Synthesis of Benzofuran and Indole Derivatives Catalyzed by Palladium on Carbon

Article abstract of DOI:10.1002/ejoc.201900577

Benzofurans and indoles are key moieties in many natural products and pharmaceuticals. Herein, we describe a cheap and easy-to-execute strategy for the synthesis of benzofurans and indoles, employing Pd/C as the promoter. A variety of substituted allyl-anilines and allyl-phenols were converted into the desired products in good to excellent yields. Recycling of Pd/C was possible up to five cycles, keeping similar levels of reactivity.

Full text of DOI:10.1002/ejoc.201900577

A Journal of
Accepted Article
Title: Palladium on Carbon-catalyzed Synthesis of Benzofuran and
Indole Derivatives
Authors: Anatoli Savvidou, Dimitrios Ioannis Tzaras, Giorgos
Koutoulogenis, Alexis Theodorou, and Christoforos G.
Kokotos
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900577
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10.1002/ejoc.201900577
European Journal of Organic Chemistry
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Palladium on Carbon-catalyzed Synthesis of Benzofuran and
Indole Derivatives
Anatoli Savvidou,[a] Dimitrios IoannisTzaras,[a] Giorgos S. Koutoulogenis,[a] Alexis Theodorou[a] and
Christoforos G. Kokotos*[a]
Abstract: Benzofurans and indoles are key moieties in many natural
products and pharmaceuticals. Herein, we describe a cheap and
easy-to-execute strategy for the synthesis of benzofurans and
indoles, employing Pd/C as the promoter. A variety of substituted
allyl-anilines and allyl-phenols were converted into the desired
products in good to excellent yields. Recycling of Pd/C was possible
up to five cycles, keeping similar levels of reactivity.
Introduction
Aromatic heterocycles and their chemistry constitute
a
fundamental field of research in Organic Chemistry.[1] Indoles
and benzofurans are very important moieties in Organic
synthesis and are molecules of great medicinal interest, due to
their presence in numerous
natural products and
pharmaceuticals. Selected examples are shown in Figure 1.
Indole-3-acetic acid (IAA) is one of the most common naturally-
occurring plant hormones of the auxin family,[2] while RO-09-
4609 is known as an antifungal agent.[3] Moreover, melatonin is
a neurohormone in higher eukaryotes, which regulates the
mammalian circadian rhythms and synchronizes biological
processes, according to light-dark cycles.[4] Furthermore,
serotonin is a neurotransmitter, which is found in all bilateral
animals,[5] while indole-3-carbinol (I3C) has been shown to be
one of the major anti-cancer substances found in cruciferous
vegetables.[6] Last but not least, ajmalicine is an indole-derived
drug used in the treatment of high blood pressure.[7] Benzofuran
derivatives are also utilized in many therapeutic treatments
against cancer, psychotic disorders, inflammation, diabetes, etc.
On the other hand, the indole core has been found in drugs, like
indomethacin or inhibitors targeting numerous diseases, like
CNS diseases, or inflammation.[8] As a consequence of their
dynamic presence in numerous natural products, their
significance in Medicinal Chemistry and due to their synthetic
utility, a great variety of synthetic methods has been developed,
in order to synthesize these molecules.
Figure 1. Representative molecules containing the indole or the benzofuran
moiety.
upon cyclization affords the desired compound.[9] Usually, these
synthetic methodologies involve the use of transition metal-
complexes,[10] such as cobalt,[11] copper,[12,13] gold,[14]
palladium,[15] ruthenium,[16] platinum[17] or indium[18] as catalysts
for the synthesis of these moieties. For example, a common
approach constitutes the metal-catalysed cyclization of ortho-
substituted anilines with alkynes (Scheme 1, A). Among the
metal catalysts employed, copper,[12,13] gold,[14] palladium,[15]
platinum[17] and indium[18] are the most common ones. Another
cyclization approach involves the use of ortho-substituted vinyl
anilines (Scheme 1, B). Similar to before, copper,[12,13]
palladium,[15] cobalt[11] or ruthenium[16] are usually employed.
The above-mentioned approaches are favouring the five-
membered ring cyclization, since, in most cases, there is no
other alternative. Unlike to these cases, the use of ortho-
substituted allyl anilines can favour either the five-membered or
the six-membered ring cyclization. In 1976, Hegedus and
coworkers employed stoichiometrically a palladium complex for
the synthesis of indoles in these types of substrates (Scheme 1,
C).[15a] A few years later, Tremont and coworkers utilized
Pd(OAc)2 for the synthesis of such substrates, while more
recently, Ghorai introduced the synthesis of functionalized
indoles utilizing Pd(OAc)2 as the catalyst and PPh3 as the ligand
(Scheme 1, C).[15b,15h]
Most approaches for the synthesis of indole and benzofuran
derivatives require an ortho-disubstituted arene group, which
[a]
A. Savvidou, D. I. Tzaras, G. S. Koutoulogenis, Dr. A. Theodorou,
Prof. C. G. Kokotos
Laboratory of Organic Chemistry
Department of Chemistry
National and Kapodistrian University of Athens
Panepistimiopolis 15771, Athens, Greece
E-mail: ckokotos@chem.uoa.gr
http://users.uoa.gr/~ckokotos/
Palladium is among the most important metals employed in
homogeneous and heterogeneous catalysis.[19] In homogeneous
catalysis, palladium (II) catalysts have been widely used in
numerous organic reactions.[20] A special position in palladium
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Optimization of the reaction conditions for the synthesis of indole 2a
from 1a.[a]
Entry
Solvent
Temperature/
Conditions
(oC)
Pd/C
(mg)
Yield (%)[b]
1
2
toluene
DMSO
o-xylene
benzene
neat
120
120
120
120
120
120
80
50
50
50
50
50
50
50
50
50
25
100
-
33
45
60
50
8
3
4
5
6
DMF
66
40
75
60
60
75
3
7
DMF
8
DMF
100
150
120
120
120
100
100
hv
9
DMF
10
11
12
13[c]
14[d]
15
DMF
DMF
DMF
DMF
50
50
50
75
75
traces
Scheme 1. Synthetic approaches for the synthesis of indoles and benzofurans.
DMF
DMF
catalysis constitutes palladium on carbon (Pd/C). Palladium on
carbon (Pd/C) has some unique advantages, like stability in air,
easy removal by simple filtration, sustainability and commercial
availability at a relatively low cost. Taking everything of the
above into serious consideration, the fact that Pd/C is employed
more frequently[21] and its applications are increasing recently in
literature, such as the construction of indole ring through a
cyclization of 2-halophenylethylamines or the Pd/C-catalyzed
Yamanaka-Larock indole synthesis.[22] Acknowledging the rising
position in catalysis of Pd/C and comparing the relative cost of
the metal complexes (Pd/C 25.30€/1g, PdCl2 73.00€/1g, PtCl2
[a] All reactions were carried out with 1a (0.30 mmol). The reaction was left
stirring for 18 h. [b]Isolated Yield. [c] Under argon atmosphere. [d] Under O2
atmosphere.
these lines, we had previously introduced organocatalytic
oxidation protocols for the synthesis of benzodihydrofurans and
indolidines.[25,26] Herein, our goal was to introduce a sustainable
methodology for the synthesis of the family of indole and
benzofurans.
