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

The redox annulation reaction of pyrrolidines and α-ketoamides proved to be effective for the creation of combinatorial libraries of perhydrogenated pyrrolo[1,2- а ]imidazoles 102a – z . It was found that N -alkyl-α-ketoamides 101а – с reacted with pyrrolidine 28a upon heating under reflux in PhMe in the presence of catalytic amounts of AcOH; in contrast, their N -aryl and N -hetaryl analogs 101d – у reacted with pyrrolidine 28a in the absence of acid. In the case of 2-phenylpyrrolidine 28b , pyrrolo[1,2- а ]imidazole 102z was obtained by heating under reflux in xylene with the addition of 20 mol % AcOH (Scheme 39 ). 59 Scheme 39 Scheme 39 Benzoic acid was used as a catalyst in the synthesis of 1,3-diphenyltetrahydro-1 H -pyrrolo[1,2- a ]imidazol-2(3 H )- one 102d , which made it possible to significantly reduce the reaction duration and obtain the target product in almost quantitative yield (Scheme 40 ). 60 A new two-step one-pot approach based on the reaction of phenylglyoxylic acid ( 103 ), phenylisocyanate, and pyrrolidine 28a was also developed for the synthesis of this compound (Scheme 40 ). 61 Scheme 40 Scheme 40 L-Proline ( 32а ) was also investigated in the cyclization reaction with decarboxylation with various α-ketoamides. It reacted smoothly and diastereoselectively with N -alkyl- (aryl,hetaryl)-α-ketoamides 101a – y , 104a – e to form the corresponding tetrahydro-1 H -pyrrolo[1,2- a ]imidazol-2(3 H )- ones 102a – y , 105a – d in the form of the trans -isomers. By using 2-oxo- N -( p -tolyl)propanamide 104e , the target product 105e was isolated as a mixture of diastereomers in a 10:1 ratio in 56% yield (Scheme 41 ). 62 Scheme 41 Scheme 41 α-Silyloxyacrylamides 106a , b can also undergo a similar transformation. In a reaction with L-proline ( 32a ) in i -PrOH under reflux, they are stereoselectively converted to tetrahydro-1 H -pyrrolo[1,2- a ]imidazol-2-ones 107а , b (Scheme 42 ). 63 Scheme 42 Scheme 42 A new biocatalytic route for the synthesis of tetrahydro-1 H -pyrrolo[1,2- a ]imidazol(e)-2(3 H )-(thi)ones 109а – g was proposed, which involves the enzymatic intramolecular C–H amination of N -substituted 2-(pyrrolidin-1-yl)acetamides 108а – g by the action of mutant cytochrome P450 BM3 (CYP102A1) enzymes and led to target products in 55–97% yields (Scheme 43 ). 64 Scheme 43 Scheme 43 These studies demonstrated the tolerance of the P450 BM3 mutants to functional groups in both the amide and pyrrolidine fragments of the substrates, as well as the high chemoselectivity of the amination of the C–H bond. In particular, methyl L-prolinate derivative 108h underwent cyclization exclusively to product 109h in 98% yield (Scheme 44 ). 64 Scheme 44 Scheme 44 The intramolecular cyclization of 2-(2-amino-5-oxopyrrolidin-1-yl)acetic acid hydrochloride ( 110 ) leading to dimiracetam ( 111) presents an efficient method for the annulation of the perhydropyrrolo[1,2- a ]imidazole ring. Its modification gave 1-arylpyrrolo[1,2- a ]imidazolediones 112 , which possess an antihyperalgesic effect against neuropathic pain induced by both chronic constriction injury of the sciatic nerve and streptozotocin (Scheme 45 ). 65 Scheme 45 Scheme 45 The nitrile group of polysubstituted succinimide 113 was used for its one-step conversion to perhydropyrrolo[1,2- a ]-imidazole 114 (Scheme 46 ). 66 Scheme 46 Scheme 46 Intramolecular cyclization of 1-aminoethylpyrrolidine 62b by the action of HgO in the presence of ethylenediaminetetraacetic acid disodium salt (Na 2 EDTA·2H 2 O) led to the preferential formation of pyrrolo[1,2- a ]imidazole 115 by dehydrogenation of the С–Н bond in position 2 of the pyrrolidine ring. The isomeric product 116 is the result of dehydrogenation at position 5 of the ring (Scheme 47 ). 