Topics in Current Chemistry (2024) 382:18

[Link]

REVIEW

Indole as a Versatile Building Block in Cycloaddition

Reactions: Synthesis of Diverse Heterocyclic Frameworks

Biswajita Baruah1 · Choitanya Dev Pegu2 · Mohit L. Deb3

Received: 2 October 2023 / Accepted: 25 March 2024 / Published online: 17 May 2024
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024

Abstract
Indole, a ubiquitous and structurally versatile aromatic compound, has emerged as
a key player in the synthesis of diverse heterocyclic frameworks via cycloaddition
reactions. These reactions are completely atom-economical and, hence, are consid-
ered as green reactions. This review article provides a comprehensive overview of
the pivotal role played by indole in the construction of complex and biologically
relevant heterocyclic compounds. Here we explore the chemistry of indole-based
cycloadditions, highlighting their synthetic utility in accessing a wide array of
heterocyclic architectures, including cyclohepta[b]indoles, tetrahydrocarbazoles,
tetrahydroindolo[3,2-c]quinoline, and indolines, among others. Additionally, we dis-
cuss the mechanistic insights that underpin these transformations, emphasizing the
strategic importance of indole as a building block. The content of this article will
certainly encourage the readers to explore more work in this area.
Graphical abstract

N
H
N N
H H
N
Cycloaddition N H
H
N
H N or
H N
N H
H
N
H

Keywords Cycloaddition reactions · Indole · Heterocycles · Diels–Alder reaction ·

Dipolar cycloaddition · Povarov reaction

Extended author information available on the last page of the article

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18 Page 2 of 48 Topics in Current Chemistry (2024) 382:18

Abbreviations
Ac Acetyl
°C Degree centigrade
Cat. Catalyst
CHD Cyclohexylidene
CPA Chiral phosphoric acid
DCM Dichloromethane
DMF Dimethylformamide
DMAP 4-(Dimethylamino)pyridine
DMSO Dimethylsulfoxide
d.r. Diastereomeric ratio
EDG Electron-donating group
EWG Electron-withdrawing group
eq. Equivalent
h Hour
i
Pr  Iso Propyl
LED Light-emitting diode
MeOH Methanol
min Minutes
Me Methyl
MS Molecular sieve
r.t. Room temperature
TFE Trifluoroethanol
THF Tetrahydrofuran
t
Bu  tertiary Butyl
W Watt

1 Introduction

Indole, an aromatic, heterocyclic organic compound consisting of a benzene ring

fused to a pyrrole ring, is a privileged structural motif in natural products, phar-
maceuticals, and bioactive molecules [1–4]. Some bioactive indole derivatives are
depicted in Fig. 1 [5–10]. The unique aromaticity and diverse reactivity of indole
have captivated the interest of synthetic chemists for decades. One of the most
attractive aspects of indoles is their ability to undergo cycloaddition reactions, which
have emerged as powerful tools in organic synthesis for the construction of complex
and diverse heterocyclic structures [11–13].
Cycloaddition reactions are powerful transformations that involve the formation
of new bonds through the concerted interaction of two or more unsaturated reactants
[14–17]. Most importantly, these reactions are 100% atom-economical and follow
one of the green chemistry principles, thus representing a valuable example of a
green and sustainable process in organic synthesis. Indole-based cycloaddition reac-
tions hold tremendous synthetic potential, as they provide rapid access to structur-
ally diverse heterocycles, including polycyclic frameworks and spirocyclic systems,
which are challenging to access through traditional synthetic methods. Different

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Topics in Current Chemistry (2024) 382:18 Page 3 of 48 18

Me
N
O N
Me

N
N N N
Cl NH H
Me Me
ondansetron 5-HT2C receptor agonist ellipticine
(suppress nausea) (antiobesity and CNS disorder) (antitumour activity)

O H2 N CO2Et
N
SMe N Me
S N
N N
N H N
H Me
Me
cyclobrassinin evodiamine GABA modulator
(antimicrobial activity in plants) (traditional chinese medicine) (used for anxiety)

Fig. 1  Some bioactive indole derivatives

indole skeletons used for the cycloaddition reaction are depicted in Fig. 2. In this
review article, we aim to explore the cycloaddition reactions involving indoles and
discuss their mechanistic underpinnings, synthetic applications, and significance in
the synthesis of natural products and bioactive compounds. Our objective is to pro-
vide a comprehensive overview of the advancements in this area and to highlight the
transformative impact of indole cycloadditions on modern organic synthesis.
The review is organized into several sections, each focusing on specific types of
cycloaddition reactions involving indoles, including [4+3], [4+2], [3+2], [5+2], and
[2+2] cycloadditions that have been employed to access diverse heterocyclic scaf-
folds. For each cycloaddition type, we discuss the methodologies and mechanistic
insights that govern the regioselectivity and stereoselectivity of these transforma-
tions. Moreover, we highlight the impact of transition metal catalysis, organocataly-
sis, and photochemical activation in promoting these cycloaddition transformations.
Beyond synthetic methodologies, the diverse applications of some indole-based

N N N N
H H H N
H H
Diene Diene Diene Dienophile 1,3-Dipole

Fig. 2  Indole skeletons used for cycloaddition reactions

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18 Page 4 of 48 Topics in Current Chemistry (2024) 382:18

cycloadditions in the synthesis of natural products, pharmaceuticals, and bioactive

compounds are also discussed. Although two review articles are available on the
cycloaddition reactions of indole, one with a specific indole pattern (vinyl indole)
and one with a specific dienophile (allene) [18, 19], a book chapter describing the
cycloaddition reaction of indole was published in 2010 which missed the new arti-
cles [20]. Therefore, we present a review on this topic incorporating the articles pub-
lished from 2011 to the present.

2 Limitations and Challenges

Despite their practical advantages, several challenges persist, leaving room for
improvement. One of these challenges is (a) regioselectivity: Indole contains numer-
ous reactive sites, such as the nitrogen atom and the aromatic ring. Consequently,
cycloaddition reactions may not consistently exhibit the desired regioselectivity,
resulting in the formation of multiple products (e.g., Scheme 31). Attaining a high
degree of regioselectivity can prove to be quite demanding. (b) Additionally, not all
indole derivatives prove suitable as substrates for cycloaddition reactions. Substitu-
ents attached to the indole ring can significantly influence reactivity and potentially
inhibit the desired reaction (e.g., Schemes 11 and 12), thereby limiting the appli-
cability of these reactions for specific substrates. (c) Furthermore, controlling the
stereochemistry of the products in these reactions can be challenging (e.g., Fig. 4,
Schemes 6, 14), often necessitating additional steps or specific reaction conditions
to achieve high stereoselectivity. (d) Similar to many chemical reactions, cycloaddi-
tion reactions involving indole may not consistently give a high yield or exhibit high
overall efficiency (e.g., Schemes 14, 16). Therefore, optimizing reaction conditions
and workup procedures often becomes necessary to maximize product yield.

3 Future Opportunities

Cycloaddition reactions involving indole represent a fascinating area of research

with numerous future opportunities. Indole, as a versatile and easily attainable start-
ing material, plays a pivotal role in various cycloaddition processes, culminating in
the creation of a wide array of potentially bioactive compounds. For example, (i)
indole-based click reactions provide efficient and selective pathways for the con-
struction of complex molecules. The utilization of indole derivatives in azide-alkyne
cycloadditions opens up exciting avenues for the synthesis of novel compounds with
diverse applications. (ii) The expansion of photochemical cycloaddition reactions
involving indole paves the way for the rapid and controlled generation of complex
structures. Light-induced reactions with indole can be explored for the synthesis of
photoresponsive materials or as tools in chemical biology. (iii) Developing more
enantioselective cycloaddition reactions involving indole is an ongoing challenge.
The discovery of new chiral catalysts and strategies can lead to the asymmetric
synthesis of biologically active compounds and pharmaceutical intermediates. (iv)
Combining indole cycloadditions with other transformations in a cascade sequence

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Topics in Current Chemistry (2024) 382:18 Page 5 of 48 18

R4 R5
2
R3
R R5
O GaIII cat. R2
N R3 R4 r.t. N
R1
R1

3 R3
HO R 4 R4 R5
R 2
R
R2
N
N
H2 O R1
R1

Scheme 1  Synthesis of cyclohepta[b]indoles by three-component [4+3]-cycloaddition

can streamline the synthesis of complex molecules. This approach can lead to the
efficient construction of diverse natural product-like structures.

