)2, reaction temperature: 130 oC. [b] Isolated yields.
Following the success in the KIO3-catalyzed C(sp2)–H
bond chalcogenation of indole 2a, this method was extended to
imidazo[1,2-a]pyridine 7 and diorganyl dichalcogenides (3, 5) as
the coupling partner (Scheme 3-4). In this case, however, 20
mol% of catalyst loading for a duration of 3 h at 110 oC (for
diselenides 3) or 130 oC (for disulfides 5) were found to be ideal.
In general, all of the tested diorganyl dichalcogenides (3, 5)
againist 7-methyl-2-phenylimidazo[1,2-a]pyridine 7a reacted well,
and afforded the selenylated-IPs (8a-l) and sulfenylated-IPs
(8m-v) in good to excellent yields (Scheme 3). The reaction
tolerated the electronic (electron-donating and electron-
withdrawing substituents) as well as steric effects. Notably,
aliphatic and heterocycle dichalcogenides led to the
corresponding products (8j-l,u-v) equally well.
Scheme 4. Scope of imidazo[1,2-a]pyridines 7 [a],[b]
The scope of the reaction regarding the IP 7 was explored
next (Scheme 4). Using diphenyl selenide 3a and disulfide 5a as
the substrate, the corresponding C-3 selenyl- and sulfenyl-IP
(9a-j and 9aa-aj, respectively), were obtained in 62-97% yields.
Interestingly, the method presented high regioselectivity (like
indole 2) because when the IP with no substituent at the C-2
position was used, the reaction exclusively afforded
chalcogenated products at C-3 (9j and 9aj) in very good yields.
[a] In the case of PhS)2, reaction temperature: 130 oC. [b] Isolated yields.
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In view of the unique features observed in this new
coupling reaction and to gain some insight into the mechanism
involved in the KIO3-catalyzed chalcogenation of indoles/IPs
through C(sp2)−H functionalization, some control experiments
were conducted (Scheme 8). A radical inhibitor did not hamper
the reaction and 4a was obtained in 82% yield (Scheme 8a).
Thus, the possibility of a radical pathway was neglected. We
have also observed that the reaction under oxygen atmosphere
had no negative effect (Scheme 8b), while under argon
atmosphere an abrupt decrease was perceived (Scheme 8c).
These results signify the importance of reaction under open
atmosphere. When iodine was used as the catalyst (Scheme 8d),
the reaction afforded 4a in low yield, indicating that this specie
most probably is not involved in the catalytic process, as
observed in our previous research. When the standard reaction
was performed in the presence of tertiary amines as the base
(Scheme 8e), the reaction showed complete tolerance. These
excludes the possibility of any acidic species, as observed in our
previous work.[10i],[11h] There was no reaction when indole 2a or
diselenide 3a or disulfide 5a was used alone under the standard
conditions (Scheme 8f). Notably, when IP 7a was used without
dichacogenide, the iodate specie of IP was detected in LCMS
(Scheme 8g, S.I.-s34). This motivated us to try the reaction of 7a
with diselenide 3a (Scheme 8h, S.I.-s35). Interestingly,
selenylated product 8a as well as iodate intermediate were also
detected in LCMS. Considering the role of glycerol in this
transformation, we are not ascertain about its contribution and a
more comprehensive study is needed.
To further demonstrate the synthetic value of this new
catalytic
system,
imidazo[1,2-a]pyrimidine
10a
and
benzo[d]imidazo[2,1-b]thiazole 10b were tested as an alternate
N-heterocyclic nucleus for the chalcogenation under the optimal
reaction conditions. The reaction furnished the desired
selenylated 11a,c and sulfenylated 11b,d products in good
yields, respectively (Scheme 5).
Scheme 5. Scope of N-heterocyclic core 10.
To extend the versatility of this method, other sulfenylating
agents were also employed. The use of 1 equiv. of thiol 12a and
sulfonyl hydrazide 12b as thiolating agents afforded the
respective thiolated products 4l and 8l in good yields (Scheme
6). However, since diorganyl dichalcogenides are odorless and
inexpensive they appear to be better options as
chalcogenylating agents.
