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

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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].

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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 molecular 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 molecular 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 cycloaddition of cycloimmonium ylides to various symmetrically and non-symmetrically substituted 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 stereo- andFrom regiochemistry a previous review aspects conducted [17–21]. In ten the years regiochemistry ago [23], it case, is clear because that the of the focus double has

beensense on of thethe mostaddition important of ylide achievements to dipolarophile, in the two chemistry reactions and pathways applications (I or of II) 1,2-diazine are possi- (pyridazineble, with the and formation phthalazine). of two Inpairs the of present regioisomers review, we(A, focusedA’and B on, B’ the, Scheme recent 3), advances according in [3to +orbital, n] cycloaddition steric and reactionselectronic in factors. the pyridazine series as well as their medicinal chemistry and optoelectronic applications in the last ten years.

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Scheme 3. Regiochemistry of addition of cycloimmonium ylides to non-symmetrically substituted dipolarophiles, with the formation of endo/exo A and A’, and B and B’ pairs of stereoisomers.

On the other hand, [3 + 2] cycloaddition reactions represent an accessible and facile tool to obtain pyridazine derivatives of potential interest in medicinal chemistry (as anti- bacterials, antifungals, antituberculars, antivirals, anticancer agents, anti-inflammatories, antihypertensives, diuretics, etc.) [22,23] and in optoelectronics (as highly fluorescent materials, sensors and biosensors, lasers, etc.) [24]. From a previous review conducted ten years ago [23], it is clear that the focus has been on the most important achievements in the chemistry and applications of 1,2-diazine (pyridazine and phthalazine). In the present review, we focused on the recent advances SchemeSchemein [3 + n 3.3.] Regiochemistry cycloadditionRegiochemistry reactions ofof additionaddition in ofof the cycloimmoniumcycloimmonium pyridazine series ylidesylides as toto well non-symmetricallynon -assymmetrical their medicinally substitutedsubstituted chem- dipolarophiles,dipolarophiles,istry and optoelectronic withwith thethe formationformation applications of of endo/exo endo/exo in the AA last andand ten A’A’, ,years. andand BB andand B’B’ pairspairs ofof stereoisomers.stereoisomers.

2.2. ResultsResultsOn the andand other DiscussionsDiscussions hand, [3 + 2] cycloaddition reactions represent an accessible and facile 2.1.tool2.1. [3 [3to + +obtain 2]2] CycloadditionCycloaddition pyridazine ReactionsReactions derivatives inin thethe of PyridaziniumPyridazinium potential interest andand PhthalaziniumPhthalazinium in medicinal YlideschemistryYlides SeriesSeries (as anti- bacterials,PopoviciPopovici antifungals, etet al.al. [[25]25] antituberculars, synthesizedsynthesized differentdifferent antivirals, pyrrolopyrrol anticancero [1,2-b]pyridazine[1,2-b]pyridazine agents, anti derivativesderivatives-inflammator ((4a4a–ies–tt),), usingantihyperteusing thethe [3[3nsives, ++ 2]2] cycloadditioncycloaddition diuretics, etc.) reactionsreactions [22,23] of ofand differentdifferent in optoelectronics pyridaziniumpyridazinium (as ylides ylideshighly ( 2a(fluorescent2a––t;t; generated generated ma- interials,in situsitu from fromsensors thethe and correspondingcorresponding biosensors, pyridazinium pyridaziniumlasers, etc.) [24]. salts salts ( (1a1a––t),t), in in the the presence presence of of triethylamine triethylamine (TEA)(TEA)From as as the the a base), previousbase), toto ethyl ethylreview propiolate, propiolate, conducted as as shown tenshown years in in Scheme agoScheme [23],4 .4. it is clear that the focus has been on the most important achievements in the chemistry and applications of 1,2-diazine (pyridazine and phthalazine). In the present review, we focused on the recent advances in [3 + n] cycloaddition reactions in the pyridazine series as well as their medicinal chemistry and optoelectronic applications in the last ten years.

2. Results and Discussions 2.1. [3 + 2] Cycloaddition Reactions in the Pyridazinium and Phthalazinium Ylides Series Popovici et al. [25] synthesized different pyrrolo [1,2-b]pyridazine derivatives (4a–t), using the [3 + 2] cycloaddition reactions of different pyridazinium ylides (2a–t; generated in situ from the corresponding pyridazinium salts (1a–t), in the presence of triethylamine (TEA) as the base), to ethyl propiolate, as shown in Scheme 4.

SchemeScheme 4.4.The The [3[3 ++ 2]2] cycloadditioncycloaddition ofof pyrrolo[1,2-b]pyridazinepyrrolo[1,2-b]pyridazine derivativesderivatives4a 4a––tt..

InIn thethe first first instance, instance the, correspondingthe corresponding intermediate intermediate dihydropyrrolo[1,2-b]pyridazines dihydropyrrolo[1,2-b]pyri- 3adazines–t were 3a obtained–t were andobtained underwent and anunderwent oxidative an dehydrogenation oxidative dehydrogenation under atmospheric under conditions, leading to the final pyrrolo[1,2-b]pyridazine derivatives 4a–t, in moderate yields (40–52%). The [3 + 2] cycloadditions occur completely regioselectively, with a single type of regioisomer (4) being obtained. Some of the obtained pyrrolo[2,1-b]pyridazines were tested in vitro against a panel of 60 human tumor cell lines at a single dose up to five doses (according to National Cancer Institute protocol). The adducts 4a, 4b, 4e, and 4f showed a very good growth inhibition effect on almost all 60 cell lines, the best results being registered on HL-60 (TB) leukemia cells, COLO205 colon cancer cells, MDA-MB-435 melanoma cells, OVCAR-3 ovarian cancer cells and A498 renal cancer cells. The most active Scheme 4. The [3 + 2] cycloaddition of pyrrolo[1,2-b]pyridazine derivatives 4a–t. compound was 4f with GI50 values <100 nM on thirteen cell lines including colon, ovarian, In the first instance, the corresponding intermediate dihydropyrrolo[1,2-b]pyridazines 3a–t were obtained and underwent an oxidative dehydrogenation under

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atmospheric conditions, leading to the final pyrrolo[1,2-b]pyridazine derivatives 4a–t, in moderate yields (40–52%). The [3 + 2] cycloadditions occur completely regioselectively, with a single type of regioisomer (4) being obtained. Some of the obtained pyrrolo[2,1- b]pyridazines were tested in vitro against a panel of 60 human tumor cell lines at a single dose up to five doses (according to National Cancer Institute protocol). The adducts 4a, 4b, 4e, and 4f showed a very good growth inhibition effect on almost all 60 cell lines, the Molecules 2021, 26, 3359 best results being registered on HL-60 (TB) leukemia cells, COLO205 colon cancer4 cell of 16s, MDA-MB-435 melanoma cells, OVCAR-3 ovarian cancer cells and A498 renal cancer cells. The most active compound was 4f with GI50 values <100 nM on thirteen cell lines includ- renal,ing colon, prostate, ovarian, brain renal, and breast prostate, cancer, brain melanoma and breast and cancer, leukemia. melanoma Docking and experiments leukemia. haveDocking been experiments performed forhave the been biologically performed active for cycloadductsthe biologically (4a ,active4b, 4e cycloadducts, 4f) and showed (4a, good4b, 4e compatibility, 4f) and showed with good the compatibility colchicine binding with the site colc ofhicine tubulin. binding The authors site of tubulin. claim that The cycloadductauthors claim4f thatcould cycloadduct serve as a useful4f could lead serve in anticancer as a useful drug lead design.in anticancer drug design. InIn continuation continuation of of their their concern concern for for new new ﬂuorescent fluorescent pyrrolodiazine pyrrolodiazine derivatives, derivatives, MoldoveanuMoldoveanu etet al.al. [[26]26] performedperformed anan interestinginteresting studystudy concerningconcerning thethe cycloadditioncycloaddition reac-reac- tionstions of of pyridazinium pyridazinium ylides ylides6 (generated6 (generated in situin situ from from the correspondingthe corresponding pyridazinium pyridazinium salts 5saltsin the 5 in presence the presence of TEA) of TEA) in activated in activated symmetrically symmetrical andly non-symmetrically and non-symmetrical substitutedly substi- dipolarophilestuted dipolarophiles with a triplewith a bond triple (dimethyl bond (dime acetylenedicarboxylate–DMADthyl acetylenedicarboxylate– andDMAD methyl and propiolate),methyl propiolate), as shown as in shown Scheme in5 Scheme. 5.

