Cycloaddition

molecules

Review Review IndolizinesIndolizines andand TheirTheir Hetero/BenzoHetero/Benzo DerivativesDerivatives inin ReactionsReactions ofof [8+2][8+2] Cycloaddition

EugeneEugene V.V. BabaevBabaev1,2,3, 1,2,3,** andand Ivan Ivan A. A.Shadrin Shadrin 1 1

11 ChemistryChemistry Department, Department, Moscow Moscow State State University, University, Leninskie Leninskie gory, Gory, 1 1 str.3, Str. 3, 119899 119899 Moscow, Moscow, Russia; Russia; [email protected]@gmail.com 22 HigherHigher School School of of Economics, Economics, National National Research Research University, University, 7 7 Vavilova Vavilova Str., 117312 Moscow, RussiaRussia 33 N.N. D. D. Zelinsky Zelinsky Institute Institute of of Or Organicganic Chemistry, Chemistry, Russian Russian Academy Academy of of Sciences, Sciences, 47 Leninsky Ave., 119991119991 Moscow, Moscow, Russia Russia ** Correspondence:Correspondence: [email protected]; [email protected]; Tel.: Tel.: +7-985-997-94-75 +7-985-997-94-75

Abstract: PeculiaritiesPeculiarities ofof [8+2][8+2] cycloaddition of acetylenesacetylenes toto indolizinesindolizines areare reviewed.reviewed. EspeciallyEspecially mentioned are are indolizines indolizines with with leaving leaving groups groups at positions at positions 3 and 3 and 5. Cycloaddition 5. Cycloaddition to aza- to and azabenzo and benzoderivatives derivatives are reviewed, are reviewed, as well as 1,10-cyclizations well as 1,10-cyclizations and processe ands processes leading to leading cyclazines to cyclazines where in- wheredolizines indolizines are intermediates. are intermediates. Mechanistic Mechanistic features features(adducts (adducts and cycloadducts) and cycloadducts) and theoretical and theoretical aspects aspects(one- or (one- two-steps or two-steps mechanism) mechanism) are reviewed. are reviewed.

Keywords: indolizine; azaindolizines; benzoindolizines;benzoindolizines; cyclazine; [8+2] cycloaddition; mechanism; 1,10-cyclizations;1,10-cyclizations; catalystscatalysts

1. Introduction

Citation: Babaev, E.V.; Shadrin, I.A. Indolizine (A, SchemeScheme1 1)) isis the the simplest simplest heteroaromatic heteroaromatic molecule molecule containing containing both both a a Indolizines and Their Hetero/Benzo π-excessive-excessive pyrrolepyrrole andand aa ππ-deficient-deficient pyridinepyridine ringring withwith onlyonly oneone bridgeheadbridgehead nitrogen, Derivatives in Reactions of [8+2] the wholewhole systemsystem beingbeing isomericisomeric withwith indoleindole andand possesspossess pharmaceutical,pharmaceutical, agrochemicalagrochemical Cycloaddition. Molecules 2021, 26, Citation: Babaev, E.V.; Shadrin, I.A. andand fluorescentfluorescent properties [1]. [1]. Although Although indolizine indolizine is iscertainly certainly aromatic, aromatic, significant significant alter- al- 2050. https://doi.org/10.3390/ Indolizines and their Hetero/Benzo ternationsnations of the of the bond bond lengths lengths around around the thering ring system system were were detected detected by X-ray, by X-ray, NMR NMR and and UV molecules26072050 Derivatives in Reactions of [8+2] UVspectroscopy spectroscopy and and even even mass mass spectrometry spectrometry in in various various substituted indolizines.indolizines. ThisThis Cycloaddition. Molecules 2021, 26, x. promptsprompts somesome tetraene-like tetraene-like character character of of the the compound, compound, in particularin particular its abilityits ability to enter to enter into Academic Editor: Ionel Mangalagiu https://doi.org/10.3390/xxxxx cycloadditioninto cycloaddition reactions. reactions.

Received: 17 March 2021 Academic Editor: Ionel Mangalagiu R R' Accepted: 30 March 2021 Received: 17 March 2021 Published: 3 April 2021 Accepted: 30 March 2021 N Published: 3 April 2021 8 H Publisher’s Note: MDPI stays neutral 1 H R' C1 withPublisher’s regard toNote: jurisdictional MDPI stays claims neu- in R N publishedtral with mapsregard and to institutional jurisdictional afﬁl- N iations. 3 claims in published maps and institu- 5 A tional affiliations. N R R' H B H R' C2 Copyright: © 2021 by the authors. R R' R LicenseeCopyright: MDPI, © 2021 Basel, by the Switzerland. authors. ThisSubmitted article for is anposs openible accessopen access article SchemeScheme 1.1. IndolizinesIndolizines ((A)A) inin [8+2][8+2] cycloadditioncycloaddition reactionreaction formingforming cycl[3.2.2]azinescycl[3.2.2]azines ( B(B).). The The reaction reaction may proceed with alkynes or alkenes via dihydro- (C1) or tetrahydro- (C2) cyclazines. distributedpublication under under the the terms terms and con- and may proceed with alkynes or alkenes via dihydro- (C1) or tetrahydro- (C2) cyclazines. conditionsditions of the of theCreative Creative Commons Commons At- Attributiontribution (CC (CC BY) BY) license license (http://crea- (https:// IndolizineIndolizine isis usuallyusually regarded regarded as as the theπ -excessiveπ-excessive heterocycle heterocycle with with the the highest highest electron elec- creativecommons.org/licenses/by/tivecommons.org/licenses/by/4.0/). populationtron population of the of carbonthe carbon atom atom C-3, C-3, and and the the major major part part of of the the chemistry chemistry of of indolizinesindolizines 4.0/). is simple electrophilic addition and substitution at this position. Cycloaddition of various

Molecules 2021, 26, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/molecules Molecules 2021, 26, 2050. https://doi.org/10.3390/molecules26072050 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 2050 2 of 34 Molecules 2021, 26, x FOR PEER REVIEW 2 of 34 Molecules 2021, 26, x FOR PEER REVIEW 2 of 34

is simple electrophilic addition and substitution at this position. Cycloaddition of var- iousdienophiles dienophiles (alkenes (alkenes and andacetylenes) acetylenes) to toindolizines indolizines leading leading to to derivatives derivatives of thethe cycl[3.2.2]azinecycl[3.2.2]azinedienophiles (alkenes ((BB,, SchemeScheme and1 )1)acetylenes) is is well-known. well-known. to indolizines TheThe mechanismmechanism leading ofof thesetothese derivatives reactionsreactions isofis fre- fre-the quentlyquentlycycl[3.2.2]azine regardedregarded (B asas, Scheme aa rarerare example example1) is well-known. ofof [8+2][8+2] cycloaddition,cycloaddition, The mechanism wherewhere of these thethe tetraene tetraenereactions carboncarbon is fre- frameworkframeworkquently regarded ofof thethe indolizineindolizine as a rare bicyclebicycleexample playsplays of [8+2thethe role]role cycloaddition, ofof anan 88 ππ-electron-electron where fragment.fragment. the tetraene InIn general,general, carbon thisthisframework processprocess may ofmay the be be indolizine either either one-step one-step bicycle (concerted) (concertedplays the orrole) or involve ofinvolve an 8 zwitterionic π zwitterionic-electron fragment. (and (and even even In biradical) general, biradi- intermediates,cal)this intermediates, process may and be thereand either there is yet one-step is no yet experimental no (concerted experimental evidence) or evidenceinvolve for zwitterionic the for naturethe nature of (and the of process.theeven process. biradical) Cyclazineintermediates,Cyclazine ((BB)) isisand anan there interestinginteresting is yet no 1212 πexperimeπ-electronic-electronicntal systemsystem evidence thatthat for breaksbreaks the nature thethe canonscanons of the process. ofof aro-aromaticity.maticity.Cyclazine According (B) is to to an X-ray X-ray interesting data data the the 12 structuresπ structures-electronic B1B1 andsystemand B2B2 are thatare not breaks not correct correct the (Scheme canons (Scheme 2),of and2aro-), andthematicity. structure the structure According rather rather has to X-ray hasa peripheral a data peripheral the delocalization structures delocalization B1 andof aromatic ofB2 aromatic are not 10 correct π 10-electronπ-electron (Scheme system system 2), andB3. B3Therefore,the. Therefore, structure cyclazine rather cyclazine hasresembles resemblesa peripheral the thefamous delocalization famous spinning spinning of toy aromatic toy B4B4 wherewhere 10 πthe-electron the handle handle system (which (which B3 is. isnotTherefore, not rotated) rotated) cyclazine corresponds corresponds resembles to nitrogen to nitrogen the famouslone lone pair. spinning pair. Hence, Hence, thetoy structure B4 the where structure has the a hassymmetryhandle a symmetry (which plane, is plane,andnot rotated)this and influences this corresponds inﬂuences the number to the nitrogen number of positional lone of positional pair. isomers, Hence, isomers, saythe structurethe say number the has number of a symmetryaza-of and azabenzo- plane, and benzo-derivativesderivativesand this influences possible possible thefor numbercyclazine for cyclazine of (Scheme positional (Scheme 3). isomers,3). say the number of aza- and benzoderivatives possible for cyclazine (Scheme 3).

SchemeScheme 2.2. DifferentDifferent imagesimages ofof thethe structurestructure ofof cyclazine.cyclazine. Scheme 2. Different images of the structure of cyclazine.

N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N

Scheme 3. Possible benzo- aza- and benzoazacyclazines discussed in this review. SchemeScheme 3. 3.Possible Possible benzobenzo- aza- aza- and and benzoazacyclazines benzoazacyclazines discussed discussed in in this this review. review. Cyclazins and their hetero/benzo derivatives are important from a practical viewpoint.CyclazinsCyclazins They are and fluorescentand their their hetero/benzo hetero/benzo compounds derivatives andderivati haveves excellent are are important important prospects from from ain practical organic a practical viewpoint.electronics view- They[2–8].point. are On They fluorescent the are other fluorescent hand, compounds biological compounds and haveactivity and excellent have was excellentfound prospects in prospects cyclazines, in organic in andorganic electronics their electronics applica- [2–8]. Ontions[2–8]. the as On other estrogens the hand, other and biological hand, anti-inflammato biological activity activity wasry compounds found was in found cyclazines, are inwell cyclazines, known and their [9–11]. and applications their applica- as estrogenstionsCyclazine as estrogens and anti-inflammatory was and first anti-inflammato obtained compounds from ryindolizine compounds are well by knownBoekelheide are well [9 –known11 ].60 years [9–11]. ago. This author CyclazinewasCyclazine the first was was who first first postulated obtained obtained from thefrom indolizine[8+2] indolizine mechanism. by by Boekelheide Boekelheide After this 60 time years60 years the ago. [8+2] ago. This reactionThis author au- was the first who postulated the [8+2] mechanism. After this time the [8+2] reaction was re- wasthor reviewedwas the first several who times. postulated The first the review[8+2] mechanism. by Acheson After appeared this time in 1963the [8+2] [12] andreaction the viewed several times. The first review by Acheson appeared in 1963 [12] and the next one by nextwas reviewedone by Taurins several intimes. 1977 The [13]. first Several review reviews by Acheson were appearedwritten on in the1963 chemistry [12] and theof Taurins in 1977 [13]. Several reviews were written on the chemistry of cyclazines [1,14–19]. cyclazinesnext one by[1,14–19]. Taurins In inthe 1977 reviews [13]. of Several Nair and reviews Abhilash were [20,21] written devoted on theto [8+2] chemistry cycload- of In the reviews of Nair and Abhilash [20,21] devoted to [8+2] cycloaddition reactions, only ditioncyclazines reactions, [1,14–19]. only Ina limitedthe reviews number of Nair of indolizine and Abhilash reactions [20,21] was devoted mentioned. to [8+2] cycload- a limited number of indolizine reactions was mentioned. ditionTherefore, reactions, this only review a limited may number be considered of indolizine as the reactionsfirst and comprehensivewas mentioned. review on the [8+2]Therefore, cycloaddition this review reactions may betweenbe considered aza/benzo as the indolizines first and comprehensiveand acetylenes leadingreview onto cyclazines.the [8+2] cycloaddition reactions between aza/benzo indolizines and acetylenes leading to cyclazines.

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2. Cyclazines from Indolizines via [8+2] Catalytic Cycloaddition The first cycloaddition to indolizine (entry 1 in Table 1) was observed by Boekelheide in 1959 [22] (Scheme 4) and later to 2 [23] by using DMAD and heating in toluene in presence of Pd-C. Recently reaction of 3 was reported with MnO2 as oxidant [4]. Boekelheide was the first who made the reaction of 4 with non-symmetric alkyne [24] and performed cycloaddition with DMAD to 2-Ph-indolizine 5 [25]; this reaction was repeated recently with 8a,b [26]. 2-Methylindolizine 6 was involved in the reaction with DMAD in 1965 [27], and the same reaction was done for 8-R-indolizines 7a–c [28]. Indolizines 9a–c obtained by desulfurization of 2-MeS derivatives were converted to Molecules 2021, 26, 2050 3 of 34 cyclazines [29]. First indolizine 10 substituted by functional groups was involved in cyclization with DMAD in 1974 [30]. Later, this methodology was used to construct cyclophanes by applying 2-MeS-3-CONH2 substituted structures 11a,b [31,32]. Later 2-MeS-3- COORTherefore, derivatives this reviewwere hydrolyzed may be considered and decarboxylated as the first and to comprehensive 12a–c and converted review on to thecyclazines [8+2] cycloaddition [29]. A similar reactions methodology between was aza/benzo used to indolizines construct cyclazine and acetylenes from 2-MeS-7- leading toNMe cyclazines.2-indolizine 13b: desulfurization gave 7-NMe2 derivative 13a and the addition of DMAD gave corresponding cyclazine [2]. 2. CyclazinesFluoro-substituted from Indolizines indolizines via [8+2] are seldom Catalytic [33] Cycloaddition but 1-fluoro derivatives 14a,b under- wentThe cycloaddition first cycloaddition in oxidative to indolizine condition (entry in1 presencein Table1 )of was Cu(II) observed salts by[34]. Boekelheide One more inex- 1959ample [22 ]to (Scheme introduce4) and functionality later to 2 [ 23to] cyclazine by using DMADis catalytic and heatingcycloaddition in toluene of 6,8-diacyl in presence in- ofdolizine Pd-C. Recently17 [35]. In reaction our recent of work,3 was we reported proved with that MAC MnO2 couldas oxidant react with [4]. 2-t-Bu Boekelheide indoliz- wasine the18 giving first who cyclazine made the in reactionopen-air of[36].4 with One non-symmetric featured reaction alkyne was[ 24cycloaddition] and performed of in- cycloadditiondolizine 19 with with Mes DMAD2B-substituted to 2-Ph-indolizine acetylene [37].5 [25 2-Styr]; thisyl reaction indolizine was reacted repeated with recently DMAD withand 8aMAC,b [26 without]. 2-Methylindolizine a catalyst [38].6 Bigwas series involved of cyclazines in the reaction (though with without DMAD the in yields) 1965 [27 was], andsynthesized the same and reaction described was done as estrogens for 8-R-indolizines [9,10]. 7a–c [28].

SchemeScheme 4. 4.Symthesis Symthesis of of cyclazines cyclazines from from indolizines indolizines (Table (Table1). 1).

Table 1. Substituents, reactionIndolizines conditions and9a– cyieldsobtained of reacti by desulfurizationons of indolizines of with 2-MeS subs derivativestituted acetylenes were convertedgiving cyclazines (Scheme 4). to cyclazines [29]. First indolizine 10 substituted by functional groups was involved in N R/R’ R1 cyclization R2 with R6 DMAD in R7 1974 [30]. R8 Later, this Cat/Solv/T°/Time methodology was usedYield to % construct Ref. cyclophanes by applying 2-MeS-3-CONH substituted structures 11a,b [31,32]. Later 2- 1 E/E a H H H H H 2 Pd-C/MePh/Δ 50–66 [22] MeS-3-COOR derivatives were hydrolyzed and decarboxylated to 12a–c and converted 2 E/E H H H H H Pd-C/MePh/Δ/24 h 68 [23] to cyclazines [29]. A similar methodology was used to construct cyclazine from 2-MeS- 3 E/E H H H H H MnO2/MePh/Δ/16 h 55 [4] 7-NMe2-indolizine 13b: desulfurization gave 7-NMe2 derivative 13a and the addition of 4 E/H H DMAD H gave corresponding H H cyclazine H [2 ]. Pd-C/MePh/Δ/24 h 11 [24] 5 E/E H PhFluoro-substituted H indolizines H are H seldom [ Pd-C/MePh/33] but 1-ﬂuoroΔ/20 derivatives h 2814a ,b under- [25] 6 E/E H went Me cycloaddition H in oxidative H condition H in presence Pd-C/MePh/ of Cu(II) saltsΔ [34]. One more60 example[27] 7a E/E H to introduceH functionality H to H cyclazine Me is catalytic Pd-C/MePh/ cycloadditionΔ/1.5 ofh 6,8-diacyl 53 indolizine [28] 7b E/E H 17 H[35 ]. In our recent H work, H we proved Pr that MAC Pd-C/MePh/ could reactΔ/1.5 with h 2-t-Bu 53indolizine [28]18 7c E/E H giving H cyclazine H in open-air [H36 ]. One Ph featured reaction Pd-C/MePh/ was cycloadditionΔ/1.5 h of 53 indolizine [28]19 8a E/E H with Ph Mes2B-substituted H acetylene H [37]. H 2-Styryl indolizine Pd-C/MePh/ reactedΔ with DMAD39 and MAC[26] 8b E/E H p-tBuPhwithout a catalyst H [38]. Big series H of cyclazines H (though Pd-C/MePh/ without theΔ yields) was75 synthesized [26] 9a E/E H and H described as H estrogens [9 H,10 ]. H Pd-C/MePh/Δ/100 h 33 [29] 9b E/E H H H H Me Pd-C/MePh/D/100 h 34 [29] Table 1. Substituents, reaction conditions and yields of reactions of indolizines with substituted acetylenes giving cyclazines 9c E/E H H Me H Me Pd-C/MePh/Δ/100 h 25 [29] (Scheme4). 10 E/E CONH2 MeS H H H Pd-C/MePh/Δ/24 h 70 [30] ◦ N11a R/R’E/H CONH R12 MeS R2 R6 H R7 H HR8 Pd-C/MePh/ Cat/Solv/T /TimeΔ/100 h Yield 45 % Ref. [31] 1 E/E a H H H H H Pd-C/MePh/∆ 50–66 [22] 2 E/E H H H H H Pd-C/MePh/∆/24 h 68 [23] 3 E/E H H H H H MnO2/MePh/∆/16 h 55 [4] 4 E/H H H H H H Pd-C/MePh/∆/24 h 11 [24] 5 E/E H Ph H H H Pd-C/MePh/∆/20 h 28 [25] 6 E/E H Me H H H Pd-C/MePh/∆ 60 [27] 7a E/E H H H H Me Pd-C/MePh/∆/1.5 h 53 [28] 7b E/E H H H H Pr Pd-C/MePh/∆/1.5 h 53 [28] 7c E/E H H H H Ph Pd-C/MePh/∆/1.5 h 53 [28] 8a E/E H Ph H H H Pd-C/MePh/∆ 39 [26] 8b E/E H p-tBuPh H H H Pd-C/MePh/∆ 75 [26] 9a E/E H H H H H Pd-C/MePh/∆/100 h 33 [29] 9b E/E H H H H Me Pd-C/MePh/D/100 h 34 [29] Molecules 2021, 26, 2050 4 of 34

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Table 1. Cont.

◦ N11b R/R’E/H CONH R12 MeS R2 HR6 Me R7 H R8 Pd-C/MePh/ Cat/Solv/T Δ/Time/100 h Yield 48 % Ref. [31] 11b E/H CONH2 MeS H Me H Pd-C/MePh/Δ/100 h 48 [31] 9c12a E/EE/E HH MeS H MeH H H H Me Pd-C/MePh/∆Δ/100 h 25 38 [29 [29]] 10 E/E CONH MeS H H H Pd-C/MePh/∆/24 h 70 [30] 12b E/E H 2 MeS H H Me Pd-C/MePh/Δ/100 h 40 [29] 11a12c E/HE/E CONHH 2 MeSMeS Me H H H Me H Pd-C/MePh/∆Δ/100 h 45 49 [31 [29]] 11b12c E/HE/E CONHH 2 MeSMeS Me H Me H Me H Pd-C/MePh/∆Δ/100/100 h 48 49 [31 [29]] 13a E/E H H H NMe2 H Pd-C/MePh/Δ 32 [2] 12a13a E/EE/E HH MeS H H H NMe H2 H H Pd-C/MePh/ Pd-C/MePh/∆/100Δ h 3832 [29[2]] 12b13b E/EE/E HH MeS MeS H H NMe H2 H Me Pd-C/MePh/ Pd-C/MePh/∆/100Δ h 4017 [29[2]] 13b E/E H MeS H NMe2 H Pd-C/MePh/Δ 17 [2] 12c E/Eb H MeS Me H Me Pd-C/MePh/∆/100 h 49 [29] 14a E’/E’ b F p-Brh H H H Cu(OAc)2/PhMe/Δ/5 h 63 [34] 13a14a E/EE’/E’ HF p-Brh H H H NMe H HH Cu(OAc) Pd-C/MePh/2/PhMe/∆Δ/5 h 32 63 [ [34]2] 14b E’/E’ F p-MeOPh H H 2 H Cu(OAc)2/PhMe/Δ/8 h 70 [34] 13b14b E/EE’/E’ HF p-MeOPh MeS H H NMe H HH Cu(OAc) Pd-C/MePh/2/PhMe/∆Δ/8 h 17 70 [ [34]2] 2 c 15 E/Hb E Me H H H Pd-C/PhH/Δ/24 h NG c [39] 14a15 E’/E’E/H FE p-Brh Me H H H H H H Cu(OAc) Pd-C/PhH/2/PhMe/Δ/24∆ /5h h NG63 [34[39]] 16a E/H 2-Py Me H H H No/NO2Ph/Δ/20 h 43 [40] 14b16a E’/E’E/H 2-Py F p-MeOPh Me H H H H H H Cu(OAc) No/NO2/PhMe/2Ph/Δ/20∆/8 h h 70 43 [34 [40]] c 1516b E/HE/E 2-Py E Me Me H H H H H H No/NOPd-C/PhH/2Ph/∆Δ/24/20 h NG 47 [39 [40]] 16b E/E 2-Py Me H H H No/NO2Ph/Δ/20 h 47 [40] 16a E/H 2-Py Me H H H No/NO2Ph/∆/20 h 43 [40] 17 E/E H Me o-OHPhCO H COMe Pd-C/MePh/Δ/16 h 54 [35] 16b E/E 2-Py Me H H H No/NO2Ph/∆/20 h 47 [40] 18 E/H H t-Bu H H H O2/MePh/Δ/4 h 79 [36] 1718 E/EE/H HH t-Bu Me o-OHPhCO H H H COMe H Pd-C/MePh/ O2/MePh/Δ∆/4/16 h h 54 79 [35 [36]] 18 E/H H t-Bu H H H O(1)/MePh/ MePh/Δ∆/3/4 d h 79 [36] 19 Me2B/H H H H H H (1)2 MePh/Δ/3 d 55 [37] 19 Me2B/H H H H H H 55 [37] 19 Me2B/H H H H H H (1) MePh/(2)∆ DDQ/3 d (2) DDQ 55 [37] 20a20a E/EE/E HH Styryl Styryl H H H H H H No/PhMe/50oo/31 h 44 44 [38 [38]] 20a E/E H Styryl H H H No/PhMe/50oo/31 h 44 [38] 20b E/H H Styryl H H H No/PhMe/20 o/120 h 64 [38] 20b E/H H Styryl H H H No/PhMe/20o/120 h 64 [38] 20b E/H H Styryl a H b H c H No/PhMe/20 /120 h 64 [38] a:: E—CO E—CO22Me, b:: E’E’ = = CO CO2Et,2Et, :c NG—not: NG—not given. given. a: E—CO2Me, b: E’ = CO2Et, c: NG—not given. 1-Methoxycarbonyl indolizine 15 (Table1) was converted to cyclazine in order to 1-Methoxycarbonyl indolizine 15 (Table(Table 1)1) waswas convertedconverted toto cyclazinecyclazine inin orderorder toto make cyclophane [39], but this methodology failed. Finally, cyclazines 21c,d were obtained make cyclophane [39], but this methodology failed. Finally, cyclazines 21c,,d werewere ob-ob- from bis-indolizinylethanes 21a,b (R = Me, t-Bu) and further converted to cyclophanes [39], tained from bis-indolizinylethanes 21a,,b (R(R == Me,Me, t-Bu)t-Bu) andand furtherfurther convertedconverted toto cycloph-cycloph- Scheme5. anes [39], Scheme 5.