44 Scheme 47 Scheme 47 A simple approach to the synthesis of fully hydrogenated pyrrolo[1,2- a ]imidazolones was developed based on the intramolecular amination of the C–H bond of pyrrolidine by the action of a simple catalytic system consisting of FeCl 2 and β-diketiminate L1 as a ligand. It was shown that heating α-azidoacylpyrrolidine 117 in MeCN with the addition of Boc 2 O to activate cyclization leads to 3-oxohexahydro-1 H -pyrrolo[1,2- a ]imidazole 118 in 33% yield. 67 Using the Fe(II)–1,2-bis(diphenylphosphino) benzene ([Fe(dppbz)]Cl 2 ) as a catalyst in the absence of a ligand made it possible to increase the yield of the target product to 92% (Scheme 48 ). Scheme 48 Scheme 48 The 1,3-dipolar cycloaddition reaction of 4,5-dihydroimidazolium ylides D obtained by the reaction of dihydroimidazole 82а , b with ethyl 2-diazoacetate 83 with fumaric acid esters 119а , b did not show high stereoselectivity and led to a diastereomeric mixture of derivatives 120а – d and 121а , b . In the case of fumarodinitrile 122 , pyrrolo[1,2- a ]imidazole 123 was isolated in low yield (Scheme 49 ). 53 Scheme 49 Scheme 49 The three-component reaction of dihydroimidazoles 82а , с , esters or nitrile of bromoacetic acid 125а – d , and activated ethylenes 126а , b was successfully used to annulate the pyrrole ring and obtain functionally substituted perhydropyrrolo[1,2- а ]imidazoles 127a – l (Scheme 50 ). 69 Similar reaction conditions proved to be suitable for the synthesis of (3 R )-phenylpyrrolo[1,2- a ]-imidazoles 127m – x using chiral dihydroimidazoles 124а – с , bromoacetic acid esters 125а – с , and vinyl sulfones 126b , с . 69 Scheme 50 Scheme 50 Upon expanding the number of activated alkenes as dipolarophiles, interesting results were obtained in the case of methacrylic acid derivatives. Thus, the reaction of (3 S )-phenyldihydroimidazole 128 , bromoacetic acid esters 125а , с , and methyl methacrylate ( 126d ) resulted in diastereoselective formation of solely endo -addition products 129a , c . Nitriles 129b , d were isolated together with a small amount of compounds 130а , b , respectively ( endo : exo = 8:1) in a similar transformation involving methacrylonitrile ( 126е ) (Scheme 51 ). Scheme 51 Scheme 51 The reaction of enantiomeric (3 R )-phenyldihydroimidazole 124b , bromoacetic acid esters 125а , с , and methyl methacrylate ( 126d ) also proceeded diastereoselectively with the formation of endo -addition products 129е , g . When using methacrylonitrile ( 126е ), the target nitrile 129f was obtained in admixture with a small amount of product 130с ( endo : exo = 11:1), while adduct 129h was produced in admixture with a small amount of exo -addition product 130d ( endo : exo = 8:1, Scheme 51 ). 70 A method for the synthesis of hexahydropyrrolo[1,2- a ]- imidazoles was developed in which 4,5-dihydroimidazolium ylides were obtained by conjugated addition with proton transfer from dihydroimidazoles and difunctionalized electron-deficient alkenes. Thus, stereoisomeric products 131 and 132 were synthesized by the reaction of 1-benzyl-4,5-dihydro-1 H -imidazole ( 82а ) with fumaric acid esters 119а , b . Modification of this reaction by the addition of N -methylmaleimide 72h was successfully used for the synthesis of diastereomeric spiro[pyrrolidine-3,5'-pyrrolo[1,2- a ]imidazoles] 133a and 134 . It is noteworthy that in the case of N -phenylmaleimide 72с the conversion proceeded diastereoselectively and led to the formation of solely product 133b (Scheme 52 ). 