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[3 + N] Cycloaddition Reactions: a Milestone Approach for Elaborating Pyridazine of Potential Interest in Medicinal Chemistry and Optoelectronics

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[3 + N] Cycloaddition Reactions: a Milestone Approach for Elaborating Pyridazine of Potential Interest in Medicinal Chemistry and Optoelectronics molecules Review [3 + n] Cycloaddition Reactions: A Milestone Approach for Elaborating Pyridazine of Potential Interest in Medicinal Chemistry and Optoelectronics Dorina Amariucai-Mantu 1, Violeta Mangalagiu 2,* and Ionel I. Mangalagiu 1,2,* 1 Faculty of Chemistry, Alexandru Ioan Cuza University of Iasi, 11 Carol 1st Bvd, 700506 Iasi, Romania; [email protected] 2 CERNESIM Centre, Institute of Interdisciplinary Research, Alexandru Ioan Cuza University of Iasi, 11 Carol 1st Bvd, 700506 Iasi, Romania * Correspondence: [email protected] (V.M.); [email protected] (I.I.M.) Abstract: During the last few decades, pyridazine derivatives have emerged as privileged structures in heterocyclic chemistry, both because of their excellent chemistry and because of their potential applications in medicinal chemistry and optoelectronics. This review is focused on the recent advances in [3 + n] cycloaddition reactions in the pyridazine series as well as their medicinal chemistry and optoelectronic applications over the last ten years. The stereochemistry and regiochemistry of the cycloaddition reactions are discussed. Applications in optoelectronics (in particular, as fluorescent materials and sensors) and medicinal chemistry (in particular, antimicrobials and anticancer) are also reviewed. Citation: Amariucai-Mantu, D.; Mangalagiu, V.; Mangalagiu, I.I. Keywords: [3 + n] cycloaddition reactions; ylides; pyridazine; stereochemistry; regiochemistry; [3 + n] Cycloaddition Reactions: A medicinal chemistry; optoelectronics Milestone Approach for Elaborating Pyridazine of Potential Interest in Medicinal Chemistry and Optoelectronics. Molecules 2021, 26, 1. Introduction 3359. https://doi.org/10.3390/ [3 + n] cycloaddition reactions represent one of the most important and efficient molecules26113359 tools in the synthesis of heterocyclic rings, consisting of the addition of a multiple bond dipolarophile to a three-atom component system (TACS). Because of their complexity, Academic Editor: [3 + 2] cycloaddition reactions have been extensively studied in the last 60 years [1–14], Francesca Mancianti with interesting and heated discussions being involved in order to explain them. The [3 + 2] dipolar cycloaddition reactions were discovered by Rolf Huisgen in the Received: 22 April 2021 early 1960s, more than 60 years ago [1,2]. The Huisgen [3 + 2] dipolar cycloaddition reac- Accepted: 1 June 2021 Published: 2 June 2021 tions represent an addition of a 1,3-dipole to a dipolarophile, leading to a five-membered heterocyclic ring [1–7], via a concerted mechanism, as presented in Scheme1. The 1,3- Publisher’s Note: MDPI stays neutral dipole is a molecule with three atoms (abc), with a sextet of electrons (consequently, with a with regard to jurisdictional claims in positive charge) to a marginal atom, and to the other marginal atom, a pair of non-bonding published maps and institutional affil- electrons (consequently, with a negative charge). The sextet formulas of the 1,3-dipole are iations. stabilized by the non-bonding electrons of the central atom, adopting another canonical structure—the octet zwitterionic form. The dipolarophile is represented by an activated alkene or alkyne. At the end of the 1960s, Firestone [9,10] proposed an alternative explanation for [3 + 2] cycloaddition reactions, via a radical mechanism (Scheme1). In his approach, Firestone Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. proposed a two-step mechanism, via the formation of a diradical intermediate. This article is an open access article Over the last decade, Domingo’s team [11–14] have revealed new, interesting con- distributed under the terms and siderations concerning the mechanistic inside of [3 + 2] cycloaddition reactions, based on conditions of the Creative Commons molecular electron density theory (MEDT). Using their research, they classify the TACS Attribution (CC BY) license (https:// in pseudo-diradical, pseudoradical, zwitterionic and carbenoid. Using MEDT theory, creativecommons.org/licenses/by/ [3 + 2] cycloaddition reactions have been classified by Domingo into the corresponding 4.0/). pseudo-diradical, pseudoradical, zwitterionic and carbenoid reactions [11–14]. Molecules 2021, 26, 3359. https://doi.org/10.3390/molecules26113359 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x 2 of 17 Molecules 2021, 26, 3359 2 of 16 Molecules 2021, 26, x 2 of 17 Scheme 1. The [3 + 2] cycloadditions approach for obtaining five-membered heterocycles: Huisgen dipolar mechanism and Firestone diradical mechanism. At the end of the 1960s, Firestone [9,10] proposed an alternative explanation for [3 + 2] cycloaddition reactions, via a radical mechanism (Scheme 1). In his approach, Firestone proposed a two-step mechanism, via the formation of a diradical intermediate. Over the last decade, Domingo’s team [11–14] have revealed new, interesting consid- erations concerning the mechanistic inside of [3 + 2] cycloaddition reactions, based on mo- lecular electron density theory (MEDT). Using their research, they classify the TACS in SchemeSchemepseudo 1.1.