Indolizines and Their Hetero/Benzo Derivatives in Reactions of [8+2] Cycloaddition

Peculiarities of [8+2] cycloaddition of acetylenes to indolizines are reviewed. Especially mentioned are indolizines with leaving groups at positions 3 and 5. Cycloaddition to aza- and benzo derivatives are reviewed, as well as 1,10-cyclizations and processes leading to cyclazines where indolizines are intermediates. Mechanistic features (adducts and cycloadducts) and theoretical aspects (one- or two-steps mechanism) are reviewed.


Introduction
Indolizine (A, Scheme 1) is the simplest heteroaromatic molecule containing both a π-excessive pyrrole and a π-deficient pyridine ring with only one bridgehead nitrogen, the whole system being isomeric with indole and possess pharmaceutical, agrochemical and fluorescent properties [1]. Although indolizine is certainly aromatic, significant alternations of the bond lengths around the ring system were detected by X-ray, NMR and UV spectroscopy and even mass spectrometry in various substituted indolizines. This prompts some tetraene-like character of the compound, in particular its ability to enter into cycloaddition reactions.

Introduction
Indolizine (A, Scheme 1) is the simplest heteroaromatic molecule containing both a π-excessive pyrrole and a π-deficient pyridine ring with only one bridgehead nitrogen, the whole system being isomeric with indole and possess pharmaceutical, agrochemical and fluorescent properties [1]. Although indolizine is certainly aromatic, significant alternations of the bond lengths around the ring system were detected by X-ray, NMR and UV spectroscopy and even mass spectrometry in various substituted indolizines. This prompts some tetraene-like character of the compound, in particular its ability to enter into cycloaddition reactions. Indolizine is usually regarded as the π-excessive heterocycle with the highest electron population of the carbon atom C-3, and the major part of the chemistry of indolizines is simple electrophilic addition and substitution at this position. Cycloaddition of various Indolizine is usually regarded as the π-excessive heterocycle with the highest electron population of the carbon atom C-3, and the major part of the chemistry of indolizines is simple electrophilic addition and substitution at this position. Cycloaddition of various dienophiles (alkenes and acetylenes) to indolizines leading to derivatives of the cycl[3.2.2]azine (B, Scheme 1) is well-known. The mechanism of these reactions is frequently regarded as a rare example of [8+2] cycloaddition, where the tetraene carbon framework of the indolizine bicycle plays the role of an 8 π-electron fragment. In general, this process may be either one-step (concerted) or involve zwitterionic (and even biradical) intermediates, and there is yet no experimental evidence for the nature of the process.
Cyclazine (B) is an interesting 12π-electronic system that breaks the canons of aromaticity. According to X-ray data the structures B1 and B2 are not correct (Scheme 2), and the structure rather has a peripheral delocalization of aromatic 10 π-electron system B3. Therefore, cyclazine resembles the famous spinning toy B4 where the handle (which is not rotated) corresponds to nitrogen lone pair. Hence, the structure has a symmetry plane, and this influences the number of positional isomers, say the number of aza-and benzo-derivatives possible for cyclazine (Scheme 3).
Molecules 2021, 26, x FOR PEER REVIEW 2 of 34 dienophiles (alkenes and acetylenes) to indolizines leading to derivatives of the cycl[3.2.2]azine (B, Scheme 1) is well-known. The mechanism of these reactions is frequently regarded as a rare example of [8+2] cycloaddition, where the tetraene carbon framework of the indolizine bicycle plays the role of an 8 π-electron fragment. In general, this process may be either one-step (concerted) or involve zwitterionic (and even biradical) intermediates, and there is yet no experimental evidence for the nature of the process. Cyclazine (B) is an interesting 12π-electronic system that breaks the canons of aromaticity. According to X-ray data the structures B1 and B2 are not correct (Scheme 2), and the structure rather has a peripheral delocalization of aromatic 10 π-electron system B3. Therefore, cyclazine resembles the famous spinning toy B4 where the handle (which is not rotated) corresponds to nitrogen lone pair. Hence, the structure has a symmetry plane, and this influences the number of positional isomers, say the number of aza-and benzoderivatives possible for cyclazine (Scheme 3). Cyclazins and their hetero/benzo derivatives are important from a practical viewpoint. They are fluorescent compounds and have excellent prospects in organic electronics [2][3][4][5][6][7][8]. On the other hand, biological activity was found in cyclazines, and their applications as estrogens and anti-inflammatory compounds are well known [9][10][11].
Therefore, this review may be considered as the first and comprehensive review on the [8+2] cycloaddition reactions between aza/benzo indolizines and acetylenes leading to cyclazines. dienophiles (alkenes and acetylenes) to indolizines leading to derivatives of the cycl[3.2.2]azine (B, Scheme 1) is well-known. The mechanism of these reactions is frequently regarded as a rare example of [8+2] cycloaddition, where the tetraene carbon framework of the indolizine bicycle plays the role of an 8 π-electron fragment. In general, this process may be either one-step (concerted) or involve zwitterionic (and even biradical) intermediates, and there is yet no experimental evidence for the nature of the process. Cyclazine (B) is an interesting 12π-electronic system that breaks the canons of aromaticity. According to X-ray data the structures B1 and B2 are not correct (Scheme 2), and the structure rather has a peripheral delocalization of aromatic 10 π-electron system B3. Therefore, cyclazine resembles the famous spinning toy B4 where the handle (which is not rotated) corresponds to nitrogen lone pair. Hence, the structure has a symmetry plane, and this influences the number of positional isomers, say the number of aza-and benzoderivatives possible for cyclazine (Scheme 3). Cyclazins and their hetero/benzo derivatives are important from a practical viewpoint. They are fluorescent compounds and have excellent prospects in organic electronics [2][3][4][5][6][7][8]. On the other hand, biological activity was found in cyclazines, and their applications as estrogens and anti-inflammatory compounds are well known [9][10][11].
Therefore, this review may be considered as the first and comprehensive review on the [8+2] cycloaddition reactions between aza/benzo indolizines and acetylenes leading to cyclazines.