Scheme 6. Thiolation using other sulfenylating agents.
To further demonstrate the synthetic utility of this new
coupling protocol, scale-up reactions at 10 mmol were carried
out (Scheme 7). Indole 2a, diphenyl diselenide 3a and disulfide
5a were selected as the reagents to be tested under optimized
conditions, affording 4a and 4l with no major decrease in the
yields. Thus, this procedure could be used as a robust method
for the larger scale synthesis of 3-chalcogenyl indoles and IPs,
which are precursors for some important bioactive molecules.
Text Paragraph.
Scheme 8. Controlled experiments.
Based on these results, a plausible mechanism for this
transformation could be proposed (Scheme 9). Initially, a
nucleophilic attack of specie A on hypervalent iodate afford the
specie B. This specie B, through intramolecular proton transfer
(IPT) leads to specie C, which on releasing KOH forms the
Scheme 7. Reaction at gram scale.
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in ppm, referenced to the solvent peak of CDCl3. Abbreviations to denote
the multiplicity of a particular signal are: s (singlet), d (doublet), t (triplet),
q (quartet), quint (quintet), sext (sextet) and m (multiplet). High resolution
mass spectra were recorded on a Bruker microTOF-Q II ESI mass
spectrometer equipped with an automatic syringe pump for sample
injection. The LC-MS analyzes were performed on system consisted of a
intermediate D (captured in LCMS). A nucleophilic attack of D on
diorganyl diselenide results in selenylated specie
E and
selenolate anion. The selenolate anion suffer oxidation by air
resulting in the diselenide (for this reason only half molar equiv.
of dichalcogenide was needed). Finally, the specie E in the
presence of KOH forms the desired product with the subsequent
regeneration of the catalyst in the reaction medium.
high performance liquid chromatograph equipped with
a mass
spectrometer (Shimadzu LC-20A-MS-2020) with a source of ionization
electrospray (ESI). The mobile phase was an acetonitrile and water
(70:30 v/v) that has been filtered and degassed with a flow rate of 0.2
mL/min. The separation was performed under isocratic conditions.
Infrared analyzes were performed on an Agilent Cary 600 Series FTIR
infrared equipment. The melting points were determined in
a
Microquimica MQRPF-301 digital model equipment with heating plate.
Column chromatography was performed using Silica Gel (230-400 mesh).
Thin layer chromatography (TLC) was performed using Merck Silica Gel
GF254, 0.25 mm thickness. For visualization, TLC plates were either
placed under ultraviolet light, or stained with iodine vapor and acidic
vanillin.
Unless otherwise stated, all reactions were carried out in Schlenk
tube; all reagents and solvents were obtained from commercial sources
and used without any further purification.
Scheme 9. Plausible mechanism.
General procedure for the KIO3-catalyzed chalcogenation of Indoles
2 using Diorganyl Chalcogenides 3 or 5
Conclusions
We have developed a synthetically attractive, robust and
greener approach for the synthesis of 3-Se/S-indole and IP
derivatives in good to excellent yields. This is an important
contribution considering the potential therapeutic application of
these compounds. The procedure provided good results in the
presence of the KIO3 as non-toxic, easily handleable and stable
catalyst combining with stoichiometric amount of glycerol with a
half molar equivalent of diorganyl dichalcogenides. The reaction
showed tolerance for various substituents with different
electronic and steric effects using an odourless source of
chalcogens and without the need of the exclusion of air and
moisture. Moreover, this method could be applied in the large-
scale synthesis of 3-chalcogenyl indoles.
The key features of this benign and robust protocol are: (1)
metal-free and solvent-free; (2) open to the air; (3) atom-
economic; (4) gram-scalable; (5) non-toxic and easily
handleable catalyst; (6) regioselective; and (7) applicable to
different sources of organochalcogenides as well as a wide
range of indoles, IPs and other N-heterocycles.
