# Multicomponent Synthesis of Fluorine-Containing Bioactive Compounds and Drugs

Ivette Morales-salazar, Perla Islas-jácome, Leonardo D Herrera-zuñiga, Samuel Couve-bonnaire, Philippe Jubault, Eduardo González-zamora, Jean-philippe Bouillon, Alejandro Islas-jácome

► To cite this version:

Ivette Morales-salazar, Perla Islas-jácome, Leonardo D Herrera-zuñiga, Samuel Couve-bonnaire, Philippe Jubault, et al.. Multicomponent Synthesis of Fluorine-Containing Bioactive Compounds and Drugs. European Journal of Organic Chemistry, 2005, 28 (38), pp.e202500572. 10.1002/ejoc.202500572 . hal-05505487

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# Multicomponent Synthesis of Fluorine-Containing Bioactive Compounds and Drugs

Ivette Morales-Salazar, Perla Islas-Jácome, Leonardo D. Herrera-Zuñiga, Samuel Couve-Bonnaire, Philippe Jubault, Eduardo González-Zamora,* Jean-Philippe Bouillon,* and Alejandro Islas-Jácome*

*Dedicated to Jieping Zhu's birthday (60 years)*

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It is well known that fluorine atoms placed strategically into bio-
active molecules often enhance essential pharmacokinetic
parameters like bioavailability, lipophilicity, and metabolic resis-
tance. In the same way, a relatively broad spectrum of marketed
drugs contains one or more fluorine atoms in their structures,
usually in the form of fluorine-, difluoromethyl-, trifluoro-
methyl-, or perfluoroalkyl aromatic moieties, being essential parts
of their corresponding pharmacophores. Besides, multicompo-
nent reactions (MCR) are highly convergent one-pot processes
in which three or more smartly substituted/functionalized

reagents are combined simultaneously, sequentially or consecu-
tively, in the same reactor to assemble complex products (includ-
ing polyheterocycles) containing most or all atoms from the
reagents. Thus, the scope of the present review is to discuss
selected MCR-based works since 2009 for the synthesis of bioac-
tive compounds and drugs that contain at least one fluorine atom
in their structures, as well as relevant results from *in silico*, in vitro,
and/or in vivo studies against a variety of important target bio-
molecules, highlighting the role of fluorine-containing moieties.

# 1. Introduction

## 1.1. Fluorine-Containing Drugs

Studies on fluorine chemistry began in the late 19th century.[1]
Thus, it is well known that fluorine-containing organic com-
pounds are practically inexistent in nature but, due to special ster-
oeoelectronic properties of fluorine atom, this class of compounds
is of high interest for academy and pharmaceutical industry since
around 20% of bioactive compounds and current marketed drugs
contain at least one fluorine atom in their structures.[2] Fluorine
atoms placed strategically into the structure of bioactive com-
pounds modulate their pharmacokinetic profile. For instance,
parameters like oral bioavailability, lipophilicity, and metabolic
resistance are dramatically enhanced.[3] The potential of fluo-
rine-containing compounds to bind important target biomole-
cules can be higher than the non-fluorinated ones.[4] In other
words, the incorporation of fluorine atoms into molecules used
for medicinal purposes (usually in the form of fluorine-, difluor-
omethyl-, trifluoromethyl-, or perfluoroalkyl aromatic moieties)
can improve aspects of biological activity compared to their
non-fluorinated analogs.[5] These improvements manifest in per-
meability toward cell membranes, and increased weak interac-
tions that favor molecular recognition, among others.[6] In
addition, bioisosteric replacement of hydrogen by fluorine atoms

or methyl by trifluoromethyl groups, for instance, is a widely used
approach both in drug design and drug discovery fields to
increase metabolic stability by blocking or decreasing the oxida-
tion processes, for instance those promoted by cytochrome P450
monooxygenases.[7] A classic example of a fluorinated drug with
metabolic stabilization is the ezetimibe, in which the crucial met-
abolic sites are replaced strategically by fluorine atoms.[8] Thus,
drugs approved recently by the FDA like tovafenib (1), vorasi-
denib (2), inavolisib (3), acoramidis (4), ensartinib (5), danicopan
(6), and seladelpar (7) may owe their biological activity and
enhanced pharmacokinetic profile to their fluorine-containing
moieties (Figure 1).[9]

## 1.2. Multicomponent Reactions

It is still necessary to design and synthesize molecular libraries
containing fluorinated moieties to evaluate their biological
potential in medicinal chemistry. In this context, multicomponent
reactions (MCR) are robust and useful one-pot synthetic tools that
combine simultaneously, sequentially, or consecutively three or
more smartly decorated reagents to obtain libraries of structurally
complex and varied molecules, including fluorine-containing pol-
yheterocycles.[10] MCR have been positioned as the methodolo-
gies of choice to carry out sustainable organic synthesis
because they meet almost all of the 12 principles of green chem-
istry such as the high atom economy, the possibility of using less
toxic solvents and reagents, the possibility of using alternative
energy sources like microwaves (µW) or ultrasound (US), the
use of catalysts able of recovery, the minimization or suppression
of protection/deprotection steps as they are performed in one-
pot manner, the reduced use of resources for work-ups and puri-
fications, among others.[11] The range of multicomponent
reactions continues increasing and getting more. Within the MCR,
there is a very peculiar class that uses isocyanides as one of their
starting reagents, known as isocyanide-based MCR (I-MCR), which
are divided into Passerini and Ugi reactions. These types of MCR
are desirable since they allow obtaining molecules with a high
degree of chemo-, regio-, and stereoselectivity.[12] Besides, there
are MCR that do not involve the use of isocyanides as start-
ing reagents, known simply as non-isocyanide-based MCR
(NI-MCR). Hantzsch reported the first NI-MCR using a fluorine-
containing reagent toward the synthesis of a bioactive dihydro-
pyridine 11 through a combination of two equivalents of ethyl

I. Morales-Salazar, P. Islas-Jácome, L. D. Herrera-Zuñiga,
E. González-Zamora, A. Islas-Jácome
Departamento de Química
Universidad Autónoma Metropolitana-Iztapalapa
Av. Ferrocarril San Rafael Atlixco 186, Col. Leyes de Reforma 1A Secc.,
Iztapalapa 09310, Ciudad de México, Mexico
E-mail: egonzalez.zamora@izt.uam.mx
aislas@izt.uam.mx

S. Couve-Bonnaire, P. Jubault, J.-P. Bouillon
Univ Rouen Normandie
INSA Rouen Normandie
CNRS, Normandie Univ
CARMeN UMR 6064, INC3M FR 3038, F-76000 Rouen, France
E-mail: jean-philippe.bouillon@univ-rouen.fr

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© 2025 The Author(s). European Journal of Organic Chemistry published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
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Ivette Morales-Salazar was born in Ecatepec, EdoMex, México, in 1989. She received her B.Sc. in Chemistry in 2018 from the Universidad Autónoma Metropolitana-Iztapalapa (UAM-I). Then, she got her M.Sc. in Chemistry in 2021 at UAM-I under mentorship of Professor Eduardo González-Zamora. She is currently pursuing her Ph.D. under the supervision of Dr. Alejandro Islas-Jácome at UAM-I where she is working on the synthesis of novel polyheterocycles with medicinal interest. As part of an ECOS-NORD program, in 2023 and 2025 she moved into short-term research stays during her Ph.D. project with Professor Jean-Philippe Bouillon at CARMeN-Lab University of Rouen in France.

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Perla Islas-Jácome was born in Cd. Nezahualcoyotl, EdoMex, México, in 1996. As a part of her Bs, in 2020 she synthesized polydentate ligands as precursors of new MOFs. In 2023, she finished her M.Sc. having worked on the synthesis of new polyheterocycles via the Ugi-Zhu reaction. She is currently studying her Ph.D. working on click processes, new MCR, and in the synthesis of new fluorine-containing bioactive compounds and drugs, all under the supervision of Professor Eduardo Gonzalez-Zamora. As a part of an ECOS-NORD program, in 2024 she moved into a short-term research stay during her Ph.D. project with Professor Jean-Philippe Bouillon at CARMeN-Lab University of Rouen in France.

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Leonardo D. Herrera-Zuñiga (Mexico City, 1980) is an Industrial Biochemical Engineer with a specialization in Biotechnology and a Ph.D. in Chemistry from the Universidad Autónoma Metropolitana – Iztapalapa (UAM-I), under the supervision of Professors Arturo Rojo-Domínguez and Gustavo Vinegra-González. He made postdoctoral fellowships at the Biotechnology Research Center (CEIB-UAEM, Mexico) and the SABNP laboratory at Université d'Evry (France) under the supervision of Dr. R. Charbel Maroun. He is currently full-time professor at UAM-Cuajimalpa. His research focuses on biological computing, protein molecular dynamics, and computer-aided drug design.

