Volume 16 Number 9 7 March 2018 Pages 1393–1610

Organic &
Biomolecular
Chemistry
rsc.li/obc

ISSN 1477-0520

REVIEW ARTICLE
Alejandro Islas-Jácome, Eduardo González-Zamora et al.
Synthesis of polyheterocycles via multicomponent reactions
Organic &
Biomolecular Chemistry
REVIEW

Synthesis of polyheterocycles via multicomponent

Cite this: Org. Biomol. Chem., 2018,
reactions
16, 1402 a
Ilich A. Ibarra, Alejandro Islas-Jácome *b and Eduardo González-Zamora *b

Polyheterocycles are one of the most desired synthetic targets due to their numerous and valuable appli-
cations in various fields. Multicomponent reactions (MCRs) are highly convergent one-pot processes, in
which three or more reagents are combined sequentially to construct complex products, with almost all
the atoms coming from the starting reagents. In this context, the syntheses of ‘heterocycles’ via MCR-
based processes have been reviewed a number of times. However, there is not a single review (recent or
otherwise) covering the synthesis of ‘polyheterocycles’ via a direct MCR or via a one-pot process involving
MCRs coupled to further cyclizations (via ionic, metal-catalyzed, pericyclic, or free-radical-mediated
cyclizations). This issue is consequently the main topic of the present review, which considers work from
Received 14th September 2017, the last decade. The work is categorized according to the key processes involved in the syntheses of poly-
Accepted 29th November 2017
heterocycles, aiming to give readers an easy understanding of this MCR-based chemistry and to provide
DOI: 10.1039/c7ob02305g insights for further investigations. The reaction mechanisms providing novel elements to these MCR-
rsc.li/obc based methods for the synthesis of polyheterocycles are also discussed.

1 Introduction
Polyheterocycles are complex organic molecules formed by two
a
Laboratorio de Fisicoquímica y Reactividad de Superficies (LaFReS), Instituto de (bis-heterocycles) or more (tris-, tetra-, and so on) heterocyclic
Investigaciones en Materiales, Universidad Nacional Autónoma de México, Circuito moieties joined in different forms or connectivities (merged,
Exterior s/n, CU, Del. Coyoacán, 04510, Ciudad de México, Mexico
b
bound, fused, linked, or spaced). According to their origin,
Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, San
Rafael Atlixco 186, Col. Vicentina, Del. Iztapalapa, 09340, Ciudad de México, Mexico.
polyheterocycles can be classified into natural1 or synthetic
E-mail: [email protected], [email protected] products.2 Representative examples of the former include

Ilich A. Ibarra was born in Alejandro Islas-Jácome was born

Mexico City in 1981. He com- in Veracruz, México, in 1981. He
pleted his BSc at UAM-I, Mexico got his BSc in 2005 and PhD in
in 2005. Later, in 2010, he 2011 under the guidance of
obtained his PhD in Chemistry Professor Eduardo González-
under the supervision of Zamora in UAM-I, México. Then,
Professor Martin Schröder at he was a post-doctoral fellow in
Nottingham University (UK). He Rocío Gámez-Montaño’s research
then took a postdoctoral posi- group in 2012–2016 at the
tion, 2010–2012, at The Universidad de Guanajuato,
University of Texas at Austin México. Currently, he is a visit-
(USA) under the supervision of ing professor in the
Ilich A. Ibarra Professor Simon Humphrey. Alejandro Islas-Jácome Departamento de Química,
Then, in 2013 he was awarded a UAM-I, México. His research
Wenner-Gren researcher position at Stockholm University interests include the sustainable synthesis of polyheterocycles via
(Sweden) under the supervision of Professor Xiaodong Zou. In multicomponent reactions, click chemistry, computational studies
2014, he moved to UNAM (IIM, Mexico), working as an assistant of reaction mechanisms, experimental determination of optical
professor. In 2017, he was promoted to associate professor. properties, as well as biomolecular chemistry.

1402 | Org. Biomol. Chem., 2018, 16, 1402–1418 This journal is © The Royal Society of Chemistry 2018
Organic & Biomolecular Chemistry Review

(±)-Aspidofractinine, (+)-Rebeccamycin, and Didemnimide A, synthesis for medicinal chemistry that has been strongly influ-
which are indole-based tris-heterocycles.3 Polyheterocycles enced by MCRs is Combinatorial Chemistry (CC). D. G. Hall
have found many interesting applications in various fields; for reviewed the synthesis of novel compounds containing the
example, in optics,4 dyes and pigments science,5 materials and same heterocyclic system (chemical libraries) under ultra-high
polymer science,6 coordination chemistry,7 and agrochemis- output modes by changing the substituents (i.e., via decora-
try.8 However, their main importance lies in medicinal chem- tion) of the starting reagents.17 In addition, from the Target
istry because a wide variety of bioactive compounds and com- Oriented Synthesis (TOS) approach, MCRs can be considered
mercially available drugs contain polyheterocyclic systems in as key synthetic tools because a variety of complex specific
their structures.9 Of course, the size, structural complexity, targets (or at least their precursors) and some natural products
and molecular weights increase directly with the number of containing polyheterocycles in their structures have been syn-
heterocycles embedded in the same polyheterocyclic mole- thesized successfully by multistep strategies in which an MCR
cules. In this context, the rules and parameters related to the was involved in the beginning, middle, or end of the synthetic
applicability of organic compounds in drugs (those favorable methodology. As a very sound example, the polyheterocyclic
for small molecules with MW < 500 Da), such as the Lipinski schistosomiasis-drug Praziquantel (PZQ) was synthesized first
rules,10 Ghose rules,11 and Veber criteria,12 are not commonly by A. Dömling using an MCR-based method in a truly excellent
obeyed by polyheterocycles. Even so, vancomycin ( potent post- overall yield (77%), considering the molecular complexity of
surgical antibiotic characterized by having macrocyclic and the PZQ and the robustness of his synthetic strategy.18 As can
polypeptidic biaryl/biaryl-ether moieties) is a clear example be seen from this example, MCRs allow the synthesis of novel
that bigger polyheterocycles can be used in medicinal chem- and complex polyheterocycles from the three key approaches
istry, despite their ‘big/XL size’.13 for organic synthesis in medicinal chemistry (DOS, CC, and
Moreover, as was discussed by M. Yus, multicomponent TOS).19
reactions (MCRs) are privileged one-pot processes, which Moreover, R. Lavilla proposed four key roles of MCRs in
should be differentiated from other kinds of processes, like heterocyclic chemistry: (i) synthesis of heterocycles via direct
tandem, cascade, and zipper processes, because they involve MCRs; (ii) synthesis of heterocycles via MCRs/further cycliza-
sequential combinations of at least three reagents in the same tions; (iii) synthesis of heterocycles using starting reagents
pot (flask, tube, reactor, etc.).14 MCRs have found their main decorated with heterocyclic moieties; and (iv) functionalization
usefulness in Diversity Oriented Synthesis (DOS),15 where a of heterocycles via MCRs.20 These four key roles of MCRs can
series of novel polyheterocycles with different skeletons have be extrapolated to ‘polyheterocyclic chemistry’ in order to
been synthesized in a one-pot manner based on the four strat- increase the molecular complexity and substrate scope of
egies proposed by R. V. A. Orru, namely: (i) Single Reactant MCR-based synthetic strategies (Scheme 1). Besides, MCRs can
Replacement (SRR); (ii) Modular Reaction Sequences (MRS); be divided into two major groups: (i) Isocyanide-based MCRs
(iii) Conditions-Based Divergence (CBD); and (iv) A combi- (I-MCRs), and those not based on the use of isocyanides as
nation of two or more MCRs.16 Another key area of organic starting reagents. It is noteworthy that the isocyanide (RNC) is

Eduardo González-Zamora, full

professor at UAM-I, Mexico, was
born in 1961 in Mexico City. He
received his MSc degree from
UAM-I in 1988. In 1994, he
moved to France and obtained
his PhD (1998) from Paris XI
University (France) under the
supervision of Professor
R. Beugelmans. After one year of
post-doctoral work with
Professor R. Cruz at the Instituto
Eduardo González-Zamora de Química (UNAM, Mexico), he
joined the “Institut de Chimie
des Substances Naturelles”, CNRS (France) in 2000 as a post-
doctoral fellow for two years working with Professor J. Zhu. In
2011, he moved to UCLA (USA) as a visiting professor in
M. A. Garcia-Garibay’s group. His research interests include the
synthesis of heterocycles by MCR, MOFs’ chemistry, peptides, and
total synthesis. Scheme 1 Synthesis of polyheterocycles via I-MCR-based processes.

