Regioselective,Unconventional Pictet–Spengler Cyclization Strategy Toward the Synthesis of Benzimidazole‐Linked Imidazoquinoxalines on a Soluble Polymer Support

A novel strategy for an unconventional Pictet–Spengler reaction has been developed for the regioselective cyclization of the imidazole ring system at the C2 position. The developed strategy was utilized to develop a diversity‐oriented parallel synthesis for bis(heterocyclic) skeletal novel analogs of benzimidazole‐linked imidazoquinoxalines on a soluble polymer support under microwave conditions. Condensation of polymer‐immobilized o‐phenylenediamines with 4‐fluoro‐3‐nitrobenzoic acid followed by nucleophilic aromatic substitution with an imidazole motif affords bis(heterocyclic) skeletal precursors for the Pictet–Spengler reaction. The unconventional Pictet–Spengler cyclization with various aldehydes was achieved regioselectively at the C2 position of the imidazole ring to furnish rare imidazole‐fused quinoxaline skeletons. During the Pictet–Spengler cyclization, aldehydes bearing electron‐donating groups afford 4,5‐dihydro‐imidazoquinoxalines, which then auto‐aromatize into benzimidazole‐linked imidazo[1,2‐a]quinoxalines. However, interestingly, aldehydes bearing electron‐withdrawing groups directly provide aromatized imidazo[1,2‐a]quinoxalines, which unexpectedly afford novel benzimidazole‐linked 4‐methoxy‐4,5‐dihydro‐imidazo[1,2‐a]quinoxalines after polymer cleavage.     

Transformations of 2-(3-Hydroxy-3-methyl-1-butynyl)adamantan-2-ol >Catalyzed by Acids

Reaction of 2-(3-hydroxy-3-methyl-1-butynyl)adamantan-2-ol with acetonitrile under Ritter reaction conditions is accompanied by isomerization and partial hydration where the water addition to the triple bond occurs nonselectively. As a result of reaction carried out in the presence of 8 equiv of sulfuric acid a mixture was obtained of N ²-[4-(1-acetylamino-2-adamantyl)-2-methyl-3-butyn-2-yl]acetamide, N ³-[1-(1-acetylamino-2-adamantyl)-3-methyl-2-oxo-3-butyl]-acetamide, and N ³-[1-(1-acetylamino-2-adamantyl)-3-methyl-1-oxo-3-butyl]acetamide in ~10:3:2 ratio. In the presence of 2 equiv of the acid the mixture obtained consisted of N ²-[4-(1-acetylamino-2-adamantyl)-2-methyl-3-butyn-2-yl]acetamide, N ³-[1-(1-acetylamino-2-adamantyl)-3-methyl-2-oxo-3-butyl]acetamide, and 1-(1-acetylamino-2-adamantyl)-3-methyl-2-buten-1-one in the same ratio. In Rupe reaction conditions we obtained instead of the expected ,-unsaturated ketones a mixture of 1-(1-hydroxy-2-adamantyl)-3-hydroxy-3-methylbutan-1-one and 1-(1-hydroxy-2-adamantyl)-3-hydroxy-3-methylbutan-2-one in a 5:3 ratio.     

Synthesis and Some Chemical Transformations of Adamantyl-Substituted Pyrazolones

1-Substituted 3-(1-adamantyl)-4,5-dihydro-1H-pyrazol–5-ones and 3-(1-adamantyl)-4,5-dihydroiso-xazol-5-one were synthesized by reaction of ethyl 3-(1-adamantyl)-3-oxopropanoate with various hydrazine derivatives and hydroxylamine hydrochloride. Nitrosation of adamantyl-substituted pyrazolones with sodium nitrite in acetic acid gave the corresponding 4-hydroxyimino derivatives. Reactions of 3-(1-adamantyl)-4,5-di-hydro-1H-pyrazol–5-ones and 3-(1-adamantyl)-4,5-dihydroisoxazol–5-one with aromatic and heterocyclic aldehydes led to the formation of condensation products at position 4 of the heteroring.     