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Samuel Couve-Bonnaire received his Ph.D. in 2001 under the supervision of Pr. Y. Castanet and J.-F. Carpentier at the Laboratory of Catalysis of Lille. Then he carried out his post-doctoral studies in Canada under the guidance of Pr. Prabhat Arya at the Steacie Institute for Molecular Sciences in Ottawa. Back to France, he was post-doctoral researcher with Sanofi-Aventis as industrial partner. Since February 2005, he is working in the group of "fluorinated biomolecules synthesis" as an associate professor, in CARMeN Institute. His main thematic research deals with fluorinated alkenes, from their synthesis to their application as fluorinated heterocycles, fluoropeptidomimetics, etc.

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Philippe Jubault received his Engineer Diploma in «Chemistry and Process» from the National Institute of Applied Sciences of Rouen. In 1992, he joined the research group of Prof. Collignon and Prof. C. Feasson at the INSA of Rouen where he obtained his Ph.D. in January 1996. After one year as a post-doctoral student at Hydro-Québec (Shawinigan, Québec, Canada), he was a Marie Curie research fellow in the laboratory of Prof. V. K. Aggarwal at the University of Sheffield. In 1998, he returned to the INSA of Rouen and assumed in 2000 an assistant professor position, becoming full professor in 2008. His research interests include the development of new methodologies for the synthesis of original fluorinated building blocks bearing $CF_2$, $SF_5$ groups, fluorinated cyclopropanes, flow chemistry, and new heterocyclic scaffolds for medicinal chemistry.

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Eduardo González-Zamora, full professor at UAM-I, Mexico, was born in 1961 in Mexico City. He received his M.Sc. degree from UAM-I in 1988. In 1994, he moved to France and obtained his Ph.D. (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 de Química (UNAM, Mexico), he joined the "Institut de Chimie des Substances Naturelles", CNRS (France) in 2000 as a postdoctoral fellow for 2 years working with Professor J. Zhu. In 2011, he moved to UCLA (USA) as a visiting professor in M. A. García-Garibay's group. His research interests include the synthesis of heterocycles by MCR, MOFs' chemistry, peptides, and total synthesis.

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Jean-Philippe Bouillon was born in Soignies (Belgium) in 1967. He got his Ph.D. in Organic Chemistry from University Catholic of Leuven, in 1994. He moved to France to carry out his first postdoctoral studies at Institut de Chimie de Substances Naturels (CNRS), and the second one at University Joseph Fourier. In 1996, he worked as CNRS researcher at the University of Reims Champagne Ardennes. Since 2004, he took a position as professor at University of Rouen in CARMeN Laboratory (Fluorinated Biomolecules Team). His research interests concern the development of new methodologies to access fluorinated building-blocks (fluoroalkenes) and fluorinated heterocycles.

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Alejandro Islas-Jácome was born in Xalapa, Veracruz, México in 1981. He got his B.Sc. in Chemistry in 2005 and Ph.D. in 2011, both under the guidance of Professor Eduardo González-Zamora in UAM-Iztapalapa, México. Then, he joined a post-doctoral position in the Rocío Gámez-Montaño's research group from 2012 to 2016 at Universidad de Guanajuato, México. He is full-time professor since 2017 at Departamento de Química in UAM-Iztapalapa, México. His research interests include the synthesis of polyheterocycles via multi-component reactions, click chemistry, studies of reaction mechanisms, studies of optical properties, as well as biomolecular and medicinal chemistry.
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<figure><img src="image_17.png" /><figcaption>**Figure 1.** Fluorine-containing drugs.</figcaption></figure>

acetoacetate (8), ammonia (9), and fluorine-containing aldehyde 10 (Scheme 1).[13]

Then, in 2009, Cao and Wu published a very interesting semi-
nal review entitled "multicomponent reactions based on fluoro-
containing building blocks".[14] Thus, the scope of the present
review is to update and deepen the discussion from selected
MCR-based strategies since 2009 for the synthesis of bioactive
compounds and marketed drugs that contain at least one fluo-
rine atom in their structures. Results from *in silico*, in vitro, and/or
in vivo structure-activity relationship studies highlighting the
influence of fluorinated moieties for the exhibited biological
activity, will also be discussed, when data is available. It is impor-
tant to highlight that just the primary difference between

<figure><img src="image_18.png" /><figcaption>**Scheme 1.** First NI-MCR-based synthesis of a fluorine-containing bioactive heterocyclic compound. Reproduced from ref. [13]</figcaption></figure>

fluorinated and non-fluorinated compounds synthesized via MCR lies in the application of the first ones in medical chemistry. Thus, despite to the best of our knowledge, there are no reports describing that fluorine atoms affect, considerably, the reactivity in the MCR (yields and/or selectivities improved upon translation to fluorine-containing compounds), some observed differences between fluorinated compounds and their non-fluorinated analogs are discussed. The number of examples in the following section referred only to the number of fluorinated products synthesized by the methodology reported.

2. Ugi-3CR-Based Strategies

The classical Ugi-4CR involves the use of amines, aldehydes, car-
boxylic acids, and isocyanides, right in that order of sequential
addition. However, there is a variant known as the Ugi-3CR, which
dispenses the use of carboxylic acids. They are usually carried
out under acidic catalysis, resulting in the generation of
α-aminoamides.[12] First, a condensation between amines **12**
and aldehydes **13** occurs to give the iminium cations **14**.
Then, a nucleophilic attack from isocyanides **15** to the intermedi-
ates **14** affords nitrilium cations **16**, which after a rearrangement
give the products **17** (Scheme **2**).

In 2009, Röschenthaler and Nenajdenko developed a MCR-
based procedure to synthesize the proline and homoproline
derivatives.[15] After finding the optimal parameters, the reaction
of imines **18a-b**, isocyanides **20a-e** or **22a-g**, and trifluoracetic
acid (19) resulted in the formation of proline and homoproline
derivatives **21a-j** and **23a-m** in moderate to very good yields
(59–89% or 44–79%, respectively) (Scheme **3**). Five- and six-
membered rings gave good yields (up to 89%) in comparison

<figure><img src="image_19.png" /><figcaption>**Scheme 2.** Ugi-3CR mechanism.</figcaption></figure>
<figure><img src="image_20.png" /></figure>

<figure><img src="image_21.png" /><figcaption>**Scheme 3.** Synthesis of proline and homoproline derivatives. Reproduced from ref. [15]</figcaption></figure>

to seven-membered ones (59% or 70%). The scope of the reaction was measured using electron-donating and withdrawing groups placed in the isocyanides. The use of Ugi-type MCR allowed the assembly of amino acid derivatives in a one-pot manner. It is worth noting also that the pharmacophoric core of proline is found in danicopan to treat paroxysmal nocturnal hemoglobinuria, in trofinetide used to treat Rett syndrome, or in daridorexant, which is used against insomnia.[16]

Related to the previous work, in 2013, Nenajdenko developed an Ugi-azide 3CR to prepare the fluorinated tetrazole-pyrrolidines **27a-m**.[17] Optimal conditions were found, and the substrate scope was measured varying the isocyanide substituents and the size of the imine ring. Imines **24a-b** were combined with isocyanides **25a-f** and trimethylsilyl azide (26) to afford the 1,5-1 H-disubstituted tetrazoles **27a-m** in moderate to good yields (58–84%) (**Scheme 4**). Six-membered rings gave better yields compared to five- and seven-membered ones. Steric hindrance

from the C₂F₅ group decreased significantly the yields in comparison with the CF₃ group. Similarly to pyrrolidine, 1,5-1 H-disubstituted tetrazole is a very important heterocycle in medicinal chemistry as it is a pharmacophoric scaffold because it mimics the cis-amide bond of peptides,[18] acting in some cases as their bioisosteres, exhibiting different pharmacological activities such as antibacterial, antifungal, anticonvulsant, analgesic, to name a few.[19]

In 2015, Stecko and Furman reported the synthesis of the polyhydroxylated pyrrolidine and piperidine peptidomimetics **31a-t** via a strategy consisting of a reduction of sugar-derived lactams **28a-b** using the Schwartz's agent to afford the imines **28'a-b**, followed by multicomponent an Ugi-Joullié-type 3CR.[20] The interest in peptidomimetics arises because such peptide isosteres have presented pharmacological properties over their corresponding natural peptides. Therefore, the authors carried out the synthesis of a series of 20 pyrrolidine and piperidine derivatives **31a-t**, where each of them incorporates a trifluoromethyl substituent from trifluoroacetic acid (30), in combination with isocyanides **29a-c**, and imines **28'a-b**. Thus, foreseeing that such molecules will show improvement in their pharmacological properties (**Scheme 5**). The pyrrolidine and piperidine heterocycles have been found in a wide variety of FDA-approved drugs such as the anticancer agents alectinib, certinib, or tepotinib, the antipsychotic amisulpride, and the antifungal rezafungin.[21]