Non-Catalytic Cycloaddition to 3-or 5-Substituted Indolizines
If a leaving group X is located at position 3 or 5 of indolizine ring, cycloaddition reaction does not require a catalyst/oxidant for dehydrogenation, because the dihydrocyclazine intermediate can lose HX, Scheme 14.

Features of Cycloaddition of 3-Cyano Indolizines and Their Benzo Derivatives
3-CN-Indolizines are the structures that looked capable to react with acetylenes without catalyst due to probable loss of HCN from intermediate. In 1980 the Matsumoto group (together with L. Paquet) reported the first reaction of 3-CN-inolizines with DMAD [57], [58]. 3-Cyanindolizine 36a and its 6,8-dimethyl analog 36b with DMAD in refluxing toluene gave expected cyclazines, though in presence of Pd-C (Scheme 16, Table 8). The later 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). The most dramatic story happened to another adduct of CN-indolizines and DMAD. In 1980 the Matsumoto group found that 7-methyl-and 7-benzyl derivatives gave 1:2 adduct with proposed structure 39a [58], Scheme 17. Later the same group tested the reaction of 3-CN indolizines 38a-g in the presence and absence of a catalyst [60,61], Table 8. Finally, the structure of the 1:2 adduct formed without the catalyst was proved by X-ray, and it was unexpectedly styryl pyrrole 39b [60,61], Scheme 17. Different mechanisms of benzene ring formation and E-group migration have been proposed.  Table 8). The most dramatic story happened to another adduct of CN-indolizines and DMAD. In 1980 the Matsumoto group found that 7-methyl-and 7-benzyl derivatives gave 1:2 adduct with proposed structure 39a [58], Scheme 17. Later the same group tested the reaction of 3-CN indolizines 38a-g in the presence and absence of a catalyst [60,61], Table 8. Finally, the structure of the 1:2 adduct formed without the catalyst was proved by X-ray, and it was unexpectedly styryl pyrrole 39b [60,61], Scheme 17. Different mechanisms of benzene ring formation and E-group migration have been proposed.
Scheme 16. Cycloaddition to 3-CN-substituted indolizines (see Table 8). The most dramatic story happened to another adduct of CN-indolizines and DMAD. In 1980 the Matsumoto group found that 7-methyl-and 7-benzyl derivatives gave 1:2 adduct with proposed structure 39a [58], Scheme 17. Later the same group tested the reaction of 3-CN indolizines 38a-g in the presence and absence of a catalyst [60,61], Table 8. Finally, the structure of the 1:2 adduct formed without the catalyst was proved by X-ray, and it was unexpectedly styryl pyrrole 39b [60,61], Scheme 17. Different mechanisms of benzene ring formation and E-group migration have been proposed. Cyano-derivative of benzo[a]indolizine is easily available from pyridinium-dicyanme thylide 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]. Cyano-derivative of benzo[a]indolizine is easily available from pyridinium-dicyanmethylide 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].
Another route to the same benzo-skeleton is cycloaddition of alkynes to benzo[a]indolizines. This reaction was studied with acetylenes containing boron substituents, alone 44a-c [37] or together with nitrogen-containing heterocycle on another end of acetylene 45a-e [5], Scheme 21, Table 11. In one experiment 46 benzyne was generated from PhBr; this resulted in dibenzocyclazine was obtained with low yield [66]. Scheme 21. Cycloaddition to benzoindolizines see Table 11). Another route to the same benzo-skeleton is cycloaddition of alkynes to benzo[a]indoli zines. This reaction was studied with acetylenes containing boron substituents, alone 44a-c [37] or together with nitrogen-containing heterocycle on another end of acetylene 45a-e [5], Scheme 21, Table 11. In one experiment 46 benzyne was generated from PhBr; this resulted in dibenzocyclazine was obtained with low yield [66].  [3] Condensed structures from 43r,s with coumarin ring were similarly obtained, Scheme 20 [3]. Another route to the same benzo-skeleton is cycloaddition of alkynes to benzo[a]indolizines. This reaction was studied with acetylenes containing boron substituents, alone 44a-c [37] or together with nitrogen-containing heterocycle on another end of acetylene 45a-e [5], Scheme 21, Table 11. In one experiment 46 benzyne was generated from PhBr; this resulted in dibenzocyclazine was obtained with low yield [66]. Scheme 21. Cycloaddition to benzoindolizines see Table 11). Scheme 21. Cycloaddition to benzoindolizines see Table 11). 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. 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 In another paper [68] 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. 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 In another paper [68] 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. 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 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 single bonds), and therefore, the process could be better treated as [2+16] rather than [2+8] cycloaddition.