This journal is © The Royal Society of Chemistry 2018 Org. Biomol. Chem., 2018, 16, 1402–1418 | 1403
Review Organic & Biomolecular Chemistry

a special kind of functional group that can act as a nucleophile

or electrophile depending on its substituents and substrates
because it has a very reactive carbenic carbon atom.21 Classic
I-MCRs, like the Van Leusen,22 Passerini,23 and Ugi reaction24
in all of its variants (3-CR, 4-CR, Ugi-azide, Ugi-Smiles, Ugi-
Nenajdenko, Ugi-Reissert, and Ugi-interrupted (Groebke–
Blackburn–Bienaymé)), represent the great majority of the
MCRs in current reports describing the synthesis of polyhe-
terocycles via MCRs. The covering of this issue is the main
objective of the present review (chapters 2 to 6). In addition, a
few reports describing the use of non-isocyanide-based MCRs
toward polyheterocycles are also covered as a miscellaneous
topic (chapter 7.1). Thus, the synthesis of polyheterocycles
(bis-, tris-, and tetra-) via direct MCRs and one-pot processes
involving MCRs coupled to further cyclizations (via ionic,
metal-catalyzed, pericyclic, or free-radical-mediated cycliza-
tions) are reviewed (Scheme 1). On the contrary, the synthesis
of ‘monoheterocycles’ via MCRs (whether or not based on the
use of isocyanides) will not be considered.20a,25 It is note-
worthy that polyheterocycles containing up to four hetero-
cycles have been synthesized successfully via MCR-involved Scheme 2 Synthesis of the mesoionic polyheterocycles 4 and 5 via a
processes, but in the same way, we considered it pertinent not novel direct 3-CR.
to address them in the present review.

2 Synthesis of polyheterocycles via

direct I-MCR
Despite it being most common to synthesize polyheterocycles
via I-MCRs/further cyclizations (chapters 3 to 6), in the present
chapter some representative direct I-MCR-based methods
toward a variety of polyheterocyclic-based compounds are
reviewed.
Thus, R. Lavilla reported in 2009 a novel synthetic method
toward various mesoionic polyheterocycles via a direct
functionalization of polysubstituted azines 3 ( pyridines, pyri-
dazines, quinolines, isoquinolines, and phthalazines) with a
variety of isocyanides 2 (alkyl and aryl) and some halogen-con-
taining acylating agents 1 using DCM as a solvent.26 The pro-
posed reaction mechanism involved an initial acylation step
for the isocyanide (cyclohexyl isocyanide was chosen to show
the mechanism) with a halogen-containing acylating agent
(TFAA was chosen to show the mechanism), followed by N-sp2
nucleophilic attack of the corresponding azine (isoquinoline
was chosen to show the mechanism) to synthesize the acid-
fluoride-functionalized polyheterocycles 4 after some sequen-
tial steps. It is noteworthy that the Arndtsen dipoles 5 (depend-
ing on the azine and isocyanide used) were obtained as bypro-
ducts (Scheme 2).
By using his previously developed methodology, in 2016,
R. Lavilla synthesized four new BODIPY-containing mesoionic
acid fluorides 9a–d via a direct 3-CR using the isoquinoline-
BODIPYs 6a–b, trifluoroacetic anhydride (7), and the isocya-
nides 8a–b under mild reaction conditions (DCM, rt, 24 h) in
29% to 35% yields (Scheme 3). The Arndsten dipoles 10a–b Scheme 3 Synthesis of the fluorescent polyheterocycles 9a–d
were detected as byproducts when BnNC (8b) was used in the (quantum yield, Φ = 45–59% in EtOH) via a direct 3-CR.

1404 | Org. Biomol. Chem., 2018, 16, 1402–1418 This journal is © The Royal Society of Chemistry 2018
Organic & Biomolecular Chemistry Review

MCRs. Compounds 9a–d were synthesized to take advantage of

the acid fluoride functional group for the fluorescent derivati-
zation of amine-containing biomolecules under mild and cata-
lysis-free conditions. In fact, the antifungal drug natamycin
was peptidically coupled to the product 9b for imaging into
fungal cells, which in turn was done successfully.27
A closer work was reported by R. Lavilla and R. Gámez-
Montaño in 2016, where a variety of polysubstituted azines 11
(isoquinolines, bis-isoquinolines, quinolines, quinoxalines,
and phtalazines) were combined sequentially with the TMSCl
(12) and a variety of isocyanides 13 (alkyl and aryl) to syn-
thesize the fused-type imidazo-isoquinolin chlorides 14 in
37% to 92% yields via a 3-CR, which involved presumably the
insertion of a first isocyanide molecule into the N–Si bond of
the corresponding N-activated azine followed by the further
nucleophilic attack of a second isocyanide molecule under a
Reissert-type process (Scheme 4). The hypothesis behind this Scheme 5 Synthesis of the polyheterocycles 18 via a direct Van Leusen
plausible reaction mechanism was supported by compu- reaction.
tational studies by calculating the Intrinsic Reaction
Coordinates (IRCs). Finally, some of the products 14 were eval-
uated in vitro against the parasites causing two of the most dis- of more resources, like solvents, materials for chromatography,
seminated tropical diseases: Trypanosona brucei (African sleep- time, and energy.
ing sickness) and Trypanosona cruzi (Chagas disease), finding In 2007, M. Adib reported a direct catalyst-free three-com-
pharmacologically relevant values of EC50, for example, of ponent reaction from the 2-aminoazines 19, aldehydes 20, and
0.50 μM against T. brucei, and 1.02 μM for T. cruzi.28 isocyanides 21 using water as a solvent to synthesize the bis-
In 2017, A. Sharma synthesized a series of novel polyhetero- heterocycles 22 (analogs of the hypnotic drug Zolpidem) and
cyclic dihydrodibenzo[b,f ]imidazo[1,2-d][1,4]azepines 18 via a 23 (analogs of the anthelmintic drug Levamisole) in excellent
Van Leusen reaction from the ortho-functionalized anilines 15 yields, 85–97% (Scheme 6).30 It is noteworthy that this I-MCR
(–OH or –SH), the ortho-chlorobenzaldehydes 16, and the iso- is an interrupted variant of the classic Ugi-3CR, which was
cyanides 17 in 73% to 94% yields using microwave as a heat then known as the Groebke–Blackburn–Bienaymé Reaction
source to improve the initial condensation step between 15 (GBB) in honor of its developers in 1998.31
and 16 (Scheme 5).29 It is noteworthy that there are few reports
describing the synthesis of this class of imidazo-fused poly-
heterocycles, but via stepwise methods, which involve the use

Scheme 4 Synthesis of the mesoionic polyheterocycles 14 via a direct

3-CR involving an unprecedent insertion of an isocyanide molecule into Scheme 6 Synthesis of the polyheterocycles 22 and 23 via a direct
a N–Si bond. 3-CR Groebke–Blackburn–Bienaymé.

This journal is © The Royal Society of Chemistry 2018 Org. Biomol. Chem., 2018, 16, 1402–1418 | 1405
Review Organic & Biomolecular Chemistry