71 Scheme 52 Scheme 52 Imidazolium salts 135a , b when treated with 1 equiv of n -BuLi were prone to cyclization to pyrrolo[1,2- a ]-imidazole spiro derivatives 136a , b , the reaction of which with synergistic mixtures of n -BuLi or PhLi and LiN(SiMe3)2 was used to synthesize saturated complexes of N-heterocyclic carbenes, in particular, homobimetallic complexes of lithium, sodium, and potassium (Scheme 53 ). 72,73 Scheme 53 Scheme 53 The catalytic redox reaction of N -alkenyl-substituted imidazolium salts 137a – e with the participation of the Ni(0)/Ni(II) redox system proved to be effective for the mild synthesis of pyrrolo[1,2- a ]imidazolium salts 138a – e (Scheme 54 ). 74 Scheme 54 Scheme 54 Principally, other synthesis methods include transformations in which the target perhydrogenated bicyclic system is formed from two, as a rule, acyclic reagents. A good example of this approach is the cyclocondensation of ethylenediamines 85а , b with ethyl levulinate ( 139 ) in EtOH leading to the formation of pyrrolo[1,2- а ]imidazoles 140а , b . 75–77 In turn, the reaction of ethylenediamine 85а with methyl 1-(2-oxoethyl)cyclohexanecarboxylate ( 141 ) gave pyrrolo[1,2- a ]imidazole spiro derivative 142 (Scheme 55 ). 78 Scheme 55 Scheme 55 Condensation of ethyl 4-oxobutanoate ( 143 ) with glycinamide hydrochloride ( 144 ) forms the basis of a one-pot industrial method for the preparation of tetrahydro-5 H -pyrrolo[1,2- а ]imidazole-2,5(3 H )-dione (dimiracetam) ( 111 ) (Scheme 56 ). 79,80 Scheme 56 Scheme 56 Cyclocondensation of L-α-aminohydroxamic acids 145a – e with 4-oxopentanoic acid ( 146 ) presents a convenient method for the synthesis of 1-hydroxytetrahydro-5 H pyrrolo[1,2- а ]imidazole-2,5(3 H )-diones 147a – e . Notably, in the case of acids 145а – с , it is expedient to carry out the reaction by heating in PhMe, whereas for their aromatic analogs 145d , е , successive heating in i -РОН and PhMe turned out to be optimal leading to target products 147d , e in almost quantitative yields (Scheme 57 ). 81 Scheme 57 Scheme 57 N -Substituted amides of alanine 148а or valine 148b were patented as effective substrates in reductive cyclization, which leads to the formation of 3-oxopyrrolo[1,2- a ]imidazoles 149а , b (no yields given), which are disposed to competitive inhibition of melanocortin receptors (Scheme 58 ). 82 Scheme 58 Scheme 58 A novel approach to the diastereoselective synthesis of hexahydro-1 H -pyrrolo[1,2- a ]imidazoles 153a – f is based on the reaction of L-ornithine methyl ester dihydrochloride ( 150 ) with aromatic aldehydes 151а – f and is realized via the formation of bis-Schiff bases 152а – f followed by intramolecular 1,3-dipolar cycloaddition (Scheme 59 ). 83 Scheme 59 Scheme 59 Cyclocondensation of L-α-amino acid phenylhydrazides 154a – f with 2,3- O -isopropylidene-L-erythruronolactone ( 155 ) in the presence of a catalytic amount of p -toluenesulfonic acid ( p -TSA) afforded diastereomerically pure 3-substituted 6,7-[propane-2,2-diylbis(oxy)]-1-(phenylamino)-tetrahydro-5 H -pyrrolo[1,2- a ]imidazole-2,5(3 H )-diones 156a – f , acid hydrolysis of which gave their 6,7-dihydroxy analogs 157a – f (Scheme 60 ). 84 Scheme 60 Scheme 60 The product of condensation of N -Boc-L-alanine ( 159 ) with 3-(1,3-dioxolan-2-yl)propanamine ( 158 ), in situ generated amide F , upon treatment with SnCl 2 ·2H 2 O was successively subjected to deacetalization/bicyclization processes, which resulted in the formation of a diastereomeric mixture of 3-oxopyrrolo[1,2- a ]imidazole 160 (Scheme 61 ). 