4 [4+3]‑Cycloaddition

Xinping and colleagues documented a successful application of gallium(III) salts as

catalysts in regio- and diastereoselective three-component [4+3]-cycloaddition reac-
tions to generate cyclohepta[b]indoles as depicted in Scheme 1 [21]. Remarkably,
these reactions took place in a single step under ambient conditions, avoiding the
need for an inert atmosphere. The flexibility of this transformative reaction meth-
odology was thoroughly investigated using a diverse array of indoles, aldehydes/
ketones, and dienes (Fig. 3). Notably, the introduction of electron-withdrawing
groups, either on the indole or on the carbonyl components, was found to accelerate
the reaction rate. Although various catalysts were tested, it became evident that the
use of Ga(OTf)3 as the catalyst was particularly advantageous when dealing with
less reactive substrates, affording superior yields and shorter reaction times. The
authors asserted that this represented a pioneering example of a [4+3]-cycloaddition
reaction wherein the 2π component derives from indole.
Zhang et al. reported a new [4+3]-cycloaddition reaction which provided a more
facile synthetic route towards a multitudinal indole-containing core of silicine and
ervatamine and other 5,7,6-tricyclic skeletons. The reaction proceeded through a
novel tandem reaction of intramolecular hydroamination and a new [4+3]-cycload-
dition catalyzed by two reagents AgOTf and ­ZnCl2 in series (Scheme 2) [22].
3-Indolyl alcohols are generally prepared from corresponding indoles and possess
certain limitations in Friedel–Craft acetylation. These restrictions have spurred con-
tinuous efforts to innovate and create novel cycloaddition precursors. In contrast to
the initial precursor, precursor A has significantly enhanced carbocation efficiency

13
18 Page 6 of 48 Topics in Current Chemistry (2024) 382:18

R1

N N
R H
R = Me, Bn , H R1 = MeO. MeO2C, Cl, Br, I

O O
MeO OMe O
H H X
Me Me
R2 O n
2
R = H, MeO, CF3 X = O, S Me n = 1, 2, 3
Me
Me

Me
Me

Fig. 3  A variety of different indoles, aldehydes/ketones, and dienes used in the three-component
[4+3]-cycloaddition reaction

R3
OH OH R3
AgOTf
R1 R1 R1
R 2 5 mol% ZnCl2
NH N R2 N R2
5-exo-dig 1.1 eq.
Ts Ts
Ts

Scheme 2  Synthesis of indole-containing 5,7,6-tricyclic skeletons

HO R2
R2 R2 R2

R1 R1 R1 R1
N N N N
PG PG PG PG
Classical precursor

OH

R1 R1 R1
N R2 N R2 N R2
Ts Ts Ts
A B C

Scheme 3  The formation of allylic cation

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Topics in Current Chemistry (2024) 382:18 Page 7 of 48 18

by transforming compound B into a more stable state, C (Scheme 3). To investigate

the potential of the tandem hydroamination/[4+3] cycloaddition sequence, a series
of experiments were conducted exploring different combinations of dienes and alco-
hols, as detailed in Fig. 4. The results revealed that several dienes successfully par-
ticipated in the desired reactions, leading to the formation of cyclohepta[b]indole
skeletons.
Li et al. pioneered a groundbreaking approach by introducing a gold-catalyzed
cascade [4+3] cycloaddition/C-H functionalization. This innovative process
marks the first-ever instance of its kind. This chemical reaction pathway offers an
efficient means to access densely functionalized cyclohepta[b]indoles with excep-
tional yields, incorporating a second molecule of propargylic ester as a supple-
mentary side chain. Through the hydrolysis of two vinyl acetates, the synthesis of
highly functionalized indole-fused bicyclo[3.2.1]octane derivatives was achieved.

R
Alcohols
R = H, Me n = 1, 0
n
R
OH

O Hb
NH Ha
N O
Ts N
Ts
R = H, 88% Ts O
R = Me, 97% endo; 72%, dr > 20:1
OH

Hb
NH Ha
N N
Ts
Ts Ts
63% endo; 56%, dr- 5:1
OH

F NH F N
N O
Ts F Ts
Ts
endo; 65%, dr- 2:1
45%
OH
F
F F

NH N
N
Ts Ts
Ts
56% endo; 41%, dr- 7:1

Fig. 4  Substrate scope for the synthesis of cyclohepta[b]indole skeletons

13
18 Page 8 of 48 Topics in Current Chemistry (2024) 382:18

OR1

Ar OR1
PicAuCl2 Ar
R
N R
DCM, r.t. N
PG OR1
[4+3]-cycloaddition PG

OAc OAc OAc

Ar
R2 R2
N N N
OAc OAc OAc
EtO2C EtO2C Ts

R2 = tBu, 99%; F, 99% Ar = 1-naphthyl, 99% R2 = H, 78%; Me, 67%

Ar = 2-thienyl, 87%

Scheme 4  Synthesis of densely functionalized cyclohepta[b]indoles

The reaction produced a single diastereomer bearing four stereogenic centers due
to an additional intramolecular transannular Aldol reaction. Based on these two
pivotal transformations, the authors developed an economically advantageous
"one-pot" procedure involving a three-step cascade reaction (Scheme 4) [23].
Under the optimized conditions, a number of desired compounds were obtained
using different N-protected indoles. Substituting the N-protecting group from car-
boxylate to tosylate resulted in apparent lower yields. A plausible mechanism is
illustrated in Scheme 5. First, the ­PicAuCl2 catalyst initiates the Rautenstrauch
rearrangement of propargylic ester. This rearrangement yields the formation of
vinyl gold-carbene B. Subsequently, B reacts with the nucleophilic 2-vinylin-
dole via a Friedel–Crafts reaction at the C3 position, resulting in the creation
of an allylgold intermediate C that bears a conjugated iminium ion. Following
this, a ring-closure process occurs, forming the electrically neutral molecule D.
The enamide moiety within intermediate D allows it to further react with another
vinyl gold-carbenoid intermediate B. This leads to the generation of a second
type of pendant allylgold intermediate, E, which bears an iminium ion. Subse-
quently, deprotonation followed by proto-demetalation transforms intermediate E
into the final product.
Gelis et al. reported a successful application of chiral phosphoric acid catalysis in
a highly selective formal [4+3]-cycloaddition reaction between 1,3-diene-1-carba-
mates and 3-indolylmethanols. This innovative approach offers an efficient pathway
for the synthesis of 6-aminotetrahydrocyclohepta[b]indoles, yielding impressive
results with high enantioselectivity (98% ee) along with predominantly complete
diastereoselectivity. The use of mild reaction conditions, combined with excellent
yields, enantioselectivities, operational simplicity, and the ability for useful derivati-
zation, underscores the practicality and versatility of this method (Scheme 6) [24].

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Topics in Current Chemistry (2024) 382:18 Page 9 of 48 18

1,2-OAc OAc
OAc Au O O migration O Au
O R
B
Au Au
N
A TS Boc
Au
Au Au
OAc
OAc OAc

N R
N R N R
Boc
Boc Boc
C'' C'
C
Au
OAc
OAc OAc
H
R H H R
R
Au OAc
N OAc N
N Boc
Boc Boc Au
OAc Au
D
B E

Scheme 5  A plausible mechanism to rationalize the reaction pathway

The authors explored the applicability of (R)-3,3′-bis(2,4,6-triisopropylphenyl)-

BINOL (TRIP) phosphoric acid as a catalyst for [4+3]-cycloaddition reactions
involving 3-indolylmethanols and various dienes (Scheme 6). For instance, diene
carbamates featuring either branched or linear alkyl groups at the C4 position
yielded the corresponding cycloadducts in favorable yields. Notably, utilizing a
chiral diene carbamate derived from (R)-citronellol resulted in a product with out-
standing enantiomeric purity. However, when non-terminal substituted dienes were
employed, the diastereoselectivity of the product was notably affected.
A rhodium-catalyzed asymmetric [4+3]-cycloaddition of vinylindoles with
vinyldiazoacetates was reported by Xu et al., affording a seven-membered ring via
dearomative cyclization in moderate to high yields up to 99% ee (Scheme 7) [25].
­Rh2(S-DOSP)4 was found to be the best catalyst for the cycloaddition of 3-vinylin-
doles with vinyldiazoacetates, whereas ­Rh2(S-TCPTTL)4 was the most efficient for
2-vinylindoles. The reactions provided cyclohepta[b]indoles. Substrate scope for
the reaction was examined using various substituents on the phenyl ring of the aryl
vinyldiazoacetates. All the substituents, including electron-donating and electron-
withdrawing groups, as well as the para-, meta-, and ortho-substitution patterns
afforded good yields of products (Scheme 7).
Pirovano et al. synthesized cyclohepta[b]indole derivatives by [4+3]-cycloaddi-
tion reaction of 2-vinyl indoles or 4H-fluro[3,2-b]indoles with in situ-generated oxy-
allyl cations. Oxyallyl cations were generated from the reaction of α-bromoketones
and a base in perfluorinated solvent [26]. The experiment was conducted under gen-
tle conditions, without the need for costly catalysts. The most favorable outcome

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18 Page 10 of 48 Topics in Current Chemistry (2024) 382:18

Ar

O O
P
O OH
R5
R1 R1
OH R5 Ar R4
4 (5 mol%)
R
R2 R3
R2
N R 3 Toluene, 4 A MS
N NHCbz
H 0 oC to r.t., 18h H
NHCbz

Me F3C
Me Me Ph Me
Ph
MeO
MeO MeO
N NHCbz
N NHCbz N NHCbz H
H H
50% yield, 99% ee,
69% yield, 94% ee 67% yield, 98% ee
3:1 dr
OMe
Br
F
Me Me Me
Me
MeO MeO

N NHCbz N NHCbz N NHCbz

H H H

46% yield, 95% ee 63% yield, 91% ee 64% yield, 95% ee

Scheme 6  Synthesis of 6-aminotetrahydrocyclohepta[b]indoles

in terms of yield and reaction speed was achieved using N,N-diisopropylethylamine

(DIPEA) as the base and 2,2,2-trifluoroethanol (TFE, 6 eq.). The resulting prod-
ucts exhibited high yields and complete diastereoselectivity. To assess the reac-
tion’s feasibility, 2-vinylindole and 2-bromocyclopentan-1-one were combined in
various combinations of bases and fluorinated solvents. The study delved into the
reaction’s versatility with a range of substituted 2-vinylindoles and α-bromoketones
(Scheme 8). Additionally, the researchers expanded the reaction’s applicability to
3-vinylindoles and aza-oxyallyl cations.
In order to expand the scope of the reaction, the authors used a diene system
embedded in the furan ring and constrained in a s-cis conformation as an attrac-
tive alternative to 2-vinyl indoles (Scheme 9). The process can be conceptual-
ized as a [4+3]-cycloaddition, wherein α-haloketones function as precursors for
oxyallyl cations (C3 fragment), and 2-vinylindoles or furoindoles serve as dienes
(C4 fragment). Furthermore, following the IUPAC convention, this process can

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Topics in Current Chemistry (2024) 382:18 Page 11 of 48 18

O Rh

N O Rh
O S O
R 4
R = 4-(C12H25)C6H4 R3 CO2Me
R3 CO2Me
N2 Rh2(S-DOSP)4 (1 mol%)
R2 R4 R2
n-hexane/CCl4 (4:1) N R 4 R1
N
R1 4A MS, -35 oC, 6-24 h Boc
Boc
Cl
Cl Cl

Cl O
N O Rh
O
O Rh
4 R1
CO2Me
R4 CO2Me
Rh2(S-TCPTTL)4 (1 mol%) R4
N2
R2 R3 R2 R3
N n-hexane/CCl4 (4:1) N
Boc R1 4A MS, -35 oC, 12-36 h Boc

CO2Me CO2Me
CO2Me CO2Me

N H N H
N H Ph N H
Boc Boc
Boc Boc

78%, 12h 73%, 12h 62%, 12h Cl 71%, 12h CN

Me
ee = 95% ee = 94% ee = 94% ee = 97%

Ph Me NC
CO2Me
H Ph CO2Me
CO2Me CO2Me H
N H H
Boc Cl N
80%, 12h N N Boc
ee = 97% Boc Boc 79%, 36h
84%, 12h, ee = 94% 61%, 24h, ee = 91% ee = 82%

Scheme 7  The synthesis of cyclohepta[b]indoles via dearomative cyclization

be categorized as a homologous counterpart to the Diels–Alder reaction, which

is a well-established [4+2]-cycloaddition, taking into account the electrons par-
ticipating in the reaction. As documented in the existing literature, these reactions
occur through various pathways, ranging from the classical pure concerted pro-
cess to more intricate stepwise mechanisms (Scheme 10).