We initiated our study utilizing mesyl-protected allyl aniline 1a,
easily prepared from commercially available aniline, as substrate
for the optimization of the reaction conditions (Table 1). This
substrate was not selected by chance, since in our previous
work,[26] it provided the best results in cyclization reactions. As
shown in Table 1, we commenced by testing various organic
solvents, such as toluene, benzene, etc., however
dimethylformamide provided the best results (Table 1, entries 1-
6). Moreover, the optimum temperature for the reaction was
366.00€/1g, AuCl 329.00€/1g, Pd(TFA)2
137.40€/1g,
[Ru(bpz)3][PF6]2 84.60€/50mg, Pd(OAc)2 84.10€/1g)[23] employed
in Scheme 1, we designed a synthetic approach for indole and
benzofuran derivatives synthesis via a selective cyclization of
ortho-substituted allyl anilines (Scheme 1, D).
o
found to be 100 C, since when the temperature was increased
Results and Discussion
or decreased, lower yields were observed (Table 1, entries 7-9).
Finally, Pd/C plays a crucial role in the reaction, since when it
was omitted, only traces of the product were observed. Also,
We have been interested for long in developing new, green and
sustainable processes for the synthesis of compounds.[24] Along
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Scheme 3. Synthesis of benzofurans – substrate scope.
is occurring after cyclization. Other protecting groups, like Boc or
benzoyl, did not afford the desired product.
Having found the optimum protection, we tried to extend our
substrate scope by adding a variety of substituents in the
aromatic ring of the allyl-aniline (Scheme 2). Both ortho-and
para-substitution were utilized, providing more or less the same
yields of the desired products, showing that the position of the
substitution does not affect the performance of the reaction.
Electron-donating groups, such as p-methoxy- or electron-
withdrawing groups, such as p-chloro- provided the desired
products 2h-j in mediocre yields. Likewise, alkyl chains led to
the desired products 2g and 2k in moderate yields. Attempts to
use trans-substituted double bonds (with benzyl or phenyl
moieties) met with failure.
Scheme 2. Synthesis of indoles – substrate scope.
changing the quantity of Pd/C, the observed yields were not
improved (Table 1, entries 10-12). Having established our
optimum reaction conditions (Table 1, entry 8), we carried out
experiments, in order to provide more insight in the reaction
mechanism (Table 1, entries 13-15).The results proved to be
interesting and decisive. First of all, the reaction provided the
same yields in air, as well as in an inert atmosphere (Table 1,
entry 8 vs 13 and 14). Therefore, oxygen does not take part in
the mechanism of the reaction. This is a key difference with
Moreover, in order to expand the substrate scope and search for
the limits of our methodology, we replaced allyl-anilines with
allyl-phenols (Scheme 3). In this case, we would be able to
investigate the differences between these two different
substrates and expand this work in the synthesis of benzofuran
derivatives. To our surprise, despite the change of the
heteroatom, the cyclization proceeded and led to the desired
products in moderate yields (Scheme 3). This could be
interpreted, by the fact that transition metal complexes usually
lack electron density and try to fill this gap by taking available
electrons from ligands. In addition, Pd is characterized by high
oxophilicity and very often tends to form complexes with
available oxygen atoms. Returning to the use of allyl-phenols,
utilizing this methodology, we could isolate a number of
benzofurans with different functional groups. para-Nitro allyl-
phenol (1l) led to the desired product 2l in 40% yield. Aryl-
substituted phenols gave benzofurans 2m and 2p in mediocre
yields. Last but not least, an analogue of phenolophthalein and
one of the natural aminoacid tyrosin led to the desired products
2n and 2o in moderate yields.
previously reported literature, where for
a
different
transformation, it was proposed that oxygen is necessary for the
activation of Pd/C.[27] Another result was that under irradiation
(household fluorescence lamps or blue LED), the yield dropped
dramatically (Table 1, entry 15). In this case, we have concluded
that
a
thermal reaction was taking place and not
a
photochemical one.
Having in hand the optimum reaction conditions, we firstly tried
to understand, how a change in the protecting group affects the
reaction (Scheme 2). Despite the fact, that the tosyl group is
usually employed in literature, in our case product 2c gave lower
yield than 2a. This can be explained by the fact that, during the
reaction, a deprotection is occurring in some extent (according
to crude NMR data). Furthermore, some other sulfonyl-based
protecting groups provided similar results, while the chiral
camphorsulfonate gave 60% yield. When we utilized the
trifluoromethansulfonyl-protecting group (1b), we observed that
was removed in the reaction conditions and the unprotected
product 2b was obtained. In addition, when unprotected allyl-
aniline was employed, no cyclization product was obtained,
which verifies the hypothesis that in the case of 1b, deprotection
In order to enhance the properties of our methodology, we tried
to examine the reusability of our catalytic system (Scheme 4).
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Conclusions
80
60
40
20
0
In conclusion, a sustainable and easy-to excute protocol for the
synthesis of nitrogen- and oxygen-heterocycles was developed.
Since a plethora of palladium catalysts have already been used,
our approach was to utilize Pd/C as the catalyst and exploit its
advantages, such as stability in air, easy removal by simple
filtration and relatively low cost. After an extensive study of the
nature of the protecting group, a variety of substitution patterns
is well tolerated leading to indoles and benzofurans in good to
moderate yields. This novel approach of using cheap and
reusable materials such as Pd/C, in order to synthesize more
complex compounds is currently being pursued in our
laboratories.
0
1
2
3
4
5
6
Number of cycles
Scheme 4. Recycling of the catalyst for the synthesis of 2a from 1a in DMF.
Experimental Section
General methods: Chromatographic purification of products was
accomplished using forced-flow chromatography on Merck® Kieselgel
60F254 230-400 mesh. Thin-layer chromatography (TLC) was performed
on aluminum backed silica plates (0.2 mm, 60 F254). Visualization of the
developed chromatogram was performed by fluorescence quenching
using phosphomolybdic acid, anisaldehyde or potassium permanganate
stains. Melting points were determined on a Buchi® 530 hot stage
apparatus and are uncorrected. Mass spectra (ESI) were recorded on a
Finningan® Surveyor MSQ LC-MS spectrometer. HRMS spectra were
recorded on Thermo® Orbitrap Velos spectrometer. 1H-, 19F- and 13C-
NMR spectra were recorded on a Varian® Mercury (200 MHz, 188 MHz
and 50 MHz respectively), and are internally referenced to residual
Scheme 5. Mechanistic experiments with radical traps.
We tested the capability for recycling Pd/C in DMF, in the
reaction of the conversion of 1a to 2a. To our delight, the
catalyst completed five catalytic circles provided around 70%
yield of the desired product 2a in every circle, before it was
deactivated in the sixth catalytic circle furnishing only 26% yield
of the product 2a. All these results proved to be very
encouraging and significant, not only by giving us the ability to
recover and reuse the catalyst, but also by providing sustainable
properties to our methodology.
In order to further understand the reaction mechanism and
exclude any radical pathways, experiments with radical traps
were performed and the results showed that no radical
mechanism is occurring (Scheme 5).