A mixture of appropriate indole 2 (0.25 mmol), diorganyl dichalcogenide 3
or 5 (0.125 mmol), KIO3 (10 mol %, 6 mg), and 4 equiv. of glycerol (1
mmol, 92 mg) were charged in a Schlenck tube. The reaction was heated
to 100 ºC in an oil bath for 6 h. After this, the reaction mixture was
dissolved in ethyl acetate (10 mL), and washed with 2 x 5 mL of brine.
The organic phase was separated, dried over MgSO4, and concentrated
under vacuum. The crude product was purified by flash chromatography
on silica gel using hexane or a mixture of hexane/ ethyl acetate (9:1) as
the eluent.
General procedure for the KIO3-catalyzed chalcogenation of
Imidazo[1,2-a]pyridines 7 using Diorganyl Chalcogenides 3 or 5
A mixture of appropriate indole 2 (0.25 mmol), diorganyl dichalcogenide 3
or 5 (0.125 mmol), KIO3 (10 mol %, 6 mg), and 4 equiv. of glycerol (1
mmol, 92 mg) were charged in a Schlenck tube. The reaction was heated
to 100 ºC in an oil bath for 6 h. After this, the reaction mixture was
dissolved in ethyl acetate (10 mL), and washed with 2 x 5 mL of brine.
The organic phase was separated, dried over MgSO4, and concentrated
under vacuum. The crude product was purified by flash chromatography
on silica gel using hexane or a mixture of hexane/ ethyl acetate (9:1) as
the eluent.
3-(Naphthalen-1-ylselanyl)-1H-indole (4i) [New compound]: Yield:
Experimental Section
o
1
65% (52.6 mg); white solid; mp: 116-118 C; H NMR (200 MHz, CDCl3)
δ = 8.33 – 8.22 (m, 2H), 7.79 (d, J = 7.5 Hz, 1H), 7.61 – 7.07 (m, 10H);
13C NMR (50 MHz, CDCl3) δ = 136.5, 133.9, 132.6, 132.4, 131.5, 130.0,
128.6, 127.0, 126.3, 126.1, 125.7, 123.0, 120.9, 120.4, 111.5, 97.4.
HRMS (APCI+) m/z calculated for C18H13NSe [M + H]+ 324.0287, found
324.0292.
General
Proton nuclear magnetic resonance spectra (1H NMR) were obtained at
200 MHz and 400 MHz on Bruker AC-200 or Varian AS-400
spectrometers, respectively. Spectra were recorded in CDCl3 solutions.
Chemical shifts are reported in ppm, referenced to the solvent peak of
CDCl3 or tetramethylsilane (TMS) as the external reference. Data are
reported as follows: chemical shift (δ), multiplicity, coupling constant (J)
in Hertz and integrated intensity. Carbon-13 nuclear magnetic resonance
spectra (13C NMR) were obtained either at 50 MHz or 101 MHz on Bruker
AC-200 NMR or Varian AS-400 spectrometers spectrometer, respectively.
Spectra were recorded in CDCl3 solutions. Chemical shifts are reported
5-Chloro-3-(phenylselanyl)-1H-indole (6a) [New compound]: Yield:
70% (53.5 mg); yellow solid; mp: 112−115oC; 1H NMR (200 MHz, CDCl3)
δ = 8.43 (s, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.30 (d,
J = 8.6 Hz, 1H), 7.23 – 7.10 (m, 6H); 13C NMR (50 MHz, CDCl3) δ =
134.8, 133.4, 132.6, 131.3, 129.2, 128.9, 126.9, 125.9, 123.5, 119.9,
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112.6, 98.1. HRMS (APCI+) m/z calculated for C14H10NClSe [M]+
306.9659, found 306.9659.
