Base‐Mediated Syntheses of Di‐ and Trisubstituted Imidazoles from Amidine Hydrochlorides and Bromoacetylenes

A new transition metal‐free method for the preparation of substituted imidazoles from easy‐to‐handle amidine hydrochlorides and bromoacetylenes has been developed. The reactions proceed in air and use inexpensive K₂CO₃ as base. Additions of 2,2′‐bipyridine and water have beneficial effects on the product yields. Various di‐ and trisubstituted imidazoles have been prepared in good yields (up to 88 %).     

Copper oxide nanoparticles catalyzed vinylation of imidazoles with vinyl halides under ligand-free conditions

Recyclable copper oxide nanoparticles catalyzed most efficient and straightforward protocol for the vinylation of imidazoles with vinyl halides under ligand-free conditions. Utilizing this protocol various imidazoles were cross-coupled with different substituted vinyl halides to get the corresponding products in excellent yields with the retention configuration.     

L-proline promoted Ullmann-type reaction of vinyl bromides with imidazoles in ionic liquids

The Ullmann-type coupling reaction of vinyl bromides and imidazoles in ILs at 90-110 degrees C gave the corresponding N-vinylimidazoles in good to excellent yields by using L-proline as the ligand; the double bond geometry of the vinyl bromides was retained under the reaction conditions.     

Functionalization of the 4(5)methyl group of imidazoles: A novel synthesis of substituted imidazoles

Acyl vinyl phosphonium salts react with amidines to form imidazolyl phosphonium salts. These imidazolyl salts can be readily converted to multifunctional imidazoles with quantitative recovery of triphenyl phosphine.     

CuSO4-glucose for in situ generation of controlled Cu(I)-Cu(II) bicatalysts: multicomponent reaction of heterocyclic azine and aldehyde with alkyne, and cycloisomerization toward synthesis of N-fused imidazoles

The catalytic efficiency of mixed Cu(I)-Cu(II) system in situ generated by partial reduction of CuSO(4) with glucose in ethanol (nonanhydrous) under open air has been explored. With this catalysis, the multicomponent cascade reaction of A(3)-coupling of heterocyclic amidine with aldehyde and alkyne, 5-exo-dig cycloisomerization, and prototropic shift has afforded an efficient and eco-friendly synthesis of therapeutically important versatile N-fused imidazoles. Diverse heterocyclic amidines, several of which are known to be poorly reactive, and aldehydes are compatible in this catalytic process.     

Stereoselective C(2)-vinylation of 1-substituted imidazoles with 3-phenyl-2-propynenitrile

First examples of direct vinylation of 1-substituted imidazoles at the 2-position of the imidazole nucleus are described. 1-Substituted imidazoles 1a-e are C(2)-vinylated with 3-phenyl-2-propynenitrile (2) at room temperature without catalyst and solvent to afford 3-(1-organyl-1H-imidazol-2-yl)-3-phenyl-2-propenenitriles 3a-e, mainly (c.a. 95%) as (Z)-isomers, in 56-88% yield. The reaction is likely to involve the zwitterionic intermediates, which prototropically isomerizes to imidazole carbene and eventually undergoes the selective 3,2-shift of the functionalized vinyl substituent.     

Synthesis of 4- and 5-disubstituted 1-benzylimidazoles,important precursors of purine analogs

(Z)-N-(2-amino-1,2-dicyanovinyl)-N'-benzylformamidine 6 has been prepared both from the reaction of benzylisonitrile with the hydrochloride salt of diaminomaleonitrile and from reaction of ethyl (Z)-N-(2-amino-1,2-dicyanovinyl)formimidate with benzylamine. Based-catalyzed cyclization of amidine 6 led to imidazoles 7 and 8 depending on the reaction conditions. Compound 7 reacts with acetone and butane-2,3-dione to give the 2,2-disubstituted-6-carbamoyl-1,2-dihydropurines 9a and 9b respectively. 2-Methyl-6-carbamoylpurine 12 was obtained from the reaction of imidazole 7 with pentane-2,4-dione. The same compound was observed in the ¹H nmr spectrum of a solution of 1,2-dihydropurine 9b in deuteriochloro-form. Benzylimidazole 7 can be acetylated with acetic anhydride leading to compound 14 . This, in solution, undergoes an acyl migration reaction to give imidazoles 15 and 17 . Imidazole 15 cyclizes in the presence of base to the corresponding 6-cyanopurine 16 . A solution of 14 in methanol is slowly converted into the 6-methoxypurine 18 , possibly via a methoxymidoyl intermediate. A similar intermediate 13 has been isolated from 7 in methanol.     