Actually, there is some controversy about the mechanism 3 Synthesis of polyheterocyles via
involved in the GBB reaction because the cyclization step to
construct the polyheterocyclic system can occur in two I-MCR/ionic cyclizations
manners: concerted or step-by-step.32 This reaction has been I-MCR/ionic cyclization strategies have been used successfully
used extensively toward a variety of fused-type polyheterocycles toward the synthesis of various polyheterocyclic products. In
with interesting applications in medicinal chemistry and this context, the following methodologies are reviewed as
agrochemistry.33 representative examples.
In 2009, L. Grimaud and L. El Kaïm reported the first E. van der Eycken reported in 2016 the synthesis of various
example of an Ugi-Smiles 4-CR to construct polyheterocyclic novel N-heterocycle-containing α,β-unsaturated-γ-lactams via
architectures. Ugi-Smiles is a variant of the Ugi reaction, in an Ugi-4CR/intramolecular Michael addition in moderate to
which carboxylic acids are replaced by deactivated phenols or good yields. Thus, the N-heterocycle ( pyridine, thiazole, imid-
hetero-aryl alcohols. It is noteworthy that L. Grimaud and L. El azole, quinoline, and benzo[d]thiazole)-containing aldehydes
Kaïm have become known as the pioneers behind this MCR- 31 were combined sequentially with the amines 32, the
based chemistry. Thus, N-(hetero-aryl)piperidines 28 were syn- α,β-alkynyl carboxylic acids 33, and the corresponding isocya-
thesized by combining sequentially the imine 25 ( prepared nides 34 in MeOH at room temperature to afford the stable
in situ from the amine 24) with the corresponding isocyanides Ugi-adducts 35, which in turn were cyclized via a 5-endo-dig
26 and the hetero-aryl alcohols 27 via a mechanism involving Michael addition to access the desired bis-heterocycles 36 in
an ionic Smiles-rearrangement (Scheme 7a). The scope of this 28% to 87% yields (Scheme 8).35
synthetic methodology was evaluated by preparing the five- In 2015, L. El Kaïm and R. Gámez-Montaño reported the
membered polyheterocyclic analogs 30 using the imine 29 synthesis of various 4-amino-pyrrolydin-2-ones via a strategy of
( prepared in situ from its corresponding amine using NCS) in Ugi-4CR/base-assisted intramolecular cyclization using aro-
the Ugi-Smiles reaction (Scheme 7b).34 matic aldehydes and cyanoacetic acid as key reagents for the
As seen, an ionic cyclization step (Smiles-type rearrange- intramolecular cyclization process (Scheme 9).36 Among the
ment) occurred in the reaction mechanism previous to the for- products prepared, the furyl-containing polyheterocycles 42a–b
mation of the polyheterocycles 28 and 30. The next chapter were synthesized by combining sequentially in MeOH at room
covers some I-MCR/ionic cyclization strategies to construct temperature for 5 h the aniline (37), 2-furylcarbaldehyde (38),
complex polyheterocyclic architectures. cyanoacetic acid (39), and the isonitriles 40a–b to give the
stable Ugi-adducts 41a–b, which by addition of substoichio-
metric amounts of potassium carbonate in MeOH at 65 °C
afforded the products 42a–b after 1 h. It is noteworthy that the
usefulness of cyanoacetic acid as a key reagent in I-MCRs
toward heterocycles was reviewed in 2008 by Shestopalov.37
In 2012, C. Hulme reported an Ugi-4CR/aldol sequence
toward a variety of linked-type polyheterocycles. Thus, amines
43 were combined sequentially with oxalyl-type aldehydes 44,
oxalyl-type carboxylic acids 45, and the N-Boc protected ortho-

Scheme 7 (a) Ugi-Smiles-based synthesis of the N-(hetero-aryl)piper- Scheme 8 Synthesis of the N-heterocyclic α,β-unsaturated-γ-lactams
idines 28 and (b) N-(hetero-aryl)pyrrolidines 30. 36 via an Ugi-4CR/intramolecular Michael addition.

1406 | Org. Biomol. Chem., 2018, 16, 1402–1418 This journal is © The Royal Society of Chemistry 2018
Organic & Biomolecular Chemistry Review

Scheme 9 Synthesis of the furyl-pyrrolidinones 42a–b via a cyanoace-

tic acid-based Ugi-4CR/base-assisted intramolecular cyclization.

amino phenyl isocyanide (46) in MeOH at room temperature to

give the Ugi-adducts 47, which after a domino aldol sequence
afforded the products 50 in 47–88% yields (Scheme 10).38 As a
selected example, the tetra-heterocycle 50a is shown. As can be
seen, the furyl moieties can be used for further transform-
ations, such as Diels–Alder cycloadditions, to increase the Scheme 11 Synthesis of the polyheterocycles 58 via a domino Ugi-
4CR/aldol strategy.
molecular complexity.
In the same report, a series of novel fused-type bis-pyrrolidi-
nones were synthesized as a racemic mixture via a smart modi-
fication of the methodology reviewed above. Thus, amines 51
were combined sequentially with the acetoacetic methyl ester
(52), oxalyl-type carboxylic acids 53, and the isocyanides (54) in
MeOH at room temperature to give the Ugi-adducts 55, which
after a domino aldol sequence allowed the synthesis of the pro-
ducts (±)-58 in 48–56% yields (Scheme 11).38 As selected
example, the tetra-heterocycle 58a is shown. As can be seen,
the furyl and thienyl moieties can be used also for further
transformations.
In 2009, A. Dömling developed an Ugi-4CR/Pictet–Spengler
strategy toward a variety of indole-based polyheterocycles.
Thus, the masked amines 59 were combined sequentially with
the aldehydes 60, carboxylic acids 61, and the tryptamine-like
isocyanide 62 in MeOH at room temperature to give the Ugi-
adducts 63. Then, formic acid was added to unprotect the alde-
hyde from the amine moiety and to trigger the Pictet–Spengler
cyclization to give the desired polyheterocycles 64 in 10% to
73% yields (Scheme 12).39 It is noteworthy that when R3 was a
methyl ester and R1 was hydrogen, mixtures of diasteroisomers
were obtained that were favorable to the trans form in ratios
from 1.6 : 1 to 2.4 : 1.
A very interesting variant of the above-reviewed method-
ology was developed in 2010 by A. Dömling also; whereby a re-
placement of the aldehyde and carboxylic acid reagents by a
bifunctional reagent allowed the construction of complex
Scheme 10 Synthesis of the polyheterocycles 50 via a domino Ugi- linear polyheterocycles. Thus, the masked amine 65 reacted
4CR/aldol strategy. together with 2-formyl benzoic acid (66) and the tryptamine-

This journal is © The Royal Society of Chemistry 2018 Org. Biomol. Chem., 2018, 16, 1402–1418 | 1407
Review Organic & Biomolecular Chemistry

Scheme 12 Synthesis of the indole-based polyheterocycles 64 via an Scheme 14 Synthesis of the polyheterocycles 75 via an Ugi-4CR/intra-
Ugi-4CR/PS cyclization. molecular N-acylation using convertible isocyanides.

like isocyanides 67 in MeOH at room temperature to construct tional (carbonyl-carboxylic acid) reagents. This is a clear
the Ugi-adducts 68. Then, formic acid was added to unprotect example that MCR/ionic-cascade-based strategies can be used
the aldehyde from the amine moiety and to trigger the Pictet– successfully toward structural diversity (DOS approach).
Spengler sequence to give the polyheterocycles 69 in 10% to In 2009, M. Krasavin reported a new strategy to construct
80% yields (Scheme 13).40 Motivated by these results, more the pharmacologically important 5,6-dihydropyrazolo[1,5-a]
analogs of 69 were synthesized by using a variety of bifunc- pyrazine-4,6-dione system via an Ugi-4CR/intramolecular
N-acylation. Thus, the aldehydes 70 were combined sequen-
tially with the amines 71, pyrazolo-containing carboxylic acids
72, and the tert-butyl isocyanide (73) in methanol to give the
Ugi-adducts 74, which after treatment using acetic acid gave
the polyheterocycles 75 in good to excellent yields (38–70%)
using MW as a heat source (Scheme 14).41 As seen, the key
idea behind this valuable strategy was the use of a convertible
isocyanide (t-BuNC) to form a leaving group to trigger the final
cyclization step via intramolecular N-acylation.
In 2008, L. A. Wessjohann reported a pioneering work for
the synthesis of indole and piperazin-dienone-based spaced-
type polyheterocycles via an Ugi-4CR/ionic intramolecular
cyclization. Thus, the aldehydes 76 were combined with the
α-amino-esters 77, N-Fmoc-protected tryptophan (78), and the
isocyanides 79 using MeOH as a solvent and conventional or
MW heating conditions to give the Ugi-adducts 80. Then,
strong acidic conditions (TFA) were used to trigger the 6-exo-
trig cyclization to construct the polyheterocycles 81 in 51% to
77% yields (Scheme 15).42 It is noteworthy that compounds 81
have potential application in medicinal chemistry because
they are structural analogs of Tryprostatin B and
Fumitremorgin B, which are potent inhibitors of mammalian
cell cycle progression at the G2/M transition.
In 2007, J. Zhu developed an exquisite 3-CR/acid-triggered
macrocyclization toward a variety of macrocyclic sugar-amino-
acid- or amino-alcohol-containing polyheterocycles. Thus, the
stepwise-prepared bifunctional (amino-alcohol) sugars 82 were
combined sequentially with the aldehydes 83 and the ring-
Scheme 13 Synthesis of the bis-indole-based polyheterocycles 69 via chain tautomerizable isocyanides 84 ( prepared from amino
an Ugi-3CR/PS reaction. acids) in methanol at reflux to give the corresponding 5-amino