85 Scheme 61 Scheme 61 An interesting example of the synthesis of diastereomers of 5-oxohexahydro-1 H -pyrrolo[1,2- a ]imidazoles 162 , 163 a , b involves ring expansion of monocyclic β-lactams. For example, upon treatment with AgBF 4 and pyridine in PhMe, cis -azetidin-2-ones 161а , b were diastereoselectively converted to the target products via rearrangement of carbocation G and intramolecular cyclization of N -acyliminium intermediates H (Scheme 62 ). 86 Scheme 62 Scheme 62 An original approach to the preparation of 5-methylidenehexahydropyrrolo[1,2- a ]imidazoles 166a , b is based on the reaction of alkynylcyclopropanes 164a , b with lithium 2-aminoethylamide generated from ethylenediamine 85a and n -BuLi. The reaction proceeds via the intermediate formation of conjugated alkynylcyclopropene I with the characteristic combination of two highly reactive functionalities, a triple bond, and an unsaturated threemembered ring. Its subsequent hydrolysis in the case of a bulky tert -butyl substituent proceeds regioselectively with the formation of the target product 165 exclusively as the E -isomer. At the same time, its 5-benzylidene analogs 166а , b were isolated as a mixture of Е - and Z -isomers in ratios of 4:1 and 4.2:1, respectively (Scheme 63 ). 87,88 Scheme 63 Scheme 63 The synthesis of 5-benzylidenepyrrolo[1,2- a ]imidazoles 166a , b as a mixture of E - and Z -isomers in the ratio of 5:1 and 4.5:1, respectively, was also carried out by cyclization of acetylenaldehydes 167a , b with ethylenediamine 72a in the superbasic DMSO–KOH medium (Scheme 64 ). 89.90 Scheme 64 Scheme 64

Pyrrolo[1,2- a ]imidazole derivatives have found wide application in various fields of organic synthesis as selective organocatalysts. Thus, 7-alkoxy-substituted chiral 6,7-dihydro-5 H -pyrrolo[1,2- a ]imidazoles 168а – d were successfully used in the asymmetric Steglich rearrangement. 26 In addition, derivatives 168а – c were first used for the catalytic asymmetric synthesis of chiral compounds (Fig. 3 ). 91 Figure 3. The catalysts for asymmetric processes 168a – d and stereoselective phosphoramidation 169 , as well as catalysts for the synthesis of remdesivir 170a , b . The catalysts for asymmetric processes 168a – d and stereoselective phosphoramidation 169 , as well as catalysts for the synthesis of remdesivir 170a , b . An original low molecular weight catalyst 169 was constructed based on the scaffold of a chiral 6,7-dihydro-5 H -pyrrolo[1,2- a ]imidazole (Fig. 3 ). It promotes the insertion of P-stereogenic phosphoramidates into nucleoside structures via a dynamic stereoselective process. 92 More recently, reports have appeared on the use of (pyrrolo[1,2- a ]imidazol-7-yl)carbamates 170а , b for organocatalytic asymmetric phosphoramidation of one of the intermediates in the synthesis of the drug remdesivir which is used to treat COVID-19 (Fig. 3 ). 93,94 Chiral esters based on pyrrolo[1,2- a ]imidazoles 171а – е proved to be effective catalysts for the enantioselective Black rearrangement (Fig. 4 ). 28 In addition, (( R )-6,7- dihydro-5 H -pyrrolo[1,2- a ]imidazol-7-yl)acetate ( 171a ) has found application in direct catalytic enantioselective C -acylation for the construction of the quaternary stereocenter of 3-substituted benzofuran-2(3 H )-ones. 95 Figure 4. The catalysts of enantioselective processes 171a – e , kinetic separation of aryl and hetaryl alkyl carbinols 172 , and polymerization initiators pyrrolo[1,2- а ]imidazoles 173a , b . The catalysts of enantioselective processes 171a – e , kinetic separation of aryl and hetaryl alkyl carbinols 172 , and polymerization initiators pyrrolo[1,2- а ]imidazoles 173a , b . ( S )-7-Cyclohexyl-3-(pyrrolidin-1-yl)-6,7-dihydro-5 H pyrrolo[ 1,2- a ]imidazole ( 172 ) was successfully used for the kinetic separation of aryl and hetaryl alkyl carbinols with high enantioselectivity (Fig. 4 ). 