SchemeScheme 5.5. TheThe [3[3 ++ 2] cycloaddition ofof pyridaziniumpyridazinium ylidesylides withwith DMADDMAD andand methylmethyl propiolate.propiolate.

AA reactionreaction withwith DMADDMAD leadsleadsto tothe theazabicycle azabicycle7 7,, while while [3 [3 + + 2]2] cycloaddition cycloaddition ofof ylideylide withwith methylmethyl propiolatepropiolate occursoccurs completelycompletely regioselectively,regioselectively, withwith aa singlesingle regioisomerregioisomer ((88)) beingbeing obtained.obtained. TheThe reactionsreactions werewere performedperformed bothboth underunder conventionalconventional thermalthermal heatingheating (TH)(TH) asas wellwell asas underunder unconventionalunconventional heatingheating (microwave(microwave (MW) (MW) irradiation). irradiation). TheThe authorsauthors claimclaim thatthat underunder MWMW irradiation,irradiation, thethe yieldsyields areare higher,higher,at at around around 10–15%. 10–15%. TheThe authorsauthors proveprove thatthat thethe cycloadductscycloadducts 77 andand 88are are intenseintense blueblue emittersemitters andand havehave aa quantum quantum yieldyield aroundaround 25%.25%. InIn continuation continuation of of their their work wo inrk thein the field field of cycloaddition of cycloaddition reactions, reactions,Zbancioc Zbancioc et al. [27 et,28 al.] reported[27,28] reported an interesting an interesting and detailed and studydetailed concerning study concerning the thermal the versus thermal speciﬁc versus effects specific of MWeffects in of the MW [3 + in 2] the cycloaddition [3 + 2] cycloaddition reactions. reactions. In this respect, In this they respect studied, they the studied [3 + 2] the cycload- [3 + 2] ditioncycloaddit reactionsion reactions of pyridazinium of pyridazinium ylides 10a ylides–f (generated 10a–f (generated in situ from in situ the correspondingfrom the corre- pyridaziniumsponding pyridazinium salts 9a–f in saltsthe presence 9a–f in of the TEA) presence to methyl of propiolate TEA) to methyl and DMAD, propiolate as shown and inDMAD, Scheme as6 .shown in Scheme 6.

Scheme 6. The [3 + 2] cycloaddition of pyridazinium ylides 10a–f with DMAD and methyl propiolate.

The cycloaddition reactions of pyridazinium ylides 10a–f to methyl propiolate occur completely regioselectively, with a single type of regioisomer being obtained, namely

pyrrolopyridazine 11a–f. The reaction with DMAD leads to the pyrrolopyridazines 12a–f. The reactions were studied under MW irradiation, in order to elucidate the intrinsic mechanism of MW effects. On the basis of their study, the authors conclude that there are no speciﬁc MW effects in the studied [3 + 2] cycloaddition reactions, the observed effects Molecules 2021, 26, x 5 of 17

Scheme 6. The [3 + 2] cycloaddition of pyridazinium ylides 10a–f with DMAD and methyl propiolate.

The cycloaddition reactions of pyridazinium ylides 10a–f to methyl propiolate occur completely regioselectively, with a single type of regioisomer being obtained, namely pyrrolopyridazine 11a–f. The reaction with DMAD leads to the pyrrolopyridazines 12a–f. The Molecules 2021, 26, 3359 reactions were studied under MW irradiation, in order to elucidate the intrinsic mecha-5 of 16 nism of MW effects. On the basis of their study, the authors conclude that there are no specific MW effects in the studied [3 + 2] cycloaddition reactions, the observed effects be- beinging purely purely thermal. thermal. Time Time-dependent-dependent density density functional functional theory theory computations computations and steady-steady- statestate electronicelectronic spectroscopy spectroscopy measurements measurements were were performed performed for thefor pyrrolopyridazinethe pyrrolopyridazine11a and11a and11e, 11e revealing, revealing that thesethat these compounds compounds possess possess an intense an intense blue blue ﬂuorescence fluorescence [28]. [28]. MantuMantu etet al.al. [[2929––3131]] performedperformed aa straightforwardstraightforward andand efﬁcientefficient studystudy concerningconcerning thethe [3[3 + + 2] 2] cycloadditioncycloaddition reactions reactions of of pyridazinium pyridazinium 15a15a––cc andand phthalazinium phthalazinium 16a16a––cc ylidesylides (generated(generated inin situsitu fromfrom thethe correspondingcorresponding pyridaziniumpyridazinium 13a13a––ccand and phthalaziniumphthalazinium 14a14a––cc saltssalts inin thethe presencepresence ofof TEA),TEA), toto 1,4-naphthoquinone,1,4-naphthoquinone, asas symmetricallysymmetrically activatedactivated cycliccyclic alkenealkene (Scheme(Scheme7 7).).

SchemeScheme 7.7. TheThe [3[3 ++ 2]2] cycloadditioncycloaddition of of pyridazinium pyridazinium and and phthalazinium phthalazinium ylides ylides to 1,4-naphthoquinone. to 1,4-naphthoquinone. The reaction leads either to polycyclic dihydrobenzo[f]pyridazino[6,1-a] isoindole 17a–c or toThe dihydrobenzo[5,6]isoindolo[1,2-a]phthalazine reaction leads either to polycyclic dihydrobenzo[f]pyridazino[6,118a–c. The reactions were-a] performed isoindole under17a–c conventionalor to dihydrobenzo[5,6]isoindolo[1,2 TH, as well as under MW-a]phthalazine or ultrasound 18a (US)–c irradiation.. The reactions The were obtained per- dataformed show under that conventional MW and US TH, irradiation as well as produce under aMW remarkable or ultrasound acceleration (US) irradiation. for reactions The (fromobtained hours data to minutes),show that theMW consumed and US irradiation energy decreases produce considerably a remarkable and acceleration the yields arefor higher.reactions The (from US irradiationhours to minutes), was found the to consumed be the most energy effective decrease method,s considerably in terms of and yields the andyields reaction are higher. time, The for obtainingUS irradiation polycyclic was found 1,2-diazines. to be th Thee mostin vitroeffectiveanticancer method, assay in terms [30] againstof yields an and NCI reaction 60 human time, tumor for obtaining cell line polycyclic panel reveals 1,2-diazines. that the polycyclicThe in vitro compounds anticancer 17aassay–c and[30] 18aagainst–c have an NCI anticancer 60 human activity. tumor The cell obtained line panel data reveal leds the that authors the polycyclic to claim com- that polycyclicpounds 17a compounds–c and 18a–17ac have–c and anticancer18a–c will activity. act as an The anticancer obtained vector data led through the authors multiple to mechanismsclaim that polycyclic of action, compounds the intercalation 17a–c withand 18a the– DNAc will prevailingact as an anticancer in competition vector with through the othermultiple mechanisms. mechanisms of action, the intercalation with the DNA prevailing in competition withZbancioc the other etm al.echanisms. [32–34] performed a thorough study concerning the [3 + 2] cycloaddition reactions of pyridazinium 21a–e and phthalazinium 22a–e ylides with the dihydroxy- Zbancioc et al. [32–34] performed a thorough study concerning the [3 + 2] cycloaddi- acetophenone skeleton (generated in situ from the corresponding pyridazinium 19a–e and tion reactions of pyridazinium 21a–e and phthalazinium 22a–e ylides with the dihydrox- phthalazinium 20a–c salts in the presence of TEA), to methyl propiolate and DMAD, as yacetophenone skeleton (generated in situ from the corresponding pyridazinium 19a–e shown in Scheme8. and phthalazinium 20a–c salts in the presence of TEA), to methyl propiolate and DMAD, The [3 + 2] cycloaddition reaction of the ylides 21a–e and 22a–e with methyl propiolate as shown in Scheme 8. occur completely regioselectively, with a single type of regioisomer being obtained—the fused pyrrolo-diazines with the dihydroxyacetophenone skeleton 23a–e and 24a–e. In the case of the cycloaddition reaction of ylides 21a–e and 22a–e with the symmetrically substituted alkynes DMAD, the aromatized fused pyrrolo-diazines with the dihydroxyacetophenone skeleton 25a–e and 26a–e are obtained. The reactions were performed under conventional TH, as well as under MW or US irradiation. Under MW and US irradiation, the yields are higher, the reaction time decreases substantially (from hours to minutes), the consumed energy decreases considerably, the amount of used solvent also decreases, and the reaction conditions are milder. As a result, these reactions could be considered environmentally friendly. Overall, the use of US proved to be more efﬁcient than MW or TH. The in vitro anticancer assay proves that some of the obtained compounds have a signiﬁcant antitumor activity and a moderate antifungal activity, while the antibacterial activity is negligible [34]. Molecules 2021, 26, 3359 6 of 16

Tucaliuc et al. [35] performed an interesting study concerning the [3 + 2] cycloaddition reactions of pyridazinium ylides 28a–c with various activated non-symmetrically substituted dipolarophiles (alkenes and alkynes) containing ﬂuorine moiety, as shown in Molecules 2021, 26, x Scheme9. 6 of 17

SchemeScheme 8.8.The The [3[3 ++ 2]2] cycloadditioncycloaddition ofof pyridaziniumpyridazinium andand phthalaziniumphthalazinium ylidesylides withwith dihydroxyace-dihydroxy- tophenoneacetophenone skeleton. skeleton.