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18 Page 12 of 48 Topics in Current Chemistry (2024) 382:18

O R5 Br
R3
Br R4
R6
or O
R2 R2
R2 O R 5 R4 O
DIPEA (1.5 eq.) H H
TFE (6 eq.) R6
or
H
Toluene (0.5 M) N N
N R1 r.t., 1h R1 R1
EtO2C EtO2C
EtO2C
R1 = Me, R2 = R3 =H, 88%
R5 = H, R4 = R6 = Me, 78%
R2 = n-Pr, R2 = R3 = H, 58%
R5 = H, R4 = R6 = Ph, 55%
R1 = Cy, R2 = R3 = H, 69%
R4 = R5 = Me, R6 = H, 37%
R1 = 4-Me-C6H4, R2 = R3 = H, 80%
R1 = 4-F-C6H4, R2 = R3 = H, 70%
R1 = 4-OMe-C6H4, R2 = R3 = H, 79%

Scheme 8  Synthesis of cyclohepta[b]indoles via [4+3]-cycloaddition

O R3 Br

Br R4
R5
or O
R1 R1 R3
O R4 O
DIPEA (1.5 eq.)
O TFE (6 eq.) R5
R2 O or O
H
N Toluene (0.5 M) N N
r.t., 1h R2
EtO2C EtO2C EtO2C

R1= R2 = H, 77% R4= H, R3 = R5 = Me, 78%

R1= F, R2= H, 70% R4= H, R3= R5= Ph, 95%
R1= Me, R2= H, 80% R3= R4= Me, R5= H, 57%
R1= OMe, R2= H, 73%

Scheme 9  Synthesis of indolin-3-one via [4+3]-cycloaddition

5 [4+2]‑Cycloaddition

Wang et al. developed a straightforward approach for synthesizing exo-

tetrahydroindolo[3,2-c]quinoline derivatives through a three-component reac-
tion involving an aromatic aldehyde, a reactive amine, and an indole, with iodine
serving as the catalyst (Scheme 11) [27]. The reaction was performed in toluene
at room temperature. Three different aromatic amines and three different indoles
were used in the reactions along with a variety of substituted aromatic and heter-
oaromatic aldehydes. The reaction gave an average to good yield (55–78%). This
method offers several benefits, including its gentle reaction conditions, moderate
yet reliable yields, stereoselectivity, utilization of a metal-free catalyst, and over-
all operational simplicity. However, N-substituted indole produced bis(indolyl)
methane under the optimized reaction conditions due to its higher reactivity
(Scheme 12).

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Topics in Current Chemistry (2024) 382:18 Page 13 of 48 18

O
O Concerted O

N
N
PG
PG
Stepwise [4+3]

O
O
O O

N N
PG PG

Scheme 10  Mechanism for the synthesis of indolin-3-one

R
HN
H H
NH2 N 5 mol % I2
ArCHO + + R H
toluene, r.t.
N Ar
H
NH2
NH2 H2N
N
N N
H Et
Br

N N
N H
H H
Me

Scheme 11  Reaction of aldehyde, amine, and indole in the presence of iodine as a catalyst

Ar

NH2 I2
ArCHO + + HN
toluene NH
N
+
Ar = 4-MeO-C6H4, 92% CH3
NH2
Ar= 4-Cl-C6H4, 90%
Ar= 4-F-C6H4, 89%

Scheme 12  Reaction of N-substituted indole with aldehyde and amine in the presence of iodine

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18 Page 14 of 48 Topics in Current Chemistry (2024) 382:18

Ar
H
NH2 Ar I N
I2 N
O N I2
I2
ArCHO
Ar H -H2O Povarov reaction
A
HN HN B
H H
H H
N Ar N Ar
H
C

Scheme 13  Possible reaction mechanism for the formation of tetrahydroindolo[3,2-c]quinoline

The mechanism suggests that iodine acts as a gentle Lewis acid catalyst. Initially,
Schiff base A is likely generated through the reaction between the aromatic aldehyde
and the amine by the elimination of a water molecule. Subsequently, the iodine-acti-
vated Schiff base B undergoes a stereoselective Povarov reaction with the indole,
leading to the formation of intermediate C in which the larger aryl and indole moie-
ties are positioned on opposite sides of the quinoline ring. This then undergoes tau-
tomerization, producing the final product (Scheme 13). The generation of intermedi-
ate A in the mechanism was justified when a Schiff base was prepared and reacted
with indole, which gave the desired product with good yield.
Pitre et al. developed a [4+2]-cycloaddition reaction of indole promoted by vis-
ible light for the synthesis of tetrahydrocarbazoles. Their methodology involved
indole as a dienophile and 1,3-cyclohexadiene (1,3-CHD) as an electron-rich diene,
mediated by platinum nanoparticles supported on titanium dioxide semiconductor
particles (Pt(0.2%)@TiO2) (Scheme 14) [28]. The reaction proceeded with a broad
scope, giving up to 72% yield. It is worth noting that the catalyst can be easily recy-
cled and reused up to three times. In the absence of acyl chloride, the reaction gave a
low yield, as the unprotected cycloadduct is prone to oxidatively triggered fragmen-
tation. However, using N-acetyl indole, no reaction was observed, which suggests
that acetylation occurs after the [4+2] cycloaddition.
A tentative mechanism of this reaction is outlined in Scheme 15. Initially, indole
molecules adsorb onto the surface of T ­ iO2, forming a complex with an absorb-
ance spectrum extending into the visible light range. Subsequently, this complex is
excited by an LED light source, leading to the injection of an electron into the con-
duction band (CB) of ­TiO2. To mitigate the occurrence of problematic back-elec-
tron transfer, the electron is initially captured by the Pt nanoparticles situated on
the ­TiO2 surface. Following this, it is quenched either by M ­ eNO2 or by O ­ 2. As the
injected electrons reach equilibrium between the Pt nanoparticles and the ­TiO2 CB,
the quenching action of ­MeNO2 or O ­ 2 serves as a strategy to further diminish the
likelihood of back-electron transfer. Once the indole radical cation is formed, it can
engage in a [4+2] radical cyclization with 1,3-cyclohexadiene. After the cycliza-
tion step, an electron originating from the Pt(0.2%)@TiO2 catalyst can then reduce

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Topics in Current Chemistry (2024) 382:18 Page 15 of 48 18

4mg/mL pt(0.2%)@TiO2 R
H
1 eq. R1COCl, 2 eq. NaHCO3
R +
MeNO2, air,
N N
H 5 eq. hv (10w 460 nm LED), 5-7 h H
R1
O
Br

H H CH3 H
Cl

N N N N
H H H CH3
O O O O
72% (5 h) 56% (5 h) 11% (5 h) 62% (5 h)
Endo:Exo =3.6:1 Endo:Exo =3.2:1 Endo:Exo =2.7:1 Endo:Exo =3.3:1

H H H
H
CO2Et
N N N
N CO2Et H
Fmoc H
t
H H Bu
O O
O
52% (5 h) 16% (5 h) 16% (5 h)
67% (5 h) Endo:Exo =2.9:1
Endo:Exo =2.1:1 Endo:Exo =2.7:1

Scheme 14  Photocatalytic Diels–Alder reaction of indole with 1,3-CHD

Scheme 15  Proposed mechanism for the photocatalytic Diels–Alder reaction of indole with 1,3-CHD
mediated by Pt(0.2%)@TiO2

13
18 Page 16 of 48 Topics in Current Chemistry (2024) 382:18

Ph
Ph
1. OTBS
N
NC H CN
OHC NC
O CN (20 mol%) CHO
CH2(CN)2 *
R3 toluene, 0 oC * R2
TiCl4, THF *
N N 2. NaBH(OAc)3 N
1 4-methylmorpholine R2 R1
AC R AC R
1
DCM, r.t. AC

CN CN CN
NC CH2OH NC CH2OH NC CH2OH
H H H
Ph C6H4-4-Cl C6H4-4-OMe
N N N
Ph Ph Ph
AC AC AC
61%, 95% ee 72%, 96% ee 58%, 98% ee

