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Synthesis of Indoles from Alkynes and a Nitrogen Source under Metal-

Free Conditions

Organic & Biomolecular Chemistry Accepted Manuscript

Jose S. S. Neto*,1 and Gilson Zeni*,2
Received (in XXX, XXX) Xth XXXXXXXXX 201X, Accepted Xth XXXXXXXXX 201X
Published on 11 June 2020. Downloaded by Western Sydney University on 6/14/2020 11:51:41 AM.

5 First published on the web Xth XXXXXXXXX 200X

DOI: 10.1039/b000000x

Abstract:

Indoles are an important nucleus of the N-heterocyles found in many natural products, active pharmaceuticals, and functional materials.
In addition, indoles have various reactive positions, each one with a different reactivity, which may be susceptible to different reactions.
10 This characteristic makes them important substrates for further transformations. The paper deals with the methodologies published in the
last ten years, which used metal-free conditions to prepare indoles starting from alkynes and nitrogen compounds.

.
source has dual role, by acting as a cyclizing agent and to
Introduction incorporate the electrophile, which is suitable to suffer further
55 transformations. The electrophilic cyclization has been
The necessity to develop most environmentally, cost-effective, demonstrated as an efficient tool in the syntheses of highly
15 green and mild methodologies for the preparation of N- functionalized indoles, employing electrophiles like I2, ICl, or
heterocycles is a global trend adopted by all laboratories in the organochalcogen derivatives. This process involves the
last decades.1 Many N-heterocycles that were previously activation of carbon-carbon triple bond of alkyne by the addition
prepared only by classical transition-metal catalyzed cyclization 60 of the electrophilic source, affording an intermediate I. The anti-
reactions can now be prepared using metal-free conditions, nucleophilic attack of the nitrogen atom on the activated
20 without losing the advantages that other methods offered.2 The intermediate gives the salt II. The removal of the group bonded
benefits to use a metal free-condition are the reduction of to nitrogen, via nucleophilic substitution by the nucleophile
chemical wastes generation, reaction time, solvent, and energy, present in the reaction mixture, generates the indole product
resulting in clear economic impacts and environmental benefits. 65 (Scheme 1).
From the synthetic point of view, the use of ionic liquids as
25 solvents and microwave-irradiated reactions were the main tools Scheme 1
used to achieve these benefits.3 There are many methodologies
R1 E
described in the scientific literature that use conditions that can + - +
E E
E E R1 - E-
led to efficient, cheaper and more sustainable reactions.4 Among + R1 R1
X X
them, base- or acid-catalyzed, radical, electrophilic cyclization X
I
X
II LG E-LG
LG LG
30 reactions and electrochemical processes have recently emerged as E
-

efficient promoters of cyclization reactions. In this review, we 3-Sulfenyl and 3-selenylindoles 1 were prepared by n-Bu4NI-
will report the methodologies published in the last ten years, induced electrophilic cyclization of N,N-dialkyl-2-(1-
which used metal-free conditions to prepare indoles starting from 70 alkynyl)anilines using arylsulfenyl or arylselenyl chlorides as
alkynes and nitrogen compounds. Indoles are an important electrophilic sources (Scheme 2).16-19 These reaction conditions
35 nucleus of the N-heterocyles found in many natural products, permitted the construction of the indole and the installation of a
active pharmaceuticals, and functional materials.5-13 In addition, sulfenyl or selenyl group in the 3-position of the indole ring. The
indoles have various reactive positions, each one with a different presence of n-Bu4NI was a critical factor to the success of the
reactivity, which may be susceptible to different reactions.14 This 75 cyclization, which acted either to remove the methyl group from
characteristic makes them important substrates for further nitrogen via nucleophilic substitution or to the in situ preparation
40 transformations.15 To facilitate presentation, the review is of arylchalcogenyl iodide, via halogen exchange reaction from
categorized based on the reaction type involved in the cyclization arylchalcogenyl chlorides.
of alkynes with nitrogen compounds. Thus, in the next sections,
we will cover the methodologies that involve electrophilic
Scheme 2
cyclization, base-promoted cyclization, radical-promoted,
45 cyclization, cyclization under microwave irradiation, oxidative YAr1
R2
nucleophilic cyclization, and electrochemical-mediated n-Bu4NI (1.0 equiv) 1
R R2
cyclization for the preparation of indoles. R1
Me
+ Ar1YCl
DCM, 70 oC N
N R3
R3
1, 42-99%
Synthesis of Indoles via Electrophilic Cyclization of Alkynes
R1 = C6H5, 4-MeO-C6H4, 2-MeO-C6H4, 4-NMe2-C6H4, 4-NC-C6H4, 3-thienyl; R2 = H, Me,
80 Br, CO2Me; R3 = Me, C6H5; Ar1 = C6H5, 4-Me-C6H4, 4-O2N-C6H4; Y = S, Se.
The electrophilic heteroatom cyclization, in particular
50 halocyclization reactions of alkynes, has emerged as powerful The iodocyclization of ortho-2,3-diyneanilines allowed the
methods to construct carbocycles and heterocycles. The main preparation, in a single step, of 2-alkynyl indoles 2 having an
advantages to use this methodology are that the electrophilic iodine functionality at the 2-position (Scheme 3).20, 21 The