TheThe [3[3+ + 2]2] cycloadditioncycloaddition reaction reaction of of ylides the ylides28a– c21ato– 2,2,2-trifluoroethyle and 22a–e with methyl acrylate propio- occur completelylate occur completely regioselectively, regioselective involvingly, a with single a single type of type regioisomer of regioisomer being being obtained, obtained with— a tetrahydropyrrolopyridazinethe fused pyrrolo-diazines with structure the dihydroxyacetophenone30a–c. The cycloaddition skeleton reaction 23a of– ylidese and 24a28a–ce.to In ethylthe case 4,4,4-trifluorobutinoate of the cycloaddition leads reaction to the of aromatized ylides 21a– pyrrolopyridazinee and 22a–e with derivativesthe symmetrical29a–cly, againsubstituted with the alkynes reaction DMAD, being completelythe aromatized regioselective. fused pyrrolo-diazines with the dihydroxy- acetophenoneWhen the skeleton dipolarophile 25a–ewas and ethyl26a–e 4,4,4-trifluorocrotonate are obtained. The reactions (E-isomer), were performed the reactions un- involvedder conventional additional TH, stereo- as well and as under regiochemical MW or US problems. irradiation. The Under cycloaddition MW and reactionUS irradia- of ylidestion, the28a yieldsand 28c areoccurs higher, completely the reaction stereo- time and decreases regioselectively, substantially with only (from isomers hours31a to andminutes),31c being the obtained.consumed In energy the case decreases of ylide c28bonsiderably,(R=Cl), the the cycloaddition amount of used reaction solvent occurs also 0 regioselectively,decreases, and withthe reaction two regisomers conditions31b areand milder.31b” beingAs a obtained,result, these in areactions molar ratio could of 1:1. be consideredThese reactions environmentally were performed friendly. under Overall, conventional the use of US TH proved and under to be MW more or USefficient irra- diationthan MW (both or inTH. liquid The phasein vitro and antica phase-transferncer assay proves catalysis). that Thesome use of ofthe MW obtained irradiation com- provedpounds to have be more a significant efficient antitumor (with the reactionactivity and time a decreasingmoderate antifungal substantially, activity, higher while yields, the smallerantibacterial amount activity of used is negligible solvent), with[34]. these reactions being considered environmentally friendly.Tucaliuc The inet vitroal. [35antimicrobial] performed an activity interesting of the study obtained concerning compounds the [3 indicated+ 2] cycloaddi- that thetion introduction reactions of of pyridazinium a trifluoromethyl ylides moiety 28a–con with the various pyridazine activated skeleton non is-symmetrical beneficial forly antimicrobialsubstituted dipolarophiles activity. Practically (alkenes all compoundsand alkynes) have containing a spectacular fluorine antimicrobial moiety, as shown activity in againstScheme Gram 9. positive germs, and very good activity against Gram negative germs. The antifungal activity of compounds was negligible. Butnariu et al. [36] performed a straightforward, efficient and selective study for obtaining hybrid trifluoromethyl-substituted γ-lactones with nitrogen heterocyclic skeletons 36a–c and 37a–c, as shown in Scheme 10. The [3 + 2] cycloaddition reaction of ylides 33a–c to 2-(trifluoromethyl)acrylic acid 34 occurs unexpectedly; instead of the cycloadducts 35a–c, a new class of organic compounds were obtained: fused γ-lactones with nitrogen heterocyclic skeletons—36a–c and 37a–c. As for regiochemistry, the cycloaddition reactions occur regioselectively, with the formation of one pair of stereoisomers (type A and A’, Scheme3), namely 36a–c (major) and 37a–c.A feasible reaction mechanism is presented for γ-lactone formation via a cascade reaction: an initial [3 + 2] cycloaddition leads to intermediary cycloadducts 35a–c, which underwent a concomitant protonation of the nitrogen atom and nucleophilic attack of the carboxylate oxygen at the adjacent endocyclic carbocation.

Molecules 2021, 26, 3359 7 of 16 Molecules 2021, 26, x 7 of 17

SchemeScheme 9.9. TheThe [3[3 ++ 2]2] cycloadditioncycloaddition ofof pyridaziniumpyridazinium ylidesylides28a 28a––ccto to various various ﬂuorine fluorine dipolarophiles dipolaro- Molecules 2021, 26, x withphiles double with double and triple and bond. triple bond. 8 of 17

The [3 + 2] cycloaddition reaction of ylides 28a–c to 2,2,2-trifluoroethyl acrylate occur completely regioselectively, involving a single type of regioisomer being obtained, with a tetrahydropyrrolopyridazine structure 30a–c. The cycloaddition reaction of ylides 28a–c to ethyl 4,4,4-trifluorobutinoate leads to the aromatized pyrrolopyridazine derivatives 29a–c, again with the reaction being completely regioselective. When the dipolarophile was ethyl 4,4,4-trifluorocrotonate (E-isomer), the reactions involved additional stereo- and regiochemical problems. The cycloaddition reaction of ylides 28a and 28c occurs completely stereo- and regioselectively, with only isomers 31a and 31c being obtained. In the case of ylide 28b (R=Cl), the cycloaddition reaction occurs regioselectively, with two regisomers 31b′ and 31b’’ being obtained, in a molar ratio of 1:1. These reactions were performed under conventional TH and under MW or US irradiation (both in liquid phase and phase-transfer catalysis). The use of MW irradiation SchemeScheme 10.10. TheThe [3[3 ++ 2]2] cycloadditioncycloaddition ofof pyridaziniumpyridazinium ylides ylides33a 33a–c–cto to 2-(trifluoromethyl)acrylic 2-(trifluoromethyl)acrylic acid. proved to be more efficient (with the reaction time decreasing substantially, higher yields, acid. 2.2.smaller [3 + n]amount Cycloaddition of used Reactionssolvent), inwith the Nitrilethese reacti Imineons series being considered environmentally friendly.GraveThe [3The et+ 2]in al. cycloadditionvitro [37], antimicrobial using [3 reaction + 3] activity cycloaddition of ylides of the 33a obtained reactions–c to 2-(tri compounds offluoromethyl)acrylic various indicated nitrile imines that acid the39 34 tooccurintroduction donor–acceptors unexpectedly of a trifluoromethyl cyclopropanes; instead of the moiety28 cycloadducts, report on the a straightforward pyridazine 35a–c, a new skeleton class and of efficient is organic beneficial synthesis compounds for anti- of tetrahydropyridazineweremicrobial obtained: activity. fused Practically derivativesγ-lactones all with40 co(23mpounds nitrogen products), haveheteroc as a shown spectacularyclic inskeleton Scheme antimicrobials— 1136a. –c and activity 37a–c. Asagainst forThe regiochemistry,Gram donor–acceptor positive germs, the cyclopropanes cycloaddition and very (Ar good reactions are activity various occur against aromatic regioselective Gram radicals: negatively phenyl,, with germs. 2-/3-/4- the The for- antifungal activity of compounds was negligible. 1 substituted-phenyl)mation of one pair of were stereoisomers activated by(type a catalytic A and A’ amount, Scheme of 3), TiCl namely4. The nitrile36a–c (major) imines and (R and37a– RcButnariu2. Aare feasible different et al. reaction radicals—phenyl,[36] performed mechanism a straightforward, substituted is presented phenyl, for efficient γ- naphthyl,lactone and formation benzoyl,selective thienyl)viastudy a cascade for were ob- generatedreaction:taining hybrid an in initial situ tri fromfl uoromethyl[3 + hydrazonyl 2] cycloaddition-substituted chlorides leads γ- bylactones to treatment intermediary with with nitrogen cycloadducts imidazole. heterocycl 35aic –skeletonc, whichs underwent36a–Madyc and 37a et a al.concomitant–c [,38 as] shown report protonation ain green, Scheme facile 10. ofand the nitrogen efficient syntheticatom and approach nucleophilic for pyrazolo[3,4- attack of the d]pyridazinescarboxylate oxygen linked at to the sulfone adjacent moiety endocyclic45a–d, carbocation. as shown in Scheme 12. In order to obtain the desired compounds 45a–d, initially, they obtain the pyrazole derivatives 44a–d, using the2.2. cycloaddition [3 + n] Cycloaddition reaction Reactions of the enaminones in the Nitrile43 Iminewith theseries nitrile imines 42 (generated in situ by the action of the base on the hydrazonoyl chlorides 41), followed by a cyclocondensation Grave et al. [37], using [3 + 3] cycloaddition reactions of various nitrile imines 39 to with hydrazine. donor–acceptor cyclopropanes 28, report a straightforward and efficient synthesis of tetrahydropyridazine derivatives 40 (23 products), as shown in Scheme 11.