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.

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.

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 [

Concerted One-Step 1,10 Processes
If one adds a multiple bond to the end of the tetraene fragment of indolizine, the ring closure becomes possible. A multiple bond can be alkene, alkyne or arene, and the "end" of the tetraene can be position 3 or 5. However, no such reactions exist for 3-vinyl/ethynyl derivatives and for 5-vinyl indolizines. The first example of such cyclization was reported for 5-ethynyl indolizine 77c [98,99] which is postulated to be intermediate, Scheme 41.

Concerted One-Step 1,10 Processes
If one adds a multiple bond to the end of the tetraene fragment of indolizine, the ring closure becomes possible. A multiple bond can be alkene, alkyne or arene, and the "end" of the tetraene can be position 3 or 5. However, no such reactions exist for 3-vinyl/ethynyl derivatives and for 5-vinyl indolizines. The first example of such cyclization was reported for 5-ethynyl indolizine 77c [98,99] which is postulated to be intermediate, Scheme 41. According to [98] reaction 77a-77b proceeded with a yield of 10-15%, later result [99] was 7%. The main product was 5-Me-3-benzoyl indolizine which could not be converted to 77b. However, we showed that 5-ethynyl indolizine 77c obtained by Sonogashira coupling [100] could not be converted to cyclazine 77b under thermal or acidic conditions. 5-Iodo-indolizine 78a in conditions of Sonogashira reaction with 2 eq of ethoxycarbonyl acetylene gave cyclazine 78b [36], Scheme 42. We supposed that the reaction started from nucleophilic attack of acetylenide anion on 78c. According to [98] reaction 77a-77b proceeded with a yield of 10-15%, later result [99] was 7%. The main product was 5-Me-3-benzoyl indolizine which could not be converted to 77b. However, we showed that 5-ethynyl indolizine 77c obtained by Sonogashira coupling [100] could not be converted to cyclazine 77b under thermal or acidic conditions. 5-Iodo-indolizine 78a in conditions of Sonogashira reaction with 2 eq of ethoxycarbonyl acetylene gave cyclazine 78b [36], Scheme 42. We supposed that the reaction started from nucleophilic attack of acetylenide anion on 78c.
According to [98] reaction 77a-77b proceeded with a yield of 10-15%, later result [99] was 7%. The main product was 5-Me-3-benzoyl indolizine which could not be converted to 77b. However, we showed that 5-ethynyl indolizine 77c obtained by Sonogashira coupling [100] could not be converted to cyclazine 77b under thermal or acidic conditions. 5-Iodo-indolizine 78a in conditions of Sonogashira reaction with 2 eq of ethoxycarbonyl acetylene gave cyclazine 78b [36], Scheme 42. We supposed that the reaction started from nucleophilic attack of acetylenide anion on 78c. 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. According to [98] reaction 77a-77b proceeded with a yield of 10-15%, later result [99] was 7%. The main product was 5-Me-3-benzoyl indolizine which could not be converted to 77b. However, we showed that 5-ethynyl indolizine 77c obtained by Sonogashira coupling [100] could not be converted to cyclazine 77b under thermal or acidic conditions. 5-Iodo-indolizine 78a in conditions of Sonogashira reaction with 2 eq of ethoxycarbonyl acetylene gave cyclazine 78b [36], Scheme 42. We supposed that the reaction started from nucleophilic attack of acetylenide anion on 78c. 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. 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. According to [98] reaction 77a-77b proceeded with a yield of 10-15%, later result [99] was 7%. The main product was 5-Me-3-benzoyl indolizine which could not be converted to 77b. However, we showed that 5-ethynyl indolizine 77c obtained by Sonogashira coupling [100] could not be converted to cyclazine 77b under thermal or acidic conditions. 5-Iodo-indolizine 78a in conditions of Sonogashira reaction with 2 eq of ethoxycarbonyl acetylene gave cyclazine 78b [36], Scheme 42. We supposed that the reaction started from nucleophilic attack of acetylenide anion on 78c. 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. 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].   [7,104,105] and the data are summarized in Table 22.
or in ECH=CH 2 ) 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 electrondonating group and indolizine is appropriately polarized (e.g., by additional 6(8)-NO 2 group), then regioselectivity is again preserved, and electronegative end of the multiple bond would be attached to π-deficient pyridine carbon C-5.