CN CN CN
NC CH2OH NC CH2OH NC CH2OH

N N N
C6H4-3-Cl C6H4-2-OMe 2-Furyl
AC AC AC
83%, 96% ee 77%, 96% ee 75%, 93% ee

Scheme 16  Asymmetric Diels–Alder reaction for the synthesis of chiral tetrahydrocarbazoles

the tetrahydrocarbazole radical cation. Finally, the tetrahydrocarbazole undergoes

rapid acylation, effectively preventing the over-oxidation and cycloreversion of the
reaction products, which are somewhat more susceptible to oxidation than the initial
indole.
An innovative 2,3-indole-diene building block was conceptualized and synthe-
sized by Gu et al. Its initial utilization involved a selective, inverse-electron-demand
Diels–Alder (IEDDA) reaction to produce tetrahydrocarbazoles. In the presence
of chiral secondary amines as organocatalyst, a diverse array of tetrahydrocarba-
zole derivatives were successfully synthesized in substantial yields by reacting
2,3-indole-diene with enone (Scheme 16) [29]. These reactions exhibited outstand-
ing stereoselectivity, achieving impressive ratios of stereoisomers (exceeding 20:1
d.r.) with exceptional enantiomeric excess (98% ee). To showcase the practical
applicability of this catalytic system, they conducted a reaction on a larger scale,
resulting in the production of cycloadduct with 80% yield and an excellent diastere-
omeric ratio (> 20:1 d.r.), and enantiomeric excess of 96%.
An acceptable explanation was put forward to rationalize the preferential forma-
tion of one enantiomer in the IEDDA reaction. Initially, the reaction between the
enone and the catalyst leads to the formation of enamine A. Subsequently, enamine
A engages in an IEDDA reaction with 2,3-indole-diene, generating intermediate B.
The backbone of enamine A and the steric hindrance posed by its OTBS substituent
establishes a chiral environment that significantly contributes to the remarkable ste-
reoselectivity achieved. Following the hydrolysis of intermediate B, compound C is
produced by releasing the catalyst. The ultimate product is then obtained through a
reduction process (Scheme 17).

13
Topics in Current Chemistry (2024) 382:18 Page 17 of 48 18

NC Ph
CN Ph
OTBS
NC N H
N NC
AC Ph

N
O Ph AC Ph Ph
N
Ph
H OTBS
Cat. H
IEEDA
Ph A
Ph
CN CN
NC NC CN N
CH2OH CHO NC
NaBH(OAc)3 H2 O Ph
Ph Ph TBSO Ph
CH Cl , r.t.
2 2 Ph
N N
Ph N
Ph AC Ph
AC AC
C B

Scheme 17  Proposed mechanism for the synthesis of tetrahydrocarbazoles

In this study, Yang et al. reported the pioneering catalytic asymmetric

Diels–Alder reaction between 3-vinylindole and nitroolefin (Scheme 18) [30].
By utilizing organocatalyst CX, they achieved the synthesis of structurally
diverse 1-nitrohydrocarbazoles in moderate to good yields and high to excel-
lent enantioselectivities. When methyl or phenyl-substituted vinyl moiety was
used, no reaction occurred. Notably, all of the resulting products were obtained
as a single diastereoisomer. Moreover, the obtained 1-nitro-hydrocarbazole com-
pounds can be further transformed into 1-aminohydrocarbazole derivatives and
complex ring-fused indoles with excellent enantioselectivity (Scheme 19).
Zhao and colleagues introduced a novel enantioselective IEDDA reaction
involving indoles and 2-(2-nitrovinyl)-1,4-benzoquinone. This transformation
was facilitated by a chiral bisoxazoline/zinc complex (Scheme 20) [31]. The
procedure led to the synthesis of diverse six-membered [2, 3]-fused indolines
with satisfactory yields (reaching up to 99%) and varying enantioselectivities
(with enantiomeric excess up to 88%). The X-ray crystal structural analysis of
one product enabled the determination of its absolute configuration. Despite the
limitations in terms of substrate scope, this work represents a valuable foray
into innovative asymmetric transformations. The suggested reaction mecha-
nism proposes that the initial step involves the activation of 2-(2-nitrovinyl)-
1,4-benzoquinone by the chiral complex. The interaction between 1,3-dimeth-
ylindole and N–H likely occurs via NH-π interaction, followed by the approach
of the Re face of 1,3-dimethylindole to 2-(2-nitrovinyl)-1,4-benzoquinone. Then
the Diels–Alder reaction yields an intermediate A. Subsequently, the unsta-
ble intermediate A undergoes an oxidation process to yield the final product
(Scheme 21).

13
18 Page 18 of 48 Topics in Current Chemistry (2024) 382:18

O
Ph S CF3
NH HN
Ph
HN
N
Catalyst CX CF3

R2
10 mol% CX R3
R2 R 3
1
4 xylene R
R
R1 R5 R5
NO2 H2O, 50 oC N R 4
+ H
N NO2
H

Br Me

Ph Ph Me Ph
N N N
H NO2 H NO2 H NO2

Yield-61%, 93% ee Yield-41%, 84% ee Yield-30%, 78% ee

NO2

Cl N CF3 N
N
H NO2 H NO2 H NO2
Yield-66%, 92% ee Yield-68%, 90% ee Yield-65%, 89% ee

Scheme 18  Synthesis of carbazoles via [4+2]-cycloaddition reaction

Zn/HCl BzCl
a) Ph MeOH Ph Et N/DMAP Ph
3
N 70% N DCM, 63% N
H NO2 H NH2 Bz NHBz

DCM PhN=O
90%
Br Br Ph
Zn/HCl HO
b)
MeOH
N 80% N
H NO2 H NH2 Ph
N
CsCO3, N2, DMSO, Bz NHBz
CuI (10 mol%)
L-proline (20 mol%) r.t.,75% 95% ee

N
H N
H
86% ee

Scheme 19  Subsequent transformations of carbazoles to different derivatives

13
Topics in Current Chemistry (2024) 382:18 Page 19 of 48 18

R2 N
H
O N N O
R
N
O
+ R1 Bn Bn O
L R2
O
NO2 L/Zn(OTf)2
R
Toluene, 70 oC N H NO2
R1
O

O O O O
O O O O

N H NO2 N H NO2 N H NO2 N H NO2

n
Me Pr Bn Me
99%, 5h, ee 88% 80%, 5h, ee 37% 66%, 5h, ee 56% 79%, 10h, ee 69%

O O O O
O O O O
Cl MeO

N H NO2 N H NO2 N H NO2 N H NO2

Me Me F Me
Me Me
73%, 10h, ee 75% 99%, 5h, ee 57% 65%, 10h, ee 66% 36%, 5h, ee 61%

Scheme 20  Synthesis of [2, 3]-fused indolines via Diels–Alder reaction

NO2
H
N
O
N
O N N O
D-A O
H A
Zn
O O Oxidation

N
N O
O

O
Re face
O N H NO2

Scheme 21  A possible reaction mechanism for the synthesis of [2, 3]-fused indolines

13
18 Page 20 of 48 Topics in Current Chemistry (2024) 382:18

O O
n n n
n
N -CO2 N N
O + CO2H O
N
N H
Bn O O O
n= 0,1,2 N N N
Bn Bn Bn
Azomethine imine intermediates

Scheme 22  Formation of 1,3-dipole by the decarboxylative condensation of isatin with different amino
acids

GWE EWG
O
EtOH N R3
+
R1 O + R3 O
N CO2H
o
r.t.- 50 C, 2h O
N N R1 N
H O
R2 L-proline R4 N R4
R2

Me
CO2Et CO2Et CO2Et CO2Et
OMe
N N N N
O O O O
N N N NH
O O O O
N Bn N Bn N N
Bn Bn Bn
87%, >99:1 dr 69%, >99:1 dr 99%, >99:1 dr 98%, >99:1 dr

COMe CO2Et F CN
COPh
Br
N N N N
O O O O
N N N N
O O O O
N Bn N Bn N Bn N Bn
Bn Bn Bn Bn

93%, >99:1 dr 75%, >99:1 dr 99%, >99:1 dr 91%, >99:1 dr

Scheme 23  Substrate scope of the 3-component 1,3-dipolar cycloaddition reaction

6 [3+2]‑Cycloaddition

An exceptional regio- and stereoselective method for the synthesis of bispirooxin-

doles was developed by Shi and coworkers [32]. This strategy involves a 1,3-dipolar
cycloaddition using azomethine ylides produced in situ from the reaction of isatin
and proline (Scheme 22). These azomethine ylides react with various electron-defi-
cient alkenes, giving the desired bispiro scaffold compounds in very good yields
(Scheme 23). This synthetic approach demonstrates high regioselectivity and oper-
ates under gentle conditions. All the reactions take place at room temperature or
50 °C in ethanol solvent. The stereochemistry of the synthesized compounds was
ascertained through analysis using single-crystal X-ray techniques.

13
Topics in Current Chemistry (2024) 382:18 Page 21 of 48 18

R2
Bn
O N O
O
O N
1 EtOH 1
R R NBn
+
O + r.t., 2h
N CO2H N OO
N
Bn H Bn
L-proline
R2

OMe OMe OMe

O O O
N N N
NBn H3 C NBn Cl NBn
OO OO OO
N N N
Bn Bn Bn
94%, >99:1 dr 75%, >99:1 dr 83%, >99:1 dr
Cl

O O
N N
NBn NBn
OO OO
N N
Bn Bn
90%, >99:1 dr 80%, >99:1 dr

Scheme 24  Substrate scope of 3-component 1,3-dipolar cycloaddition reaction involving different alk-
enes

Another set of electron-deficient alkenes were used in the reactions which pro-
ceeded smoothly to give the [3+2] annulation products in 75–94% yields along
with > 99:1 d.r. values (Scheme 24). Since these compounds gradually decom-
posed during recrystallization, their stereochemistry was not determined. The
authors also investigated other amino acids including L-pipecolic acid or sarco-
sine instead of L-proline and observed the desired bispiro product in almost quan-
titative yield with single stereoisomer (up to 99% yield and > 19:1 d.r.).
Wu and coworkers reported a diastereoselective [3+2] dearomative annulation
of 3-substituted indoles with α-haloketones to synthesize highly functionalized
cyclopenta-fused indoline compounds, which are common structures of many
natural products. The reactions were carried out in the presence of sodium car-
bonate as a base in trifluoroethanol (TFE) solvent (Scheme 25) [33].
Under optimized reaction conditions, the reaction gave good results with dif-
ferent substituents, producing higher yields and diastereoselectivities. In the case
of electron-rich indoles, the reactions were accelerated, whereas indoles having a
strong electron-withdrawing group (such as 5-CO2Me) appeared unreactive. Both
the cyclic and open-chain α-halo ketones were used successfully.