In 2017, Milen and collaborators reported the synthesis of the α-amino amides **35a-i** via an Ugi-type 3CR.[22] Thus, combination of aldehydes **32a-e**, amines **33a-d**, and isocyanides **34a-b** using propylphosphonic anhydride (T3P) in ethyl acetate as the solvent afforded the α-amino amides **35a-i** in moderate to good yields (47–72%). The authors proposed a plausible mechanism, highlighting the role of propylphosphonic anhydride T3P (**Scheme 6**). As the first step, a condensation between aldehydes **32a-e** and amines **33a-d** occurs to give the corresponding imines **36a-i**, which reacted with 1,5-dihydroxy-1,3,5-tripropyltriphosphoxane 1,3,5-trioxide (QOH) **37** to obtain iminium cations **38a-i**. Nucleophilic attack by isocyanides **34a-b** to intermediates **38a-i** achieved nitrilium ions **39a-i**. Then a nucleophilic addition performed by anions (QO⁻) to intermediates **39a-i** afforded the compounds **40a-i**. α-Amino amides **35a-i** were synthesized by hydrolysis of phosphonic acid esters **40a-i**, and tautomerization of imidic acids **41a-i**. It is noteworthy that the procedure used

<figure><img src="image_22.png" /><figcaption>**Scheme 4.** Synthesis of tetrazole-containing bound-type *bis*-heterocycles. Reproduced from ref. [17] Copyright (2013), with permission from Wiley-VCH GmbH.</figcaption></figure>

<figure><img src="image_23.png" /><figcaption>**Scheme 5.** Synthesis of polyhydroxylated pyrrolidine- and piperidine-based peptidomimetics. Reproduced from ref. [20] Copyright (2015), with permission from ACS.</figcaption></figure>
<figure><img src="image_24.png" /></figure>

<figure><img src="image_25.png" /></figure>

<figure><img src="image_26.png" /><figcaption>**Scheme 6.** Synthesis of α-amino amides. Reproduced from ref. [22]
Copyright (2017), with permission from Elsevier.</figcaption></figure>

propylphosphonic anhydride in the Ugi reaction, for the first time. α-Amino amides have been positioned as pharmacophoric fragments that have a good bioavailability in several prodrugs, for example, derivatives of the bronchodilator theophylline or pilocarpine used to treat glaucoma.[23]

In 2017, Zhu's research group reported the synthesis of proline-containing amides **45a-c** via an Ugi-Joullié-type 3CR.[24] Through sequential combination of alkynyl-containing amines **42a-c**, tert-butyl isocyanide (43), and trifluoroacetic acid (44) using a silver-based catalyst in toluene as the solvent, proline-based compounds **45a-c** were afforded in good to excellent yields (86–98%) (**Scheme 7**). The authors suggested a mechanism, which, surprisingly, would take place first in the reaction flask and then would continue during the purification step. The first part involves intermediate **46**, formed by complexation of the silver-based catalyst with isocyanide **43**. Adding propargylamines **42a-c** and trifluoroacetic acid (44) to intermediate **46** affords complexes **47a-c**, which undergoes a 5-endo-dig cyclization to give intermediates **48a-c** in equilibrium with their corresponding salts **49a-c**. Regeneration of complex **46** affords dihydropyrroles **50a-c**. The second part would take place on silica gel during the purification step (column chromatography): dihydropyrroles **50a-c** are in equilibrium with iminium ions **51a-c**, which react with isocyanide **43** to give the nitrilium cations **52a-c**. Finally, the latter are trapped by water. Then, the

<figure><img src="image_27.png" /></figure>

<figure><img src="image_28.png" /><figcaption>**Scheme 7.** Synthesis of N-acyl prolines. Reproduced from ref. [24]
Copyright (2017), with permission from Wiley-VCH GmbH.</figcaption></figure>

tautomerization process affords products **45a-c**. In this procedure, the use of alkynyl-containing amines **42a-c** as a bifunctional-orthogonal reagent in a multicomponent reaction is noteworthy as well as a gram-scale synthesis. Proline analogs can be found in natural products such as the toxins phalloidine and α-amanitine isolated from *Amanita phalloides* or in pharmaceutical products such as the antibiotic telomycin.[25]

Ruijter and collaborators reported in 2023 the total synthesis of a protease inhibitor known as nirmatrelvir (57) via an Ugi-3CR as the key step (**Scheme 8**).[26] A combination of chiral isocyanide 53, cyclic imine 54, and fluorinated α-amino acid 55 afforded the product 56 in a good yield (68%) and diastereoselectivity (more than 25:1 dr). Further reactions were alcoholysis of ester and oxidation of alcohol to nitrile, to name a few. Nirmatrelvir in combination with ritonavir is an antiviral cocktail developed by Pfizer and was approved by the FDA in 2021 for the treatment of human SARS-CoV-2.[27]

De Los Santos and coworkers reported the synthesis of phosphorylated N-acylaziridines **61a-d** through an Ugi-Joullié 3CR.[28] It combines 2 H-azirin-2-yl phosphine oxides **58a-b**, isocyanides **59a-b**, and carboxylic acids **60a-b** to give the products **61a-d** (27–76%, *dr* up to 96:4) using ZnCl₂ as a Lewis catalyst at room temperature (**Scheme 9**). This interesting approach involved a
<figure><img src="image_29.png" /></figure>

<figure><img src="image_30.png" /><figcaption>**Scheme 8.** Synthesis of Nirmatrelvir. Reproduced from ref. [26] Copyright (2023), with permission from ACS.</figcaption></figure>

mechanism pathway where zinc chloride starts the catalytic cycle. Then, a coordination bridge between the nitrogen of azirines **58a-b**, the oxygen of carboxylic acids **60a-b**, and zinc promote the nucleophilic addition of isocyanides **59a-b** to give the complexes **62a-d**, which through a Mumm rearrangement affords the complexes **63a-d**. After an imidic acid tautomerization of intermediates **64a-d**, products **61a-d** were afforded. It is worth highlighting the efficient selectivity of the process, which is directed by the nature of azirines **58a-b** and carboxylic acids **60a-b**. Also, the procedure can be carried out in gram-scale. Aziridine motif is considered a pharmacophore itself, particularly in natural or synthetic alkaloids such as the compounds isolated from *Petasites japonicus*, a herbaceous plant native from Japan.[29] Three different aziridine-containing alkaloids were isolated from such source. In addition, the family of epothilones are azirine-containing metabolite derived from *Sorangium cellulosum*.[30]

### 3. Ugi-4CR-Based Strategies

The Ugi-4CR is based on a combination of a carbonyl compounds (usually aldehydes), primary amines, isocyanides, and carboxylic acids to synthesize peptide-like molecules such as α-amido

<figure><img src="image_31.png" /><figcaption>**Scheme 9.** Synthesis of phosphorylated *N*-acylaziridines. Reproduced from ref. [28] (open access).</figcaption></figure>

<figure><img src="image_32.png" /><figcaption>**Scheme 10.** Ugi-4CR mechanism.</figcaption></figure>

amides (Scheme 10).[31] The mechanism begins with condensation between amines **65** and aldehydes or ketones **66** to give imines **67**, which are protonated by carboxylic acids **68** to afford the iminium cations **69**. Then, isocyanides **71** perform a
<figure><img src="image_33.png" /></figure>

nucleophilic attack on intermediates **69** to afford nitrilium cations **72**. Finally, carboxylates **70** react with nitrilium ions **72** to give the intermediates **73**, which through a Mumm rearrangement complete the formation of the products **75**.

