Electrophilic Imine Research Articles

Triflic anhydride mediated cyclization of 5-hydroxy-substituted pyrrolidinones for the preparation of alpha-trifluoromethylsulfonamido furans.

The reaction of alpha-angelica lactone with alkylamines under aqueous conditions afforded 5-hydroxy-5-methylpyrrolidinones in high yield. When the reaction was carried out under anhydrous conditions, the only products obtained were the corresponding 4-oxopentanoic acid amides. Treatment of either class of compound with triflic anhydride (Tf(2)O) in pyridine resulted in the formation of various substituted sulfonamidofurans. The suggested mechanism involves initial formation of an iminium ion which is subsequently transformed into a transient imino triflate. Cyclization of the highly electrophilic imine onto the oxygen atom of the adjacent carbonyl group generates an imino dihydrofuran intermediate. This species reacts further with another equivalent of Tf(2)O to give the observed product. The nature of the Lewis acid used was found to affect the outcome of the cyclization reaction. In certain cases, the sulfonamide furan was utilized as a cycloaddition substrate for the synthesis of indolines and related heterocyclic systems.

α‐Imino Esters: Versatile Substrates for the Catalytic, Asymmetric Synthesis of α‐ and β‐Amino Acids and β‐Lactams

AbstractFor Abstract see ChemInform Abstract in Full Text.

Several convenient methods for the synthesis of 2-amido substituted furans.

Several new methods for the synthesis of differently substituted 2-amidofurans are described. The thermolysis of furan-2-carbonyl azide results in a Curtius rearrangement and the resulting furanyl isocyanate was trapped with various organometallic reagents. A second method consists of a C-N cross-coupling reaction of a bromo-substituted furan with various amides, carbamates, and lactams. The CuI-catalyzed cross-coupling reaction between furanyl bromides and amides furnished 2- and 3-substituted amidofurans in 45-95% yield. The third protocol used involves the reaction of cyclic carbinol amides with triflic anhydride. The reaction proceeds under very mild conditions to provide alpha-(trifluoromethyl)sulfonamido-substituted furans in high yield. The resulting iminium ion derived from the reaction of the hydroxy pyrrolidinone with Tf(2)O undergoes a facile ring opening as a consequence of the adjacent hydroxyl group to produce an imino triflate intermediate. Subsequent cyclization of this highly electrophilic imine with the oxygen atom of the adjacent carbonyl group leads to an imino dihydrofuran that reacts further with another equivalent of Tf(2)O to give the observed product.

New Methodology for the Preparation of 3‐Hydroxy‐2‐pyridinone (3,2‐HOPO) Chelators — Reaction of Amines with a Novel Electrophilic 3,2‐HOPO Precursor.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Alpha-imino esters: versatile substrates for the catalytic, asymmetric synthesis of alpha- and beta-amino acids and beta-lactams.

The catalytic asymmetric addition of organic nucleophiles to alpha-imino esters has emerged as one of the most promising and intensely investigated routes to optically enriched alpha- and beta-amino acid derivatives and beta-lactams. The importance of alpha-imino esters stems not only from the vast appeal of the potential product classes,(1) but also from their remarkable reactivity as highly electrophilic imines. With each passing year, the number of publications concerning the asymmetric alkylation of imino esters grows significantly. The asymmetric alkylation of imines(2) and N,O-acetals has been in itself a subject of intense interest.(3) In this Account, we wish to illustrate our contribution to this timely field, as well as to highlight the seminal contributions of others.

New methodology for the preparation of 3-hydroxy-2-pyridinone (3,2-HOPO) chelators—reaction of amines with a novel electrophilic 3,2-HOPO precursor

The preparation of the new electrophilic iminium ester mesylate salt 5 and its reaction with primary and secondary amines have been investigated. Aniline, t-butylamine, and secondary amines react with 5 via ring opening to give the corresponding HOPO derivatives in high yields. The usefulness of this methodology has been demonstrated by the preparation of two new di-HOPO derivatives 19 and 21 . This method allows the introduction of the HOPO ligand onto a variety of amine platforms without the concomitant formation of an amide bond and provides access to HOPO chelators of increased water solubility.

ChemInform Abstract: Fluorine‐Containing α‐Alkynyl Amino Esters and Access to a New Family of 3,4‐Dehydroproline Analogues.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Fluorine-containing α-alkynyl amino esters and access to a new family of 3,4-dehydroproline analogues

New α-alkynyl, α-CF3 amino esters have been prepared from electrophilic imines and used to produce 3-alkenyl-3,4-dehydroproline derivatives, ia enyne metathesis with the precatalyst [RuCCCPh2(Cl)(PCy3)(arene)]O3SCF3. These new conjugated fluorine-containing dienes are active substrates for the Diels–Alder reaction and lead to a new class of bicyclic amino esters.

Oxidative metabolites of 5-S-cysteinyldopamine inhibit the alpha-ketoglutarate dehydrogenase complex: possible relevance to the pathogenesis of Parkinson's disease.

