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

Abstract

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.

1. 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.

Scheme 1.

Indolizines (A) in [8+2] cycloaddition reaction forming cycl[3.2.2]azines (B). The reaction may proceed with alkynes or alkenes via dihydro- (C1) or tetrahydro- (C2) cyclazines.

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).

Scheme 2.

Different images of the structure of cyclazine.

Scheme 3.

Possible benzo- aza- and benzoazacyclazines discussed in this review.

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].

Cyclazine was first obtained from indolizine by Boekelheide 60 years ago. This author was the first who postulated the [8+2] mechanism. After this time the [8+2] reaction was reviewed several times. The first review by Acheson appeared in 1963 [12] and the next one by Taurins in 1977 [13]. Several reviews were written on the chemistry of cyclazines [1,14,15,16,17,18,19]. In the reviews of Nair and Abhilash [20,21] devoted to [8+2] cycloaddition reactions, only a limited number of indolizine reactions was mentioned.

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.

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].

Table 1.

Substituents, reaction conditions and yields of reactions of indolizines with substituted acetylenes giving cyclazines (Scheme 4).

N	R/R’	R1	R2	R6	R7	R8	Cat/Solv/T°/Time	Yield %	Ref.
1	E/E a	H	H	H	H	H	Pd-C/MePh/Δ	50–66	[22]
2	E/E	H	H	H	H	H	Pd-C/MePh/Δ/24 h	68	[23]
3	E/E	H	H	H	H	H	MnO2/MePh/Δ/16 h	55	[4]
4	E/H	H	H	H	H	H	Pd-C/MePh/Δ/24 h	11	[24]
5	E/E	H	Ph	H	H	H	Pd-C/MePh/Δ/20 h	28	[25]
6	E/E	H	Me	H	H	H	Pd-C/MePh/Δ	60	[27]
7a	E/E	H	H	H	H	Me	Pd-C/MePh/Δ/1.5 h	53	[28]
7b	E/E	H	H	H	H	Pr	Pd-C/MePh/Δ/1.5 h	53	[28]
7c	E/E	H	H	H	H	Ph	Pd-C/MePh/Δ/1.5 h	53	[28]
8a	E/E	H	Ph	H	H	H	Pd-C/MePh/Δ	39	[26]
8b	E/E	H	p-tBuPh	H	H	H	Pd-C/MePh/Δ	75	[26]
9a	E/E	H	H	H	H	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]
9c	E/E	H	H	Me	H	Me	Pd-C/MePh/Δ/100 h	25	[29]
10	E/E	CONH2	MeS	H	H	H	Pd-C/MePh/Δ/24 h	70	[30]
11a	E/H	CONH2	MeS	H	H	H	Pd-C/MePh/Δ/100 h	45	[31]
11b	E/H	CONH2	MeS	H	Me	H	Pd-C/MePh/Δ/100 h	48	[31]
12a	E/E	H	MeS	H	H	H	Pd-C/MePh/Δ/100 h	38	[29]
12b	E/E	H	MeS	H	H	Me	Pd-C/MePh/Δ/100 h	40	[29]
12c	E/E	H	MeS	Me	H	Me	Pd-C/MePh/Δ/100 h	49	[29]
13a	E/E	H	H	H	NMe2	H	Pd-C/MePh/Δ	32	[2]
13b	E/E	H	MeS	H	NMe2	H	Pd-C/MePh/Δ	17	[2]
14a	E’/E’ b	F	p-Brh	H	H	H	Cu(OAc)2/PhMe/Δ/5 h	63	[34]
14b	E’/E’	F	p-MeOPh	H	H	H	Cu(OAc)2/PhMe/Δ/8 h	70	[34]
15	E/H	E	Me	H	H	H	Pd-C/PhH/Δ/24 h	NG c	[39]
16a	E/H	2-Py	Me	H	H	H	No/NO2Ph/Δ/20 h	43	[40]
16b	E/E	2-Py	Me	H	H	H	No/NO2Ph/Δ/20 h	47	[40]
17	E/E	H	Me	o-OHPhCO	H	COMe	Pd-C/MePh/Δ/16 h	54	[35]
18	E/H	H	t-Bu	H	H	H	O2/MePh/Δ/4 h	79	[36]
19	Me2B/H	H	H	H	H	H	(1) MePh/Δ/3 d (2) DDQ	55	[37]
20a	E/E	H	Styryl	H	H	H	No/PhMe/50o/31 h	44	[38]
20b	E/H	H	Styryl	H	H	H	No/PhMe/20o/120 h	64	[38]