Cao and Qian reported in 2009 the synthesis of some new difluorinated pseudopeptides **80a-d** via an Ugi-4CR.[32] Thus, sequential combination of aromatic aldehydes **76a-c**, primary amines **77a-c**, the fluorinated isocyanide **78**, and aromatic or aliphatic carboxylic acids **79a-b** produced the amides **80a-d** in moderate to good yields (62–78%) (**Scheme 11**). This strategy allowed the synthesis of new fluorinated building blocks, which were used in a MCR-based on Isocyanides (I-MCR). Pseudopeptides are a class of compounds that have high relevance in drug design due to their stability in comparison with natural peptides. For instance, a type of fluorinated pseudopeptides with antimicrobial activity are the fluorinated α,α-disubstituted β-aminoamides.[33]

Fan and co-workers reported in 2010 the synthesis of 1,2,3-thiadiazoles **85a-z**, which were evaluated in vitro and in vivo for their fungicidal and antiviral activities.[34] In this Ugi-4CR, the fluorinated aldehydes **81a-b**, amines **82a-b**, isocyanides **83a-b**, and carboxylic acid **84** were combined to synthesize the products according to the procedure reported by Bakulev et al.[35] The synthesis of the 1,2,3-thiadiazoles **85a-z** was done using methanol as the solvent, obtaining moderate to excellent yields (39–92%) (**Scheme 12**). The antifungal activity was studied on 12 fungi that belong to different families: *Alternaria solani*, *Botrytis cinerea*, *Cercospora arachidicola*, *Cercospora beticola*, *Colletotrichum lagenarium*, *Fusarium oxysporum*, *Gibberella zeae*, *Phytophthora*

<figure><img src="image_34.png" /><figcaption>**Scheme 11.** Synthesis of difluorinated pseudopeptides. Reproduced from ref. [32] Copyright (2009), with permission from Elsevier.</figcaption></figure>

<figure><img src="image_35.png" /><figcaption>**Scheme 12.** Synthesis of 1,2,3-thiadiazoles derivatives. Reproduced from ref. [34] Copyright (2010), with permission from ACS.</figcaption></figure>

*infestans*, *Physalospora piricola*, *Pellicularia sasakii*, *Puccinia triticina Eriks*, and *Rhizoctonia solani*. In the same way, antiviral activity was evaluated against the tobacco mosaic virus (TMV). In both cases, four 1,2,3-thiadiazoles (two of them fluorinated) presented potential fungicidal and antiviral activities; in particular, three compounds showed good antifungal activities against *Colletotrichum lagenarium*, which was attributed to the presence of fluorine atoms in their structures. Also, four compounds exhibited inactivation activities against TMV (69–73% at 100 µg mL⁻¹).

Neamati reported in 2011 the synthesis of N-propynoyl α-aminophenylacetamides **90a-h**, which were evaluated in vitro and in vivo against several human carcinoma cell lines such as MDA-MB-435, HT29, HEY, to name a few.[36] For the Ugi-4CR, a sequential combination of aromatic aldehydes **86a-b**, amines **87a-d**, aromatic or aliphatic isocyanides **88a-c**, and propynoic acid **89** in methanol as solvent afforded amides **90a-h** in moderate to good yields (56–93%) (**Scheme 13**). The synthetic procedure can be carried out in gram-scale. The *in silico* evaluation of propynoic acid carbamoyl methyl amides containing fluorinated moieties predicted good anticancer activity, highlighting their pharmacokinetic (ADME studies) and pharmacodynamic (interaction with biological targets) profiles. Then, in vitro assays were

<figure><img src="image_36.png" /><figcaption>**Scheme 13.** Synthesis of propynoic acid carbamoyl methyl amides. Reproduced from ref. [36] Copyright (2011), with permission from ACS.</figcaption></figure>
performed, finding that one of the fluorinated compounds exhibited cytotoxicity against carcinoma cell lines HT29 (1.8 ± 1.7 µM), HEY (1.5 ± 0.8 µM), MDA-MB-435 (1.4 ± 0.2 µM), and NCI/ADR-RES (1.0 ± 0.3 µM), to name a few. Then, a fluorinated compound was selected for further in vivo studies, exhibiting significative size reduction in tumors after administration of 26 days in consecutive doses of 10 mg Kg⁻¹, 20 mg Kg⁻¹, and up to 40 mg Kg⁻¹.

Dömling and co-workers reported in 2012 the synthesis of the fluorinated 2-carboxyindoles **96a-s** via an Ugi-4CR, which were evaluated *in silico* as inhibitors of receptor p53-MDM2 involved in cancer.[³⁷] Combination of indole-containing aldehydes **91**, fluorinated benzylamines **92a-e**, *tert*-butyl isocyanide (93), and formic acid (94) in methanol at room temperature afforded the products **95a-s** in moderate to good yields (38–84%) (*Scheme* **14**). Finally, further transformation was carried out through the saponification of **95a-s** leading to the products **96a-s**. The *in silico* evaluation predicted good interactions between the aromatic fluorine fragment and the protein MDM2, highlighting the presence of a fluorine atom to potentiate the effect of the compounds.

O'Hagan et al. reported in 2016 the synthesis of some new chiral methyl-substituted all-*cis* tetrafluorocyclohexyl-containing peptidomimetics **101a-l**.[³⁸] First, fluorine-containing aldehydes **97a-b** were prepared in multi-step synthesis and submitted to Ugi-4CRs with aromatic or allylic amines **98a-b**, aliphatic or aromatic isocyanides **99a-b**, and carboxylic acids **100a-c** in DCM or methanol as the solvents, affording the products **101a-l** in moderate to good yields (up to 80%) (*Scheme* **15**). Passerini products were also obtained. It is noteworthy that the presence of the fluorinated-cyclohexyl group increases lipophilicity and in general the pharmacokinetic profile of such compounds.[³⁹]

<figure><img src="image_37.png" /><figcaption>**Scheme 14.** Synthesis of 2-carboxyindoles. Reproduced from ref. [37] Copyright (2012), with permission from Wiley-VCH GmbH.</figcaption></figure>

<figure><img src="image_38.png" /><figcaption>**Scheme 15.** Synthesis of tetrafluorocyclohexyl ring-containing peptidomimetics. Reproduced from ref. [38] Copyright (2016), with permission from RSC.</figcaption></figure>

Yen and co-workers reported in 2018 the synthesis of ivosidenib analogs **106a-n** using an Ugi-4CR as the key reaction. Such products were studied in vitro and in vivo against the enzyme IDH1 related to different types of cancer.[⁴⁰] Through a combination of benzaldehydes **102a-b**, fluoro-anilines **103a-d**, isocyanides **104a-b**, and carboxylic acids **105a-h** in methanol or 2,2,2-trifluoroethanol (TFE) as solvent, products **106a-n** were obtained in moderate yields (33–67%) (*Scheme* **16**). Further transformations such as Buchwald reaction, amidation, and alkylation of amines, achieved the analogs of ivosidenib, which is used to treat leukemia under commercial name of Tibsovo developed by Agios Pharmaceuticals and approved by FDA in 2023.[⁴¹] These analogs presented potential activity on the cell lines mutant IDH1-R132H homodimer and HT1080 chondrosarcoma cell line with an IC₅₀ of 9 and 3 nM, respectively. In vivo studies revealed rapid oral absorption, tumoral reduction of 92% at 50 mg Kg⁻¹.

Vazdar reported in 2018 the synthesis of amino-β-lactam-containing peptidomimetics **111a-b** via Ugi-4CRs.[⁴²] The multi-component reactions were carried out between benzaldehyde (107), β-lactam **108**, isocyanide **109**, and fluorinated carboxylic acids **110a-b** in TFE as the solvent to afford the products **111a-b** in good yields (up to 68%) but in moderate diastereoselectivity (up to 67:33) (*Scheme* **17**). Amino-β-lactam has the particularity of being contained in the structure of antibiotics from the family of penicillin, cephalosporin, and cephamycin, to name a few.[⁴³]

Tang reported in 2021 the synthesis of seven new indole-derivatives **118a-g**, which were evaluated as MDM2 protein degraders, related to tumoral growth.[⁴⁴] Synthesis of compounds **116a-g** was carried out via Ugi-4CR by a sequential combination of the indole-containing aldehyde **112**, fluorinated benzylamine **113**, isocyanide **114**, and alkynyl-containing carboxylic acids **115a-g** in TFE as the solvent, and µw as a heat source to obtain the products **116a-g** in low to moderate yields (15–51%).
<figure><img src="image_39.png" /></figure>

<figure><img src="image_40.png" /></figure>

<figure><img src="image_41.png" /><figcaption>**Scheme 16.** Synthesis of ivosidenib analogs. Reproduced from ref. [40] Copyright (2018), with permission from ACS.</figcaption></figure>

<figure><img src="image_42.png" /></figure>

<figure><img src="image_43.png" /><figcaption>**Scheme 18.** Synthesis of indole-derivatives. Reproduced from ref. [44] Copyright (2021), with permission from Elsevier.</figcaption></figure>

<figure><img src="image_44.png" /><figcaption>**Scheme 17.** Synthesis of amino-β-lactam-containing peptidomimetics. Reproduced from ref. [42] Copyright (2018), with permission from Elsevier.</figcaption></figure>

(Scheme 18). A further transformation was a Sonogashira coupling between the compound **117** and isoindolinone-derivatives **116a-g** to afford the products **118a-g** moderate to good yields (20–53%). In the series of those compounds, only one presented a lead value of IC₅₀ (1.2 nM), which means an MDM2 degradation in the leukemia cell lines RS4; 11, MV-4-11, MOLM-13; tumor cell line A549, HepG2 and WM115; and TP53 mutant cells. That compound is a candidate for further in vivo studies.