171 °C; (C20H15N2SCl) 1H NMR (400 MHz, CDCl3) δ (ppm): 8.19 – 8.14
(m, 2H), 8.05 (d, J = 6.9 Hz, 1H), 7.47 (s, 1H), 7.44 – 7.39 (m, 2H), 7.37
– 7.31 (m, 1H), 7.16 – 7.09 (m, 2H), 6.91 – 6.85 (m, 2H), 6.65 (dd, J =
7.0, 1.2 Hz, 1H), 2.39 (s, 3H); 13C NMR (101 MHz, CDCl3) δ (ppm): 151.5,
147.6, 138.0, 134.1, 133.4, 132.0, 129.5, 128.6, 128.4, 128.3, 126.8,
123.4, 116.3, 115.8, 104.9, 21.3; IR (KBr) (cm-1): 3072, 3053, 3023,
1930, 1880, 1798, 1745, 1646, 1493, 1473, 1440, 1085, 1006, 809, 771,
689; HRMS (APCI, m/z) calculated for C20H16N2SCl [M+H]+: 351.0717,
found: 351.0721.
5-Iodo-3-(phenylselanyl)-1H-indole (6c) [New compound]: Yield: 69%
o
(68.8 mg); white solid; mp: 124-127 C; 1H NMR (200 MHz, CDCl3) δ =
8.46 (s, 1H), 7.98 (s, 1H), 7.51 – 7.12 (m, 8H); 13C NMR (50 MHz, CDCl3)
δ = 135.6, 133.4, 132.6, 132.1, 131.5, 129.2, 129.2, 128.8, 125.9, 113.4,
97.6, 84.7; HRMS (APCI+) m/z calculated for C14H10NISe [M]+ 398.9018,
found 398.9019.
7-Methyl-3-((4-nitrophenyl)thio)-2-phenylimidazo [1,2-a] pyridine (8r)
(New compound): Yield: 76% (137 mg); yellow solid; mp: 197-198 °C;
(C20H15N3SO2) H NMR (400 MHz, CDCl3) δ (ppm): 8.11 – 8.07 (m, 2H),
8.06 – 7.99 (m, 3H), 7.52 (s, 1H), 7.43 – 7.33 (m, 3H), 7.07 – 7.01 (m,
2H), 6.74 (dd, J = 7.0, 1.6 Hz, 1H), 2.44 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ (ppm): 152.2, 148.0, 146.0, 145.3, 138.6, 133.0, 128.9, 128.5,
128.2, 125.2, 124.5, 123.3, 116.6, 116.3, 115.5, 102.8, 21.4; IR (KBr)
(cm-1): 3088, 3051, 2915, 1947, 1830, 1805, 1646, 1575, 1509, 1336,
1105, 1081, 857, 771, 742, 698; HRMS (APCI, m/z) calculated for
C20H16N3SO2 [M+H]+: 362.0958, found: 362.0959.
5-Iodo-3-(phenylthio)-1H-indole (6ac) [New compound]: Yield: 70%
o
(61.4 mg); white solid; mp: 111-113 C; 1H NMR (200 MHz, CDCl3) δ =
1
8.41 (s, 1H), 7.96 (s, 1H), 7.53 – 7.09 (m, 8H); 13C NMR (50 MHz, CDCl3)
δ = 138.8, 135.7, 131.7, 131.5, 128.9, 128.5, 126.0, 125.1, 113.6, 102.6,
84.9; HRMS (APCI+) m/z calculated for C14H10NIS [M]+ 350.9573, found
350.9575.
3-(Phenylthio)-1H-indole-4-carbonitrile (6af) [New compound]: Yield:
71% (44.4 mg); yellow solid; mp: 166-167 oC; 1H NMR (200 MHz, DMSO-
d6) δ = 12.40 (s, 1H), 8.09 (d, J = 2.6 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H),
7.60 (d, J = 7.4 Hz, 1H), 7.40 – 7.06 (m, 6H); 13C NMR (50 MHz, DMSO-
d6) δ = 139.5, 137.1, 136.4, 128.8, 127.7, 127.4, 125.5, 124.9, 122.0,
117.7, 117.6, 101.1, 99.4; HRMS (APPI+) m/z calculated for C15H10N2S
[M]+ 250.0565, found 250.0568.