Synthesis and transformations of 2-(2-furyl)-and 2-[β;-(2-furyl)vinyl]naphth[1,2-d]imidazoles

The corresponding 2-(2-furyl)naphth[1,2-d]imidazoles were obtained by heating Schiff bases, prepared from 1,2-naphthalenediamine and furfural and 5-bromo- and 5-nitrofurfurals, in nitrobenzene. 2-[-(2-Furyl)vinyl]naphth[1,2-d]imidazoles were synthesized by condensation of 2-methylnaphth[1,2-d]imidazole with furfural and 5-bromo- and 5-nitrofurfural. The methylation, nitration, and acetylation of the compounds obtained were studied, and the replacement of the bromine atom in the furan ring by a nitro group was also investigated.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1555–1557, November, 1972.     

Isoprene-catalysed lithiation: deprotection and functionalisation of imidazole derivatives

The isoprene-catalysed lithiation of different 1-substituted imidazoles (1) (such as trityl, allyl, benzyl, vinyl, N,N-dimethylsulfamoyl, para-toluenesulfonyl, tert-butoxycarbonyl, acetyl, trimethylsilyl, tert-butyldimethylsilyl derivatives) leads to the cleavage of the protecting group producing 1H-imidazole. The use of 1-(diethoxymethyl)imidazole (3) in the same lithiation reaction allows the preparation of the corresponding 2-lithio intermediate, which by reacting with different electrophiles leads to 2-functionalised imidazoles 4.     

Synthesis of complementary double-stranded helical oligomers through chiral and achiral amidinium-carboxylate salt bridges and chiral amplification in their double-helix formation

A series of complementary molecular strands from 2-mer to 5-mer that are composed of m-terphenyl units bearing chiral/achiral amidine or achiral carboxyl groups linked via Pt(II) acetylide complexes were synthesized by sequential stepwise reactions, and their chiroptical properties on the double-helix formation were investigated by circular dichroism (CD) and (1)H NMR spectroscopies. In CHCl(3), the "all-chiral" amidine strands consisting of (R)- or (S)-amidine units formed preferred-handed double helices with the complementary achiral carboxylic acid strands through the amidinium-carboxylate salt bridges, resulting in characteristic induced CDs in the Pt(II) acetylide complex regions, indicating that the chiral substituents on the amidine units biased a helical sense preference. The Cotton effect patterns and intensities were highly dependent on the molecular lengths. The complementary double-helix formation was also explored using the chiral/achiral amidine strands with different sequences in which a chiral amidine unit was introduced at the center (center-chiral) or a terminus (edge-chiral) of the amidine strands. The effect of the sequences of the chiral and achiral amidine units on the amplification of chirality (the "sergeants and soldiers" effect) in the double-helix formation was investigated by comparing the CD intensities with those of the corresponding all-chiral amidine double helices with the same molecular lengths. Variable-temperature CD experiments of the all-chiral and chiral/achiral amidine duplexes demonstrated that the Pt(II)-linked complementary duplexes are dynamic and their chiroptical properties including the chirality transfer from the chiral amidine unit to the achiral amidine ones are significantly affected by the molecular lengths, sequences, and temperatures. On the basis of the above results together with molecular dynamics simulation results, key structural features of the Pt(II)-linked oligomer duplexes and the effect of the chiral/achiral amidine sequences on the amplification of chirality are discussed.     

Syntheses of side-chain fluorinated biologically important imidazoles and indoles

We review in this report the preparation of several side-chain fluorinated analogues of biologically important imidazoles and indoles. The building blocks used should also have applications in other synthetic problems. The addition of “FBr” to vinyl imidazole derivatives was used to prepare β-fluoro- and β,β-difluorohistamine and histidinols, as well as β-fluorourocanic acid. Deoxyfluorination of intermediate acylindoles was used to prepare a series of β,β-difluorotryptamine derivative, including the fluorinated analogue of the important neurotransmitter, serotonin.     

Phase-Transfer Reactions Catalyzed by Polymer-Supported Imidazoles

Abstract

Polymer-supported imidazoles were prepared by copolymerization of vinyl monomers containing imidazole moiety, styrene, and divinylbenzene with AIBN. The resulting polymers accelerated the reaction of octyl bromide with potassium thiocyanate, and the alkylation of an active methylene compound, benzyl cyanide, under phase-transfer conditions. The latter catalytic reaction afforded monoalkylated compound exclusively, although dialkylated compound was also obtained in monomeric alkylimidazole catalyzed reaction. Further, these polymers served as phase-transfer catalysts for the reduction of acetophenone by sodium borohydride. The relationship between the structure and catalytic activity, and the factors governing these catalytic reactions were examined.     