Scheme 5. Synthesis of bis-cyclazinylethanes from bis-indolizinylethanes. SchemeScheme 5. 5.Synthesis Synthesis of of bis-cyclazinylethanes bis-cyclazinylethanes from from bis-indolizinylethanes. bis-indolizinylethanes.

1-(2-Pyridyl)indolizine1-(2-Pyridyl)indolizine in in reaction reaction with with acetylenes acetylenes16a 16a,b,,formedb formedformed cyclazine cyclazinecyclazine [40 [40],[40],], Table TableTable1. The1. The product product was was converted converted to to indolizino-cyclazine indolizino-cyclazine16c 16c, and,, andand DMAD DMADDMAD was waswas added addedadded for forfor the thethe secondsecond time time giving giving bi-cyclazine bi-cyclazine16d 16d(20 (20(20 h inhh inin boiling boilingboiling xylene xylenexylene without withoutwithout catalyst) catalyst)catalyst) with withwith a yield aa yieldyield of 30%,of 30%, Scheme Scheme6. 6.

Scheme 6. i N-bromsuccinimide. 6h; ii K2CO3. Scheme 6. i N-bromsuccinimide. 6h; ii K2CO3. Scheme 6. i N-bromsuccinimide. 6 h; ii K2CO3.

Analogous structure bearing 2-CO2Et group 22a [41] was converted to condensed in- AnalogousAnalogous structurestructure bearingbearing 2-CO 2EtEt group group 22a22a [41][41 ]was was converted converted to to condensed condensed indolizino-cyclazinone structure 22b. from2 which cyclazino-cyclazinone 22c was obtained indolizino-cyclazinonedolizino-cyclazinone structure structure 22b22b.. from from which cyclazino-cyclazinonecyclazino-cyclazinone 22c22cwas was obtained obtained with the yield 73% (Pd/C, NO2Ph, 20 h), Scheme 7. withwith the the yield yield 73% 73% (Pd/C, (Pd/C, NONO22Ph, 20 h), Scheme7 7..

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SchemeSchemeScheme 7. 7.7.Synthesis SynthesisSynthesis of ofof cyclazino-cyclazinone. cyclcyclazino-cyclazinone.azino-cyclazinone.

AAA Japanese JapaneseJapanese group groupgroup made mademade an anan effort efforteffort to toto prepare prepprepareare cyclazines cyclazinescyclazines from fromfrom 1,8-cycloannelated 1,8-cycloannelated1,8-cycloannelated in-in-in- dolizinesdolizinesdolizines 23 2323 [ [42–44]42[42–44]–44] containing containingcontaining propylene propylenepropylene and andand butylene butylebutylenene bridges, bridges,bridges, Scheme SchemeScheme8 ,8,8, Table TableTable2. 2.2. The TheThe majormajormajor ﬁnding findingfinding was waswas the thethe use useuse of ofof DDQ DDQDDQ in inin reaction reactireactionon with withwith dibenzoyl dibenzoyldibenzoyl acetylene acetyleneacetylene (DBZA) (DBZA)(DBZA) under underunder extremelyextremelyextremely mild mildmild conditions. conditions.conditions. FurtherFurtherFurther studiesstudiesstudies ononon oxo-derivativesoxo-derivativesoxo-derivatives 242424 [ [45]45[45]] allowed allowedallowed to toto make makemake cyclazinecyclazinecyclazine bearing bearingbearing (in (in(in 1 11 and andand 8 88 positions) popositions)sitions) oxo-propyl oxo-propyloxo-propyl group. group.group.

SchemeScheme 8.8. SynthesisSynthesis ofof cyclazinescyclazines fromfrom 1,8-cycloannelated1,8-cycloannelated indolizinesindolizines (see(see TableTable 2).2). Scheme 8. Synthesis of cyclazines from 1,8-cycloannelated indolizines (see Table2).

TableTable 2.2. SubstituentsSubstituents andand yieldsyields ofof cycloaddcycloadditionition ofof acetylenesacetylenes toto indolizinesindolizines 2323––2525 annelatedannelated byby aa Tableringring acrossacross 2. Substituents thethe positionspositions and C1C1 yields andand of C-8C-8 cycloaddition (Scheme(Scheme 8).8). of acetylenes to indolizines 23–25 annelated by a ring across the positions C1 and C-8 (Scheme8). NN R/R’R/R’ R8-R1 R8-R1 R2R2 Cat/Solv/T°Cat/Solv/T°//TimeTime YieldYield %% Ref. Ref. ◦ N R/R’ R8-R12 4 R2 Cat/Solv/T /Time Yield % Ref. 23a23a E/HE/H (CH(CH2))4 MeMe Pd-C/PhMe/Pd-C/PhMe/ΔΔ/50/50 hh 75 75 [42] [42] 2 3 23a23b23b E/HE/HE/H (CH(CH(CH2)42))3 MeMe Pd-C/PhMe/Pd-C/PhMe/ Δ∆Δ/50/50 h h 75 75 75 [42] [42] [42] 23b E/H (CH2)32 4 Me Pd-C/PhMe/∆/50 h 75 [42] 23c23c E/EE/E (CH(CH2))4 MeMe Pd-C/PhMe/Pd-C/PhMe/ΔΔ/50/50 hh 85 85 [42] [42] 23c E/E (CH ) Me Pd-C/PhMe/∆/50 h 85 [42] 2 42 3 23d23d E/EE/E (CH(CH2))3 PhPh Pd-C/PhMe/Pd-C/PhMe/ΔΔ/50/50 hh 58 58 [42] [42] 23d E/E (CH2)3 Ph Pd-C/PhMe/∆/50 h 58 [42] 23d E/E (CH2)4 Ph Pd-C/PhMe/Δ/50 h 61 [42] 23d23d E/EE/E (CH(CH2)42)4 Ph Pd-C/PhMe/ Pd-C/PhMe/Δ∆/50 h 61 61 [42] [42] 2 3 23e23e23e E/EE/EE/E (CH(CH(CH2)32))3 MeMe Pd-C/PhMe/Pd-C/PhMe/ Δ∆Δ/50/50 h h 77 77 77 [42] [42] [42] ◦ 24f24f COPh/COPhCOPh/COPh (CH(CH2)42)4 MeMe DDQ/THF/0DDQ/THF/0°/1/1 h 86 86 [42] [42] 24f COPh/COPh (CH2)4 Me DDQ/THF/0°/1◦ h 86 [42] 23g COPh/COPh (CH2)42 4 Ph DDQ/THF/0 /1 h 92 [42] 23g23g COPh/COPhCOPh/COPh (CH(CH2))4 PhPh DDQ/THF/0°/1DDQ/THF/0°/1◦ hh 9292 [42][42] 23h COPh/COPh (CH2)3 Me DDQ/THF/0 /1 h 68 [42] 2 3 23h COPh/COPh (CH2 )3 Me DDQ/THF/0°/1◦ h 68 [42] 23i23h COPh/COPhCOPh/COPh (CH(CH2)3 ) MePh DDQ/THF/0°/1 DDQ/THF/0 /1 h h 68 52 [42] [42] 23i COPh/COPh (CH2)3 Ph DDQ/THF/0°/1 h 52 [42] 24a23i COPh/COPhE/E O=C(CH(CH2)32 Ph DDQ/MePh/DDQ/THF/0°/1∆/2 h h 52 92 [42] [45] 2 2 24b24a E/EE/E O=C(CHO=C(CH2)22 )2 PhE’ DDQ/MePh/∆Δ/2/2 h 92 98 [45] [45] 24a E/E O=C(CH ) Ph DDQ/MePh/◦Δ/2 h 92 [45] 25a COPh/COPh CH2-NE’-CH2 2 H DDQ/THF/0 /10 m 66 [46] 24b24b E/EE/E O=C(CHO=C(CH2))2 E’E’ DDQ/MePh/DDQ/MePh/ΔΔ/2/2 hh 98 98 [45] [45] 25b COPh/COPh CH -NE’-(CH ) H DDQ/THF/0◦/10 m 84 [46] 2 2 2 2 2 25a25a COPh/COPhCOPh/COPh CHCH2-NE’-CH-NE’-CH2 HH DDQ/THF/0°/10DDQ/THF/0°/10 mm 66 66 [46] [46] 2 2 2 25b25b COPh/COPhCOPh/COPh CHCH2-NE’-(CH-NE’-(CH2))2 HH DDQ/THF/0°/10 DDQ/THF/0°/10 mm 84 84 [46] [46] Finally, fused indolizines 25 with saturated piperidyl or hexamethyleneimine bridges acrossFinally,Finally, 1,8-positions fusedfused were indolizinesindolizines [46] prepared 2525 withwith and saturatedsaturated involved inpiperidylpiperidyl cycloaddition oror hexamethyleneiminehexamethyleneimine with DBZA giving expectedbridgesbridges acrossacross cyclazines, 1,8-positions1,8-positions Scheme were9were. Table [46][46]2. preparedprepared However, andand an involved attemptinvolved to inin perform cycloadditioncycloaddition similar withwith reaction DBZADBZA with DMAD caused cyclazine formation with unsaturated azepine ring. givinggiving expectedexpected cyclazines,cyclazines, SchemeScheme 9.9. TableTable 2.2. However,However, anan attemptattempt toto performperform similarsimilar reactionreaction withwith DMADDMAD causedcaused cyclazinecyclazine foformationrmation withwith unsaturatedunsaturated azepineazepine ring.ring.

MoleculesMolecules2021 2021, ,26 26,, 2050 x FOR PEER REVIEW 6 ofof 3434 Molecules 2021, 26, x FOR PEER REVIEW 6 of 34

Scheme 9. Abnormal cycloaddition to 1,8-cycloannelated indolizine combined with dehydrogena- Schemetion.Scheme 9. 9.Abnormal Abnormal cycloaddition cycloaddition to to 1,8-cycloannelated 1,8-cycloannelated indolizine indolizine combined combined with with dehydrogenation. dehydrogenation. NovelNovel reactionreaction conditionsconditions werewere foundfound forfor cycloadditioncycloaddition reaction,reaction, soso thatthat thethe rolerole ofof oxidantoxidantNovel was was played reactionplayed by byconditions O 2Oin2 presencein presence were of foundPd(OAc) of Pd(OAc) for2 cycloaddition[472], [47], Scheme Scheme 10 reaction,. Many 10. Many 1-alkoxycarbonylso that 1-alkoxycar- the role of derivativesbonyloxidant derivatives was (26a played–l) were(26a by– involvedlO) 2were in presence involved in the of reaction inPd(OAc) the withreaction2 [47], acetylenes Scheme with acetylenes of 10. the Many type of1-alkoxycar- ArC the≡ CAr,type TableArCbonyl≡3CAr,. derivatives Table 3. (26a–l) were involved in the reaction with acetylenes of the type ArC≡CAr, Table 3.

Scheme 10. 10 mol % Pd(OAc)2, DMSO, O2 (1 atm), no base. Scheme 10. 10 mol % Pd(OAc)2, DMSO, O2 (1 atm), no base. Scheme 10. 10 mol % Pd(OAc)2, DMSO, O2 (1 atm), no base. Table 3. Substituents and yields of cycloaddition of diarylalkynes to indolizines (Scheme 10). TableTable 3. 3.Substituents Substituents and and yields yields of of cycloaddition cycloaddition of of diarylalkynes diarylalkynes to to indolizines indolizines (Scheme (Scheme 10 10).). N R R’ R1 R2 Yield % Ref. N R R’ R1 R2 Yield % Ref. 26aN PhR Ph R’ E’ R1 E’R2 Yield92 % [47]Ref. 26b26a 4-MePhPh 4-MePh PhPh E’ EE’ E’ HE’ 92 8892 [47[47][47]] 26b 4-MePh4-MePh 4-MePh4-MePh E E H H 88 88 [47][47] 26c26c PhPh PhPh EE EE 9898 [47[47]] 26c Ph Ph E E 98 [47] 26d26d 4-FPh4-FPh 4-FPh4-FPh E E E E 85 85 [47[47]] 26e26d26e 3-BrPh3-BrPh4-FPh 3-BrPh3-BrPh4-FPh E E E E E E 56 56 85 [47[47][47]] 26e26f 4-NO3-BrPhPh 4-MeOPh3-BrPh E E E E 80 (6:1) 56 [47[47]] 26f 4-NO22Ph 4-MeOPh E E 80 (6:1) [47] 26g26f 4-NO22Ph 4-MeOPh Ph E E E E 68 (20:1) 80 (6:1) [47][47] 26g 4-NO2Ph Ph E E 68 (20:1) [47] 26h 4-FPh 4-MeOPh E E 91 (2:1) [47] 26g 4-NO2Ph Ph E E 68 (20:1) [47] 26h26i 4-FPhC≡CPh 4-MeOPh Ph E E E E 41;3991 (2:1) [47[47]] 26h 4-FPh 4-MeOPh E E 91 (2:1) [47] 26i26j C≡CPhPh PhPh CO2nBu E CO2nBu E 7941;39 [47[47]] 26i C≡CPh Ph E E 41;39 [47] 26j26k PhPh PhPh ECO2nBu PhCO2nBu 20 *79 [47 [47]] 26k26j26l PhPh PhPhPh CO2tBuCOE2 nBu HCOPh2nBu 552079 * [47[47]] [47] 26k26l Ph PhPh HE EPh 7020 * [47[47]] 26l Ph Ph CO2tBu H 55 [47] 26m Ph Ph CONMe2 H 76 [47] 26l Ph Ph CO2tBu H 55 [47] 26l26n PhPh PhPh E’H HE 8770 [47[47]] 26l Ph Ph H E 70 [47] 26m26o PhPh PhPh ECONMe2 HH 90 76 [47[47]] 26n26m26p PhPh PhPhPh CNCONMeE’ 2 HHH 5987 76 [47[47][47]] * Not26o determined.26n PhPh PhPh EE’ HH 9087 [47][47] 26p26o PhPh PhPh CNE HH 5990 [47][47] A range of indolizine 27 smoothly underwent visible-light-induced intermolecular Molecules 2021, 26, x FOR PEER REVIEW 26p Ph Ph CN H 59 [47]7 of 34 cyclization with internal alkynes with acceptor group to afford cyclazines in good to excellentA range yields of with indolizine high regioselectivity 27 smoothly underwent [48], Scheme visible-light-induced 11, Table4. intermolecular cyclizationA range with of internalindolizine alkynes 27 smoothly with acceptor underwent group visible-light-induced to afford cyclazines inintermolecular good to ex- cellentcyclization yields with with internal high regioselectivity alkynes with acceptor[48], Scheme group 11, to Table afford 4. cyclazines in good to excellent yields with high regioselectivity [48], Scheme 11, Table 4.

SchemeScheme 11. 11.Bengal Bengal rose rose KI, KI, air, air, DMSO, DMSO, 8 8 h, h, 20 20 W, W, blue blue LED. LED.

Table 4. Substituents and yields of photochemical cycloaddition to indolizines (Scheme 11).

N R’ R” R1 R2 R6 R7 R8 Yield, % Ref. 27a CHO Ph H Ph H H H 87 [48] 27b CHO n-C5H11 H Ph H H H 61 [48] 27c CHO 2-Thienyl H Ph H H H 66 [48] 27d CHO 3-Cl-Ph H Ph H H H 79 [48] 27e CHO 3-Ac-Ph H Ph H H H 58 [48] 27f CHO 4-Me-Ph H Ph H H H 77 [48] 27g CHO 3,4-Me2Ph H Ph H H H 57 [48] 27h CHO 2-Naphtyl H Ph H H H 59 [48] 27i COPh Ph H Ph H H H 58 [48] 27j Ph Ph H Ph H H H 0 [48] 27k CHO Ph H 4-OMe-Ph H H H 70 [48] 27l CHO Ph H 4-F-Ph H H H 81 [48] 27m CHO Ph H 4-NO2-Ph H H H 58 [48] 27n CHO Ph H 4-Br-Ph H H H 64 [48] 27o CHO Ph H 4-CF3-Ph H H H 71 [48] 27 CHO Ph H 2-F-Ph H H H 73 [48] 27p CHO Ph H 3-Me-Ph H H H 63 [48] 27q CHO Ph H 3,4-Cl2-Ph H H H 58 [48] 27r CHO Ph H 2,4-Cl2-Ph H H H 78 [48] 27s CHO Ph H 3,4-(OMe)2-Ph H H H 84 [48] 27t CHO Ph H 1,3-Benzo-dioxolyl-5 H H H 67 [48] 27u CHO Ph H Furyl H H H 62 [48] 27v CHO Ph H 2-Naphtyl H H H 60 [48] 27w CHO Ph E’ H H H H 59 [48] 27x CHO Ph H Ph Et H H 61 [48] 27y CHO Ph H Ph H Me H 73 [48] 27z CHO Ph H Ph H OMe H 70 [48] 27a1 CHO Ph H Ph Me H Me 61 [48] 27b1 E’ H H Ph H H H 88 [48] 27c1 E’ H H Ph H H H 70 [48] 27d1 E’ E’ H Ph H H H 77 [48] 27e1 E’ E’ H Ph H H H 70 [48]

An efficient visible-light-induced intermolecular [8+2] alkenylation–cyclization process was developed for indolizines 28 [49], Scheme 12, Table 5. In this reaction alkene (not alkyne) formed cyclazine derivatives with oxygen as an oxidant via cascade reaction.

Scheme 12. Bengal Rose, TFA, CH2Cl2, O2, 10 h, 20 W blue LED.

Molecules 2021, 26, x FOR PEER REVIEW 7 of 34

Scheme 11. Bengal rose KI, air, DMSO, 8 h, 20 W, blue LED. Molecules 2021, 26, 2050 7 of 34 Table 4. Substituents and yields of photochemical cycloaddition to indolizines (Scheme 11).

N R’ R” R1 R2 R6 R7 R8 Yield, % Ref. Table27a 4. SubstituentsCHO andPh yields of photochemicalH Ph cycloaddition H to indolizinesH H (Scheme87 11). [48] 27b CHO n-C5H11 H Ph H H H 61 [48] N27c R’CHO 2-Thienyl R” R1H Ph R2 H R6 H R7 H R8 Yield, 66 % Ref. [48] 27a27d CHOCHO 3-Cl-Ph Ph HH Ph Ph H HH H H H 79 87 [[48]48] 27b27e CHOCHO n-C3-Ac-Ph5H11 HH Ph Ph H HH H H H 58 61 [[48]48] 27c27f CHOCHO 2-Thienyl4-Me-Ph HH Ph Ph H HH H H H 77 66 [[48]48] 27d CHO 3-Cl-Ph H Ph H H H 79 [48] 27g CHO 3,4-Me2Ph H Ph H H H 57 [48] 27e CHO 3-Ac-Ph H Ph H H H 58 [48] 27h CHO 2-Naphtyl H Ph H H H 59 [48] 27f CHO 4-Me-Ph H Ph H H H 77 [48] 27i COPh Ph H Ph H H H 58 [48] 27g CHO 3,4-Me2Ph H Ph H H H 57 [48] 27h27j CHOPh 2-Naphtyl Ph HH Ph Ph H HH H H H 0 59 [[48]48] 27i27k COPhCHO PhPh HH 4-OMe-Ph Ph H HH H H H 70 58 [[48]48] 27j27l PhCHO PhPh HH 4-F-Ph Ph H HH H H H 81 0 [[48]48] 27k27m CHOCHO PhPh HH 4-NO 4-OMe-Ph2-Ph H HH H H H 58 70 [[48]48] 27l27n CHOCHO PhPh HH 4-Br-Ph 4-F-Ph H HH H H H 64 81 [[48]48] 27m CHO Ph H 4-NO2-Ph H H H 58 [48] 27o CHO Ph H 4-CF3-Ph H H H 71 [48] 27n CHO Ph H 4-Br-Ph H H H 64 [48] 27 CHO Ph H 2-F-Ph H H H 73 [48] 27o CHO Ph H 4-CF3-Ph H H H 71 [48] 2727p CHOCHO PhPh HH 3-Me-Ph 2-F-Ph H HH H H H 63 73 [[48]48] 27p27q CHOCHO PhPh HH 3,4-Cl 3-Me-Ph2-Ph H HH H H H 58 63 [[48]48] 27q27r CHOCHO PhPh HH 2,4-Cl 3,4-Cl2-Ph2-Ph H HH H H H 78 58 [[48]48] 27r27s CHOCHO PhPh HH 3,4-(OMe) 2,4-Cl2-Ph2-Ph H HH H H H 84 78 [ [48]48] 27s27t CHOCHO PhPh HH 1,3-Benzo-dioxolyl-5 3,4-(OMe)2-Ph H HH H H H 67 84 [[48]48] 27t 27u CHOCHO PhPh HH 1,3-Benzo-dioxolyl-5 Furyl H HH H H H 62 67 [[48]48] 27u CHO Ph H Furyl H H H 62 [48] 27v CHO Ph H 2-Naphtyl H H H 60 [48] 27v CHO Ph H 2-Naphtyl H H H 60 [48] 27w27w CHOCHO PhPh E’E’ H H H HH H H H 59 59 [[48]48] 27x27x CHOCHO PhPh HH Ph Ph Et EtH H H H 61 61 [[48]48] 27y27y CHOCHO PhPh HH Ph Ph H HMe Me H H 73 73 [[48]48] 27z27z CHOCHO PhPh HH Ph Ph H H OMeOMe HH 70 70 [[48]48] 27a127a1 CHOCHO PhPh HH Ph Ph Me Me H H Me Me 61 61 [[48]48] 27b127b1 E’E’ HH HH Ph Ph H HH H H H 88 88 [[48]48] 27c1 E’ H H Ph H H H 70 [48] 27c1 E’ H H Ph H H H 70 [48] 27d1 E’ E’ H Ph H H H 77 [48] 27e127d1 E’E’ E’E’ HH Ph Ph H HH H H H 77 70 [[48]48] 27e1 E’ E’ H Ph H H H 70 [48]

AnAn efﬁcient efficient visible-light-induced visible-light-induced intermolecular intermolecular [8+2] [8+2] alkenylation–cyclization alkenylation–cyclization pro- pro- cesscess was was developed developed for for indolizines indolizines28 28[ 49[49],], Scheme Scheme 12 12,, Table Table5. 5. In In this this reaction reaction alkene alkene (not (not alkyne)alkyne) formed formed cyclazine cyclazine derivatives derivatives with with oxygen oxygen as as an an oxidant oxidant via via cascade cascade reaction. reaction.