Scheme 11. The [3 + 3] cycloaddition reactions of nitrile imines to donor–acceptor cyclopropanes.

The donor–acceptor cyclopropanes (Ar are various aromatic radicals: phenyl, 2-/3-/4- substituted-phenyl) were activated by a catalytic amount of TiCl4. The nitrile imines (R1 and R2 are different radicals—phenyl, substituted phenyl, naphthyl, benzoyl, thienyl) were generated in situ from hydrazonyl chlorides by treatment with imidazole. Mady et al. [38] report a green, facile and efficient synthetic approach for pyrazolo[3,4-d]pyridazines linked to sulfone moiety 45a–d, as shown in Scheme 12. In order to obtain the desired compounds 45a–d, initially, they obtain the pyrazole derivatives 44a– d, using the cycloaddition reaction of the enaminones 43 with the nitrile imines 42 (generated in situ by the action of the base on the hydrazonoyl chlorides 41), followed by a cyclocondensation with hydrazine.

Molecules 2021, 26, x 8 of 17

Scheme 10. The [3 + 2] cycloaddition of pyridazinium ylides 33a–c to 2-(trifluoromethyl)acrylic acid.

The [3 + 2] cycloaddition reaction of ylides 33a–c to 2-(trifluoromethyl)acrylic acid 34 occurs unexpectedly; instead of the cycloadducts 35a–c, a new class of organic compounds were obtained: fused γ-lactones with nitrogen heterocyclic skeletons—36a–c and 37a–c. As for regiochemistry, the cycloaddition reactions occur regioselectively, with the formation of one pair of stereoisomers (type A and A’, Scheme 3), namely 36a–c (major) and 37a–c. A feasible reaction mechanism is presented for γ-lactone formation via a cascade reaction: an initial [3 + 2] cycloaddition leads to intermediary cycloadducts 35a–c, which underwent a concomitant protonation of the nitrogen atom and nucleophilic attack of the carboxylate oxygen at the adjacent endocyclic carbocation.

2.2. [3 + n] Cycloaddition Reactions in the Nitrile Imine series Grave et al. [37], using [3 + 3] cycloaddition reactions of various nitrile imines 39 to Molecules 2021, 26, 3359 donor–acceptor cyclopropanes 28, report a straightforward and efficient synthesis of8 of tet- 16 rahydropyridazine derivatives 40 (23 products), as shown in Scheme 11.

Molecules 2021, 26, x 9 of 17 Molecules 2021, 26, x SchemeScheme 11.11. TheThe [3[3 ++ 3]3] cycloadditioncycloaddition reactionsreactions ofof nitrilenitrile iminesimines toto donor–acceptordonor–acceptor cyclopropanes.cyclopropan9 es.of 17

SchemeScheme 12.12. Two-stepTwoTwo--stepstep synthesis sysynthesisnthesis of ofof pyrazolo[3,4-d]pyridazines pyrazolo[3,4pyrazolo[3,4--d]pyridazinesd]pyridazines 45a 45a45a–––ddd...

TheThe reactionsreactions werewere performedperformedperformed usingusingusing bothbothboth CTCTCT heatingheatingheating andandand MWMWMW irradiation,irradiation,irradiation, withwithwith thethethe reactions under MW being more efﬁcient in terms of yields and time. The pyrazolo[3,4- reactionsreactions underunder MWMW beingbeing moremore efficientefficient inin termsterms ofof yieldsyields andand time.time. TheThe pyrazolo[3,4pyrazolo[3,4-- d]pyridazined]pyridazine derivatives derivatives derivatives45a 45a45a–d––dwered werewere tested tested tested for theirfor for their their antimicrobial antimicrobial antimicrobial activity, activity, activity, the compounds the the com- com- havingpoundspounds a havinghaving very good aa veryvery antibacterial goodgood antibacterialantibacterial activity but activityactivity not antifungal. butbut notnot antifungal.antifungal. ZakiZaki et et al. al. [[ 3939]] synthesizedsynthesized aa a seriesseries series ofof of pyrazolo[3,4pyrazolo[3,4 pyrazolo[3,4-d]pyridazines--d]pyridazinesd]pyridazines 50a50a50a––cc–,, c asas, as shownshown shown inin inSchemeScheme Scheme 13.13. 13 InIn. order Inorder order toto obtainobtain to obtain thethe the desireddesired desired compoundscompounds compounds 50a50a50a––cc,, –initiallyinitiallyc, initially theythey they obtainobtain obtain thethe thepy-py- pyrazolerazolerazole derivativesderivatives derivatives 49a49a49a––cc usingusing–c using thethe thecycloadditioncycloaddition cycloaddition reactionreaction reaction ofof thethe of nitrilenitrile the nitrile iminesimines imines 47a47a––cc47a (gen-(gen-–c (generatederateeratedd inin situsitu in situ byby bythethe the actionaction action ofof ofthethe the basebase base TEATEA TEA onon on thethe the hydrazonoylhydrazonoyl hydrazonoyl chlorideschlorides 46a46a––cc)) withwithwith 48 thiazolethiazolethiazole derivativederivativederivative 4848,,, followedfollowedfollowed bybyby aaa cyclocondensationcyclocondensationcyclocondensation withwithwith hydrazine. hydrazine.hydrazine.

SchemeScheme 13.13. Two-stepTwoTwo--stepstep synthesis synthesissynthesis of ofof pyrazolo[3,4-d]pyridazines pyrazolo[3,4pyrazolo[3,4--d]pyridazinesd]pyridazines 50a 50a50a–––ccc...

TheThe pyrazolo[3,4pyrazolo[3,4--d]pyridazined]pyridazine derivativesderivatives 50a50a––cc werewere testedtested forfor theirtheir antimicrobialantimicrobial activity,activity, thethe compoundscompounds havinghaving aa goodgood antibacterialantibacterial activityactivity (both(both onon GGramram positivepositive andand GGramram negativenegative bacteria)bacteria) butbut notnot antifungal.antifungal. EldebssEldebss etet al.al. [40[40]] synthesizedsynthesized aa seriesseries ofof pyrazolopyrazolo--pyridazinespyridazines 55a55a––ff,, asas shownshown inin SchemeScheme 14.14. InIn orderorder toto obtainobtain thethe desireddesired compoundscompounds 55a55a––ff,, initiallyinitially theythey obtainobtain thethe py-py- razolerazole derivativesderivatives 54a54a––ff,, usingusing thethe cycloadditioncycloaddition reactionreaction ofof thethe nitrilenitrile iminesimines 52a52a––ff (gen-(gen- eratederated inin situsitu byby thethe actionaction ofof thethe basebase TEATEA onon thethe hydrazonoylhydrazonoyl chlorideschlorides 51a51a––ff)) withwith enaminoneenaminone--pyrrolopyrrolo derivativederivative 5353,, followedfollowed byby aa cyclocondensationcyclocondensation withwith hydrazine.hydrazine. TheThe cycloadditioncycloaddition reactionreaction occuroccur regioselective,regioselective, inin goodgood yields.yields.

