Synthesis of pyrido[1,2-a]indole malonates and amines through aryne annulation

Pyrido[1,2-a]indoles are known as medicinally and pharmaceutically important compounds, but there is a lack of efficient methods for their synthesis. We report a convenient and efficient route to these privileged structures starting from easily accessible 2-substituted pyridines and aryne precursors. A small library of compounds has been synthesized utilizing the developed method, affording variously substituted pyrido[1,2-a]indoles in moderate to good yields.     

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.     

Design of a cyclopropyl quinone methide reductive alkylating agent. 2

A cyclopropyl quinone methide is formed by elimination of a leaving group from an appropriately functionalized hydroquinone. The presence of a carbon spacer results in the formation of a fused ring rather than the classic methide species. Discussed herein is cyclopropyl quinone methide formation from a pyrido[1,2-a]indole ring system. Both nucleophilic and electrophilic attack on the fused cyclopropane ring results in pyrido[1,2-a]indole and azepino[1,2-a]indole products. The stereoelectronic effect plays less a role in the relatively flexible pyrido[1,2-a]indole system compared to its role in the pyrrolo[1,2-a]-indole system. A 13C label on the fused cyclopropane ring permitted the rapid identification of complex rearrangement products observed in this study.     

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 practical two-step synthesis of imidazo[1,2-a]pyridines from N-(prop-2-yn-1-yl)pyridin-2-amines

The Sandmeyer reaction of differently C-2 substituted N-(prop-2-yn-1-ylamino)pyridines is an efficient, mild, new and practical method for the stereospecific synthesis of (E)-exo-halomethylene bicyclic pyridones bearing the imidazo[1,2-a]pyridine heterocyclic ring system.     

Halogenoalkyl isocyanates as bifunctional reagents in an Aza-Wittig/heterocyclization reaction on the solid phase: efficient entry into new tetracyclic benzimidazole systems

An efficient one-pot procedure for the solid-phase synthesis of new tetracyclic 1,3,5-triazino[1,2-a]benzimidazolium derivatives starting from resin-bound benzimidazoles is described. The synthetic strategy involves an unprecedented one-pot Aza-Wittig/heterocyclization/substitution reaction sequence using halogenoalkyl isocyanates. The structure of the tetracyclic ring system was determined by two-dimensional NMR experiments and X-ray analysis.     

Palladium-catalyzed intramolecular N-arylation of heteroarenes: a novel and efficient route to benzimidazo[1,2-a]quinolines

An efficient new route for the synthesis of benzimidazo[1,2-a]quinolines has been developed via the palladium-catalyzed intramolecular Buchwald-Harwtig aryl amination of newly synthesized 2-(2'-bromoanilino)quinolines.     

Solid-phase synthesis of imidazo[1,2-a]pyridine using sodium benzenesulfinate as a traceless linker

[formula: see text] The preparation of the first library of imidazo[1,2-a]pyridine derivatives on a solid support is described. A sulfone linker strategy was applied in the synthesis. Key steps involved in the solid-phase synthetic procedure include (i) alpha-haloketone resin formation by sulfinate-->sulfone alkylation, (ii) imidazo[1,2-a]pyridine ring formation by treatment with 2-aminopyridine, (iii) sulfone anion alkylation, and (iv) traceless product release by oxidation-elimination. A library of 12 imidazo[1,2-a]pyridines was synthesized.     

Aryne [3 + 2] cycloaddition with N-sulfonylpyridinium imides and in situ generated N-sulfonylisoquinolinium imides: a potential route to pyrido[1,2-b]indazoles and indazolo[3,2-a]isoquinolines

The aryne [3 + 2] cycloaddition process with pyridinium imides breaks the aromaticity of the pyridine ring. By equipping the imide nitrogen with a sulfonyl group, the intermediate readily eliminates a sulfinate anion to restore the aromaticity, leading to the formation of pyrido[1,2-b]indazoles. The scope and limitation of this reaction are discussed. As an extension of this chemistry, N-tosylisoquinolinium imides, generated in situ from N'-(2-alkynylbenzylidene)-tosylhydrazides via an AgOTf-catalyzed 6-endo-dig electrophilic cyclization, readily undergo aryne [3 + 2] cycloaddition to afford indazolo[3,2-a]-isoquinolines in the same pot, offering a highly efficient route to these potential anticancer agents.     