1408 | Org. Biomol. Chem., 2018, 16, 1402–1418 This journal is © The Royal Society of Chemistry 2018
Organic & Biomolecular Chemistry Review

Scheme 15 Synthesis of the indole and piperazin-dienone-based poly-

heterocycles 81 via an Ugi-4CR/ionic intramolecular cyclization.

oxazoles 85, which after treatment with LiOH and TFA trig-
gered a domino macrocyclization toward the sugar-containing
macrocyclic polyheterocycles 86 and 87 in 30% to 61% yields
(Scheme 16).43 The utility of ring-chain tautomerizable isocya-
nides toward diverse macrocyclic polyheterocycles is note-
worthy. Indeed, J. Zhu and H. Bienaymé are the pioneers
behind the use of ring-chain taumerizable isocyanides in
MCRs from the early 2000s.44 Besides, L. A. Wessjohann Scheme 16 Synthesis of the sugar-based macro-polyheterocycles 86
and 87 via an Ugi-3CR/acid-assisted macrocyclization.
reviewed MCR/macrocyclization-based strategies toward macro-
cycle diversity up to 2009.45
As the last example of an I-MCR/ionic-based strategy herein
reviewed, in 2007, L. El Kaïm reported a pioneering work polyheterocycles containing two sp3-quaternary carbon atoms
about the use of α-ketoacids toward polyheterocyclic 2,5-di- via an Ugi-4CR/Cu(II)-catalyzed oxidative cyclization at the pep-
ketopiperazines, which are very important frameworks in tidyl position. Thus, tryptamine (94), aldehydes 95, carboxylic
medicinal chemistry.46 acids 96, and isocyanides 97 were combined sequentially in
Thus, the aldehydes or ketones 88 were combined sequen- MeOH at room temperature to give the Ugi-adducts 98 in 83%
tially with the amines 89, the α-ketoacids 90, and 3,4- to 94% yields, which were cyclized to afford the polyhetero-
dimethoxyphenethyl isocyanide (91) in MeOH at room temp- cycles 99 in 37% to 76% yields (Scheme 18).50
erature to give the Ugi-adducts 92. Then, TFA was added to The product 99a ( prepared from 98a) was selected to be
trigger the Pictet–Spengler cyclization to construct the poly- shown in Scheme 18 because is a tetra-heterocycle. As seen,
heterocycles 93 in 41% to 73% yields (Scheme 17).47 the scope and robustness of this methodology was evaluated
by synthesizing some bigger polyheterocycles, like 99a. It is
noteworthy that five of the products 99 were synthesized in a
one-pot manner coupling both sequential processes (Ugi-3CR
4 Synthesis of polyheterocyles via and Cu(II) catalyzed cyclization) in the same flask. Copper(II) is
I-MCR/metal-catalyzed cyclizations one of the greenest metals for catalysis in organic chemistry,
and which can be useful to construct polyheterocyclic architec-
Metal-catalyzed post-I-MCR methods toward a variety of hetero- tures with potential applications in medicinal chemistry.51
cycle-containing products were summarized masterfully by Another interesting fact is that when an aliphatic aldehyde was
T. J. J. Müller (up to 2005)48 and E. Van der Eycken (up to used (EtCHO), the cyclization process did not occur.
2015).49 Thus, in this chapter, three representative examples of In 2016, E. Van der Eycken reported a diversity oriented syn-
the synthesis of ‘polyheterocyles’ via I-MCRs/metal-catalyzed thesis of novel tris-heterocyclic imidazo-pyrrolo-( pyrazines/di-
cyclizations are described. In 2011, L. Grimaud, L. D. Miranda azepines/diazocines) via a domino Ugi-4CR/Michael/Ag(I)-cata-
and L. El Kaïm synthesized a variety of indole-based complex lyzed heteroannulation process. Thus, the imidazole-2-carbal-

This journal is © The Royal Society of Chemistry 2018 Org. Biomol. Chem., 2018, 16, 1402–1418 | 1409
Review Organic & Biomolecular Chemistry

Scheme 17 Synthesis of the polyheterocycles 93 via Ugi-4CR/PS

cyclization.
Scheme 19 Synthesis of the fused-type polyheterocycles 106 via a
Ugi-4CR/Ag(I)-catalyzed domino-heteroannulation.

dehyde (100) was combined sequentially with the alkynyl

amines 101, α,β-alkynyl carboxylic acids 102, and the corres-
ponding isocyanides 103 in MeOH at room temperature for
24 h to afford the Ugi-adducts 104, which were cyclized via a
5-endo-dig Michael addition to access the imidazo-pyrrolido-
none type bis-heterocycles 105,35 which was cyclized via a
6-exo-dig Ag(I)-catalyzed heteroannulation to construct the
complex polyheterocycles 106 (Scheme 19).52
It is important to highlight that the polyheterocycle 106a
was synthesized in a one-pot manner by coupling sequentially
the three processes in the same flask. However, the overall
yield was decreased to 26%. As seen, one of the goals of the
I-MCR-based methodologies toward polyheterocycles is to
carry out all the synthetic strategy in a one-pot manner to
decrease the use of solvents and workup procedures and to
gain a time-saving.
In 2015, D. D. Vachhani and E. Van der Eycken reported an
elegant remote amide moiety-controlled Au(I)-catalyzed stereo-
selective hydro-heteroarylation strategy as a post-Ugi cycliza-
tion toward a variety of biologically important tetrahydro-
β-carboline-type polyheterocycles. Thus, indole-2-carbalde-
hydes 107, amines 108, atropic acids analogs 109, and the
corresponding isocyanides 110 were combined sequentially in
2,2,2-trifluoroethanol at 50 °C to give the indole-containing
Scheme 18 Synthesis of the indole-based polyheterocycles 99 via Ugi- Ugi-adducts 111, which were then treated with 5% mol of
3CR/Cu(II) catalyzed oxidative cyclization. freshly prepared Au(PPh3)BF4 in CHCl3 at 50 °C for 15 to 20 h

1410 | Org. Biomol. Chem., 2018, 16, 1402–1418 This journal is © The Royal Society of Chemistry 2018
Organic & Biomolecular Chemistry Review

Scheme 20 Stereoselective synthesis of the 1,2,3,4-tetrahydro-

β-carboline-type polyheterocycles 112 via an Ugi-4CR/Au(I)-catalyzed
hydro-heteroarylation.

Scheme 21 Synthesis of the tetrazole-containing polyheterocycles 118

to afford the products 112 in 30% to 98% yields (Scheme 20).53 via Ugi-azide/further cyclization.
It is noteworthy that all the attempts to use N-unprotected
indole, pyrrole, benzofurane, and benzothiophene instead of a
protected indole as pivotal heterocycles for the heteroarylation amines 113, hydrazoic acid (114), and isocyanides 115 were
process proved unsuccessful. As seen, the role of the acryl- reacted together to give the intermediates 116, which by a
amide substituent (R3) was crucial to direct the indole 6-exo- thermal 1,5-electrocyclization process afforded the lactam-con-
trig attack (cyclization) to the more hindered α-position of the taining 1,5-disubstituted-tetrazoles 117. These latter com-
alkene-Au(I) coordinated site. As seen, the three examples of pounds were the direct precursors of the tetrazole-lactam-con-
metal-catalyzed post I-MCR strategies toward polyheterocycles taining polyheterocycles 118 (Scheme 21). As selected
described above used Cu(I), Ag(I), and Au(I). However, there are examples, the products 118a (58%) and 118b (10% overall) are
reports describing the use of other transition metals.49 shown, which contain three heterocycles (interesting for med-
icinal chemistry) embedded in the same molecule.
It is noteworthy that C. Hulme, L. El Kaïm, S. Marcaccini,
5 Synthesis of polyheterocyles via A. Dömling, R. Gámez-Montaño, and A. Maleki56 are con-
I-MCR/pericyclic cyclizations sidered the pioneers behind Ugi-azide-based methods toward
heterocycles and polyheterocycles. In the same context, some
Pericyclic reactions (electrocyclizations, cycloadditions and σ- Passerini-azide based methods toward some polyheterocycles
rearrangements) have been used also as post I-MCR transform- have been reported very recently.57 Finally, the Groebke–
ations toward heterocycles, and a little less frequently, toward Blackburn–Bienaymé reaction (which involves a [4 + 1] dipolar
polyheterocycles. Of course, this approach (I-MCR/pericyclic cycloaddition) was used by C. Hulme to construct a variety of
cyclization) is an opportunity area for further investigations novel nitrogen-enriched polyheterocycles.58
toward novel polyheterocycle-based products with potential In addition to electrocyclizations, cycloadditions have been
application in medicinal chemistry due to the wide substrate used successfully as post I-MCR transformations to construct a
scope that can be reached easily and quickly. wide variety of interesting polyheterocyclic systems. For
As an example, in 2013, C. Hulme reported the synthesis of example, in 2015, L. D. Miranda reported an exquisite Ugi-
various 1,5-disubstituted-tetrazole-based polyheterocycles 4CR/microwave-assisted azide–alkyne 1,3-dipolar cycloaddition
coupled to substituted lactams in a bound manner using as a (CuAAC)59 method toward a series of new macrocycles contain-
key process an Ugi-azide reaction, which is a variant of the ing indole and 1,2,3-triazole heterocyclic systems embedded in
classic Ugi reaction that involves the use of hydrazoic acid the same complex molecules linked by a peptoid moiety. Thus,
(commonly generated in situ by proton exchange between the the orthogonal-bifunctional tryptamine-azides 119 (syn-
protic solvents or water and TMSN3 or NaN3) instead of car- thesized from N-Boc-tryptamine) were combined sequentially
boxylic acids.54 It is noteworthy that in 2017, R. Gámez- with the alkyne-containing benzaldehyde 120, carboxylic acids
Montaño investigated experimentally the Ugi-azide reaction 121, and the corresponding isocyanides 122 in MeOH as a
mechanism.55 Thus, the carbonyl-containing compounds 112, solvent at room temperature for 48 h to afford the Ugi-adducts