-diradical, TheThe [3[3 ++ 2] pseudoradical, cycloadditions approach zwitterionic for obtaining and carbenoid five-memberedfive-membered. Using heterocycles:MEDTheterocycles: theory, Huisgen [3 + 2] dipolardipolarcycloaddition mechanismmechanism reactions andand FirestoneFirestone have been diradicaldiradical classified mechanism.mechanism. by Domingo into the corresponding pseudo- diradical, pseudoradical, zwitterionic and carbenoid reactions [11–14]. AnAtAn the interesting interesting end of the case case 196 of of0 [3s, [3 +Firestone + 2]2] cycloadditioncycloaddition [9,10] proposed reactionsreactions an is isalternative representedrepresented explanationby by thethe cycloaddi-cycloaddi- for [3 + tion2]tion cycloaddition of of cycloimmonium cycloimmonium reactions, ylides ylides via to a variousradicalto various mechanism symmetrically symmetric (Schemeally and and non-symmetrically 1). nonIn his-symmetric approach substitutedally, Firestone substi- dipolarophiles,proposedtuted dipolarophiles a two Scheme-step mechanism,, Scheme2. The [3 2 +. viaThe 2] cycloaddition the [3 formation+ 2] cycloaddition reactions of a diradical ofreactions cycloimmonium intermediate. of cycloimmonium ylides to symmetricallyylidesOver to symmetricallythe last substituted decade, substituted ZDomingo’s(or cis) and Z team (orE (or cis[11trans) –and14)] olefinshaveE (or reveal trans involve)ed olefins new interesting, interestinginvolve problems interesting consid- of stereochemistry,erationsproblems concerning of stereochemistry, these the reactions mechanistic these being reactionsinside highly of stereospecific [3being + 2] cycloadditionhighly [stereospecific8,15,16 reactions]. [8,15,16], based. on mo- lecular electron density theory (MEDT). Using their research, they classify the TACS in pseudo-diradical, pseudoradical, zwitterionic and carbenoid. Using MEDT theory, [3 + 2] cycloaddition reactions have been classified by Domingo into the corresponding pseudo- diradical, pseudoradical, zwitterionic and carbenoid reactions [11–14]. An interesting case of [3 + 2] cycloaddition reactions is represented by the cycloaddi- tion of cycloimmonium ylides to various symmetrically and non-symmetrically substi- tuted dipolarophiles, Scheme 2. The [3 + 2] cycloaddition reactions of cycloimmonium ylides to symmetrically substituted Z (or cis) and E (or trans) olefins involve interesting problems of stereochemistry, these reactions being highly stereospecific [8,15,16]. SchemeScheme 2. 2.Stereochemistry Stereochemistry ofof additionaddition ofof cycloimmoniumcycloimmonium ylides to symmetrically substituted substituted ciscis andandtrans transolefins. olefins. TheThe [3 [3 + + 2] 2] cycloaddition cycloaddition reactions reactions of of cycloimmonium cycloimmonium ylides ylides to to non-symmetrically non-symmetrically substitutedsubstituted dipolarophiles dipolarophiles (with (with double double or or triple triple bond) bond) involve involve interesting interesting combined combined stereo- ste- andreo- regiochemistry and regiochemistry aspects aspects [17–21 [17]. In–21 the]. In regiochemistry the regiochemistry case, because case, because of the doubleof the double sense ofsense the additionof the addition of ylide of to ylide dipolarophile, to dipolarophile, two reactions two reactions pathways pathways (I or II) are (I or possible, II) are possi- with theble, formation with the formation of two pairs of oftwo regioisomers pairs of regioisomers (A, A’ and B(A, B’, A’, Schemeand B, B’3),, Scheme according 3), to according orbital, stericto orbital, and electronic steric and factors. electronic factors. SchemeOn 2. the Stereochemistry other hand, [3of +addition 2] cycloaddition of cycloimmonium reactions ylides represent to symmetrically an accessible substituted and facile cis tooland trans to obtain olefins. pyridazine derivatives of potential interest in medicinal chemistry (as an- tibacterials, antifungals, antituberculars, antivirals, anticancer agents, anti-inflammatories, antihypertensives,The [3 + 2] cycloaddition diuretics, etc.) reactions [22,23 ]of and cycloimmonium in optoelectronics ylides (as to highlynon-symmetrical fluorescently materials,substituted sensors dipolarophiles and biosensors, (with double lasers, or etc.) triple [24 ].bond) involve interesting combined ste- reo- andFrom regiochemistry a previous review aspects conducted [17–21]. In ten the years regiochemistry ago [23], it case, is clear because that the of
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