Shindo and Ojida described in 2022 the synthesis of chlorofluoroacetamides **123a-o**, which were tested *in silico* as inhibitors of the SARS-CoV-2 M<sub>pro</sub>.<sup>[45]</sup> The synthesis was carried out *via* an Ugi-4CR through sequential combination of heterocyclic aldehydes **119a-e**, anilines **120a-e**, isocyanides **121a-e**, and

α-fluorinated carboxylic acid **122** in methanol as solvent at room temperature to give a mixture of separable diastereomers **123a-o** in low to good yields (7%–88%) (**Scheme 19**). *In silico* studies revealed that chlorofluoroacetamides are interesting inhibitors of the protease M<sub>pro</sub> due to the formation of N-F bonds on their active sites. *In vitro* studies exhibited that three compounds presented the best IC₅₀ of 0.31, 2.72, and 2.95 µM respectively, as potential M<sub>pro</sub> inhibitors.

<figure><img src="image_45.png" /></figure>

$$R^1 = 4-t-BuC_6H_4, 4-i-PrC_6H_4, 4-CF_3C_6H_4, 4-SF_5C_6H_4$$

<figure><img src="image_46.png" /></figure>

$$R^2 = 3-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyrimidyl, 2-pyrazinyl$$

$$R^3 = 3-fluorophenethyl, t-Bu, (2-pyridinyl)ethyl, (3-pyridinyl)ethyl, 7-isoquinolinyl$$

<caption>**Scheme 19.** Synthesis of chlorofluoroacetamides. Reproduced from ref. [45] Copyright (2021), with permission from RSC.</caption>
<figure><img src="image_47.png" /></figure>

## 4. Passerini-Based Strategies

Passerini three-component reaction (P-3CR) was developed in 1921. This multicomponent reaction involves a combination of a carbonyl compound, usually aldehydes or ketones, isocyanides, and carboxylic acids to give α-acyloxycarboxamides (Scheme 20).[46] First, carboxylic acids 124 and carbonyl compounds 125 react to give the complexes 126. A nucleophilic attack from isocyanides 127 to complexes 126 takes place to give the intermediates 128, which after a Mumm rearrangement afford the products 129.

Nenajdenko reported in 2009 that the $CF_3$-containing peptides 134a-z were synthesized via a P-3CR.[47] Thus, the carbonyl compounds 130a-e or hemiacetal 131 were combined with carboxylic acids 132a-f, and isocyanides 133a-e to obtain the fluorinated peptides 134a-z in low to excellent yields (14%–96%) (Scheme 21). The authors explored the influence of isocyanides, carbonyl compounds, and carboxylic acids, finding that aromatic isocyanides promoted better the reactions. The substituents of carbonyl compounds did not affect significantly the yields. Indeed, the reactions proceeded smoothly. On the contrary, trifluoroacetic and formic acids afforded the products with a free OH group, which may be useful for further transformations. Unfortunately, chiral amino acids did not promote

stereoinduction, affording the products as 1:1 diastereomeric mixtures. The $CF_3$ substituent has an interesting property in the products of pharmaceutical interest such as increased solubility or avoiding metabolic oxidation, even modulated stereoelectronic properties that are useful to follow the Lipinsky and Veber rules.[3]

Qu and Kung developed a strategy to prepare the potential cell labeling fluorine-containing glutamine 142 using the Passerini reaction as a key step.[48] Aldehyde 135, carboxylic acid 137, and isocyanide 136 were combined sequentially in DCM to give glutamine derivative 138. Alcohol 139 was obtained through the removal of chloroacetyl group and then underwent diastereoemer separation and tosylation to give the precursor 140, which is viable to prepare on a gram-scale (Scheme 22). For the fluorination process, it was necessary to test different fluorine sources such as KF, tetra-butylammonium fluoride (TBAF), or tetra-butylammonium difluorotriphenylsilicate (TBAT), and it was found that tris(dimethylamino) sulfonium difluorotrimethylsilicate (TASF) promotes the fluorination of the compound 140 to give the fluorinated ester 141 in good yield. With the fluorinated compound in hands, a deprotection process afforded compound 142. Following the same strategy with D-aspartic acid, authors were then able to finally obtain all four stereoisomers of 4-fluoro-glutamines. Another recurring application of it, the fluorinated compound 142 is a metabolic imaging agent in positron emission tomography (PET), a technique to visualize tumor cells.

Zhao developed an environmentally friendly Passerini-3CR-based strategy to prepare the trifluoroatrolactamides 147a-au, which were tested for their fungicidal activities.[49] A combination of fluorinated ketones 143a-f, isocyanides 144a-k, and acetic acid (145) resulted in the formation of products 146a-z under

<figure><img src="image_48.png" /><figcaption>Scheme 20. Passerini-3CR mechanism.</figcaption></figure>

<figure><img src="image_49.png" /><figcaption>Scheme 21. Synthesis of $CF_3$-containing peptides. Reproduced from ref. [47] Copyright (2009), with permission from Wiley-VCH GmbH.</figcaption></figure>

<figure><img src="image_50.png" /><figcaption>Scheme 22. Synthesis of 4-fluoro-glutamines. Reproduced from ref. [48] Copyright (2011), with permission from ACS.</figcaption></figure>
<figure><img src="image_51.png" /></figure>

<figure><img src="image_52.png" /><figcaption>**Scheme 23.** Synthesis of trifluoroatrolactamides. Reproduced from ref. [49] Copyright (2014), with permission from ACS.</figcaption></figure>

ultrasound conditions (Scheme 23). An electron-donating group was incorporated on isocyanides 144a-k, increasing the ratio between compounds 147a-au and the cyclic unstable by-products 148. A basic hydrolysis was carried out to avoid the ring-closing conversion. Finally, Passerini reaction and basic hydrolysis were performed via a one-pot process under ultrasound conditions that allow the synthesis of complete trifluoroatrolactamides 147a-au. The antifungal studies were performed in families of Fusarium vasinfectum, Cercospora arachidicola, Physalospora piricola, Alternaria solani, Gibberella zeae, Phytophthora infestans, Sclerotinia sclerotiorum, Botrytis cinerea, Thanatephorus cucumeris, and Phytophthora capsici where some compounds presented potential antifungal activity in the aforementioned strains (up to 90% inhibition at 50 µg/mL), as well as EC₅₀ up to 1.1 µg mL⁻¹.

Ruijter reported in 2018 the synthesis of fifteen new β-amino alcohols **154a-q** through a Passerini 3-CR replacing a carboxylic acid by 1,1,1,3,3,3-hexafluoroisopropanol (HFIP).[50] First, the authors optimized the reaction conditions, finding that DCM was the most efficient solvent, and room temperature was the condition of choice to give the products **153a-q** in highest yields (Scheme 24). Also, a wide variety of aldehydes **149a-c** and isocyanides **150a-d** were tested, for example, both aromatic or aliphatic isocyanides reacted smoothly, and aliphatic aldehydes as well as one activated aromatic aldehyde were effective. The chemoselectivity was evaluated by a competition reaction between acetic acid and HFIP promoting the exclusive formation of classical Passerini products instead of imidates **153a-q**. Having the optimal reaction parameters, amino alcohols **154a-q** were obtained by treating imidates **153a-q** with borane ammonia complex and TFA using HFIP as the solvent, all via a one-pot process.

<figure><img src="image_53.png" /><figcaption>**Scheme 24.** Synthesis of β-amino alcohols. Reproduced from ref. [50] Copyright (2018), with permission from ACS.</figcaption></figure>

In general, amino alcohols can be found in a wide variety of natural and synthetic compounds of pharmaceutical interest such as antimalarial, antibacterial, and anticancer agents, to name a few.[51] Another example of biological activity from amino alcohols was reported by McCluskey in 2022, where amino alcohols exhibited antibiotic and antifungal activity.[52]

Couturaud, Thurecht, and O'Reilly described the synthesis of the fluorinated monomer **158** through a Passerini-3CR, which can be used as a unit in a radical polymerization process to achieve a host–guest probe label, useful for drug delivery purposes.[53] Passerini monomer was synthesized via the combination of trifluoracetaldehyde (**155**), acrylic acid (**156**), and 1-adamantyl isocyanide (**157**) to give the product **158** in quantitative yield (Scheme 25). The latter may be due to the high electrophilicity of the aldehyde **155**. Then, a radical polymerization process was carried out just from product **158**, pentafluorophenylacrylate (**159**) as a comonomer, and 4-cyano-4-(phenylcarbonothioylthio) pentanoic acid (CPPA, **160**) as a reagent for the reversible addition–fragmentation transfer polymerization (RAFT). Finally, a post-polymerization modification was carried out from compound **161** adding DL-1-amino-2-propanol and triethylamine to give the polymer **162**. Pentafluorophenyl acrylate provides a highly reactive ester, which could later react with hydrophilic aminoalcohol nucleophile to enhance the final water solubility of the target polymer. The objective of this study was to use magnetic resonance imaging because this technique is applied to the detection of tumors into living systems.