Scheme 12. Bengal Rose, TFA, CH2Cl2, O2, 10 h, 20 W blue LED. Scheme 12. Bengal Rose, TFA, CH2Cl2,O2, 10 h, 20 W blue LED.

Table 5. Substituents and yields of oxidative cycloaddition of alkenes to indolizines (Scheme 12).

N R R2 R5 R6 R7 R8 Yield, % Ref. 28a E Ph H H H H 80 [49] 28b CO2nBu Ph H H H H 69 [49] 28c CO2CH2CHOH Ph H H H H 68 [49] 28d CONHt-Bu Ph H H H H 67 [49] 28e 2-Py Ph H H H H 65 [49] 28f E Ph Me H H H 78 [49] 28g 2-Py Ph H H H Me 69 [49] 28h E Ph H H Me H 77 [49] Molecules 2021, 26, 2050 28i E Ph H Et H H 70 8[49] of 34 28j E 4-FPh H H H H 75 [49] 28k E 4-BrPh H H H H 78 [49] 28l E 4-MePh H H H H 74 [49] Table28m 5. Cont. E 4-MeOPh H H H H 71 [49] 28n E 3-FPh H H H H 75 [49] N R R2 R5 R6 R7 R8 Yield, % Ref. 28o E 3-ClPh H H H H 66 [49] 28n E 3-FPh H H H H 75 [49] 28p E 3-BrPh H H H H 70 [49] 28o E 3-ClPh H H H H 66 [49] 28q28p EE 3-BrPh3-MePh HH HH HH HH 7071 [49[49]] 2828qr 2-PyE 3-MePh3-MePh HH HH HH HH 7166 [49[49]] 28s28r 2-PyE 3-MePh3-MeOPh HH HH HH HH 6668 [49[49]] 28s E 3-MeOPh H H H H 68 [49] 28t28t EE 3-FPh3-FPh HH HH HH HH 6565 [49[49]] 28u28u EE 3,4-Cl3,4-Cl2Ph2Ph HH H H H H H H 70 70 [49 [49]] 28v28v EE 3,4-(MeO)3,4-(MeO)2Ph2Ph HH H H H H H H 66 66 [49 [49]] 28x 28x EE 2-Thienyl2-Thienyl HH HH HH HH 6969 [49[49]]

AnnulationsAnnulations ofof 1-cyanoIndolizine1-cyanoIndolizine withwith unsaturatedunsaturated carboxyliccarboxylic acidsacids 29a29a––ff waswas ob-ob- servedserved duringduring thethe catalysis catalysis with with Pd(OAc) Pd(OAc)22 [[50],50], viavia similarsimilar cascadecascade reactionreaction SchemeScheme 13 13,, TableTable6. 6.

Scheme 13. 10 mol % Pd(OAc)2, 1 eq benzoquinone, O2, 2 eq KOAc, DMF. 120°,◦ 12 h. Scheme 13. 10 mol % Pd(OAc)2, 1 eq benzoquinone, O2, 2 eq KOAc, DMF. 120 , 12 h. Table 6. Yields of catalytic cycloaddition of acrylates (Scheme 13) to 1-cyanoindolizine. Table 6. Yields of catalytic cycloaddition of acrylates (Scheme 13) to 1-cyanoindolizine. N R Yield, % Ref. N R Yield, % Ref. 29a Me 39 [50] 29a 29b MePh 3952 [50] [50] 29b Ph 52 [50] 29c 29c 4-Cl-Ph4-Cl-Ph 4646 [50] [50] 29e 29e 4-OMePh4-OMePh 5959 [50] [50] 29f 29f 1-Naphtyl1-Naphtyl 4545 [50] [50]

3.3. Non-CatalyticNon-Catalytic Cycloaddition Cycloaddition to to 3- 3- or or 5-Substituted 5-Substituted Indolizines Indolizines IfIf a a leaving leaving group group X X is is located located at at position position 3 or3 or 5 of5 of indolizine indolizine ring, ring, cycloaddition cycloaddition reac- re- Molecules 2021, 26, x FOR PEER REVIEWtionaction does does not requirenot require a catalyst/oxidant a catalyst/oxidant for dehydrogenation, for dehydrogenation, because because the dihydrocyclazine the dihydrocy-9 of 34

intermediateclazine intermediate can lose can HX, lose Scheme HX, 14Scheme. 14.

Scheme 14. Cycloaddition of indolizines with 3(5)-leaving groups. Scheme 14. Cycloaddition of indolizines with 3(5)-leaving groups.

Such groups X can be -OR or -OCOR. -SR, -NR2 or -NR-NR2, halogen and some oth- Such groups X can be -OR or -OCOR. -SR, -NR2 or -NR-NR2, halogen and some others, Schemeers, Scheme 15. 15.

Scheme 15. Examples of 3(5)-substituted indolizines involved in cycloaddition (see Table 7).

Table 7. Substituents, conditions and yields in cycloaddition of acetylenes to 3(5)-substituted indolizines giving cyclazines (Scheme 15).

N R/R’ R3/R5 R1 R2 R6 R7 R8 Cat/Solv/T°/Time Yield % Ref. 30a E/H OCOMe/H H H H H H No/Ac2O/Δ/0.5 h 86 [51] 30b E/H OCOEt/H H H H H H No/Ac2O/Δ/0.5 h 100 [51] 30c E/H OCOMe/H Ph H H H H No/Ac2O/Δ/0.5 h 90 [51] 30d E/H OCOMe/H CH2E’ E’ H H H No/Ac2O/Δ/0.5 h 100 [51] 31 E/E i-PrS/H i-PrS i-PrS H H H No/PhMe/Δ/40 h 96 [52] 32a E/E NE’NHE’/H Ph H H H H No/PhH/Δ/5 h 5.6 [53] 32b E/E NE’NHE’/H H H H H H No/PhH/Δ/5 h 32 [53] 32c E/E NE’NHE’/H NE’NHE’ H H H H No/PhH/Δ/5 h 66 [53] 33a E/E H/OTms H H OMe OMe OH No/PhMe/Δ/23 h 56 [54] 33b E/E H/OTms H H OMe Ph OH No/PhMe/Δ/23 h 79 [54] 33c E/E H/OTms H H OMe n-Bu OH No/PhMe/Δ/23 h 52 [54] 33d E/E H/OTms H H OMe n-BuC≡C OH No/PhMe/Δ/23 h 67 [54] 33e E/E H/OTms H H OMe PhC≡C OH No/PhMe/Δ/23 h 66 [54] 33f E/E H/OTms H H n-Bu n-Bu OH No/PhMe/Δ/23 h 53 [54] 34 E/E H/Morph H p-NO2Ph H H H No/PhH/Δ/16 h 82 [55] 35 E/E H/Br Me t-Bu H H H No/PhMe/80°/2 h 53 [56]

Thus, 3-acyloxy indolizines 30a–d were converted to cyclazines with excellent yield [51]. Tris-1,2,3-(iso-propylthio)indolizine 31 also underwent such cycloaddition [52]. 3- Hydrazine-substituted derivatives 32a–c lost the attaching group forming cyclazines [53].

Molecules 2021, 26, 2050 9 of 34

Molecules 2021, 26, x FOR PEER REVIEW 9 of 34 Table 7. Substituents, conditions and yields in cycloaddition of acetylenes to 3(5)-substituted indolizines giving cyclazines (Scheme 15).

N R/R’ R3/R5 R1 R2 R6 R7 R8 Cat/Solv/T◦/Time Yield % Ref.

30a E/H OCOMe/H H H H H H No/Ac2O/∆/0.5 h 86 [51] 30b E/H OCOEt/H H H H H H No/Ac2O/∆/0.5 h 100 [51] 30c E/H OCOMe/H Ph H H H H No/Ac2O/∆/0.5 h 90 [51] 30d E/H OCOMe/H CH2E’ E’ H H H No/Ac2O/∆/0.5 h 100 [51] 31 E/E i-PrS/H i-PrS i-PrS H H H No/PhMe/∆/40 h 96 [52] 32a E/E NE’NHE’/H Ph H H H H No/PhH/∆/5 h 5.6 [53] 32b E/E NE’NHE’/H H H H H H No/PhH/∆/5 h 32 [53] 32c E/E NE’NHE’/H NE’NHE’ H H H H No/PhH/∆/5 h 66 [53] 33a E/E H/OTms H H OMe OMe OH No/PhMe/∆/23 h 56 [54] 33b E/E H/OTms H H OMe Ph OH No/PhMe/∆/23 h 79 [54] 33c E/E H/OTms H H OMe n-Bu OH No/PhMe/∆/23 h 52 [54] 33d E/E H/OTms H H OMe n-BuC≡C OH No/PhMe/ ∆/23 h 67 [54] 33e ≡ E/E H/OTmsScheme H 14. Cycloaddition H of OMeindolizines PhC withC 3(5)-leavingOH No/PhMe/groups. ∆/23 h 66 [54] 33f E/E H/OTms H H n-Bu n-Bu OH No/PhMe/∆/23 h 53 [54] 34 E/E H/Morph H p-NO2Ph H H H No/PhH/∆/16 h 82 [55] 35 E/E H/Br MeSuch groups t-Bu X can be -OR H or -OCOR. H -SR, H-NR2 No/PhMe/80 or -NR-NR2,◦ /2halogen h and 53 some [56 oth-] ers, Scheme 15.

Scheme 15. Examples of 3(5)-substituted indolizines involved in cycloaddition (see Table 7). Scheme 15. Examples of 3(5)-substituted indolizines involved in cycloaddition (see Table7).

Table 7. Substituents, conditionsThus, and yields 3-acyloxy in cycloaddition indolizines of30a acet–ylenesd were to converted 3(5)-substituted to cyclazines indolizines with giving excellent cyclazines yield [51]. (Scheme 15). Tris-1,2,3-(iso-propylthio)indolizine 31 also underwent such cycloaddition [52]. 3-Hydrazine- N R/R’ R3/R5 substituted R1 derivatives R232a –c lost R6 the attaching R7 group R8 formingCat/Solv/T° cyclazines/Time [Yield53]. Quite % Ref. sim- 30a E/H OCOMe/Hilarly behaved H 5-substituted H indolizines. H H After refluxingH No/Ac in aromatic2O/Δ/0.5 h solvents, 86 5-OTms [51] 30b E/H OCOEt/H indolizines H33a –f [54], H 5-morpholyl H 34 [55H] and 5-bromoH No/Ac derivatives2O/Δ/0.5 h35 [56 100]smoothly [51] 30c E/H OCOMe/Hformed the Ph expected cyclazine H structures H in H the absenceH ofNo/Ac catalyst.2O/Δ/0.5 h 90 [51] 30d E/H OCOMe/H CH2E’ E’ H H H No/Ac2O/Δ/0.5 h 100 [51] 31 E/E i-PrS/H 4. Features i-PrS of Cycloadditioni-PrS of 3-CyanoH IndolizinesH H andNo/PhMe/ Their BenzoΔ/40 h Derivatives 96 [52] 32a E/E NE’NHE’/H 3-CN-Indolizines Ph are H the structures H that H lookedH capable No/PhH/ to reactΔ/5 with h acetylenes 5.6 with- [53] 32b E/E NE’NHE’/Hout catalyst H due to probable H loss of H HCN from H intermediate.H No/PhH/ In 1980Δ/5 the h Matsumoto 32 group [53] 32c E/E NE’NHE’/H(together NE’NHE’ with L. Paquet)H reported H the first reaction H ofH 3-CN-inolizines No/PhH/Δ/5 with h DMAD 66 [57], [53] [58]. 33a E/E H/OTms 3-Cyanindolizine H 36a and H its 6,8-dimethylOMe OMe analog OH36b withNo/PhMe/ DMADΔ/23 in h refluxing 56 toluene [54] 33b E/E H/OTms gave expected H cyclazines, H thoughOMe in presencePh of Pd-COH (Scheme No/PhMe/ 16, TableΔ/23 8h). The 79 later group [54] 33c E/E H/OTms of Tominaga H converted H 2-MeS-derivativesOMe n-Bu of 3-CN-indolizines-OH No/PhMe/37a,bΔ/23 hto MeS-cyclazines 52 [54] 33d E/E H/OTms (again in the H presence of H the sameOMe catalyst) n-BuC [59≡C] (SchemeOH 16No/PhMe/, Table8Δ)./23 h 67 [54] 33e E/E H/OTms H H OMe PhC≡C OH No/PhMe/Δ/23 h 66 [54] 33f E/E H/OTms H H n-Bu n-Bu OH No/PhMe/Δ/23 h 53 [54] 34 E/E H/Morph H p-NO2Ph H H H No/PhH/Δ/16 h 82 [55] 35 E/E H/Br Me t-Bu H H H No/PhMe/80°/2 h 53 [56]

Molecules 2021, 26, x FOR PEER REVIEW 10 of 34

Quite similarly behaved 5-substituted indolizines. After refluxing in aromatic solvents, 5- OTms indolizines 33a–f [54], 5-morpholyl 34 [55] and 5-bromo derivatives 35 [56] Quite similarly behaved 5-substituted indolizines. After refluxing in aromatic solvents, 5- smoothly formed the expected cyclazine structures in the absence of catalyst. OTms indolizines 33a–f [54], 5-morpholyl 34 [55] and 5-bromo derivatives 35 [56] smoothly formed the expected cyclazine structures in the absence of catalyst. 4. Features of Cycloaddition of 3-Cyano Indolizines and Their Benzo Derivatives 4. Features3-CN-Indolizines of Cycloaddition are the of structures 3-Cyano that Indolizines looked capable and Their to react Benzo with Derivatives acetylenes without catalyst due to probable loss of HCN from intermediate. In 1980 the Matsumoto group 3-CN-Indolizines are the structures that looked capable to react with acetylenes with- (together with L. Paquet) reported the first reaction of 3-CN-inolizines with DMAD [57], out catalyst due to probable loss of HCN from intermediate. In 1980 the Matsumoto group [58]. 3-Cyanindolizine 36a and its 6,8-dimethyl analog 36b with DMAD in refluxing tolu- (together with L. Paquet) reported the first reaction of 3-CN-inolizines with DMAD [57], ene gave expected cyclazines, though in presence of Pd-C (Scheme 16, Table 8). The later [58]. 3-Cyanindolizine 36a and its 6,8-dimethyl analog 36b with DMAD in refluxing tolu- group of Tominaga converted 2-MeS-derivatives of 3-CN-indolizines-37a,b to MeS- ene gave expected cyclazines, though in presence of Pd-C (Scheme 16, Table 8). The later Molecules 2021, 26, 2050 cyclazines (again in the presence of the same catalyst) [59] (Scheme 16, Table 8). 10 of 34 group of Tominaga converted 2-MeS-derivatives of 3-CN-indolizines-37a,b to MeS- cyclazines (again in the presence of the same catalyst) [59] (Scheme 16, Table 8).

Scheme 16. Cycloaddition to 3-CN-substituted indolizines (see Table 8). Scheme 16. Cycloaddition to 3-CN-substituted indolizines (see Table 8). SchemeTable 8. 16. Substituents,Cycloaddition conditions to 3-CN-substituted and yields in indolizinescycloaddition (see of Table acetylene8). acetylenes to 3-CN-substituted indolizines giving cyclazines (Scheme 16). TableTable 8. 8. Substituents,Substituents, conditions conditions and and yields yields in incycloa cycloadditionddition of acetylene of acetylene acetylenes acetylenes to 3-CN-sub- to 3-CN- substitutedstitutedN R/R’ indolizines indolizines R1 R2giving givingR6 cyclazines cyclazinesR7 (Scheme (SchemeR8 16). 16 ). Cat/Solv/T°/Time Yield % Ref. 36a E/E H H H H H Pd-C/PhH/Δ/24 h 40 [58] N R/R’ R1 R2 R6 R7 R8 Cat/Solv/T°/Time◦ Yield % Ref. 36bN E/E R/R’ H R1 H R2Me R6H R7Me R8 Pd-C/PhH/ Cat/Solv/TΔ/Time/24 h Yield 25% Ref. [58] 36a E/E H H H H H Pd-C/PhH/Δ/24 h 40 [58] 36a37a E/E H HMeS HH HH HH HPd-C/PhH/ Pd-C/PhH/Δ∆/30/24 h h 40 22 [58 [59]] 36b E/E H H Me H Me Pd-C/PhH/Δ/24 h 25 [58] 36b37b E/E H HMeS HMe MeH HMe Me Pd-C/PhH/ Pd-C/PhH/Δ∆/30/24 h h 25 12 [58 [59]] 37a E/EE/E H HMeSMeS H HH HH HPd-C/PhH/ Pd-C/PhH/Δ∆/30/30 h h 22 22 [59 [59]] 38a E/E H H H H H Pd’C/MePh/Δ/24 h 40 [60] 37b E/EE/E H HMeSMeS Me MeH HMe Me Pd-C/PhH/ Pd-C/PhH/Δ∆/30/30 h h 12 12 [59 [59]] 38b E/E H H H Me H Pd’C/MePh/Δ/25–74 h 10-7 [60] 38a E/EE/E H HH HH HH HH H Pd’C/MePh/ Pd’C/MePh/Δ∆/24/24 h h 40 40 [60 [60]] 38b38c E/E H H H H H H PhCH Me2 H H Pd’C/MePh/ Pd’C/MePh/∆Δ/25–74/30 h h 10-7 5 [60 [60]] 38b E/E H H H Me H Pd’C/MePh/Δ/25–74 h 10-7 [60] 38c38d E/E H H H H H H Ph PhCH H2 H Pd’C/MePh/ Pd’C/MePh/Δ∆/215/30 h 5 13 [60 [60]] 38d38c E/EE/E H H H H H H PhCH Ph2 H H Pd’C/MePh/ Pd’C/MePh/Δ∆/30/215 h h 13 5 [60 [60]] 38e E/E H H Me H Me Pd’C/MePh/Δ/77 h 25 [60] 38d38e E/EE/E H H H H H Me Ph H H Me Pd’C/MePh/ Pd’C/MePh/Δ∆/215/77 h h 25 13 [60 [60]] 38f E/E H H H CN H Pd’C/MePh/Δ/260 h 7 [60] 38e38f E/EE/E H HH HMe HH CNMe H Pd’C/MePh/ Pd’C/MePh/Δ∆/77/260 h h 7 25 [60 [60]] 38g E/E H H H E H Pd’C/MePh/Δ/336 h 2 [60] 38g38f E/EE/E H HH HH HCN EH H Pd’C/MePh/ Pd’C/MePh/Δ∆/260/336 h h 2 7 [60 [60]] 38g E/E H H H E H Pd’C/MePh/Δ/336 h 2 [60] TheThe most most dramatic dramatic story story happened happened to to another another adduct adduct of of CN-indolizines CN-indolizines and and DMAD. DMAD. In 1980 the Matsumoto group found that 7-methyl- and 7-benzyl derivatives gave 1:2 ad- In 1980The the most Matsumoto dramatic groupstory happened found that to 7-methyl-another adduct and 7-benzylof CN-indolizines derivatives and gave DMAD. 1:2 duct with proposed structure 39a [58], Scheme 17. Later the same group tested the reaction adductIn 1980 withthe Matsumoto proposed structuregroup found39a that[58], 7-methyl- Scheme 17 and. Later 7-benzyl the samederivatives group gave tested 1:2 the ad- of 3-CN indolizines 38a–g in the presence and absence of a catalyst [60,61], Table 8. Finally, reactionduct with of proposed 3-CN indolizines structure38a 39a–g [58],in the Scheme presence 17. and Later absence the same of a group catalyst tested [60, 61the], reaction Table8. the structure of the 1:2 adduct formed without the catalyst was proved by X-ray, and it Finally,of 3-CN the indolizines structure 38a of– theg in 1:2 the adduct presence formed and absence without of the a catalyst catalyst [60,61], was proved Table by8. Finally, X-ray, was unexpectedly styryl pyrrole 39b [60,61], Scheme 17. Different mechanisms of benzene andthe itstructure was unexpectedly of the 1:2 adduct styryl pyrroleformed 39bwithou[60,t61 the], Scheme catalyst 17 was. Different proved mechanismsby X-ray, and of it ring formation and E-group migration have been proposed. benzenewas unexpectedly ring formation styryl and pyrrole E-group 39b migration[60,61], Scheme have been17. Different proposed. mechanisms of benzene ring formation and E-group migration have been proposed.

Molecules 2021, 26, x FOR PEER REVIEW 11 of 34

SchemeScheme 17. 17.Structure Structure of of 1:2 1:2 adduct adduct of of 3-cyanoindolizine 3-cyanoindolizine and and DMAD. DMAD. Scheme 17. Structure of 1:2 adduct of 3-cyanoindolizine and DMAD. Cyano-derivativeCyano-derivative of of benzo[a]indolizine benzo[a]indolizine is easily is easily available available from from pyridinium-dicyanme pyridinium-dicy- thylideanmethylide and dehydrobenzene. and dehydrobenzene. Matsumoto Matsumoto ﬁrst published first published the results the results of cycloaddition of cycloaddition of dibenzoylacetylene to the structures 40a–d (Scheme 18, Table9)[ 62,63]. Again, the reaction of dibenzoylacetylene to the structures 40a–d (Scheme 18, Table 9) [62,63]. Again, the re- required a catalyst. Tominaga group made this cycloaddition 41 with DMAD [64]. Finally, action required a catalyst. Tominaga group made this cycloaddition 41 with DMAD [64]. this reaction was tested extensively with various acetylenes 42 [65]. Finally, this reaction was tested extensively with various acetylenes 42 [65].

SchemeScheme 18. 18.Cycloaddition Cycloaddition to to 3-CN-substituted 3-CN-substituted benzoindolizines benzoindolizines (see (see Table Table9). 9).

Table 9. Substituents, conditions and yields in cycloaddition of acetylene to 3-CN-substituted benzoindolizines giving benzocyclazines (Scheme 18).

N R/R’ R7 Cat/Solv/T°/Time Yield % Ref. 40a COPh/COPh H Pd-C/PhH/rt/46 h 82 [62,63] 40b COPh/COPh Me Pd-C/PhH/rt/24 h 82 [62] 40c COPh/COPh Ph Pd-C/PhH/rt/24 h 69 [62] 40d COPh/COPh COPh Pd-C/PhH/Δ/5.5 h 59 [62] 41 E/E H Pd-C/PhMe/Δ/20 h 54 [64] 42a E/E H Pd-C/PhMe/Δ/2 h 13 [65] 42b E”/E” a H Pd-C/PhMe/Δ/20 h 14 (R’ = H) [65] 42c Ac/Ac H Pd-C/PhMe/Δ/20 h 8 [65] 42d E/H H Pd-C/PhMe/Δ/34 h NG [65] 42e E/SiMe3 H Pd-C/PhMe/Δ/72 h 11:14 b [65] 42f E/Ph H Pd-C/PhMe/Δ/72 h 52:6 b [65] 42g Ac/Ph H Pd-C/PhMe/Δ/72 h 48:7 b [65] a: E”—CO2tBu; b: regioisomers.