^a: E—CO₂Me, ^b: E’ = CO₂Et, ^c: NG—not given.

Scheme 4.

Symthesis of cyclazines from indolizines (Table 1).

Indolizines 9a–c obtained by desulfurization of 2-MeS derivatives were converted to 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-COOR derivatives were hydrolyzed and decarboxylated to 12a–c and converted to cyclazines [29]. A similar methodology was used to construct cyclazine from 2-MeS-7-NMe₂-indolizine 13b: desulfurization gave 7-NMe₂ derivative 13a and the addition of DMAD gave corresponding cyclazine [2].

Fluoro-substituted indolizines are seldom [33] but 1-fluoro derivatives 14a,b underwent cycloaddition in oxidative condition in presence of Cu(II) salts [34]. One more example to introduce functionality to cyclazine is catalytic cycloaddition of 6,8-diacyl indolizine 17 [35]. In our recent work, we proved that MAC could react with 2-t-Bu indolizine 18 giving cyclazine in open-air [36]. One featured reaction was cycloaddition of indolizine 19 with Mes₂B-substituted acetylene [37]. 2-Styryl indolizine reacted with DMAD and MAC without a catalyst [38]. Big series of cyclazines (though without the yields) was synthesized and described as estrogens [9,10].

1-Methoxycarbonyl indolizine 15 (Table 1) was converted to cyclazine in order to make cyclophane [39], but this methodology failed. Finally, cyclazines 21c,d were obtained from bis-indolizinylethanes 21a,b (R = Me, t-Bu) and further converted to cyclophanes [39], Scheme 5.

Scheme 5.

Synthesis of bis-cyclazinylethanes from bis-indolizinylethanes.

1-(2-Pyridyl)indolizine in reaction with acetylenes 16a,b formed cyclazine [40], Table 1. The product was converted to indolizino-cyclazine 16c, and DMAD was added for the second time giving bi-cyclazine 16d (20 h in boiling xylene without catalyst) with a yield of 30%, Scheme 6.

Scheme 6.

i N-bromsuccinimide. 6 h; ii K₂CO₃.

Analogous structure bearing 2-CO₂Et group 22a [41] was converted to condensed indolizino-cyclazinone structure 22b. from which cyclazino-cyclazinone 22c was obtained with the yield 73% (Pd/C, NO₂Ph, 20 h), Scheme 7.

Scheme 7.

Synthesis of cyclazino-cyclazinone.

A Japanese group made an effort to prepare cyclazines from 1,8-cycloannelated indolizines 23 [42,43,44] containing propylene and butylene bridges, Scheme 8, Table 2. The major finding was the use of DDQ in reaction with dibenzoyl acetylene (DBZA) under extremely mild conditions. Further studies on oxo-derivatives 24 [45] allowed to make cyclazine bearing (in 1 and 8 positions) oxo-propyl group.

Scheme 8.

Synthesis of cyclazines from 1,8-cycloannelated indolizines (see Table 2).

Table 2.

Substituents and yields of cycloaddition of acetylenes to indolizines 23–25 annelated by a ring across the positions C1 and C-8 (Scheme 8).