Polindara-García developed an olefination process based on the substrate **166** obtained by the Passerini 3CR as the key step.[54] This substrate was synthesized through a combination of 2-cyanobenzaldehyde (**164**), tert-butyl isocyanide (**165**), and fluorinated phenylacetic acid **163** using a ball mill grinder in good yield (Scheme 26). With product **166** in hands, a post-transformation process combining ethyl acrylate (**167**), N-acetyl glycine, a palladium complex as catalyst, and silver acetate in
<figure><img src="image_54.png" /></figure>

<figure><img src="image_55.png" /></figure>

<figure><img src="image_56.png" /></figure>

<figure><img src="image_57.png" /><figcaption>**Scheme 25.** Synthesis of fluorinated polymer probe. Reproduced from ref. [53] Copyright (2018), with permission from ACS.</figcaption></figure>

hexafluoroisopropanol as solvent afforded the acrylate **168** in good yield and with excellent regio- and stereo-selectivity as well as the ability to be prepared on a gram scale. For the last synthetic step, it was proposed a mechanism pathway starting from a palladium II complex. Then, a metalation-deprotonation process afforded the intermediate **169**, which coordinated with ethyl acrylate (**167**) gave the complex **170**. A 1,2-migratory insertion on complex **170** afforded intermediate **171**. Through a β-hydride elimination carried out the product **168** and a palladium complex was recovered. Finally, the regeneration of the palladium catalyst is performed after a reductive elimination–reoxidation process. Usually, acrylates are employed as plastic precursors, but in biological systems, acrylates could be used as polymers for transdermal drug delivery[55] or resonance magnetic bioimaging agents.[56]

## 5. Non-Isocyanide MCR-Based Strategies

Other kind of multicomponent reactions are those that are not based on the use of isocyanides as reagents, such as the

<figure><img src="image_58.png" /></figure>

<figure><img src="image_59.png" /><figcaption>**Scheme 26.** Synthesis of acrylate-derivatives. Reproduced from ref. [54] Copyright (2024), with permission from Wiley-VCH GmbH.</figcaption></figure>

Biginelli, Mannich, and Petasis reactions, to name a few. In this section, a selection of these types of three or four-component reactions is discussed.

Jiang and Zhu reported the synthesis of fluorinated tetrahydrocarbazoles **180a-c** via a one-pot three-component reaction.[57] Thus, a combination of fluorinated ketoester **172a-c**, paraformaldehyde (**173**), and indole **175** afforded the tetrahydrocarbazoles **180a-c** in moderate to good yields (**Scheme 27**). To understand formation of such product, a plausible mechanism was proposed, where the first step was a Knoevenagel condensation between ketoesters **172a-c** and paraformaldehyde (**173**) to give vinyl compounds **174a-c**. Then, indole **175** trapped the vinylic compounds **174a-c** through a Michael-type addition leading to unstable intermediate **176a-c**. A sequence of double-bond isomerization,
<figure><img src="image_60.png" /></figure>

<figure><img src="image_61.png" /><figcaption>**Scheme 27.** Synthesis of fluorinated tetrahydrocarbazoles. Reproduced from ref. [57] Copyright (2011), with permission from Elsevier.</figcaption></figure>

cyclization and proton loss and rearomatization afforded the tetrahydrocarbazoles **180a-c** in moderate to good yields. The authors mentioned that the reaction is promoted by acidic media. Carbazoles are found in several natural alkaloids as well as in pharmacological products such as ondansetron (used to prevent and treat nausea and vomiting caused by chemotherapy), the antimigraine frovatripran, or the anti-rhinitis ramatroban.[58]

Jeong reported the synthesis of fluorinated imidazoles **191a-o** via an environmentally friendly one-pot three-component process promoted by indium trifluoride catalysis.[59] A combination of diketones **181**, aromatic or aliphatic aldehydes **184a-o**, and ammonium acetate as an ammonia source afforded 2,4,5-trisubstituted imidazoles **191a-o** in moderate to good yields (**Scheme 28**). The authors proposed a mechanism. The first step of indium trifluoride probably coordinates with oxygen from carbonyl compounds **181** and **184a-o**. Iminoketones **183** were prepared through nucleophilic attacks from ammonia to activated carbonyl on diketones **182**. In the same way, aldimines **186a-o** were obtained after nucleophilic attack from ammonia to

<figure><img src="image_62.png" /><figcaption>**Scheme 28.** Synthesis of fluorinated imidazoles. Reproduced from ref. [59] Copyright (2012), with permission from Elsevier.</figcaption></figure>

carbonyl on aldehydes **184a-o**. Then, imines **186a-o** attack the activated carbonyl on iminoketones **183** to give the products **187a-o**, which undergo an intramolecular cyclization to afford the intermediates **188a-o**. After a proton transfer, **189a-o** were obtained, and then, the release of water and recovery of catalyst yielded compounds **190a-o**. Finally, an aromatization process of compounds **190a-o** resulted in the formation of the imidazoles **191a-o**. A moderate quantity of catalyst (10 mol%) gave the best yields. Also, the catalyst was recovered and re-used four times without losing efficiency. A wide variety of aldehydes with electron-donating and electron-withdrawing groups were tested in the reactions with no side products. Imidazole is a heterocycle found in several drugs to treat hepatitis C such as daclatastvir, grazoprevir, ledipasvir, and sofosbuvir, benznidazole for the treatment of Chagas disease, and the antibiotic secnidazole.[21]

Prakash and Mathew reported the synthesis of new β-fluoroethylamines **197a-z** through a Mannich-like
<figure><img src="image_63.png" /></figure>

multicomponent process. Sequential combination of amines 192a-z, with formaldehyde (193), and α-fluoro-α-nitro(phenylsulfonyl)-methane 196a or α-fluorobis-(phenylsulfonyl)methane 196b performed the products 197a-z in moderate to good yields with or without basic media (Scheme 29).[60] To avoid formation of side products, the authors used formalin (193, 37% formaldehyde in water) instead of solid polymeric paraformaldehyde to favor the formation of hemiaminal 194a-z to direct the reaction. In both series, the α-fluoro-α-nitro(phenylsulfonyl)-methane, or α-fluorobis(phenylsulfonyl)-methane, as well as primary and secondary amines were used, where primary amines react more effectively than secondary ones. In the same way, aliphatic or aromatic amines were tested. However, aromatic amines were less effective in the case of series with α-fluorobis(phenylsulfonyl)ethylamines.

Song described the synthesis of a series of new tetrahydropyrans **204a-q** via a N1-multicomponent reaction. Thus, a sequential combination of aromatic aldehydes **198a-q**, malonitrile (199) and 2-fluoroacetoacetate (201) in ethanol as the solvent and sodium hydroxide as the catalyst achieved the chiral products **204a-q** (Scheme 30).[61] The authors proposed a reaction mechanism where the first step was a Knoevenagel condensation to give the compounds **200a-q**. Then, a Michael addition took place between vinylic compounds **200a-q** and anion **201** to afford the intermediates **202a-q**, which tautomerized to ketenimine compounds **203a-q**. A nucleophilic attack to the intermediates **203a-q** from ethanol followed by an intramolecular cyclization afforded tetrahydropyrans **204a-q**. Authors used other alcohols such as methanol, isopropanol, or tert-butanol as well as water but, the reaction only proceeds in methanol and not with the other ones due to steric hindrance of alcohols or poor solubility of reactants. A wide variety of aromatic aldehydes were tested and furnished the desired products whereas one test with aliphatic aldehyde proved to be unsuccessful. Pyran core is found in benzopyrans, flavonoids, coumarins, etc. Some drugs containing the pyran core are zanamivir and the prodrug laninamivir octanoate, which is an influenza prophylactic agent.[62]

<figure><img src="image_64.png" /><figcaption>**Scheme 29.** Synthesis of β-fluoroethylamines. Reproduced from ref. [60]
Copyright (2013), with permission from Wiley-VCH GmbH.</figcaption></figure>

<figure><img src="image_65.png" /><figcaption>**Scheme 30.** Synthesis of 4 H-pyran derivatives. Reproduced from ref. [61]
Copyright (2015), with permission from Elsevier.</figcaption></figure>