13
18 Page 22 of 48 Topics in Current Chemistry (2024) 382:18

R2 O R2
X R4 Na CO (1.5 eq.)
R3 2 3 R4
R3
N TFE N H
R1 X = Cl, Br R1
O O O O

i
Pr Me
Br

N H N H N H N H
Bn Bn Bn Me
87%, dr- 11:1 84%, dr- 18:1 83%, dr- 11:1 88%, dr- 4.5:1
20 h 23 h 22 h 20 h
Ph
Me O i O O O
Pr Me Me
MeO
Ph
N Me N H N H N H
Bn Bn Bn Bn
81%, 43 h 72%, 45 h 76%, 90 h 47%, 40 h

Scheme 25  Synthesis of highly functionalized cyclopenta-fused indolines

A plausible mechanism is depicted in Scheme 26. The diminished acidity of A’s

α-proton, in contrast to B’s, makes A more resistant against enolization. Further-
more, A’s kinetic acidity may be reduced due to the specific geometric alignment
needed for enolization or tautomerization, which requires the α-proton to be copla-
nar with the carbonyl π-system. Conversely, it is suggested that the enolization of
B ­(kRE2) occurs more rapidly than that of ­kRE1. Density functional theory (DFT)
calculations suggest that the preferred mechanism for the formal cycloaddition may
proceed via hydroxyallyl cations rather than the corresponding oxyallyl cations.
An O-alkylated intermediate is initially formed, followed by isomerization to the
desired product.
Jeffrey and coworkers successfully developed a regioselective dearomative aza-
[3+2] cycloaddition process involving substituted indoles and α-halohydroxamates,
as illustrated in Scheme 27 [34]. This chemical reaction is facilitated by the base
­Na2CO3 and employs hexafluoroisopropanol (HFIP) as the solvent at room tem-
perature. The outcome of this transformation offers a prompt route to highly func-
tionalized pyrroloindolines which are represented in a large number of bioactive
compounds. Different substituted indoles were examined in this reaction. N-alkyl-,
N-benzyl-, N-allyl-, and N-TBS-protected indoles effectively yielded the desired
product. Conversely, unprotected and N-Cbz-protected indoles did not furnish the
targeted cycloadducts. Notably, when dealing with indoles lacking substitution

13
Topics in Current Chemistry (2024) 382:18 Page 23 of 48 18

O kRE1 OH
Ph Ph
RDS
H
Cl Cl kRE1<kRE2
A less acidic OH
Ph

H
O OH
Ph kRE2 Ph
Cl Cl
H H N
Bn
B more acidic

Ph N
Bn H
O
HO
N H H
Bn Ph
KRE4

RDS KRE3 > KRE4 KRE3

O O

Ph Ph
N H N H
Bn Bn
thermodynamilcally kinetically
favoured favoured

Scheme 26  A plausible mechanism for the synthesis of highly functionalized cyclopenta-fused indolines

at the C-3 position, the reaction exclusively yielded the C-2 substituted product
(Scheme 28), accompanied by a minute quantity of cycloadduct. This methodology
was further applied to the streamlined synthesis of the natural product physostig-
mine, starting from pyrroloindoline (Scheme 29).
Santhini et al. developed a multi-component reaction for the synthesis of
pentaleno(1,2-b)indoles involving indole, aldehyde, and pentafulvene in acetonitrile
at room temperature (Scheme 30) [35]. The reaction was catalyzed by a Lewis acid,
Sn(OTf)3. A variety of indoles and aldehydes were successfully used for the reac-
tion. N-Benzoyl- and N-Boc-protected indoles did not respond to this reaction. The
reaction proceeds through a [3+2]-cycloaddition of in situ-generated indolylmeth-
anol and pentafulvene. This strategy provides easy access to biologically relevant
indole derivatives.
Initially, a Lewis acid catalyzes the reaction between indole and aldehyde,
which forms either an intermediate carbocation C or a vinyliminium intermediate

13
18 Page 24 of 48 Topics in Current Chemistry (2024) 382:18

Me Me
R1 O
O R1
R2 Me OBn Na2CO3(2 eq.)
+ N R2 N
N HFIP, r.t. OBn
Me Br H N
R R

Me Me Me Me Me Me
i
Pr O i O Bn O
Pr
MeO
N N N
OBn OBn OBn
N N N
Me Me Me
50%, 3h 63%, 12h 76%, 3h

Me Me Me Me Me Me
O Me O Me O
Me
Br
N N N
OBn OBn OBn
N N N
Me Bn Et
80%, 20h 76%, 20h 79%, 16h

Scheme 27  Synthesis of pyrroloindolines via aza-[3+2] cycloaddition

O O OBn
Na2CO3(2 eq.) NH
+ Me OBn
N Me
N Me Br HFIP, r.t.,3h N
H Me
Me 88%
Me

Scheme 28  Reaction of indole unsubstituted at C-3 position and α-halohydroxamate

Cl O
Me O Me
O Sml2, THF NaOH, CH3I
Me
N
NH DMF, 3h, Me
N 12h, 97% N
OBn N 85%
N Me
Me
Me

Me
Me MeHN O
LAH, 80 oC
N
N Me
THF, 2h Me O N
95% N
Me
Me

Scheme 29  Formal synthesis of physostigmine from the pyrroloindoline

13
Topics in Current Chemistry (2024) 382:18 Page 25 of 48 18

R1

O R2 R2
R2
H Sn(OTf)2 R2
R + R1 +
N MeCN
H r.t., 2h R N
H

Cl

Ph Br Ph Ph
Ph Ph Ph

N N N
H H H
(62%) (55%) (56%)
Me
Cl
Cl
Ph
Ph
Ph
Ph Me

N N
N H
H Me
(40%) (70%) (52%)

Scheme 30  Multicomponent [3+2]-cycloaddition reaction of indole, aldehyde, and diaryl fulvene

D. Subsequently, these intermediates can undergo a cycloaddition with pentaful-

vene to form the desired product. This cycloaddition can happen through either
a simultaneous concerted process or a step-by-step pathway. The initial step
involves a [2+2] cycloaddition of intermediate C/D with a pentafulvene. This is
then followed by a ring expansion through a 1,2-migration mechanism. This con-
certed process results in the formation of the desired product cyclopentalenoin-
doles. Alternatively, the stepwise route involves modification of the fulvene struc-
ture within the ring, using the indole core C/D to generate intermediate E in a
selective location. This is followed by the loss of a proton, leading to the eventual
formation of cyclopentalenoindole product from intermediate F (Scheme 31). A
small amount of hydroheteroarylated product B is formed as a side product.
A highly enantioselective formal [3+2] cycloaddition reaction between azoalk-
enes and 3-vinylindoles efficiently catalyzed by chiral phosphoric acid was devel-
oped by Lu and coworkers (Scheme 32) [36]. This transformation took place
under mild reaction conditions, facilitating the smooth progress of the projected

13
18 Page 26 of 48 Topics in Current Chemistry (2024) 382:18

R1 R1 R1
OH H
LA +

Aldehyde N N N
R R R
C D
A
Ph Ph
N
R

Ph Ph
Path a Path b
Concerted Stepwise
LA

Ph Ph
Ph Ph Ph
R1 H
Ph
R1
N
N R
R N E
B R

R1 Ph R1 Ph
H Ph H Ph

- H+
N N
H H
R R
F

Scheme 31  Plausible reaction pathways for the multicomponent [3+2]-cycloaddition reaction

cycloaddition. As a result, a diverse range of 2,3-dihydropyrroles were pro-

duced with very good yields and exceptional enantioselectivity. Furthermore,
the process exhibited diastereospecificity. Unlike the conventional employment
of 4-atom synthons found in earlier literature, the azoalkenes in this study act
as 3-atom synthons, introducing a novel aspect. The observed selectivity is vali-
dated through primary theoretical calculations. However, the current approach is
unsuitable for the synthesis of 2,3-dihydropyrroles using N-methyl-substituted
vinylindole and 2-methyl-substituted vinylindole as starting materials.
A probable reaction mechanism was suggested (Scheme 33) in which the asym-
metric 1,4-addition of vinylindole to azoalkene is initiated through a hydrogen-bond-
ing activation. In this process, the CPA catalyst serves to activate both participating

13
Topics in Current Chemistry (2024) 382:18 Page 27 of 48 18

SiPh3

O O
P
O OH

SiPh3
EtO2C Ar Catalyst EtO2C
Ar
(1 mol%)
R 1
N + R1
CHCl3, r.t. N
N N
CO2Me H > 20:1 dr NH NH
MeO2C

Me
Me
EtO2C EtO2C EtO2C

N N N
NH NH NH NH NH NH
MeO2C MeO2C MeO2C
96%, 94% ee 99%, 90% ee 99%, 90% ee

Cl F NO2

EtO2C EtO2C
EtO2C

N N
N NH NH NH
NH
NH NH MeO2C MeO2C
MeO2C
80%, 94% ee 92%, 94% ee 91%, 95% ee

OMe OMe Me
EtO2C EtO2C EtO2C
Ph Ph Ph
Et
N N N
NH NH NH NH NH
NH
MeO2C MeO2C MeO2C
90%, 95% ee 85%, 90% ee 88%, 90% ee

Scheme 32  Asymmetric synthesis of 2,3-dihydropyrroles

substrates simultaneously within its chiral pockets. To approach the electrophilic site
in azoalkene, the vinylindole assumes the s-cis conformation. The resultant inter-
mediate A adopts a conformation that ensures a 5-exo attack [3+2] of the iminic
N onto the spatially adjacent C=C bond (path a). This leads to the formation of the
product followed by subsequent steps involving proton transfer and tautomerization.
An alternative route involves the potential for hydrazone-enamine tautomerization,
generating intermediate B. This intermediate subsequently undergoes cyclization,
giving rise to the observed [3+2] product through path b.