A characteristic change in the substantia nigra of Parkinson's disease patients is an apparent accelerated rate of dopamine oxidation as evidenced by an increased 5-S-cysteinyldopamine (5-S-CyS-DA) to dopamine ratio. However, 5-S-CyS-DA is more easily oxidized than dopamine to give 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1). Previous studies have demonstrated that DHBT-1 can be accumulated by intact rat brain mitochondria and inhibits complex I but not complex II respiration. In this study, it is shown that DHBT-1 also inhibits the alpha-ketoglutarate dehydrogenase complex (alpha-KGDH) but not cytochrome c oxidase (complex IV). The inhibition of alpha-KGDH is dependent on the oxidation of DHBT-1, catalyzed by an unknown constituent of the inner mitochondrial membrane, to an electrophilic o-quinone imine that covalently modifies active site sulfhydryl residues. The latter conclusion is based on the ability of > or = equimolar glutathione to block the inhibition of alpha-KGDH by DHBT-1, without altering its rate of mitochondrial membrane-catalyzed oxidation, by scavenging the electrophilic o-quinone intermediate forming glutathionyl conjugates which have been isolated and spectroscopically characterized. Activities of mitochondrial alpha-KGDH and complex I, but not other respiratory complexes, are decreased in the parkinsonian substantia nigra. Such changes together with evidence for accelerated dopamine oxidation, increased formation of 5-S-CyS-DA and the ease of oxidation of this conjugate to DHBT-1 which inhibits alpha-KGDH and complex I, without affecting other respiratory enzyme complexes, suggests that the latter putative metabolite might be an endotoxin that contributes to the alpha-KGDH and complex I defects in Parkinson's disease.

New α-trifluoromethyl-substituted α-amino phosphonates

The title α-amino phosphonates with orthogonal protective groups (Cbz/OMe, OEt) were obtained on addition of C-nucleophiles to highly electrophilic imines PG–N=C(CF 3 )P(O)(OR) 2 .

α-CF3-Substituted Phosphorus Containing Analogs of α-Amino Acids. Novel Six- and Seven-Membered α-Amino Phosphonates via Ring Closing Metathesis with LnRu=C=C=CR2Precatalyst

α-CF3-substituted α-amino phosphonates with two alkene chains, 1,7-dienes and 1,8-dienes, were obtained by nucleophilic addition to highly electrophilic imines PG-N=C(CF3)P(O)(OR)2. They were treated with the ring closing metathesis catalyst [Ru=C=C=CPh2(Cl)(PCy3)2 (p-cymene)]OTf to give the α-CF3-substituted phosphorus-containing analogs of dehydropipecolinic and tetrahydroazepin-2-carboxylic acids.

Thioether adducts of a new imine reactive intermediate of the pneumotoxin 3-methylindole.

Cytochrome P450 enzymes can potentially oxygenate 3-methylindole to form 2,3-epoxy-3-methylindoline which could rearrange to the stable metabolite 3-methyloxindole or open to form 3-hydroxy-3-methylindolenine, a putative electrophilic imine. The purpose of the current work was to determine if the imine was formed, and to characterize it via its adducts with thiol nucleophiles. Thiols were added to incubations of goat lung microsomes with 3-methylindole and deuterated analogues of 3-methylindole to trap the imine intermediate as its thioether conjugates. The N-acetylcysteine conjugate of 3-hydroxy-3-methylindolenine was detectable by LC/MS, but a molecular ion was not observed because the adduct rapidly dehydrated to form the 2-substituted indole. However, the imine was S-alkylated, and the intermediate carbinol was intramolecularly trapped using thioglycolic acid as a trapping agent that induced cyclocondensation to a lactone. The retention of one atom of deuterium from [2-2H]-3-methylindole and three from 3-[2H3-methyl]indole substantiated the mechanism in which the lactone adduct was produced by sulfur addition to either 3-hydroxy-3-methylindolenine or the epoxide. Tandem mass spectrometry of the lactone adduct produced a daughter ion spectrum consistent with this adduct. These studies demonstrated the existence of a new reactive intermediate of 3-methylindole, 3-hydroxy-3-methylindolenine, which may play a role in the pneumotoxicity of this chemical.

Catalytic Preparation of Aziridines with an Iron Lewis Acid.

The iron Lewis acid, [(eta(5)-C(5)H(5))Fe(CO)(2)(THF)](+)[BF(4)](-), was found to be an effective catalyst for the preparation of aziridines. This new method provides a facile, one-step route to predominantly cis-aziridines, with yields up to 95%, from compounds with a diazo functionality and a variety of substituted N-benzylidene imines with N-aryl or N-alkyl groups. The reaction mechanism is believed to proceed through an electrophilic iminium ion intermediate. To support this idea, the iron Lewis acid-imine complex [(eta(5)-C(5)H(5))Fe(CO)(2)(PhCH=NPh)](+)[BF(4)](-) was prepared, characterized, and reacted with different diazo compounds to provide the resultant cis-aziridines. Alternatively, it may be possible that the aziridines were derived from an electrophilic carbenoid intermediate, as is often proposed. Thus, the iron carbene [(eta(5)-C(5)H(5))Fe(CO)(2)(CHPh)](+)[SO(3)CF(3)](-) was prepared and treated with N-benzylideneaniline; however, the resultant aziridine was not formed.