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DOI: 10.1039/D0OB00670J

authors found that the effect of solvent polarity and the addition, was a useful way to the preparation of indoles 7 in a on
nucleophilicity of nitrogen group were parameters that influence pot procedure (Scheme 6).24, 25 This methodology was further
the yields of the indole derivatives. In addition, the 2-alkynyl 35 successful applied to the synthesis quinoline and quinolone
indoles 2 were used as starting material for the Sonogashira derivatives using the same starting material just by a simple
cross-coupling leading to the preparation of enediynes fused to modification in the reaction conditions. The authors proposed a

Organic & Biomolecular Chemistry Accepted Manuscript

5

indoles. It was also found that N-arylindoles 4 could be prepared very clear reaction mechanism, in which an iminium ion 6 could
by ortho-alkynylanilines and diphenyliodonium be one of the key intermediates for the second cyclization step.
hexafluorophosphate in t-BuOH under air at 60 0C.22 The authors 40 The same group successfully applied the iodocyclization of
carried out some control experiments, which indicated that the ortho-alkynylbenzimidate for the preparation of thieno-fused
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10 structure 3 is the key intermediate of the cyclization and that the indoles 8 (Scheme 7).26
aryl transfer to nitrogen atom occurred during the cyclization
process rather than as an arylation of 1H-indole (Scheme 4). Scheme 6

Scheme 3 I
N I I I
OH O O + OH
R3 R1 R1 R1 + R1
R2 DCM N N
N N OH OH
I R3 + R3
R2 R3 R2 R3 R2 R2
+ Pd/Cu
E , MeCN R1
R1 R2 R1 R2 6
Me or DCM N R3 H
N N
R3 R3 I
Me R1 = H, 4-Me; R2 = C6H5, 4-MeO-C6H4, 4-Me-C6H4, EtO;
2, 51-89%
R3 = H, C6H5, 4-Me-C6H4, OEt.
R1
R1 = H, 4-MeO2C, 4-EtO2C; R2 = n-C8H17, C6H5, HO(CH2)4, TBDMSO(CH2)4; R3 = n-C6H13, HOCH2CH2CH2, N
O
TMs, C6H5, 4-MeO-C6H4; E+ = I2, ICl, IPy2BF4.
R2 R3
7, 43-94%
15

Scheme 4 45 Scheme 7

R2 - SMe I+ SMe I
PF6 I
+ t-BuOH, 60 oC, air
1 + 1 I 1 R1 R2 I I 78%
R Ar Ar - I- + SMe SMe
H N N - MeI N
N N DCM, r.t., 1h N
Ar1
H Ph Ph
4, 59-84% MeO Ph MeO Ph Me O O
- -
PF6 I
+
I Ar1-I
Ar1 Ar1 Ph
R2 I
Ph
R2 I
Sonogashira's
1 1
R R reaction I2 S
+ H H SMe SMe
N N H Ph DCE, 20 oC, 1h N
H H+ N N
I +I
Ar1 Ar1 Ar1 Ar1 Ph Ph Ph
O O O
3
8, 89%
R1 = H, 4-Me, 4-Cl, 4-F; R2 = C6H5, 3-Me-C6H4, 4-Me-C6H4, 4-MeO-C6H4, 4-Br-C6H4, 4-
Cl-C6H4, 4-F-C6H4, 4-O2N-C6H4, 2-thienyl; Ar1 = C6H5, 2-Me-C6H4, 4-Me-C6H4, 4-t-Bu-
C6H4, 4-EtO2C-C6H4, 2-Br-C6H4, 4-Br-C6H4, 4-Cl-C6H4, 4-F-C6H4.
The cyclization of 1-(2-aminoaryl)propynols to 1H-indole-2-
carbaldehydes 9 has been achieved with NIS as the electrophilic
The utility of triphenylphosphine as activating of iodine atom source and a mixture of H2O/acetone (25:1) as solvent (Scheme
from NIS was tested in the electrophilic cyclization reaction of 50 8).27 The mechanism proposed by the authors involves the
20 ortho-alkynylanilines giving 3-iodoindole derivatives 5 as nucleophilic addition of nitrogen to the alkyne associated with
products (Scheme 5).23 The authors studied the effects of various capture of the iodine from NIS, giving the vinyl iodide
reaction parameters, such as the use of different phosphines, intermediate 10. Activation of the hydroxyl group by another
solvents, temperature, and N-protecting groups on ortho- molecule of NIS, followed by nucleophilic substitution by H2O,
alkynylanilines, which could affect the yields. The results 55 affords the indole after elimination of HI and nitrogen
25 indicated that the reaction rate depends on the triphenylphosphine deprotection (Scheme 9).
as a catalyst and the presence of sulfonamides as an N-protecting
group. Scheme 8

Scheme 5 R2 OH R2
R2 I O
NIS (2.2 equiv) 1
NIS (2.0 equiv) R1 R
R1 R2 H H2O/acetone (25:1 v/v), reflux, 24 h N H
R1 PPh3 (10 mol %)
N
H N X
N X
DCE, r.t. Ts 9, 51-91%
Ts
5, 60-99%
R1 = H, 4-Me, 4-MeO, 4-Br, 4-Cl, 2,4-(Me)2; R2 = H, C6H5, 2-Me-C6H4, 4-Me-C6H4, 4-Cl-
R1 = H, 4-Me, 5-Me, 4-MeO, 4-Br, 4-Cl, EtO2C; R2 = C6H5, 3-Me- C6H4, 2-F-C6H4, Me, Et; X = H, Ts, Ac.
C6H4, 4-Me-C6H4, 2-MeO-C6H4, 4-MeO-C6H4, 4-Cl-C6H4, 4-F-
C6H4, 4-F3C-C6H4, t-Bu, c-C3H5.
Scheme 9
30 The application of a Schiff’s base, easily prepared by
condensation of ortho-iodoanilines with carbonyls compounds, in
a tandem electrophilic cyclization, followed by nucleophilic