7-Methyl-3-(naphthalen-2-ylthio)-2-phenylimidazo [1,2-a] pyridine
(8t) (New compound): Yield: 81% (148 mg); white solid; mp: 162-
163 °C; (C24H18N2S) 1H NMR (400 MHz, CDCl3) δ (ppm): 8.25 – 8.17 (m,
2H), 8.14 – 8.09 (m, 1H), 7.74 – 7.69 (m, 1H), 7.67 (d, J = 8.7 Hz, 1H),
7.57 – 7.53 (m, 1H), 7.52 – 7.47 (m, 1H), 7.43 – 7.31 (m, 6H), 7.15 (dd, J
= 8.6, 1.9 Hz, 1H), 6.61 (dd, J = 7.0, 1.6 Hz, 1H), 2.39 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ (ppm): 151.6, 147.7, 138.0, 134.0, 133.7, 133.1,
131.9, 129.3, 128.6, 128.5, 128.4, 127.8, 127.1, 126.8, 125.8, 123.9,
123.8, 123.5, 116.4, 115.8, 105.5, 21.4; IR (KBr) (cm-1): 3049, 2972,
2917, 1956, 1888, 1843, 1752, 1699, 1646, 1593, 1440, 1352, 1234, 806,
773, 744, 700; HRMS (APCI, m/z) calculated for C24H19N2S [M+H]+:
367.1263, found: 367.1264.
3-(Benzylselanyl)-7-methyl-2-phenylimidazo [1,2-a] pyridine (8k)
(New compound): Yield: 54% (103 mg); yellow liquid; (C21H18N2Se) 1H
NMR (400 MHz, CDCl3) δ (ppm): 8.12 – 8.08 (m, 2H), 8.15 – 8.07 (m,
1H), 7.94 (d, J = 7.0 Hz, 1H), 7.43 – 7.39 (m, 2H), 7.36 – 7.30 (m, 2H),
7.06 – 6.95 (m, 3H), 6.89 – 6.81 (m, 2H), 6.45 (dd, J = 7.0, 1.4 Hz, 1H),
3.79 (s, 2H), 2.34 (s, 3H); 13C NMR (101 MHz, CDCl3) δ (ppm): 150.9,
147.6, 138.1, 136.9, 134.3, 128.6, 128.5, 128.4, 128.1, 128.0, 127.0,
124.5, 115.7, 114.8, 103.3, 33.1, 21.3; IR (KBr) (cm-1): 3062, 3027,
2978, 2915, 1951, 1890, 1810, 1646, 1495, 1464, 1440, 1348, 1232, 855,
775, 759, 696; HRMS (APCI, m/z) calculated for C21H19N2Se [M+H]+:
379.0709, found: 379.0705.
7-Methyl-2-phenyl-3-(pyridin-4-ylthio) imidazo [1,2-a] pyridine (8u)
(New compound): Yield: 77% (122 mg); pale yellow solid; mp: 160-
161 °C; (C19H15N3S) 1H NMR (400 MHz, CDCl3) δ (ppm): 8.35 – 8.32 (m,
2H), 8.11 – 8.07 (m, 2H), 8.02 (d, J = 7.0 Hz, 1H), 7.53 – 7.48 (m, 1H),
7.43 – 7.38 (m, 2H), 7.36 – 7.32 (m, 1H), 6.85 – 6.82 (m, 2H), 6.70 (dd, J
= 7.0, 1.6 Hz, 1H), 2.41 (s, 3H); 13C NMR (101 MHz, CDCl3) δ (ppm):
152.1, 149.8, 147.8, 147.3, 138.3, 133.0, 128.7, 128.4, 128.1, 123.2,
119.7, 116.4, 116.0, 102.1, 21.2; IR (KBr) (cm-1): 3043, 2919, 1939,
1842, 1731, 1696, 1646, 1571, 1468, 1403, 1356, 1240, 808, 771, 691;
HRMS (APCI, m/z) calculated for C19H16N3S [M+H]+: 318.1059, found:
318.1058.