A novel and convenient synthesis of thiazolo[3,2-a]pyrimidin-7-ones and pyrido[1,2-a]pyrimidin-2-ones using Vilsmeier reagent

A novel route for the synthesis of thiazolo[3,2-a]pyrimidin-7-ones and pyrido[1,2-a]pyrimidin-2-ones from acetylated 2aminothiazoles and 2-aminopyridines under Vilsmeier conditions has been developed.The plausible mechanism has also been proposed.     

Research on imidazo[1,2-a]benzimidazole derivatives.

3-Alkoxycarbonyl-2-arylimidazo[1,2-a]benzimidazoles were synthesized by alkaline cleavage of 3-trichloromethyl ketones of the imidazo[1,2-a]benzimidazole series, which are formed by acylation of this three-ring system with trichloroacetyl chloride. The same compounds were also obtained by esterification of the corresponding 3-carboxylic acid. The haloform reaction with 3-acetyl-2-phenylimidazo[1,2-a]benzimidazole proceeds anomalously and leads to bis(9-methy1-2-phenylimidazo[1,2-a]benzimidazo1-3-yl)-2-buten-1,4-dione, the structure of which was confirmed by independent synthesis.See [1] for communication XV.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 522–525, April, 1978.     

Mitomycin synthetic studies: stereocontrolled and convergent synthesis of a fully elaborated aziridinomitosane

Full details of a stereocontrolled and convergent synthetic route to 9a-desmethoxymitomycin A (1) are reported. The target molecule possesses the parent tetrahydropyrrolo[1,2-a]indole ring system characteristic of the mitomycin family of antitumor agents. The synthesis was based on the diastereocontrolled addition of a fully elaborated cinnamylstannane to a pyrrolidine-based N-acyliminium ion as the key convergent step, which resulted in the installation of the C9 and C9a stereogenic centers.     

Imidazo[1,2-a]pyridines susceptible to excited state intramolecular proton transfer: one-pot synthesis via an Ortoleva-King reaction

A short and efficient route to a broad range of imidazo[1,2-a]pyridines from 2-aminopyridines and acetophenones is achieved by a tandem, one-pot process starting with an Ortoleva-King reaction. Optimal conditions for the first step were established after examining various reaction parameters (solvent, reagent ratios, and temperature). The conditions identified (1st step, neat, 2.3 equiv of 2-aminopyridine, 1.20 equiv of I(2), 4 h, 110 °C; 2nd step, NaOH(aq), 1 h, 100 °C) resulted in the formation of imidazo[1,2-a]pyridines in 40-60% yields. The synthesis is compatible with various functionalities (OH, NMe(2), Br, OMe). Products containing a 2-(2'-hydroxyphenyl) substituent undergo excited state intramolecular proton transfer (ESIPT) in nonpolar and polar-aprotic solvents. Although ESIPT-type emission in nonpolar solvents is weak, the Stokes shifts are very high (11000 cm(-1)). The comparison of the properties of six ESIPT-capable imidazo[1,2-a]pyridines shows the influence of various substituents on emission characteristics. All of them also display strong, solid-state emission in blue-green-yellow region. 2-Aryl-imidazo[1,2-a]pyridines not capable of ESIPT emit in the blue region, displaying high fluorescence quantum yield.     

Synthesis by radical cyclization and cytotoxicity of highly potent bioreductive alicyclic ring fused [1,2-a]benzimidazolequinones

The key step in the synthesis of new five, six and seven-membered alicyclic ring [1,2-a]-fused bioreductive benzimidazolequinones was radical cyclisation. Six and seven-membered tributyltin hydride-mediated homolytic aromatic substitutions of nucleophilic N-alkyl radicals onto the benzimidazole-2-position occurred in high yields (63-70 %) when quaternising the pyridine-like 3-N of imidazole with camphorsulfonic acid and using large excesses of the azo-initiator, 1,1'-azobis(cyclohexanecarbonitrile), to supplement the non-chain reaction. Elaboration of benzimidazoles to the benzimidazolequinones occurred in excellent yields. The IC50 values for the cytotoxicity of benzimidazolequinones towards the human skin fibroblast cell line GM00637 were in the nanomolar range, as determined by using the MTT assay. The benzimidazolequinones were much more cytotoxic than indolequinone analogues. 1,2,3,4-Tetrahydropyrido[1,2-a]benzimidazole-6,9-dione was the most potent compound prepared being more than 300 times more cytotoxic than the clinically used bioreductive drug, mitomycin C. The latter benzimidazolequinone was more potent under hypoxic conditions (associated with solid tumors), being 4.4 times more cytotoxic than under aerobic conditions, while mitomycin C was 1.8 times more selective towards hypoxia. The cyclopropane fused pyrido[1,2-a]benzimidazolequinone, 1a,2,3,9b-tetrahydro-1H-cyclopropa[3,4]pyrido[1,2-a]benzimidazole-5,8-dione was less cytotoxic and selective than the five-membered ring analogue, 1,1a,8,8a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-a]benzimidazole-3,6-dione. Modifying the structure of the most potent pyrido[1,2-a]benzimidazolequinone by attaching methyl substituents onto the quinone moiety increased reductive potentials and decreased cytotoxicity and selectivity towards hypoxia.     

