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.     

Relative stabilities of the tautomeric forms of conjugate acids and kinetics of deuterium exchange in derivatives of indolizine,pyrrolo [1,2-a] imidazole,and pyrrolo [1,2-a]benzimidazole

The effect of the temperature and the acidicity of the medium on the ratio of the two tautomeric forms of the conjugate acids of derivatives of indolizine, pyrrolo[1,2-a]imidazole, and pyrrolo[1,2-a]benzimidazole was investigated by PMR spectroscopy. The change in the ratio of the forms with time was studied under fixed reaction conditions. The position of the tautomeric equilibrium in a number of the investigated systems was established. A correspondence between the relative stabilities of the protonated forms and the rate constants for electrophilic deuterium exchange in the neutral molecules was observed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 70–75, January, 1976.     

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.     

Mass spectra of pyrrolo [1,2-a]benzimidazole and imidazo[1,2-a]benzimidazole derivatives

The closeness of the electronic structures of the ions formed in the first act of disintegration of the ions is responsible for the monotypic character of the subsequent fragmentation of pyrrolo[1,2-a]benzimidazole and imidazo[1,2-a]benzimidazole derivatives. The mass-spectrometric disintegration of the investigated systems has something in common with the fragmentation of thiazolo[3,2-a]benzimidazole derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, 1124–1127, August, 1975.     

Protonation of pyrrolo[1,2-a] imidazole derivatives

The protonation of a number of pyrrolo[1,2-a]imidazole derivatives in trifluoroacetic acid was studied by PMR spectroscopy. The 5,7-unsubstituted compounds form a mixture of two forms of cations, the structures of which correspond to the addition of a proton to the C₅ and C₇ atoms of the two-ring system with predominance (60–90%) of the 5-C cation. The introduction of a CH₃ group into the 5 position changes the direction of protonation to favor predominant (95%) formation of the 7-C cation. The 7-methyl derivatives of pyrroloimidazole are protonated exclusively at the C₅ atom. It is demonstrated that the basicity of the pyrroloimidazoles considerably surpasses the basicity of indolicine derivatives. The comparative proton-acceptor capacity of these systems is compared with the energy indexes and the reactivity indexes calculated by the simple MO LCAO method.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 492–497, April, 1972.     

Reamination in the recyclization of pyrrolo-[1,2-a]pyrazine salts into 6- and 8-aminoindolizines. General process scheme

Rearrangement of the methyl iodides of 1- and 3-alkyl-substituted pyrrolo[1,2-a]pyrazines in the presence of various alkylamines afforded a mixture of 8- and 6-aminoindolizines, respectively, with and without exchange of the methylamine fragment. The ratio of the products of direct and exchange recyclization was dictated by the size of the N-alkyl substituents in the reagent and starting salt. Rearrangement of the 1-alkylpyrrolo[1,2-a]pyrazinium salts proceeded via the breaking of the C₍₃₎ -N₍₂₎ bond, and rearrangement of the 3-alkylpyrrolo-[1,2-a]pyrazinium salts via the breaking of the C₍₁₎ -N₍₂₎ bond.Translated from Khimiya Geterotsiklicheskikikh Soedinenii, No. 11, pp. 1485–1490, November, 1992.     

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.     

Synthesis of pyrrolo[1,2-a]quinoxaline derivatives by the reaction of 2-hydroxy-1,5-diketones with o-phenylenediamine

The reaction of 2-hydroxy-1,5-diketones with o-phenylenediamine leads to the formation of 4,5-dihydropyrrolo[1,2-a]quinoxaline derivatives, which are dehydrogenated by the action of MnO₂ to give the corresponding pyrrolo[1,2-a]quinoxaline derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 112–115, January, 1992.     

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.     

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.     

Chloral as a formylating agent for some bridge heterosystems

The interaction of condensed nitrogen-containing bridge systems with chloral has been studied and the high sensitivity of the reaction to the -excess of the initial heteroaromatic system has been established. It has been shown that chloral is a convenient formylating agent for systems with a moderate -excess —imidazo[l,2-a]imidazole, 9H-imidazo[1,2-a]benzimidazole, imidazo[1,2-a]pyridine, imidazo[1,2-a]naphtho[2,3-d]imidazole. Heterocycles with a high -excess (indolizine, pyrrolo[1,2-a]benzimidazole) form cyanine dyes under the action of chloral. Systems with a lowered -excess (1H-imidazo[1,2-a]benzimidazole, imidazo[1,2-a]quinoline, imidazo[2,1-a]isoquinoline, imidazo[1,2-a]perimidine, imidazo[5,1-b]benzoxazole, imidazo[1,2-a]benzothiazole, and imidazo[1,2-a]pyrimidine) do not react with chloral in a neutral medium. However, in a number of cases their foraylation can be carried out in an acid medium.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 528–537, April, 1980.     

Investigations in the imidazole field

It has been established that various inorganic and organic bases can be used for the cyclization of 1,2-dialkyl-3-(-oxoalkyl[aralkyl])benzimidazolium halides into derivatives of pyrrolo[1,2-a]benzimidazole. The action of strong bases on quaternary benzimidazolium salts gives O-betaines—intermediates in the closure of the pyrrole ring.For part XL, see [1].     