Molecules 2021, 26, 3359 9 of 16

The pyrazolo[3,4-d]pyridazine derivatives 50a–c were tested for their antimicrobial activity, the compounds having a good antibacterial activity (both on Gram positive and Gram negative bacteria) but not antifungal. Eldebss et al. [40] synthesized a series of pyrazolo-pyridazines 55a–f, as shown in Scheme 14. In order to obtain the desired compounds 55a–f, initially they obtain the pyrazole derivatives 54a–f, using the cycloaddition reaction of the nitrile imines 52a–f (generated in situ by the action of the base TEA on the hydrazonoyl chlorides 51a–f) with enaminone-pyrrolo derivative 53, followed by a cyclocondensation with hydrazine. The Molecules 2021, 26, x 10 of 17 Molecules 2021, 26, x cycloaddition reaction occur regioselective, in good yields. 10 of 17

Scheme 14. Two-step synthesis of pyrazolo-pyridazines 55a–f. SchemeScheme 14.14. Two-stepTwo-step synthesissynthesis ofof pyrazolo-pyridazinespyrazolo-pyridazines55a 55a––ff..

TheThe pyrazolo pyrazolo-pyridazinepyrazolo--pyridazinepyridazine derivativesderivatives derivatives 55a55a55a––f–f f werewerewere testedtested tested forfor for theirtheir their proteinprotein protein kinasekinase kinase inhib-inhib- in- itoryhibitoryitory activitiesactivities activities againstagainst against 2525 25 kinaseskinases kinases (belonging(belonging (belonging toto to fourfour four kinasekinase kinase groups),groups), groups), with with the the obtainedobtained resultsresults revealing revealing revealing that that that the the the compounds compounds compounds are selective are are selectiveselective and very and and good very very inhibitors good good inhibitors inhibitors against VEGFR- against against VEGFR-2, EGFR and CHK1, with IC50 values in the sub-micromolar range. 2,VEGFR EGFR- and2, EGFR CHK1, and with CHK1, IC50 withvalues IC50 in values the sub-micromolar in the sub-micromolar range. range. GomhaGomha etet al.al. [[41[4141]] reportreport thethethe synthesissynthesissynthesis ofofof aaa largelargelarge variety varietyvariety of ofof pyrazolo-azaheterocycles pyrazolopyrazolo--azaheterocyclesazaheterocycles ofof potential potential interestinterest inin in medicinalmedicinal medicinal chemistry,chemistry, chemistry, asas as shownshown shown ininin SchemeScheme Scheme 15.15. 15 InIn. order Inorder order toto obtainobtain to obtain thethe desiredthedesired desired compoundscompounds compounds 60a60a60a––cc,, – initiallycinitially, initially theythey they obtainobtain obtain thethe the pyrazolepyrazole pyrazole derivativesderivatives derivatives 59a59a––cc,, using usingusing aaa regioselectiveregioselective cycloaddition cycloaddition of of nitrile nitrile imines imines 57a57a––cc (generated(generated inin situsitu byby thethe actionaction ofof thethethe basebase onon thethe hydrazonoylhydrazonoyl chlorideschlorides 56a56a––cc)) with with enaminone enaminone 5858,,, followed followedfollowed by byby a aa cycloconden- cycloconden-cyclocondensation with hydrazine hydrate when the corresponding pyrazolo[3,4-d]pyridazines 60a–c sationsation withwith hydrazinehydrazine hydratehydrate whenwhen thethe correspondingcorresponding pyrazolo[3,4pyrazolo[3,4--d]pyridazinesd]pyridazines 60a60a––cc are obtained. areare obtained.obtained.

Scheme 15. TwoTwo-step-step synthesissynthesis of pyrazolo[3,4-d]pyridazinespyrazolo[3,4-d]pyridazines 60a60a––cc.. Scheme 15. Two-step synthesis of pyrazolo[3,4-d]pyridazines 60a–c. Using a similar strategy, Elwahy et al. [42] report an interesting study concerning UsingUsing aa similarsimilar strategy,strategy, ElwahyElwahy etet al.al. [42[42]] reportreport anan interestinginteresting studystudy concerningconcerning synthesis of bis-pyrazolo[3,4-d]pyridazines 65a,b, as shown in Scheme 16. In order to obtain synthesissynthesis ofof bisbis--pyrazolo[3,4pyrazolo[3,4--d]pyridazinesd]pyridazines 65a65a,,bb,, asas shownshown inin SchemeScheme 16.16. InIn orderorder toto ob-ob- the desired compounds 65a,b, initially they obtain the bis-pyrazole derivatives 64, using the taintain thethe desireddesired compoundscompounds 65a65a,,bb,, initiallyinitially theythey obtainobtain thethe bisbis--pyrazolepyrazole derivativesderivatives 6464,, usingusing thethe cycloadditioncycloaddition reactionsreactions ofof nitrilenitrile iminesimines 6262 (generated (generated inin situsitu byby thethe actionaction ofof thethe basebase onon thethe hydrazonoylhydrazonoyl chlorideschlorides 6161)) withwith bisbis(enaminones)(enaminones) 6363,, followedfollowed byby aa cyclocon-cyclocon- densationdensation with with hydrazine hydrazine hydrate hydrate when when the the corresponding corresponding bisbis--pyrazolo[3,4pyrazolo[3,4--d]pyri-d]pyri- dazinesdazines 65a,b65a,b areare obtained.obtained.

Molecules 2021, 26, 3359 10 of 16

cycloaddition reactions of nitrile imines 62 (generated in situ by the action of the base on the hydrazonoyl chlorides 61) with bis(enaminones) 63, followed by a cyclocondensation with hydrazine hydrate when the corresponding bis-pyrazolo[3,4-d]pyridazines 65a,b are obtained. Molecules 2021,, 26,, xx 11 of 17

SchemeScheme 16.16. Two-stepTwo-step synthesissynthesis ofof bisbis-pyrazolo[3,4-d]pyridazines-pyrazolo[3,4-d]pyridazines65a 65a,b,b..

TheseThese reactionsreactions werewere performedperformed underunder conventionalconventional THTH andand MWMW irradiation.irradiation. TheThe authorauthor claims that that MW MW irradiation irradiation is isbeneficial beneﬁcial for for the the reaction reaction pathway, pathway, the reaction the reaction con- conditionsditions are aremilder, milder, the the yields yields are are higher higher and and the the reaction reaction time time decrease decreases.s. Abranyi-BaloghAbranyi-Balogh et al. al. [43 [43]] report report a a convenient convenient and and direct direct one one-pot-pot synthesis synthesis of ofcyclo- cy- clopenta[d]pyridazines,penta[d]pyridazines, as asshown shown in Scheme in Scheme 17. 17 In. order In order to obtain to obtain the the desired desired compound compound 69, 69they, they use usethe cycloaddition the cycloaddition reactions reactions of nitrile of nitrile imine imine 67 (generated67 (generated in situ in from situ the from hydra- the they use the cycloaddition reactions1 of nitrile imine 67 (generated in situ from the hydra- hydrazonoylzonoyl chlorides chlorides 66; R1 66= methyl,;R = methyl, iso-propyl, iso-propyl, tert-butyl, tert-butyl, cyclohexyl, cyclohexyl, 3-OMe 3-OMe-phenyl;-phenyl; R2 = 4- zonoyl2 chlorides 66; R = methyl, iso-propyl,3 tert-butyl, cyclohexyl, 3-OMe-phenyl; R = 4- R = 4-OMe-phenyl) with fulvene3 68 (R = H, methyl), using Ag2CO3 as the catalyst. OMe-phenyl) with fulvene 68 (R3 = H, methyl), using Ag2CO3 as the catalyst.

SchemeScheme 17.17. SynthesisSynthesis ofof cyclopenta[d]pyridazinescyclopenta[d]pyridazines 6969 byby cycloadditioncycloaddition reactions.reactions.

TheseThese reactionsreactions were were performed performed under under mild mild conditions conditions and and the yieldsthe yields were were good good to high. to high. 2.3. Pyridazine Derivatives Obtained by Cycloaddition and/or by Click Reactions of Azomethine Ylides or Imines 2.3. Pyridazine Derivatives Obtained by Cycloaddition and/or by Click Reactions of Azomethine YlidesRichter or Imines et al. [44,45] performed an in-depth study concerning the optoelectronic properties of and obtaining some polycyclic aromatic hydrocarbons with pyrrolopyridazine Richter et al. [44,45] performed an in-depth study concerning the optoelectronic core 74a,b, as shown in Scheme 18. properties of and obtaining some polycyclic aromatic hydrocarbons with pyrrolopyridazine core 74a,b, as shown in Scheme 18.

