Synthesis of imidazo[4,5-<Emphasis Type="Italic">b</Emphasis>]pyridines with a chiral substituent at the nitrogen atom and their conversion to piperazine derivatives

Imidazopyridine and benzimidazole derivatives have been prepared with chiral substituents at the nitrogen atom and have been converted to the corresponding condensed structures fused with a piperazine ring. A method has been developed for the synthesis of novel class of compounds – 6,7,8,9-tetra-hydropyrido[3',2':4,5]imidazo[1,2-a]pyrazine derivatives.     

A versatile synthesis of substituted benzimidazolium salts by an amination/ring closure sequence

[reaction: see text]. A new method to produce benzimidazolium salts based on a successive Buchwald-Hartwig amination and ring closure is reported. A variety of different benzimidazolium salts can be prepared using this procedure. Amines that bear an alpha-chiral group undergo the reaction to furnish chiral benzimidazolium salts. The salts that lack a C2 substituent on the heterocycle are readily deprotonated to give nucleophilic carbenes.     

Electronic effects in dianion radicals of nitro derivatives of 2-phenylbenzimidazole

The EPR spectra of the dianion radicals of 5(6)-nitro-2-(4-aminophenyl)benzimidazole (I), 5(6)-nitro-2-phenylbenzimidazole (II), 5(6)-nitro-2-(4-nitrophenyl)benzimidazole (III), 5(6)-nitro-2-(3-nitrophenyl)benzimidazole (IV), and 2-(4-nitrophenyl) benzimidazole (V), obtained by electrochemical reduction in dimethylformamide (DMF) in a Bu₄NClO₄ -base electrolyte in the presence of Bu₄NOH (VI), were studied. Under the influence of VI, these compounds split out a proton from the imidazole ring and give anions I–V, which are capable of adding an electron reversibly. It was shown that the unpaired electron in I and II is localized in the benzimidazole system and that the splitting of the nitrogen atom of the nitro group does not depend significantly on the substituent in the phenyl ring. The introduction of a nitro group in the phenyl ring (III–V) leads to localization of the unpaired electron on it. The nature of the substituent in the benzimidazole system has a significant effect on the splitting constant for the nitrogen atom of the nitro group.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 530–531, April, 1979.We thank T. A. Maslennikova for kindly providing us with the compounds for the investigation.     

Chiral benzimidazoles and their applications in stereodiscrimination processes

Chiral aspects of benzimidazoles have been over-shadowed for a long time due to the large number of reports on benzimidazoles in the medical field in numerous categories of therapeutic agents. The vigorous research activity in chiral applications of benzimidazole derivatives started after bifunctional benzimidazoles made their appearance especially in the last 2–3 decades. Thus, chiral benzimidazoles form a comparatively young branch of chiral chemistry. The presence of pyridine and pyrrole type of nitrogens along with the fused benzene ring confer on this class of molecules, special properties including useful nucleophilicity, hydrogen bonding ability and a rigid backbone, all of which play decisive roles in proven chiral applications. The present review aims to cover the synthetic routes to access chiral benzimidazoles and their applications in a plethora of chiral fields including enantioselective organocatalysis, metal-based catalysis, asymmetric transformations involving benzimidazole-N-heterocyclic carbenes, kinetic resolution, benzimidazole-based macrocyclic hosts in chiral supramolecular chemistry and other miscellaneous chiral applications.     

Synthesis of chiral N,N′-disubstituted 1,2-benzenediamines from o-dibromobenzene

Palladium-catalyzed amination of o-dibromobenzene provided chiral N,N′-disubstituted 1,2-benzenediamines in good to excellent yields. The amination was executed stepwise and in one pot to give unsymmetrically and symmetrically substituted 1,2-benzenediamines. Incorporation of chiral primary amines was possible without racemization using catalytic Pd₂dba₃–BINAP.     

Chiral benzimidazole-derived mono azacrowns: synthesis and enantiomer recognition studies with chiral amines and their ammonium salts

Benzimidazole fused chiral mono aza-15-crown-5 2, was obtained in a single step from (S)-(?)-2-(α-hydroxyethyl) benzimidazole 1. This new class of aza-crown has a unique structure with the chiral unit being held in a stable conformation due to adjacent benzimidazole ring contributing to its stereodiscrimination ability. The interactions between the host aza-crown and enantiomerically pure amine guests in ionic and neutral forms exhibited the enantio-discrimination ability. The preliminary evaluation of the chiral sensing was monitored using ¹H NMR and circular dichroism (CD) analysis of the complexes at their molar equivalence. The binding parameters were determined using electronic absorption spectroscopy.     