Dong and Hu described the multicomponent synthesis of some new 3-amino-3-hydroxymethyloxindoles **208a-m**, which were evaluated for their anticancer properties.[63] Thus, combination of 3-diazooxindoles **205a-f**, formalin (206), and fluorinated anilines **207a-f** in ethyl acetate as solvent, and rhodium (II) acetate as catalyst afforded the 3-amino-3-hydroxymethyloxindoles **208a-m** in moderate to good yields (53–89%) (Scheme 31). The authors stated that these compounds were designed to increase cytotoxic activity by targeting the strategic positions of aromatic substituents on anilines **207a-f**, N-alkyl or N-benzyl on 3-diazooxindoles **205a-f**, as well as various groups in the aromatic ring on 3-diazooxindoles **208a-m**. Anticancer studies were performed using the following cell lines: colon, bone, leukemia, epidermal, and hepatocellular carcinoma. As a result, a few compounds exhibited potential cytotoxic activity (IC₅₀ up to 3.14 µM), and one of the fluorinated compounds showed anti-proliferating

<figure><img src="image_66.png" /><figcaption>**Scheme 31.** Synthesis of 3-amino-3-hydroxymethyloxindoles. Reproduced from ref. [63] Copyright (2017), with permission from RSC.</figcaption></figure>
<figure><img src="image_67.png" /></figure>

effects against SJSA-1 cell line and potential pro-apoptotic effects, making it a candidate for further in vivo studies.

Sandford group described the synthesis of β-fluoro (dicarbonyl)ethylamines 213a-p through a traditionall synthesis process and a semi-continuous flow process.[64] With optimal conditions in hands, the process was carried out through a Mannich-type reaction (condition a) or a semi-continuous flow reaction (condition b). In the multicomponent process, the reaction of 2-fluoro-ethylacetoacetate or diethyl 2-fluoro-malonate ester (210a-b), aldehydes 211a-b, and aromatic or aliphatic amines 212a-g in DCM as the solvent at room temperature for 12 h performed products 213a-p in moderate to excellent yields (43–98%) (Scheme 32). The aldehydes 211a-b and amines 212a-g were combined before adding the fluorinated dicarbonyl compound 210a-b to avoid aldol condensation. On the contrary, in the first stage of the continuous flow, the fluorination to ketoester 209a-b in a gas–liquid process was carried out to form the fluorinated ketoester 210a-b. Then, aldehydes 211a-b and amines 212a-g solution were added to the reactor to give the products 213a-p. This process opens the possibility of performing post-transformations or functionalization. It is known that continuous flow process may be carried out on a gram scale. The β-fluoro(dicarbonyl)ethylamines contain a β-amino acid-type moiety as well as an ester fragment, which is well known to be metabolized into corresponding carboxylic acids.[65] The β-amino acids are found in some examples as their natural form, and the most common β-amino acid is the β-alanine.[66] In synthetic form, β-amino acids are found in the antibiotic Streptomycin F by taking advantage of the family of bacteria Streptomyces, which produces β-lysine.[67]

Kim and coworkers reported the synthesis of the arenesulfonyl fluorides **217a-w** via a three-component reaction.[68] A sequential combination of 2-(trimethylsilyl)phenyl triflate (214) as aryne precursor, aliphatic and aromatic amines **215a-w**, and sulfuryl fluoride (216) gave the arenesulfonyl fluorides **217a-w** in moderate to good yields (40–90%) (Scheme 33). The authors proposed a mechanism where the first step is the formation of benzyne (218) through a fluoride source and compound 214.

<figure><img src="image_68.png" /><figcaption>**Scheme 32.** Synthesis of β-fluoro(dicarbonyl)ethylamines. Reproduced from ref. [64] Copyright (2018), with permission from Elsevier.</figcaption></figure>

<figure><img src="image_69.png" /><figcaption>18-crown-6 = 1,4,7,10,13,16-Hexaoxacyclo
octadecane
R¹ = alkyl, Me
R² = alkyl, aryl</figcaption></figure>

<figure><img src="image_70.png" /><figcaption>**Scheme 33.** Synthesis of sulfonyl fluoride derivatives. Reproduced from ref. [68] Copyright (2019), with permission from ACS.</figcaption></figure>

Then, nucleophilic attack from amines **215a-w** to intermediate **218** afforded zwitterions **219a-w**, which could react with sulfuryl fluoride **216** to obtain the intermediates **220a-w** or to react with the proton from ammonium salt to give by-products **221a-w**. Finally, a nucleophilic attack of sulfuryl fluoride was carried out by intermediates **220a-w** to give the products **217a-w**. The hydrogen bond between ammonium salt and sulfuryl fluoride promotes the nucleophilic capture because sulfuryl fluoride has enough electrophilicity to avoid the protonation pathway. A wide variety of nucleophiles such as anilines, primary and secondary amines, imines, nitriles even triphenylphosphine were tested and proved to be compatible in the reaction conditions. Precursors of aryne bearing other substituents such as 4-methylbenzyne, 6-methylbenzyne, and 4-fluorobenzyne led to mixture of regioisomers in a ration from 1.3:1 to 10:1. Symmetrical arynes with naphthyl and dimethoxy groups gave a single multicomponent product in good yields. The fluorine source as reagent was changed with N-disubstituted sulfamoyl fluorides instead of sulfuryl fluoride but no reaction was observed. A fluoride source was screened using CsF, tetra-butylammonium fluoride (TBAF), and difluorotriphenylsilicate (TBAT), which were less efficient than KF. Sulfonyl fluorides have been positioned as a scaffold of privilege due to their interaction with amino acids such as cysteine, tyrosine, lysine, or serine, that could inhibit an enzymatic processes.[69]

Haroun and Geronikaki reported the synthesis of the thiazole-thiazolidinone hybrids **225a-j** and in vitro assays to test antibacterial and microbial resistance.[70] The authors performed a rational drug design behind these compounds. Once the best ligands were found, it was proposed to perform a 3CR involving a sequential combination of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (222), substituted benzaldehydes **223a-j**, and thioglycolic acid (224) under microwave (μw) heating conditions
<figure><img src="image_71.png" /></figure>

<figure><img src="image_72.png" /><figcaption>**Scheme 34.** Synthesis of thiazole-thiazolidinone hybrids. Reproduced from ref. [70] Copyright (2021), with permission from Elsevier.</figcaption></figure>

(Scheme 34). Note that no chemical yield is reported in the article. The in vitro studies were carried out in bacterial strains such as *E. coli*, *L. monocytogenes*, *S. typhimurium*, and *S. aureus* where one compound exhibited potential antibacterial activity regarding minimal bactericidal and minimal inhibitory concentrations (up to 0.25–1.0 mg mL⁻¹ and 0.10–0.25 mg mL⁻¹, respectively). On the other side, on the resistant strains *P. aeruginosa*, *E. coli*, and *Methicillin-resistant S. aureus*, five compounds exhibited good activity regarding minimal bactericidal (MBC) and minimal inhibitory (MIC) concentrations in values between 0.12 to 0.5 mg mL⁻¹ and 0.12 mg to 1 mg mL⁻¹, respectively. Nevertheless, these fluorinated compounds did not present higher activity than reference drugs.

# 6. Miscellaneous

## 6.1. Radicals on MCR

Wu reported the synthesis of the perfluoroalkyl amidines **229a-t** via a metal-free 3CR involving a free-radical mediated pathway.[71] The multicomponent reaction between perfluoroalkyl iodides **226a-c** aromatic and aliphatic amines **227a-d**, and *tert*-butyl isocyanide (228) in basic media and using 1,4-dioxane as solvent afforded the amidines **229a-t** in moderate to good yields (32–98%). The authors proposed a mechanism where perfluoroalkyl iodides **226a-c** produce alkyl radicals **230a-c** through thermal conditions (Scheme 35). Then, isocyanide 228 reacts with alkyl radicals **230a-c** to obtain the radicals **231a-c**, which react with perfluoroalkyl iodides **226a-c** to afford the intermediates **232a-c**, regenerating alkyl radicals **230a-c**. Finally, a nucleophilic attack from amines **227a-d** to compounds **232a-c** gave the products **229a-t**. Another possibility is that perfluoroalkyl iodides **226a-c** oxidized radicals **230a-c** to afford nitrilium ions, which produced amidines **229a-t** after reacting with amines **227a-d** and regenerating perfluoroalkyl radicals **231a-c**. The addition of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as a radical scavenger in the media totally suppressed the formation of the desired product, supporting the radical pathway. Perfluoroalkyl amidines are found in drugs such as the anticancer fulvestrant.[72]

Xu and Zeng reported the synthesis of the quinoxalinone derivatives **236a-z** through an electrochemical Minisci-type 3C-alkylation.[73] A mixture of quinoxalinone **233a-i**, alkene **234a-f**,

