Research in the imidazole series

The reduction of pyrrolo[1,2-a]imidazole-2-one and pyrrolo[1,2-a]benzimidazole derivatives, which leads to the formation of 2,3-dihydropyrrolo[1,2-a]imidazole derivatives and derivatives of the previously unknown 1,2,3,3a-tetrahydropyrrolo[1,2-a]benzimidazole, was studied. A method was developed for the preparation of 5- and 7-amino derivatives of pyrrolo[1,2-a]imidazole by reduction of the corresponding nitroso- and arylazo-substituted pyrrolo[1,2-a]-imidazoles.See [1] for communication XCI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 225–228, February, 1977.     

Synthesis of isoxazolo[2,3-a]quinoxalines and pyrrolo[1,2-a]quinoxalines by 1,3-dipolar cycloaddition reaction

The isoxazolo[2,3-a]quinoxalines 11a,b and pyrrolo[1,2-a]quinoxalines 12a,b were selectively synthesized from the 2-substituted 6-chloroquinoxaline 4-oxides 10a,b . The pyrrolo[1,2-a]quinoxalines 12a,b were clarified to be produced by the ring transformation of the isoxazolo[2,3-a]quinoxalines 11a,b . The pyrrolo[1,2-a]quinoxalines 14a,b were obtained from both 2,6-dichloroquinoxaline 4-oxide 9 and compounds 12a,b .     

A new method for the synthesis of pyrrolo[1,2-a]pyrazines and pyrrolo[1,2-a] quinoxalines

A new method is proposed for the synthesis of pyrrolo[1,2-a]pyrazines and pyrrolo[1,2-a]-quinoxalines. By the alkylation of sodium derivatives of 2-acylpyrroles with -bromo carbonyl compounds or their acetals and subsequent treatment of the reaction products with ammonium acetate in acetic acid, a number of derivatives of pyrrolo[1,2-a]pyrazine, including the first member of the class, pyrrolo[1,2-a]pyrazine itself, have been obtained. Similarly, from 2-benzoylpyrrole and the dimethyl ketal of -bromocyclohexanone was obtained 4-phenyltetrahydropyrrolo[1,2-a]quinoxaline, which readily dehydrogenates in the presence of Raney nickel to form 4-phenylpyrrolo[1,2-a]quinoxaline.Translated from Khimiya Geterotsiklicheskikh Soedinenii, Vol. 6, No. 8, pp.1048–1050, August, 1970.     

One-pot synthesis of pyrrolo[1,2-a]quinoxalines

A transition metal-free process for the regioselective synthesis of pyrrolo[1,2-a]quinoxalines under mild conditions in one-pot is described. The reaction afforded a variety of products in good to excellent yields. Indolo[1,2-a]quinoxalines were also synthesized from indole-2-carboxamides under the same conditions.     

One-pot synthesis of pyrrolo[1,2-a]quinoxaline and pyrrolo[1,2-a]pyrazine derivatives via the three-component reaction of 1,2-diamines,ethyl pyruvate and α-bromo ketones

A simple synthetic protocol has been developed involving the three-component reaction between 1,2-diamines, ethyl pyruvate and a-bromo ketones in the presence of Fe Cl3 as a catalyst. A number of pyrrolo[1,2-a]quinoxaline and pyrrolo[1,2-a]pyrazine derivatives were synthesized in excellent yields using this protocol.     

A thermal cascade route to pyrroloisoindolone and pyrroloimidazolones

Flash vacuum pyrolysis (FVP) of indol-1-ylacrylate derivatives 11 and 15 or the isomeric indol-3-ylacrylates 21, 22, and 24 at 925 degrees C (0.05 Torr) provides pyrrolo[1,2-a]indol-3-ones 2, 18, 28, and 29 in 53-90% yield by a cascade mechanism that involves a sigmatropic migration, elimination, electrocyclization sequence. Pyrrolo[1,2-a]imidazol-5-ones 3 and pyrrolo[1,2-c]imidazol-5-ones 4 were similarly obtained by FVP of corresponding 2,5-unsubstituted imidazol-1-ylacrylates (e.g., 33), with the former isomer predominating in ca. 80:20 ratio. Migration to the 2-position is therefore favored in the initial sigmatropic shift. FVP of 2-substituted imidazol-1-ylacrylates 35, 37, and 51 (825-875 degrees C) instead give pyrrolo[1,2-c]imidazol-5-ones 56-58 only (88-91%), and that of 4,5-disubstituted imidazol-1-ylacrylates 39 and 41 (825-850 degrees C) provide pyrrolo[1,2-a]imidazol-5-ones 59 and 60 exclusively (93-95%), and thus the selectivity of the initial shift can be controlled by the presence of substituents on the imidazole 2- and 5-positions. FVP of the benzimidazole analogues 61 and 62 at 950 degrees C gave the pyrrolo[1,2-a]benzimidazol-1-ones 6 (71%) and 63 (36%), respectively.     

