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.     

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

The formylation of pyrrolo[1,2-a]pyrazines containing alkyl, aryl, or hetaryl substituents in positions 1 and 6 of the heterocycle has been studied. It has been shown that formylation of 1-phenyl-and 1-(2 thienyl)pyrrolo[1,2-a]pyrazine occurs selectively at the α-position of the pyrrole ring. In all of the remaining examples the reaction course depends on substituent, reagent ratio, and reaction time. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 88–93, January, 2008.     

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

A study was carried out on the reaction of pyrrolo[1,2-a]pyrazines containing an alkyl, aryl, or aralkyl substituent at C-1 with trifluoroacetic anhydride. Trifluoroacetylation products may be formed either by reaction in the pyrrole ring or at the aryl or aralkyl groups at C-1. Products of electrophilic substitution at C-6 are formed in the trifluoroacetylation of pyrrolo[1,2-a]pyrazines containing at C-1 a substituent bulkier than a methyl group but lacking substituents at C-6 (the α-position of the pyrrole ring). __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1226–1233, August, 2007.     

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.     

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 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 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 versatile enantioselective synthesis of azabicyclic ring systems: a concise total synthesis of (+)-grandisine D and unnatural analogues

Closing in on azacines: We have developed a new six step approach for the rapid and enantioselective synthesis of indolizidine, pyrrolo[1,2-a]azepine, and pyrrolo[1,2-a]azocine azabicyclic systems and their respective lactam congeners, which are found in a host of natural products as well as pharmaceutical preparations. This protocol enables a concise enantioselective total synthesis of (+)-grandisine?D in 16.4?% overall yield from commercial materials (see scheme).     

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.     

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.     

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.     

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.     

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.     

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.     

A modular CuI-L-proline catalyzed one-pot route for the rapid access of constrained and privileged hetero-atom-linked medium-sized ring systems

An efficient CuI-L-proline catalyzed one-pot synthesis was developed to generate a collection of skeletally diverse heterocyclic ring systems with sizes ranging from 6 to 9. A salient feature of this design strategy is its modular synthetic utility using an S_N2 reaction followed by a microwave assisted CuI-L-proline hetero-arylation, which has granted access to a series of heterocyclic frameworks including: benzo[e]pyrrolo[1,2-a][1,4]diazepin, benzo[e]pyrrolo[1,2-a][1,4]diazocin, benzo[e]pyrido[1,2-a][1,4]diazocinones, dibenzo[b,f][1,5]diazoninones, dihydrodibenzo[b,e][1,4]thiazepine, dibenzo[b,e][1,4]thiazocine and benzo[6,7][1,4]diazepino[1,2-a]indole. Moreover, the synthetic procedures described herein, allows rapid entries to synthetically challenging medium-sized heterocyclic systems with good overall yields.     

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.     

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.