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O
In this context, ortho-alkynylanilines were transformed to the
O
I N corresponding indoles 13 via reaction of KH at room temperature
R2 OH
I
N HO R2 HO
R2
I
O for 3 h (Scheme 12).30 In a similar way, treatment of ortho-
O I
R1
H
R1 R1 diyneanilines with the same reaction conditions gave 2-
-NHS N
N N
alkynylindoles 14 in 73-83% yields (Scheme 13).31, 32

Organic & Biomolecular Chemistry Accepted Manuscript

H2O 35
X 10 X X

-HOI
-NHS Scheme 12
2 2 2
R R R
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-HOAc R1 R3 R1
O O -HI OH
(for = OAc) FG
R1 R1 R1 FG
KH
N H N H N I R3
H NMP, 21 oC, 3 h N
H X X R2 N R2
Cl H Cl H
13, 62-98%
The comparison of reactivity between alkynes and alkenes, in the
R1 = Br, NC, EtO2C, MeS, PhOC, 4-NC-C6H4; R2 = Cl, EtO2C, NC;
electrophilic cyclization of ortho-alkynylanilines having an R3 = C6H5, n-C4H9.
alkene chain in the terminus position, has been reported to the
5 preparation of 4-iodomethyl substituted tetrahydro-β-carboline
Scheme 13
indoles 11 (Scheme 10).28 The results indicated that this
methodology involved two electrophilic iodocyclization R1
reactions, in which the carbon-carbon from alkynes was cyclized
first then alkenes. In addition, the authors also used this approach KH
R1
10 to the formal synthesis of natural product oxopropaline G. N
H NMP, r.t. N
H
H
14, 73-83%
Scheme 10 R1 = H, C6H5, 4-Me-C6H4, 2-MeO-C6H4, 4-MeO-C6H4, 4-H2N-C6H4,
2-naphthyl.
I

N
N R
2 40 In another approach, 2-substituted indoles 15 were prepared using
R2
R1
Me
I2
R1 NaOH to mediate a 5-endo-dig cyclization of ortho-
DCE, 70-85 oC N
N
R3 Me alkynylanilines as the key step. A one-pot version of this
Me
11, 80-95% cyclization, starting from ortho-iodoanilines and terminal
1
N alkynes, was also efficient for the indoles formation; moreover,
R
N 45 under these conditions the use of a palladium and copper(I) salts
OH
Me O were required (Scheme 14).33 The base-catalyzed cyclization of
oxoprolaline G
ortho-iodoanilines having a sulfur substituent, afforded the 2-
R1 = H, 4-Me, 3-MeO, 4-Cl, 4-O2N; R2 = Ts, Ms, Bn; R3 = Me, Bn. methylthio-indoles 16 in 54-89% yields (Scheme 15).34 The
presence of sulfur group was essential for the use of catalytic
The halogen functionalization of the 3-position of indoles, via the 50 amounts of DBU. In this case, a propargyl-allenyl intermediate is
electrophilic cyclization reaction of ortho-alkynylanilines is easy formed by the presence of base and assistance of the sulfur
15 extensively used, whereas the functionalization of the 6-position atom, which activate the carbon-carbon triple bond towards the
is quite rare. An efficient regioselective [3 + 2]- nitrogen nucleophilic attack.
cycloaddition/iodocyclization cascade reaction involving ortho-
alkynylchalcones/cinnamates and toluenesulfonylmethyl Scheme 14
isocyanide has been described to the preparation of 6-iodoindole
R1
20 derivatives 12 (Scheme 11).29 The key steps for this cyclization NaOH (3.0 equiv), DMF
140 oC, 2-9 h
are the formation of pyrrole ring via a [3 + 2]-cycloaddition of H
R1
or NaOH ( 1.5 equiv), DMA N
cinnamates with toluenesulfonylmethyl isocyanide, followed by N
H MW (170 oC, 7-40 min) H
an intramolecular 6-endo-dig halo cyclization. 15, 72-91%

Scheme 11
1) PdCl2(PPh3)2 (3 mol%)
I
+ H R1 CuI (5 mol%), Et2NH, r.t., 1-2 h
R1 H R1
N or MW, 70 oC, 3-40 min N
Ar1 Ar1
EWG H 2) NaOH (10.0 equiv), 140 oC H
R1 R1
NC Ts I2 (2.0 equiv) or NaOH (4.0 equiv), DMA, MW 15, 40-88%
EWG NaH (2.5 equiv) t2, r.t. N
N H I
DCM, t1, r.t. Ar1 H
EWG R1 = C6H5, 4-Me-C6H4, 2-H2N-C6H4, 4-F-3-Me-C6H3, 3-Cl-C6H4, c-C6H9, c-C6H11, n-
12, 35-83% C5H11, 3-thienyl, 2-pyridyl.
55
R1 = H, Cl; Ar = C6H5, 4-Br-C6H4, 4-Cl-C6H4, 4-F-C6H4, 3-Me-C6H4, 4-Me-C6H4, 4-MeO-C6H4, 2-thienyl,
25 c-C3H5.
Scheme 15

SPh SPh
Synthesis of Indoles via Base-Promoted Cyclization of DBU
R1 R1 R1
Alkynes N
H
N H N SPh
R2 R2 R2
16, 54-89%
Base-promoted annulation reaction of alkynes is one of the most
R1 = H, 4-Me; R2 = H, n-C4H9, 4-Me-C6H4CH2, 4-Cl-C6H4CH2, Bn, 2-furyl, Ms, Ac.
30 convenient methods for the synthesis of heterocyclic compounds.