1-(Trifluoromethyl)-3,4-dihydropyrrolo-[1,2-<Emphasis Type="Italic">a</Emphasis>] pyrazines: synthesis and reactions with O- and N-nucleophiles

The method of synthesis has been developed and reactions of 1-(trifluoromethyl)-3,4-dihydro-pyrrolo[1,2-a]pyrazines with O- and N-nucleophiles have been studied. It was found that reactions of nucleophiles with 1-(trifluoro-methyl)pyrrolo[1,2-a]pyrazines transforms the trifluoromethyl group to amide and amidine groups together with aromatization of the pyrrolo[1,2-a]pyrazine system as a result of the formal elimination of a molecule of hydrogen fluoride.     

A novel synthesis of arylpyrrolo[1,2-a]pyrazinone derivatives

Some aryl-2-methyl-1-pyrrolo[1,2-a]pyrazinones were designed and prepared to study the Structure-Activity Relationships (SAR) of pyrrolo[1,2-a]pyrazinone derivatives. With methyl pyrrole-2-carboxylate as the starting material, the title compounds were prepared through N-alkylation and two novel cyclizations. Eleven aryl-2-methyl-1- pyrrolo[1,2-a]pyrazinone derivatives not previously reported in the literature are presented in this paper. Some of them show potent anti-inflammatory and analgesic activities.     

Efficient One-pot Synthesis of Pyrrolo[2,1-a]isoquinoline and Pyrrolo[1,2-a]quinoline Derivatives

A one-pot sequential reaction for efficient synthesis of pyrrolo[2,1-a]isoquinoline and pyrrolo[1,2-a]-quinoline derivatives has been developed. The reaction included firstly the Cu-catalyzed three-component reaction of isoquinoline(quinoline), acetylenedicarboxylate and alkynylbenzene and then Cs₂CO₃-promoted intramolecular cyclization reaction of initially formed 1-alkenyl-2-alkynyl-1,2-dihydroisoquinoline(1,2-dihydroquinoline).     

Formal fusion of a pyrrole ring onto 2-pyridyl and 2-pyrimidyl cations: one-step gas-phase synthesis of indolizine and its derivatives

Two ortho-hetarynium ions, the 2-pyridyl and 2-pyrimidyl cations, react promptly with 1,3-dienes in the gas phase by annulation, formally by fusion, onto the ions of a pyrrole ring. This novel reaction proceeds through an initial polar [4 + 2+] cycloaddition across the C[triple bond]N+ bond, followed by fast ring opening, a [1,4-H] shift, and finally a recyclization that results in a contraction of a six- to a five-membered ring and dissociation by the loss of a methyl radical. For the 2-pyridyl cation, this reaction yields ionized indolizines (pyrrolo[1,2-a]pyridines), while for the 2-pyrimidyl cation, it gives ionized pyrrolo[1,2-a]pyrimidines. The annulation reaction, performed in the rf-only collision quadrupole of a pentaquadrupole (QqQqQ) mass spectrometer, occurs readily with both 1,3-butadiene and isoprene, and is thermodynamically and kinetically favored as predicted by ab initio calculations. Ortho-hetarynium ions and 1,3-dienes provide, therefore, the two building blocks for the efficient one-step gas-phase synthesis of ionized bicyclic pyrrolo[1,2-a]pyridine (indolizine) and pyrrolo[1,2-a]pyrimidine, as well as their analogues and derivatives.     