N	R/R’	R8-R1	R2	Cat/Solv/T°/Time	Yield %	Ref.
23a	E/H	(CH2)4	Me	Pd-C/PhMe/Δ/50 h	75	[42]
23b	E/H	(CH2)3	Me	Pd-C/PhMe/Δ/50 h	75	[42]
23c	E/E	(CH2)4	Me	Pd-C/PhMe/Δ/50 h	85	[42]
23d	E/E	(CH2)3	Ph	Pd-C/PhMe/Δ/50 h	58	[42]
23d	E/E	(CH2)4	Ph	Pd-C/PhMe/Δ/50 h	61	[42]
23e	E/E	(CH2)3	Me	Pd-C/PhMe/Δ/50 h	77	[42]
24f	COPh/COPh	(CH2)4	Me	DDQ/THF/0°/1 h	86	[42]
23g	COPh/COPh	(CH2)4	Ph	DDQ/THF/0°/1 h	92	[42]
23h	COPh/COPh	(CH2)3	Me	DDQ/THF/0°/1 h	68	[42]
23i	COPh/COPh	(CH2)3	Ph	DDQ/THF/0°/1 h	52	[42]
24a	E/E	O=C(CH2)2	Ph	DDQ/MePh/Δ/2 h	92	[45]
24b	E/E	O=C(CH2)2	E’	DDQ/MePh/Δ/2 h	98	[45]
25a	COPh/COPh	CH2-NE’-CH2	H	DDQ/THF/0°/10 m	66	[46]
25b	COPh/COPh	CH2-NE’-(CH2)2	H	DDQ/THF/0°/10 m	84	[46]

Finally, fused indolizines 25 with saturated piperidyl or hexamethyleneimine bridges across 1,8-positions were [46] prepared and involved in cycloaddition with DBZA giving expected cyclazines, Scheme 9. Table 2. However, an attempt to perform similar reaction with DMAD caused cyclazine formation with unsaturated azepine ring.

Scheme 9.

Abnormal cycloaddition to 1,8-cycloannelated indolizine combined with dehydrogenation.

Novel reaction conditions were found for cycloaddition reaction, so that the role of oxidant was played by O₂ in presence of Pd(OAc)₂ [47], Scheme 10. Many 1-alkoxycarbonyl derivatives (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.

Table 3.

Substituents and yields of cycloaddition of diarylalkynes to indolizines (Scheme 10).

N	R	R’	R1	R2	Yield %	Ref.
26a	Ph	Ph	E’	E’	92	[47]
26b	4-MePh	4-MePh	E	H	88	[47]
26c	Ph	Ph	E	E	98	[47]
26d	4-FPh	4-FPh	E	E	85	[47]
26e	3-BrPh	3-BrPh	E	E	56	[47]
26f	4-NO2Ph	4-MeOPh	E	E	80 (6:1)	[47]
26g	4-NO2Ph	Ph	E	E	68 (20:1)	[47]
26h	4-FPh	4-MeOPh	E	E	91 (2:1)	[47]
26i	C≡CPh	Ph	E	E	41;39	[47]
26j	Ph	Ph	CO2nBu	CO2nBu	79	[47]
26k	Ph	Ph	E	Ph	20 *	[47]
26l	Ph	Ph	CO2tBu	H	55	[47]
26l	Ph	Ph	H	E	70	[47]
26m	Ph	Ph	CONMe2	H	76	[47]
26n	Ph	Ph	E’	H	87	[47]
26o	Ph	Ph	E	H	90	[47]
26p	Ph	Ph	CN	H	59	[47]

* Not determined.

A range of indolizine 27 smoothly underwent visible-light-induced intermolecular cyclization with internal alkynes with acceptor group to afford cyclazines in good to excellent yields with high regioselectivity [48], Scheme 11, Table 4.

Scheme 11.