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Tandem-type cyclization carboxylation reactions using ortho- 35 followed by in situ cyclization of ortho-alkynylanilines, also
alkynylaniline derivatives provided 3-carboxylated indoles 17 afforded the corresponding indoles.
(Scheme 16).35 The complete optimization of the reaction
conditions indicated that K2CO3 is the only reagent required to Scheme 19
mediate the process. The reaction proceeds efficiently under 10

Organic & Biomolecular Chemistry Accepted Manuscript

5

atm of CO2 in the complete absence of any transition metal R2

R1 R1
catalyst. The sequential alkylation/cyclization/isomerization of CsCO3 ( 2.0 equiv)
R2
o
ethyl 3-(otrifluoroacetamidoaryl)-1-propargyl esters was applied N
H toluene, 150 C, 24 h
N
COR3
to the synthesis of 2-acyl and 2-ethoxycarbonyl-3-alkenyl indoles COR3
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20, 59-96%
10 18 (Scheme 17).36 The reaction proceeded via formation of an
R1 = H, NC, MeO2C; R2 = H, C6H5, n-Pr, PhOCOCH2CH2; R3 = Me, C6H5.
allenyl intermediate, which after isomerization and hydrolysis of
the trifluoroacetamido group affords the free 1H-indole
derivatives. Base-promoted sequential reaction has been also Scheme 20
extended to N ‑ [2-(1-alkynyl)phenyl]carbodiimides with
F F
15 isocyanides, which led to the preparation of N-imidazole indole R1 I R1
1) PdCl2(PPh3)2,CuI
derivatives 19 (Scheme 18).37 The studies suggested that an H
+ H R3
Et3N, MeCN, 50 oC, 1 h
R3
R2 N R2 N
initial [3 + 2] cycloaddition of isocyanide to carbodiimide, F H 2) KOH, MeCN, reflux F H
followed by the intramolecular cyclization are involved in this 21, 8-90%
process. 40
1 2 3
R = H, F; R = F3C, F; R = H, n-C4H9, HO(CH3)2CH, THPOCH2, C6H5.

20 Scheme 16 It was found that a catalytic amount of t-BuOK in DMSO at room

temperature can be utilized to promote the intramolecular
R2 CO2H cyclization of ortho-alkynyl-N,N-dialkylarylanilines leading to 2-
K2CO3 (10.0 equiv), CO2 (10 atm)
R2
aryl indoles 22 (Scheme 21).40 The reaction mechanism involves
R1 R1
N
H DMF, 65 oC, 24 h N 45 the -aminoalkyl radical intermediates, in which the t-
Ts
Ts
17, 58-96%
BuOK/DMSO system probably works as the crucial initiator.
R1 = H, 3-MeO-C6H4, 4-MeO-C6H4, 4-MeO2C-C6H4, 4-Br-C6H4, 3-Cl-C6H4, 4-Cl-
C6H4, 4-F-C6H4; R2 = C6H5, n-C4H9, t-C4H9. Scheme 21

R1 R1
Scheme 17
t-BuOK (0.1 equiv)
R3
N R3 DMSO, r.t. N
R3 R3
R2 R2
OCO2Et OCO2Et 22, 54-95%
R1 K2CO3 R1
o - R1 = C6H5, 4-Cl-C6H4, 4-F-C6H4, 4-MeO-C6H4, 4-F3C-C6H4,
CH2COR4 DMSO, 40 C
N N COR4 naphthyl, n-C4H9; R2 = Me, Bn; R3 = H, C6H5, 4-Cl-C6H4, 4-F-C6H4,
2 2
R COCF3 R COCF3 4-MeO-C6H4, 4-F3C-C6H4, naphthyl, 4-NC-C6H4.

R3
R3 The nucleophilic aromatic substitution, followed by a 5-endo-dig
R 1
O R 1
50 cyclization reaction between ortho-fluoro-arylalkynes and a
COR4 nucleophile, such as p-toluidine, under t-BuOK conditions was an
N R4 N
R2 H COCF3
efficient methodology to prepare 2-substituted-indoles 23
R2
18, 50-86%
(Scheme 22).41 It was mentioned that carbon-carbon from
alkynes has a dual role acting as an electron-withdrawing group
R1 = H, Cl, Me; R2 = H, Me, Cl, F; R3 = H, C6H5; R4 = C6H5, EtO.
55 to activate the substrate for SNAr, and to deliver the carbon-
carbon group for the formation of the indole ring.
Scheme 18

R2 R1
Scheme 22
Cs2CO3 R2
R1 N + NC R4 N R1
C R3 DMSO, 40 oC R3 R1
N N -
4
R p-Me-C6H4NH
N H
F SNAr N
19, 51-81%
Tol-p
R1 = H, Me, Cl; R2 = C6H5, 4-Me-C6H4, 4-MeO-C6H4, 4-Cl-C6H4, c-C3H5; R3 = C6H5, 4-Me- -
C6H4, 4-MeO-C6H4, 4-F-C6H4, 4-O2N-C6H4, n-C4H9, c-C6H11; R4 = EtO2C, t-BuO2C, Ts. p-Me-C6H4NH
25
t-BuO
H R1
H
The use of cesium carbonate to promote the cyclization of ortho- 5-endo-dig
alkynylanilides is another methodology available for the N
R1
cyclization -
NH
synthesis of N-substituted-indoles 20 (Scheme 19).38 The Tol-p Tol-p
reaction was carried out with Cs2CO3 in toluene at 150 0C for 24 23, 52-88%