5. Cycloaddition to Benzoindolizines: Synthesis of Benzo Derivatives of Cyclazines Cycloaddition of benzyne (generated differently) to indolizine 43 is the simplest route to benzo derivatives of cyclazine [3], Scheme 19, Table 10. The resulting structures are strongly fluorescent.

Scheme 19. CsF, MeCN, 90°. A—ortho-substituted benzene with SiMe3 and OSO2CF3; B—1-Ami- nobenzotriazole/Pb(OAc)4.

Table 10. Substituents and yields of cycloaddition of benzynes to indolizines (Scheme 19).

N Benzyne R1 R2 R3 R5 R6 R7 R8 Yield, % Ref. 43a A H Ph H H H H H 23 [3] 43b A Me Ph H H H H H 49 [3]

Molecules 2021, 26, x FOR PEER REVIEW 11 of 34

Cyano-derivative of benzo[a]indolizine is easily available from pyridinium-dicy- anmethylide and dehydrobenzene. Matsumoto first published the results of cycloaddition of dibenzoylacetylene to the structures 40a–d (Scheme 18, Table 9) [62,63]. Again, the reaction required a catalyst. Tominaga group made this cycloaddition 41 with DMAD [64]. Finally, this reaction was tested extensively with various acetylenes 42 [65].

Molecules 2021, 26, 2050 Scheme 18. Cycloaddition to 3-CN-substituted benzoindolizines (see Table 9). 11 of 34

Table 9. Substituents, conditions and yields in cycloaddition of acetylene to 3-CN-substituted benzoindolizines giving benzocyclazines (Scheme 18). Table 9. Substituents, conditions and yields in cycloaddition of acetylene to 3-CN-substituted benzoindolizinesN givingR/R’ benzocyclazines R7 (SchemeCat/Solv/T 18). °/Time Yield % Ref. 40a COPh/COPh H Pd-C/PhH/rt/46 h 82 [62,63] N R/R’ R7 Cat/Solv/T◦/Time Yield % Ref. 40b COPh/COPh Me Pd-C/PhH/rt/24 h 82 [62] 40a40c COPh/COPhCOPh/COPh HPh Pd-C/PhH/rt/46Pd-C/PhH/rt/24 h h 82 69 [62 [62],63] 40b COPh/COPh Me Pd-C/PhH/rt/24 h 82 [62] 40d COPh/COPh COPh Pd-C/PhH/Δ/5.5 h 59 [62] 40c COPh/COPh Ph Pd-C/PhH/rt/24 h 69 [62] 40d41 COPh/COPhE/E COPhH Pd-C/PhH/Pd-C/PhMe/∆/5.5Δ/20 h h 59 54 [62 [64]] 42a41 E/EE/E HH Pd-C/PhMe/Pd-C/PhMe/∆/20Δ/2 h h 54 13 [64 [65]] 42a42b E”/E”E/E a HH Pd-C/PhMe/Pd-C/PhMe/∆Δ/2/20 h h 14 (R’ 13 = H) [65 [65]] 42b E”/E” a H Pd-C/PhMe/∆/20 h 14 (R’ = H) [65] 42c Ac/Ac H Pd-C/PhMe/Δ/20 h 8 [65] 42c Ac/Ac H Pd-C/PhMe/∆/20 h 8 [65] 42d42d E/HE/H HH Pd-C/PhMe/Pd-C/PhMe/∆/34Δ/34 h h NG NG [65 [65]] b b 42e42e E/SiMeE/SiMe3 3 HH Pd-C/PhMe/Pd-C/PhMe/∆/72Δ/72 h h 11:14 11:14 [65[65]] 42f42f E/PhE/Ph HH Pd-C/PhMe/Pd-C/PhMe/∆/72Δ/72 h h 52:6 52:6b b [65[65]] b 42g42g Ac/PhAc/Ph HH Pd-C/PhMe/Pd-C/PhMe/∆/72Δ/72 h h 48:7 48:7 b [65[65]] a b :a E”—CO: E”—CO2tBu;2tBu;: regioisomers. b: regioisomers.

5.5. Cycloaddition Cycloaddition to to Benzoindolizines: Benzoindolizines: Synthesis Synthesis of of Benzo Benzo Derivatives Derivatives of of Cyclazines Cyclazines CycloadditionCycloaddition of of benzyne benzyne (generated (generat differently)ed differently) to indolizine to indolizine43 is the43 simplestis the simplest route toroute benzo to derivativesbenzo derivatives of cyclazine of cyclazine [3], Scheme [3], Scheme 19, Table 19, 10Table. The 10. resulting The resulting structures structures are stronglyare strongly ﬂuorescent. fluorescent.

Scheme 19. CsF, MeCN, 90°.◦ A—ortho-substituted benzene with SiMe3 and OSO2CF3; B—1-Ami- Scheme 19. CsF, MeCN, 90 . A—ortho-substituted benzene with SiMe3 and OSO2CF3; B—1- nobenzotriazole/Pb(OAc)4. Aminobenzotriazole/Pb(OAc)4. Table 10. Substituents and yields of cycloaddition of benzynes to indolizines (Scheme 19). Table 10. Substituents and yields of cycloaddition of benzynes to indolizines (Scheme 19). N Benzyne R1 R2 R3 R5 R6 R7 R8 Yield, % Ref. N Benzyne R1 R2 R3 R5 R6 R7 R8 Yield, % Ref. 43a A H Ph H H H H H 23 [3] 43a43b AA H Me PhPh HH HH HH H H HH 23 49 [3[3]] 43b A Me Ph H H H H H 49 [3] 43c A H Ph H H H H Me 44 [3] 43d A H Ph H H H Me H 55 [3] 43e A CN H H H H Me H 51 [3]

43f A E H H H H H H 50 [3] 43g A E E H H H H H 50 [3] 43h A E’ E’ H H H H H 37 [3] 43i A E’ E’ H H H Me H 30 [3] 43j A E E CN H Me H H 75 [3] 43k A COPh Ph H H H Me H 51 [3] 43l B Me Ph H H H H H 40 [3] 43m B H Ph H H H H Me 18 [3] 43m B H Ph H H H Me H 42 [3] 43o A E H H H H 7,8-Benzo 60 [3] 43p A CN H H H H 7,8-Benzo 52 [3] 43q A E’ E’ H H H 7,8-Benzo 58 [3]

Condensed structures from 43r,s with coumarin ring were similarly obtained, Scheme 20[3]. Molecules 2021, 26, x FOR PEER REVIEW 12 of 34 Molecules 2021, 26, x FOR PEER REVIEW 12 of 34

43c A H Ph H H H H Me 44 [3] 43c A H Ph H H H H Me 44 [3] 43d A H Ph H H H Me H 55 [3] 43d A H Ph H H H Me H 55 [3] 43e A CN H H H H Me H 51 [3] 43e A CN H H H H Me H 51 [3] 43f A E H H H H H H 50 [3] 43f A E H H H H H H 50 [3] 43g A E E H H H H H 50 [3] 43g A E E H H H H H 50 [3] 43h A E’ E’ H H H H H 37 [3] 43h A E’ E’ H H H H H 37 [3] 43i A E’ E’ H H H Me H 30 [3] 43i A E’ E’ H H H Me H 30 [3] 43j A E E CN H Me H H 75 [3] 43j A E E CN H Me H H 75 [3] 43k A COPh Ph H H H Me H 51 [3] 43k A COPh Ph H H H Me H 51 [3] 43l B Me Ph H H H H H 40 [3] 43l B Me Ph H H H H H 40 [3] 43m B H Ph H H H H Me 18 [3] 43m B H Ph H H H H Me 18 [3] 43m B H Ph H H H Me H 42 [3] 43m B H Ph H H H Me H 42 [3] 43o A E H H H H 7,8-Benzo 60 [3] 43o A E H H H H 7,8-Benzo 60 [3] 43p A CN H H H H 7,8-Benzo 52 [3] 43p A CN H H H H 7,8-Benzo 52 [3] 43q A E’ E’ H H H 7,8-Benzo 58 [3] 43q A E’ E’ H H H 7,8-Benzo 58 [3] Molecules 2021, 26, 2050 12 of 34 Condensed structures from 43r,s with coumarin ring were similarly obtained, Condensed structures from 43r,s with coumarin ring were similarly obtained, Scheme 20 [3]. Scheme 20 [3].

Scheme 20. CsF, MeCN, 90°. 43r (R7R8 = H, 93%), 43s (R7,R8 = benzo, 62%), Method A. SchemeScheme 20. 20.CsF, CsF, MeCN, MeCN, 90 90°.◦. 43r 43r(R7R8 (R7R8 = = H,H, 93%),93%),43s 43s(R7,R8 (R7,R8 == benzo,benzo, 62%),62%), MethodMethod A.A. Another route to the same benzo-skeleton is cycloaddition of alkynes to benzo[a]in- AnotherAnother route route to to the the same same benzo-skeleton benzo-skeleton is cycloadditionis cycloaddition ofalkynes of alkynes to benzo[a]indoli to benzo[a]indolizines. This reaction was studied with acetylenes containing boron substituents, alone zines.dolizines. This This reaction reaction was was studied studied with with acetylenes acetylenes containing containing boron boron substituents, substituents, alone alone 44a–c [37] or together with nitrogen-containing heterocycle on another end of acetylene 44a44a––cc[ 37[37]] or or together together with with nitrogen-containing nitrogen-containing heterocycle heterocycle on on another another end end of of acetylene acetylene 45a–e [5], Scheme 21, Table 11. In one experiment 46 benzyne was generated from PhBr; 45a45a––ee[ 5[5],], Scheme Scheme 21 21,, Table Table 11 11.. In In one one experiment experiment46 46benzyne benzynewas was generated generatedfrom fromPhBr; PhBr; this resulted in dibenzocyclazine was obtained with low yield [66]. thisthis resulted resulted in in dibenzocyclazine dibenzocyclazine was was obtained obtained with with low low yield yield [ 66[66].].

Scheme 21. Cycloaddition to benzoindolizines see Table 11). SchemeScheme 21. 21.Cycloaddition Cycloaddition to to benzoindolizines benzoindolizines see see Table Table 11 11).). Table 11. Substituents and yields (ratio of isomers) of cycloaddition to benzoindolizines (Scheme 21). Table 11. Substituents and yields (ratio of isomers) of cycloaddition to benzoindolizines (Scheme 21). Table 11. Substituents and yields (ratio of isomers) of cycloaddition to benzoindolizines (Scheme 21). N R1 R2 Solv/T°/Time/Oxidant Yield, % Ref. N R1 R2 Solv/T°/Time/Oxidant Yield, % Ref. N44a Mes R12B H R2 Solv/T PhMe/rt/30m/DDQ◦/Time/Oxidant Yield, % 89 Ref.[37] 44a Mes2B H PhMe/rt/30m/DDQ 89 [37] 44b 2-(Mes2B)Ph H PhMe/Δ/3d/DDQ 75 [37] 44a44b 2-(MesMes22BB)Ph H H PhMe/rt/30m/DDQ PhMe/Δ/3d/DDQ 8975 [37[37]] 44c 4-(Mes2B)Ph H PhMe/Δ/3d/DDQ 83 [37] 44b44c 2-(Mes4-(Mes22B)PhB)Ph H H PhMe/ PhMe/∆Δ/3d/DDQ/3d/DDQ 7583 [37[37]] 45a 4-(Mes2B)Ph 2-Py (1) PhMe/120 °C/5–6d; (2) DDQ/rt/0.5 h 79:2 [5] 44c45a 4-(Mes4-(Mes22B)PhB)Ph 2-Py H (1) PhMe/120 PhMe/ °C/5–6d;∆/3d/DDQ (2) DDQ/rt/0.5 h 83 79:2 [37 [5]] ◦ 45a45b 4-(Mes2-(Mes2B)Ph2B)Ph 2-Py 2-Py (1) (1) PhMe/120 PhMe/120C/5–6d; °C/5–6d; (2) (2) DDQ/rt/0.5 DDQ/rt/0.5 hh 79:2 82:4 [5] [5] 45b 2-(Mes2B)Ph 2-Py (1) PhMe/120◦ °C/5–6d; (2) DDQ/rt/0.5 h 82:4 [5] 45b45c 2-(Mes2-(Mes2B)Ph2B)Ph 2-Isoquinolyl 2-Py (1) (1) PhMe/120 PhMe/120C/5–6d; °C/5–6d; (2) (2) DDQ/rt/0.5 DDQ/rt/0.5 hh 82:4 72:18 [5] [5] 45c 2-(Mes2B)Ph 2-Isoquinolyl (1) PhMe/120◦ °C/5–6d; (2) DDQ/rt/0.5 h 72:18 [5] 45c45d 2-(Mes2-(Mes2B)Ph2B)Ph 2-Benzotiazolyl 2-Isoquinolyl (1) (1) PhMe/120 PhMe/120C/5–6d; °C/5–6d; (2) (2) DDQ/rt/0.5 DDQ/rt/0.5 hh 72:18 62:19 [5] [5] 45d 2-(Mes2B)Ph 2-Benzotiazolyl (1) PhMe/120◦ °C/5–6d; (2) DDQ/rt/0.5 h 62:19 [5] 45d45e 2-(Mes2-(Mes2B)Ph2B)Ph 2-Benzotiazolyl 2-Tiazolyl (1) (1) PhMe/120 PhMe/120C/5–6d; °C/5–6d; (2) (2) DDQ/rt/0.5 DDQ/rt/0.5 hh 62:19 68:14 [5] [5] 45e45e 2-(Mes2B)Ph 2-Tiazolyl (1) PhMe/120◦ °C/5–6d; (2) DDQ/rt/0.5 h 68:14 [5] 2-(Mes2B)Ph 2-Tiazolyl (1) PhMe/1202,2,6,6-tetramethylpC/5–6d;iperidine, (2) DDQ/rt/0.5 n-BuLi, h 68:14 [5] Molecules 2021, 26, x FOR PEER REVIEW46 Benzo 2,2,6,6-tetramethylpiperidine,2,2,6,6-tetramethylpiperidine, n-BuLi, n-BuLi, 6.6 13 [66]of 34 4646 BenzoBenzo PhBr/THF/−78 °C/1 h 6.66.6 [66[66]] PhBr/THF/PhBr/THF/−−7878 ◦°C/1C/1 h h

TominagaTominaga showed showed that that indolizines indolizines47a 47a,b,bhaving having annelated annelated benzene benzene ring ring across across the the bondbond C7–C8 C7–C8 underwent underwent [8+2] [8+2] cycloaddition cycloaddition forming forming benzo[g]cycl[3.2.2]azines benzo[g]cycl[3.2.2]azines [29[29,67],,67],

SchemeScheme 22 22..

2 2 SchemeScheme 22. 22.Pd-C/PhMe/ Pd-C/PhMe/Δ∆/30h. 47a47a RR 2== H H (33%), (33%), 47b47b RR 2= =MeS MeS (27%). (27%).

InIn another another paper paper [68 [68],], he demonstratedhe demonstrated a similar a similar reaction reaction of dibenzoindolizine of dibenzoindolizine48 with 48 DMADwith DMAD leading leading to dibenzo[a,h]cycl[3.2.2]azine, to dibenzo[a,h]cycl[3.2.2]azine, Scheme Scheme 23. 23.

E E

N N 26%

48 CN E E Scheme 23. MePh + HOAc/Δ/20 h.

Isomeric indolizines 49a,b annelated across the bond C6–C7 with benzothiophene underwent cycloaddition with DEAD (PhMe/Δ/6h) without any catalyst [69], Scheme 24.

Scheme 24. Example of cycloaddition to fused indolizines.

The last example is 1,2,5,6-dibenzocycl[2,2,3]azine obtained with a yield of 54% from dibenzoindolizine and DEAD in presence of Pd-C [70], Scheme 25.

Scheme 25. Pd-C/PhMe/Δ/14 h.

This reaction is featured, firstly, because it was the first cycloaddition in the history of indolizines that even made an influence on Boekelheide. Second, is that the structure of dibenzoindolizine is extremely polyenic (annelation in indolizine appears across two

Molecules 2021, 26, x FOR PEER REVIEW 13 of 34 Molecules 2021, 26, x FOR PEER REVIEW 13 of 34 Molecules 2021, 26, x FOR PEER REVIEW 13 of 34

Tominaga showed that indolizines 47a,b having annelated benzene ring across the bondTominaga C7–C8 underwent showed that [8+2] indolizines cycloaddition 47a,b fohavingrming annelated benzo[g]cycl[3.2.2]azines benzene ring across [29,67], the Tominaga showed that indolizines 47a,b having annelated benzene ring across the Schemebond C7–C8 22. underwent [8+2] cycloaddition forming benzo[g]cycl[3.2.2]azines [29,67], bondScheme C7–C8 22. underwent [8+2] cycloaddition forming benzo[g]cycl[3.2.2]azines [29,67], Scheme 22.

Scheme 22. Pd-C/PhMe/Δ/30h. 47a R2 = H (33%), 47b R2 = MeS (27%). 2 2 Molecules 2021, 26, 2050 Scheme 22. Pd-C/PhMe/Δ/30h. 47a R = H (33%), 47b R = MeS (27%). 13 of 34 Scheme 22. Pd-C/PhMe/Δ/30h. 47a R2 = H (33%), 47b R2 = MeS (27%). In another paper [68], he demonstrated a similar reaction of dibenzoindolizine 48 with InDMAD another leading paper to [68], dibenzo[a,h]cycl[3.2.2]azine, he demonstrated a similar Scheme reaction 23. of dibenzoindolizine 48 withIn DMAD another leading paper to [68], dibenzo[a,h]cycl[3.2.2]azine, he demonstrated a similar Scheme reaction 23. of dibenzoindolizine 48 with DMAD leading to dibenzo[a,h]cycl[3.2.2]azine, Scheme 23.

E E E E E E N N 26% N N 26% N 48N CN 26% 48 CN E E 48 CN E E E Scheme 23. MePh + HOAc/Δ/20 h. E SchemeScheme 23. 23.MePh MePh ++ HOAc/HOAc/Δ∆/20 h. h. Scheme 23. MePh + HOAc/Δ/20 h. IsomericIsomeric indolizinesindolizines 49a49a,b,b annelatedannelated acrossacross thethe bondbondC6–C7 C6–C7with with benzothiophene benzothiophene Isomeric indolizines 49a,b annelated across the bond C6–C7 with benzothiophene underwentunderwent cycloadditioncycloaddition with with DEAD DEAD (PhMe/ (PhMe/∆Δ/6h)/6h) without any catalyst [69], [69], Scheme 2424.. underwentIsomeric cycloaddition indolizines 49awith,b DEAD annelated (PhMe/ acrossΔ/6h) the without bond C6–C7any catalyst with benzothiophene[69], Scheme 24. underwent cycloaddition with DEAD (PhMe/Δ/6h) without any catalyst [69], Scheme 24.

Scheme 24. Example of cycloaddition to fused indolizines. SchemeScheme 24. 24.Example Example ofof cycloadditioncycloaddition toto fused fused indolizines. indolizines. Scheme 24. Example of cycloaddition to fused indolizines. The last example is 1,2,5,6-dibenzocycl[2,2,3]azine obtained with a yield of 54% from TheThe lastlast exampleexample isis 1,2,5,6-dibenzocycl[2,2,3]azine1,2,5,6-dibenzocycl[2,2,3]azine obtained obtained with with a a yield yield of of 54% 54% from from dibenzoindolizineThe last example and is DEAD 1,2,5,6-dibenzocycl[2,2, in presence of Pd-C3]azine [70], obtainedScheme 25. with a yield of 54% from dibenzoindolizinedibenzoindolizine and and DEAD DEAD in in presence presence of of Pd-C Pd-C [ 70[70],], Scheme Scheme 25 25.. dibenzoindolizine and DEAD in presence of Pd-C [70], Scheme 25.

Scheme 25. Pd-C/PhMe/Δ/14 h. Scheme 25. Pd-C/PhMe/Δ/14 h. Scheme 25. Pd-C/PhMe/Δ/14 h. SchemeThis 25. reactionPd-C/PhMe/ is featured,∆/14 h. firstly, because it was the first cycloaddition in the history of indolizinesThis reaction that evenis featured, made anfirstly, influence because on Boekelheide.it was the first Second, cycloaddition is that the in structure the history of This reaction is featured, firstly, because it was the first cycloaddition in the history dibenzoindolizineof indolizinesThis reaction that is evenis featured, extremely made firstly,an polyenicinfluence because (annelationon itBoekelheide. was the in first indolizine Second, cycloaddition is appearsthat the in thestructureacross history two of ofofdibenzoindolizine indolizinesindolizines that evenis extremely made an an influencepolyenic influence on(annelation on Boekelheide. Boekelheide. in indolizine Second, Second, is isappearsthat that the the structureacross structure two of ofdibenzoindolizine dibenzoindolizine is isextremely extremely polyenic polyenic (annelation (annelation in in indolizine indolizine appears acrossacross twotwo single bonds), and therefore, the process could be better treated as [2+16] rather than [2+8] cycloaddition.

6. Cycloadditions Where Indolizines Are Intermediates

There are many examples of cyclazine synthesis where the intermediates are indolizines. First, there are so-called 3 component reactions: picoline and bromoketone in the presence of a base (Chichibabin combination to obtain indolizine) and alkyne. Two examples of such combination were reported in microwave conditions [71,72], Scheme 26, Table 12. Molecules 2021, 26, x FOR PEER REVIEW 14 of 34

single bonds), and therefore, the process could be better treated as [2+16] rather than [2+8] cycloaddition.

6. Cycloadditions Where Indolizines Are Intermediates There are many examples of cyclazine synthesis where the intermediates are indoliz- Molecules 2021, 26, 2050 ines. First, there are so-called 3 component reactions: picoline and bromoketone14 in of the 34 presence of a base (Chichibabin combination to obtain indolizine) and alkyne. Two examples of such combination were reported in microwave conditions [71,72], Scheme 26, Table 12.

SchemeScheme 26. 26.Microwave Microwave three-component three-component synthesis synthesis of of cyclazines cyclazines (see (see Table Table 12 12).).