Tuneable asymmetric copper-catalysed allylic amination and oxidation reactions

Asymmetric allylic amination or oxidation can be achieved by reaction of an alkene with a peroxycarbamate catalysed by a chiral copper bis-oxazoline complex, and the reaction can be tuned to give either the amination or oxidation product by reagent choice.     

Investigations in the field of benzimidazole derivatives

The influence of the electron-donating groups CH₃O, N(CH₃)₂, OH, NH₂, CH₃ in various positions of the benzimidazole molecule on the occurrence of the Chichibabin reaction in this series has been studied. While all monosubstituted 1-alkylbenzimidazoles undergo amination with sodium amide with greater or smaller readiness, 5,5-dimethoxy-and 5,6-methylenedioxybenzimidazoles do not take part in this reaction. The behavior of benzimidazole derivatives toward sodium amide is discussed from the point of view of the electron density at the pyridine nitrogen atom and at the C₂ atom of the imidazole ring, which was evaluated on the basis of molecular orbital calculations, ionization constants, and the chemical shifts of the protons attached to the C₂ atom in the PMR spectra.For Communication XXI, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, Vol. 6, No. 8, pp. 1060–1065, August, 1970.     

Asymmetric Michael addition of a recyclable chiral amine: inversion of stereoselectivity caused by the difference of ethereal solvents

The Michael addition of a chiral amine [(-)- 6] to alpha,beta-unsaturated esters ( 4) was attained and the stereoselectivity was inverted by changing the solvent from diethyl ether to tetrahydrofuran when alpha,beta-unsaturated esters having an aromatic ring at the beta-position were employed. In addition, the chiral auxiliary in the Michael adducts ( 9A) was facilely removed with N-iodosuccinimide to afford beta-amino esters ( 10A) and 2-methoxy- d-bornylaldehyde ( 11), which can be reclaimed to the chiral amine ( 6) by reductive amination.     

Pd-catalyzed asymmetric allylic amination using aspartic acid derived P-chirogenic diaminophosphine oxides: DIAPHOXs

[reaction: see text] A Pd-catalyzed asymmetric allylic amination using aspartic acid derived P-chirogenic diaminophosphine oxides (DIAPHOXs) is described. Asymmetric allylic amination of both linear and cyclic substrates proceeded at room temperature to give the chiral allylic amines in 72-99% ee.     

新型含氮三齿钯(II)配合物的合成及其催化性能研究

以白屈氨酸为原料, 经酯化、还原、溴化、胺化等反应合成了4位带活性基团的新型含氮(NN'N)三齿配体, 配体进一步与氯化钯反应制得了Pd(II)的配合物, 并用红外、核磁、元素分析等手段进行了表征. 考察了这种钳形配合物的催化性能, 结果表明该配合物对卤代苯与乙烯基化合物的Heck芳基化反应具有较高的催化活性.     

Enantioselective total synthesis of pyrinodemin A

Pyrinodemin A 1, a cytotoxic marine alkaloid, was synthesized in a convergent and enantioselective fashion. The key steps are an asymmetric intramolecular dipolar cycloaddition of an oxazoline N-oxide to introduce the bicyclic ring system of the molecule, a cuprate coupling for the extension of the saturated chain and a B-alkyl Suzuki coupling for the introduction of a 3-pyridyl moiety. Reductive amination allowed the coupling of the second side-chain onto the nitrogen atom to give 1. Additionally, attempts to prepare 1 from a trienic precursor by a double B-alkyl Suzuki reaction are described.     

Total Syntheses of (+)‐Grandilodine C and (+)‐Lapidilectine B and Determination of their Absolute Stereochemistry

Enantioselective total syntheses of the Kopsia alkaloids (+)‐grandilodine C and (+)‐lapidilectine B were accomplished. A key intermediate, spirodiketone, was synthesized in 3 steps and converted into the chiral enone by enantioselective deprotonation followed by oxidation with up to 76 % ee. Lactone formation was achieved through stereoselective vinylation followed by allylation and ozonolysis. The total synthesis of (+)‐grandilodine C was achieved by palladium‐catalyzed intramolecular allylic amination and ring‐closing metathesis to give 8‐ and 5‐membered heterocycles, respectively. Selective reduction of a lactam carbonyl gave (+)‐lapidilectine B. The absolute stereochemistry of both natural products was thereby confirmed. These syntheses enable the scalable preparation of the above alkaloids for biological studies.     

