Di-, tetra-, and perhydropyrrolo[1,2-a]imidazoles: The Methods of Synthesis and Some Aspects of Application

DOI 10.1007/s10593-023-03142-w Chemistry of Heterocyclic Compounds 2022, 58(12), 661–680 REVIEW Di-, tetra-, and perhydropyrrolo[1,2-a]imidazoles: the methods of synthesis and some aspects of application Lesya M. Saliyeva1*, Irina V. Dyachenko2, Ivanna Yu. Danyliuk3, Mykhailo V. Vovk3 1 Lesya Ukrainka Volyn National University, 13 Voli Ave., Lutsk 43025, Ukraine; e-mail: 2 Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001 12e Nord Ave., Sherbrooke J1H 5N4, Quebec, Canada; e-mail: 3 Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Akademika Kukhara St., Kyiv 02094, Ukraine; е-mail: Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2022, 58(12), 661–680 Submitted July 7, 2022 Accepted August 3, 2022 The review summarizes and systematizes the literature data on the synthesis and some aspects of application of pyrrolo[1,2-a]imidazoles. Synthetic approaches are grouped according to the degree of saturation of the product pyrroloimidazole ring. The bibliography of the review includes 110 sources over the last 15 years. Keywords: hydrogenated pyrrolo[1,2-a]imidazoles, cyclization, cycloaddition, cyclocondensation. Partially and fully hydrogenated pyrrolo[1,2-a]imidazole heterocyclic systems are valuable synthetic blocks and have a wide spectrum of biological activity. Depending on the degree of saturation, dihydropyrrolo[1,2-a]imidazoles (structures I–III, Fig. 1), tetrahydropyrrolo[1,2-a]imidazoles (structures IV–VI), and perhydropyrrolo[1,2-a]imidazoles (structure VII) may be distinguished. To date, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles I and fully hydrogenated pyrrolo[1,2-a]imidazoles VII are the most studied due to the discovery among them of dimiracetam (Fig. 2), a nootropic drug of the racetam family,1 as well as of compound VIII, a potent α1A-adrenergic receptor partial agonist with good selectivity for α1B, α1D, and α2A receptor subtypes.2 An analysis of literature sources indicates that interest in these compounds appeared as early as the 1960s,3,4 while advances in the chemistry of pyrroloimidazoles were first summarized in a 1995 review.5 Research over the next two decades, which relate to synthetic methods, chemical transformations, and biological activity, was partially summarized in concise reviews in 20086 and 2022.7 Several examples of annulation of a pyrroloimidazole scaffold are described in a microreview published in 2016.8 Unfortunately, these publications do not provide a Figure 1. The structure types of pyrrolo[1,2-a]imidazoles I–VII. Figure 2. The structures of the nootropic drug dimiracetam and the α1A-adrenergic receptor partial agonist VIII. complete picture of the advances in the chemistry of pyrroloimidazoles over the past 15 years. In addition, the questions of the practical application of pyrrolo[1,2-a]imidazoles and their powerful biological potential remained outside of their scope. * Here and further the corresponding author is marked with *. 0009-3122/22/58(12)-0661©2022 Springer Science+Business Media, LLC 661 Chemistry of Heterocyclic Compounds 2022, 58(12), 661–680 Scheme 2 For this reason, it seemed to us reasonable to comprehensively generalize and systematize the array of data on the synthesis methods, use in organic synthesis, and medical and biological studies of hydrogenated pyrrolo[1,2-a]imidazoles. 