Preparation,lithiation and transformation of N-(benzotriazol-1-ylmethyl) heterocycles

Indole, carbazole, pyrrole, imidazole, benzimidazole, 2-methyl- and 2-phenylbenzimidazole, and 1, 2, 4-triazole have each been converted into their N-(benzotriazol-1-ylmethyl) derivatives. The pyrrole, indole, and carbazole adducts undergo smooth lithiation at the inter-ring methylene group and subsequent reaction there with electrophiles. For the imidazole, benzimidazole, and triazole systems, lithiations at other molecular positions competed.     

Adamantylazoles: IV. Acid-Catalyzed Adamantylation of Pyrazoles

Pyrazoles with pK _{B H} ⁺ no more than 0.8 and having substituents in 3(5) position with effective van der Waals radii not exceeding 2 Å in a mixture of phosphoric and acetic acids at weight ratio 4:1 (H ₀ -1,8) react with 1-adamantanol to afford the corresponding 1-(1-adamantyl)- or 1,4-di(1-adamantyl)pyrazoles.     

Synthesis and Antibacterial Activity of Benzazolyl Azolyl Sulfamoyl Acetamides

A new class of benzazolyl azolyl sulfamoyl acetamides was prepared from azolyl sulfamoyl acetates and benzazolyl amines in the presence of KO^tBu in tetrahydrofuran. Compounds with benzothiazole‐thiazole, benzimidazole‐thiazole, benzothiazole‐imidazole, and benzimidazole‐imidazole moieties exhibited excellent antibacterial activity against Bacillus subtilis.     

Polyfunctional imidazoles: II. Synthesis and reactions with nucleophilic reagents of 1-substituted 2,4-dichloro-1<Emphasis Type="Italic">H</Emphasis>-imidazole-5-carbaldehydes

1-Alkyl(aryl)imidazolidine-2,4-diones reacted with Vilsmeier-Haack reagent affording 1-alkyl(aryl)-2,4-dichloro-1H-imidazole-5-carbaldehydes whose reactions with sodium azide, sodium alkoholates, with phenols, thiols, and secondary cycloalkylamines led to the substitution of chlorine in the position 2 of the imidazole ring. The reaction with primary amines resulted in the condensation products at the aldehyde group.     

Synthesis of some benzimidazole-, pyridine- and imidazole-derived chelating agents

Procedures are described for the preparation of various bidentate and potentially tridentate chelating agents. These incorporate pyridyl, benzimidazole, imidazole or phenolic moieties. Phillips condensations of carboxylic acids with o-phenylenediamines were carried out in 4 M hydrochloric acid. Syntheses are reported for 2, 6-bis(N′-methylimidazol-2′-ylthiomethyl)pyridine, 2, 6-bis(benzimidazol-2′-ylthiomethyl)pyridine, 2-(4′-piperidyl)benzimidazole, 2-(3′-piperidyl)benzimidazole, 2-(3-N′-methylpiperidyl)benziinidazole, 2-(3-N′-methylpiperidyl)-N-methylbenzimidazole, 2-(2′-hydroxybenzyl)benzimidazole and 2-(2′-hydroxyben-zyl)N-methylbenzimidazole. The compounds were characterized where appropriate by their mass, uv, and ¹H-nmr spectra. 2-(2′-Hydroxybenzyl)benzimidazole hydrochloride acts as a gelling agent in aqueous solution.     