13
18 Page 28 of 48 Topics in Current Chemistry (2024) 382:18

EtO2C Ph EtO2C
Ph
(catalyst
N + 1 mol%)
N
N
CO2Me NH NH NH
MeO2C
a
CPA th path b [3+2]
pa

]
+2
*O

[3
*O *O
O P O O P O
H O P O
O O H
N O H
H N N
O H H
N Ph O O
N N Ph N
MeO N N Ph
CO2Et MeO MeO H
CO2Et CO2Et
(H-bonding activation mode)
A B

Scheme 33  A plausible reaction mechanism for the synthesis of 2,3-dihydropyrroles

Scheme 34  Photocatalyzed (3+2) cycloaddition

13
Topics in Current Chemistry (2024) 382:18 Page 29 of 48 18

Scheme 35  Photocatalyzed [3+2] cycloaddition with C2/C3-substituted indoles

Ferreira and coworkers recently reported a direct dearomative photocatalyzed

[3+2] cycloaddition reaction between indoles and vinyldiazo reagents [37]. The con-
version is enabled by the use of a novel oxidizing Cr(III) photocatalyst under a com-
pact fluorescent light (CFL) at around 30 °C in a solvent mixture of nitromethane/
dichloromethane (1:1) in the presence of a base (Scheme 34). A protective reagent is
also used in the reaction to protect the –NH group of indole moiety in the product.
Different acyl halides, including 2,2,2-trichloroethoxycarbonyl chloride (TrocCl),
benzyl chloroformate (CbzCl), and benzoyl chloride (BzCl), were utilized as protec-
tive reagents. The reaction gave moderate to excellent yields of the products.
Indoles having C2 and/or C3 substitution gave poor yield under standard con-
ditions. It was presumed that in the presence of the base which was necessary for
N-acylation, the radical cation intermediate could be competitively deprotonated,
generating a radical species that complicates reactivity. Therefore, a base-free reac-
tion was performed which gave a very good yield of the corresponding products
(Scheme 35). It is worth mentioning that trimethylacetic formic anhydride was effec-
tive as a protective reagent in this case, generating N-formyl cycloadduct in excel-
lent yield. A tentative mechanism was proposed wherein oxidation of the indole
by the Cr(III) excited state generates a radical cation [A] which then adds to the
vinyldiazo compound to yield intermediate [B]. This then undergoes ring closure to
[C], and subsequent reduction by either Cr(II) or indole provides fused indoline [D].
Acylation of [D] then gives the desired product (Scheme 36).

13
18 Page 30 of 48 Topics in Current Chemistry (2024) 382:18

H
R CO2Et
N H
R1
[Cr*]3+ R1-Cl
R [Cr]3+
N base
H
H
R CO2Et
N H
[Cr] 2+ H
R [D] [A]
N H
H
[A] R CO2Et
N H
H Indole
-N2 H CO2Et [C]

CO2Et R N
H
N2 [B]

Scheme 36  Plausible mechanism for the photocatalyzed [3+2] cycloaddition

Sun and coworkers developed a base-controlled dearomative [3+2] cycloaddition

reaction between 3-nitroindoles and fumaric acid amide esters in dichloromethane
[38]. Depending on the base used in the reaction, they isolated three kinds of func-
tionalized pyrrolo[2,3-b]indole derivatives A, B, and C with excellent chemoselec-
tivities and diastereoselectivities [Scheme 37]. Bases including diisopropylamine
(DIPA), triethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were used in
different amounts. In the last case, when the DBU base (4.0 eq.) was added dropwise
(over 20 min) into the reaction, the yield of the corresponding product was surpris-
ingly increased.
A mechanism was proposed based on the control experiments (Scheme 38). Ini-
tially, 3-nitroindole reacts with fumaric acid amide ester to give product A. This then
undergoes an elimination reaction with triethylamine generating intermediate A1,
which then undergoes a reversible tautomerization for generating the correspond-
ing anion A3. Racemic product B is then formed after the protonation. As the –OBn
group has a trans configuration with the adjacent H atom, compound B undergoes
one more elimination reaction with more alkaline DBU to give an intermediate B1
and finally produces product C after the aromaticity-driven tautomerization.
Winne and coworkers reported the [3+2] cycloaddition reactions of various
indoles with a dithioallyl cation in acetonitrile solvent that provided regioselective,
chemoselective, and diastereoselective dearomatized cyclopentannulated derivatives
(Scheme 39) [39]. The reaction was performed at a low temperature (−35 to 0 °C).

13
Topics in Current Chemistry (2024) 382:18 Page 31 of 48 18

Scheme 37  Base-controlled dearomative [3+2] cycloaddition reaction between 3-nitroindoles and fuma-
ric acid amide esters

The reaction uses an excess of a powerful Brønsted acid (triflic acid, 3 eq.) that
paradoxically prevents carbocationic side reactions which are vital to the reaction’s
success. The reaction tolerates many functional groups such as basic amines or free
hydroxyls. The synthetic application of this method is promising, especially for
the quick de novo synthesis of polycyclic scaffolds from easily accessible, reliable
heterocyclic building blocks and for the late-stage alteration of functional indole
substrates.
In a proposed mechanism, the indole reacts with the allylic moiety under acidic
conditions, giving indolenium ion intermediate (I). This intermediate then under-
goes cyclization to give the cyclopentannulated product A in racemic form (path
b). On the other hand, intermediate I undergoes a C3 to C2 rearrangement in the

13
18 Page 32 of 48 Topics in Current Chemistry (2024) 382:18

CO2Et
CO2Et
EtO2C
NO2 O O
path-2
N N
O OBn OBn
N HN N
N
Ts OBn A2 Ts A3 Ts

i
Pr2NH Et3N, - H+ Et3N.H+ Et3N, - H+ Et3N.H+

CO2Et CO2Et CO2Et

H O
O 2N O O
Et3N N
N N
OBn OBn OBn
N H -Et3N.HNO2 N N
Ts Ts Ts
A1 B (0% ee)
A (50% ee)
CO2Et CO2Et
DBU
O O -BnOH

NH aromatization N
N N
Ts
C Ts B1

Scheme 38  Proposed mechanism for the dearomative [3+2] cycloaddition

Scheme 39  Substrate scope and functional group tolerance. a2 eq. of the indole substrate was used. bThis
adduct was isolated as its N-acyl amide

13
Topics in Current Chemistry (2024) 382:18 Page 33 of 48 18

R R S R
S a path-a S
HX
S OH
N -H2O N b S N H S
H X
(I) H H (II)
path-b -H
-H
S
R S R
S

N H S
H N
H
A (rac.) B
Major Minor

Scheme 40  A tentative mechanism for the [3+2] cycloaddition reactions of indoles with dithioallyl cat-
ion

Scheme 41  Cascade hydrogenative and dearomative [3+2] cycloaddition

indole ring, generating intermediate II (path a), which upon deprotonation gives
the minor product B (Scheme 40).
Shang et al. developed the oxidative and hydrogenative dearomative [3+2]
cycloaddition of readily accessible 1H-indole N-tethered o-alkynylbenzalde-
hydes catalyzed by ­PtI4. The strategy provided an efficient process for the che-
moselective synthesis of two structurally distinct benzofused cyclohepta[b]indo-
lines demonstrating exclusive exoselectivity [40]. In the first reaction, toluene as

13
18 Page 34 of 48 Topics in Current Chemistry (2024) 382:18

Scheme 42  THF-enabled ­PtI4-catalyzed hydrogenative and dearomative [3+2] cycloaddition/deacetali-

zation/acetylation

a solvent and an additive phenylmethylsulfoxide (PMSO) were used for 12 h at

80 °C (Scheme 41). In the second reaction, 10 mol% of tetrabutylammonium tri-
bromide (TBATB) was used along with Pt catalyst in MeOH/THF (1:1 v/v) at
room temperature. After the work-up, the reaction mixture was further treated
with 5 mol% DMAP (a base) and acetic anhydride in dichloromethane solvent at
room temperature which gave an acetylated product (Scheme 42).
The proposed mechanism suggests that the initial coordination of ­PtI4 to the C–C
triple bond of alkynylbenzaldehydes generates the Pt(IV)-complex A, which under-
goes 6-endo-dig cyclization to furnish the Pt-bound benzopyrylium intermediate B
or C. Then an intramolecular [3+2] cycloaddition takes place between the reactive
oxonium moiety and the electron-rich C(2)=C(3) bond of the indolyl moiety, giv-
ing the platinum carbene species D. This carbene then undergoes oxidation in the
presence of PMSO to form intermediate E followed by the formation of the desired
product. On the other hand, using solvent THF in the absence of oxidant, the plati-
num carbene species D may undergo hydrogenation to provide platinum intermedi-
ate F along with the tetrahydrofuran cation. A β-oxygen elimination from intermedi-
ate F followed by the migration of the metal produces the oxyplatinum intermediate
G. This then reacts with tetrahydrofuran cation to furnish the corresponding adduct
H and eventually forms the second desired product via intermediate I (Scheme 43).