Concise Synthesis of Chiral Tricyclic Lactams by Tandem Dynamic Kinetic Asymmetric Reductive Amination/Lactamization Using Ammonium Salts

The atom- and step-efficient synthesis of chiral fused tricyclic lactams from readily available ketoesters using cheap ammonium salts as the nitrogen source is reported. This ruthenium-catalyzed system operates through an efficient tandem dynamic kinetic asymmetric reductive amination (ARA)/lactamization and produces chiral fused tricyclic lactams in high yields with excellent diastereo- and enantioselectivity (up to >99 % ee, >20 : 1 dr and 98 % yield). The robust method was also applied to the concise synthesis of key intermediates in the synthesis of rivastigmine analogues and chiral N-heterocyclic carbene catalysts.     

Practical Approach for Synthesis of 2-Amino-benzoxazole in Water

A practical copper-catalyzed amination of benzoxazole with secondary amine in water has been developed. This reaction has proved to be effective to some cyclic amines, and the substituted group of nitrogen has a great impact on the amination reaction. A copper-catalyzed/ amine-induced ring opening of the benzoxazole and recyclization/oxidation mechanism was also proposed.     

New chiral building blocks of β-peptoid analogs

The synthesis of chiral functionalized β-amino esters via the hydride reductive amination of chiral allenes was explored. These compounds can be regarded as β-peptoids building blocks bearing a chiral side chain at the nitrogen and at the same time retaining the β-amino acid side chain. β-Enamino esters were obtained from the nucleophilic addition of α-amino esters (l-Ala, d-Ala, l-Phe, l-Leu, l-Trp and d-Trp methyl esters) to 2,3-allenoates bearing a chiral auxiliary, which determines the stereochemistry outcome of the subsequent reduction reaction. It was also demonstrated that in the reduction of β-enamino esters derived from l-Pro and d-Pro methyl esters the chirality of the new chiral center is controlled by the α-amino ester moiety.     

Ring expansion approach for the synthesis of the (3S,4S)-hexahydroazepine core of balanol and ophiocordin

A new and efficient formal total synthesis of (3S,4S)-balanol, a potent protein kinase C inhibitor, was accomplished from tri-O-acetyl-d-glucal. Balanol and ophiocordin consists of a chiral hexahydro azepine-containing fragment and a benzophenone fragment. The azepine core was prepared in chiral form through intramolecular aza Wittig reaction. A triphenylphosphine mediated ring expansion process was employed to form the seven-membered nitrogen heterocycle. The aldehyde equivalent key intermediate was treated with triphenylphosphine to give the azepine core. To demonstrate the applicability of the new route, a synthesis of the balanol is described.     

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.     

Chiral ligand-controlled asymmetric conjugate amination of enoates with lithium mesitylmethyl(trimethylsilyl)amide

Lithium mesitylmethyl(trimethylsilyl)amide behaved as a nice amination agent in a chiral ligand-controlled conjugate addition reaction of tert-butyl cinnamate to give the conjugate amination product with 99% ee in 90% yield. Other acyclic and cyclic enoates were also aminated in reasonably high enantioselectivity, while the deprotonation of abstractable proton of enoates caused yield loss of the conjugate amination products, due to the bulkiness and enriched basicity of the lithium amide. Although such steric bulkiness made hard the hydrogenolytic cleavage of a mesitylmethyl-N bond of the adducts, a new protocol comprising N-chlorination-regioselective dehydrochlorination-transoximation was developed for N-dearylmethylation, giving 3-aminoalkanoates in reasonably good yields.     

Imidazole derivatives containing potentially labile groupings attached to N1

A number of 1-aralkylbenzimidazoles, the amination of which with sodium amide gives 1-aralkyl-2-aminobenzimidazoles, were obtained by the reaction of substituted benzyl chlorides or benzhydryl chlorides with benzimidazole or its silver salt. The successful amination of 1-benzhydrylbenzimidazole attests to the insignificant influence of steric effects on the Chichibabin reaction in the benzimidazole series [2]. 1-Methoxymethyl-2-aminobenzimidazole was obtained by the reaction of methoxymethyl chloride with the sodium salt of 2-aminobenzimidazole in absolute dioxane.See [1] for communication V.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 809–811, June, 1972.