Adamantylazoles: XII. Alkylation of 1-R-tetrazole-5-thiones and 1-R-tetrazol-5-ones with tertiary alcohols in sulfuric acid

In the reaction of 1-(1-adamantyl)-4,5-dihydro-1H-tetrazole-5-thione with 1-adamantyl in sulfuric acid 2-(1-adamantyl)-5-(1-adamantylsulfanyl)-2H-tetrazole and 1,3-bis(1-adamantyl)-5-(1-adamantylsulfanyl)-1H-tetrazolium salt are formed. Methylation of 1-(1-adamantyl)-4,5-dihydro-1H-tetrazole-5-thione in alkaline medium affords 1-(1-adamantyl)-5-methylsulfanyl-1H-tetrazole while its interaction with formaldehyde affoeds 1-(1-adamanttl)-4-(hydroxymethyl)-4,5-dihydro-1H-tetrazole-5-thione.     

Synthesis of 1-Substituted Benzimidazoles Using N,N'-Thionyldibenzimidazole or N-Chlorosulfinylbenzimidazole

N,N'-Thionyldiimidazole has been known as an imidazole transfer reagent^2–4 and form a new class of compound with a wide range of synthetic application. Continuing our studies on the imidazole transfer reaction, we succeeded with the benzimidazole transfer reaction using N,N'-thionyldibenzimidazole. The present communication deals with a new procedure providing 1-substituted benzimidazoles.     

A novel ferrocenylalkylating reagent. Ferrocenylalkylation of imidazole and its derivatives

Reactions of α-(1-benzotriazolyl)ethylferrocene (1) with 1,2,4-triazole, imidazole, benzimidazole, and edenine have been studied in the MeOH−HCl, MeOH, and AcOH systems. Compound 1 is a novel ferrocenylalkylating reagent which, unlike α-hydroxyalkylferrocenes, is capable of alkylating imidazole, benzimidazole (even in the absence of an acid catalyst), and adenine (regioselectively at the N(3) position). The antitumor activity discovered for ferrocenylalkylazoles of the type 1 may be attributed to the ability of such compounds to ferrocenylalkylate nucleic bases. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 172–174, January, 1997.     

2‐(4‐methylpyridin‐2‐yl)‐1H‐benzimidazole derivatives. Part II,lH nmr characterization

A selected series of 2‐(4‐methylpyridin‐2‐yl)‐1H‐benzimidazole derivatives, bases and cyclic mono‐ and bis‐salts, were synthesized. Complete ^'1H nmr characterization is reported. Ambiguous assignments were solved using ¹H‐¹H NOESY analysis. Significant ir and ¹H nmr data are presented concerning: i) tautomeric equilibrium of imidazole hydrogen; ii) hydrogen bonds; iii) conformational inversion of partially saturated rings.     

Favorskii Rearrangement in the Reaction of 3-(1-Adamantyl)-1-chloro-2-propanone with Amines

The reaction of 3-(1-adamantyl)-1-chloro-2-propanone with amines [diethylamine, (1-adamantyl)methylamine, p-toluidine, and piperidine] in diethyl ether at room temperature involves the Favorskii rearrangement and yields N,N-disubstituted amides of 3-(1-adamantyl)propanoic acid.     

A Cucurbit[8]uril 2:2 Complex with a Negative pKa Shift

A viologen derivative carrying a benzimidazole group ( V-P-I ²⁺; viologen–phenylene–imidazole V-P-I ) can be dimerized in water using cucurbit[8]uril (CB[8]) in the form of a 2:2 complex resulting in a negative shift of the guest pK_a, by more than 1 pH unit, contrasting with the positive pK_a shift usually observed for CB-based complexes. Whereas 2:2 complex protonation is unclear by NMR, silver cations have been used for probing the accessibility of the imidazole groups of the 2:2 complexes. The protonation capacity of the buried imidazole groups is reduced, suggesting that CB[8] could trigger proton release upon 2:2 complex formation. The addition of CB[8] to a solution containing V-P- I ³⁺ indeed released protons as monitored by pH-metry and visualized by a coloured indicator. This property was used to induce a host/guest swapping, accompanied by a proton transfer, between V-P-I ³⁺ ⋅ CB[7] and a CB[8] complex of 1-methyl-4-(4-pyridyl)pyridinium. The origin of this negative pK_a shift is proposed to stand in an ideal charge state, and in the position of the two pH-responsive fragments inside the two CB[8] which, alike residues engulfed in proteins, favour the deprotonated form of the guest molecules. Such proton release triggered by a recognition event is reminiscent of several biological processes and may open new avenues toward bioinspired enzyme mimics catalyzing proton transfer or chemical reactions.     