Novel synthesis of bicycles with fused pyrrole, indole, oxazole, and imidazole rings

Reactions of benzotriazol-1-yl(1H-pyrrol-2-yl)methanone 10 and benzotriazol-1-yl(1H-indol-2-yl)methanone 11 with diverse ketones, isocyanates, and isothiocyanates in the presence of base afforded pyrrolo[1,2-c]oxazol-1-ones 1, oxazolo[3,4-a]indol-1-ones 2, pyrrolo[1,2-c]imidazoles 3, and imidazo[1,5-a]indoles 4 by a simple one-step procedure.     

Nitration of Pyrrolo[1,2-<Emphasis Type="Italic">a</Emphasis>]pyrazines

We have synthesized nitro derivatives of pyrrolo[1,2-a]pyrazines using a nitrating mixture and acetyl nitrate. We have obtained the products of oxidation of the side chain of 1,6-substituted pyrrolo[1,2-a]-pyrazines. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1579–1586, October, 2005.     

Acylation of pyrrolo[1,2-a]pyrazines

The acylation of pyrrolo[1,2-a]pyrazines with acetic anhydride and the acid chlorides of various carboxylic acids has been studied. It has been shown that pyrrole[1,2-a]pyrazines are selectively acylated at the α-position of the pyrrole ring when it is free. Products of the condensation of 1-methylsubstituted pyrrolo[1,2-a]pyrazines have been obtained for the first time in the process of acetylation. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, 263–272, February, 2008.     

Synthesis of pyrido[2,3-e]pyrrolo[1,2-a]pyrazine derivatives via tandem iminium cyclization and smiles rearrangement

The tandem iminium cyclization and Smiles rearrangement of pyridinyloxyacetaldehyde 1 and a primary amine generated a novel pyrido[2,3-e]pyrrolo[1,2-a]pyrazine scaffold. TFA was discovered to be an efficient catalyst in the reactions with aromatic amines, whereas TiCl4 was found to be superior in the case of aliphatic amines. This methodology proved to be efficient in the preparation of a library of diversified pyrido[2,3-e]pyrrolo[1,2-a]pyrazine derivatives.     

Chemistry of pyrrolo[1,2-a]indole- and pyrido[1,2-a]indole-based quinone methides. Mechanistic explanations for differences in cytostatic/cytotoxic properties

In the present study we investigate pyrido[1,2-a]indole- and pyrrolo[1,2-a]indole-based quinones capable of forming quinone methide and vinyl quinone species upon reduction and leaving group elimination. Our goals were to determine the influence of the 6-membered pyrido and the 5-membered pyrrolo fused rings on quinone methide and vinyl quinone formation and fate as well as on cytostatic and cytotoxic activity. We used the technique of Spectral Global Fitting to study the fleeting quinone methide intermediate directly. Conclusions regarding quinone methide reactivity are that carbonyl O-protonation is required for nucleophile trapping and that the pKa value of this protonated species is near neutrality. The abnormally high protonated carbonyl pKa values are due to the formation of an aromatic carbocation species upon protonation. The fused pyrido ring promotes quinone methide and vinyl quinone formation but slows nucleophile trapping compared to the fused pyrrolo ring. These findings are explained by the presence of axial hydrogen atoms in the fused pyrido ring resulting in more steric congestion compared to the relatively flat fused pyrrolo ring. Consequently, pyrrolo[1,2-a]indole-based quinones exhibit more cytostatic activity than the pyrido[1,2-a]indole analogues due to their greater nucleophile trapping capability.     

Pyrrolo[1,2-a]benzimidazoles in the hetarylation reaction

The direct incorporation of isoquinoline, benzimidazole, and acridine residues in pyrrolo[1,2-a]benzimidazole and its derivatives was accomplished by the reaction of N-heteroaromatic compounds with pyrrolo[1,2-a]benzimidazole and its analogs in the presence of acylating agents.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1108–1110, August, 1978.     