Based on the above results, a plausible reaction mechanism is
suggested in Scheme 6. Firstly, Pd/C undergoes an oxidative
addition in the X-H bond of the substrate. In the second step, the
double bond is coordinating and then inserting onto Pd, leading
to intermediate III, which upon β-hydride elimination provides
intermediate V. Spontaneous isomerisation-aromatization of the
latter affords the desired product.[15f]
1
solvent signals. Data for H-NMR are reported as follows: chemical shift
(δ ppm), integration, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br s = broad signal), coupling constant and
assignment. Data for 19F-NMR are reported in terms of chemical shift (δ
ppm) and are internally referenced to trifluoroacetic acid. Data for 13C-
NMR are reported in terms of chemical shift (δ ppm). Mass spectra and
conversions of the reactions were recorded on a Shimadzu® GCMS-
QP2010 Plus Gas Chromatograph Mass Spectrometer utilizing a MEGA®
column (MEGA-5, F.T.: 0.25 μm, I.D.: 0.25 mm, L: 30m, Tmax: 350 oC,
Column ID# 11475).
General Procedure for the Synthesis of Substituted Protected Allyl-
anilines: In a round-bottom flask, substituted aniline (6.00 mmol) was
dissolved in DMF (7 mL). In this solution, K2CO3 (830 mg, 6.00 mmol)
and allylbromide (242 mg, 2.00 mmol) were added and the reaction
o
mixture was heated at 80 C for 18 h. The reaction mixture was filtered,
concentrated in vacuo and the crude product was purified by column
chromatography, eluting with petroleum ether:ethyl acetate (95:5).
In a pressure vessel, allyl-aniline (2.00 mmol) was dissolved in xylene
(2 mL) at 0 oC. BF3.Et2O (242 mg, 2.00 mmol) was added dropwise
under an argon atmosphere. The reaction mixture was stirred for 10
o
minutes at room temperature and then was heated at 180 C for 3h. The
reaction mixture was quenched with aq. NaOH 2N (10 mL). The aqueous
layer was extracted with diethyl ether (2 x 20 mL). The combined organic
layers were washed with brine (20 mL), dried over Na2SO4, filtered and
purified by column chromatography eluting with petroleum ether:ethyl
acetate (90:10).
In a round-bottom flask, ortho allyl-aniline (1.00 mmol) was dissolved in
dry CH2Cl2 (4 mL) at 0 oC. Pyridine (0.24 mL, 3.00 mmol) was added,
followed by the addition of sulfonyl chloride (1.20 mmol). The resulting
Scheme 6. Plausible reaction mechanism.
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suspension was stirred at room temperature for 18 h. The reaction
mixture was quenched with H2O (10 mL). The aqueous layer was
extracted with CH2Cl2 (2 x 10 mL). The combined organic layers were
washed with brine (20 mL), dried over Na2SO4, filtered and purified by
column chromatography eluting with petroleum ether:ethyl acetate
(70:30).
N-(2-Allyl-6-methoxyphenyl)methanesulfonamide (1h): White solid;
mp 87-90 oC; 190 mg, 79% yield; 1H NMR (CDCl3): δ 7.21 (1H, t, J = 8.0
Hz, ArH), 6.84 (2H, t, J = 8.0 Hz, ArH), 6.06 (1H, br s, NH), 6.01-5.79 (1H,
m, =CH), 5.15-4.99 (2H, m, =CH2), 3.85 (3H, s, OCH3), 3.58 (2H, d, J =
6.3 Hz, CH2), 3.15 (3H, s, CH3). 13C NMR (CDCl3) δ: 154.7, 141.2, 136.8,
128.7, 122.9, 122.9, 116.6, 109.1, 55.9, 40.3, 36.2. HRMS exact mass
calculated for [M-H]- (C11H15NO3S) requires m/z 240.0694, found m/z
240.0697.
N-(2-Αllylphenyl)methanesulfonamide (1a)[26]: Brown oil; 177 mg, 84%
yield; 1H NMR (CDCl3): δ 7.48 (1H, d, J = 7.3 Hz, ArH), 7.32-7.10 (3H, m,
ArH), 6.73 (1H, br s, NH), 5.95 (1H, ddt, J = 16.3, 10.2 and 6.1 Hz, =CH),
5.23- 4.98 (2H, m, =CH2), 3.44 (2H, dd, J = 6.1 and 1.4 Hz, CH2), 2.98
(3H, s, CH3).13C NMR (CDCl3): δ 135.6, 134.9, 130.8, 127.8, 126.1,
123.1, 123.0, 117.0, 39.8, 36.1. MS (ESI) 212 [M+H]+.
N-(2-allyl-4-chlorophenyl)methanesulfonamide (1i)[26]: White solid; mp
72-74 oC; 208 mg, 85% yield; 1H NMR (CDCl3): δ 7.40 (1H, d, J = 9.3 Hz,
ArH), 7.29-7.13 (2H, m, ArH), 6.75 (1H, br s, NH), 5.90 (1H, ddt, J = 16.3,
10.1 and 6.1 Hz, =CH), 5.21-4.99 (2H, m, =CH2), 3.40 (2H, d, J = 6.1 Hz,
CH2), 2.97 (3H, s, CH3). 13C NMR (CDCl3): δ 134.8, 134.2, 133.3, 131.6,
130.5, 127.7, 124.8, 117.6, 39.8, 35.6. MS (ESI) 268 [M+Na]+.
N-(2-Allylphenyl)-1,1,1-trifluoromethanesulfonamide (1b): Brown oil;
146 mg, 55% yield; 1H NMR (200 MHz, CDCl3): δ 7.17-6.96 (2H, m, ArH),
6.83-6.61 (2H,m,ArH), 6.19-5.72 (1H, m, =CH), 5.28-4.92 (2H, m, =CH2),
3.68 (1H, br s, NH), 3.31(2H, d, J = 6.2 Hz, CH2). 13C NMR (75 MHz,
CDCl3): δ 144.8, 135.9, 130.1, 127.5, 123.9 (q, J = 272.3 Hz), 118.8,
117.9, 116.1, 115.8, 36.5.19F NMR (188 MHz, CDCl3): δ -31.4. HRMS
exact mass calculated for [M-H]- (C10H10F3NO2S) requires m/z 264.0305,
found m/z 264.0308.
N-(2-Allyl-4-methoxyphenyl)methanesulfonamide (1j)[26]: White solid;
mp 85-87 oC; 190 mg, 79% yield; 1H NMR (CDCl3): δ 7.34 (1H, d, J = 9.5
Hz, ArH), 6.81-6.73 (2H, m, ArH), 6.39 (1H, br s, NH), 5.93 (1H, ddt, J =
17.9, 10.2 and 6.1 Hz, =CH), 5.19-4.98 (2H, m, =CH2), 3.78 (3H, s,
OCH3), 3.73 (2H, d, J = 6.1 Hz, CH2), 2.96 (3H, s, CH3). 13C NMR
(CDCl3): δ 158.3, 136.4, 135.6, 127.3, 126.9, 116.9, 115.9, 112.4, 55.3,
39.5, 36.1. MS (ESI) 242 [M+H]+.