96 Chiral dialkylaluminum complexes of 6,7-dihydro-5 H pyrrolo[1,2- а ]imidazol-7-ols 173а , b were tested as effective initiators of ring opening of ε-caprolactone during polymerization (Fig. 4 ). 97 Another area of practical application of functionalized pyrrolo[1,2- a ]imidazoles is ionic liquids. Affinity ionic liquids of pyrrolo[1,2- a ]imidazolium 174a , b are capable of binding to peptides and proteins, which has been used for liquid-liquid extraction and purification of hexahistidinetagged (His-tagged) proteins (Fig. 5 ). 37,98 Figure 5. The affinity ionic liquids 174a , b capable of binding to biomacromolecules. The affinity ionic liquids 174a , b capable of binding to biomacromolecules. Quartz crystal microbalance (QCM) chips thinly coated with sensitive ionic liquids 175а – d proved effective for the chemoselective detection of aldehydes, ketones, and amines in gases. 99,100 The use of 1-butylpyrrolo[1,2- a ]-imidazolium (trifluoromethanesulfonyl)imide ( 175c ) for the separation of Th-227 and Ac-225 isotopes by extraction with N , N , N ', N '-tetraoctyldiglycolamide also deserves attention (Fig. 6 ). 38 Figure 6. Ionic liquids 175a – d (for effective gas detection and isotope separation), 176a , b (for the determination of gaseous amines and alcohols), and 177a , b (for the determination of organic azides). Ionic liquids 175a – d (for effective gas detection and isotope separation), 176a , b (for the determination of gaseous amines and alcohols), and 177a , b (for the determination of organic azides). In turn, the 1,3,5-triazine-containing ionic liquids 176a , b on QCM chips seem to be very promising for chemoselective detection of gaseous amines and alcohols (Fig. 6 ). 101 Equally important is the development of the specialized ionic liquids 177a , b on QCM chips for on-line and chemoselective real-time detection of organic azides (Fig. 6 ). 102 Heterocyclic compounds based on the pyrrolo[1,2- a ]- imidazole ring are attractive objects for biomedical research. Thus, 3-(3,4-dichlorophenyl)-1-[(4-phenoxyphenylcarbamoyl) methyl]-6,7-dihydro-5 H -pyrrolo[1,2- a ]-imidazol-1-ium chloride ( 178 ) has a wide spectrum of antimicrobial activity against Staphylococcus aureus , Escherichia coli , Klebsiella pneumoniae , Acinetobacter baumannii , and Cryptococcus neoformans . Notably, compound 178 is characterized by high hemolytic activity against human erythrocytes and cytotoxicity against the HEK-293 cell line, but has low in vivo toxicity in mice (LD 50 >2000 mg/kg) (Fig. 7 ). 15 Figure 7. The quaternary salt of pyrrolo[1,2- a ]imidazol-1-ium 178 with antimicrobial activity. The quaternary salt of pyrrolo[1,2- a ]imidazol-1-ium 178 with antimicrobial activity. Effective inhibitors of the WIN region of the WDR5 scaffolding protein, which regulates chromatin and is overexpressed in various types of cancer, were identified among 2-aryl-6,7-dihydro-5 H -pyrrolo[1,2- a ]imidazoles. Derivatives 179а – с are characterized by dissociation constants <10 nM and micromolar cellular activity against acute myeloid leukemia (Fig. 8 ). 12 Figure 8. The selective inhibitors of the WIN region of the WDR5 scaffolding protein 179а – с . The selective inhibitors of the WIN region of the WDR5 scaffolding protein 179а – с . Modified pyrrolo[1,2- a ]imidazoles 180 were evaluated as degraders of the WDR5 protein, but despite only inhibiting a subset of WDR5 protein interactions, chemically induced proteasomal degradation of the WDR5 protein could represent an elegant way to target all oncogenic processes (Fig. 9 ). 