30 h. KOH has been also found to be an efficient base for the R1 =C6H5, 2-Me-C6H4, 3-Me-C6H4, 4-Me-C6H4,
conversion of polyfluorined ortho-alkynylanilines to the 2-t-Bu-C6H4, 2-F3C-C6H4, 2-NC-C6H4.

corresponding indoles 21 (Scheme 20).39 A one-pot version of

this cyclization using a sequence of cross-coupling of Synthesis of Indoles via Radical-promoted Cyclization of
polyfluorinated ortho-iodoanilines with terminal alkynes, 60 Alkynes

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R3
Radical cyclization reactions have found extensive use in organic R2 O S
O
synthesis, as they are well suited for the construction of both O
S
TBHP (0.4 equiv)
R1 +
R3 R1 R2
carbocyclic and heterocyclic rings. This process involves the N3
OH DMF, 80 oC, 24 h N
selective radical generation, radical cyclization, and conversion of - N2 H
25, 25-99%
the cyclized radical to the carbo- and heterocycles. The radical

Organic & Biomolecular Chemistry Accepted Manuscript

5

cyclization has gained prominence because of the mild reaction
conditions associated with high regio‐ and stereochemistry and
high functional group tolerance. Accordingly, 3-aroylindoles 24
were conveniently prepared by ortho-alkynylanilines in an
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R1 = H, 4-Me, 4-Br, 4-Cl, 4-F, 4-F3C; R2 = C6H5, 4-MeO-C6H4, 4-Me-C6H4, 4-Cl-C6H4,
3-F-C6H4, 4-MeO-C6H4, 4-C6H5, 2-naphthyl, 2-pyridyl, 2-thienyl, 3-thienyl; R3 = C6H5,
4-Me-C6H4, 4-Cl-C6H4, 3-Cl-C6H4, 2-Me-C6H4, 1-naphthyl, 2-naphthyl, 2-thienyl, Me,
Et, Oct.

10 intramolecular oxidative coupling pathway using TBAI as a 45 Scheme 25

catalyst and TBHP as the oxidant. In this protocol, there was the
simultaneously formation of carbon-carbon and carbon-oxygen R3
bonds at the expense of two sp3 carbon-hydrogen bonds (Scheme 2
R
23).42 The mechanism proposed starts with the formation of an O
R3 1,4-cyclohexadiene
15 aminyl radical cation via a single electron transfer (SET) R1 + S Cl
Eosin Y,Na2HPO4, MeCN
R1 R2
N
sequence, followed by the iminium intermediate formation via N3 O
Blue LEDs H
abstraction of a hydrogen radical. The attack of water or TBHP 26, 31-84%
at the triple bond gives the vinyl ether intermediate species, R1 = H, 4-Cl, 3-F, 4-F, 3,4(Cl)2, 4-MeO, 3-Me; R2 = t-Bu, C6H5, 4-MeO-C6H4, 4-F-C6H4, 2-
thienyl, 1-naphthyl; R3 = H, 2-Me, 3-Me, 4-Me, 4-MeO, 4-Cl, 4-F, naphthyl, 2-thienyl, F3C.
which after oxidation and aromatization processes afford the 3-
20 aroylindoles (Scheme 23).
Scheme 26
Scheme 23
R2 Ar1

1
+ - 1,4-cyclohexadiene
HOOBu-t R1 + Ar -N2BF4 R1 R2
Eosin Y, Na2HPO4, MeCN N
N3
R2 R2 R2 Blue LEDs H
27, 49-80%
TBAI -H 1
1
R R1 R +
N t-BuOOH N N R1 = H, 4-Cl, 2-F, 4-F, 4-MeO, 3-Me; R2 = C6H5, 4-MeO-C6H4, 4-F-C6H4, 2-thienyl, t-Bu; Ar1 =
SET C6H5, 4-Cl-C6H4, 4-F-C6H4, 2-Me-C6H4, 3-Me-C6H4, 4-Me-C6H4, 4-MeO-C6H4, 4-NC-C6H4.

O O R2
Scheme 27
R2 R2 OOBu-t

[O] OH
R1 R1 R1
N N N
CO2R3
DMSO, 80 oC, 12 h
R1 + R2O2C CO2R3 R1 CO2R2
24, 61-81% H O2 N
N
H
H 28, 35-94%
R1 = H, 4-Me, 4-Cl; R2 = C6H5, 3-Me-C6H4, 4-t-Bu-C6H4, 4-MeO-C6H4, 4-Br-C6H4, 5-F-C6H4.
hydroamination
reduced by DMSO
OOH
The tert-butyl hydroperoxide-promoted cascade R1 CO2R3
H
sulfonation/cyclization of ortho-alkynylarylazides was used to N
R1 CO2R2
25 prepare 3-sulfonylindoles 25 (Scheme 24).43 Based on the R2O2C N
H
CO2R3
experimental evidence, the author concluded that in this
annulation reaction the TBHP is the sulfonyl radical initiator, [2+2]
heating
1,5-HAT