N-(2-Allylphenyl)-4-methylbenzenesulfonamide (1c)[28]: White solid;
mp 68-70 oC; 258 mg, 90% yield; 1H NMR (CDCl3):δ 7.61 (2H, d, J = 8.2
Hz, ArH), 7.40-7.32 (1H, m, ArH), 7.25-7.04 (5H, m, ArH), 6.93 (1H, br s,
NH), 5.75 (1H, ddt, J = 16.5, 10.1 and 6.1 Hz, =CH), 5.10-4.85 (2H, m,
=CH2), 3.07 (2H, d, J = 6.1 Hz, CH2), 2.35 (3H, s, CH3). 13C NMR
(CDCl3): δ 143.6, 136.4, 135.5, 134.5, 132.5, 130.2, 129.4, 127.3, 126.9,
126.1, 124.5, 116.6, 35.6, 21.3. MS (ESI) 288 [M+H]+.
N-(2-Allyl-6-ethylphenyl)methanesulfonamide (1k)[26]
: Colorless oil;
194 mg, 81% yield; 1H NMR (CDCl3): δ 7.28-7.07 (3H, m, ArH), 6.28 (1H,
br s, NH), 5.94 (1H, ddt, J = 16.6, 10.2 and 6.3 Hz, =CH), 5.17-5.01 (2H,
m, =CH2), 3.58 (2H, d, J = 6.3 Hz, CH2), 3.10 (3H, s, CH3), 2.82 2.63 (2H,
q, J = 7.6 Hz, CH2), 1.24 (3H, t, J = 7.6 Hz, CH3). 13C NMR (CDCl3): δ
143.2, 138.6, 136.4, 132.0, 128.3, 128.1, 127.4, 116.6, 41.7, 36.8, 24.7,
14.6. MS (ESI) 240 [M+H]+.
N-(2-Allylphenyl)-1-phenylmethanesulfonamide (1d)[26]: White solid;
mp 55-58 oC; 215 mg, 75% yield; 1H NMR (CDCl3):δ 7.56-7.07 (9H, m,
ArH), 6.42 (1H, br s, NH), 5.78 (1H, ddt, J = 16.3, 10.1 and 6.1 Hz, =CH),
5.09-4.83 (2H, m, =CH2), 4.37 (2H, s, SCH2), 3.14 (2H, d, J = 6.1 Hz,
CH2).13C NMR (CDCl3): δ 135.4, 135.1, 131.3, 130.7, 130.6, 128.7, 128.6,
128.4, 127.8, 125.1, 120.4, 117.2, 57.7, 36.2. MS (ESI) 288 [M+H]+.
General Procedure for the Synthesis of Allyl-Phenols: Substituted
phenol (20.00 mmol) was dissolved in acetone (40 mL) at room
temperature, followed by addition of potassium carbonate (3.45 g, 25.00
mmol), potassium iodide (322 mg, 2.00 mmol) and allyl bromide (3.03 g,
25.00 mmol). The reaction mixture was stirred at 60 °C for 18 h. The
solvent was removed in vacuo. The crude residue was diluted with aq.
NaOH 1N (30 mL) and extracted with ethyl acetate (3 x 40 mL). The
combined organic layers were washed with brine (30 mL), dried (Na2SO4),
and the solvent was removed in vacuo. The crude mixture was used in
the next step.
N-(2-Allylphenyl)benzenesulfonamide (1e)[26]: Brown oil; 240 mg, 88%
yield; 1H NMR (CDCl3): δ 7.72 (2H, dd, J = 7.1 and 1.5 Hz, ArH), 7.56-
7.31 (4H, m, ArH), 7.21-7.00 (3H, m, ArH), 6.96 (1H, br s, NH), 5.73 (1H,
ddt, J = 18.4, 10.2 and 6.1 Hz, =CH), 5.08-4.83 (2H, m, =CH2), 3.03 (2H,
d, J = 6.1 Hz, CH2).13C NMR (CDCl3): δ 139.3, 135.4, 134.4, 132.8, 132.7,
130.2, 128.8, 127.3, 126.8, 126.3, 124.7, 116.7, 35.5. MS (ESI) 274
[M+H]+.
The crude ether was dissolved in nitrobenzene (0.5 mL/mmol) and the
reaction mixture was stirred at 210 oC for 2-18 h, depending on the
substrate. The mixture was dissolved in diethylether (10 mL) and
extracted with aq. KOH 20% w/v (4 x 20 mL). The combined aqueous
layers were acidified with HCl (50% w/v) (until pH=1) and extracted with
chloroform (3 x 20 mL). The combined organic layers were dried over
Na2SO4, filtered and concentrated in vacuo. The allyl-phenol was used
without further purification.
N-(2-Allylphenyl)-1-((1R,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-
1- yl)methanesulfonamide (1f)[26]: Colorless oil; 243 mg, 70% yield; 1H
NMR (CDCl3): δ 7.46-7.29 (2H, m, ArH), 7.24-7.05 (2H, m, ArH), 5.92
(1H, ddt, J = 16.5, 10.2 and 6.2 Hz, =CH), 5.13-4.95 (2H, m, =CH2), 3.58-
3.41 (3H, m, PhCH2 and SCHH), 2.95 (1H, d, J = 15.0 Hz, SCHH), 2.45-
1.81 (7H, m, 3 x CH2 and CH), 0.98 (3H, s, CH3), 0.84 (3H, s, CH3). 13C
NMR (CDCl3):δ 216.1, 135.8, 135.0, 132.9, 130.4, 127.2, 125.7, 123.2,
2-Allyl-4-nitrophenol (1l)[25]: Pale yellow solid; mp 77-78 oC; 139 mg,
78% yield; 1H NMR (CDCl3): δ 8.08-7.96 (2H, m, ArH), 7.02 (1H, br s,
OH), 6.92 (1H, d, J = 9.2 Hz, Ar), 5.99 (1H, ddt, J = 17.0, 10.7 and 6.5 Hz,
=CH), 5.22-5.10 (2H, m, =CH2), 3.45 (2H, d, J = 6.5 Hz, CH2). 13C NMR
(CDCl3): δ. 160.3, 141.0, 134.6, 127.1, 126.2, 124.2, 117.5, 115.5, 34.1.
MS (ESI) 180 [M+H]+.
116.4, 59.0, 49.8, 48.3, 42.5, 42.4, 35.6, 26.7, 26.3, 19.6, 19.3. [α]23
=
D
+39.5 (c 1, CHCl3); MS (ESI) 348 [M+H]+.
N-(2-Allyl-4-methylphenyl)methanesulfonamide (1g)[26]: White solid;
mp 45-47 oC; 164 mg, 73% yield; 1H NMR (CDCl3): δ 7.35 (1H, d, J = 8.0
Hz, ArH), 7.09-7.01 (2H, m, ArH), 6.50 (1H, br s, NH), 5.94 (1H, ddt, J =
16.4, 10.2 and 6.0 Hz, =CH), 5.20-4.99 (2H, m, =CH2), 3.41 (2H, d, J =
6.1 Hz, CH2), 2.97 (3H, s, CH3), 2.31 (3H, s, CH3). 13C NMR (CDCl3): δ
136.3, 135.8, 132.3, 132.1, 131.4, 128.4, 123.9, 116.8, 39.6, 36.2, 20.8.
MS (ESI) 226 [M+H]+.