MoleculesMolecules 20212021,, 2626,, 3359x 1112 ofof 1617 Molecules 2021, 26, x 12 of 17

Scheme 18. Two-step synthesis of polycyclic aromatic compounds with pyrrolopyridazine core 74a,b. SchemeScheme 18. 18.Two-step Two-step synthesis synthesis of of polycyclic polycyclic aromatic aromatic compounds compounds with with pyrrolopyridazine pyrrolopyridazine core core74a ,b. 74a,b. The synthesissynthesis waswas performedperformed in in two two steps: steps: an an initial initial cycloaddition cycloaddition reaction reaction of azome-of azo- thinemethineThe ylides ylides synthesis71a ,71ab (generated, bwas (generated performed from from the in saltstwothe saltssteps:70a, b70a andan,b initial TEA)and TEA) cycloaddition to symmetrically to symmetrical reaction substitutedly substi-of azo- dipolarophilestutedmethine dipolar ylidesophiles with 71a, ab triple with(generated bonda triple (namely, from bond the 1,4-diphenylbut-2-yne-1,4-dione (namelysalts 70a, ,b1,4 and-diphenylbut TEA) to symmetrical-2-yne72-1,4) leads-dionely substi- to the72) intermediaryleadstuted to dipolar the intermediary ullazineophiles 73a with, bullazine; thisa triple reaction 73a bond,b; isthis followed (namely reaction, by1,4 is a -followeddiphenylbut cyclocondensation by a- 2cyclocondensation-yne- of1,473a-dione,b with 72) hydrazine,ofleads 73a ,tob withthe when intermediary hydrazine the desired, when ullazine products the 73adesired,74ab; this,b productare reaction obtained.s 74a is followed,b In are the obtained. obtained by a cyclocondensation In polycyclic the obtained aro- maticpolycyof 73a hydrocarbons,clicb with aromatic hydrazine hydrocarbons with,pyrrolopyridazine when the with desired pyrrolopyridazine coreproduct74, interestings 74a, bcore are 74 intramolecularobtained., interesting In the intramolec- push–pull obtained phenomenaularpolycy pushclic– pullaromatic between phenomena hydrocarbons the ullazine between part with the (as pyrrolopyridazine ullazine donor) and part the (as pyridazine donor) core 74 and, interesting core the (as pyridazine acceptor intramolec- part)core were(asular acceptor observed,push–pull part) whichphenomena were makes observed, between these which compounds the makeullazines suitablethese part compounds (as candidates donor) andsuitable for the organic pyridazine candidates ﬁeld effect core for transistororg(asanic acceptor field (OFET) part)effect applications weretransistor observed, (OFET) or chemical/bio-sensing. which applications makes these or chemical/bio compounds Similar results-sensing. suitable were Similar candidates obtained results infor thiswereorganic group obtained field (Berger) effect in this fortransistor group other (Berger azaheterocycles (OFET)) for applications other [45 azaheterocycles]. or chemical/bio [45].-sensing. Similar results wereXu obtained etet al.al. [ 46[46,47 in,47 this]] synthesized synthesized group (Berger a seriesa series) for of other of substituted substituted azaheterocycles 1,2,3,6-tetrahydropyridazine 1,2,3,6 -[45tetrahydropyridazine]. deriva- de- tivesrivatives77aXu –et77h ,al.a– usingh [46,47, using the] synthesizedthe dirhodium-catalyzed dirhodium a series-catalyzed of substituted [3 [ +3 3]+ 3 cycloaddition] cycloaddition 1,2,3,6-tetrahydropyridazine reactions reactions of of differentdifferent de- Nrivatives-acylimino-pyridinium-acylimino 77a-–pyridiniumh, using the ylides dirhodium 76a–g-,catalyzed toto enolenol diazoacetatesdiazoacetates [3 + 3] cycloaddition 7575 [TIPS[TIPS reactions == tritriisopropylsilyl],isopropylsilyl], of different asN - shownacylimino in SchemeScheme-pyridinium 1919.. ylides 76a–g, to enol diazoacetates 75 [TIPS = triisopropylsilyl], as shown in Scheme 19.

Scheme 19. Synthesis of tetrahydropyridazine derivativesderivatives 80a80a––hh byby cycloadditioncycloaddition reactions.reactions. Scheme 19. Synthesis of tetrahydropyridazine derivatives 80a–h by cycloaddition reactions. The reactionsreactions occuroccur regioselectively, regioselectively with, with high high yields, yields, and and excellent excellent enantio-selectivities, enantio-selectiv- controlled by the reaction conditions and catalysts. The sequence of reactions is trig- ities, controlledThe reactions by theoccur reaction regioselective conditionsly, withand catalysts.high yields, The and sequence excellent of reactionsenantio-selectiv- is trig- gered by Rh(II)-catalyzed dinitrogen extrusion, followed by vinylogous addition with geredities, controlledby Rh(II)- catalyzedby the reaction dinitrogen conditions extrusion, and catalysts.followed Theby vinylogous sequence of addition reactions with is trig- N- N-acyliminopyridinium ylides. acyliminopyridiniumgered by Rh(II)-catalyzed ylides. dinitrogen extrusion, followed by vinylogous addition with N- Using the cycloaddition reactions of azometine imines to π-deﬁcient alkynyl hetarenes acyliminopyridiniumUsing the cycloaddition ylides. reactions of azometine imines to π-deficient alkynyl he- (used as dipolarophiles), Nelina-Nemtseva et al. [48] obtained various classes of fused tarenesUsing (used the as cycloadditiondipolarophiles), reactions Nelina -Nemtseva of azometine et al. imines [48] obtained to π-deficient various alkynyl classes he-of azaheterocycles,fused azaheterocycles, these including these including pyrimido[4,5-c]pyridazine pyrimido[4,5-c]pyridazine derivatives derivatives80a–c, as shown80a–c, inas Schemetarenes 20(used. as dipolarophiles), Nelina-Nemtseva et al. [48] obtained various classes of shownfused azaheterocycles,in Scheme 20. these including pyrimido[4,5-c]pyridazine derivatives 80a–c, as shown in Scheme 20.

Molecules 2021, 26, 3359 12 of 16 Molecules 2021, 26, x 13 of 17 Molecules 20212021,, 2626,, xx 1313 off 1717

Scheme 20. Copper-catalyzed [3 + 2] cycloaddition reactions for synthesis of 80a–c. SchemeScheme 20.20. Copper-catalyzedCopper--catalyzedcatalyzed [3[3[3 +++ 2]2] cycloadditioncycloaddition reactionsreactions forfor synthesissynthesis ofofof 80a80a––ccc... In order to obtain the fused pyridazine derivatives 80a–c, the authors used the cop- In order to obtain the fused pyridazine derivatives 80a–c, the authors used the copper-catalyzedInIn orderorder to to[3 obtain obtain+ 2] cycloaddition the the fused fused pyridazine pyridazine reactions. derivatives derivatives In this respect80a 80a–c,–, thec 2, -thearylidene authors authors used-5 -usedoxopyrazoli- the the copper- cop- per-catalyzed [3 + 2] cycloaddition reactions. In this respect, 2-arylidene-5-oxopyrazoli- catalyzeddinper--2catalyzed-ium- [31-ides + [3 2] + cycloaddition78a 2] –cycloadditionc were coupled reactions. reactions. with In 3 this In-ethynyl this respect, respect-6,8 2-arylidene-5-oxopyrazolidin--dimethylpyrimido[4,5, 2-arylidene-5-oxopyrazoli--c]pyri- 2-ium-1-idesdin-2-ium-1-ides78a– c78awere–c coupledwere coupled with 3-ethynyl-6,8-dimethylpyrimido[4,5-c]pyridazine- with 3-ethynyl-6,8-dimethylpyrimido[4,5-c]pyri- dazinedin-2-ium-5,7(6H,8H)-1-ides 78a-dione–c were 79 (as coupled dipolarophile), with 3- ethynylusing Cu(I)-6,8- dimethylpyrimido[4,5as the catalyst. The reactions-c]pyri- 5,7(6H,8H)-dionedazine-5,7(6H,8H)79-dione(as dipolarophile), 79 (as dipolarophile), using Cu(I) using as theCu(I) catalyst. as the Thecatalyst. reactions The reactions occur in occurdazine in-5,7(6H,8H) moderate -todione excellent 79 (as yields. dipolarophile), using Cu(I) as the catalyst. The reactions moderateoccur in moderate to excellent to excellent yields. yields. occurBirkenfelder in moderate et to al. excellent [49] synthesized yields. a series of 3,6-bis(4-triazolyl)pyridazines by using BirkenfelderBirkenfelder etet al.al. [[4949]] synthesizedsynthesized aa seriesseries ofof 3,6-3,6-bisbis(4-triazolyl)pyridazines(4-triazolyl)pyridazines byby usingusing a facileBirkenfelder copper-catalyzed et al. [49 [3] synthesized+ 2] cycloaddition a series reaction, of 3,6-bis as(4 shown-triazolyl)pyridazines in Scheme 21. by using aa facilefacile copper-catalyzedcopper--catalyzed [3[3[3 + ++ 2]2] cycloadditioncycloaddition reaction,reaction, asas shownshown inin SchemeScheme 2121..