Research on imidazo[1,2-a]benzimidazole derivatives

The debenzylation of N-benzylimidazo[1,2-a]benzimidazoles with sodium in liquid ammonia was studied. The debenzylation of the 2-phenyl-substituted derivative is accompanied by hydrogenation of the outer imidazole ring to give 2-phenyl-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole, the alkylation of which in alkaline media and neutral media, respectively, gives the 1-methyl derivative and the 9-methyl derivative. The 1-methyl derivative was subjected to quaternization and bromination; the latter proceeds in the condensed benzene ring. Debenzylation of the 2-methyl derivative of imidazo[1,2-a]benzimidazole is not accompanied by hydrogenation but gives 2-methyl-1(9)H-imidazo[1,2-a]benzimidazole.See [1] for communication VI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 791–796, June, 1973.     

Iron-catalyzed synthesis of polycyclic-fused azo[l,2-a]indolones via an S_NAr/acylation cascade reactions

An efficient method has been developed for the cascade synthesis of azo[1,2-a]indolones from azoles and2-fluoroaldehydes based on an iron-catalyzed S_NAr and a direct acylation reaction.A number of azo[1,2-a]indolones containing different azole rings and substituents were obtained in good yields.     

A simple and efficient route to 2-arylimidazo[1,2-a]pyridines and zolimidine using automated grindstone chemistry

A green and efficient mechanochemical method for the synthesis of a series of 2-arylimidazo[1,2-a]pyridines was developed using an electrical grinder. I₂ catalyzed mechanochemical grinding facilitates the cyclocondensation reaction between various aryl methyl ketones and 2-aminopyridines to afford 2-arylimidazo[1,2-a]pyridines in good yields at ambient temperature. The method was successfully used for the gram-scale synthesis of a marketed drug, zolimidine. The noticeable advantages of this environmentally sustainable protocol include mild conditions, simple instrumentation, inexpensive catalyst, atom economy, short reaction time etc.     

Palladium-catalyzed regioselective arylation of imidazo[1,2-a]pyrimidine

Imidazo[1,2-a]pyrimidine can be arylated at the 3-position with aryl bromides in the presence of base and a catalytic amount of palladium. This provides an efficient one-step synthesis of 3-arylimidazo[1,2-a]pyrimidines from the unsubstituted heterocycle. [reaction: see text]     

NEW HETEROCYCLIC SYSTEM SYNTHESIS I REACTION OF DIHYDRO-1,5-BENZO-DIAZEPINES AND THIAZEPINES WITH (ETHOXYCARBONYL)CARBENES

Dihydro-1-benzoyl-1,5-benzodiazepines react with (ethoxycarbonyl)carbenes to give 4H-azirino-[1,2-a][1,5]-benzodiazepines and unexpected new tin9 system 1H-pyrrolo-[1,2-a][1,5]-benzodiazepines. Dihydro-1,5-benzothiazepines react with (ethoxycarbonyl)carbenes in cyclohexane to gire unexpected rin9 cleavage products ethyl (2E, 4E)-3-aryl-2-arylthiohexadienoates.     

A convergent approach to the mitomycin ring system

[structure: see text]. A novel stereoselective approach to the ring system of the mitomycins is described. The synthesis was based on a convergent strategy involving a stereocontrolled addition of a beta-phenyl silyl enol ether to a pyrroline N-acyliminium ion followed by an intramolecular palladium-catalyzed aryl triflate amination to afford the (9R*,9aR*)-tetrahydropyrrolo[1,2-a]indole ring system.