1-Allylnaphthalen-2-ol (1m)[29]: Yellow solid; mp 55-56 oC; 133 mg, 72%
yield; 1H NMR (400 MHz, CDCl3):δ 7.95 (1H, d, J = 8.6 Hz, ArH), 7.82
(1H, d, J = 8.1 Hz, ArH), 7.71 (1H, d, J = 8.8 Hz, ArH), 7.52 (1H, t, J = 7.7
Hz, ArH), 7.38 (1H, t, J = 7.5 Hz, ArH), 7.13 (1H, d, J = 8.8 Hz, ArH),
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10.1002/ejoc.201900577
European Journal of Organic Chemistry
FULL PAPER
6.21–5.99 (1H, m, =CH), 5.21 (1H, s, OH), 5.19–5.04 (2H, m, =CH2),
3.87 (2H, d, J = 5.7 Hz, CH2). 13C NMR (100 MHz, CDCl3): δ 151.2,
135.8, 133.2, 129.5, 128.6, 128.4, 126.5, 123.2, 123.0, 118.0, 116.8,
116.0, 29.3. MS (ESI) 185 [M+H]+.
ArH), 4.47 (2H, s, PhCH2), 1.95 (3H, s, CH3). 13C NMR (50 MHz, CDCl3):
δ 139.2, 136.5, 133.5, 130.7, 129.3, 128.6, 126.8, 123.7, 120.1, 115.6,
113.7, 107.7, 59.4, 14.8. HRMS exact mass calculated for [M+H]+
(C16H15NO2S) requires m/z 286.0901, found m/z 286.0905.
3-(Bis(3-allyl-4-hydroxyphenyl)methyl)isobenzofuran-1(3H)-one
(1n)[25]: Pale yellow solid; mp 145-147 oC; 203 mg, 51% yield; 1H NMR
(CDCl3): δ 7.93-7.89 (1H, m, ArH), 7.72-7.64 (1H, m, ArH), 7.54-7.47 (2H,
m, ArH), 7.04-6.93 (4H, m, ArH), 6.80- 6.75 (2H, m, ArH), 6.53 (2H, s, 2 x
OH), 6.00-5.80 (2H, m, 2 x =CH), 5.07-4.97 (4H, m, 2 x =CH2), 3.32 (4H,
d, J = 6.2 Hz, 2 x CH2). 13C NMR (CDCl3): δ 171.6, 154.3, 152.8, 135.9,
134.5, 132.2, 129.1, 126.5, 125.8, 124.8, 123.9, 116.2, 115.4, 92.9, 34.7.
MS (ESI) 399 [M+H]+.
2-Methyl-1-(phenylsulfonyl)-1H-indole (2e)[33]: Yellow oil; 37 mg, 45%
yield; 1H NMR (200 MHz, CDCl3): δ 8.24-8.10 (1H, m, ArH), 7.84-7.68
(2H, m, ArH), 7.61-7.14 (6H, m, ArH), 6.35 (1H, s, ArH), 2.60 (3H, s,
CH3).13C NMR (50 MHz, CDCl3):δ 139.2, 137.3, 137.0, 133.6, 129.6,
129.2, 126.2, 123.8, 123.5, 120.0, 114.4, 109.7, 15.8. MS (ESI) 272
[M+H]+.
(1R,4R)-7,7-Dimethyl-1-(((2-methyl-1H-indol-1-
yl)sulfonyl)methyl)bicycle[2.2.1]heptan-2-one (2f): Yellow oil; 62 mg,
60% yield; 1H NMR (200 MHz, CDCl3): δ 8.15-7.96 (1H, m, ArH), 7.60-
7.40 (1H, m, ArH), 7.34-7.19 (2H, m, ArH), 6.42 (1H, s, ArH), 3.49 (1H, d,
J = 14.6 Hz, SCHH), 2.98 (1H, d, J = 14.6 Hz, SCHH), 2.63 (3H, s, CH3),
2.55-1.30 (7H, m, 3 x CH2 and CH), 1.17 (3H, s, CH3), 0.83 (3H, s, CH3).
13C NMR (50 MHz, CDCl3): δ 214.0, 137.4, 136.6, 129.5, 123.8, 123.4,
120.1, 113.8, 109.0, 58.4, 50.3, 47.9, 42.8, 42.4, 26.8, 25.2, 19.9, 19.7,
Methyl-(S)-3-(3-allyl-4-hydroxyphenyl)-2-
(((benzyloxy)carbonyl)amino)propanoate (1o)[25]: White solid; mp 78-
80 oC; 214 mg, 58% yield; 1H NMR (CDCl3): δ 7.32-7.25 (5H, m, ArH),
6.83-6.64 (3H, m, ArH), 6.07-5.87 (1H, m, =CH), 5.49 (1H, br s, NH),
5.10-5.03 (4H, m, =CH2 and OCH2), 4.64 (1H, dd, J = 5.8 and 5.1 Hz,
NCH), 3.70 (3H, s, OCH3), 3.65 (1H, s, OH), 3.34 (2H, d, J = 6.3 Hz,
CH2), 3.05 (1H, dd, J = 14.3 and 5.8 Hz, PhCHH), 2.98 (1H, dd, J = 14.3
and 5.1 Hz, PhCHH). 13C NMR (CDCl3): δ 172.2, 155.8, 153.2, 136.4,
135.8, 130.7, 128.3, 128.0, 127.8, 126.7, 126.0, 115.7, 115.3, 66.9, 54.8,
52.2, 37.1, 34.0;.[α]23D = +52.1 (c 0.33, CHCl3); MS (ESI) 370 [M+H]+.
15.7. [α]23 = +31.0 (c 1, CHCl3); HRMS exact mass calculated for
D
[M+H]+ (C19H23NO3S) requires m/z 346.1477, found m/z 346.1482.
2,5-Dimethyl-1-(methylsulfonyl)-1H-indole (2g): Yellow oil; 34 mg,
50% yield; 1H NMR (200 MHz, CDCl3): δ 7.84 (1H, d, J = 8.5 Hz, ArH),
7.30-7.22 (1H, m, ArH), 7.08 (1H, d, J = 8.5 Hz, ArH), 6.35 (1H, s, ArH),
3.00 (3H, s, SCH3), 2.56 (3H, s, CH3), 2.42 (3H, s, CH3). 13C NMR (50
MHz, CDCl3): δ 137.4, 134.8, 133.2, 129.9, 125.2, 120.1, 113.6, 109.3,
40.4, 21.2, 15.6. HRMS exact mass calculated for [M+H]+ (C11H13NO2S)
requires m/z 224.0745, found m/z 224.0750.
3-Allyl-(1,1’-biphenyl)-4-ol (1p)[25]: Colorless solid; mp 74-76 oC; 134
1
mg, 64%; H NMR (CDCl3): δ 7.69-7.36 (6H, m, ArH), 7.02-6.96 (2H, m,
ArH), 6.28-6.08 (1H, m, =CH), 5.58 (1H, s, OH), 5.37-5.28 (2H, m, =CH2),
3.59 (2H, d, J = 6.3 Hz, CH2). 13C NMR (CDCl3): δ 153.3, 140.6, 136.1,
133.9, 129.0, 128.6, 126.6, 126.5, 126.3, 125.6, 116.6, 116.0, 35.0. MS
(ESI) 211 [M+H]+
7-Methoxy-2-methyl-1-(methylsulfonyl)-1H-indole (2h): Yellow oil; 43
mg, 60% yield; 1H NMR (200 MHz, CDCl3): δ 7.56-6.97 (2H, m, ArH),
6.90-6.77 (1H, m, ArH), 6.29 (1H, s, ArH), 3.99 (3H, s, OCH3), 3.59 (3H,
s, SCH3), 2.57 (3H, s, CH3). 13C NMR (50 MHz, CDCl3): δ 147.0, 139.9,
132.2, 126.5, 124.2, 113.2, 108.8, 107.6, 56.5, 44.1, 16.6. HRMS exact
mass calculated for [M+H]+ (C11H13NO3S) requires m/z 240.0694, found
m/z 240.0699.