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. The last type of dipolar cycloaddition (nucleophilic addition (iv)-electrophilic ring closure (v)) would be expected for the reaction of 6-nitroindolizine with aminoethylene, After the addition of alkyne to position C-3 of indolizine, the initially formed zwitterion 88a could be transformed to a covalent structure either forming the cycloadduct 88b (i.e., dihydrocyclazine) or underwent shift of H-3 from acidic position C-3 to vinyl anion thus forming 3-vynyl derivative 88c. Scheme 51.

Substituent in Alkene
Indolizine 6-Nitroindolizine However, indolizines (even activated by 6-or 8-NO 2 -group) failed to react with enamines or enols [107], although reaction with dialkylaminoacetylene is possible, Scheme 50. Although the 1:1 adduct was definitely not the 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. After the addition of alkyne to position C-3 of indolizine, the initially formed zwitterion 88a could be transformed to a covalent structure either forming the cycloadduct 88b (i.e., dihydrocyclazine) or underwent shift of H-3 from acidic position C-3 to vinyl anion thus forming 3-vynyl derivative 88c. Scheme 51.

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 Scheme 50. Abnormal cycloadditon to 6-nitroindolizine.
After the addition of alkyne to position C-3 of indolizine, the initially formed zwitterion 88a could be transformed to a covalent structure either forming the cycloadduct 88b (i.e., dihydrocyclazine) or underwent shift of H-3 from acidic position C-3 to vinyl anion thus forming 3-vynyl derivative 88c. Scheme 51. After the addition of alkyne to position C-3 of indolizine, the initially formed zwitterion 88a could be transformed to a covalent structure either forming the cycloadduct 88b (i.e., dihydrocyclazine) or underwent shift of H-3 from acidic position C-3 to vinyl anion thus forming 3-vynyl derivative 88c. Scheme 51.

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 Scheme 51. Possible channels of transformation of initially formed zwitter-ion.

Dihydrocyclazines
First, 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 assigned the protons to be located as in 95 (Scheme 53), i.e., far from the attached DMAD. In 1984 Japanese chemists tried to prove the structure of all intermediated in the reaction of indolizines with DMAD in the absence of catalyst [108]. They proved two types of structures 96a and 96b (together with 3-vinyl adducts 89) obtained with the yields 4-27% for 96a and 5-6% for 96b. Bis-(indolizinyl)etane 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]. Scheme 52. 3-Vinyl derivatives of aza/benzo/indolizines isolated as intermediates (see Table 24).

Dihydrocyclazines
First, 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 assigned the protons to be located as in 95 (Scheme 53), i.e., far from the attached DMAD. In 1984 Japanese chemists tried to prove the structure of all intermediated in the reaction of indolizines with DMAD in the absence of catalyst [108]. They proved two types of structures 96a and 96b (together with 3-vinyl adducts 89) obtained with the yields 4-27% for 96a and 5-6% for 96b. Bis-(indolizinyl)etane 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]. 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 reaction with the excess of DMAD give the macrocyclic cyclazine derivative 100b [111] with the structure proved by X-ray, and it was not the structure of the 1:2 adduct (100c) postulated in [108]. 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/∆/3h) giving the expected nitrocyclazine 99a (Scheme 54) together with the cyclazine 99b without NO 2 group (31%:7%), which is formed presumably by elimination of HNO 2 from dihydrocyclazine 99c. 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 reaction with the excess of DMAD give the macrocyclic cyclazine derivative 100b [111] with the structure proved by X-ray, and it was not the structure of the 1:2 adduct (100c) postulated in [108].  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 reaction with the excess of DMAD give the macrocyclic cyclazine derivative 100b [111] with the structure proved by X-ray, and it was not the structure of the 1:2 adduct (100c) postulated in [108].
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 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.

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

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 , MnO 2 , 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.