Some reactions of fluorosulfonyldifluoroacetic acid with N-heterocyclic compounds

Difluorocarbene generated from the decomposition of fluorosulfonyldifluoroacetic acid (2)reacted with various sodium salts of N-heterocyclic compounds(1) giving the corresponding difluoro-methylated products in acetonitrile at 10—40℃.Benzotriazole(1a),benzimidazole(1b) and imidazole(1c) were converted into 1-(difluoromethyl)benzotriazole(3a),1-(difluoromethyl)benzimidazole(3b) and1-(difluoromethyl)imidazole(3c)respectively.Indole(1d)reacted with 2 to give -(fluorosulfonyldifluoro-acetate)indole(2d) rather than the expected difluoromethylated derivatives.     

Synthesis of 2-aryl-3H-naphtho[1,2-d]imidazoles containing an adamantane fragment

N ²-[1-(1-Adamantyl)alkyl]naphthalene-1,2-diamines reacted with benzoyl chlorides in chloroform in the presence of triethylamine to give N-{2-[1-(1-adamantyl)alkylamino]naphthalen-1-yl}benzamides which underwent intramolecular cyclization to 2-aryl-3H-naphtho[1,2-d]imidazoles on heating in toluene in the presence of p-toluenesulfonic acid. 3-[(1-Adamantyl)methyl]-2-(3-nitrophenyl)-3H-naphtho[1,2-d]imidazole was synthesized from N ²-[(1-adamantyl)methyl]naphthalene-1,2-diamine and 3-nitrobenzaldehyde.     

Use of MEKC for the analysis of reactant and product of Baylis–Hillman reaction

A facile, fast and high efficiency micellar EKC has been explored for the analysis and UV detection of p‐nitrobenzaldehyde and 2‐[hydroxy(4‐nitrophenyl)methyl]‐2‐cyclopenten‐1‐one with a buffer electrolyte of 30.0 mM tetraborate and 50.0 mM sodium taurodeoxycholate at pH 9.3. Under the optimal conditions, a linear range from 7.8×10^–2 to 5.0×10² mM for those analytes (r² > 0.99) was achieved. The LOD was 3.9 μM for 2‐[hydroxy(4‐nitrophenyl)methyl]‐2‐cyclopenten‐1‐one and 7.8 μM for p‐nitrobenzaldehyde, respectively (S/N = 3). The applicability of this new method for the analysis of reactants (p‐nitrobenzaldehyde and cyclopent‐2‐enone), catalysts (imidazole or N‐methyl imidazole or 1‐benzyl‐imidazole) and product (2‐[hydroxy(4‐nitrophenyl)methyl]‐2‐cyclopenten‐1‐one) on offline Baylis–Hillman reaction was examined. The relationship between the reaction time and the amount of product has been studied. Meanwhile, three different kinds of catalysts were investigated for getting the desired moderate to good amount products. It was found that comparing with N‐methyl imidazole or 1‐benzyl‐imidazole catalyst, imidazole‐catalyzed reaction could produce more products within the same reaction time. Furthermore, the results indicated that the rate law for the investigated Baylis–Hillman reaction was second‐order reaction. The rate constant for the reaction is 1.34 (±0.01)×10^–3 mol^–1 m³/s.     