whereas the sulfinic acid is the sulfonating reagent. The cascade CO2R3
O
O
annulation involving ortho-alkynylarylazides and arylsulfonyl O2 H
CO2R3
30 chlorides proceed through the visible-light initiated cyclization CO2R3
heating
R1 CO2R2 R1 CO2R2
R1
reaction to give the unsymmetrical 2,3-disubstituted indoles 26 N CO2R2 N N
H H H
(Scheme 25).44 Recently, an alternative route to prepare
unsymmetrical 2,3-diaryl-substitued indoles 27 was developed. R1 = H, 4-Me, 4-Et, 4- n-Bu, 4-t-Bu, 3-MeO, 4-MeO, 4-EtO, 4-MeO2C, 4-EtO2C, 4-Cl, 4-Br, 4-F, 4-
Ph, 4-F3CO, 2,4(Me)2, 2-(Me)-3-(F); R2 = R3 = Me, Et, n-Pr, i-Pr, t-Bu, CH2CH=CH2; R2 = Me and
The reaction involved the visible light and eosin Y to catalyze the R3 = F3C, F5C2, Ph; R2 = CN and R3 = Ph; R2 = Et and R3 = Ph.
50
35 cyclization reaction of ortho-alkynylarylazides with aryl
diazonium salts via a photoredox process (Scheme 26).45 In
The oxidative cyclization of ortho-alkynylanilines with diorganyl
addition, a number of studies have shown that tryptophol
dichalcogenides induced by visible-light irradiation, in the
derivatives 28 can be prepared by reaction of ortho-
presence of H2O2, under transition metal- and photocatalyst free
alkynylanilines with allkynes. The reaction took place through
conditions, proceeds smoothly to form 3-
40 the carbon-carbon hemolytic cleavage, followed by oxygen
55 organochalcogenylindoles 29 (Scheme 28).47 The control
trapping with a subsequent intramolecular 1,5-hydrogen atom
experiments carried out by the authors indicated that the first
transfer and peroxide tryptophol reduction (Scheme 27).46
reaction step consists of the cyclization of ortho-alkynylaniline
promoted by hydroxyl radical, initiated by cleavage of H2O2
Scheme 24 under blue LED irradiation. The reaction is finalized with
60 dichalcogenides, which lead to the indole derivatives. The tert-
butoxyl and tert-butylperoxy radicals and iodine can both
promote the cascade radical annulation of ortho-alkynylanilines

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with sulfonyl hydrazides, introducing the sulfanyl 30 fragmentation, aromatization and N-Boc deprotection cascade,
functionalization at 3-carbon of the indoles 30 (Scheme 29).45 gave 3,4-disubstituted 5-hydroxyindoles 32 in yields ranging
When the reactions were carried out in the absence of TBHP the from 15 to 66%.50 When the trimethylsilyl group was directly
corresponding 3-arylsulfanylindoles were obtained, via classical bonded to terminal alkynes, a 1,3-silatropic rearrangement was
electrophilic annulation reactions. observed, giving silyl- protected alcohol derivatives as product

Organic & Biomolecular Chemistry Accepted Manuscript

5

35 (Scheme 31).
Scheme 28
Scheme 31
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R2 R2

R2 HO 1 R2 HO 1
R1 R1 R1 + R2 R2 R - H R
H - R1 O
N HO HO N H N [4+2]
H O N O +
Ts Ts Ts
hv N N
Boc OH
H2O2 Boc Boc
H+
YR3 R2 R1 R2 HO 1
R3YYR3 HO R
R1 R2 HO
R 1 R2
N N
N N
Ts Ts
Boc Boc
29, 43-97% 32, 15-66%

R1 = H, 4-Me, 4-MeO, 3-Cl, 4-Cl, 4-F, 4-NC, 4-Cl-2-F; R2 = n-C5H11, c-C3H5,

R1 = n-C6H13, c-C3H5, c-C6H11, C6H5, 2-naphthyl, 2-thienyl, benzofuryl,
C6H5, 4-Me-C6H4, 4-MeO-C6H4, 4-Cl-C6H4, 3-F-C6H4, 2-F-C6H4, 4-F-C6H4, 4-F3C-
PhCH2CH2; R2 = n-C4H9, t-C4H9, C6H5, 4-Me-C6H4, 3-MeO-C6H4, 4-F3C-C6H4, 4-
C6H4; R3 = 4-Me-C6H4, 4-t-Bu-C6H4, 4-MeO-C6H4, 2-Cl-C6H4, 3-Cl-C6H4, 4-Cl-
F-C6H4, Cl(CH2)2CH2, c-C6H9.
C6H4, 4-F-C6H4, 4-F3C-C6H4, 2-4-(Cl)2-C6H3, Bn, 2-naphthyl; Y = S, Se.