Scheme 21. Copper-catalyzed [3 + 2] cycloaddition reactions for synthesis of 83a–h. SchemeScheme 21.21. Copper-catalyzedCopper--catalyzedcatalyzed [3[3[3 +++ 2]2] cycloadditioncycloaddition reactionsreactions forfor synthesissynthesis ofofof 83a83a––hh... In this respect,respect, 3,6-ethynylpyridazine3,6-ethynylpyridazine 81 (used as dipolarophile with a triple bond)bond) InIn thisthis respect,respect, 3,63,6--ethynylpyridazine 81 (used(used asas dipolarophile with a tripletriple bond)bond) was treated with the corresponding azidesazides 82a82a––hh (CuAAC(CuAAC waswas usedused asas a catalystcatalyst forfor click was treated with the corresponding azides 82a–h (CuAAC(CuAAC waswas usedused asas a catalyst for click reactions), leading toto thethe desireddesired 3,6-3,6-bisbis(4-triazolyl)pyridazines(4-triazolyl)pyridazines 83a83a––hh.. ElectrochemistryElectrochemistry reactions),reactions), leadingleading toto thethe desireddesired 3,63,6--bis(4(4--triazolyl)pyridazinestriazolyl)pyridazines 83a–h.. ElectrochemistryElectrochemistry and optical spectroscopy of the obtained 3, 3,6-6-bis(4-triazolyl)pyridazines(4-triazolyl)pyridazines 83a83a––hh suggestsuggest thatthat and optical spectroscopy of the obtained 3,6--bis(4(4--triazolyl)pyridazinestriazolyl)pyridazines 83a–h suggest that these compoundscompounds havehave anann n-type-type organic organic semiconductor semiconductor behavior, behavior, which which make make them them useful use- thesethese compoundscompounds havehave aan n--typetype organicorganic semiconductorsemiconductor behavior,behavior, whichwhich makemake themthem use-use- asfulelectron-transporting/hole-blocking as electron-transporting/hole-blocking materials materials in optoelectronics.in optoelectronics. fulful asas electronelectron--transporting/holetransporting/hole--blocking materials in optoelectronics. Yang et al. [50 [50]] synthesized synthesized a a series series of of pyrrolo pyrrolo-pyridazyl-triazolyl-pyridazyl-triazolyl derivatives derivatives 86a86a–d–, Yang et al. [50[50]] synthesizedsynthesized aa seriesseries ofof pyrrolopyrrolo--pyridazylidazyl--triazolyltriazolyl derivativesderivatives 86a–d,, dby, by using using a a facile facile copper copper-catalyzed-catalyzed azide azide-alkyne-alkyne cycloaddition cycloaddition reaction, reaction, as as shown in in by using a facile copper--catalyzed azide--alkyne cycloaddition reaction, as shown in Scheme 2222.. Scheme 22.

Scheme 22. AzideAzide-alkyne-alkyne cycloaddition reactions for synthesis of pyridazine derivatives 86a86a––dd.. Scheme 22. Azide--alkyne cycloaddition reactions for synthesis of pyridazine derivatives 86a–d.. In thisthis respect,respect, pyrrolo-pyridazinepyrrolo-pyridazine derivative 84 (used(used asas dipolarophiledipolarophile withwith tripletriple In this respect, pyrrolo-pyridazine derivative 84 (used as dipolarophile with triple bond)In was this treated respect, with pyrrolo the corresponding-pyridazine derivative azidesazides 85a85a 84––dd (used(using(using as CuAACCuAAC dipolarophile asas catalystcatalyst with forfor triple click bond) was treated with the corresponding azides 85a–d (using CuAAC as catalyst for click reactions),bond) was treated leading with to the corresponding desired pyrrolo azides-pyridazyl 85a–d- (usingtriazolyl CuAAC derivatives as catalyst 86a –ford. click The reactions),reactions), leading leading to to the the desired desired pyrrolo pyrrolo--pyridazyl--triazolyltriazolyl derivatives derivatives 86a–d.. The The

Molecules 2021, 26, 3359 13 of 16

Molecules 2021, 26, x 14 of 17 reactions), leading to the desired pyrrolo-pyridazyl-triazolyl derivatives 86a–d. The authors suggestauthors thatsuggest these that compounds these compounds could have could applications have applications in optoelectronics in optoelectronics as π-conjugated as π- D1-A1-D2-A2conjugated D1 materials.-A1-D2-A2 materials.

2.4. Miscellaneous [3 + n n]] Cycloaddition Reactions Molecules 2021, 26, x Swarup et al. [[5151]] synthesizedsynthesized aa seriesseries ofof 1,2,3-triazolo-pyridazine1,2,3-triazolo-pyridazine derivativesderivatives 919114 andandof 17 92,, usingusing aa straightforward straightforward and and efﬁcient efficient procedure. procedure. In In this this respect, respect, initially initially they they obtain obtain the authors suggest that these compounds could have applications in optoelectronics as π- 4,5-disubstituted-1,2,3-triazolesthe 4,5-disubstituted-1,2,3-triazoles89 and 89 90and, through 90, through the cycloaddition the cycloaddition reactions reactions of R-benzo- of R- conjugated D1-A1-D2-A2 materials. orbenzo 2-methylthio-- or 2-methylthio 1,4-ene-dione- 1,4-ene- (compoundsdione (compounds87 and 8788) andand 88) sodium and sodium azide azide (Scheme (Scheme 23), followed23), followed by a by cyclocondensation a cyclocondensation with with hydrazine. hydrazine. 2.4. Miscellaneous [3 + n] Cycloaddition Reactions Swarup et al. [51] synthesized a series of 1,2,3-triazolo-pyridazine derivatives 91 and 92, using a straightforward and efficient procedure. In this respect, initially they obtain the 4,5-disubstituted-1,2,3-triazoles 89 and 90, through the cycloaddition reactions of R- benzo- or 2-methylthio- 1,4-ene-dione (compounds 87 and 88) and sodium azide (Scheme 23), followed by a cyclocondensation with hydrazine.

Scheme 23. Two-stepTwo-step synthesissynthesis ofof 1,2,3-triazolo-pyridazine1,2,3-triazolo-pyridazine 9191 andand 9292..

The triazolo triazolo-pyridazine-pyridazine derivatives, derivatives, especially especially 9292, could, could be beused used as key as keystarting starting ma- materialsterials for forobtaining obtaining solar solar cells. cells. Nair etet al.al. [52[52]] synthesized synthesized a a series series of of highly highly functionalized functionalized pyridazine pyridazine esters esters96a 96a–i by–i cycloadditionby cycloaddition reactions, reactions, as shown as shown in Scheme in Scheme 24. As 24. 1,3-dipole, As 1,3-dipole they, usedthey used an α-diazoester an α-diaz- anionoesterScheme 94anion 23.(generated Two 94 -(generatedstep sy innthesis situ in fromofsitu 1,2,3 from the-triazolo theα-diazo- α--pyridazinediazoβ-ketoester-β-ketoester 91 and93 92 93.in in the the presence presence of of aa base,base, EtONa), which undergoes aa [3[3 ++ 3]3] annulation with chalcone epoxides 95a95a––hh.. TheThe reactionstriazolo-pyridazine occur in moderate derivatives, yields especially but completely 92, could regioselectively, be used as key in starting mild condi- ma- tions,terials and for withobtaining a wide solar variety cells. of functional groups. TranNair etet al.al. [[5253]] synthesizedsynthesized differenta series of fluoro-pyridazine highly functionalized derivatives pyridazine100a– jesters, using 96a the–i [3by + cycloaddition 2] cycloadditions reactions, of different as shown R2-diazoacetate in Scheme derivatives 24. As 1,3-99adipole–c, in, they the presenceused an ofα- TEA,diaz- 1 tooester different anion 1-R 94 (generated-2,2-difluorocyclopropene in situ from the 98aα-diazo–j (generated-β-ketoester in situ 93 in from the thepresence corresponding of a base, acetylenicEtONa), which derivatives undergoes97a– jaand [3 + difluorocarbene),3] annulation with as chalcone shown in epoxides Scheme 2595a. –h.