Synthesis of Functionalised Azabicycles via a Regiospecific Intramolecular Aldol Reaction

A series of ketoaldehydes (1) undergo aldol-type cyclisation in the presence of a secondary amine to give the azabicyclic enones (2). Optimal reaction conditions involve use of 2,2,6,6-tetramethylpiperidine followed by silica gel, and participation of an electrophilic iminium species is suggested.

Synthesis of .alpha.-substituted .alpha.-amino acids via cationic intermediates

A novel synthetic approach to racemic α-substituted α-amino acids is described. The key intermediates of this methodology are highly electrophilic iminium ions, bearing carbonyl substituents at both the iminium carbon and nitrogen atom. The preparation of precursors 8, 10a-c, and 12 includes electrochemical oxidation techniques according to literature pressures. When an α-methyl precursor (8 or 10a) was used, reactions with sylsilanes and silyl enol ethers led to the desired products, but elimination to dehydroalanine derivatives appeared to be an important side reaction. A major improvement in the yields of the desired products could be effected by using longer reaction times

Amino Acids, XIV; (±)‐Pipecolic Acid Derivatives, IV: An Efficient Synthetic Method for the Preparation of (±)‐Baikiain and its Derivatives

Abstract[4+2] Cycloaddition of the highly electrophilic imine 2 to 1,3‐butadiene (1) furnished the Diels‐Alder product 3. Hydrolysis of the geminal diester provided (±)‐Baikiain hydrochloride (4). Cis‐Hydroxylation of the double bond of 3 afforded 8. The trans product 9 was prepared via ring opening of the epoxide 5. The regioselective hydroboration/oxidation of 3 provided 7 which was oxidized to 11. Halolactonization of the N‐tosyl derivative 12 of Baikiain furnished after functional group transformation the 2‐hydroxymethyl‐piperidine‐4‐ol 15.

Synthesis and reactions of highly electrophilic imines containing the N-cyano group. [Erratum to document cited in CA112(15):138588k

Synthesis and reactions of highly electrophilic imines containing the N-cyano group. [Erratum to document cited in CA112(15):138588k

Identification of a cysteinyl adduct of oxidized 3-methylindole from goat lung and human liver microsomal proteins.

3-Methylindole is a selective pneumotoxin that is oxidized by cytochrome P-450 enzymes to a reactive intermediate. 3-Methyleneidolenine, a methylene imine electrophile, is the postulated reactive intermediate, and it binds to proteins, a reaction that probably initiates the pneumotoxicity of 3-methylindole. Thioether adducts of this electrophile are formed with glutathione in vitro, but the identity of the adducted electrophile with amino acid residues of microsomal proteins had not previously been determined. 3-Methylindole was incubated with NADPH and goat lung or human liver microsomal proteins, and the proteins were hydrolyzed. 3-(Cystein-S-ylmethyl)indole was isolated and identified as the major amino acid adduct of 3-methyleneindolenine, demonstrating that cysteine thiols preferentially attack the exocyclic methylene position and result in a covalently (thioether) attached 3-methylindole residue to these pulmonary and hepatic proteins. These results demonstrate that the putative methylene imine intermediate is indeed the active electrophile that binds to proteins and presumably initiates the toxic events.

Strong electrophilic imines of methyltrifluoropyruvate: universal conditions for synthesis of α-trifluoromethyl-containing α-aminoacids

Preparative methods of the synthesis of acyl- and sulphonylimines of methyltrifluoropyruvate are developed. A new approach to the synthesis of varied α-trifluoromethyl-substituted α-aminoacids and their derivatives is elaborated, based on the reactions of the imines with: 1. NH-, PH-, CH-acids; 2. aromatic and heteroaromatic compounds of π-donor nature; 3. unsaturated compounds of different types, which undergo cycloaddition reactions. This has resulted in α-alkyl-, aryl-, hetaryl-β, β, β-trifluoroalanines, α-CF 3- containing derivatives of aminomalonic and aspartic acids, lactones of homoserines and oxyproline being prepared.

A reaction of strong electrophilic CF 3-substituted unsaturated compounds with nitrogen containing Π-systems

Hexafluoroacetone, esters of trifluoropyruvic acid as well as obtained from the strong electrophilic imines and 1,1-dicyanoethylenes can C-alkylate π-donor aryl amines, nitrogen containing heterocycles and enamines under the mild conditions. For amino group containing compounds this process is complicated by the competitive reaction of N-alkylation. However, its reversibility allows to obtain C-alkylation products. As a rule, the substitution is regiospecific, its orientation not always being ordinary. The reaction products composition and the reaction rates significantly depend on a nucleophylic reagent stereochemical peculiarity. C- and N-alkylation may be accompanied by the formation of CF 3-substituted heterocycles. In some cases the substitution is connected with dehydration dehydro-genation reactions under the effect of unsaturated compounds. The results of a systematic investigation of the above mentioned process as well as special cases of purines and pyrimidines modification will be discussed.