N-allyl-N-sulfonyl ynamides as synthetic precursors to amidines and vinylogous amidines. An unexpected N-to-C 1,3-sulfonyl shift in nitrile synthesis

A detailed study of amidine synthesis from N-allyl-N-sulfonyl ynamides is described here. Mechanistically, this is a fascinating reaction consisting of diverging pathways that could lead to deallylation or allyl transfer depending upon the oxidation state of palladium catalysts, the nucleophilicity of amines, and the nature of the ligands. It essentially constitutes a Pd(0)-catalyzed aza-Claisen rearrangement of N-allyl ynamides, which can also be accomplished thermally. An observation of N-to-C 1,3-sulfonyl shift was made when examining these aza-Claisen rearrangements thermally. This represents a useful approach to nitrile synthesis. While attempts to render this 1,3-sulfonyl shift stereoselective failed, we uncovered another set of tandem sigmatropic rearrangements, leading to vinyl imidate formation. Collectively, this work showcases the rich array of chemistry one can discover using these ynamides.     

Tuning the Reactivity of Isocyano Group: Synthesis of Imidazoles and Imidazoliums from Propargylamines and Isonitriles in the Presence of Multiple Catalysts

The reaction of propargyl amines with tert‐butylisonitrile in the presence of a catalytic amount of both Yb(OTf)₃ and AgOTf afforded imidazoles, whereas the same reaction with primary and secondary alkylisonitriles, as well as arylisonitriles, in the presence of three metal salts [Yb(OTf)₃/AgOTf/KOTf] resulted in the 1,3,4,5‐tetrasubstituted imidazoliums in excellent yields. Both chiral amines and chiral isonitriles can be used to provide corresponding chiral heterocycles without racemization. In this multiple catalytic system, Yb(OTf)₃ catalyzed the insertion of isonitriles to the N? H bond of amines, AgOTf catalyzed the 5‐exo‐dig cyclization of the resulting amidine nitrogen to the tethered triple bond, and KOTf promoted the salt metathesis, thus providing at the same time the counterion to the imidazolium. Against common knowledge, the isocyano group acted in these reactions as a polarized triple bond instead of conventional carbene‐like function.     

An investigation of imidazole and oxazole syntheses using aryl-substituted TosMIC reagents

This article describes efficient and mild protocols for preparing polysubstituted imidazoles in a single pot from aryl-substituted tosylmethyl isocyanide (TosMIC) reagents and imines generated in situ. Traditional imine-forming reactions employing virtually any aldehyde and amine followed by addition of the TosMIC reagent delivers 1,4,5-trisubstituted imidazoles with predictable regiochemistry. Employing chiral amines and aldehydes, particularly those derived from alpha-amino acids, affords imidazoles with asymmetric centers appended to N-1 or C-5 with excellent retention of chiral purity. 1,4-Disubstituted imidazoles are also readily prepared by a simple variant of the above procedure. Selecting glyoxylic acid as the aldehyde component of this procedure leads to intermediates such as 48, which readily undergo decarboxylation and elimination of the tosyl moiety to deliver 1,4-disubstituted imidazoles in high yields. Alternatively, using NH(4)OH as the amine component in conjunction with a variety of aldehydes delivers 4, 5-disubstituted imidazoles in moderate to good yields in a single pot while avoiding the need for protecting groups. Finally, the facile preparation of mono- and disubstituted oxazoles from these TosMIC reagents and aldehydes is described.     

Induced fit conformational changes of a "reversed amidine" heterocycle: optimized interactions in a DNA minor groove complex