13 Figure 9. The WDR5 protein degraders pyrrolo[1,2- а ]imidazoles 180 . The WDR5 protein degraders pyrrolo[1,2- а ]imidazoles 180 . 3-Aryl-substituted 6,7-dihydro-5 H -pyrrolo[1,2- a ]imidazoles 14d , f may find application in the treatment of castration-resistant prostate cancer. These molecules have been shown to block the nuclear localization of androgen receptors in prostate cancer (Fig. 10 ). 9,103 Figure 10. Pyrrolo[1,2- a ]imidazoles 14d , f with anticancer activity. Pyrrolo[1,2- a ]imidazoles 14d , f with anticancer activity. (1 S ,3 R )-3-Acetamido- N -[4-(6,7-dihydro-5 H -pyrrolo[1,2- a ]-imidazol-3-yl)pyridin-2-yl]cyclohexanecarboxamides 181а – с inhibit cyclin-dependent kinase CDK9 and may be useful important is the effect of compounds 181 on phosphorylation of the Ser2 residue of RNA polymerase II in the breast cancer cell line (MCF7) and on MV4-11 cells of biphenotypic B-myelomonocytic leukemia (Fig. 11 ). 16 Figure 11. The inhibitors of cyclin-dependent kinase CDK9 181а – с . The inhibitors of cyclin-dependent kinase CDK9 181а – с . Structural modification of the pyrrolo[1,2- a ]imidazole ring was used to construct derivative 182 containing a cereblon ligand that binds to E3 ubiquitin ligase, as well as a fragment capable of binding to the androgen receptor and inhibiting it (Fig. 12 ). 17 Figure 12. The androgen receptor inhibitor 182 . The androgen receptor inhibitor 182 . The optically pure pyrrolo[1,2- a ]imidazoles 22 , 183а , b are progesterone receptor (PR) antagonists and are useful in the treatment of endometriosis, uterine fibroids, and related conditions as well as in the treatment of breast, ovarian, or endometrial cancer (Fig. 13 ). 18 Figure 13. The progesterone receptor antagonists 22 , 183а , b . The progesterone receptor antagonists 22 , 183а , b . 6,7-Dihydro-5 H -pyrrolo[1,2- a ]imidazole-2-sulfonamide 184 has the ability to inhibit the activation of the NLRP3 inflammasome and may be useful in the treatment of a wide range of diseases in which the NLRP3 inflammasome is considered the key inflammation-regulating factor. 41 In turn, N -(pyrrolo[1,2- а ]imidazol-3-yl)acetamide 185 was tested as an inhibitor of human tropomyosin receptor kinase A (hTrkA) (Fig. 14 ). 104 Figure 14. The biologically active pyrrolo[1,2- а ]imidazoles 184 – 187 . The biologically active pyrrolo[1,2- а ]imidazoles 184 – 187 . Perhydropyrrolo[1,2- a ]imidazole 186 was revealed as a selective antagonist of the melanocortin-4 receptor (p A 2 = 8.086 M) and also weakens the binding of an agonist, including α-melanocyte-stimulating hormone, and of an inverse agonist, including a protein related to the melanocortin receptor (Fig. 14 ).105–108 1-( p -Tolyl)tetrahydro-5 H -pyrrolo[1,2- a ]imidazole-2,5(3 H )-dione ( 187 ) may be promising for treatment and prevention of peripheral neurotoxicity induced by chemotherapy (Fig. 14 ). 109,110 To conclude, the analysis of literature sources indicates that, in most cases, the construction of various pyrroloimidazole systems uses the annulation of the imidazole ring to the pyrrole ring or vice versa . However, ring expansion reactions, rearrangements, recyclizations, cascade and multicomponent reactions, as well as one-pot methods for the formation of the pyrroloimidazole framework are of considerable interest among the methods of synthesis of pyrrolo[1,2- a ]imidazoles. The practical significance of partially and fully hydrogenated pyrrolo[1,2- a ]imidazoles is due to their use in organic synthesis as selective catalysts, ionic liquids in analytical sensors, and for the creation of pharmacologically active substances.