Table 12. Substituents and yields of microwave three-component synthesis of cyclazines (Scheme 26). Table 12. Substituents and yields of microwave three-component synthesis of cyclazines (Scheme 26). N R R’ R2 R7 R8 Yield, % Ref. N R R’ R2 R7 R8 Yield, % Ref. 51a E E Ph H H 90 [71] a 51a E E Ph H H 90 [71] a 51b E E 4-Me-Ph H H 92 [71] 51b E E 4-Me-Ph H H 92 [71] 51c51c EE EE 4-Cl-Ph 4-Cl-Ph H H H H 60 60 [[71]71] 51d51d EE EE 4-NO2-Ph 4-NO2-Ph HH H H 20 20 [[71]71] 51e51e EE EE PolycyclicPolycyclic R R HH H H 78 78 [[71]71] 51f51f EE EE 1-Cyclohexenyl1-Cyclohexenyl HH H H 74 74 [[71]71] 51g * H E’ Ph H H 78 [71] 51g51h * HH E’E’ Ph Ph Me H H H 78 80 [[71]71] 51h51i ** HH E’E’ 4-Me-Ph Ph Me H H 80 74 [[71]71] 51i51j * HH E’E’ 4-Cl-Ph 4-Me-Ph Me H MeH 74 65 [[71]71] 51j51k * * HH E’E’ 4-NO2-Ph 4-Cl-Ph H H Me Me 65 22 [[71]71] 52a E E Ph H H 37 [72] b 51k * H E’ 4-NO2-Ph H Me 22 [71] 52b E E 4-NO2Ph H H 78 [72] b 52a52c EE EE 4-ClPh Ph H H H H 37 46 [72] [72] 52b52d EE EE 4-MeOPh 4-NO2Ph HH H H 78 23 [[72]72] 52c52e EE EE 4-MePh 4-ClPh H H H H 46 39 [[72]72] 52d52f EE EE 4-OHPh4-MeOPh HH H H 23 36 [[72]72] 52g E E 4-BrPh H H 49 [72] 52e52h EE EE 4-FPh4-MePh H H H H 39 42 [[72]72] a 52f E ◦ E b 4-OHPh H H 36 [72] :K2CO3, water MW, 100 C 2–5 min; : Alumina, 300 W, 2 min; * Attention: unexpected products, place of R and R’ groups52g shouldE be reversed.E Probably mistake 4-BrPh made by the authors. H H 49 [72] 52h E E 4-FPh H H 42 [72] a: K2AnotherCO3, water example MW, 100 is °C given 2–5 min; by cycloaddition b: Alumina, 300 to W, pyridone 2 min; * Atte53antion:giving unexpected cyclazine products,53b [73], Molecules 2021, 26, x FOR PEER REVIEWSchemeplace of 27 R .and Evidently, R’ groups intermediates should be revers areed. (partially Probably isolated) mistake indolizine made by the55e authors.which is obtained15 of 34

by sequence 55c–55d. Another example is given by cycloaddition to pyridone 53a giving cyclazine 53b [73], Scheme 27. Evidently, intermediates are (partially isolated) indolizine 55e which is obtained by sequence 55c–55d.

SchemeScheme 27. 27.PhMe/ PhMe/∆Δ/30/30 h.h.

AnotherAnother example example of of cyclazine cyclazine54b 54bsynthesis synthesis from from pyridine pyridine54a 54awith with ethyl ethyl propiolate propiolate viavia indolizine indolizine54c 54c [74 [74]] is is illustrated illustrated in in Scheme Scheme 28 28.. Indolizine Indolizine54c 54ccould could be be isolated. isolated.

Scheme 28. TEA (1.2 eq), ethyl propiolate (1.5 eq), CH3CN + DMF, rt, 24 h.

A similar reaction is between the same pyridine and benzyne [75–77] forming dibenzoindolizine, Scheme 29, Table 13.

Scheme 29. Synthesis of benzocyclazines from pyridinium ylides (Table 13).

Table 13. Substituents and yields of benzocyclazines from pyridinium ylide (Scheme 29).

N R A, Yield, % B, Yield, % C, Yield, % Ref. 55a H 11 (20) 4 (35) 39 [76] 55b Me 5 (22) 2 (12) 33 [76] 55c Ph 3 (44) 2 (10) 38 [76] 55d PhCO 0.5 (21) 17 (24) 25 [76] 55e MeOCO 3 (33) 32 - [76] 55f MeCO Trace (27) 18 - [76] 56a 1,2-Me 12 - - [77] 56b 1,3-Me 5 - - [77]

In brackets—yield of benzoindolizine. A—diphenyliodonium-2-carboxylate monohydrate 200 °C; B—anthranilic acid and isopentyl nitrite in refluxing chloroform-acetone; C—6-cyanobenzo[a]indolizine diphenyliodonium-2-carboxylatem monohydrate in DME 200 °C. 3 h

MoleculesMolecules 20212021,, 2626,, xx FORFOR PEERPEER REVIEWREVIEW 1515 ofof 3434

SchemeScheme 27.27. PhMe/PhMe/ΔΔ/30/30 h.h. Molecules 2021, 26, 2050 15 of 34 AnotherAnother exampleexample ofof cyclazinecyclazine 54b54b synthesissynthesis fromfrom pyridinepyridine 54a54a withwith ethylethyl propiolatepropiolate viavia indolizineindolizine 54c54c [74][74] isis illustratedillustrated inin SchemeScheme 28.28. IndolizineIndolizine 54c54c couldcould bebe isolated.isolated.

3 Scheme 28. TEA (1.2 eq), ethyl propiolate (1.5 eq), CH 3CN + DMF, rt, 24 h. SchemeScheme 28. 28.TEA TEA (1.2 (1.2 eq), eq), ethyl ethyl propiolate propiolate (1.5 (1.5 eq), eq), CH CH3CNCN + + DMF, DMF, rt, rt, 24 24 h. h.

AAA similar similarsimilar reaction reactionreaction is isis between betweenbetween the thethe same samesame pyridine pypyridineridine and andand benzyne benzynebenzyne [ 75[75–77][75–77]–77] forming formingforming diben- diben-dibenzoindolizine,zoindolizine,zoindolizine, Scheme SchemeScheme 29 29,29,, Table TableTable 13 13.13..

Scheme 29. Synthesis of benzocyclazines from pyridinium ylides (Table 13). SchemeScheme 29. 29.Synthesis Synthesis of of benzocyclazines benzocyclazines from from pyridinium pyridinium ylides ylides (Table (Table 13 13).). Table 13. Substituents and yields of benzocyclazines from pyridinium ylide (Scheme 29). TableTable 13. 13.Substituents Substituents and and yields yields of of benzocyclazines benzocyclazines from from pyridinium pyridinium ylide ylide (Scheme (Scheme 29 29).). N R A, Yield, % B, Yield, % C, Yield, % Ref. NN R R A, A,Yield, Yield, % % B, B,Yield, Yield, % % C, C, Yield, %% Ref. Ref. 55a55a HH 1111 (20)(20) 44 (35)(35) 39 39 [76] [76] 55a55b MeH 5 (22) 11 (20) 2 (12) 4 (35) 33 39 [76 [76]] 55b55b MeMe 5 (22) 5 (22) 2 2(12) (12) 33 [76 [76]] 55c55c55c PhPhPh 3 3 (44)(44) 3 (44) 2 2 (10) 2(10) (10) 38 38 [76 [76] [76]] 55d55d55d PhCOPhCOPhCO 0.50.5 0.5 (21)(21) (21) 17 17 17 (24)(24) (24) 25 25 [76 [76] [76]] 55e55e55e MeOCOMeOCOMeOCO 33 (33)(33) 3 (33) 32 32 32 - - [76 [76] [76]] 55f55f MeCOMeCO Trace Trace (27) (27) 18 18 - [76 [76]] 56a55f MeCO1,2-Me Trace 12(27) 18 - - [77 [76]] 56b56a56a 1,2-Me1,2-Me1,3-Me 1212 5 - - - - [77 [77] [77]] 56b56b 1,3-Me1,3-Me 55 - - - - [77] [77] In brackets—yield of benzoindolizine. A—diphenyliodonium-2-carboxylate mono- In brackets—yield of benzoindolizine. A—diphenyliodonium-2-carboxylate mono- Molecules 2021, 26, x FOR PEER REVIEWhydrate In 200brackets—yield◦C; B—anthranilic of benzoindolizine. acid and isopentyl A—diphenyliodonium-2-carboxylate nitrite in reﬂuxing chloroform-acetone; 16mono- of 34 hydrate 200 °C; B—anthranilic acid and isopentyl nitrite in refluxing chloroform-acetone; C—6-cyanobenzo[a]indolizinehydrate 200 °C; B—anthranilic diphenyliodonium-2-carboxylatem acid and isopentyl nitrite in refluxing monohydrate chloroform-acetone; in DME C—6-cyanobenzo[a]indolizine diphenyliodonium-2-carboxylatem monohydrate in DME 200C—6-cyanobenzo[a]indolizine◦C 3 h. diphenyliodonium-2-carboxylatem monohydrate in DME 200 °C. 3 h 200 Interesting°C.Interesting 3 h multistep multistep reaction reaction starting starting from from pyridine pyridine57a 57aand and ﬁnishing finishing with with cyclazine cyclazine 57b57bwith with the the yields yields 15–70% 15–70% was was observed observed independently independently by Achesonby Acheson and and Pohjala Pohjala[51,78 [51,78––82], Scheme82], Scheme 30. The 30. The mechanism mechanism of this of this process process included included Perkin Perkin reaction reaction and and intermediate intermediate formationformation of of indolizine indolizine skeleton skeleton57c 57c. .

SchemeScheme 30. 30.Multistep Multistep reaction reaction ending ending with with cyclazines. cyclazines.

7. Cycloaddition to Azacyclazines and Their Benzo-Derivatives The first cycloaddition to aza-analogs of indolizine was observed by Boekelheide [83] in the reaction of imidazo[1,2-a]pyridine 58 with DMAD in presence of Pd-C, Scheme 31 and Table 14. It was also shown that 6-azaindolizine 59 [84] (but not 7-aza-derivative [25]) can be involved in a similar process. Soon it was proved also for 8-aza-indolizine 60a and its 7-oxo-analog 61b [85]. 1-Azaindolizine bearing 2-SO2Me group failed to go in such cycloaddition [86], whereas the same structures with 2-SMe group 61a,b [87] and their [h]- benzannelated derivatives 62 [88] formed the desired azacyclazines with DMAD. In our recent work, we proved that MAC could react with 1-azaindolizine 63 giving azacyclazine in the open air [36]. Diphenylacetylene was capable to transform imidazopyridine 64 to azacyclazine under the action of Pd(OAc)2/Cu(OAc)2 [89].

Scheme 31. Synthesis of azacyclazines from azaindolizines (Table 14).

Table 14. Substituents, conditions and yields of azacyclazines from azaindolizines (Scheme 31).

N R/R’ X R2 Z R7 Y Cat/Solv/T°/Time Yield, %Ref. 58 E/E N Ph H H H Pd-C/MePh/Δ/25 h 29 [83] 59 E/E H Ph N Me H Pd-C/MePh/Δ/21 h 28 [84] 60a E/E H Me H Me N Pd-C/MePh/Δ/ 66 [85] 60b E/E H Me H O= NMe Pd-C/MePh/Δ/ 59 [85] 61 E/E NSMe H (CH=CH)2 Pd-C/MePh/Δ/30 h 6 [88] 62a E/E NSMe H H H Pd-C/MePh/Δ/30 h 36 [87] 62b E/E NSMeMeC H MeC Pd-C/MePh/Δ/30 h 40 [87] 63 E/H Nt-Bu H H H O2/MePh/Δ/4 h 75 [36] 64 Ph/PhN H H H H Pd(OAc)2/Cu(OAc)2 LiOAc/DMAc/120°/8 h 49 [89]

Mesoionic structure 65a underwent cycloaddition with DMAD giving fully covalent structure 65b proved by X-ray [55], Scheme 32.

Molecules 2021, 26, x FOR PEER REVIEW 16 of 34

Interesting multistep reaction starting from pyridine 57a and finishing with cyclazine 57b with the yields 15–70% was observed independently by Acheson and Pohjala [51,78– 82], Scheme 30. The mechanism of this process included Perkin reaction and intermediate formation of indolizine skeleton 57c.

Molecules 2021, 26, 2050 16 of 34

Scheme 30. Multistep reaction ending with cyclazines.

7.7. CycloadditionCycloaddition toto AzacyclazinesAzacyclazines andand TheirTheir Benzo-DerivativesBenzo-Derivatives TheThe ﬁrstfirst cycloadditioncycloaddition to to aza-analogs aza-analogs of of indolizine indolizine was was observed observed by by Boekelheide Boekelheide [ 83[83]] inin the the reaction reaction of of imidazo[1,2-a]pyridine imidazo[1,2-a]pyridine58 58with withDMAD DMADin inpresence presenceof ofPd-C, Pd-C,Scheme Scheme 31 31 andand TableTable 14 14.. It It waswas alsoalso shownshown thatthat 6-azaindolizine6-azaindolizine59 59[ [84]84](but (but notnot 7-aza-derivative7-aza-derivative [ [25])25]) cancan bebe involvedinvolved in in a a similar similar process. process. SoonSoon itit waswas proved proved also also for for 8-aza-indolizine 8-aza-indolizine60a 60aand and its 7-oxo-analog 61b [85]. 1-Azaindolizine bearing 2-SO Me group failed to go in such its 7-oxo-analog 61b [85]. 1-Azaindolizine bearing 2-SO2Me2 group failed to go in such cy- cycloadditioncloaddition [86], [86 ],whereas whereas the the same same structures structures with with 2-SMe 2-SMe group group 61a61a,b [87],b [ 87and] and their their [h]- [h]-benzannelatedbenzannelated derivatives derivatives 6262 [88][88 formed] formed the the desired desired azacyclazines azacyclazines with DMAD.DMAD. InInour our recentrecent work, work, we we proved proved that that MAC MAC could could react react with with 1-azaindolizine 1-azaindolizine63 63giving giving azacyclazine azacyclazine inin thethe open open air air [ 36[36].]. Diphenylacetylene Diphenylacetylene waswas capablecapable toto transform transform imidazopyridine imidazopyridine64 64to to azacyclazine under the action of Pd(OAc)2/Cu(OAc)2 [89]. azacyclazine under the action of Pd(OAc)2/Cu(OAc)2 [89].

Scheme 31. Synthesis of azacyclazines from azaindolizines (Table 14). Scheme 31. Synthesis of azacyclazines from azaindolizines (Table 14).

Table 14. Substituents, conditions and yields of azacyclazines from azaindolizines (Scheme 31). Table 14. Substituents, conditions and yields of azacyclazines from azaindolizines (Scheme 31). N R/R’ X R2 Z R7 Y Cat/Solv/T°/Time Yield, %Ref. N R/R’ X R2 Z R7 Y Cat/Solv/T◦/Time Yield, % Ref. 58 E/E N Ph H H H Pd-C/MePh/Δ/25 h 29 [83] 5958 E/EE/E H Ph N N Ph Me H H H H Pd-C/MePh/ Pd-C/MePh/Δ/21 ∆h/25 h 29 28 [84][83] 59 E/E H Ph N Me H Pd-C/MePh/∆/21 h 28 [84] 60a E/E H Me H Me N Pd-C/MePh/Δ/ 66 [85] 60a E/E H Me H Me N Pd-C/MePh/∆/ 66 [85] 60b60b E/EE/E H Me H H Me O= NMe H O= NMe Pd-C/MePh/Pd-C/MePh/Δ/ ∆/ 5959 [85][85] 6161 E/EE/E NSMe N H SMe(CH=CH) H2 (CH=CH)2Pd-C/MePh/Pd-C/MePh/Δ/30 ∆h/30 h 6 6 [88][88] 62a62a E/EE/E NSMe N H SMe H H H H H Pd-C/MePh/ Pd-C/MePh/Δ/30 ∆h/30 h 36 36 [87][87] 62b E/E N SMe MeC H MeC Pd-C/MePh/∆/30 h 40 [87] 62b E/E NSMeMeC H MeC Pd-C/MePh/Δ/30 h 40 [87] 63 E/H N t-Bu H H H O2/MePh/∆/4 h 75 [36] 63 E/H Nt-Bu H H H O2/MePh/Δ/4 h 75 [36] Pd(OAc)2/Cu(OAc)2 64 Ph/Ph NHHHH ◦ 49 [89] 64 Ph/PhN H H H H Pd(OAc)2/Cu(OAc)LiOAc/DMAc/1202 LiOAc/DMAc/120°/8/8 h h 49 [89]

Molecules 2021, 26, x FOR PEER REVIEW MesoionicMesoionic structurestructure65a 65aunderwent underwent cycloaddition cycloaddition with with DMAD DMAD giving giving fully fully covalent covalent17 of 34

structurestructure65b 65bproved proved by by X-ray X-ray [ 55[55],], Scheme Scheme 32 32..

SchemeScheme 32. 32.Synthesis Synthesis of of azacyclazinone azacyclazinone from from mesoionic mesoionic structure. structure.

ImidazopyridinesImidazopyridines66 66are transformedare transformed to azacyclazines to azacyclazines under the under action the of Pd(OAc) action 2/of Cu(OAc)Pd(OAc)22[/Cu(OAc)90] and [912 [90]], Scheme and [91], 33, Scheme Table 15 33,. Table 15.

Scheme 33. Pd(OAc)2, Cu(OAc)2, DMSO, 110 °C, 12 h [90]. Pd-Se complex Cu(OAc)2, KOtBu, DMAC, 120 °C, 16 h [91].

Table 15. Substituents and yields of reaction of 2-arylimidazopiridines and diarylacetylenes (Scheme 33).

N Ar R2 R6 R7 R8 Yield, % Ref. 66a Ph Ph H H H 78 [90] 66b Ph Ph H H Me 76 [90] 66c Ph Ph H Me H 75 [90] 66d Ph Ph Cl H H 68 [90] 66e Ph 4-MePh H H H 79 [90] 66f Ph 4-FPh H H H 75 [90] 66g Ph 4-ClPh H H Me 73 [90] 66h Ph 4-CNPh H H H 71 [90] 66i Ph 4-NO2Ph H H H 67 [90] 66j Ph CF3 H H H 64 [90] 66k Ph i-Bu H H H 63 [90] 66l 4-MePh Ph H H H 77 [90] 66m 4-MePh Ph H Me H 74 [90] 66n 4-MeOPh Ph H H H 70 [90] 66o 4-MeOPh Ph H Me H 69 [90] 66p 4-MeOPh i-Bu H H H 61 [90] 67a Ph Ph H H H 68 [91] 67b Ph 1-Naphtyl H H H 69 [91] 67c Ph Ph H Cl Cl 57 [91] 67d Ph Ph H Br Br 51 [91] 67e Ph Ph Me H H 76 [91] 67f Ph 4-CN-Ph H H H 64 [91] 67g Ph 4-F-Ph H H H 68 [91] 67h Ph 4-Br-Ph H H H 66 [91] 67i Ph 4-MeO-Ph H H H 73 [91] 67j Ph 4-F-Ph Me H H 61 [91] 67k Ph 2-Tienyl H H H 67 [91] 67l Ph Ph H H H 63 [91] 67m 4-Br-Ph Ph H H H 78 [91] 67n E’ Ph H H H 31 [91]

Molecules 2021, 26, x FOR PEER REVIEW 17 of 34

Scheme 32. Synthesis of azacyclazinone from mesoionic structure. Molecules 2021, 26, 2050 17 of 34 Imidazopyridines 66 are transformed to azacyclazines under the action of Pd(OAc)2/Cu(OAc)2 [90] and [91], Scheme 33, Table 15.

Scheme 33. Pd(OAc)2, Cu(OAc)2, DMSO, 110 °C,◦ 12 h [90]. Pd-Se complex Cu(OAc)2, KOtBu, Scheme 33. Pd(OAc)2, Cu(OAc)2, DMSO, 110 C, 12 h [90]. Pd-Se complex Cu(OAc)2, KOtBu, DMAC, 120 °C, 16 h [91]. DMAC, 120 ◦C, 16 h [91].

Table 15. Substituents and yields of reaction of 2-arylimidazopiridines and diarylacetylenes Table(Scheme 15. 33).Substituents and yields of reaction of 2-arylimidazopiridines and diarylacetylenes (Scheme 33). N Ar R2 R6 R7 R8 Yield, % Ref. 66aN Ph Ar Ph R2H R6H R7 R8H Yield,78 % Ref.[90] 66a66b PhPh Ph PhH HH HMe H 7876 [90[90]] 66b66c PhPh Ph PhH HMe H MeH 7675 [90[90]] 66c66d PhPh Ph PhCl HH Me H 7568 [90[90]] 66d66e PhPh 4-MePh Ph H ClH HH 6879 [90 [90]] 66e66f PhPh 4-FPh 4-MePh H HH HH 7975 [90[90]] 66f66g PhPh 4-ClPh 4-FPh H HH HMe H 7573 [90[90]] 66g Ph 4-ClPh H H Me 73 [90] 66h Ph 4-CNPh H H H 71 [90] 66h Ph 4-CNPh H H H 71 [90] 66i Ph 4-NO2Ph H H H 67 [90] 66i Ph 4-NO2Ph H H H 67 [90] 66j Ph CF3 H H H 64 [90] 66j Ph CF3 H H H 64 [90] 66k66k PhPh i-Bu i-BuH HH HH 6363 [90[90]] 66l66l 4-MePh4-MePh Ph Ph H HH HH 7777 [90 [90]] 66m66m 4-MePh4-MePh Ph Ph H HMe Me H 7474 [90 [90]] 66n66n 4-MeOPh4-MeOPh Ph Ph H H H HH 70 70 [90 [90]] 66o66o 4-MeOPh4-MeOPh Ph Ph H HMe Me H 69 69 [90 [90]] 66p66p 4-MeOPh4-MeOPh i-Bu i-Bu H H H H H 61 61 [90 [90]] 67a Ph Ph H H H 68 [91] 67a Ph Ph H H H 68 [91] 67b Ph 1-Naphtyl H H H 69 [91] 67b Ph 1-Naphtyl H H H 69 [91] 67c Ph Ph H Cl Cl 57 [91] 67d67c PhPh Ph PhH HCl BrCl Br 5157 [91[91]] 67e67d PhPh Ph PhH MeBr HBr H 7651 [91[91]] 67f67e PhPh Ph 4-CN-Ph Me HH HH 6476 [91[91]] 67g67f PhPh 4-CN-Ph 4-F-Ph H HH HH 68 64 [91 [91]] 67h67g PhPh 4-F-Ph 4-Br-Ph H HH HH 6668 [91[91]] 67i67h PhPh 4-Br-Ph 4-MeO-Ph H HH HH 7366 [91 [91]] 67j67i PhPh 4-MeO-Ph 4-F-Ph H MeH H H 61 73 [91 [91]] 67k Ph 2-Tienyl H H H 67 [91] 67j Ph 4-F-Ph Me H H 61 [91] 67l Ph Ph H H H 63 [91] 67k Ph 2-Tienyl H H H 67 [91] 67m 4-Br-Ph Ph H H H 78 [91] Molecules 2021, 26, x FOR PEER REVIEW 18 of 34 67n67l PhE’ Ph PhH HH HH 3163 [91[91]] 67m 4-Br-Ph Ph H H H 78 [91] 67n E’ Ph H H H 31 [91] Imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines readily reacted with diaryl Imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines readily reacted with diaryl acetylenes in presence of catalyst [92], Scheme 34, Table 16. acetylenes in presence of catalyst [92], Scheme 34, Table 16.

Scheme 34. Pd-NHC complex, Cu(OAc)2, TBAB, DMA, 90◦ °C, 12 h. Scheme 34. Pd-NHC complex, Cu(OAc)2, TBAB, DMA, 90 C, 12 h.

Table 16. Substituents and yields of reaction of 2-arylimidazopiridines and diarylacetylenes (Scheme 34).