Scheme 29 The synthesis of functionalized 2-styrylindoles, 2-arylindoles, 2-

alkynylindoles, and 2-alkylindoles 33 was reported by cyclization
R2 SO2R4
40 of ortho-alkynyldimethylamines in the presence of ethanol using
4 I2, TBHP 1 2
microwave irradiation (Scheme 32).51 This environmentally
R1 + R SO2-NHNH2 R R
N
Me EtOAc, 80 oC N friendly protocol provided the target compounds in high yields
R3 R3 via a 5-endo-dig cyclization followed by a demethylation process.
30, 11-97%
The authors studied the reaction mechanism and the role of the
1 2
R = H, 4-Br, 3-Cl, 4-Cl, 4-F, 4-Me; R = C6H5, 4-Me-C6H4, 4-MeO-C6H4, 4-F- 45 solvent using DFT calculations.
C6H4, 3-F3C-C6H4, 2-Br-C6H4, 3-Br-C6H4, 4-Br-C6H4, 4-O2N-C6H4, 2,4,5-(Me)3-
C6H2, 2-naphthyl, n-C6H13, R3 = Et, (CH2)3CH2I; R4 = C6H5, 4-Me-C6H4, 2,4-(Me)2-
C6H3, 4-Br-C6H4, 4-Cl-C6H4, 4-O2N-C6H4, 3-F-C6H4. Scheme 32

10 Synthesis of Indoles via Cyclization of Alkynes under R2

Microwave Irradiation R1 EtOH, 120 0C

R1 R2
N(Me)2 MW, 2-10 h N
Me
The microwave irradiation application has been of the grant 33, 42-95%
interest for researchers in diverse areas of chemistry. The rapid 1 2
R = H, 3-Br, R = H, n-C4H9, HOCH2(CH2)2CH2,
progress in microwave irradiation and its use in organic synthesis ClCH2(CH2)2CH2, C6H5, 4-MeO-C6H4, 3-F-C6H4, 2-thienyl, 2-
15 have become a consistent method for the synthesis of carbo- and pyridyl, TMS, 4-MeO-C6H4CH=CH, 4-Ac-C6H4CH=CH, Cl2C=CH,
MeO2CCH=CH.
heterocycles. Microwave-assisted synthesis of indole derivatives
31 was described through the intramolecular hydroamination
Synthesis of Indoles via Oxidative Nucleophilic Cyclization of
process, followed by cycloisomerization of ortho-alkynylanilines
Alkynes
(Scheme 30).48, 49 The studies indicated that the addition of a
20 catalytic amount of inorganic salts or bases, such as KCl,
NaHCO3, or pyrrolidine, proved to be very efficient to improve 50 The oxidative nucleophilic cyclization of ortho-alkynylanilines
the yields. In addition, the authors compared the results with with thiophenols gave the 3-sulfenylindoles 34 via PhI(OAc)2-
thermal heating conditions, finding that microwave irradiation is mediated oxidative dearomatization and Brønsted acid-promoted
essential for the product formation in a short reaction time and in nucleophilic cyclization (Scheme 33).52 The authors carried out a
25 good yields. series of control experiments and DFT calculation to further
55 understand the reaction mechanism. They concluded that there
are at least two possible reaction pathways, in which the
Scheme 30
structures of III and IV were the key intermediates for the
R2
cyclization (Scheme 34).
H2O, basic or acid salt
R1 R1 R2
X N
H MW heating
X N Scheme 33
H H
31, 9-99%

R1 = H, 4-MeO, 4-Cl, 4-MeOC; R2 = H, C6H5, 4-MeO-C6H4, 4-Me-C6H4,

4-Cl-C6H4; X = N, CH.

The microwave-promoted the intramolecular [4 + 2]-

cycloaddition of alkynols to furan derivatives, followed by a

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DOI: 10.1039/D0OB00670J

R3 4 R1
S R
R1 R1
1) PhI(OAc)2 (1.1 equiv), MeOH, r.t., 5 min R3 -
H C C
R2 N 2) R4SH (2.0 equiv), toluene, reflux, 10-12 h R2 N N N
Ts Ts R 1

34, 51-76% + MgBr

Organic & Biomolecular Chemistry Accepted Manuscript

N N
R1 = H, Me, Et, i-Pr, n-Bu; R2 = H, Me, Br; R3 = n-Bu, C6H5, 4-Me-C6H4, 4-MeO-C6H4, 4-Cl- C
-
C
C6H4, 4-F3C-C6H4, 4-O2N-C6H4, 2-thienyl, EtO2C; R4 = C6H5, 2-Me-C6H4, 3-Me-C6H4, 4-Me-
C6H4, 4-MeO-C6H4, 4-Br-C6H4, 4-Cl-C6H4, 4-F-C6H4.
R1
R1 R1 R1
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Scheme 34

Ph -
N - N - N
Me Ar1 SH - - -
N N N
+
NH2
HS Ar1
Ts
Ph Ph R1 R1 R1
Me Me
MeO
+ +
H N N R1
Ts III Ts
H + R1 = H, 2-Me, 4-Me, 3-MeO, 3-Me2N, 4-F3C, 3-F, 4-F, 4-PhO, naphthyl.