Synthesis and Biological Evaluation of Novel 2‐Aryl Benzimidazoles as Chemotherapeutic Agents

Here, we describe the synthesis and preliminary biological evaluation of novel N‐unsubstituted and N‐methylated 2‐aryl benzimidazole derivatives that contain fluorinated or hydroxylated alkyl substituents in the 4‐N‐aryl position and different substitution patterns (H vs Br vs I) in the benzimidazole ring. For the selected compounds and for comparison purposes, the congener benzothiazoles were also tested. The cytotoxic effect of 11 benzazole derivatives was evaluated in a panel of human cancer cell lines, such as breast (MCF7), melanoma (A375), cervix (HeLa), and glioblastoma (U87). In general, the compounds exerted a moderate cytotoxic activity against all cells tested. In particular, for the A375 and HeLa cells, the N‐unsubstituted benzimidazoles 2 and 3 displayed a better cytotoxic profile than the respective N‐methylated benzimidazole congeners ( 5 and 7 ). The biodistribution of compound 2 , which has shown the highest cytotoxic activity active in the U87 glioblastoma cells (IC₅₀ = 45.2 ± 13.0), was evaluated in CD1 mice using its ¹⁸F‐labeled counterpart ( [¹⁸F]2 ). These studies showed that compound 2 can cross the blood brain barrier with a reasonable brain uptake (1.24 and 2.81%I.A./g at 5 and 60 min p.i., respectively), which is a crucial issue for systemic chemotherapy of glioblastoma. Altogether, the in vitro antitumoral activity of benzimidazole 2 against the U87 cells and the ability of its ¹⁸F‐congener to cross the blood brain barrier provide a strong rationale to consider the reported fluoroalkylated 2‐aryl benzimidazoles as lead candidates for the generation of chemotherapeutic agents, in particular, against highly aggressive brain tumors such as glioblastoma.     

Orthocarbonsäure-ester mit 2,4,10-Trioxaadamantanstruktur als Carboxylschutzgruppe; Verwendung zur Synthese von substituierten Carbonsäuren mit Hilfe von Grignard-Reagenzien

Ortho Esters with 2,4,10-Trioxaadamantane Structure as Carboxyl Protecting Group; Applications in the Synthesis of Substituted Carboxylic Acids by Means of Grignard Reagents The surprising stability of 2,4,10-trioxa-3-adamantyl derivatives 1 against nucleophilic substitution by organomagnesium compounds is discussed and shown to be caused by unfavourable stereoelectronic and steric factors governing the substitution of these cage compounds (Scheme 2). As a consequence, a number of Grignard reagents 2 containing the carboxyl group masked as 2,4,10-trioxa-3-adamantyl group could be prepared and have been reacted in a second step with various electrophiles (cf. Scheme 4). In the products 7–13 and 15b the carboxyl masking group is removed by mild acid hydrolysis and saponification (cf. Scheme 3) to yield the corresponding acids 16a–21a, 22 , and 23a. Acids 21a and 23a have been further transformed to give the macrocyclic lactones 24 and 26 , isolated from Galbanum oleo-gum-resin, and acid 22 to give 12-methyl-13-tridecanolide (25) , isolated from Angelica root oil. In addition 1-bromo-ω-(2,4, 10-trioxa-3-adamantyl)alkanes 1c and 1b have been used to synthesize (±)-methyl recifeiolate (29b) and pure cis-ambrettolic acid ((Z)- 32a ).     

Polyethylene glycol-promoted synthesis of pyrimido[1,2-a]benzimidazole and pyrano[2,3-c]pyrazole derivatives in water

Synthesis of pyrimido[1,2-a]benzimidazole and pyrano[2,3-c]pyrazole derivatives were achieved using polyethylene glycol (PEG-400) as promoting reaction medium in water under catalyst-free conditions at reflux and room temperature, respectively. The structure of pyrimido[1,2-a]benzimidazole was confirmed using ¹H NMR, ¹³C NMR, DEPT, and HMBC experiments. The promising points for the present methodology are efficiency, generality, high yield, short reaction time, cleaner reaction profile, ease of product isolation, simplicity, potential of recycling reaction medium, and finally agreement with green chemistry protocols.