N Ar/Ar R2 R8 Yield, % Ref. 69a Ph Me H 67 [92] 69b 4-Me-Ph Me H 71 [92] 69c 2-Me-Ph Me H 60 [92] 69e 4-MeO-Ph Me H 63 [92] 69f 4-F-Ph Me H 68 [92] 69g 4-Cl-Ph Me H 68 [92] 69h 4-Br-Ph Me H 63 [92] 69i Ph t-Bu H 78 [92] 69j 4-Me-Ph t-Bu H 75 [92] 69k 4-F-Ph t-Bu H 74 [92] 69l 4-Cl-Ph t-Bu H 80 [92] 69m 4-Br-Ph t-Bu H 66 [92] 69n Ph t-Bu N 63 [92] 69o 4-Cl-Ph t-Bu N 68 [92] 69p Ph Me Me 61 [92] 69q 4-F-Ph Me Me 59 [92] 69r Ph Mes H 66 [92] 69s 4-Cl-Ph Me H 72 [92]

Separate catalyzed reaction of imidazopyrimidines 70 with diaryl acetylenes gave library of compounds with anti-inflammatory activity [11], Scheme 35, Table 17.

Scheme 35. DMF, PEG-1500, sealed tube Pd(OAc)2, Cu(OAc)2, TBAB 90 °C, 12 h.

Table 17. Substituents and yields of reaction of imidazopyrimidines and diarylacetylenes (Scheme 35).

N Ar R2 Yield, % Ref. 70a Ph Ph 76 [11] 70b Ph 2-MeOPh 72 [11] 70c 4-FPh 2-MeOPh 78 [11] 70d E 2-MeOPh 74 [11] 70e E 4-MeOPh 70 [11] 70f 4-FPh 3-CNPh 61 [11] 70g Ph 3-CNPh 82 [11] 70h 2-Pyridyl 3-CNPh 65 [11] 70i 4-MePh 4-CNPh 68 [11]

Molecules 2021, 26, x FOR PEER REVIEW 18 of 34

Imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines readily reacted with diaryl acetylenes in presence of catalyst [92], Scheme 34, Table 16.

Scheme 34. Pd-NHC complex, Cu(OAc)2, TBAB, DMA, 90 °C, 12 h. Molecules 2021, 26, 2050 18 of 34 Table 16. Substituents and yields of reaction of 2-arylimidazopiridines and diarylacetylenes (Scheme 34).

TableN 16. SubstituentsAr/Ar and yields of reaction R2 of 2-arylimidazopiridinesR8 Yield, and diarylacetylenes% Ref. (Scheme69a 34). Ph Me H 67 [92] 69bN 4-Me-Ph Ar/Ar R2Me R8H Yield, %71 Ref.[92] 69c 2-Me-Ph Me H 60 [92] 69a Ph Me H 67 [92] 69e69b 4-Me-Ph4-MeO-Ph MeMe HH 7163 [92][92] 69f69c 2-Me-Ph4-F-Ph MeMe HH 6068 [92][92] 69g69e 4-MeO-Ph4-Cl-Ph MeMe HH 6368 [92][92] 69f 69h 4-F-Ph4-Br-Ph MeMe HH 6863 [92][92] 69g 4-Cl-Ph Me H 68 [92] 69i69h 4-Br-PhPh Met-Bu HH 6378 [92][92] 69j69i 4-Me-PhPh t-But-Bu HH 7875 [92][92] 69k69j 4-Me-Ph4-F-Ph t-But-Bu HH 7574 [92][92] 69l69k 4-F-Ph4-Cl-Ph t-But-Bu HH 7480 [92][92] 69l 4-Cl-Ph t-Bu H 80 [92] 69m69m 4-Br-Ph4-Br-Ph t-But-Bu HH 6666 [92][92] 69n69n PhPh t-But-Bu NN 6363 [92][92] 69o69o 4-Cl-Ph4-Cl-Ph t-But-Bu NN 6868 [92][92] 69p69p PhPh MeMe MeMe 6161 [92][92] 69q 4-F-Ph Me Me 59 [92] 69q 4-F-Ph Me Me 59 [92] 69r Ph Mes H 66 [92] 69r69s 4-Cl-PhPh MeMes HH 7266 [92][92] 69s 4-Cl-Ph Me H 72 [92] Separate catalyzed reaction of imidazopyrimidines 70 with diaryl acetylenes gave Separate catalyzed reaction of imidazopyrimidines 70 with diaryl acetylenes gave li- library of compounds with anti-inﬂammatory activity [11], Scheme 35, Table 17. brary of compounds with anti-inflammatory activity [11], Scheme 35, Table 17.

◦ SchemeScheme 35. 35.DMF, DMF, PEG-1500, PEG-1500, sealed sealed tube tube Pd(OAc) Pd(OAc)2,2, Cu(OAc) Cu(OAc)22,, TBABTBAB 9090 °C,C, 1212 h.h.

TableTable 17. 17.Substituents Substituents andand yieldsyields ofof reactionreaction ofof imidazopyrimidinesimidazopyrimidines and diarylacetylenes (Scheme (Scheme 35).35).

NN Ar Ar R2 R2 Yield, Yield, % % Ref.Ref. 70a Ph Ph 76 [11] 70a Ph Ph 76 [11] 70b70b Ph Ph2-MeOPh 2-MeOPh 72 72 [11 [11]] 70c70c 4-FPh4-FPh 2-MeOPh 2-MeOPh 78 78 [11 [11]] 70d70d E E2-MeOPh 2-MeOPh 74 74 [11 [11]] 70e70e E E4-MeOPh 4-MeOPh 70 70 [11 [11]] 70f 4-FPh 3-CNPh 61 [11] 70f70g 4-FPh Ph3-CNPh 3-CNPh 82 61 [11 [11]] 70g70h Ph2-Pyridyl 3-CNPh 3-CNPh 65 82 [11 [11]] 70h70i 2-Pyridyl4-MePh 3-CNPh 4-CNPh 68 65 [11 [11]] 70i70j 4-MePhPh 4-CNPh 2-NO2Ph 64 68 [11 [11]] 70k Ph 4-MeOPh 74 [11] 70l 4-MePh 4-MeOPh 65 [11]

The new class of excited-state intramolecular proton transfer-capable molecules, benzo[a]cyclazines, bearing the 2-hydroxyphenyl substituent were prepared in a straight- forward manner from imidazo[1,2-a]pyridines 71 via a tandem [8+2] cycloaddition–[2+6+2] dehydrogenation reaction using microwave [6], and similar reaction also involved imidazopyrimidine derivatives 72 [93], Scheme 36, Table 18. Molecules 2021, 26, x FOR PEER REVIEW 19 of 34

Molecules 2021, 26, x FOR PEER REVIEW 19 of 34

70j Ph 2-NO2Ph 64 [11] 70k Ph 4-MeOPh 74 [11] 70l70j 4-MePhPh 4-MeOPh2-NO2Ph 6564 [11] 70k Ph 4-MeOPh 74 [11] The70l new class4-MePh of excited-state 4-MeOPh intramolecular proton transfer-capable 65 molecules, [11] benzo[a]cyclazines, bearing the 2-hydroxyphenyl substituent were prepared in a straight- forwardThe mannernew class from of excited-stateimidazo[1,2-a]pyridines intramolecular 71 viaproton a tandem transfer-capable [8+2] cycloaddition– molecules, [2+6+2]benzo[a]cyclazines, dehydrogenation bearing reaction the 2-hydroxyphenyl using microwave substituent [6], and similar were preparedreaction also in a involved straight- Molecules 2021, 26, 2050 imidazopyrimidineforward manner from derivatives imidazo[1,2-a]pyridines 72 [93], Scheme 36, 71 Table via a18. tandem [8+2] cycloaddition–19 of 34 [2+6+2] dehydrogenation reaction using microwave [6], and similar reaction also involved imidazopyrimidine derivatives 72 [93], Scheme 36, Table 18.

Scheme 36. Reaction of azaindolizines with benzynes (Table 18).

SchemeTableScheme 18. 36. 36. SubstituentsReaction Reaction ofof and azaindolizinesazaindolizines yields of reaction withwith benzynes benzynes of azaindolizines (Table (Table 18 18). ).and benzynes (Scheme 36).

TableN 18. Substituents and R2 yields of reaction of azaindolizines X Y *and benzynes Yield, (Scheme % 36). Ref. Table 18. Substituents and yields of reaction of azaindolizines and benzynes (Scheme 36). 71a 2-HOPh H A 23 [6] N R2 X Y * Yield, % Ref. 71bN 2-HO-4-MeOPh R2 XH Y *A Yield, 21% Ref. [6] 71a 2-HOPh H A 23 [6] 71c71a 2-HO-5-FPh2-HOPh HH AA 2319 [6][6] 71b 2-HO-4-MeOPh H A 21 [6] 71d71b 2-HO-5-MePh2-HO-4-MeOPh HH AA 2121 [6][6] 72a71c71c 2-HO-5-FPh2-HO-5-FPhPh HH AAB 197419 [6[93]][6] 72b71d71d 2-HO-5-MePh2-HO-5-MePh4-MeOPh HH AAB 213921 [6[93]][6] 72a Ph H B 74 [93] 72c72a 4-FPhPh H B 4974 [93] 72b72b 4-MeOPh4-MeOPh HH BB 3939 [93[93]] 72d72c 4-NO2Ph4-FPh HH BB 4951 [93[93]] 72e72c72d 3,5-(BnO)2Ph4-NO2Ph4-FPh HH BB 5149 [93[93]] 72d72f72e 3,5-(BnO)2Ph4-NO2PhPh HNH BB 495851 [93[93]] 72f Ph N B 58 [93] 72g72e 3,5-(BnO)2Ph4-MeOPh NH B 5449 [93] 72f72g 4-MeOPhPh NN BB 5458 [93[93]] 72h72h 4-FPh4-FPh NN BB 3838 [93[93]] 72g72i72i 4-MeOPh4-MeOPh HHN CCB 43 (3’)4354 (3’) [93[93]] 72h72j72j 4-MeOPh4-MeOPh4-FPh NN CCB 34 (3’)3438 (3’) [93[93]] 72k 4-MeOPh H D 39 (4’) [93] 72k72i 4-MeOPh H DC 3943 (4’)(3’) [93] 72j72l 4-MeOPh4-MeOPh HN DC 18 (5’)34 (3’) [93[93]] 72l72m 4-MeOPhE’ HH BD 5118 (5’) [93[93]] 72k 4-MeOPh H D 39 (4’) [93] * Not72m determined. E’ H B 51 [93] 72l 4-MeOPh H D 18 (5’) [93] 72m E’ H B 51 ◦ [93] A—1-TMS-2-OSOA—1-TMS-2-OSO22CF33-benzene, CsF, 18-Crown-6,18-Crown-6, MWMW (25(25 min,min, 160160 °C);C); B—1-TMS-B—1-TMS- ◦ 2-OSO2-OSO22CFCF33-benzene, CsF, CsF, 18-Crown-6, MW (90 W,W, 4040 psi,psi, 1515 min,min, 8080 °C);C); C—1-TMS-2-C—1-TMS-2- A—1-TMS-2-OSO2CF3-benzene, CsF, 18-Crown-6, MW (25 min, 160◦ °C); B—1-TMS- OSOOSO22CFCF33-3-MeO-benzene,-3-MeO-benzene, CsF,CsF, 18-Crown-6,18-Crown-6, MW MW (90 (90 W,W, 50 50 psi,psi, 1515 min,min, 8080 °C);C); D—1-TMS-D—1-TMS- 2-OSO2CF3-benzene, CsF, 18-Crown-6, MW (90 W, 40 psi, 15 min, 80 °C); ◦C—1-TMS-2- 2-OSO2-OSO22CFCF33-4-MeO-benzene, CsF,CsF, 18-Crown-6,18-Crown-6, MWMW (90(90 W,W, 50 50 psi, psi, 15 15 min, min, 80 80 °C)C) OSOAA2CF basebase3-3-MeO-benzene, promoted promoted protocol protocol CsF, for18-Crown-6, for the the synthesis synthe MWsis of(90 benzo[a]cyclazinesof W, benzo[a]cyclazines 50 psi, 15 min, 80 from °C); from imidazopy- D—1-TMS- imidaz- ridinesopyridines2-OSO and2CF3 benzyne-4-MeO-benzene,and benzyne precursors precursors CsF, under 18-Crown-6, metal-free under metal-free MW conditions (90 W, conditions was 50 psi, developed 15 wasmin, [ developed9480], °C)Scheme [94], 37, TableScheme A19 . base37, Table promoted 19. protocol for the synthesis of benzo[a]cyclazines from imidazopyridines and benzyne precursors under metal-free conditions was developed [94], Scheme 37, Table 19.

Scheme 37. Reaction of imidazopyridines with benzynes (Table 19). Scheme 37. Reaction of imidazopyridines with benzynes (Table 19). Scheme 37. Reaction of imidazopyridines with benzynes (Table 19). Table 19. Substituents and yields of reaction of imidazopiridines and benzynes (Scheme 37).

Table 19. Substituents and yields of reaction of imidazopiridines and benzynes (Scheme 37).

N R2 R6 R7 R8 Method * Reagent Yield, % Ref. 73a Ph H H H A [Benzyne] 75 [94] 73b 4-MeO-Ph H H H A [Benzyne] 72 [94] 73c 4-Et-Ph H H H A [Benzyne] 81 [94] 73d 4-F-Ph H H H A [Benzyne] 69 [94] 73e 4-CN-Ph H H H A [Benzyne] 82 [94] 73f 2-F-Ph H H H A [Benzyne] 70 [94] 73g 2-Cl-Ph H H H A [Benzyne] 66 [94] Molecules 2021, 26, 2050 73h 2-Me-Ph H H H A [Benzyne] 71 20 [94] of 34 73i 2-Br-Ph * H H H A [Benzyne] 55 (de-brom) [94] 73j 4-Cl-Ph Me H H A [Benzyne] 83 [94] 73k 2-Cl-Ph H H Me A [Benzyne] 63 [94] Table73l 19. Cont.Ph Me H H A [Benzyne] 71 [94] 73m 4-Et-Ph H H Me A [Benzyne] 65 [94] N73n 4-Et-Ph R2 Me R6 R7 H R8 H Method A * [Benzyne] Reagent Yield, 60 % [94] Ref. 73k73o 4-MeO-Ph2-Cl-Ph Me H H H Me H A A [Benzyne] [Benzyne] 72 63 [94] [94] 73l73p 2-F-PhPh H Me H H HMe A [Benzyne] [Benzyne] 60 71 [94] [94] 73m73q 4-Et-PhPh H H HH MeMe A [Benzyne] [Benzyne] 75 65 [94] [94] 73n 73r 4-Et-Ph4-Cl-Ph H Me Me H HH A A [Benzyne] [Benzyne] 32 60 [94] [94] 73o 4-MeO-Ph Me H H A [Benzyne] 72 [94] 73s 4-Et-Ph Br * H H A [Benzyne] 54 (de-brom) [94] 73p 2-F-Ph H H Me A [Benzyne] 60 [94] 73q73t PhH H H CO2Me H MeH A [Benzyne] [Benzyne] 50 75 [94] [94] 73r73u 4-Cl-PhH Cl H MeH HH A [Benzyne] [Benzyne] 78 32 [94] [94] 73s73v 4-Et-PhH BrH * HH HH A [Benzyne] [Benzyne] 54 (de-brom)45 [94] [94] 73t73x HHH H CO2MeH HH B A [1-MeO-benzyne-2] [Benzyne] 70 50 [94] [94] 73u73y HH H Cl H H H H CA [1-Me-benzyne-3] [Benzyne] 65 (2 isom.) 78 [94] [94] 73v73 4-Et-PhH H H H H H H CA [1-Me- [Benzyne]benzyne-3] 72 (2 isom.) 45 [94] [94] 73x H H H H B [1-MeO-benzyne-2] 70 [94] 73z 4-Cl-Ph H H H C [1-Me-benzyne-3] 69 (2 isom.) [94] 73y H H H H C [1-Me-benzyne-3] 65 (2 isom.) [94] 7373a1 4-CN-Ph4-Et-Ph H H H H H H D C [1-MeO-benzyne-2] [1-Me-benzyne-3] 72 80 (2(3’) isom.) [94] [94] 73z73b1 4-Cl-Ph4-CN-Ph H H H H H H EC [1-Me-benzyne-3] [1-Me-benzyne-3] 75 69(2 (2isom.) isom.) [94] [94] 73a173c1 4-CN-Ph4-Et-Ph H H H H H H FD [1-MeO-benzyne-2] [1-MeO-benzyne-2] 73 80 (3’) [94] [94] 73b173d1 4-CN-Pht-Bu H H HH HH G E [1-Me-benzyne-3] [Benzyne] 75 62 (2 isom.) [94] [94] 73c1 4-Et-Ph H H H F [1-MeO-benzyne-2] 73 [94] * A—1-TMS-2-OSO2CF3-benzene 18-crown-6-ether, K2CO3; acetone, 45 °C, 24 h; B—1-TMS-2- 73d1 t-Bu H H H G [Benzyne] 62 [94] OSO2CF3-3-MeO-benzene; C—1-TMS-2-OSO2CF3-4-Me-benzene;◦ D—1-TMS-2-OSO2CF3-3-MeO- * A—1-TMS-2-OSO2CF3-benzene 18-crown-6-ether, K2CO3; acetone, 45 C, 24 h; B—1-TMS-2-OSO2CF3-3-MeO- benzene; E—1-TMS-2-OSO2CF3-4-Me-benzene; F—1-TMS-2-OSO2CF3-3-MeO-benzene; G—1-TMS- benzene; C—1-TMS-2-OSO2CF3-4-Me-benzene; D—1-TMS-2-OSO2CF3-3-MeO-benzene; E—1-TMS-2-OSO2CF3-4- 2 3 Me-benzene;2-OSO CF -benzene. F—1-TMS-2-OSO 2CF3-3-MeO-benzene; G—1-TMS-2-OSO2CF3-benzene.

AnAn interestinginteresting reactionreaction thatthat formallyformally ﬁtfit thethe [8+2] [8+2] cycloadditioncycloaddition waswas developeddeveloped forfor interactioninteraction of of imidazopyridinesimidazopyridines74 74and and 1,2-dihalobenzenes1,2-dihalobenzenesin in presencepresence ofof Pd-catalystPd-catalyst [[95],95], SchemeScheme 38 38.. TableTable 20 20..

Scheme 38. Pd/xphos, K2CO3, DMF, 160 °C,◦ 24 h. Scheme 38. Pd/xphos, K2CO3, DMF, 160 C, 24 h.

TableTable 20. SubstituentsSubstituents and andyields yields of reaction of reaction of imidazopyridines of imidazopyridines and 1,2-dihalobenzenes and 1,2-dihalobenzenes (Scheme 38). (Scheme 38). N R2 R6 R7 R8 Yield, % Benzene * Ref 74aN Ph R2H R6H R7H R8 Yield, 77 % Benzene A *[95] Ref 74b74a 4-Me-PhPh H H H H H H 79 77 A A [95] [95] 74c74b 4-MeOPh4-Me-Ph H H H H H H 54 79 A A [95] [95] 74d74c 4-ClPh4-MeOPh H H H H H H 45 54 A A [95] [95] 74e74d 4-CF3Ph4-ClPh H H H H H H 74 45 A A [95] [95] 74e 4-CF3Ph H H H 74 A [95] 74f 3-MeOPh H H H 83 A [95] 74g 2-MePh H H H 60 A [95] 74h 2-Naphtyl H H H 52 A [95] 74i Ph H H Me 83 A [95] 74j Ph H Me H 87 A [95] 74k Ph H Cl H 27 A [95] 74l Ph Me H H 73 A [95] 74m Ph H H N 95 A [95] 74n Ph H H H 80 B [95] 74o Ph H H H 69 C [95] 74p Ph H H H 82 D [95] 74q Ph H H H 86 E [95]

* Benzene: A 1,2-Br2, B 1-Br-2-Cl, 1-I-2-Br, D 1,2-Br2-4,5-Me2, E 1-Br-2-Cl-4-Me. Molecules 2021,, 26,, xx FORFOR PEERPEER REVIEWREVIEW 21 of 34

74f 3-MeOPh H H H 83 A [95] 74g 2-MePh H H H 60 A [95] 74h 2-Naphtyl H H H 52 A [95] 74i Ph H H Me 83 A [95] 74j Ph H Me H 87 A [95] 74k Ph H Cl H 27 A [95] 74l Ph Me H H 73 A [95] 74m Ph H H N 95 A [95] 74n Ph H H H 80 B [95] 74o Ph H H H 69 C [95] Molecules 2021, 26, 2050 74p Ph H H H 82 D [95]21 of 34 74q Ph H H H 86 E [95] * Benzene: A 1,2-Br22,, BB 1-Br-2-Cl,1-Br-2-Cl, 1-I-2-Br,1-I-2-Br, DD 1,2-Br1,2-Br22-4,5-Me-4,5-Me22,, EE 1-Br-2-Cl-4-Me.1-Br-2-Cl-4-Me.

TheThe systemsystem containingcontaining twotwo fusedfused imidazopyridinesimidazopyridines 7575 waswaswas placed placedplaced in inin reaction reactionreactionwith withwith DMADDMAD [ 96[96],], Scheme Scheme 39 39.. One One ring ring of imidazopyridineof imidazopyridine entered entered into [8+2]into [8+2] cycloaddition cycloaddition with the yields 22–30% on heating in benzene. with the yields 22–30% on heating in benzene.

SchemeScheme 39.39. CycloadditionCycloaddition ofof tetraazapentalenetetraazapentalene derivatives.derivatives.

AA rarerare exampleexample ofof benzonitrilebenzonitrile enteredentered intointo [8+2][8+2] cycloadditioncycloaddition toto produceproduce diazacy-diazacy- clazineclazine 76b76b waswas reported reported [97],[97], [97], SchemeScheme Scheme 40. 40.40 .AzaindolizineAzaindolizine Azaindolizine 76a76a reactedreactedreacted withwith with BuLiBuLi BuLi givinggiving giving di-di- dipolarpolar structure structure 76c76c whichwhich underwent underwent cyclization. cyclization.

SchemeScheme 40.40. SynthesisSynthesis ofof diazacyclazine.diazacyclazine.

8.8. ConcertedConcerted One-StepOne-Step 1,101,10 ProcessesProcesses IfIf oneone addsadds aa multiplemultiple bondbond toto thethe endend ofof thethe tetraenetetraene fragmentfragment of of indolizine,indolizine, the the ring ring closureclosure becomesbecomes possible.possible. AA multiplemultiple bondbond cancan bebe alkene,alkene, alkynealkyne oror arene,arene, andand thethe “end”“end” ofof thethe tetraenetetraene cancan be be position position 3 3 or or 5. 5. However,However, no no such such reactions reactions exist exist for for 3-vinyl/ethynyl 3-vinyl/ethynyl Molecules 2021, 26, x FOR PEER REVIEWderivatives and for 5-vinyl indolizines. The ﬁrst example of such cyclization was reported22 of 34 derivatives and for 5-vinyl indolizines. The first example of such cyclization was reported forfor 5-ethynyl5-ethynyl indolizineindolizine77c 77c[ [98,99][98,99]98,99] which whichwhich is isis postulated postulatedpostulatedto totobe bebe intermediate, intermediate,intermediate, Scheme SchemeScheme 41 41.41..