This journal is © The Royal Society of Chemistry 2018 Org. Biomol. Chem., 2018, 16, 1402–1418 | 1411
Review Organic & Biomolecular Chemistry

Scheme 22 Synthesis of the macrocyclic polyheterocycles 124 via Ugi-

4CR/click process.

123 in 26% to 85% yields. Then, these latter compounds

reacted with 0.4 equiv. CuBr and 1.0 equiv. DBU in toluene
[0.005 M] at 110 °C (MW) for 4 h to give the desired macro-
polyheterocycles 124 in 38% to 92% yields (Scheme 22).60
As part of our ongoing research program to develop short,
efficient and versatile I-MCR/pericyclic cyclization-based meth-
odologies toward linear polyheterocyclic systems, we syn-
thesized a series of novel aza-analogs of natural alkaloids, like
(±)-Nuevamine, (±)-Lenoxamine, and Magallanesine. Our most
recent results are herein summarized.
Thus, the amines 125 were combined sequentially with
aldehydes 126 and the chain-ring tautomerizable isocyanides
127 to afford the 5-aminooxazoles 128 via a MW-assisted Ugi-
3CR. Then, maleic anhydride (129) was in situ added to con- Scheme 23 Diversity oriented synthesis of the pyrrolo[3,4-b]pyridin-5-
one based polyheterocycles 131 via Ugi-3CR/aza Diels–Alder cyclo-
struct the pyrrolo[3,4-b]pyridin-5-ones 130 via a triple process
addition/further cyclizations.
involving an aza Diels–Alder cycloaddition, a N-acylation, and
a further aromatization. It is noteworthy that the conversion of
128 to 130 can follow two reaction routes: (a) intermolecular
N-acylation/intramolecular DA cycloaddition/aromatization, or Pomeranz-Fritsch65 cyclizations, toward the synthesis of a
(b) intermolecular DA cycloaddition/intramolecular variety of fused-type linear polyheterocycles 131 (Scheme 23).
N-acylation/aromatization (Scheme 23). DFT-based compu- In the same context, we developed an oxidative66 and a repeti-
tational calculations suggested that (b) is the most kinetic and tive version67 of the methodology used in Ugi-3CR/aza Diels–
thermodynamically viable reaction pathway due to the stereo- Alder/N-acylation/aromatization toward aza-analogs of the
electronic effects coming from the 5-aminooxazole moiety and natural alkaloid (±)-Nuevamine and the hexamethylene-bis-(3-
a sufficient GAP to carry out the aza Diels–Alder cycloaddition pyridine)amide (HMBPA), respectively.
before the N-acylation step.61 Finally, as previously mentioned, P. R. Andreana synthesized tricyclic- and spiro-polyhetero-
the one-pot Ugi-3CR/(intermolecular aza DA cycloaddition/ cycles via a combination of an Ugi-4CR with either, Diels–
intramolecular N-acylation/aromatization) process was com- Alder cycloaddition or intramolecular Michael addition,
bined successfully with further cyclization methods, like free- depending on the solvent used. Thus, 2-thiophenyl carbalde-
radical mediated,62 Pummerer,63 Pictet–Spengler,64 and hyde (132) was combined sequentially with the 4-methoxy-

1412 | Org. Biomol. Chem., 2018, 16, 1402–1418 This journal is © The Royal Society of Chemistry 2018
Organic & Biomolecular Chemistry Review

tunity area to populate the chemical space. In this context, we

review some representative examples to show the potential of
this synthetic strategy for the synthesis of polyheterocycles of
high interest in medicinal chemistry.
In 2013, R. Gámez-Montaño reported the synthesis of nine
novel tris-heterocyclic-type 3-tetrazolyl-azepino[4,5-b]indol-4-
ones via a sequential combination of a one-pot process (Ugi-
azide/N-acylation/SN2)/xanthate free-radical-mediated cycliza-
tion. Thus, tryptamine (139) was combined sequentially with
the aldehydes 140, azidotrimethylsilane (141), and the isocya-
nides 142 using methanol as the solvent at room temperature
for 24 h to give the corresponding indole-tetrazoles 143, which
underwent a N-acylation with chloroacetyl chloride 144 to give
the chlorides 145. These latter compounds afforded the bis-
heterocyclic xanthates 147 in 47% to 71% yields after a SN2
reaction with potassium ethyl xanthogenate salt 146. Then,
DLP was added portion-wise in 1,2-dichloroethane at 85 °C
(using conventional or MW heating modes) to generate the
carbamoylmethyl free-radicals 148, which performed a highly
favored 7-endo-trig cyclization to construct the azepino[4,5-b]
indol-4-one heterocyclic system present in the final tris-hetero-
cycles 149 with yields of 45% to 82% (Scheme 25).69

Scheme 24 Synthesis of the fused-type tricyclic polyheterocycle 137

via Ugi-4CR/intramolecular Diels–Alder cycloaddition and the spirocyc-
lic polyheterocycle 138 via Ugi-4CR/intramolecular Michael addition.

benzyl amine (133), mono-ethyl ester fumaric acid (134), and

the benzyl isocyanide (135) to give the Ugi-adduct 136 in a
quantitative yield. Then, the intermediate 136 underwent an
intramolecular Diels–Alder cycloaddition to give the poly-
heterocycle 137 in a 25% yield as a mixture of diasteroisomers
in a 10 : 1 ratio using the non-polar DCM as a solvent.
Moreover, when water was used as the solvent, the product was
the spiro[cyclohexendienone-3,3′-pyrrolidinone] 138 in an 83%
yield as a mixture of diasteroisomers in a 7 : 1 ratio via an
intramolecular Michael addition (Scheme 24).68

6 Synthesis of polyheterocyles via

I-MCR/free-radical-mediated
cyclizations
I-MCR/free-radical-mediated cyclization-based strategies are
powerful tools toward molecular complexity and, hence, they
have been used to successfully synthesize polyheterocyclic
compounds. However, most reports describing the use of these
strategies involve the preparation of mono-heterocyclic com- Scheme 25 Synthesis of the 3-tetrazolyl-azepino[4,5-b]indol-4-ones
pounds. On this basis, it is noteworthy that the combination 148 via a one-pot (Ugi-azide/N-acylation/SN2)/xanthate free-radical-
of I-MCRs with free-radical-based cyclizations is also an oppor- mediated cyclization.

This journal is © The Royal Society of Chemistry 2018 Org. Biomol. Chem., 2018, 16, 1402–1418 | 1413
Review Organic & Biomolecular Chemistry

Scheme 26 Synthesis of the 3-acetamide-azepino[4,5-b]indol-4-ones

155 via a one-pot (Ugi-4CR/SN2)/xanthate free-radical-mediated Scheme 27 Synthesis of the pyrazolyl-thiazole bound-type bis-hetero-
cyclization. cycles 159 via an ‘in water’ direct non-isocyanide-based 3-CR.

