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.     

Research in the imidazole series

The hydrolysis of 7-cyano derivatives of pyrrolo[1,2-a]imidazole in 85–90% sulfuric acid at 100°C gives amides of pyrroloimidazole-7-carboxylic acids. Under more severe conditions, the resulting carboxylic acids are decarboxylated to the corresponding pyrroloimidazole derivatives with a free 7 position.See [1] for communication XC.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1658–1659, December, 1976.     

Research in the imidazole series

The Mannich reaction in the 6-aryl-7-cyanopyrrolo[1,2-a] imidazole series was studied, and the corresponding 5-dialkylaminomethyl derivatives of this heterocycle were obtained.See [1] for communication LXXXIX.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1552–1553, November, 1976.     

Investigations in the imidazole series

The synthesis of derivatives of 2,3-dihydropyrrolo[1,2-a]imidazole from 1,2-dialkylimidazolines or 1,2-diarylkylimidazolines and phenacyl bromides with subsequent heating of the 1,2-disubstituted 3-phenacyl-imidazolinium bromides in aqueous or ethanolic solution in the presence of bases has been effected.For part XXXVIII, see [7].     

Studies in the imidazole series

Methods were developed for the synthesis of dihydro and tetrahydro derivatives of imidazo-[1,2-a]- and imidazo[1,2-c]pyrimidine and imidazo[2,1-b]-5-quinazolone from 2-amino- and 4-aminopyrimidines, 2-amino-4-quinazolones, and -haloethanols or 1,2-dihaloethanes. Dihydroimidazo[1,2-c]quinazoline, which was also obtained by cyclization of 4-(-hydroxyethylamino)-quinazoline, was synthesized by reaction of 4-chloroquinazoline with -haloethylamines.See [1] for communication LXXXV.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 834–836, June, 1976.     

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.     

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].     

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.     

Studies in the imidazole series

By quaternization of 1-alkyl(aryl, aralkyl)-2-methyl-4, 5-diarylimidazoles with -bromo ketones and by subsequent cyclization of the quaternary salts of imidazole, a number of arylpyrrolo[1,2-a]imida~ zoles were obtained. A study was made of the effect of different bases on the process of cyclization and the yield of pyrroloimidazole derivatives. The structure was established of certain intermediate products of the reaction involving the closure of the pyrrole ring.For Part XXXVI, see [11].     

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 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.     

Investigations in the imidazole series

Imidazo[1,2-a]imidazole derivatives were synthesized by the reaction of 1-acylmethyl-2-bromo-4,5-diphenylimidazoles with ammonia and primary amines.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1243–1247, September, 1971.     

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.     

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.     

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.     

Facile and versatile annulation of the imidazole ring: Single and sequential cyclization reactions of Fischer carbene complexes with 1,4-diazafulvenes

We examined the reactivity of dimethylaminodiazafulvene 1 toward Fischer alkenylcarbene 2 and alkynylcarbene 3 complexes. Diazafulvene 1 reacts with alkenylcarbenes 2 through a formal [6+3] heterocyclization in a regio- and stereoselective manner to afford dihydroimidazo[1,2-a]pyridines 4. Acid-promoted dimethylamine elimination in compound 4 c gives rise to the aromatic imidazo pyridine 5. A likely mechanism for this reaction is a 1,2-nucleophilic addition/[1,2]-shift metal-promoted cyclization sequence. On the other hand, diazafulvene 1 and alkynyl carbenes 3 undergo a [6+2] cyclization to afford pyrrolo[1,2-a]imidazole carbene complex 6 that can be readily oxidized to the corresponding esters 7. When enynylcarbenes 3 e-i are treated with diazafulvene 1, consecutive and diastereoselective [6+2]/cyclopentannulation cyclization reactions take place affording new polycyclic complex systems 8, 9, and 12 that can be appropriately demetallated to the corresponding imidazole-based polyfused systems 10, 11, and 13 respectively. Finally, enynylcarbenes 3 d,f undergo consecutive [6+2]/[5+1] cyclization reactions with diazafulvene 1 and tBuNC, respectively, to yield tetracyclic adducts 14 and 15. All these processes result in high yields and provide a route to the preparation of imidazopyridines and pyrroloimidazoles as well as other polycyclic molecules that contain imidazole groups, which are interesting from a pharmacological and biological point of view.     

A simple and effective approach to the synthesis of isoquinoline derivatives under solvent-free conditions

An efficient synthesis of dialkyl pyrrolo[2,1-a]isoquinoline-2,3-dicarboxylates, pyrrolo[1,2-a]quinoline-1,2- dicarboxylates and indolizines is described via one-pot reactions of isoquinoline, quinoline or pyridine and phenacyl bromids with dialkyl acetylenedicarboxylates or diaryloylacetylene under solvent-free conditions at 50°C. The mild reaction conditions and high yields of the products exhibit the good synthetic advantage of these methods.     

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

The protonation of a number of pyrrolo[1,2-a]benzimidazole derivatives in trifluoroacetic acid was studied by PMR spectroscopy. 1,3-Unsubstituted compounds are protonated exclusively at the C₁ atom. Under similar conditions, pyrrolobenzimidazoles that have a methyl group in the 1 position form a mixture of two protonated forms, which correspond to the addition of a proton to C₁ and C₃, respectively. The relative percentage of the C₃-protonated form decreases successively (from 81 to 18%) on passing from the 3-unsubstituted compound to the corresponding 3-phenyl and 3-methyl derivatives. The basicity constants of the pyrrolobenzimidazoles decrease symbatically with an increase in the relative percentage of this form. The relative proton-acceptor capacity of indolicine, pyrrolo[1,2-a]-imidazole, and pyrrolo[1,2-a]benzimidazole were examined on the basis of the protonation data and the reactivity indexes, calculated by the simple Hückel MO method.Translated from Khimiya Geterotsiklicheskih Soedinenii, No. 8, pp. 1132–1137, August, 1972.     

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.