4-((7-Methyl-2-phenylimidazo [1,2-a] pyridin-3-yl)thio) aniline (8o)
(New compound): Yield: 78% (129 mg); yellow solid; mp: 240-242 °C;
(C20H17N3S) 1H NMR (400 MHz, CDCl3) δ (ppm): 8.31 – 8.20 (m, 2H),
8.17 (dd, J = 7.2, 0.7 Hz, 1H), 7.46 – 7.33 (m, 3H), 7.29 – 7.16 (m, 1H),
6.94 – 6.79 (m, 2H), 6.66 (dd, J = 7.2, 1.9 Hz, 1H), 6.57 – 6.48 (m, 2H),
3.59 (s, 2H), 2.39 (s, 3H); 13C NMR (101 MHz, CDCl3) δ (ppm): 150.5,
147.2, 145.5, 137.6, 134.0, 133.9, 129.6, 128.6, 128.6, 128.5, 128.4,
128.4, 123.8, 122.9, 116.2, 116.2, 115.5, 115.5, 107.9, 21.5; IR (KBr)
(cm-1): 3404, 3327, 3210, 3051, 3025, 1965, 1945, 1873, 1794, 1733,
1624, 1601, 1495, 1352, 1301, 1171, 816, 775, 699; HRMS (APCI, m/z)
calculated for C20H18N3S [M+H]+: 332.1216, found: 332.1216.
2-(Naphthalen-2-yl)-3-(phenylselanyl) imidazo [1,2-a] pyridine (9i)
(New compound): Yield: 71% (142 mg); pale yellow solid; mp: 142-
143 °C; (C23H16N2Se) 1H NMR (400 MHz, CDCl3) δ (ppm): 8.67 (d, J =
1.0 Hz, 1H), 8.35 (dd, J = 8.6, 1.7 Hz, 1H), 8.28 (dt, J = 6.9, 1.0 Hz, 1H),
7.88 – 7.85 (m, 2H), 7.79 (dd, J = 6.1, 3.4 Hz, 1H), 7.70 (dd, J = 9.0, 0.9
Hz, 1H), 7.42 (dd, J = 6.3, 3.2 Hz, 2H), 7.23 – 7.19 (m, 1H), 7.09 (s, 5H),
6.72 (td, J = 6.8, 1.1 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ (ppm): 151.5,
147.8, 133.3, 131.3, 130.9, 129.7, 128.6, 128.4, 128.2, 127.8, 127.6,
126.7, 126.5, 126.4, 126.3, 126.0, 125.5, 117.4, 113.0, 103.4; IR (KBr)
(cm-1): 3066, 3027, 1930, 1809, 1705, 1628, 1573, 1489, 1473, 818, 763,
734, 685, 663; HRMS (APPI, m/z) calculated for C23H17N2Se [M+H]+:
401.0553, found: 401.0550.
3-((4-(tert-Butyl)phenyl)
thio)-7-methyl-2-phenylimidazo
[1,2-
a]pyridine (8p) (New compound): Yield: 88% (164 mg); colorless liquid;
(C24H24N2S) 1H NMR (400 MHz, CDCl3) δ (ppm): 8.25 – 8.19 (m, 2H),
8.13 – 8.02 (m, 1H), 7.49 – 7.46 (m, 1H), 7.44 – 7.28 (m, Hz, 3H), 7.21 –
7.16 (m, 2H), 6.93 – 6.89 (m, 2H), 6.64 – 6.56 (m, 1H), 2.37 (s, 3H), 1.21
(s, 9H); 13C NMR (101 MHz, CDCl3) δ (ppm): 151.1, 149.2, 147.4, 137.7,
133.6, 134.0, 128.4, 128.4, 128.3, 126.4, 125.5, 123.7, 116.1, 115.5,
106.0, 34.4, 31.2, 21.3; IR (KBr) (cm-1): 3068, 2957, 2866, 1946, 1887,
1805, 1754, 1640, 1493, 1440, 1352, 1269, 1236, 1169, 1118, 1010, 816,
795, 775, 691; HRMS (APCI, m/z) calculated for C24H25N2S [M+H]+:
373.1733, found: 373.1731.