13
Topics in Current Chemistry (2024) 382:18 Page 35 of 48 18

H OAc H OH H O O
Ac2O TBATB
N N N
O H O H O H
H H H
I
product H
alkynylbenzaldehyde
Pt(IV)
H
6-endo-dig N O
cyclization O [Pt]
H
A PhSMe
N O
O H O[Pt]
H
O N
product O H
O
H H
N [Pt] O G
O N O
O H -O-elimination
B O S Ph
[Pt] H
Me
E N O
O O H
H
S oxidation F [Pt]
Me Ph Path a
O
N H THF
[Pt]
O O Hydrid transfer
C N Path b
dearomative H [Pt]
O
[3+2] cycloaddition
D

Scheme 43  Proposed reaction mechanism for the ­PtI4-catalyzed [3+2] cycloaddition

O
O
Et3N
O 150 oC O
N N
Ts AcO Ts
B
A
70% 5+2

N
H
Ts

Scheme 44  Synthesis of the pentacyclic core by intramolecular [5+2] cycloaddition

13
18 Page 36 of 48 Topics in Current Chemistry (2024) 382:18

EtO2C CO2Et EtO2C O

OTBS MeOTf solvent EtO2C
OMe
40 oC, 12h O
O O then CsF in
N N
DCM/DMF (1:1) H
R R
25 oC, 7h

EtO2C EtO2C EtO2C O

O O
EtO2C EtO2C EtO2C
OMe OMe OMe
O O O

N N N
H H H
Me Ts H

80% 64% 63%

EtO2C O EtO2C EtO2C

EtO2C EtO
OMe 2C EtO2C
MeO O OMe OMe
MeO O F O
N N O O
H H N
Me H
Me Me
90% 85% 45%

Scheme 45  Intramolecular [5+2] cycloaddition

7 [5+2]‑Cycloaddition

Li and coworkers developed an innovative dearomative indole [5+2] cycload-

dition process utilizing an oxidopyrylium ylide [41]. This breakthrough intro-
duces a new framework for the efficient synthesis of highly functionalized and
stereochemically intricate oxa-cyclohepta[b]indoles. They first attempted an
intramolecular reaction with acetoxypyranone A in the presence of triethyl-
amine in C­ H3CN at 150 °C. Although they obtained the expected pentacyclic
core, the high temperature of the reaction limits the overall scope and utility
of this reaction (Scheme 44). They then developed a similar reaction by using
MeOTf as a methylating reagent to form the methoxy pyrylium salt at a low
temperature, followed by the generation of the oxidopyrylium ylide using a fluo-
ride source. It was observed that the reaction proceeded smoothly under very
mild conditions and provided a variety of desired products with average to good
yields (Scheme 45). Under similar reaction conditions, they performed an inter-
molecular dearomative [5+2] cycloaddition reaction of indole and maltol which
occurred smoothly to give the tetracyclic core (Scheme 46). Notably, this study
marks a pioneering instance of a [5+2] cycloaddition reaction, wherein the 2π
component originates from the C2=C3 bond of an indole. These reactions, both

13
Topics in Current Chemistry (2024) 382:18 Page 37 of 48 18

R3 O R3
MeOTf R2
R2 OH H
40 oC, 12h; OMe
+ O

N Me2NPh
O Me N O
R1 25oC, 7h H
R1 Me

H Cl
H OMe H
OMe O OMe
O O

N O N O N O
H H H
Me Me Bn Me Me Me

61% 56% 47%

Me
F
H H
OMe OMe
O O

N O N O
H H
Me Me Me Me
32% 63%

Scheme 46  Intermolecular [5+2] cycloaddition

CsF(4.0 eq.)
TMS
18-crown-6 (2.5 eq.)
R Ar R1 R R1
N + CH3CN,r.t, 0.5h, air
H OTf N
Ar

N N N
N
Me
76% 65% CN 70% 74%
CF3
Me
OMe
Br
Me

N N
N Ph Ph N
Ph Me Ph
52% 67% 63% 72%

Scheme 47  [5+2] Cycloadditions of 2-aryl-1H-indoles with 2-(trimethylsilyl) aryl trifluoromethanesul-

fonates

13
18 Page 38 of 48 Topics in Current Chemistry (2024) 382:18

CsF(4.0 eq.) Ar
TMS
18-crown-6 (2.5 eq.)
R + Ar
CH3CN, r.t, 1h, air N R
N OTf
H
Ar

Me

Me

Me N Me
N
N Me N F
Me

Me
71% 82% 77%
74%

N Bn
Me N N
N

69% 86% 83% 53%

Scheme 48  [2+2] Cycloaddition of 1H-indoles with 2-(trimethylsilyl) aryl trifluoromethanesulfonates

intramolecular and intermolecular, occur under remarkably gentle conditions,

showcasing exclusive endo selectivity.
Chen et al. reported a unique [5+2] cycloaddition reaction that enables
the synthesis of a variety of dibenzo[b,e]azepine derivatives in moderate to
good yields [42]. They achieved the reaction by reacting indoles with ortho-
(trimethylsilyl)aryl triflates in acetonitrile solvent at room temperature. A stoi-
chiometric amount of a base (CsF) was used along with 18-crown-6 as additive
(Scheme 47).
They observed that when steric hindrance at the C2-position of 1H-indoles
increased, it led to the [2+2] cycloaddition under similar reaction conditions
(Scheme 48). In this case the reaction time was a bit longer than the earlier one.
Mechanistic investigations suggest that the reaction of 1H-indoles with arynes
initially undergoes a [2+2] cycloaddition step, which is followed by a ring
expansion to the [5+2] cycloaddition product (Scheme 49).

13
Topics in Current Chemistry (2024) 382:18 Page 39 of 48 18

(1) [5+2] cyclization pathway

TMS
CsF
OTf

Ph Ph
N N N Ph
H H I H II
H2O
H3O
H2O or H3O

N N
Ph Ph III

(2) [2+2] cyclization pathway

Me N-arylation
Me Me
N
H N N
H Ph

Me
N
II'
N Me Ph
Ph

Scheme 49  Proposed reaction mechanism for the synthesis of dibenzo[b,e]azepine derivatives

8 [2+2]‑Cycloaddition

Bandini and coworkers pioneered an exceedingly enantioselective approach to

synthesize densely functionalized 2,3-indoline-cyclobutanes. This was achieved
utilizing chiral gold catalysis at low temperatures in dichloromethane solvent
(Scheme 50) [43]. Through intermolecular formal [2+2]-cycloaddition reactions
involving substituted indoles and allenamides, they achieved a direct route to
methylenecyclobutane-fused indolines. Remarkably, this method creates two con-
secutive quaternary stereogenic centers with stereochemical control (with a dias-
tereomeric ratio exceeding 20:1 and enantiomeric excess reaching 99%). When
the reaction was performed with N-free-2,3-dimethylindole under optimal reac-
tion conditions, only 8% indoline product was obtained, highlighting the impor-
tance of introducing a N-EWG. N-Cbz-indole also performed very well, giving
high enantiomeric excess.

13
18 Page 40 of 48 Topics in Current Chemistry (2024) 382:18

O PAr2
O PAr2

O
Ar = 3,5(tBu)2-4-(OMe)C6H2
R3 O L R3
R O [Link] (5 mol%) R
R2 N
N L (2.5 mol%)
N R2 N O
C AgOTf (5 mol%)
R1 R1
DCM, 16 h, -16 oC O

MeO Me Br

N N O N N O N O
N N O N
Boc Boc Boc
O Boc O
O O

96%, ee-94% 94%, ee-95% 96%, ee-98% 41%, ee-99%

Me MeO Me

N O N O N O N N O
N N Et N
Boc Boc Boc Cbz
O O O O

90%, ee-81% 90%, ee-86% 72%, ee-92% 60%, ee-96%

Scheme 50  Synthesis of densely functionalized 2,3-indoline-cyclobutanes

The proposed catalytic cycle in Scheme 51 outlines the reaction mechanism.

Initially, the chiral cationic gold complex coordinates with the allenamide, result-
ing in the formation of the electrophilic intermediate A. Subsequently, the indole
molecule selectively attacks the γ-position of A, generating the gold-alkenyl inter-
mediate B. At this point, two reaction pathways are possible: Path (a) involves a
secondary ring-closure facilitated by the nucleophilicity of the enamine segment,
leading to the formation of the alkyl-gold intermediate C. The final rearrange-
ment in this pathway restores the catalytic species, yielding the end product. Con-
versely, in path (b), the gold-alkenyl intermediate B directly transforms into the
final cyclobutane product via a concerted-like process. Notably, the remarkably
high stereoselectivity observed during the second ring-closure event (the forma-
tion of the exo-C=C double bond with Z configuration) supports the likelihood of
the concerted-like reaction (path b) as the primary route.
A novel accomplishment in the field of catalytic intramolecular reactions was
achieved by You and coworkers. Specifically, an innovative approach was devel-
oped to facilitate the intramolecular [2+2] cycloaddition of indoles or pyrroles with
alkyne moiety through the utilization of visible-light-mediated energy-transfer catal-
ysis (Scheme 52) [44]. An iridium complex was chosen as the photosensitizer and
blue LED as the light source for the reaction This groundbreaking technique enabled
the efficient formation of cyclobutene-fused indolizidines, a class of compounds

13
Topics in Current Chemistry (2024) 382:18 Page 41 of 48 18

N O

O +
[Au] A
O X N
N Boc
C
product a O

b N O
[Au(I)]X a
path b
N [Au] B
Boc

[Au]
N O path a
Boc N
N N O
O C Boc
O

Scheme 51  Proposed catalytic cycle for the enantioselective [2+2]-cycloaddition

that are typically challenging to synthesize. Remarkably, this process resulted in

high yields and exceptional selectivity. The progression of the reactions has been
comprehensively explored through the application of DFT calculations. Further-
more, the applicability of this method extends to the creation of cyclobutane-fused
indolizidines and analogous structures (Scheme 53). The versatility of this proto-
col is demonstrated through the successful attainment of various product variations.
Significant characteristics of this approach encompass a wide range of applicable
substrates, accommodating various functional groups effectively. Additionally, the
procedure itself is straightforward and easy to carry out. It is worth noting that the
demonstrated scalability and the ability to introduce functional groups at later stages
highlight its potential value in pharmaceutical and agrochemical research endeavors.