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

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]
28i	E	Ph	H	Et	H	H	70	[49]
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]
28m	E	4-MeOPh	H	H	H	H	71	[49]
28n	E	3-FPh	H	H	H	H	75	[49]
28o	E	3-ClPh	H	H	H	H	66	[49]
28p	E	3-BrPh	H	H	H	H	70	[49]
28q	E	3-MePh	H	H	H	H	71	[49]
28r	2-Py	3-MePh	H	H	H	H	66	[49]
28s	E	3-MeOPh	H	H	H	H	68	[49]
28t	E	3-FPh	H	H	H	H	65	[49]
28u	E	3,4-Cl2Ph	H	H	H	H	70	[49]
28v	E	3,4-(MeO)2Ph	H	H	H	H	66	[49]
28x	E	2-Thienyl	H	H	H	H	69	[49]

Annulations of 1-cyanoIndolizine with unsaturated carboxylic acids 29a–f was observed during the catalysis with Pd(OAc)₂ [50], via similar cascade reaction Scheme 13, Table 6.

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.

N	R	Yield, %	Ref.
29a	Me	39	[50]
29b	Ph	52	[50]
29c	4-Cl-Ph	46	[50]
29e	4-OMePh	59	[50]
29f	1-Naphtyl	45	[50]

3. 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.

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 others, Scheme 15.

Scheme 15.

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

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]. 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] smoothly formed the expected cyclazine structures in the absence of catalyst.

4. 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).

Table 8.

Substituents, conditions and yields in cycloaddition of acetylene acetylenes to 3-CN-substituted indolizines giving cyclazines (Scheme 16).

N	R/R’	R1	R2	R6	R7	R8	Cat/Solv/T°/Time	Yield %	Ref.
36a	E/E	H	H	H	H	H	Pd-C/PhH/Δ/24 h	40	[58]
36b	E/E	H	H	Me	H	Me	Pd-C/PhH/Δ/24 h	25	[58]
37a	E/E	H	MeS	H	H	H	Pd-C/PhH/Δ/30 h	22	[59]
37b	E/E	H	MeS	Me	H	Me	Pd-C/PhH/Δ/30 h	12	[59]
38a	E/E	H	H	H	H	H	Pd’C/MePh/Δ/24 h	40	[60]
38b	E/E	H	H	H	Me	H	Pd’C/MePh/Δ/25–74 h	10-7	[60]
38c	E/E	H	H	H	PhCH2	H	Pd’C/MePh/Δ/30 h	5	[60]
38d	E/E	H	H	H	Ph	H	Pd’C/MePh/Δ/215 h	13	[60]
38e	E/E	H	H	Me	H	Me	Pd’C/MePh/Δ/77 h	25	[60]
38f	E/E	H	H	H	CN	H	Pd’C/MePh/Δ/260 h	7	[60]
38g	E/E	H	H	H	E	H	Pd’C/MePh/Δ/336 h	2	[60]

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 17.

Structure of 1:2 adduct of 3-cyanoindolizine and DMAD.

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]. Finally, this reaction was tested extensively with various acetylenes 42 [65].

Scheme 18.

Cycloaddition to 3-CN-substituted benzoindolizines (see Table 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-Aminobenzotriazole/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]
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].

Scheme 20.

CsF, MeCN, 90°. 43r (R7R8 = H, 93%), 43s (R7,R8 = benzo, 62%), Method A.

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).

Table 11.

Substituents and yields (ratio of isomers) of cycloaddition to benzoindolizines (Scheme 21).

N	R1	R2	Solv/T°/Time/Oxidant	Yield, %	Ref.
44a	Mes2B	H	PhMe/rt/30m/DDQ	89	[37]
44b	2-(Mes2B)Ph	H	PhMe/Δ/3d/DDQ	75	[37]
44c	4-(Mes2B)Ph	H	PhMe/Δ/3d/DDQ	83	[37]
45a	4-(Mes2B)Ph	2-Py	(1) PhMe/120 °C/5–6d; (2) DDQ/rt/0.5 h	79:2	[5]
45b	2-(Mes2B)Ph	2-Py	(1) PhMe/120 °C/5–6d; (2) DDQ/rt/0.5 h	82:4	[5]
45c	2-(Mes2B)Ph	2-Isoquinolyl	(1) PhMe/120 °C/5–6d; (2) DDQ/rt/0.5 h	72:18	[5]
45d	2-(Mes2B)Ph	2-Benzotiazolyl	(1) PhMe/120 °C/5–6d; (2) DDQ/rt/0.5 h	62:19	[5]
45e	2-(Mes2B)Ph	2-Tiazolyl	(1) PhMe/120 °C/5–6d; (2) DDQ/rt/0.5 h	68:14	[5]
46	Benzo		2,2,6,6-tetramethylpiperidine, n-BuLi, PhBr/THF/−78 °C/1 h	6.6	[66]

Tominaga showed that indolizines 47a,b having annelated benzene ring across the bond C7–C8 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%).