General Procedure for the Synthesis of Benzofurans and Indole
Derivatives: N-protected allyl-aniline or allyl-phenol (0.30 mmol) was
dissolved in dimethylformamide (3 mL), followed by addition of Pd/C
(10%) (50 mg) and the resulting residue was stirred at 100 oC for 18 h.
The crude reaction mixture was filtered through Celite and purified by
column chromatography, eluting with petroleum ether:ethyl acetate
(80:20).
5-Chloro-2-methyl-1-(methylsulfonyl)-1H-indole (2i): Yellow oil; 44 mg,
60% yield; 1H NMR (200 MHz, CDCl3): δ 7.97-7.81 (1H, m, ArH), 7.45-
7.41 (1H, m, ArH), 7.28-7.16 (1H, m, ArH), 6.36 (1H, s, ArH), 3.03 (3H, s,
SCH3), 2.57 (3H, s, CH3). 13C NMR (50 MHz, CDCl3): δ 138.8, 134.8,
130.8, 129.3, 123.9, 119.7, 114.8, 108.6, 40.9, 15.6. HRMS exact mass
calculated for [M+H]+ (C10H10ClNO2S) requires m/z 244.0199, found m/z
244.0124.
2-Methyl-1-(methylsulfonyl)-1H-indole (2a)[30]: Yellow oil; 45 mg, 72%
yield; 1H NMR (200 MHz, CDCl3): δ 8.05- 7.90 (1H, m, ArH), 7.52-7.42
(1H, m, ArH), 7.31-7.17 (2H, m, ArH), 6.41 (1H, s, ArH), 3.02 (3H, s,
SCH3), 2.58 (3H, s, CH3). 13C NMR (50 MHz, CDCl3): δ137.3, 136.5,
129.6, 123.8, 123.6, 120.1, 113.8, 109.3, 40.7, 15.6. MS (ESI) 209
[M+H]+.
2-Methyl-1H-indole (2b)[31]: White solid; mp 58-59°C; 16.5 mg, 42%
yield; 1H NMR (200 MHz, CDCl3): δ 7.72 (1H, br s, NH), 7.53-7.01 (4H, m,
ArH), 6.21 (1H, s, ArH), 2.45 (3H, s, CH3). 13C NMR (50 MHz, CDCl3): δ
136.1, 135.1, 129.1, 120.9, 119.7, 110.3, 100.4, 13.7. MS (ESI) 132
[M+H]+.
5-Methoxy-2-methyl-1-(methylsulfonyl)-1H-indole (2j): Yellow oil; 39
mg, 55% yield; 1H NMR (200 MHz, CDCl3): δ 7.91-7.73 (1H, m, ArH),
7.03-6.75 (2H, m, ArH), 6.35 (1H, s, ArH), 3.83 (3H, s, OCH3), 2.98 (3H,
s, SCH3), 2.55 (3H, s, CH3). 13C NMR (50 MHz, CDCl3): δ 156.5, 138.0,
131.1, 130.6, 114.7, 112.3, 109.5, 102.9, 55.6, 40.3, 15.6. HRMS exact
mass calculated for [M+H]+ (C11H13NO3S) requires m/z 240.0694, found
m/z 240.0701.
2-Methyl-1-tosyl-1H-indole (2c)[32]: White solid; mp 63-65 °C; 43 mg,
50% yield; 1H NMR (200 MHz, CDCl3): δ 8.22-8.07 (1H, m ArH), 7.76-
7.57 (2H, m, ArH), 7.46-7.34 (1H, m ArH), 7.28-7.10 (4H, m, ArH), 6.32
(1H, s, ArH), 2.99 (3H, s, SCH3), 2.32 (3H, s, CH3). 13C NMR (50 MHz,
CDCl3): δ 144.7, 137.3, 136.3, 129.8, 129.0, 127.2, 126.3, 123.7, 123.3,
120.0, 114.4, 109.5, 21.5, 15.7. MS (ESI) 286 [M+H]+.
7-Ethyl-2-methyl-1-(methylsulfonyl)-1H-indole (2k): Yellow oil; 48 mg,
68% yield; 1H NMR (200 MHz, CDCl3): δ 7.40-7.06 (3H, m, ArH), 6.50
(1H, s, ArH), 3.13 (2H, q, J = 7.3 Hz, CH2), 2.70 (3H, s, SCH3), 2.55 (3H,
s, CH3), 1.29 (3H, t, J = 7.3 Hz, CH3). 13C NMR (50 MHz, CDCl3): δ 141.1,
138.1, 134.8, 133.4, 126.3, 125.3, 117.8, 114.8, 37.6, 26.9, 16.8, 15.0.
HRMS exact mass calculated for [M+H]+ (C12H15NO2S) requires m/z
238.0901, found m/z 238.0908.
1-(Benzylsulfonyl)-2-methyl-1H-indole (2d): Yellow oil; ; 39 mg, 45%
yield; 1H NMR (200 MHz, CDCl3): δ 8.00-7.84 (1H, m, ArH), 7.54-7.39
(1H, m, ArH), 7.38-7.12 (5H, m, ArH), 6.94-6.73 (2H, m, ArH), 6.19 (1H, s,
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10.1002/ejoc.201900577
European Journal of Organic Chemistry
FULL PAPER
2-Methyl-5-nitrobenzofuran (2l)[34]: White solid; mp 75-83 oC; 21 mg,
40% yield; 1H NMR (200 MHz, CDCl3): δ 8.39 (1H, s, ArH), 8.22-8.06 (1H,
m, ArH), 7.45 (1H, d, J = 9.1 Hz, ArH), 6.51 (1H, s, ArH), 2.50 (3H, s,
CH3). 13C NMR (50 MHz, CDCl3): δ 159.1, 157.6, 144.3, 129.5, 119.2,
116.5, 110.8, 103.5, 14.2; MS (ESI) 178 [M+H]+.
[4]
L. B. Diss, S. D. Robinson, Y. Wu, S. Fidalgo, M. S. Yeoman, B. A.
Patel, ACS Chem. Neurosci. 2013, 4, 879-887.
[5]
[6]
S. N. Young, J. Phys. Neurosci. 2007, 32, 394-399.
M. G. Kokotou, P.-K. Revelou, C. Pappas, V. Constantinou-Kokotou,
Food Chem. 2017, 237, 566-573.
[7]
[8]
W. G. W. Kurz, K. B. Chatson, F. Constabel, J. P. Kutney, L. S. L. Choi,
P. Kolodziejczyk, S. K. Sleigh, K. L. Stuart, B. R. Worth, Planta Med.
1981, 42, 22-31.
2-Methylnaphtho[2,1-b]furan (2m)[35]: Pale yellow oil; 33 mg, 60% yield;
1H NMR (200 MHz, CDCl3): δ 8.31-7.83 (2H, m, ArH), 7.79-7.34 (4H, m,
ArH), 6.87 (1H, s, ArH), 2.56 (3H, s, CH3). 13C NMR (50 MHz, CDCl3): δ
154.6, 151.9, 131.0, 130.2, 128.6, 127.4, 125.9, 124.1, 123.7, 123.4,
112.0, 101.7, 14.2; MS (ESI) 183 [M+H]+.
a) R. J. Syndberg in Comprehensive Heterocycle Chemistry (Eds.: A. R.