To better understand the molecular basis for recognition of the DNA minor groove by heterocyclic cations, a series of "reversed amidine" substituted heterocycles has been prepared. Amidine derivatives for targeting the minor groove have the amidine carbon linked to a central heterocyclic system, whereas in the reverse orientation, an amidine nitrogen provides the link. The reverse system has a larger dihedral angle as well as a modified spatial relationship with the groove relative to amidines. Because of the large dihedral, the reversed amidines should have reduced binding to DNA relative to similar amidines. Such a reduction is observed in footprinting, circular dichroism (CD), biosensor-surface plasmon resonance (SPR), and isothermal titration calorimetric (ITC) experiments with DB613, which has a central phenyl-furan-phenyl heterocyclic system. The reduction is not seen when a pyrrole (DB884) is substituted for the furan. Analysis of a number of derivatives defines the pyrrole and a terminal phenyl substituent on the reversed amidine groups as critical components in the strong binding of DB884. ITC and SPR comparisons showed that the better binding of DB884 was due to a more favorable binding enthalpy and that it had exceptionally slow dissociation from DNA. Crystallographic analysis of DB884 bound to an AATT site shows that the compound was bound in the minor groove in a 1:1 complex as suggested by CD solution studies. Surprisingly, unlike the amidine derivative, the pyrrole -NH of DB884 formed an H-bond with a central T of the AATT site and this accounts for the enthalpy-driven strong binding. The structural results and molecular modeling studies provide an explanation for the differences in binding affinities for related amidine and reversed amidine analogues.     

Naphthalene amidine imide dyes by transamination of naphthalene bisimides

Derivatives of naphthalene-1,4,5,8-tetracarboxylic acid with amidine structures have been prepared. The light absorption of the bisimide derivatives in the UV region is shifted to the visible for the amidine imides, which also fluoresce with a large Stokes shift. It has been shown how the bisimide-lactam rearrangement can be extended to amidine structures.     

Synthesis of 1H‐quinazoline‐2,4‐diones from 2‐aminobenzonitriles by fixation of carbon dioxide with amidine moiety supported polymer at atmospheric pressure

1H‐Quinazoline‐2,4‐diones, which are key intermediates in the synthesis of medicines, were successfully synthesized from 2‐aminobenzonitriles by the fixation of CO₂ in the presence of a polystyrene derivative bearing amidine moiety [poly(amidine)]. A model reaction, that is, the reaction of 2‐aminobenzonitrile ( 1a ) with CO₂ in the presence of N‐methyltetrahydropyrimidine ( MTHP ) revealed that a catalytic amount of MTHP afforded 1H‐quinazoline‐2,4‐dione ( 2a ) quantitatively at atmospheric pressure. Several 1H‐quinazoline‐2,4‐diones ( 2a ‐ 2c ) were successfully synthesized from the corresponding 2‐aminobenzonitriles ( 1a ‐ 1c ) in the presence of poly(amidine). The poly(amidine) could easily be separated from the reaction mixture by filtration and reused in subsequent reactions owing to the heterogeneous system. These demonstrated that poly(amidine) is a useful heterogeneous polymer‐supported reagent for the synthesis of 1H‐quinazoline‐2,4‐diones from CO₂. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 653–657, 2009     

Preparation of Anion Exchange Membrane Based on Imidazolium Functionalized Poly(arylene ether ketone)

The authors presented a novel synthetic route for the imidazolium functionalized poly(arylene ether ketone)s, derived from an engineering plastics polymer, a poly(arylene ether ketone) with 3,3',5,5'-tetramethyl-4,4'-dihydroxybiphenyl moiety(PAEK-TM). The preparation of anion exchange membranes comprised converting benzylic methyl groups to bromomethyl groups by a radical reaction, followed by the functionalization of bromomethylated PAEK with alkyl imidazoles, i.e., methyl, butyl or vinyl imidazole. The structure of imidazolium functionalized PAEK was proved by ¹H NMR spectra. A class of flexible and tough membranes was then achieved by subsequent film-forming and anion exchange processes. The water uptake and hydroxide conductivities of membranes are comparable or superior to those of quaternary ammonium(QA) anion exchange membranes. This work demonstrated a new route for non-QA anion exchange membrane design, avoiding the chloromethylation reagent and precisely controlling the degree and location of imidazolium groups.     

Synthesis and Reactivity of Cyclic Borane‐Amidine Conjugated Molecules Formed by Direct 1,2‐Carboboration of Carbodiimides with 9‐Borafluorenes

Efficient 1,2‐carboboration reactions to the C=N bond of carbodiimides with 9‐borafluorenes, which give rise to cyclic borane‐amidine conjugates with a seven‐membered BNC₅ ring, are reported. The resulting cyclic borane‐amidine conjugates can be hydrolyzed into an acyclic bifunctional biaryl compound carrying both boronic acid and amidine groups, rendering the utility of the two‐step protocol for the synthesis of multi‐functionalized molecular systems with a potential as a supramolecular building block. Furthermore, the conjugated structure of the cyclic boron‐amidine compounds can be changed upon alkylation of the boron atom that increases the coordination number of boron. The combination of Lewis acid (borane) and conjugated base (amidine) provides rich structural diversity of heteroatom‐containing π‐conjugated systems.