More recently R. Gámez-Montaño and J. Robles synthesized

in vitro assays against three human cancer cell lines: A549
a series of nine new bis-heterocyclic analogs of the compounds
(lung cancer), MCF-7 (breast cancer), and HeLa (cervical
149 based on the non-classic bioisosterism relationship
cancer). Thus, the β-aminocarbonylic compounds 156 were
between 1,5-disubstituted tetrazoles and the cis-amide bond of
combined sequentially with the thiosemicarbazide (157), para-
peptides. Thus, they modified the methodology described
substituted bromo-acetophenones 158 and sulfamic acid in
above to result in a combination of a one-pot (Ugi-4CR/SN2)/
water under reflux for 3 to 6 h, obtaining the polyheterocyclic
free-radical-mediated cyclization from the tryptamine (150),
products 159 in 64% to 89% yields (Scheme 27).73 It is note-
aldehydes 151, chloroacetic acid (152), isocyanides 153, and
worthy to highlight the good substrate scope and the compat-
the potassium ethyl xanthogenate salt 154 to afford the 3-acet-
ibility of MCR-based processes with green conditions, such as
amide azepino[4,5-b]indol-4-one type bis-heterocycles 155 in
the use of water as the solvent.
64% to 80% overall yields (Scheme 26).70 It is noteworthy that
Continuing with the green approach of non-isocyanide-
both series (149 and 155) were in vitro tested as 5-Ht6 receptor
based MCRs, in 2017, A. Maleki reported an ultrasound-
ligands.
assisted 3CR method toward ten fused-type polyheterocycles
Both the synthetic strategies reviewed above involved peri-
using the nanomagnetic catalyst Fe3O4@SiO2-CO-Ph-NH2.
cyclic reactions (1,5-electrocyclization to construct the tetrazole
Thus, the series of polysubstituted 2-aminopyridines 160 were
ring) and ionic reactions (N-acylation and SN2) as post I-MCR
combined sequentially with the ortho-phtalaldehyde (161) and
transformations. However, the final and key step to construct
the TMSCN (162) in ethanol as the solvent to access the novel
the polyheterocycles was a free-radical mediated cyclization,
pyridoimidazo-isoquinolines 163 in 85% to 95% yields
which used a xanthate functional group and DLP as both a
(Scheme 28).74 This methodology can be considered as a non-
free-radical initiator and oxidant.71 Other reagents having the
isocyanide-based version of the Groebke–Blackburn–Bienaymé
same functionality as the AIBN/tributyltin hydride system,
reaction, which is a very useful I-MCR-based strategy toward
such as Et3B or SmI2, have also been used to synthesize poly-
the synthesis of fused-type polyheterocyclic compounds.
heterocyclic compounds.72

7 Miscellaneous
7.1 Synthesis of polyheterocyles via non-isocyanide-based
MCRs
A considerably smaller number of reports describing the syn-
thesis of polyheterocycles via non-isocyanide-based MCRs
(with respect to I-MCR-based ones) have been developed over
many years. However, they mostly adopted the approach of
‘heterocyclic chemistry’. Thus, we herein show a few represen-
tative methodologies toward polyheterocycles of interest in
medicinal chemistry.
H. M. Meshram and A. Kamal reported in 2017 an ‘in water’
synthesis of 26 new pyrazolyl-thiazoles via a sulfamic acid-cata- Scheme 28 Synthesis of the fused polyheterocycles 163 via a nano-
lyzed non-isocyanide-based three-component reaction and catalyzed and sonicated 3-CR.

1414 | Org. Biomol. Chem., 2018, 16, 1402–1418 This journal is © The Royal Society of Chemistry 2018
Organic & Biomolecular Chemistry Review

By using the same methodology, but replacing the 3-amino-

pyrazol-5-ones 164 by the 5-amino-1-phenyl-3-methylpyrazole
(168), 3-amino-1,2,4-triazole (169), or 6-aminouracyl (170), the
polyheterocycles 171–173 were synthesized successfully in
65%, 53%, and 57% yields, respectively (Scheme 30).75
In 2016, G. E. Negrón-Silva reported the use of a Biginelli
reaction toward a series of five novel dihydropyrimidinones.76
One of them was the spaced-type 1,2,3-triazolyl-containing bis-
heterocycle 177, which was synthesized by combining urea
(174) with ethyl acetoacetate (175) and the triazolyl-containing
benzaldehyde 176 in ethanol at room temperature for 3 days
using cerium(III) triflate in substoichiometric amounts (20%
mol) to improve the yield (85%) (Scheme 31). As an alternative
Scheme 29 Synthesis of the polyheterocycles 167 via a non-isocya- route toward 177, the alkynyl-containing benzaldehyde 178
nide-based 3-CR. was used instead of 176 to afford the Biginelli-adduct 179 in
an 82% yield, which reacted immediately with the 4-bromo-
benzyl bromide via a click77 Cu(II)-catalyzed azide–alkyne
In 2011, I. V. Magedov synthesized a series of polyhetero- dipolar cycloaddition (CuAAC) to give the polyheterocycle 177
cycles via a non-isocyanide-based 3CR and performed in vitro in an 86% yield (Scheme 31).
studies against Staphylococcus epidermis and Staphylococcus
aureus, obtaining promising values of MIC. Thus, the 3-amino- 7.2 Synthesis of polyheterocylic-based natural products via
pyrazol-5-ones 164 were reacted with substituted salicylic alde- MCRs
hydes 165 and the ethyl acetoacetate (166) in acetic acid as a Natural products were the first contact of research with bio-
solvent at reflux for 3 h to afford the novel 2,3-dihydrochro- active products and drugs (in the current context).9 Many of
meno[4,3-d]pyrazolo[3,4-b]pyridin-1,6-diones 167 in 53% to them contain polyheterocycles in their structures.78
82% yields (Scheme 29).75 Consequently, MCR-involved synthetic strategies have been

Scheme 30 Synthesis of the polyheterocycles 171–173 via a non-iso- Scheme 31 Synthesis of the spaced-type polyheterocycles 177 via an
cyanide-based 3-CR. MCR/[2 + 3] dipolar cycloaddition.

This journal is © The Royal Society of Chemistry 2018 Org. Biomol. Chem., 2018, 16, 1402–1418 | 1415
Review Organic & Biomolecular Chemistry

allowed the synthesis of the natural product (±)-Plicamine.

Thus, the para-hydroxyphenol (180) was combined sequen-
tially with piperonylamine (181), carboxylic acids 182, and
the isocyanides 183 to access the α-substituted bis-amides
184 as Ugi-adducts. Then, these compounds underwent a
cascade (dearomative phenolic coupling (185)/intramolecular
Michael addition) to give the polyheterocycles 186
(Scheme 32).79
Then, starting from a polyheterocycle 186 (R1 = Me; R2 = H),
the (±)-Plicamine was synthesized successfully. Thus, a step-
wise sequence reduction-methoxylation (187)/N-formyl
reduction (188)/alkylation-oxidation allowed the construction
of the targeted polyheterocyclic natural product (Scheme 33).79
As seen, an I-MCR (Ugi-4CR) was used to assemble the
structural skeleton of the natural product (±)-Plicamine.
However, several further steps were required for its formal syn-
thesis. It is important to bear in mind the usefulness of MCR-
involved processes for the Target Oriented Synthesis.
Scheme 32 Synthesis of the polyheterocycles 186 via an MCR/cascade
process.
8 Conclusions and outlook
developed to synthesize both natural products, like polyhetero- Direct MCRs or their combination with further cyclization pro-
cycles, and their structural analogs due to ‘Diversity Oriented cesses (via ionic, metal-catalyzed, pericyclic, and free-radical
Synthesis’, ‘Combinatorial Chemistry’ and ‘Target Oriented mediated cyclizations) are powerful synthetic tools toward the
Synthesis’ approaches that can be achieved by using MCRs or rapid access to a wide variety of heterocyclic and polyhetero-
their combination with further cyclization processes (i.e., cyclic products with potential application in several fields,
ionic, metal-catalyzed, pericyclic and/or free-radical-mediated mainly in medicinal chemistry. From this latter approach, the
cyclizations). Thus, a selected representative example is interest behind the synthesis of polyheterocycles lies in their
reviewed to show the potential application of MCRs toward the ability to contain two or more pharmacophores, which can
synthesis of natural products. result in hybrid compounds. The synthesis of polyheterocycles
In 2016, L. D. Miranda reported the synthesis of 17 new via MCRs is an opportunity field to explore and populate the
indolo[3,3a–c]-isoquinolin-3,6-dione-type polyheterocycles via chemical space. In fact, DOS, CC, and TOS approaches toward
a sequential process Ugi-4CR/one-pot ( phenolic oxidation/ the synthesis of new/novel polyheterocycles can be achieved by
intramolecular coupling). Then, one of these compounds using MCR-involved synthetic procedures. Thus, further efforts
to synthesize natural products, bioactive molecules, and
pharmaceuticals containing polyheterocycles in their struc-
tures need to be investigated. We hope this review covering the
progress over the last decade on the synthesis of bis-, tris-, and
tetra-heterocycles via MCRs can provide new insights for
further investigations behind new reactions and/or novel one-
pot-based strategies.