Scheme 24. Synthesis of pyridazine esters 96a–i by [3 + 3] annulation reactions.

The reactions occur in moderate yields but completely regioselectively, in mild conditions, and with a wide variety of functional groups. Tran et al. [53] synthesized different fluoro-pyridazine derivatives 100a–j, using the [3 + 2] cycloadditions of different R2-diazoacetate derivatives 99a–c, in the presence of SchemeTEA,Scheme to 24. 24.different Synthesis 1- ofRof1 pyridazine-pyridazine2,2-difluorocyclopropene estersesters 96a96a––ii byby [3[3 ++98a 3]3] annulation–j (generated reactions. in situ from the corresponding acetylenic derivatives 97a–j and difluorocarbene), as shown in Scheme 25. The reactions occur in moderate yields but completely regioselectively, in mild conditions, and with a wide variety of functional groups. Tran et al. [53] synthesized different fluoro-pyridazine derivatives 100a–j, using the [3 + 2] cycloadditions of different R2-diazoacetate derivatives 99a–c, in the presence of TEA, to different 1-R1-2,2-difluorocyclopropene 98a–j (generated in situ from the corresponding acetylenic derivatives 97a–j and difluorocarbene), as shown in Scheme 25.

Molecules 2021, 26, x 15 of 17

Molecules 2021, 26, 3359 14 of 16 Molecules 2021, 26, x 15 of 17

SchemeScheme 25.25. Synthesis ofof ﬂuoro-pyridazinefluoro-pyridazine derivativesderivatives 100a100a––jj byby [3[3 ++ 2]2] cycloadditioncycloaddition reactions.reactions.

SchemeOverall,Overall, 25. Synthesis the the reaction reaction of fluoro pathway pathway-pyridazine is directis direct derivatives and and efficient, efficient,100a– withj by with[3 the + desired2] the cycloaddition desired 5-fluoro-pyridazines 5- reactions.fluoro-pyri- 100adazines–j being 100a obtained–j being obtained in modest in tomodest good yieldsto good (30 yields−86%). (30−86%). BenOverall,Ben HamadiHamadi the reaction etet al.al. [[5454 ]pathway] reportreport anan is efﬁcientefficientdirect and andand efficient, straightforwardstraightforward with the synthesissynthesisdesired 5 -ofoffluoro saturatedsaturated-pyri- pyrazolo-pyridazinonedazinespyrazolo 100a-pyridazinone–j being obtained viavia cycloadditioncycloaddition in modest reactions,reactions,to good yieldsas as shownshown (30−86%). inin SchemeScheme 26 26.. InIn thisthis respect, theythey Ben useuse aHamadia [3[3 ++ 2]2] et cycloadditioncycloaddition al. [54] report reactionreaction an efficient ofof diazopropanediazopropane and straightforward 102 toto pyridazinonespyridazinones synthesis of saturated 101a–d,, whenpyrazolowhen thethe- correspondingpyridazinonecorresponding via saturatedsaturated cycloaddition pyrazolo[3,4-d]pyridazinonespyrazolo[3,4 reactions,-d]pyridazinones as shown in Scheme103a 103a––d d26are are. In obtained.obtained. this respect, they use a [3 + 2] cycloaddition reaction of diazopropane 102 to pyridazinones 101a–d, when the corresponding saturated pyrazolo[3,4-d]pyridazinones 103a–d are obtained.

SchemeScheme 26.26. Synthesis ofof pyrazolo[3,4-d]pyridazinonespyrazolo[3,4-d]pyridazinones 103a103a––dd byby [3[3 ++ 2] cycloaddition reactions.reactions.

These reactions were performed under conventional TH and US irradiation, conclud- SchemeThese 26. Synthesisreactions of were pyrazolo[3,4 performed-d]pyridazinones under conventional 103a–d by TH [3 and+ 2] cycloadditionUS irradiation, reactions. conclud- inging thatthat thethe useuse ofof US irradiation hashas substantial advantages,advantages, withwith yieldsyields beingbeing higher,higher, thethe reactionreactionThese timetime reactions decreasing,decreasing, were and andperformed thethe toxicitytoxicity under decreasingdecreasing conventional byby usingusing TH and nontoxicnontoxic US irradiation, solvents.solvents. conclud- 3.ing Concluding that the use Remarks of US irradiation has substantial advantages, with yields being higher, the reaction3. Concluding time decreasing, Remarks and the toxicity decreasing by using nontoxic solvents. InIn conclusion, it it is is clear clear that that the the [3 + [3 n +] cycloaddition n] cycloaddition reactions reactions in the in pyridazine the pyridazine series seriesremain3. Concluding remain a versatile a Remarks versatile and useful and usefultool to tool obtain to obtainnew compounds new compounds of potential of potential interest interest in me- in medicinal chemistry and optoelectronics. The theoretical and experimental aspects of dicinal chemistry and optoelectronics. The theoretical and experimental aspects of stereo- stereochemistryIn conclusion, and it regiochemistry is clear that the involved [3 + n] cycloaddition in the [3 + n] reactions cycloadditions in the pyridazine are complex series and chemistry and regiochemistry involved in the [3 + n] cycloadditions are complex and at- attractive,remain a versatile and continue and useful to rouse tool the to interest obtain ofnew scientific compounds community. of potential interest in me- dicinaltractive, chemistry and continue and optoelecto rouse tronics.the interest The oftheoretical scientific and community. experimental aspects of stereo- Authorchemistry Contributions: and regiochemistryDesign and involved conception in the were [3 carried+ n] cycloadditions out by V.M. and are I.I.M.complex All authorsand at- Author Contributions: Design and conception were carried out by V.M. and I.I.M. All authors con- contributedtractive, and to writing,continue reviewing to rouse and the approving interest of the scientific final version. community. All authors have read and agreed tributed to writing, reviewing and approving the final version. All authors have read and agreed to to the published version of the manuscript. Authorthe published Contributions: version of Design the manuscript. and concepti on were carried out by V.M. and I.I.M. All authors con- Funding: This work was supported by a grant from the Romanian Ministry of Education and tributed to writing, reviewing and approving the final version. All authors have read and agreed to Research,Funding: CNCS-UEFISCDI,This work was supported project number by a grant PN-III-P4-ID-PCE-2020-0371, from the Romanian Ministry within of Education PNCDI III. and Re- search,the published CNCS -versionUEFISCDI, of the project manuscript. number PN-III-P4-ID-PCE-2020-0371, within PNCDI III. Acknowledgments: Acknowledgment is given to infrastructure support from the Operational Pro- Funding: This work was supported by a grant from the Romanian Ministry of Education and Re- gramAcknowledgments: Competitiveness Acknowledgment 2014–2020, Axis is 1, given under to POC/448/1/1 infrastructure Research support infrastructurefrom the Operational projects Pro- for search, CNCS-UEFISCDI, project number PN-III-P4-ID-PCE-2020-0371, within PNCDI III. publicgram Competitiveness R&D institutions/Sections 2014–2020, F Axis 2018, 1, through under POC/448/1/1 the Research Research Center with infrastructure Integrated Techniquesprojects for forAcknowledgments:public Atmospheric R&D institutions/Sections Aerosol Acknowledgment Investigation F 2018, inis throughgiven Romania to infrastructurethe (RECENT Research AIR) Center support project, with from under Integrated the grantOperational Techniques agreement Pro- MySMISgramfor Atmospheric Competitiveness no. 127324. Aerosol 2014 Investigation–2020, Axis in 1, Romania under POC/448/1/1 (RECENT AIR) Research project, infrastructure under grant projects agreemen fort MySMIS no. 127324. Conflictspublic R&D of Interest:institutions/SectionsThe authors F declare 2018, through no conflict the of Research interest. Center with Integrated Techniques Conflictsfor Atmospheric of Interest: Aerosol The Investigationauthors declare in Romaniano conflict (RECENT of interest. AIR) project, under grant agreement References MySMIS no. 127324. 1.ReferencesHuisgen, R.; Grashey, R.; Gotthardt,Conflicts H.; of Schmidt, Interest: R. The 1,3-Dipolar authors declare additions no ofconflict sydnones of interest. to Alkynes. A new route into the pyrazole series. Angew. Chem. Int. Ed. Engl. 1962, 1, 48–49. [CrossRef] 2.References Huisgen, R. 1,3-Dipolar cycloadditions. Past and future. Angew. Chem. Int. Ed. Engl. 1963, 2, 565–598. [CrossRef]

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