Ph HN
Me
SAr1 NH
MeO Me
N Ph
N
Ts
34 Ts
Ar1 SH 35, 19-85% R1

15

SAr1
Me
MeO
Ph
SAr1
Synthesis of Indoles via Electrochemical-Mediated
N
Me + H Cyclization of Alkynes
Ph
Ts N
SAr1 Ts
H+ Me
Ph Even though electrochemical-mediated reactions represent an
MeO
H+
efficient tool for organic transformation, the preparation of
N
IV Ts
20 indoles using this methodology is rarely found in the literature, in
the last ten years. Following an electrochemical approach, 2-
substituted indole derivatives 36 were prepared by cyclization
Recently, the double ortho-alkynyl isocyanides cyclization was
reaction of ortho-alkynylanilines with cyanomethyl anion
5 reported to the preparation of bis-(2-aryl-1H-indol-3-yl)ethynes
(Scheme 36).54 The cyclization was carried out by using the
35 (Scheme 35).53 The cyclization reaction initialized with the
25 solvent-supporting electrolyte system [CH3CN/0.1 M
aryl Grignard reagent as nucleophile, using THF as a solvent, for
tetraethylammonium tetrafluoroborate (TEATFB)] with platinum
10 min at room temperature. The authors investigated the
electrodes in a divided cell under galvanostatic control (J =
structural and physicochemical features of the indole derivatives,
25mAcm–2) at 0 0C. The generation of the cyanomethyl anion
10 by DFT calculations, and established that the −electron systems
occurred via two-electron process becoming a catalytic reaction.
and orbital energy levels can be tuned by various aromatic
30 Scheme 36
substituents at 2,2′-positions of the two indoles group.
1) e-
Scheme 35 CH3CN 0.1 M TEATFB R1
N
R3
R3
H
2) R1 36, 67-97%
H
N
R2

R1 = H, 2,4(Cl)2, 3-F3C, 2-Cl-4-O2N; R2 = H, EtO2C; R3 = H, C6H5, 3-F3C-C6H4, 4-

Cl-C6H4, 4-MeO-C6H4, PhCH=CH2, (Et)(Me)(OH)CH.

Miscellaneous strategies

The indolization of nitrosoarenes was carried out by using

terminal alkynes in toluene at 80 0C for the preparation of 3-(2-
35 chloropyrimidinyl)-indoles 37 in moderate to good yields
(Scheme 37).55 The scale-up procedure for one reaction starting
from 2 g of starting material gave the products in very similar
yields, indicating that this methodology is robust without the
necessity of adaptation in the reaction conditions for gram-scale
40 preparation. The methodology was applied in the syntheses of
meridianins and meridianin analogues, which are marine
alkaloids known as kinase inhibitors.

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Scheme 37 In this manuscript, we have described the last ten years of

advances in the synthesis of indoles using the reaction of alkynes
N
Cl and nitrogen compounds under metal free conditions. As we have
Cl N shown, the necessity to develop most environmentally, cost-
N toluene, 80 oC effective, green and mild methodologies for the preparation of N-

Organic & Biomolecular Chemistry Accepted Manuscript

35
R1 + N R1
N N heterocycles is a global trend adopted by all laboratories in the
H
O
37, 19-71%
last decades. Many N-heterocycles that were previously prepared
R1 = H, 2-CH3, 3-Br, 4-Br, 2-F3C, 2-O2N, 4-O2N, 4-NC, 4-HO2C, 4-MeO.
only by classical transition-metal catalyzed cyclization reactions
can now be prepared using metal-free conditions, without losing
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40 the advantages that other methods offered. The benefits to use a

When the condensation of ortho-alkynylanilines with aldehydes metal free-condition are the reduction of chemical wastes
was carried out under Brønsted acid catalysis, 2,2′-disubstituted generation, reaction time, solvent, and energy, resulting in clear
5 1H,1′H ‑ 3,3′ ‑ biindoles 38 was formed from 48 to 89% yields economic impacts and environmental benefits. Thus, in this
(Scheme 38).56 The procedure required only a catalytic amount review we described the synthesis of indoles involving
of HCl in acetonitrile to form four new chemical bonds and two 45 electrophilic cyclization, base-promoted cyclization, radical-
indole rings in a one step reaction. ortho-Alkynylanilines were promoted, cyclization, cyclization under microwave irradiation,
also used as substrates in a chiral Brønsted base catalyzed oxidative nucleophilic cyclization, and electrochemical-mediated
10 asymmetric annulation for the synthesis of axially chiral cyclization of alkynes and nitrogen compounds.
naphthyl-C2-indoles via vinylidene ortho-quinone methide
(VQM) intermediates.
Acknowledgments
Scheme 38 50 We are grateful to FAPERGS, CAPES, and CNPq for financial
support. CNPq and CAPES are also acknowledged for the
H
N
fellowships (J. S. S. N. and G. Z.).
H
H N

R1 +
1
Ar -CHO
H+
Ar1 Notes and references
H CH3CN, reflux R1 Ar1
N 1 Jose. S. S. Neto, Departamento de Química, Universidade Federal de
N
H H
55 Santa Catarina, Florianópolis, Santa Catarina, 88040-900. E-mail:
38, 48-89%
zeneto.qmc@gmail.com
1 1
R = H, 2-Cl, 2-F, 3-F3C; Ar = C6H5, 2-F-C6H4, 4-F-C6H4, 4-Me-C6H4, 4-MeO-
C6H4, 4-Cl-C6H4, 3-Br-C6H4, 4-Br-C6H4, 4-F3C-C6H4, 3,4-(Cl)2-C6H3, 1-naphthyl. 2 Laboratorio de Sintese, Reatividade, Avaliaçao Farmacologica e
Toxicologica de Organocalcogenios, CCNE, UFSM, Santa Maria - Rio
15 By continuing on the subject of carbonyl compound and alkyne Grande do Sul – Brasil - 97105-900. E-mail: gzeni@ufsm.br
uses in a metal-free conditions to prepare indoles, the
condensation reaction of 2-amino acetophenones and alkynes in 60 † Footnotes relating to the title and/or authors should appear here.
the presence of I2 (1.5 equiv), K2CO3 (1.0 equiv) in DMSO at 100 Electronic Supplementary Information (ESI) available: [details of any
0C was employed to prepare 2-acylindoles 39 (Scheme 39).57 supplementary information available should be included here]. See
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