Crowned Macrocycles Containing Two Pyrrolo[1,2-a] Indoles Created By Intramolecular Fusion

Heterocyclic fused-ring systems are of utmost importance because of their presence in many natural products with biological activity. Pyrroloindoles are tricyclic heterocycles that are present in various bioactive and medicinally valuable compounds. Herein, we report the synthesis of phenylene-bridged bis-pyrrolo[1,2-a]indole crowned macrocycles 1 – 3 in which the pyrrolo[1,2-a]indole moieties were formed via intramolecular fusion. The macrocycles were thoroughly characterized by 1D and 2D NMR, HRMS and X-ray crystallographic studies. The X-ray structure revealed that the two pyrrolo[1,2-a]indole moieties were parallel to each other, and one pyrrolo[1,2-a]indole unit was deviated by an angle of 9.54° while the other pyrrolo[1,2-a]indole unit was deviated by an angle of 12.0° from the mean plane defined by 28 core atoms. The macrocycles 1 – 3 absorb in the visible region and readily undergo oxidations because of their electron rich nature. The macrocycles 1 – 3 upon treatment with trifluoroacetic acid (TFA) generates the corresponding cation radicals 1 – 3 ^.+ which were stable in the open air for a week. The cation radicals 1 – 3 ^.+ absorb strongly in the NIR region and the experimental observations on crowned macrocycles 1 – 3 were corroborated by DFT and TD-DFT studies.     

An efficient approach to azirino and pyrrolo-fused dibenzazepines. Conformations of substituted dibenzo[c,f]pyrrolo[1,2-a]azepines

An effective approach to azepino-fused heterocycles is described. trans-1-Aryl-7,11b-dihydro-1H-azirino[1,2-a]dibenzo[c,f]azepines were synthesised via a domino sequence: isomerization of gem-dichloroaziridine-intramolecular Friedel-Crafts acylation of the tethered benzene ring catalysed by SnCl(4) and subsequent hydride induced intramolecular cyclization. Cycloaddition of dibenzazepinium ylides, generated by heating these aziridines, to activated C[double bond]C, C[triple bond]C dipolarophiles and fullerene C(60), leads to derivatives of dibenzo[c,f]pyrrolo[1,2-a]azepine. The reaction proceeds with complete stereoselectivity via cycloaddition of only W-ylide, which due to the high barrier does not undergo E,Z-isomerization under the reaction conditions. It was found that 2,3,9,13b-tetrahydro-1H-dibenzo[c,f]pyrrolo[1,2-a]azepine systems can exist in conformations of two types depending on the substituents at the pyrrolidine carbons in β-position with respect to nitrogen. Details of cycloaddition reactions and the conformational behavior of cycloadducts were studied by DFT calculations at the B3LYP/6-31G(d) level.     

Unusual reactions of 5,5-dimethyl-2-(indenyl-2)-3-pyrazolidinone with acetylenedicarboxylates

[reaction: see text] Reaction of 5,5-dimethyl-3-pyrazolidinone (1) with 2-indanone (2) gave 5,5-dimethyl-2-(1H-indenyl-2)-3-pyrazolidinone (3) instead of the expected azomethine imine 4. Although reaction of 2-substituted 3-pyrazolidinones with acetylenedicarboxylates usually gives ring expansion products, such as 1,2-diazepines, treatment of 3 with dialkyl acetylenedicarboxylates (5, R = Me; 6 R = Et) resulted in the formation of rel-(7aR,12aS)-6,7-bis(alkoxycarbonyl)-3,4-dihydro-4,4-dimethyl-7aH-indano[1,2-b]pyrrolo[1,2-a]pyrimidin-2-ones (7, R = Me; 9, R = Et) as major products and 3,4-bis(alkoxycarbonyl)-7,7-dimethyl-2-(indenyl-2)-6,7-dihydro-2H,6H-1,2-diazepin-5-ones (8, R = Me: 10, R = Et) as minor products.     

Investigations in the imidazole series LXXIV. Electrophilic substitution reactions in the pyrrolo[1,2-a]imidazole series

The formylation, acetylation, hydroxymethylation, azo coupling, nitrosation, nitration, and chloromercuration of pyrrolo[1,2-a]imidazole derivatives were studied. The PMR spectra were used to establish that all of these reactions proceed at the 5 position or, if it is occupied, at the 7 position of the two-ring system. When the 5 and 7 positions are free, the formation of 5,7-disubstituted pyrrolo[1,2-a]imidazoles is possible.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 405–409, March, 1972.