9 Miscellaneous

An intermolecular formal cycloaddition of indoles with various bicyclo[1.1.0]

butanes (BCBs) was reported by Ni et al. The reaction provided a direct construction
of polycyclic indoline skeletons. It was catalyzed by Lewis acid Yb(OTf)3 in dichlo-
romethane at room temperature under a nitrogen atmosphere (Scheme 54) [45]. It is
worth mentioning that the reaction also tolerates various electron-donating and elec-
tron-withdrawing substituents on the indole benzene ring as well as BCBs and could
be performed at gram scale. The structure of the product was unambiguously deter-
mined by single-crystal X-ray analysis. First, to optimize the reaction conditions,

13
18 Page 42 of 48 Topics in Current Chemistry (2024) 382:18

CF3
F
t
Bu
N
N
F
Ir
F PF6
N
N
t
Bu
F
CF3 R2 1
R3 R2 R
Photosensitizer R3
X R1 N
N DMSO, r.t., X
blue LED n=1,2
O O n
n

CO2Et CO2Me Ph CO2Et

F

N N N N

O O O O
84% 79% 98% 86%

CO2Me CN CO2Et
CO2Et
MeO

N N N
N N
O O
O O
43% 21% 75% 49%

Scheme 52  Synthesis of cyclobutene-fused indolizidines irradiated by visible light

3-methylindole was used in the presence of Cu(OTf)2 as the Lewis acid. Although
the desired cycloaddition reaction took place, a BCB substitution on indole nitrogen
occurred, which indicated the need for N-protected indole in the reaction. However,
N-Boc indole did not give the reaction.
The proposed mechanism shows that, initially, a nucleophilic addition of indole
with Lewis acid-activated BCB takes place to form indole iminium intermediate A.
Subsequently, an intramolecular Mannich cyclization of the tetrasubstituted enolate
and indole iminium carbon produces the desired product (Scheme 55).
Sun et al. investigated an acid-catalyzed cycloaddition reaction between
3-(indol-3-yl)maleimides with different structural varieties of (indol-2-yl)
methanols [46]. p-Toluene sulphonic acid was used as the catalyst, and chlo-
roform or acetonitrile was used as a solvent. Depending on the structures of
(indol-2-yl)methanols, the reaction gave different products via formal [4+3]
cycloaddition and formal [3+2] cycloaddition processes. It was observed that
an unusual rearrangement of the maleimide moiety occurred from the C3- to
C2-position of the indole ring in the reaction. This reaction successfully

13
Topics in Current Chemistry (2024) 382:18 Page 43 of 48 18

R2 R2 1
R3 Photosensitizer R
(1 mol%)
R3
X R1 MeOH, r.t., N
N X
blue LED n=1,2
O O n
n

CO2Et CO2Me Ph CO2Et

F

N N N N

O O O O
99% 99% 99% 99%

CO2Me CN CHO CO2Et

N N N N N

O O O O

97% 85% 88% 98%

Scheme 53  Synthesis of cyclobutane-fused (benz)indolizidines

Scheme 54  Synthesis of complex polycyclic indolines

13
18 Page 44 of 48 Topics in Current Chemistry (2024) 382:18

LA
O O
R3 O
R1 1 R3 R
R 1
Mannich R3
3 N
R2 cyclization
N Lewis acid R2
R N R2
R1
R1= H, alkyl R

Scheme 55  Possible reaction pathways of formal cycloaddition reactions with indoles and BCBs

R R
N O
O N O
O
Me
Ar p-TsOH N
Ar
N N OH CHCl3, 65 oC N
H H Ar Ar
Me
A
R = Ar = Ph; 76%
R = Me, Ar = Ph; 78%
R = Bn, Ar = Ph; 78%
R = Me, Ar = 4-F-C6H4; 85%
R = Bn, Ar = 4-Me-C6H4; 72%

Scheme 56  Synthesis of functionalized pyrrolo[3′,4′:6,7]cyclohepta[1,2-b:4,5-b′]diindoles

R1 R1
O H R1 O
N O
O
N
O N O O N O
R 3 R3
HO N N
R2 p-TsOH
O CH3CN N N
HN HN
N N 60 oC Me Me
Me R3
B C R2
R2

R1 = Me, R2 = H, R3 = Bn; 88% B, 0% C

R1 = Me, R2 = Me, R3 = Bn; 87% B, 0% C
R1 = Ph, R2 = H, R3 = Bn; 66% B, 17% C
R1 = Ph, R2 = F, R3 = Bn; 65% B, 17% C

Scheme 57  Synthesis of functionalized spiro[indoline-3,9′-pyrrolo[3′,4′:4,5] cyclopenta[1,2-b]indoles

provides simplified and efficient methods for the synthesis of functional-

ized pyrrolo[3′,4′:6,7]cyclohepta[1,2-b:4,5-b′]diindoles A (Scheme 56) and
spiro[indoline-3,9′-pyrrolo[3′,4′:4,5] cyclopenta[1,2-b]indole derivatives B and
C (Scheme 57) in satisfactory yields having high diastereoselectivity. When they
used 2-hydroxy-2-(indol-3-yl)-indene-1,3-diones having unsubstituted NH of

13
Topics in Current Chemistry (2024) 382:18 Page 45 of 48 18

R1 R1
O R1 O
N O O N
O O N O R2
O
N
OH
p-TsOH
CH3CN N N
N N O
O 60 oC Me R2 O Me
Me N O
R2
D E
1 2
R = Me, R = H ; 76% D, 18% E
R1 = Ph, R2 = H ; 78% D, 17% E
R1 = Bn, R2 = H ; 75% D, 21% E

Scheme 58  Synthesis of functionalized spiro indene derivatives

indole moiety in the reaction, functionalized spiro[indene-2,9′-pyrrolo[3′,4′:4,5]

cyclopenta[1,2-b]indoles] D were formed as major products and spiro[indene-
2,9′-pyrrolo[3′,4′:6,7]-cyclohepta[1,2-b:4,5-b′]diindole] E as minor products
(Scheme 58).
In the proposed mechanism (Scheme 59), an active protonated species (I) is
first formed in the presence of acid, which then reacts with 3-(indol-3-yl)maleim-
ide, giving the intermediate (II). An intramolecular Michael addition then takes
place, giving a cyclic intermediate (III) followed by a carbocation rearrange-
ment which gives a new carbocation intermediate (IV). An elimination of a pro-
ton from the intermediate (IV) furnishes the intermediate (V) followed by aerial
oxidation which gives the product A. In the case of 3-hydroxy-3-(indol-3-yl)-
indolin-2-ones in the reaction, the initial protonation generates a similar active
carbocation (VI). Next, the electrophilic addition reaction of carbocation (VI) to
the C=C double bond of 3-(indol-3-yl)maleimide forms the carbocation (VII),
which subsequently undergoes intramolecular Friedel–Crafts reaction to give the
cyclopentyl intermediate (VIII) and eventually furnishes the diastereoisomeric
products B and C upon deprotonation.

10 Conclusions

Cycloaddition reactions are highly attractive as they are fully atom-economical, pro-
ducing zero by-products in the reaction. Therefore, organic chemists are continu-
ously trying to expand this area toward sustainable development. The cycloaddition
reactions of indoles represent a captivating domain of synthetic organic chemistry,
offering a treasure trove of diverse and valuable heterocyclic motifs. Throughout this
review, we have explored diverse cycloadditions of indoles, including [4+3], [4+2],
[3+2], [5+2], and [2+2] formal cycloadditions and their possible applications. Bio-
logically important indole derivatives such as carbazoles, pyrrolo[2,3-b]indoles,
azepine derivatives, indolizidines, and cyclohepta diindoles can efficiently be syn-
thesized via cycloaddition of indoles. The ability of indoles to engage in versatile
and regioselective cycloadditions has not only extended the synthetic toolbox but
also paved the way for the efficient construction of complex heterocyclic structures.

13
18 Page 46 of 48 Topics in Current Chemistry (2024) 382:18

R
N O
O
Ph O O
Ph OH Ph
Ph OH2 R R
N N
N O NH O NH
NH NH
H Me Ph Ph
Ph Ph
-H2O N N
Me Me
(I) (II) (III)

HN HN HN
Ph Ph Ph
Ph Ph Ph
O [O] O O
-H+

N N N N N N
R R R
Me O Me O Me O
(V) (IV)
Product A R1
N O Me
O N
H O
H R1
N N N
H
HO N N
H2 O O
H Me
O O
-H2O
N N N O
R R
(VI) R (VII)
Me Me
N N
O O
R1 R1
N N
H -H H
N N
O O

N O N O
R R
(VIII) Product B and C

Scheme 59  Probable mechanism for the synthesis of polycyclic compounds

This review article can serve as a valuable resource for researchers interested in
indole-based cycloadditions, inspiring further exploration and innovation in the field
of organic synthesis.
Acknowledgements The author MLD acknowledge the University of Science and Technology, Megha-
laya, for the library facility, and BB acknowledge Pandu College for the same.

Data availability The data reported in this review article is available in the original paper mentioned in
the references.

13
Topics in Current Chemistry (2024) 382:18 Page 47 of 48 18

Declarations
Conflict of interest The authors declare no conflicts of interest.

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Authors and Affiliations

Biswajita Baruah1 · Choitanya Dev Pegu2 · Mohit L. Deb3

* Biswajita Baruah
biswajitabaruah@[Link]
* Mohit L. Deb
[Link]@[Link]
1
Department of Chemistry, Pandu College, Guwahati, Assam 781012, India
2
Department of Chemistry, Madhabdev University, Lakhimpur, Assam 784164, India
3
Advanced Research Centre and Department of Chemistry, University of Science
and Technology Meghalaya, Ri‑Bhoi, Meghalaya 793101, India

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