Conflicts of interest
There are no conflicts to declare.

Acknowledgements
I. A. I. acknowledges PAPIIT-UNAM-Mexico (IN101517) and
CONACYT (1789) for financial support. A. I.-J. acknowledges
QI-DQ-CBI-UAMI for his position as visiting professor (40966)
and PRODEP-SEP for financial support (12413143). E. G.-Z.
acknowledges CONACyT-México (236879) for financial
Scheme 33 Synthesis of the (±)-Plicamine. support.

1416 | Org. Biomol. Chem., 2018, 16, 1402–1418 This journal is © The Royal Society of Chemistry 2018
Organic & Biomolecular Chemistry Review

Notes and references 21 (a) R. M. Wilson, J. L. Stockdill, X. Wu, X. Li, P. A. Vadola,

P. K. Park, P. Wang and S. J. Danishefsky, Angew. Chem.,
1 S. Wetzel, R. S. Bon, K. Kumar and H. Waldmann, Angew. Int. Ed., 2012, 51, 2834; (b) A. V. Lygin and A. de Meijere,
Chem., Int. Ed., 2011, 50, 10800. Angew. Chem., Int. Ed., 2010, 49, 9094; (c) S. Sadjadi and
2 M. Butters, D. Catterick, A. Craig, A. Curzons, D. Dale, M. M. Heravi, Tetrahedron, 2011, 67, 2707; (d) L. El Kaïm
A. Gillmore, S. P. Green, I. Marziano, J.-P. Sherlock and and L. Grimaud, Tetrahedron, 2009, 65, 2153.
W. White, Chem. Rev., 2006, 106, 3002. 22 T. Kaur, P. Wadhwa and A. Sharma, RSC Adv., 2015, 5,
3 T. Bach and J. P. Hehn, Angew. Chem., Int. Ed., 2011, 50, 52769.
1000. 23 A. R. Kazemizadeh and A. Ramazani, Curr. Org. Chem.,
4 (a) L. Levi and T. J. J. Müller, Chem. Soc. Rev., 2016, 45, 2012, 16, 418.
2825; (b) L. Levi and T. J. J. Müller, Eur. J. Org. Chem., 2016, 24 (a) S. S. van Berkel, B. G. M. Bögels, M. A. Wijdeven,
2907; (c) A. Wróblewska, G. Mlostoń and H. Heimgartner, B. Westermann and F. P. J. T. Rutjes, Eur. J. Org. Chem.,
Tetrahedron: Asymmetry, 2015, 26, 1448. 2012, 3543; (b) M. M. Heravi and S. Moghimi, J. Iran. Chem.
5 A. Vasilev, T. Deligeorgiev, N. Gadjev, S. Kaloyanova, Soc., 2011, 8, 306; (c) A. Dömling, Chem. Rev., 2006, 106, 17;
J. J. Vaquero, J. Alvarez-Builla and A. G. Baeza, Dyes Pigm., (d) I. Akritopolou-Zanze, Curr. Opin. Chem. Biol., 2008, 12,
2008, 77, 550. 324; (e) A. Dömling, Curr. Opin. Chem. Biol., 2002, 6, 306;
6 J. C. Gustafsson, O. Inganäs and A. M. Andersson, Synth. (f) A. Dömling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39,
Met., 1994, 62, 17. 3168.
7 G. Aromí, L. A. Barrios, O. Roubeau and P. Gámez, Coord. 25 (a) L. Banfi, A. Basso, C. Lambruschini, L. Moni and
Chem. Rev., 2011, 255, 485. R. Riva, Chem. Heterocycl. Compd., 2017, 53, 382;
8 (a) A. Andreani, M. Rambaldi, A. Leoni, A. Locatelli, (b) M. Haji, Beilstein J. Org. Chem., 2016, 12, 1269;
F. Andreani and J.-C. Gehret, Pharm. Acta Helv., 1996, 71, (c) A. Váradi, T. C. Palmer, R. N. Dardashti and
247; (b) A. Andreani, M. Rambaldi, A. Locatelli and S. Majumdar, Molecules, 2016, 21, 19; (d) B. H. Rostein,
F. Andreani, Collect. Czech. Chem. Commun., 1991, 56, 2436; S. Zaretsky, V. Rai and A. K. Yudin, Chem. Rev., 2014, 114,
(c) A. Andreani, M. Rambaldi and A. Locatelli, Pharm. Acta 8323; (e) H. Eckert, Molecules, 2012, 17, 1074;
Helv., 1995, 70, 325. (f) A. V. Ivachtchenko, Y. A. Ivanenkov, V. M. Kysil,
9 R. M. Wilson and S. J. Danishefsky, Angew. Chem., Int. Ed., M. Y. Krasavin and A. P. Ilyin, Russ. Chem. Rev., 2010, 79,
2010, 49, 6032. 787; (g) J. D. Sunderhaus and S. F. Martin, Chem. – Eur. J.,
10 (a) C. A. Lipinski, Drug Discovery Today: Technol., 2004, 1, 2009, 15, 1300; (h) J. Sapi and J.-Y. Laronze, ARKIVOC, 2004,
337; (b) T. H. Keller, A. Pichota and Z. Yin, Curr. Opin. 7, 208; (i) J. Zhu, Eur. J. Org. Chem., 2003, 1133.
Chem. Biol., 2006, 10, 357. 26 M. J. Arévalo, N. Kielland, C. Masdeu, M. Miguel,
11 A. K. Ghose, V. N. Viswanadhan and J. J. Wendoloski, N. Isambert and R. Lavilla, Eur. J. Org. Chem., 2009, 617.
J. Comb. Chem., 1999, 1, 55. 27 M. Sintes, F. D. Moliner, D. Caballero-Lima,
12 D. F. Veber, S. R. Johnson, H.-Y. Cheng, B. R. Smith, D. W. Denning, N. D. Read, N. Kielland, M. Vendrell and
K. W. Ward and K. D. Kopple, J. Med. Chem., 2002, 45, R. Lavilla, Bioconjugate Chem., 2016, 27, 1430.
2615. 28 K. G. Kishore, O. Ghashghaei, C. Estarellas, M. M. Mestre,
13 A. V. R. Rao, M. K. Gurjar, K. L. Reddy and A. S. Rao, Chem. C. Monturiol, N. Kielland, J. M. Kelly, A. F. Francisco,
Rev., 1995, 95, 2135. S. Jayawardhana, D. Muñoz-Torrero, B. Pérez, F. J. Luque,
14 D. J. Ramón and M. Yus, Angew. Chem., Int. Ed., 2005, 44, R. Gámez-Montaño and R. Lavilla, Angew. Chem., Int. Ed.,
1602. 2016, 55, 8994.
15 J. E. Biggs-Houck, A. Younai and J. T. Shaw, Curr. Opin. 29 D. Saha, T. Kaur and A. Sharma, Asian J. Org. Chem., 2017,
Chem. Biol., 2010, 14, 371. 6, 527.
16 E. Ruijter, R. Scheffelaar and R. V. A. Orru, Angew. Chem., 30 M. Adib, M. Mahdavi, M. A. Noghani and P. Mirzaei,
Int. Ed., 2011, 50, 6234. Tetrahedron Lett., 2007, 48, 7263.
17 A. Ulaczyk-Lesanko and D. G. Hall, Curr. Opin. Chem. Biol., 31 (a) K. Groebke, L. Weber and F. Mehlin, Synlett, 1998, 661;
2005, 9, 266. (b) C. Blackburn, B. Guan, P. Fleming, K. Shiosaki and
18 H. Cao, H. Liu and A. Dömling, Chem. – Eur. J., 2010, 16, S. Tsai, Tetrahedron, 1998, 39, 3635; (c) H. Bienaymé and
12296. K. Bouzid, Angew. Chem., Int. Ed., 1998, 37, 2234.
19 S. Oh and S. B. Park, Chem. Commun., 2011, 47, 12754. 32 K. G. Kishore, A. Islas-Jácome, A. Rentería-Gómez,
20 (a) N. Isambert and R. Lavilla, Chem. – Eur. J., 2008, 14, A. S. Conejo, U. M. V. Basavanag, K. Wrobel and R. Gámez-
8444; (b) E. Vicente-García, N. Kielland and R. Lavilla, in Montaño, Tetrahedron Lett., 2016, 57, 3556.
Multicomponent Reactions in Organic Synthesis, ed. J. Zhu, 33 (a) B. Yang, C. Tao, J. Gong and C. Che, Beilstein J. Org.
Q. Wang and M.-X. Wang, Wiley-VCH Verlag GmbH & Co. Chem., 2016, 12, 1487; (b) S. Shaaban and B. F. Abdel-
KGaA, Boschstr. 12 69469 Weinheim Germany, 1st edn, Wahab, Mol. Diversity, 2016, 20, 233; (c) N. Devi,
2015, ch. 6, p. 159. R. K. Rawal and V. Singh, Tetrahedron, 2015, 71, 183.