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

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 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.

Scheme 26.

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

Table 12.

Substituents and yields of microwave three-component synthesis of cyclazines (Scheme 26).

N	R	R’	R2	R7	R8	Yield, %	Ref.
51a	E	E	Ph	H	H	90	[71] a
51b	E	E	4-Me-Ph	H	H	92	[71]
51c	E	E	4-Cl-Ph	H	H	60	[71]
51d	E	E	4-NO2-Ph	H	H	20	[71]
51e	E	E	Polycyclic R	H	H	78	[71]
51f	E	E	1-Cyclohexenyl	H	H	74	[71]
51g *	H	E’	Ph	H	H	78	[71]
51h *	H	E’	Ph	Me	H	80	[71]
51i *	H	E’	4-Me-Ph	Me	H	74	[71]
51j *	H	E’	4-Cl-Ph	H	Me	65	[71]
51k *	H	E’	4-NO2-Ph	H	Me	22	[71]
52a	E	E	Ph	H	H	37	[72] b
52b	E	E	4-NO2Ph	H	H	78	[72]
52c	E	E	4-ClPh	H	H	46	[72]
52d	E	E	4-MeOPh	H	H	23	[72]
52e	E	E	4-MePh	H	H	39	[72]
52f	E	E	4-OHPh	H	H	36	[72]
52g	E	E	4-BrPh	H	H	49	[72]
52h	E	E	4-FPh	H	H	42	[72]

^a: K₂CO₃, water MW, 100 °C 2–5 min; ^b: Alumina, 300 W, 2 min; * Attention: unexpected products, place of R and R’ groups should be reversed. Probably mistake made by the authors.

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.

Scheme 27.

PhMe/Δ/30 h.

Another example of cyclazine 54b synthesis from pyridine 54a with ethyl propiolate via indolizine 54c [74] is illustrated in Scheme 28. Indolizine 54c could be 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 [75,76,77] 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.

Interesting multistep reaction starting from pyridine 57a and finishing with cyclazine 57b with the yields 15–70% was observed independently by Acheson and Pohjala [51,78,79,80,81,82], Scheme 30. The mechanism of this process included Perkin reaction and intermediate formation of indolizine skeleton 57c.

Scheme 30.

Multistep reaction ending with 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	N	SMe	H	(CH=CH)2		Pd-C/MePh/Δ/30 h	6	[88]
62a	E/E	N	SMe	H	H	H	Pd-C/MePh/Δ/30 h	36	[87]
62b	E/E	N	SMe	MeC	H	MeC	Pd-C/MePh/Δ/30 h	40	[87]
63	E/H	N	t-Bu	H	H	H	O2/MePh/Δ/4 h	75	[36]
64	Ph/Ph	N	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.

Scheme 32.

Synthesis of azacyclazinone from mesoionic structure.

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, 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]

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.

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]
70j	Ph	2-NO2Ph	64	[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 straightforward 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.

Scheme 36.

Reaction of azaindolizines with benzynes (Table 18).

Table 18.

Substituents and yields of reaction of azaindolizines and benzynes (Scheme 36).