SchemeScheme 41. 41.Cyclization Cyclization of of 6-ethynylpyridinium 6-ethynylpyridinium salts. salts.

AccordingAccording to to [ 98[98]] reaction reaction77a 77a––77b77bproceeded proceeded with with a a yield yield of of 10–15%, 10–15%, later later result result [ 99[99]] waswas 7%. 7%. TheThe main main product product was was 5-Me-3-benzoyl 5-Me-3-benzoyl indolizine indolizine which which could could not not be be converted converted toto 77b77b.. However, However, we we showed showed that that 5-ethynyl 5-ethynyl indolizine indolizine 77c77c obtainedobtained by Sonogashira by Sonogashira cou- couplingpling [100] [100 could] could not not be beconverted converted to tocyclazine cyclazine 77b77b underunder thermal thermal oror acidic acidic conditions. conditions. 5-Iodo-indolizine5-Iodo-indolizine 78a78a inin conditionsconditions ofof SonogashiraSonogashira reactionreaction withwith 22 eqeq ofof ethoxycar-ethoxycar- bonylbonyl acetylene acetylene gave gave cyclazine cyclazine78b 78b[ 36[36],], Scheme Scheme 42 42.. We We supposed supposed that that the the reaction reaction started started fromfrom nucleophilic nucleophilic attack attack of of acetylenide acetylenide anion anion on on78c 78c. .

Scheme 42. Pd(PPh3)2Cl2/CuI/MeCN/Et3N/rt.

5-Ethynyl derivatives of imidazopyridines 79a–c behaved in an expected way [99], Scheme 43.

Scheme 43. 79a–c Me, n-Bu, Ph (70–80%).

In one case the double bond of benzene ring at position 3 of indolizine 80a underwent catalytic ring closure to benzocyclazine 80b [35], Scheme 44.

Molecules 2021, 26, x FOR PEER REVIEW 22 of 34 Molecules Molecules 20212021,, 2626,, xx FORFOR PEERPEER REVIEWREVIEW 2222 ofof 3434

Scheme 41. Cyclization of 6-ethynylpyridinium salts. SchemeScheme 41.41. CyclizationCyclization ofof 6-ethynylpyridinium6-ethynylpyridinium salts.salts. According to [98] reaction 77a–77b proceeded with a yield of 10–15%, later result [99] AccordingAccording toto [98][98] reactionreaction 77a77a––77b77b proceededproceeded withwith aa yieldyield ofof 10–15%,10–15%, laterlater resultresult [99][99] was 7%. The main product was 5-Me-3-benzoyl indolizine which could not be converted waswas 7%.7%. TheThe mainmain productproduct waswas 5-Me-3-benzoyl5-Me-3-benzoyl indolizineindolizine whichwhich couldcould notnot bebe convertedconverted to 77b. However, we showed that 5-ethynyl indolizine 77c obtained by Sonogashira cou- toto 77b77b.. However,However, wewe showedshowed thatthat 5-ethynyl5-ethynyl indolizineindolizine 77c77c obtainedobtained byby SonogashiraSonogashira cou-coupling [100] could not be converted to cyclazine 77b under thermal or acidic conditions. plingpling [100][100] couldcould notnot bebe convertedconverted toto cyclazinecyclazine 77b77b underunder thermalthermal oror acidicacidic conditions.conditions. 5-Iodo-indolizine 78a in conditions of Sonogashira reaction with 2 eq of ethoxycar- Molecules 2021, 26, 2050 5-Iodo-indolizine5-Iodo-indolizine 78a78a inin conditionsconditions ofof SonogashiraSonogashira rereactionaction withwith 22 eqeq ofof ethoxycar-ethoxycar-22 of 34 bonyl acetylene gave cyclazine 78b [36], Scheme 42. We supposed that the reaction started bonylbonyl acetyleneacetylene gavegave cyclazinecyclazine 78b78b [36],[36], SchemeScheme 42.42. WeWe supposedsupposed thatthat thethe reactionreaction startedstarted from nucleophilic attack of acetylenide anion on 78c. fromfrom nucleophilicnucleophilic attackattack ofof acetylenideacetylenide anionanion onon 78c78c..

3 2 2 3 Scheme 42. Pd(PPh3)2Cl2/CuI/MeCN/Et3N/rt. SchemeSchemeScheme 42. 42.42. Pd(PPhPd(PPhPd(PPh33))22ClCl2/CuI/MeCN/Et/CuI/MeCN/Et/CuI/MeCN/Et3N/rt.N/rt.3N/rt. 5-Ethynyl5-Ethynyl derivativesderivatives ofof imidazopyridinesimidazopyridines 79a–cc behavedbehaved inin anan expectedexpected wayway [[99],99], 5-Ethynyl5-Ethynyl derivativesderivatives ofof imidazopyridinesimidazopyridines 79a79a––cc behavedbehaved inin anan expectedexpected wayway [99],[99], SchemeScheme 4343.. SchemeScheme 43.43.

Scheme 43. 79a–c Me, n-Bu, Ph (70–80%). SchemeSchemeScheme 43. 43.43. 79a79a79a–––ccc Me, Me,Me, n-Bu,n-Bu,n-Bu, Ph PhPh (70–80%). (70–80%).(70–80%). In one case the double bond of benzene ring at position 3 of indolizine 80a underwent InInIn oneoneone casecasecase thethethe doubledoubledouble bondbondbond ofofof benzenebenzenebenzene ring ringring at atat positionpositionposition 3 33 ofofof indolizineindolizineindolizine 80a 80a80a underwent underwentunderwent catalytic ring closure to benzocyclazine 80b [35], Scheme 44. catalyticcatalyticcatalytic ring ringring closure closureclosure to toto benzocyclazine benzocyclazinebenzocyclazine 80b 80b80b [ [35],35[35],], Scheme SchemeScheme 44 44.44..

◦ Scheme 44. Pd(OAc)2 10 mol %. PPh3,K2CO3. PhMe/115 C/60 h.

A similar process was employed to obtain highly fluorescent benzo derivatives of azacyclazine starting from Br-substituted 3-aryl imidazopyridines 81, Scheme 45, Table 20[8,101].

Table 21. Substituents and yields of the ring closure reaction on Scheme 45.

N Ar R8 Yield, % Ref. 81a Ph H 100 [8] **, [101]* 81b 4-(Ph)-Ph H 100 [8] 81c 4-t-Bu-Ph H 89 [8] 81d 4-BnO-Ph H 90 [8] 81e 4-(O(CH2)2OBz)-Ph H 89 [8] 81f 4-NMe2-Ph H 98 [8] 81g 4-F-Ph H 98 [8] 81i 4-Cl-Ph H 94 [8] 81j 4-CO2Me-Ph H 95 [8] 81k 4-CN-Ph H 99 [8] 81l 3,4,5-(Me)3-Ph H 93 [8] Molecules 2021, 26, x FOR PEER REVIEW 23 of 34

Scheme 44. Pd(OAc)2 10 mol %. PPh3, K2CO3. PhMe/115 °C/60 h.

A similar process was employed to obtain highly fluorescent benzo derivatives of azacyclazine starting from Br-substituted 3-aryl imidazopyridines 81, Scheme 45, Table 20 [8,101].

Scheme 45. Cyclization of Br-substituted 3-arylimidazopyridines (Table 21).

Molecules 2021, 26, 2050 Table 21. Substituents and yields of the ring closure reaction on Scheme 45. 23 of 34 N Ar R8 Yield, % Ref. 81a Ph H 100 [8] **, [101] * Table81b 21. Cont. 4-(Ph)-Ph H 100 [8] 81c 4-t-Bu-Ph H 89 [8] N Ar R8 Yield, % Ref. 81d 4-BnO-Ph H 90 [8] 81m 2-EtO-4-NO -Ph H 92 [8] 81e 4-(O(CH2)2OBz)-Ph2 H 89 [8] Molecules 2021, 26, x FOR PEER REVIEW 81n 2,3,4,5-(F)4-Ph H 66 [8] 23 of 34 81f81o 4-NMe2-MeO-Ph2-Ph HH 9898 [8[8]] 81g81p 1-Naphtyl4-F-Ph HH 9798 [8[8]] 81i81q 2-Fluorenonyl4-Cl-Ph HH 6194 [8[8]] 81r 2 2-Furyl3 2 3 H 40 [8] Scheme81j 44. Pd(OAc) 104-CO mol 2%.Me-Ph PPh , K CO . PhMe/115H °C/60 h. 95 [8] 81s 2-Tienyl H 65 [8] 81k 4-CN-Ph H 99 [8] A 81tsimilar process 2-Propenylwas employed to obtain H highly fluorescent 87 benzo derivatives [8] of 81l81u 3,4,5-(Me)2-Styryl3-Ph HH 2893 [8 [8]] azacyclazine starting from Br-substituted 3-aryl imidazopyridines 81, Scheme 45, Table 20 * Pd (dba)81m , HP(t-Bu) BF2-EtO-4-NO, DMF, 90 ◦C, 162-Ph h. ** Pd (dba) , HP(t-Bu)H BF ,K CO92, DMF 120 ◦C, 2.5 h. [8] [8,101].2 3 3 4 2 3 3 4 2 3 81n 2,3,4,5-(F)4-Ph H 66 [8] 81o 2-MeO-Ph H 98 [8] 81p 1-Naphtyl H 97 [8] 81q 2-Fluorenonyl H 61 [8] 81r 2-Furyl H 40 [8] 81s 2-Tienyl H 65 [8] 81t 2-Propenyl H 87 [8]

81u 2-Styryl H 28 [8] Scheme 45. Cyclization of Br-substituted 3-arylimidazopyridines (Table 21). Scheme* Pd2(dba) 45.3, CyclizationHP(t-Bu)3BF of4, Br-substitutedDMF, 90 °C, 16 3-arylimidazopyridines h. ** Pd2(dba)3, HP(t-Bu) (Table3BF4, K212CO). 3, DMF 120 °C, 2.5 h.

Table 21. Substituents and yields of the ring closure reaction on Scheme 45. WeWe foundfound thatthat 5-chloro-3-benzoyl5-chloro-3-benzoyl indolizinesindolizines 82a82a,b,b inin acidicacidic conditionsconditions closedclosed thethe ring [102,103], Scheme 46, forming benzocyclazine derivatives 82c,d (X = Cl 83%, ring [102,103],N Scheme 46, Arform ing benzocyclazineR8 derivativesYield, 82c ,%d (X = Cl 83%,Ref. X = NO2 X = NO 90%). Here the protonation opened direct link to 1,10-polyene which under- 90%). Here2 the protonation opened direct link to 1,10-polyene which underwent ring clo- went81a ring closure. Ph H 100 [8] **, [101] * sure.81b 4-(Ph)-Ph H 100 [8]

81c E 4-t-Bu-PhE HE 89 [8] 81d 4-BnO-Ph H 90 [8]

E 2 2 E E 81e + 4-(O(CH ) OBz)-Ph N H 89 [8] N H N 81f 4-NMe2-Ph H 98 [8]

Cl O Cl OH 81g 4-F-Ph H O 98 [8] 81i 4-Cl-Ph H 94 [8] 82a,b ` 82c,d 81j 4-CO2Me-Ph X H 95 [8] Molecules 2021, 26, x FOR PEER REVIEW 24 of 34 X 81k X 4-CN-Ph H 99 [8] SchemeScheme81l 46.46. UnusualUnusual ringring3,4,5-(Me) closureclosure ofof3-Ph 5-chlorindolizines.5-chlorindolizines. H 93 [8] 81m 2-EtO-4-NO2-Ph H 92 [8] 9. Concurrence of [8+2] and [4+2] Cycloadditions 9. Concurrence81n of [8+2]2,3,4,5-(F) and [4+2]4-Ph Cycloadditions H 66 [8] 2-Styrylindolizine81o2-Styrylindolizine 2-MeO-Ph 83a83a reactedreacted withwith methylmethylH acrylateacrylate (Scheme(Scheme98 4747)) givinggiving the[8]the usualusual

productproduct81p of of oxidativeoxidative [8+2][8+2]1-Naphtyl cycloaddition—cyclazinecycloaddition—cyclazine H 83b83btogether together97 withwith [4+2] [4+2] cycloadductcycloadduct[8] 83c without catalyst [38]. After more prolonged heating (from 122 h to 288 h) the ratio 83c without81q catalyst 2-Fluorenonyl[38]. After more prolongedH heating (from61 122 h to 288 h)[8] the ratio 83b:83c changed from 3:68 to 38:10. A somewhat similar result was obtained in reaction 83b:83c81r changed from 3:682-Furyl to 38:10. A somewhatH similar result40 was obtained in[8] reaction withwith N-ethylmaleimideN-ethylmaleimide where [4+2] [4+2] adduct adduct (33%) (33%) was was formed formed together together with with isomeric isomeric di- dihydrocyclazines81s (43%).2-Tienyl H 65 [8] hydrocyclazines81t (43%).2-Propenyl H 87 [8] 81u 2-Styryl H 28 [8] * Pd2(dba)3, HP(t-Bu)3BF4, DMF, 90 °C, 16 h. ** Pd2(dba)3, HP(t-Bu)3BF4, K2CO3, DMF 120 °C, 2.5 h.

We found that 5-chloro-3-benzoyl indolizines 82a,b in acidic conditions closed the ring [102,103], Scheme 46, forming benzocyclazine derivatives 82c,d (X = Cl 83%, X = NO2 90%). Here the protonation opened direct link to 1,10-polyene which underwent ring clo- SchemeSchemesure. 47.47. ExampleExample ofof concurrenceconcurrence betweenbetween [8+2][8+2] andand [8+2][8+2] cycloaddition.

E Possibility of concurrenceE between [8+2] and [4+2]E cycloaddition appeared in the case of 2-aryl substituted azaindolizines, Scheme 48. At least three papers appeared on this E E E + N topic N[7,104,105]H and the Ndata are summarized in Table 22.

Cl O Cl OH O

82a,b ` 82c,d X

X X Scheme 46. Unusual ring closure of 5-chlorindolizines.

Scheme 48. Concurrence in cycloaddition for 2-arylimidazopyridines (Table 22).

Table 22. Substituents, yields and ratio of isomers in concurrent 2+4 and 2+8 cycloadditions of 2- arylazaindolizines and acetylenes (Scheme 48).

N Ar Ar R2 R5 R6 R7 R8 Yield, % (4+2/8+2) Ref. 84a Ph Ph H H H H H 85 (82/18) [104] a 84b 4-FPh 4-FPh H H H H H 79 (68/32) [104] 84c 4-Me-Ph 4-Me-Ph H H H H H 89 (60/40) [104] 84d Ph Ph H H H H Me 88 (46/54) [104] 84e Ph Ph H Me H H H 74 (100/0) [104] 85a Ph Ph H H H H H 65/18 [105] b 85b Ph Ph 4-Me H H H H 72/15 [105] 85c Ph Ph 4-MeO H H H H 75/13 [105] 85d Ph Ph 4-F H H H H 50/33 [105] 85e Ph Ph 4-CF3 H H H H 39/42 [105] 85f Ph Ph 2-Me H H H H 40/45 [105] 85g Ph Ph 2-Tienyl H H H H 80/9 [105] 85h Ph Ph 1-Naphtyl H H H H 43/35 [105] 85i Ph Ph H H H Me H 55/29 [105] 85j Ph Ph H H H H Me 60/26 [105] 85k Ph Ph H H Cl H H 69/7 [105] 85l Ph Ph H H CF3 H H 77/0 [105] 85m 4-MeO-Ph 4-MeO-Ph H H H H H 61/16 [105] 85n 4-Cl-Ph 4-Cl-Ph H H H H H 60/20 [105] 85o 4-CF3-Ph 4-CF3-Ph H H H H H 63/15 [105] 85p 2-Me-Ph 2-Me-Ph Ph H H H H 66/20 [105] 85q E’ E’ H H H H H 51/14 [105] 85r Ph Me Ph H H H H 56/14 [105] 85s Ph n-Pr Ph H H H H 47/16 [105]

Molecules 2021, 26, x FOR PEER REVIEW 24 of 34

9. Concurrence of [8+2] and [4+2] Cycloadditions 2-Styrylindolizine 83a reacted with methyl acrylate (Scheme 47) giving the usual product of oxidative [8+2] cycloaddition—cyclazine 83b together with [4+2] cycloadduct 83c without catalyst [38]. After more prolonged heating (from 122 h to 288 h) the ratio 83b:83c changed from 3:68 to 38:10. A somewhat similar result was obtained in reaction with N-ethylmaleimide where [4+2] adduct (33%) was formed together with isomeric dihydrocyclazines (43%).

Molecules 2021, 26, 2050 24 of 34

Scheme 47. Example of concurrence between [8+2] and [8+2] cycloaddition.

PossibilityPossibility of of concurrenceconcurrence between between [8+2] [8+2] and and [4+2] [4+2] cycloadditioncycloaddition appearedappeared in in the the case case ofof 2-aryl2-aryl substitutedsubstituted azaindolizines,azaindolizines, SchemeScheme 4848.. AtAt leastleast threethree paperspapers appearedappeared onon thisthis topictopic [[7,104,105]7,104,105] andand thethe datadata areare summarized summarized in in Table Table 22 22..

SchemeScheme 48.48. ConcurrenceConcurrence inin cycloadditioncycloaddition forfor 2-arylimidazopyridines2-arylimidazopyridines (Table (Table 22 22).).

Table 22. Substituents, yields and ratio of isomers in concurrent 2+4 and 2+8 cycloadditions of 2- Table 22. Substituents, yields and ratio of isomers in concurrent 2+4 and 2+8 cycloadditions of arylazaindolizines and acetylenes (Scheme 48). 2-arylazaindolizines and acetylenes (Scheme 48). N Ar Ar R2 R5 R6 R7 R8 Yield, % (4+2/8+2) Ref. Yield, % N84a ArPh ArPh R2H R5H R6H R7H H R8 85 (82/18) [104]Ref. a (4+2/8+2) 84b 4-FPh 4-FPh H H H H H 79 (68/32) [104] 84a Ph Ph H H H H H 85 (82/18) [104] a 84c 4-Me-Ph 4-Me-Ph H H H H H 89 (60/40) [104] 84b 4-FPh 4-FPh H H H H H 79 (68/32) [104] 84c84d 4-Me-PhPh 4-Me-PhPh HH H H H H Me H 88 89 (46/54) (60/40) [[104]104] 84d84e PhPh PhPh HH Me H H H H H Me 74 88 (100/0) (46/54) [[104]104] 84e85a PhPh PhPh HH MeH H H H H H 7465/18 (100/0) [105] [104] b 85a Ph Ph H H H H H 65/18 [105] b 85b85b PhPh PhPh 4-Me4-Me H H H H H H 72/15 72/15 [[105]105] 85c85c PhPh PhPh 4-MeO4-MeO H H H H H H 75/13 75/13 [[105]105] 85d85d PhPh PhPh 4-F4-F H H H H H H 50/33 50/33 [[105]105] 85e85e PhPh PhPh 4-CF34-CF3 H H H H H H 39/42 39/42 [[105]105] 85f Ph Ph 2-Me H H H H 40/45 [105] 85g85f PhPh PhPh 2-Tienyl2-Me H H H H H H 40/45 80/9 [[105]105] 85h85g PhPh PhPh 1-Naphtyl2-Tienyl H H H H H H 43/3580/9 [[105]105] 85i85h PhPh PhPh 1-Naphtyl H H H MeH H H 43/35 55/29 [[105]105] 85j Ph Ph H H H H Me 60/26 [105] 85k85i PhPh PhPh HH H ClH Me H H H 55/29 69/7 [[105]105] 85l85j PhPh PhPh HH H CFH3 HH Me H 60/26 77/0 [[105]105] 85m85k 4-MeO-PhPh 4-MeO-PhPh HH H Cl H H H H H 61/1669/7 [[105]105] 85n 4-Cl-Ph 4-Cl-Ph H H H H H 60/20 [105] 85l Ph Ph H H CF3 H H 77/0 [105] 85o 4-CF3-Ph 4-CF3-Ph H H H H H 63/15 [105] 85p85m 2-Me-Ph4-MeO-Ph 2-Me-Ph4-MeO-Ph Ph H H H H H H H 61/16 66/20 [ [105]105] 85q85n 4-Cl-PhE’ 4-Cl-Ph E’ H H H H H H H H 60/20 51/14 [ [105]105] 85r85o 4-CFPh3-Ph 4-CF Me3-Ph PhH H H H H H H 63/15 56/14 [ [105]105] 85s Ph n-Pr Ph H H H H 47/16 [105] 85t85p 2-Me-PhPh 2-Me-Ph Ph Ph Ph Me H H H H H H 66/20 60/0 [ [105]105] 85u85q PhE’ PhE’ 4-MeH MeH H H H H H 51/14 65/0 [[105]105] 85v85r PhPh PhMe 4-CFPh3 MeH H H H H H 56/14 51/0 [[105]105] 85w85s PhPh Phn-Pr 4-FPh MeH H H H H H 47/16 56/0 [[105]105] 85x Ph Ph 2-Me Me H H H 52/0 [105] 85y Ph Ph 3-Me Me H H H 68/0 2 isomers [105] 85z Ph Ph Mes H H H H 0/77 [105] 85a1 Ph Ph Mes H H H Me 0/81 [105] 85b1 Ph Ph Mes H H Me H 0/79 [105] 85c1 Ph Ph Mes H Me H H 0/77 [105] 85d1 Ph Ph Mes H H MeO H 0/86 [105] 85e1 Ph Ph Mes H Cl H H 0/65 [105] 86a 4-BrPh 4-BrPh Ph H H H H 22/27 [7] c 86b 4-BrPh 4-BrPh 4-CNPh H H H H 22/35 [7] c a ◦ b ◦ c : Pd-cat NHC complex Cu(OAc)2, TBAB, DMA, 90 C, 12 h; : Pd(OAc)2, Cu(OAc)2,O2, TBAB, DMF, 100 C; : ◦ Pd(OAc)2, Cu(OAc)2, TBAB, DMAC, 90 C.

10. Understanding the Mechanism: Michael Adducts, Hydrogenated Structures and Others Reactions of [8+2] type of indolizines and their aza/benzo derivatives with acetylenes and alkenes are regioselective due to pronounced polarization of indolizine and (if any) of a multiple bond. Thus, the positive end of the double/triple bond (e.g., in E-C≡CH Molecules 2021, 26, 2050 25 of 34

or in ECH=CH2) would be deﬁnitely attached to π-excessive pyrrole carbon C-3 without any exception, as is evident from all the tables. If the alkene/acetylene bears an electron- donating group and indolizine is appropriately polarized (e.g., by additional 6(8)-NO2 group), then regioselectivity is again preserved, and electronegative end of the multiple bond would be attached to π-deﬁcient pyridine carbon C-5.