2-(Naphthalen-2-yl)-3-(phenylthio) imidazo [1,2-a] pyridine (9ai) (New
compound): Yield 63% (111 mg); pale yellow solid; mp: 129-130 °C;
(C23H16N2S) 1H NMR (400 MHz, CDCl3) δ (ppm): 8.73 (s, 1H), 8.39 (dd, J
= 8.6, 1.7 Hz, 1H), 8.23 (d, J = 6.8 Hz, 1H), 7.89 – 7.85 (m, 2H), 7.82 –
7.77 (m, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.45 – 7.40 (m, 2H), 7.27 – 7.23
3-((4-Chlorophenyl)thio)-7-methyl-2-phenylimidazo[1,2-a]
pyridine
(8q) (New compound): Yield: 80% (140 mg); white solid; mp: 169-
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10.1002/chem.201705404
Chemistry - A European Journal
FULL PAPER
(m, 1H), 7.18 – 7.13 (m, 2H), 7.10 – 7.05 (m, 1H), 7.03 – 6.97 (m, 2H),
6.76 (td, J = 6.8, 0.9 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ (ppm): 151.2,
147.2, 135.2, 133.41, 130.9, 128.7, 128.0, 127.9, 127.6, 126.7, 126.4,
126.2, 126.1, 126.0, 125.8, 124.5, 117.6, 113.1, 106.9; IR (KBr) (cm-1):
3096, 3068, 2957, 2925, 1941, 1909, 1874, 1850, 1815, 1791, 1630,
1581, 1475, 1230, 818, 765, 734, 685; HRMS (APPI, m/z) calculated for
C23H17N2S [M+H]+: 353.1107, found: 353.1105.
Huang, X. Ji, X. Tang, M. Zhang, X. Li, H. Jiang, Org. Lett. 2013, 15,
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13C NMR (50 MHz, CDCl3) δ (ppm): 154.2, 151.5, 133.9, 133.7, 132.5,
130.3, 129.9, 128.4, 128.3, 128.3, 128.2, 126.8, 126.2, 125.0, 124.0,
114.6, 104.2; IR (KBr) (cm-1): 3066, 2921, 1942, 1893, 1577, 1479,
1436, 1369, 1314, 1261, 1122, 1069, 1020, 771, 734, 689, 665, 628, 569,
461; HRMS (APCI, m/z) calculated for C21H15N2SSe [M+H]+: 407.0116,
found: 407.0119.
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Acknowledgements
We gratefully acknowledge CAPES, CNPq, CERSusChem
GSK/FAPESP (grant 2014/50249-8), INCT-Catálise and
FAPESC-Pronex for financial support. J.R., S.S (postdoctoral
fellows) and M.S.F., L.B. (doctoral fellows) are grateful to
CAPES and CNPq for fellowships. The authors also
acknowledge CEBIME for the HRMS analysis.
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Keywords: Nitrogen heterocycles • selenium • sulfur • KIO3 •
green chemistry
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10.1002/chem.201705404
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Dr. Jamal Rafique, Dr. Sumbal Saba,
Marcelo S. Franco, Luana Bettanin, Alex
R. Schneider, Lais T. Silva, Prof. Dr.
Antonio L. Braga*
Page No. – Page No.
Direct, metal-free C(sp2)-H
chalcogenation of indoles and
imidazopyridines with
KIO3 catalysed C(sp2)-H bond chalcogenation: An efficient and scalable C(sp2)-
H bond chalcogenation (Se/S) of 5-membered N-heterocyclic arenes, using KIO3 as
a stable and easily handleable catalyst under solvent free conditions, has been
developed. Compared to other chalcogenation methods, this alternate sustaible
system has significantly increased the substrate scope and avoids the use of non-
stable and toxic catalyst.
dichalcogenides, catalysed by KIO3
This article is protected by copyright. All rights reserved.