N	R2	X	Y *	Yield, %	Ref.
71a	2-HOPh	H	A	23	[6]
71b	2-HO-4-MeOPh	H	A	21	[6]
71c	2-HO-5-FPh	H	A	19	[6]
71d	2-HO-5-MePh	H	A	21	[6]
72a	Ph	H	B	74	[93]
72b	4-MeOPh	H	B	39	[93]
72c	4-FPh	H	B	49	[93]
72d	4-NO2Ph	H	B	51	[93]
72e	3,5-(BnO)2Ph	H	B	49	[93]
72f	Ph	N	B	58	[93]
72g	4-MeOPh	N	B	54	[93]
72h	4-FPh	N	B	38	[93]
72i	4-MeOPh	H	C	43 (3’)	[93]
72j	4-MeOPh	N	C	34 (3’)	[93]
72k	4-MeOPh	H	D	39 (4’)	[93]
72l	4-MeOPh	H	D	18 (5’)	[93]
72m	E’	H	B	51	[93]

* Not determined.

A—1-TMS-2-OSO₂CF₃-benzene, CsF, 18-Crown-6, MW (25 min, 160 °C); B—1-TMS-2-OSO₂CF₃-benzene, CsF, 18-Crown-6, MW (90 W, 40 psi, 15 min, 80 °C); C—1-TMS-2-OSO₂CF₃-3-MeO-benzene, CsF, 18-Crown-6, MW (90 W, 50 psi, 15 min, 80 °C); D—1-TMS-2-OSO₂CF₃-4-MeO-benzene, CsF, 18-Crown-6, MW (90 W, 50 psi, 15 min, 80 °C)

A base promoted 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).

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]
73h	2-Me-Ph	H	H	H	A	[Benzyne]	71	[94]
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]
73l	Ph	Me	H	H	A	[Benzyne]	71	[94]
73m	4-Et-Ph	H	H	Me	A	[Benzyne]	65	[94]
73n	4-Et-Ph	Me	H	H	A	[Benzyne]	60	[94]
73o	4-MeO-Ph	Me	H	H	A	[Benzyne]	72	[94]
73p	2-F-Ph	H	H	Me	A	[Benzyne]	60	[94]
73q	Ph	H	H	Me	A	[Benzyne]	75	[94]
73r	4-Cl-Ph	H	Me	H	A	[Benzyne]	32	[94]
73s	4-Et-Ph	Br *	H	H	A	[Benzyne]	54 (de-brom)	[94]
73t	H	H	CO2Me	H	A	[Benzyne]	50	[94]
73u	H	Cl	H	H	A	[Benzyne]	78	[94]
73v	H	H	H	H	A	[Benzyne]	45	[94]
73x	H	H	H	H	B	[1-MeO-benzyne-2]	70	[94]
73y	H	H	H	H	C	[1-Me-benzyne-3]	65 (2 isom.)	[94]
73	4-Et-Ph	H	H	H	C	[1-Me-benzyne-3]	72 (2 isom.)	[94]
73z	4-Cl-Ph	H	H	H	C	[1-Me-benzyne-3]	69 (2 isom.)	[94]
73a1	4-CN-Ph	H	H	H	D	[1-MeO-benzyne-2]	80 (3’)	[94]
73b1	4-CN-Ph	H	H	H	E	[1-Me-benzyne-3]	75 (2 isom.)	[94]
73c1	4-Et-Ph	H	H	H	F	[1-MeO-benzyne-2]	73	[94]
73d1	t-Bu	H	H	H	G	[Benzyne]	62	[94]

* A—1-TMS-2-OSO₂CF₃-benzene 18-crown-6-ether, K₂CO₃; acetone, 45 °C, 24 h; B—1-TMS-2-OSO₂CF₃-3-MeO-benzene; C—1-TMS-2-OSO₂CF₃-4-Me-benzene; D—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-2-OSO₂CF₃-benzene.

An interesting reaction that formally fit the [8+2] cycloaddition was developed for interaction of imidazopyridines 74 and 1,2-dihalobenzenes in presence of Pd-catalyst [95], Scheme 38. Table 20.

Scheme 38.

Pd/xphos, K₂CO₃, DMF, 160 °C, 24 h.

Table 20.

Substituents and yields of reaction of imidazopyridines and 1,2-dihalobenzenes (Scheme 38).