This journal is © The Royal Society of Chemistry 2018 Org. Biomol. Chem., 2018, 16, 1402–1418 | 1417
Review Organic & Biomolecular Chemistry

34 L. El Kaïm, L. Grimaud, J. Oble and S. Wagschal, 60 L. Chavez-Acevedo and L. D. Miranda, Org. Biomol. Chem.,
Tetrahedron Lett., 2009, 50, 1741. 2015, 13, 4408.
35 Z. Li, A. Kumar, A. Peshkov and E. Van der Eycken, 61 A. Islas-Jácome, A. Rentería-Gómez, M. A. Rentería-Gómez,
Tetrahedron Lett., 2016, 57, 754. E. González-Zamora, J. O. C. Jiménez-Halla and R. Gámez-
36 N. V. Alvarez-Rodríguez, A. Dos Santos, L. El Kaïm and Montaño, Tetrahedron Lett., 2016, 57, 3496.
R. Gámez-Montaño, Synlett, 2015, 26, 2253. 62 A. Zamudio-Medina, M. C. García-González, J. Padilla and
37 A. M. Shestopalov, A. A. Shestopalov and E. González-Zamora, Tetrahedron Lett., 2010, 51, 4837.
L. A. Rodinovskaya, Synthesis, 2008, 1. 63 A. Islas-Jácome, E. González-Zamora and R. Gámez-
38 Z. Xu, F. D. Moliner, A. P. Capeli and C. Hulme, Angew. Montaño, Tetrahedron Lett., 2011, 52, 5245.
Chem., Int. Ed., 2012, 51, 8037. 64 A. Islas-Jácome, L. E. Cárdenas-Galindo, A. V. Jerezano,
39 H. Liu and A. Dömling, J. Org. Chem., 2009, 74, 6895. J. Tamariz, E. González-Zamora and R. Gámez-Montaño,
40 W. Wang, E. Herdtweck and A. Dömling, Chem. Commun., Synlett, 2012, 23, 2951.
2010, 46, 770. 65 O. Vázquez-Vera, J. S. Sánchez-Badillo, A. Islas-Jácome,
41 M. Nikulnikov, S. Tsirulnivov, V. Kysil, A. Ivachtchenko and M. A. Rentería-Gómez, S. G. Pharande, C. J. Cortes-García,
M. Krasavin, Synlett, 2009, 260. M. A. Rincón-Guevara, I. A. Ibarra, R. Gámez-Montaño and
42 C. R. B. Rhoden, B. Westermann and L. A. Wessjohann, E. González-Zamora, Org. Biomol. Chem., 2017, 15, 2363.
Synthesis, 2009, 2077. 66 A. Islas-Jácome, A. Gutiérrez-Carrillo, M. A. García-Garibay
43 C. Bughin, G. Masson and J. Zhu, J. Org. Chem., 2007, 72, and E. González-Zamora, Synlett, 2014, 25, 403.
1826. 67 A. Zamudio-Medina, M. C. García-González, A. Gutiérrez-
44 X. Sun, P. Janvier, G. Zhao, H. Bienaymé and J. Zhu, Org. Carrillo and E. González-Zamora, Tetrahedron Lett., 2015,
Lett., 2001, 3, 877. 56, 627.
45 L. A. Wessjohann, D. G. Rivera and O. E. Vercillo, Chem. 68 S. Santra and P. R. Andreana, Org. Lett., 2007, 9, 5035.
Rev., 2009, 109, 796. 69 R. E. Gordillo-Cruz, A. Rentería-Gómez, A. Islas-Jácome,
46 A. D. Borthwick, Chem. Rev., 2012, 112, 3641. C. J. Cortes-García, E. Díaz-Cervantes, J. Robles and
47 L. El Kaïm, M. Gageat, L. Gaultier and L. Grimaud, Synlett, R. Gámez-Montaño, Org. Biomol. Chem., 2013, 11, 6470.
2007, 500. 70 A. Rentería-Gómez, A. Islas-Jácome, E. Díaz-Cervantes,
48 D. M. D’Souza and T. J. J. Müller, Chem. Soc. Rev., 2007, 36, T. Villaseñor-Granados, J. Robles and R. Gámez-Montaño,
1095. Bioorg. Med. Chem. Lett., 2016, 26, 2333.
49 U. K. Sharma, N. Sharma, D. D. Vachhani and E. Van der 71 P. E. Reyes-Gutierrez, R. O. Torres-Ochoa, R. Martínez and
Eycken, Chem. Soc. Rev., 2015, 44, 1836. L. D. Miranda, Org. Biomol. Chem., 2009, 7, 1388.
50 L. El Kaïm, L. Grimaud, X.-F. L. Goff, M. Menes-Arzate and 72 K. C. Nicolaou, S. P. Ellery and J. S. Chen, Angew. Chem.,
L. D. Miranda, Chem. Commun., 2011, 47, 8145. Int. Ed., 2009, 48, 7140.
51 S. R. Chelmer, Beilstein J. Org. Chem., 2015, 11, 2252. 73 B. Sridevi, Y. Tangella, K. S. Babu, J. B. Nanubolu,
52 Z. Li, Y. Zhao, G. Tian, Y. He, G. Song, L. V. Meervelt and R. S. Rani, C. G. Kumar, H. M. Meshram and A. Kamal,
E. Van der Eycken, RSC Adv., 2016, 6, 103601. New J. Chem., 2017, 41, 3745.
53 H. H. Butani, D. D. Vachhani, U. C. Bhoya, A. K. Shah and 74 A. Maleki and M. Aghaei, Ultrason. Sonochem., 2017, 38,
E. Van der Eycken, Eur. J. Org. Chem., 2015, 2124. 115.
54 S. Gunawan and C. Hulme, Org. Biomol. Chem., 2013, 11, 75 L. V. Frolova, I. Malik, P. Y. Uglinskii, S. Rogelj,
6036. A. Kornienko and I. V. Magedov, Tetrahedron Lett., 2011, 52,
55 S. G. Pharande, A. R. Corrales-Escobosa and R. Gámez- 6643.
Montaño, Green Chem., 2017, 19, 1259. 76 R. González-Olvera, V. Román-Rodríguez, G. E. Negrón-
56 (a) A. Sarvary and A. Maleki, Mol. Diversity, 2015, 19, 189; Silva, A. Espinoza-Vázquez, F. J. Rodríguez-Gómez and
(b) A. Maleki and A. Sarvary, RSC Adv., 2015, 5, 60938. R. Santillan, Molecules, 2016, 21, 250.
57 Z.-L. Ren, J.-C. Liu and M.-W. Ding, Synthesis, 2017, 49, 77 H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem.,
745. Int. Ed., 2001, 40, 2004.
58 G. Martínez-Ariza, M. Ayaz, F. Medda and C. Hulme, J. Org. 78 L. Zheng, Y. Bin, Y. Wang and R. Hua, J. Org. Chem., 2016,
Chem., 2014, 79, 5153. 81, 8911.
59 M. S. Singh, S. Chowdhury and S. Koley, Tetrahedron, 2016, 79 M. V. Mijangos and L. D. Miranda, Org. Biomol. Chem.,
72, 5257. 2016, 14, 3677.

1418 | Org. Biomol. Chem., 2018, 16, 1402–1418 This journal is © The Royal Society of Chemistry 2018