<figure><img src="image_73.png" /><figcaption>**Scheme 35.** Synthesis of perfluoroalkyl amidines. Reproduced from ref. [71] Copyright (2017), with permission from Elsevier.</figcaption></figure>

and trifluoromethyl thianthrenium triflate (TT-CF₃⁺OTf⁻) (235) using tetraethylammonium hexafluorophosphate/acetonitrile as conductive electrolytic solution in electrochemical conditions afforded the products **236a-z** in fair to good yields. To understand this process, a mechanism was proposed in which the first step consisted in a cathodic reduction forming the CF3· radical and thianthrene **238** (Scheme 36). Then, the vinylic compound **234a-f** was added to perform the radical **239a-f**, which reacts with quinoxalinone **233a-i** to give radical **240a-z**. A 1,2-hydrogen transfer from radical **240a-z** afforded radical **241a-z**. Then, the oxidation process gave the product **236a-z**. This procedure only can be carried out through electrolysis. A broad variety of functional groups such as silyl, alkynyl, and ester, to name a few are well tolerated in the process. The use of trifluoromethyl thianthrenium triflate avoids the formation of byproducts, resulting in a high selectivity process. A few quinoxaline-containing FDA-approved drugs are the anticancer erdafitinib, grazoprevir, glecaprevir and pibrentasvir, and sofosbuvir, velpatasvir, voxilaprevir for the treatment of hepatitis C.[21]

## 6.2. Novel Rearrangements in MCR

El Kazzouli, Akssira, and Guillaumet described the synthesis of imidazo[1,5-*a*]imidazoles **245a-d** and imidazo[1,5-*a*]pyrimidines **246a-d** via a 3CR as key step.[74] Thus, sequential combination of propargylic aldehydes **242a-d**, 5-aminoimidazole-4-carbonitrile (243), and *tert*-butyl isocyanide (244) using perchloric acid as catalyst achieved imidazo-imidazoles **245a-d** in moderate to good yields (71%–81%). Then, a further transformation of product **245a-d** after adding iodine in mild conditions gives the imidazo[1,5-*a*]pyrimidines **246a-d** (Scheme 37). To explain this cyclization, the authors proposed a plausible mechanism. First, the formation of hydrogen peroxide assisted by air and iodine opened the heterocycles **245a-d** to give the intermediates **247a-d**. Then, a rearrangement of intermediates **247a-d** produces the intermediates **248a-d**. Finally, the amine fragment from
<figure><img src="image_74.png" /></figure>

<figure><img src="image_75.png" /><figcaption>**Scheme 36.** Synthesis of quinoxalinones derivatives. Reproduced from ref. [73] Copyright (2024), with permission from ACS.</figcaption></figure>

imidazoles **248a-d** attacks the benzylic position of the ethynyl-benzene fragment to afford the products **246a-d**. To explain these mechanisms the authors performed the reaction in different conditions: a) using 1,4-cyclohexadiene as radical scavenger but, the reaction did not proceed; b) without an oxidizing agent in an inert atmosphere and the product was not produced again; c) under an argon atmosphere and hydrogen peroxide afforded the product **246a-d** in low yield. These experiments allowed concluding the formation in situ of hydrogen peroxide involved in the reaction. Pyrimidine and imidazole motifs are present in a wide variety of pharmaceuticals, for example, the antidiarrheal telotristat ethyl, the anticancer encorafenib, and in the antibiotic pretomanid, where the combination of both fragments of imidazole and pyrimidine increases the probability of interaction on the system receptor-ligand.[21]

<figure><img src="image_76.png" /><figcaption>**Scheme 37.** Synthesis of imidazo[1,5-a]pyrimidine hybrids. Reproduced from ref. [74]</figcaption></figure>

## 6.3. Photocatalysis in MCR

Hu reported the synthesis of β-trifluoromethyl imides **253a-ee** through a Ritter-type 4CR photocatalyzed by visible light.[75] Combination of vinylic compounds **249a-c**, carboxylic acids **250a-e**, isocyanides **251a-c**, and halides **252a-c** using fac-IrIII(ppy)₃ (tris[2-phenylpyridinato-C2,N]iridium(III)) as photocatalyst afforded the imides **253a-ee** in low to good yields (15%-77%) as well as the ability to be prepared on a gram scale. A mechanism pathway was proposed (**Scheme 38**). As the first step, the formation of the excited state of photocatalyst fac-IrIII(ppy)₃ **255** reduced halide **252a-c** promoting the oxidation of photocatalysts and giving trifluoromethyl radicals **256a-c** via a single electron transfer (SET) process. The radicals **256a-c** react with the vinyl compounds **249a-c** leading to radicals **258a-i**. Thus, a SET process between radicals **258a-i** and oxidative photocatalyst **257** gives the carbocations **259a-i** and regenerated the photocatalyst **254**. By-products **260a-i** and **261a-i** were obtained also but in minor amounts. Then, nitrilium cations **262a-aa** were performed by nitrile trapping from carbocations **259a-i**. Finally, a capture of nitrilium cations **262a-aa** by carboxylic acid **250a-e**
<figure><img src="image_77.png" /></figure>

<figure><img src="image_78.png" /></figure>

$R^1 = R^2 = \text{aryl}$

$R^3 = \text{H, Me}$

$R^4 = \text{aryl, alkyl, heteroaryl, naphtyl, pyridyl}$

$R^5 = \text{aryl, alkyl, } \text{CD}_3$

$R^6 = \text{CF}_3, -\text{C}_4\text{F}_9, -\text{C}_{10}\text{F}_{21}$

$\text{fac-Ir}^{\text{III}}(\text{ppy})_3 = \text{fac-Tris}(2-\text{phenylpyridine})\text{iridium}(\text{III})$

<figure><img src="image_79.png" /><figcaption>**Scheme 38.** Synthesis of β-trifluoromethyl imides. Reproduced from ref. [75]</figcaption></figure>

in basic media gave the intermediates **263a-ee**, which through a Mumm rearrangement afforded the products **253a-ee**. To propose a more plausible mechanism, several control experiments

were performed. Authors gave a few remarks: a) visible light and catalyst are crucial for the reaction; b) a radical scavenger was used to inhibit the reaction; c) steric and electronic effects of the substituents did not affect the reaction course; d) isolation of by-products were done; e) the use of potassium benzoate instead carboxylic acid demonstrated the presence of the active carboxylate moiety during the reaction. Besides, imides are found in a wide variety of natural products such as the family of alkaloids cladoniamides A-G with anticancer activity, naramycin A with antibiotic and anti-tumor activities, and sesbanimides A-C with antileukemic properties.[76]

## 7. Summary and Outlook

The benefits of multicomponent reactions are well known regarding green chemistry principles, for example, atom economy, use of environmental solvents or heat source, and reduced protection/deprotection steps to name a few. Moreover, fluorinated compounds have a special interest in medicinal chemistry mainly because fluorine is a hydrogen bioisostere, almost often resulting in increased metabolic stability/resistance and membrane permeability. This review joined both important fields (MCR and fluorine chemistry), focusing on synthetic procedures, reaction mechanisms, biological applications, and the role of fluorine atoms placed strategically into pharmacophores of bioactive compounds and drugs. This work contributes to the scientific community searching for new multicomponent strategies toward fluorine-containing compounds and pharmacophoric hybrid polyheterocycles.

### Acknowledgements

I.M.-S. (947606) and P.I.-J. (1098528) thank SECIHTI—México for their Ph.D. scholarships. This work was carried out as part of the ECOS Nord program, supported on the French side by MESR and MEAE (M22PS01) and on the Mexican side by SECIHTI and ANUIES (322585). This work has also been partially supported by University of Rouen Normandy, the Centre National de la Recherche Scientifique (CNRS), INSA Rouen Normandy, European Regional Development Fund (ERDF), Labex SynOrg (ANR-11-LABX-0029), Carnot Institute I2C, and the graduate school for research XL-Chem (ANR-18-EURE-0020XL CHEM). L.D.H.-Z. thanks Maite Mikal Herrera-Martinez and Valearia Alexandra Duran-Mora for scientific encouragement. E.G.Z acknowledges DCBI-UAM-I/PEAPDI 2024 for financial support. A.I.-J. acknowledges "Proyecto Apoyado por el Fondo Sectorial de Investigación para la Educación CONACYT-SEP CB-2017-2018 (A1-S-32582)" for financial support.

### Conflict of Interest

The authors declare no conflict of interest.
<figure><img src="image_80.png" /></figure>

Keywords: bioactive compounds • drugs • fluorinated compounds • multicomponent reactions • SAR

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Manuscript received: May 30, 2025

Revised manuscript received: August 4, 2025

Version of record online: August 19, 2025