Katrizky, C. W. Rees), Pergamon, Oxford, 1984, vol. 4, pp. 313-376; b)
R. D. Taylor, M. MacCoss, A. D. G. Lawson, J. Med. Chem. 2014, 57,
5845-5859; c) A. Radadiya, A. Shah, Eur. J. Med. Chem. 2015, 97,
356-376; d) R. J. Nevagi, S. N. Dighe, S. N. Dighe, Eur. J. Med. Chem.
2015, 97, 561-581; e) M.-Z. Zhang, Q. Chen, G.-F. Yang, Eur. J. Med.
Chem. 2015, 89, 421-441; f) H. Khanam, Shamsuzzaman, Eur. J. Med.
Chem. 2015, 97, 483-504.
3-(Bis(2-methylbenzofuran-5-yl)methyl)isobenzofuran-1(3H)-one
(2n): Yellow oil; 59 mg, 50% yield; 1H NMR (200 MHz, CDCl3) :δ 7.94
(1H, dt, J = 7.5 and 1.1 Hz, ArH), 7.77-7.00 (9H, m, ArH), 6.29 (2H, s,
ArH), 2.42 (6H, s, 2 x CH3). 13C NMR (50 MHz, CDCl3): δ 169.9, 156.6,
154.4, 152.8, 135.7, 134.0, 129.1, 129.0, 125.9, 125.5, 124.3, 122.7,
122.5, 118.9, 110.5, 102.7, 92.6, 14.1. HRMS exact mass calculated for
[M+H]+ (C26H18O4) requires m/z 395.1283, found m/z 395.1288.
[9]
a) M. Inman, C. J. Moody, Chem. Sci. 2013, 4, 29; b) A. A. Abu-
Hashem, H. A. R. Hussein, A. S. Aly, M. A. Gouda, Synth. Commun.
2014, 44, 2285-2312.
[10] a) For a review, see: G. Chelucci, Coord. Chem. Rev. 2017, 331, 37-
53; b) For a selected example, see: T. Guo, F. Huang, L. Yu, Z. Yu,
Tetrahedron Lett. 2015, 56, 296-302.
Methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-(2-methylbenzofuran-5-
yl)propanoate (2o): White oil; 63 mg, 57% yield; 1H NMR (200 MHz,
CDCl3): δ 7.56-6.83 (8H, m, ArH), 6.29 (1H, s, ArH), 5.34-5.14 (1H, m,
NH), 5.09 (2H, s, OCH2), 4.95-4.43 (1H, m, NCH), 3.71 (3H, s, OCH3),
3.19-3.15 (2H, m, CH2), 2.44 (3H, s, CH3). 13C NMR (50 MHz, CDCl3): δ
172.1, 155.9, 155.6, 153.9, 136.2, 129.6, 128.5, 128.1, 128.0, 124.2,
[11] For a selected example, see: J. Ghorai, A. C. S. Reddy, P. Anbarasan,
Chem. Eur. J. 2016, 22, 16042-16046.
[12] a) For a review, see: S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Biomol.
Chem. 2011, 9,641-652; b) For a selected example, see: K. Hiroya, S.
Itoh, T. Sakamoto, Tetrahedron 2005, 61, 10958-10964.
120.6, 110.6, 102.4, 66.9, 55.1, 52.3, 38.1, 14.1. [α]23 = +0.055 (c 1,
D
[13] a) For a review, see: S. R. Chemler, P. H. Fuller, Chem. Soc. Rev.
2007, 36, 1153-1160; b) For a recent example, see: T. W. Liwosz,
S. R. Chemler, Synlett 2015, 26, 335-339.
CHCl3); HRMS exact mass calculated for [M+H]+ (C21H21NO5) requires
m/z 368.1498, found m/z 368.1502.
[14] a) C. Praveen, K. Karthikeyan, P. T. Perumal, Tetrahedron 2009, 65,
9244-9255; b) A. Gimeno, M. Medio-Simon, C. Ramirez de Arellano, G.
Asensio, A. B. Cuenca, Org. Lett. 2010, 12, 1900-1903; c) G. Abbiati, F.
Marinelli, E. Rossi, A. Arcadi, Isr. J. Chem. 2013, 53, 856-868; d) T.
Wang, S. Shi, D. Pflästerer, E. Rettenmeier, M. Rudolph, F. Rominger,
A. S. K. Hashmi, Chem. Eur. J. 2014, 20, 292-296; e) M. Michalska, K.
Grela, Synlett 2016, 27, 599-603.
2-Methyl-5-phenylbenzofuran (2p)[36]: White solid; mp 85-88 oC; 25 mg,
40% yield; 1H NMR (200 MHz, CDCl3): δ 8.27-7.02 (8H, m, ArH), 6.42
(1H, s, ArH), 2.48 (3H, s, CH3). 13C NMR (50 MHz, CDCl3): δ 156.1,
154.3, 141.8, 136.1, 129.7, 128.7, 127.4, 126.7, 122.7, 118.6, 110.7,
102.8, 14.2; MS (ESI) 209 [M+H]+.
[15] For selected examples, see: a) L. S.Hegedus, G. F. Allen, E. L.
Waterman, J. Am. Chem. Soc. 1976, 98, 2674-2676; b) S. J. Tremont,
H. U. Rahman, J. Am. Chem. Soc. 1984, 106, 5759-5760; c) E. C.
Taylor, A. H. Katz, H. Salgado-Zamora, A. McKillop, Tetrahedron Lett.
1985, 26, 5963-5966; d) D. E. Rudisill, J. K. Stille, J. Org. Chem. 1989,
54, 5856-5866; e) A. I. Roshchin. N. A. Bumagin, Chem. Heterocycl.
Compd. 1999,35, 171-175; f) S. Cacchi, G. Fabrizi, Chem. Rev. 2011,
111, PR215-PR283; g) F. Zhao, D. Zhang, Y. Nian, L. Zhang, W. Yang,
H. Liu, Org. Lett. 2014, 16, 5124-5127; h) R. Nallagonda, M. Rehan, P.
Ghorai, Org. Lett. 2014, 16, 4786-4789; i) S. W. Yoon, S. R Lee, Org.
Biomol. Chem. 2015, 13, 4652-4656; j) Y. Morimoto, S. Shimizu, A.
Mokuya, N. Ototake, A. Saito, O. Kitagawa, Tetrahedron 2016, 72,
5221-5229; k) L. Chen, X. Luo, Y. Li, Monantsch. Chem. 2017, 148,
957-961.
Acknowledgements
The authors would like to thank the Special Account for
Research (ELKE) and the Laboratory of Organic Chemistry of
the Department of Chemistry of the National and Kapodistrian
University of Athens for financial support. Also, the authors
would like to thank Dr. Maroula Kokotou for her assistance in
acquiring HRMS data and COST Action C-H Activation in
Organic Synthesis (CHAOS) CA15106 is acknowledged for
helpful discussions.