Studies of imidazo[1,2-a]benzimidazole derivatives. 21. Synthesis of haloketones in the imidazo[1,2-a] benzimidazole series

Methods for the synthesis of imidazo[1,2-a]benzimidazole haloketone derivatives have been investigated. It has been found that -bromoketone derivatives of this heterocycle can be prepared either by bromination of 3-acylimidazo[1,2-a]benz-imidazoles with bromine in glacial acetic acid or by acylation of 3-unsubstituted imidazo[1,2-a]benzimidazoles with haloanhydride derivatives of -bromoalkanoic acids. Treatment of imidazo[1,2-a]benzimidazoles with 3-chloropropionyl chloride results in the formation of imidazo[1,2-a]benzimidazolyl-3-propionyl chloride and bis(imidazo[1,2-a]benzimidazolyl)propan-3-one derivatives as side products. Reaction of 2-phenylimidazo[1,2-a]benzimidazoles with 3-bromopropionic acid in polyphosphoric acid gives benzocyclohepten[5,6:4,5]imidazo[1,2-a]benzimidazole derivatives.For Communication 20, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 339–345, March, 1986.     

Research on imidazo[1,2-a]benzimidazole derivatives XII. 3-Acyl-substituted imidazo[1,2-a]benzimidazoles

Stable 3-acetyl derivatives of imidazo[1,2-a]benzimidazole were synthesized by the action of acetic anhydride on 2,9-disubstituted imidazo[1,2-a]benzimidazole. The former were also obtained by cyclization of 1-alkyl (aralkyl) -3-acylmethyl-2-iminobenzimidazoline hydrobromides in acetic anhydride in the presence of anhydrous sodium acetate. 3-Benzoyl-substituted imidazo[1,2-a]benzimidazoles, which are unstable in acidic media, were synthesized by the action of benzoyl chloride in the presence of pyridine or excess starting imidazo [1,2-a] benzimidazole.See [1] for communication XI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 121– 125, January, 1976.     

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.     

Some novel heterocyclic systems derived from 7-amino-2,3-dihydro-8-nitro-1H-pyrrolo[1,2-α]benzimidazole and the corresponding diamine

The preparation of 7-amino-2,3-dihydro-8-nitro-1H-pyrrolo[1,2-a]benzimidazole from 1,4-diacetamido-2,3-dinitrobenzene is described. Reaction of this compound with 2,5-dimethoxytetrahydrofuran produces 2,3-dihydro-8-nitro-7-N-pyrrolo-1H-pyrrolo[1,2-a]benzimidazole, which can be cyclised to produce two new heterocyclic ring systems, 9,10-dihydro-8H-pyrrolo[1,2-a]pyrrolo(1′,2′:1,2]imidazo[5,4-f]quinoxaline and 9,10-dihydro-8H-pyrrolo[2,1-c]pyrrolo[1′,2′:1,2]imidazo[4,5-h][1,2,4]benzotriazine. The corresponding diamine, 7,8-diamino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole undergoes a variety of condensation reactions to produce several new heterocyclic systems, for example, with formic acid, 1,7,8,9-tetrahydroimidazo-[4,5-e]pyrrolo[2,1-6]benzimidazole is formed and with diacetyl, 9,10-dihydro-2,3-dimethyl-8H-pyrrolo-[1′,2′:1,2]imidazo[5,4-y]quinoxaline is obtained.     

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).     

Synthesis of substituted pyrimidine using ZnFe2O4 nanocatalyst via one pot multi-component reaction ultrasonic irradiation

A highly efficient, eco-friendly, recyclable heterogeneous ZnFe₂O₄ nanocatalyzed synthesis of 2-amino-4-substituted 1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carbonitrile (4a-j) derivatives via one pot multicomponent reaction of benzimidazole ( 1 ), substituted aromatic aldehyde ( 2a-j ) and malononitrile ( 3 ) under ultrasonic irradiations. Significance of this synthetic approach is short reaction time, easy handling, simplicity, efficiency, high yield, and recoverable catalyst.     

First synthesis of an aziridinyl fused pyrrolo[1,2-a]benzimidazole and toxicity evaluation towards normal and breast cancer cell lines

Anionic aromatic ipso-substitution has allowed an aziridine ring to be fused onto pyrrolo[1,2-a]benzimidazole. This diazole analogue of aziridinomitosene, and N-[(aziridinyl)methyl]-1H-benzimidazole are shown to be significantly more cytotoxic towards the human breast cancer cell lines MCF-7 and HCC1937 than towards a human normal fibroblast cell line (GM00637). The aziridinyl fused pyrrolo[1,2-a]benzimidazole is less cytotoxic than the non-ring fused aziridinyl analogue towards all three cell lines. The BRCA1-deficient HCC1937 cells are more sensitive to mitomycin C (MMC) compared to GM00637 and MCF-7 cells. The evidence provided indicates that different pathways may mediate cellular response to benzimidazole-containing aziridine compounds compared to MMC.     

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.