10.1. Theory There are theoretical quantum chemical calculations on [8+2] cycloaddition of alkenes to indolizines [106,107] with a variation of the polar nature of substituents in alkenes and comparing indolizine and 6-nitroindolizine. An ab initio and semiempirical (AM1 and SINDO1) calculations clearly conﬁrm the possibility of three different mechanisms (Scheme 49). The concerted one-step mechanism (iii) is preferable, if there are no polar groups in a dienophile and indolizine. Another type of stepwise cycloaddition (electrophilic addition (i)—nucleophilic ring closure (ii)) should be realized for the case of nitroethylene. Molecules 2021, 26, x FOR PEER REVIEW 26 of 34 The last type of dipolar cycloaddition (nucleophilic addition (iv)—electrophilic ring closure (v)) would be expected for the reaction of 6-nitroindolizine with aminoethylene, Table 23.

Scheme 49. Scheme 49. TheoreticallyTheoretically possiblepossible mechanismsmechanisms ofof [8+2][8+2] cycloadditioncycloaddition toto indolizines.indolizines.

Table 23. Possible mechanisms of [8+2] cycloaddition depending on the nature of groups in alkene and indolizne as shown on Scheme 49. Ph Ph N Ph O N N O2N N O2N Substituent in Alkene Indolizine 6-Nitroindolizine H NEt2 H 37% H Nitroethylene (i), (ii)O (i), (ii) NEt2 Methyl87a acrylate (iii)87b (iii) Acrylonitrile (iii)NEt2 (iii) Scheme 50. EthyleneAbnormal cycloadditon to 6-nitroindolizine. (iii) (iii) N,N-Dimethylaminoethylene (iii) (iv), (v) After the addition of alkyne to position C-3 of indolizine, the initially formed zwitter- ion 88aHowever, could be indolizines transformed (even to activated a covalent by st 6-ructure or 8-NO either2-group) forming failed the to reactcycloadduct with enam- 88b ines(i.e., ordihydrocyclazine) enols [107], although or underwent reaction with shift dialkylaminoacetyleneof H-3 from acidic position is possible, C-3 to vinylScheme anion 50. Althoughthus forming the 1:13-vynyl adduct derivative was deﬁnitely 88c. Scheme not the 51. product of [8+2] cycloaddition 87a, rather it was [4+2] adduct of acetylene across the nitroethylene 87b, its structure conﬁrmed the regioselectivity of attack of aminnoacetylene to the position C-5 of indolizine.

N N

R R' H H R' R 88b

N N H H 88c R R' 88a R R' Scheme 51. Possible channels of transformation of initially formed zwitter-ion.

10.2. 3-Vinyl Derivatives In few cases, 3-vinyl substituted intermediates were isolated and characterized from reactions of indolizines and acetylenes, Scheme 52, Table 24. In the first experiment of reaction of indolizines with DMAD without any catalyst, the cis- and trans-adducts 89 were formed [108]. Cis- and trans-derivatives of pyrrolopyrimidone 90 and DMAD did not undergo further cyclization to azacyclazine in presence of Pd-C [85]. 1.8-Annelatyed

MoleculesMolecules 20212021,, 2626,, xx FORFOR PEERPEER REVIEWREVIEW 2626 ofof 3434

Molecules 2021, 26, 2050 26 of 34

SchemeScheme 49.49. TheoreticallyTheoretically possiblepossible mechanismsmechanisms ofof [8+2][8+2] cycloadditioncycloaddition toto indolizines.indolizines.

PhPh N Ph PhPh N Ph N O N OO NN N O22N O N NN O22N NEt HH NEt22 HH H 37% H 37% OO NEtNEt2 87a 2 87b87b 87a NEt NEt22 SchemeScheme 50.50.50. AbnormalAbnormal cycloadditoncycloadditon toto 6-nitroindolizine.6-nitroindolizine.

AfterAfter thethe additionaddition ofof alkynealkyne toto positionposition C-3C-3 ofof indolizine, indolizine, thethe initially initially formed formed zwitter- zwitter- ionionion 88a88a88a could couldcould bebebe transformed transformedtransformed tototo aaa covalent covalentcovalent structure ststructureructure either eithereither forming formingforming thethethe cycloadduct cycloadductcycloadduct 88b 88b88b (i.e.,(i.e.,(i.e., dihydrocyclazine)dihydrocyclazine)dihydrocyclazine) ororor underwentunderwentunderwent shiftshiftshift ofofof H-3H-3H-3 fromfromfrom acidicacidicacidic positionpositionposition C-3C-3C-3 tototo vinyl vinylvinyl anion anionanion thusthusthus formingformingforming 3-vynyl3-vynyl3-vynyl derivativederivativederivative 88c 88c88c... SchemeSchemeScheme 51 51.51..

NN NN R R' R R' HH HH R R'R' R 88b88b

NN NN HH HH 88c R' 88a 88c RR R' 88a R' RR R' SchemeScheme 51.51.51. PossiblePossible channelschannels ofof transformationtransformation ofofof initiallyinitiallyinitially formed formedformed zwitter-ion. zwitter-ion.zwitter-ion.

10.2.10.2. 3-Vinyl3-Vinyl DerivativesDerivatives InInIn fewfewfew cases,cases,cases, 3-vinyl3-vinyl3-vinyl substitutedsubstitutedsubstituted intermediatesintermediatesintermediates werewerewere isolatedisolatedisolated andandand characterizedcharacterizedcharacterized from fromfrom reactionsreactionsreactions ofofof indolizinesindolizinesindolizines andandand acetylenes,acetylenes,acetylenes, SchemeSchemeScheme 5252,52,, TableTableTable 24 24.24.. InInIn thethethe ﬁrstfirstfirst experimentexperimentexperiment ofofof reactionreactionreaction ofofof indolizinesindolizinesindolizines withwithwith DMADDMADDMAD withoutwithoutwithout anyanyany catalyst,catalyst,catalyst, thethethe cis-cis-cis- andandand trans-adductstrans-adductstrans-adducts 898989 werewerewere formedformedformed [[108].108[108].]. Cis-Cis-Cis- andandand trans-derivativestrans-derivativestrans-derivatives ofofof pyrrolopyrimidonepyrrolopyrimidonepyrrolopyrimidone 909090 andandand DMADDMADDMAD diddiddid notnot undergoundergoundergo furtherfurtherfurther cyclizationcyclizationcyclization tototo azacyclazine azacyclazineazacyclazine ininin presence presencepresence of ofof Pd-C Pd-CPd-C [ [85].85[85].]. 1.8-Annelatyed 1.8-Annelatyed1.8-Annelatyed indolizines gave purple 3-vinyl adducts 91 with DBZA [46] which underwent further dehydrogenation without cyclization (see Scheme9). Benzoindolizines 92 [29] and their aza- derivative 93 [88] even in presence of catalysis gave the adducts together with cyclazines. 2-Isopropenyl indolizine 94 after prolonged heating with DMAD gave the mixture of isomeric 3-vinyl derivatives [109]. Molecules 2021, 26, x FOR PEER REVIEW 27 of 34

indolizines gave purple 3-vinyl adducts 91 with DBZA [46] which underwent further dehydrogenation without cyclization (see Scheme 9). Benzoindolizines 92 [29] and their aza- Molecules 2021, 26, 2050 derivative 93 [88] even in presence of catalysis gave the adducts together with cyclazines.27 of 34 2-Isopropenyl indolizine 94 after prolonged heating with DMAD gave the mixture of isomeric 3-vinyl derivatives [109].

SchemeScheme 52.52. 3-Vinyl3-Vinyl derivativesderivatives ofof aza/benzo/indolizinesaza/benzo/indolizines isolated isolated as as intermediates intermediates (see (see Table Table 24).24).

TableTable 24. 24.Stereochemistry, Stereochemistry, conditions conditions and and yields yields of of synthesis synthesis of of vinyl vinyl indolisines indolisines on on Scheme Scheme 52 52.. N R Yield (trans/cis), % Conditions Ref. N R Yield (trans/cis), % Conditions Ref. 89a R = H 13:4 No/Me2CO/rt/15 h [108] 89a R = H 13:4 No/Me2CO/rt/15 h [108] 89b89b R6 R6= Me = Me 11:5 11:5 [108 [108]] 89c89c R7 R7= Me = Me 16:0 16:0 [108 [108]] 89d89d R8 R8= Me = Me 20:0 20:0 [108 [108]] 9090 18:1318:13 Pd/PhMe/Pd/PhMe/∆/21Δ/21 h h [85 [85]] 91a n = 1 62 * No/0◦/THF [46] 91a n = 1 62 * No/0°/THF [46] 91b n = 2 62 * No/0◦/THF [46] 91b92a nR2 = =2 SMe 6226:17 * Pd-C/PhMe/ No/0°/THF∆/30 h [29 [46]] 92a92b R2 =R2 SMe = H 26:17 0:11 Pd-C/PhMe/ Pd-C/PhMe/∆/30Δ/30 h h [29 [29]] 92b93 R2 = H 0:114 * Pd-C/PhMe/ Pd-C/PhMe/∆/30Δ/30 h h [88 [29]] 9394 144 * ** No/PhMe/rt/120Pd-C/PhMe/Δ/30 h h [109 [88]] * Not determined, ** In a mixture. 94 14 * No/PhMe/rt/120 h [109] 10.3.* Not Dihydrocyclazinesdetermined, ** In a mixture. 10.3.First, Dihydrocyclazines dihydrocyclazine was obtained by Boekelheide [23] with a yield of 15% together with cyclazine. He tried to prove the position of protons by chemical tools and ﬁnally First, dihydrocyclazine was obtained by Boekelheide [23] with a yield of 15% to- assigned the protons to be located as in 95 (Scheme 53), i.e., far from the attached DMAD. gether with cyclazine. He tried to prove the position of protons by chemical tools and In 1984 Japanese chemists tried to prove the structure of all intermediated in the reaction offinally indolizines assigned with the DMADprotons into thebe located absence as of in catalyst 95 (Scheme [108 ].53), They i.e., provedfar from two the typesattached of structuresDMAD. In96a 1984and Japanese96b (together chemists with tried 3-vinyl to prove adducts the structure89) obtained of all with intermediated the yields 4–27% in the forreaction96a and of 5–6%indolizines for 96b with. Bis-(indolizinyl)etane DMAD in the absence formed of catalyst the bis-dihydrocyclazine [108]. They proved derivative two types 97of withstructures a yield 96a of and 26% 96b [39 ].(together Azaindolizinone with 3-vinyl reacted adducts with 89 DMAD) obtained in presencewith the yields of Pd-C 4– giving27% for about 96a and 4% of5–6% dihydro-compound for 96b. Bis-(indolizinyl)etane98 [85]. formed the bis-dihydrocyclazine derivative 97 with a yield of 26% [39]. Azaindolizinone reacted with DMAD in presence of Pd-C giving about 4% of dihydro-compound 98 [85].

Molecules 2021, 26, 2050 28 of 34 Molecules 2021, 26, x FOR PEER REVIEW 28 of 34 Molecules 2021, 26, x FOR PEER REVIEW 28 of 34

SchemeScheme 53.53. DihydrocyclazinesDihydrocyclazines obtainedobtained inin thethe synthesis. synthesis.

TheThe structurestructure of of dihydrocyclazine dihydrocyclazine depends depends on on thethe the naturenature nature ofof substituentssubstituents of substituents inin thethe in ring.ring. the ring.Thus, Thus, in our in ourearly early work work [110] [110 we] we found found that that 6-nitroindolizine 6-nitroindolizine reacted withwith DMADDMAD (PhMe/(PhMe/Δ∆/3h) giving giving the expectedexpected nitrocyclazinenitrocyclazine99a 99a(Scheme (Scheme(Scheme 54 )54)54) together togethertogether with withwith the cy-thethe clazinecyclazine99b 99bwithout without NO NOgroup2 group (31%:7%), (31%:7%), which which is formed is formed presumably presumably by eliminationby elimination of cyclazine 99b without NO2 2 group (31%:7%), which is formed presumably by elimination HNOof HNO2 from2 from dihydrocyclazine dihydrocyclazine99c 99c. . of HNO2 from dihydrocyclazine 99c.

Scheme 54. Unusual cycloaddion to 6-nitroindolizine with the loss of NO2 group. Scheme 54. Unusual cycloaddion to 6-nitroindolizine with the loss of NO2 group. Scheme 54. Unusual cycloaddion to 6-nitroindolizine with the loss of NO2 group. In the paper [111] it was shown that 5-Me-indolizine derivative under the action of InIn thethe paperpaper [[111]111] itit was was shown shown that that 5-Me-indolizine 5-Me-indolizine derivativederivative underunder thethe actionaction ofof DMAD (PhH, rt) gave dihydrocyclazine 100a with a yield of 54%, Scheme 55. Further re- DMADDMAD (PhH,(PhH, rt) gave dihydrocyclazine dihydrocyclazine 100a100a withwith aa yield yield of of 54%, 54%, Scheme Scheme 55. 55 Further. Further rereactionaction with with the the excess excess of ofDMAD DMAD give give thethe the macrocyclicmacrocyclic macrocyclic cyclazinecyclazine cyclazine derivativederivative derivative 100b100b [111][111][ 111withwith] withthe structure the structure proved proved by X-ray, by X-ray, and it and was it not was the not structure the structure of the of1:2 the adduct 1:2 adduct (100c) (postu-100c) postulatedlated in [108]. in [ 108].

E E E E H H H H H H Ph Ph N Ph Ph N H Ph Ph H N N N N H E H E Me 100a 100b 100c Me 100a 100b E 100c Me E Me E E E E E E E E E E E E Scheme 55. 1:1 and 1:2 cycloadducts of 5-methylindolizine and DMAD.

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Scheme 53. Dihydrocyclazines obtained in the synthesis.

The structure of dihydrocyclazine depends on the nature of substituents in the ring. Thus, in our early work [110] we found that 6-nitroindolizine reacted with DMAD (PhMe/Δ/3h) giving the expected nitrocyclazine 99a (Scheme 54) together with the cyclazine 99b without NO2 group (31%:7%), which is formed presumably by elimination of HNO2 from dihydrocyclazine 99c.

Scheme 54. Unusual cycloaddion to 6-nitroindolizine with the loss of NO2 group.

In the paper [111] it was shown that 5-Me-indolizine derivative under the action of DMAD (PhH, rt) gave dihydrocyclazine 100a with a yield of 54%, Scheme 55. Further re- Molecules 2021, 26, 2050 action with the excess of DMAD give the macrocyclic cyclazine derivative 100b [111]29 ofwith 34 the structure proved by X-ray, and it was not the structure of the 1:2 adduct (100c) postulated in [108].

E E H H H

N Ph Ph H N N H E 100a 100b Me E 100c Me E E E E Molecules 2021, 26, x FOR PEER REVIEW E E 29 of 34

SchemeScheme 55.55. 1:11:1 andand 1:21:2 cycloadductscycloadducts ofof 5-methylindolizine5-methylindolizine andand DMAD.DMAD.

TheThe reactionreaction ofof MesMes22B-substituted acetylene withwith benzoindolizinebenzoindolizine atat rtrt gave dihydro- 101 cyclazinecyclazine 101 withwith 90%90% yieldyield [[37]37] (Scheme(Scheme 56 56)) whichwhich cancan bebe furtherfurther aromatized.aromatized. TheThe samesame structurestructure underwentunderwent cycloaddition with with hetearyl hetearyl acetylenes acetylenes [66] [66 (CH] (CH2ClCH2ClCH2Cl/2Cl/Δ/6∆ h)/6 giv- h) givinging another another type type of dihydrocyclazines of dihydrocyclazines 102 102(R =(R 2-pyridyl, = 2-pyridyl, 54% 54%and andR = 2-quinoline, R = 2-quinoline, 42%) 42%)which which were wereconverted converted to benzocyclazines to benzocyclazines under underthe action the actionof sulfur of sulfur(PhCl/Δ (PhCl//10 h with∆/10 the h withyields the 59% yields and 59%42%). and 3-CN 42%). substituted 3-CN substituted benzo[a]indolizine benzo[a]indolizine with DMAD with (Pd-C/PhMe/ DMAD (Pd-Δ/2 C/PhMe/h) gave 7%∆ /2of the h) gave adduct 7% of the adductstructure of 103 the structure(together 103with(together benzocyclazine) with benzocyclazine) and with di- andt-BuOCO-acetylene with di-t-BuOCO-acetylene the yield of thecycl yieldoadduct of cycloadduct is higher (42%) is higher [65]. (42%) [65].

SchemeScheme 56.56. DifferentDifferent cycloadductscycloadducts obtainedobtained fromfrom benzoindolizine.benzoindolizine.

10.4.10.4. AlkenesAlkenes TheThe reactionreaction ofof indolizinesindolizines withwith alkenesalkenes hashas attractedattracted a a lotlot ofof attention.attention. TheThe followingfollowing potentialpotential dienophilesdienophiles werewere usedused asas 22ππ-components-components forfor potentialpotential [8+2][8+2] cycloaddition:cycloaddition: ni-ni- trooleﬁns,troolefins, acrylonitrile,acrylonitrile, benzoquinone,benzoquinone, methylvinylketone,methylvinylketone, alkylalkyl acrylates,acrylates, alkylalkyl maleate,maleate, alkylalkyl fumarate,fumarate, maleicmaleic acid,acid, maleicmaleic anhydride,anhydride, N-substitutedN-substituted maleimide,maleimide, 4-substituted-4-substituted- 1,2,4-triazoline-3,5-dione,1,2,4-triazoline-3,5-dione, dialkyldialkyl azodicarboxylates,azodicarboxylates, nitrilenitrile oxide,oxide, 1.2-dicyanocyclobutene1.2-dicyanocyclobutene andand somesome otherother [[38,53,112–115].38,53,112–115]. InIn mostmost reactions,reactions, twotwo typestypes ofof productsproducts areare observed:observed: ﬁrstfirst fromfrom protonproton shiftsshifts inin anan intermediateintermediate zwitter-ion zwitter-ion leading leading ultimately ultimately to to the the isolated isolated Michael Michael addition addition product product at the at positionthe position 3 of the3 of indolizine the indolizine or, second, or, second, deriving deriving from hydrogen from hydrogen loss or shifts loss or in theshifts primary in the adductprimary giving adduct [2+8] giving cycloadducts [2+8] cycloadducts of tetrahydro-, of tetrahydro-, dihydro- dihydro- or (in rarest or (in cases)rarest aromaticcases) ar- cyclazines.omatic cyclazines. In particular, indolizines reacted with maleates and acrylates giving [8+2] cycloadducts In particular, indolizines reacted with maleates and acrylates giving [8+2] cycload- with the subsequent 1,5-hydrogen shift as in 104a, Scheme 57[ 112]. In most other cases ducts with the subsequent 1,5-hydrogen shift as in 104a, Scheme 57 [112]. In most other Michael adducts at C-3 104b were formed. Benzo[a]indolizines with some dipolarophiles cases Michael adducts at C-3 104b were formed. Benzo[a]indolizines with some dipolar- produced kinetically controlled cycloadducts 105a which isomerized to Michael adducts ophiles produced kinetically controlled cycloadducts 105a which isomerized to Michael 105b [113]. For further discussion on the mechanism see ref. [116]. adducts 105b [113]. For further discussion on the mechanism see ref. [116].

Scheme 57. Structure of some adducts and cycloadducts of indoliznes and alkenes.

11. Conclusions As is evident from all the schemes and tables, [8+2] cycloaddition of indolizines, their aza- and benzo derivatives leading to (aza/benzo) cyclazines is a big portion of modern organic chemistry, its concrete and powerful tool with its own achievements and secrets. There are a lot of catalyst and oxidants proposed to make the final aromatic structure, starting from oxygen, sulfur, Pd-C, Pd(OAc)2 and Pd complexes, Cu(OAc)2, MnO2,

Molecules 2021, 26, x FOR PEER REVIEW 29 of 34

The reaction of Mes2B-substituted acetylene with benzoindolizine at rt gave dihydrocyclazine 101 with 90% yield [37] (Scheme 56) which can be further aromatized. The same structure underwent cycloaddition with hetearyl acetylenes [66] (CH2ClCH2Cl/Δ/6 h) giving another type of dihydrocyclazines 102 (R = 2-pyridyl, 54% and R = 2-quinoline, 42%) which were converted to benzocyclazines under the action of sulfur (PhCl/Δ/10 h with the yields 59% and 42%). 3-CN substituted benzo[a]indolizine with DMAD (Pd-C/PhMe/Δ/2 h) gave 7% of the adduct of the structure 103 (together with benzocyclazine) and with di- t-BuOCO-acetylene the yield of cycloadduct is higher (42%) [65].

Scheme 56. Different cycloadducts obtained from benzoindolizine.

10.4. Alkenes The reaction of indolizines with alkenes has attracted a lot of attention. The following potential dienophiles were used as 2π-components for potential [8+2] cycloaddition: ni- troolefins, acrylonitrile, benzoquinone, methylvinylketone, alkyl acrylates, alkyl maleate, alkyl fumarate, maleic acid, maleic anhydride, N-substituted maleimide, 4-substituted- 1,2,4-triazoline-3,5-dione, dialkyl azodicarboxylates, nitrile oxide, 1.2-dicyanocyclobutene and some other [38,53,112–115]. In most reactions, two types of products are observed: first from proton shifts in an intermediate zwitter-ion leading ultimately to the isolated Michael addition product at the position 3 of the indolizine or, second, deriving from hydrogen loss or shifts in the primary adduct giving [2+8] cycloadducts of tetrahydro-, dihydro- or (in rarest cases) aromatic cyclazines. In particular, indolizines reacted with maleates and acrylates giving [8+2] cycloadducts with the subsequent 1,5-hydrogen shift as in 104a, Scheme 57 [112]. In most other Molecules 2021, 26, 2050 cases Michael adducts at C-3 104b were formed. Benzo[a]indolizines with some dipolar-30 of 34 ophiles produced kinetically controlled cycloadducts 105a which isomerized to Michael adducts 105b [113]. For further discussion on the mechanism see ref. [116].

SchemeScheme 57. 57.Structure Structure of of some some adducts adducts and and cycloadducts cycloadducts of of indoliznes indoliznes and and alkenes. alkenes.

11.11. ConclusionsConclusions AsAs isis evident from from all all the the schemes schemes and and tables, tables, [8+2] [8+2] cycloaddition cycloaddition of indolizines, of indolizines, their theiraza- aza-and benzo and benzo derivatives derivatives leading leading to (aza/benzo) to (aza/benzo) cyclazines cyclazines is a big is portion a big portionof modern of modernorganic organicchemistry, chemistry, its concrete its concreteand powerful and powerfultool with its tool own with achievements its own achievements and secrets. andThere secrets. are a Therelot of arecatalyst a lot ofand catalyst oxidants and proposed oxidants proposedto make the to makefinal aromatic the ﬁnal aromaticstructure, structure,starting from starting oxygen, from oxygen,sulfur, Pd-C, sulfur, Pd(OAc) Pd-C, Pd(OAc)2 and Pd2 and complexes, Pd complexes, Cu(OAc) Cu(OAc)2, MnO2,2, MnO2, quinones (DDQ, benzoquinone), new tools appeared to stimulate reaction (blue LED, microwaves, etc.). The dependence of the process on the nature of substituents in the benzo/aza-substituted indolizines and alkynes/alkenes, the intermediacy of open chains cyclic derivatives made clearer the entire mechanism. Even 60 years after its ﬁrst discovery, [8+2] cycloadditions continue to play an important part in organic synthesis.

Author Contributions: E.V.B. formulated the goals, managed performance of all work and wrote the review. I.A.S. prepared all tables with the yields. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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