N	R2	R6	R7	R8	Yield, %	Benzene *	Ref
74a	Ph	H	H	H	77	A	[95]
74b	4-Me-Ph	H	H	H	79	A	[95]
74c	4-MeOPh	H	H	H	54	A	[95]
74d	4-ClPh	H	H	H	45	A	[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.

The system containing two fused imidazopyridines 75 was placed in reaction with DMAD [96], Scheme 39. One ring of imidazopyridine entered into [8+2] cycloaddition with the yields 22–30% on heating in benzene.

Scheme 39.

Cycloaddition of tetraazapentalene derivatives.

A rare example of benzonitrile entered into [8+2] cycloaddition to produce diazacyclazine 76b was reported [97], Scheme 40. Azaindolizine 76a reacted with BuLi giving dipolar structure 76c which underwent cyclization.

Scheme 40.

Synthesis of diazacyclazine.

8. 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.

Scheme 41.

Cyclization of 6-ethynylpyridinium salts.

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.

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.

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).

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 closure.

Scheme 46.

Unusual ring closure of 5-chlorindolizines.

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%).

Scheme 47.

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

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

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]
85t	Ph	Ph	Ph	Me	H	H	H	60/0	[105]
85u	Ph	Ph	4-Me	Me	H	H	H	65/0	[105]
85v	Ph	Ph	4-CF3	Me	H	H	H	51/0	[105]
85w	Ph	Ph	4-F	Me	H	H	H	56/0	[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: Pd-cat NHC complex Cu(OAc)₂, TBAB, DMA, 90 °C, 12 h; ^b: Pd(OAc)₂, Cu(OAc)₂, O₂, TBAB, DMF, 100 °C; ^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 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. 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.

Theoretically possible mechanisms of [8+2] cycloaddition to indolizines.

Table 23.

Possible mechanisms of [8+2] cycloaddition depending on the nature of groups in alkene and indolizne as shown on Scheme 49.

Substituent in Alkene	Indolizine	6-Nitroindolizine
Nitroethylene	(i), (ii)	(i), (ii)
Methyl acrylate	(iii)	(iii)
Acrylonitrile	(iii)	(iii)
Ethylene	(iii)	(iii)
N,N-Dimethylaminoethylene	(iii)	(iv), (v)

However, indolizines (even activated by 6- or 8-NO₂-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.

Scheme 50.

Abnormal cycloadditon to 6-nitroindolizine.

After the addition of alkyne to position C-3 of indolizine, the initially formed zwitter-ion 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.

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 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-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].

Scheme 52.

3-Vinyl derivatives of aza/benzo/indolizines isolated as intermediates (see Table 24).

Table 24.

Stereochemistry, conditions and yields of synthesis of vinyl indolisines on Scheme 52.

N	R	Yield (trans/cis), %	Conditions	Ref.
89a	R = H	13:4	No/Me2CO/rt/15 h	[108]
89b	R6 = Me	11:5		[108]
89c	R7 = Me	16:0		[108]
89d	R8 = Me	20:0		[108]
90		18:13	Pd/PhMe/Δ/21 h	[85]
91a	n = 1	62 *	No/0°/THF	[46]
91b	n = 2	62 *	No/0°/THF	[46]
92a	R2 = SMe	26:17	Pd-C/PhMe/Δ/30 h	[29]
92b	R2 = H	0:11	Pd-C/PhMe/Δ/30 h	[29]
93		4 *	Pd-C/PhMe/Δ/30 h	[88]
94		14 **	No/PhMe/rt/120 h	[109]

* Not determined, ** In a mixture.

10.3. 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 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 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].

Scheme 55.

1:1 and 1:2 cycloadducts of 5-methylindolizine and DMAD.

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: nitroolefins, 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 [38,53,112,113,114,115].

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 cases Michael adducts at C-3 104b were formed. Benzo[a]indolizines with some dipolarophiles produced kinetically controlled cycloadducts 105a which isomerized to Michael 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, 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.

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]

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]
81m	2-EtO-4-NO2-Ph	H	92	[8]
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]

* 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.

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.