1. THE SYNTHESIS METHODS OF DIHYDROPYRROLO[1,2-a]IMIDAZOLES 1.1. Annulation of the imidazole ring to the pyrrole ring The pyrrolo[1,2-a]imidazole scaffold was formed by the condensation of aminopyrrolines with halocarbonyl compounds, which, however, did not result in high yields of the target products. In particular, the reaction of 3,4-dihydro-2H-pyrrol-5-amine (1) with 2-bromo ketones 2а–n in EtOAc at room temperature led to 3-substituted pyrrolo[1,2-a]imidazole hydrobromides 3а–n (no yields given).9 At the same time, in the case of pyridyl bromo ketone 2о, heating in DMF in the presence of Na2CO3 gave isomeric 2-substituted pyrrolo[1,2-a]imidazole 4 in only 14% yield (Scheme 1).10 Scheme 3 Scheme 1 compound 10 with amino ketone hydrochlorides 13а–е resulted in the formation of 3-arylpyrrolo[1,2-a]imidazoles 14a–e (no yields given, Scheme 4).15 Scheme 4 Treatment of iminopyrrolidines 5а–d with α-phenacyl bromides 2р–r in MeCN followed by heating in acetic anhydride led to the formation of pyrrolo[1,2-a]imidazolium bromides 6a–е. The latter were smoothly partially reduced with NaBH4 in DMF to afford tetrahydro-1Hpyrrolo[1,2-a]imidazoles 7a–е (Scheme 2).11 Intramolecular cyclization of 2-(2-oxopyrrolidin-1-yl)acetamide (8) by the action of POBr3 or POCl3 gave 2-halosubstituted pyrrolo[1,2-a]imidazoles 9a,b (Scheme 3).12 The microwave modification of this method made it possible to synthesize compound 9a in 82% yield.13 Cyclocondensation of 2-methoxypyrroline 10 with aminoacetonitrile hydrochloride (11) in i-PrOH under reflux led to 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol3-amine hydrochloride (12),14 while cyclocondensation of The reaction of pyrroline 10 with 2,2-dimethoxyethanamine (15a) in the CH2Cl2–MeOH system gave aminopyrroline 16, the cyclization of which in formic acid gave the simplest 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (17a) (Scheme 5).16,17 Its 6,6-dimethyl analog 17b was obtained in quantitative yield by similar transformations from 3,3-dimethyl-5(methylsulfanyl)-3,4-dihydro-2H-pyrrole hydroiodide (18) and amine 15а (Scheme 6).16 A four-step synthesis of (S)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-ol (22) was developed based on silylation of 4-hydroxypyrrolidin-2-one (19a), transformation of the 662 Chemistry of Heterocyclic Compounds 2022, 58(12), 661–680 Scheme 5 Scheme 8 Scheme 6 Scheme 9 obtained derivative 19b into cyclic imidate 20, its subsequent amination with aminoacetal 15b, and cyclization of the resulting amidine 21 (Scheme 7).18,19 intermediate hydrazone A in the presence of a base (no yield given, Scheme 9). The synthesis of dihydropyrrolo[1,2-a]imidazole2,3-dicarboxylate 30 is based on the reaction of pyrrolidine 28а with acetylenedicarboxylate 29а and involves the one-pot formation of four C–N bonds, which is realized via the steps of hydroamination/azidation/cyclization (Scheme 10).22 Scheme 7 O 1. t-BuSi(Me)2Cl, imidazole DMF, rt, 16 h 2. 0.2 M aq HCl, rt, 10 min H N 100% 19a O Me Si t-Bu Me 19b OH 1. Cs2CO3, DCM, rt, 5 min 2. Et3OBF4, rt, 16 h 97% EtO H N O Scheme 10 OEt N EtO NH2 15b O 1 M HCl, EtOH Me Si rt, 16 h Me t-Bu 78% 20 EtO To obtain 2,3-disubstituted pyrrolo[1,2-а]imidazoles 33а–g, one-pot three-component condensation of aryl 1,2diketones 31а–g, L-proline (32а), and NH4OAc in a ratio of 1:1:1 was employed. The microwave modification of this method proved to be suitable for 3-hydroxy-L-proline (32b) and was employed to access pyrrolo[1,2-а]imidazol6-ols 33h–k (Scheme 11).23 The one-pot synthesis of 6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles 35a–f was developed on the basis of a cascade of [3+2] c (...truncated)