Keywords: Benzofurans • Heterocycles • Heterogeneous
catalysis • Indoles • Pd/C
[16] For a selected example, see: S. Maity, N. Zheng, Angew. Chem. Int. Ed.
2012, 51, 9562-9566.
[17] For a selected example, see: A. Fürstner, P. W. Davies, J. Am. Chem.
Soc. 2005, 127, 15024-15025.
[1]
a) G. R. Humphrey, J. T. Kuethe, Chem. Rev. 2006, 106, 2875-
2911; b) A. Padwa, S. K. Bur, Tetrahedron 2007, 63, 5341-5378; c)
D. M. D’Souza, T. J. Muller, Chem. Soc. Rev. 2007, 36, 1095-1108;
d) V. Polshettiwar, R. S. Varma, Curr. Opin. Drug. Discov. 2007, 10,
723-737.
[18] For selected examples, see: a) N. Sakai, K. Annaka, T. Konakahara,
Tetrahedron Lett.2006, 47, 631-634; b) N. Sakai, K. Annaka, A. Fujita,
A. Sato, T. Konakahara, J. Org. Chem. 2008, 73, 4160-4165.
[19] N. T. S. Phan, M. Van Der Sluys, C. W. Jones, Adv. Synth. Catal.
2006, 348, 609-679.
[2]
[3]
C. Won, X. Shen, K. Mashiguchi, Z. Zheng, X. Dai, Y. Cheng, H.
Kasahara, Y. Kamiya, J. Chory, Y. Zhao, Proc. Natl. Acad. Sci. USA,
2011, 108, 18518-18523.
[20] J. Tsuji in Organic Synthesis with Palladium Compounds 1st Ed.
(Ed.: J. Tsuji), Springer Verlag, Berlin Heidelberg, 1980, pp. 1-201.
[21] a) M. Seki, Synthesis 2006, 18, 2975-2992; b) F.-X. Felpin, T. Ayad, S.
Mitra, Eur. J. Org. Chem. 2006, 2679-2690; c) J. Chen, K. Natte, X.-F.
Wu, Tetrahedron Lett. 2015, 56, 6413-6416; d) N. Panda, I. Mattan, D.
H. Ebiike, M. Masubuchi, P. Liu, K. Kawasaki, K. Morikami, S. Sogabe,
M. Hayashe, T. Fujii, K. Sakata, H. Shindoh, Y. Shiratori, Y. Aoki, T.
Ohtsuka, N. Shimma, Bioorg. Med. Chem. Lett. 2002, 12, 607-610.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900577
European Journal of Organic Chemistry
FULL PAPER
K. Nayak, J. Org. Chem. 2015, 80, 6590–6597;e) X. Liu, D. Astruc, Adv.
Synth.Catal. 2018, 360, 3426-3459.
[25] I. Triantafillidi, I. K. Sideri, D. I. Tzaras, N. Spiliopoulou, C. G. Kokotos,
Synthesis 2017, 49, 4254-4260.
[22] a) M. Pal, V. Subramanian, V. R. Batchu, I. Dager, Synlett 2004, 11,
1965-1969; b) N. Batail, A. Bendjeriou, T. Lomberget, R. Barret, V.
Dufaud, L. Djakovitch, Adv. Synth. Catal. 2009, 351, 2055-2062; c) Y.
Monguchi, S. Mori, S. Aoyagi, A. Tsutsui, T. Maegawa, H. Sajiki, Org.
Biomol. Chem. 2010, 8, 3338-3342; d) Y. Monguchi, T. Marumoto, H.
Takamatsu, Y. Sawama, H. Sajiki, Adv. Synth. Catal. 2014, 356, 1866-
1872; e) Y. Shimomoto, R. Matsubara, M. Hayashi, Adv. Synth.
Catal. 2018, 360, 3297-3305; f) S. Mao, X. Shi, J-F. Soule, H.
Doucet, Adv. Synth. Catal. 2018, 360, 3306-3317.
[26] A. Theodorou, C. G. Kokotos, Adv. Synth. Catal. 2017, 359, 1577-1581.
[27] X.-S. Ning, X.Liang,K.-F.Hu, C.-Z.Yao,J.-P.Qu,Y.-B. Kang, Adv. Synth.
Catal. 2018, 360, 1590-1594.
[28]
L. Wu, Y. Meng, J. Ferguson, L. Wang, F. Zeng, J. Org. Chem. 2017,
82, 4121-4128.
[29] P. Kaswan, G. M. Shelke, V. K. Rao, A. Kumar, Synlett 2016, 27, 2553-
2556.
[30] J. K. Laha, R. A. Bhimpuria, D. V. Prajapati, N. Dayal, S. Sharma, Chem.
Commun. 2016, 52, 4329-4332.
[23] All prices are from commercial vendors in January 2019.
[24] a) A. Theodorou, C. G. Kokotos, Green Chem. 2017, 19, 670-674; b) E.
Voutyritsa, A. Theodorou, M. G. Kokotou, C. G. Kokotos, Green Chem.
2017, 19, 1291-1298; c) N. Kaplaneris, A. Bisticha, G. N. Papadopoulos,
D. Limnios, C. G. Kokotos, Green Chem. 2017, 19, 4451-4456; d) G. N.
Papadopoulos, E. Voutyritsa, N. Kaplaneris, C. G. Kokotos, Chem.
Eur.J. 2018, 24, 1726-1731; e) I. Triantafillidi, D. I. Tzaras, C. G.
Kokotos, ChemCatChem 2018, 10, 2521-2535; f) I. K. Sideri, E.
Voutyritsa, C. G. Kokotos, Org. Biomol. Chem. 2018, 16, 4596-4614; g)
A. Theodorou, I. Triantafillidi, C. G. Kokotos, Adv. Synth.Catal. 2018,
360, 951-957.
[31] Y.-Q. Huang, H.-J. Song, Y.-X.Liu, Q.-M. Wang, Chem. Eur. J. 2018, 24,
2065-2069.
[32] S. Ortgies, A. Breder, Org. Lett. 2015, 17, 2748-2751.
[33] V. Saravanan, B. M. Ramalingam, A. Mohanakrishnan, Eur. J. Org.
Chem. 2014, 1266-1279.
[34] S. Agasti, U. Sharma, T. Naveen, D. Maiti, Chem. Commun. 2015, 51,
5375-5378.
[35] A. K. Mishra, S. Biswas, J. Org. Chem. 2016, 81, 2355-2363.
[36] U. Sharma, T. Naveen, A. Maji, S. Manna, D. Maiti, Angew. Chem. Int.
Ed. 2013, 52, 12669-12673.
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Entry for the Table of Contents
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Palladium on Carbon-catalyzed Synthesis of
Benzofuran and Indole Derivatives
Heterocycles Synthesis
Anatoli Savvidou, Dimitrios Ioannis
Tzaras, Alexis Theodorou, Giorgos S.
Koutoulogenis and Christoforos G.
Kokotos*
Page No. – Page No.
Palladium on Carbon-catalyzed
Synthesis of Benzofuran and Indole
Derivatives
A cheap, easy-to-execute and sustainable
synthetic methodology for the synthesis of
indoles and benzofurans was developed
utilizing Pd/C as the promoter. A great variety
of substituted ortho-allyl anilines or phenols
were utilized, leading to products in moderate
yields. Recycling of the catalyst up to five
times has been achieved.
This article is protected by copyright. All rights reserved.