Simple and efficient methods of synthesis of 3,3-diarylcyclobutanone and 3,3-diarylcyclobutylamine derivatives using the TiCl4/R3N reagent system

[reaction: see text] The iminium ions generated in situ by the oxidation of N,N-diisopropyl-N-benzylamine using iodine react with diaryl ketones in the presence of TiCl4/R3N to give the corresponding 3,3-diarylcyclobutanones in moderate to good yields (49-86%). The 3,3-diarylcyclobutanone iminium ions formed in this transformation was reduced in situ with B2H6 to produce the corresponding 3,3-diarylcyclobutylamines (52-79% yields), a class of compounds with potential antidepressant activity. In addition, a series of N,N-dimethyl-3,3-diarylcyclobutylamines were synthesized by the reductive amination of the corresponding 3,3-diarylcyclobutanone derivatives.     

Enantioselective olefin epoxidation using novel biphenyl and binaphthyl azepines and azepinium salts

Homologous biphenyl and (diastereomeric) binaphthyl tertiary azepines and quaternary iminium salts were prepared from (S)- and (R)-3,3-dimethylbutan-2-amine. Both the amines and iminium ions behave as effective catalysts for the enantioselective epoxidation of unfunctionalized olefins (ee up to 87%).     

Aminocatalytic Cross‐Coupling Approach via Iminium Ions to Different CC Bonds

Given the attractive ability of iminium ions to functionalize molecules directly at ostensibly unreactive positions, the reactivity of iminium ions, in which an α CH₂ group is replaced by C?O was explored. Background studies on the ability of such iminium cations to promote reactions via an iminium‐catalyzed or iminium‐equivalent pathway are apparently unavailable. Previously, tandem cross‐coupling reactions were reported, in which an iminium ion undergoes nucleophilic 1,2‐addition to give a putative three‐component intermediate that abstracts a proton in situ and undergoes self‐deamination followed by unprecedented DMSO/aerobic oxidation to generate α‐ketoamides. However, later it was observed that iminium ions can generate valuable α‐ketoamides through simple aerobic oxidation. In all reactions, iminium ions were generated in situ by reaction of 2‐oxoaldehydes with secondary amines.     

A Facile Route to 4-Dialkylamino-1-(Trimethylsilyl)-1,2-Butadienes

The synthesis of pure trimethylsilylsubstituted alpha-allenic amines was obtained by reaction of 1,1-bis(trimethylsilyl)-2-propyne with iminium ions, via an aminomethano desilylation process.     

Counterion effects in iminium-activated electrophilic aromatic substitutions of pyrroles

Electrophilic substitution of pyrroles by α,β-unsaturated iminium ions is slow in acetonitrile when only weakly basic counterions are present. When the reactions are carried out in the presence of KCF(3)CO(2), fast deprotonation of the intermediate σ-adducts occurs, and the rate constant for the rate-determining CC bond-forming step can be predicted from the electrophilicity parameter E of the iminium ion and the N and s parameters of the pyrroles.     

Enantioselective olefin epoxidation using homologous amine and iminium catalysts—a direct comparison

Homologous biphenyl and (diastereomeric) binaphthyl tertiary azepines and quaternary iminium salts were prepared from (+)-(S,S)-l-acetonamine. Both the amines and iminium ions behave as effective catalysts for the enantioselective epoxidation of unfunctionalized olefins (ee up to 83%).     

Synthesis of benzo-fused 1-azabicyclo[m.n.0]alkanes via the Schmidt reaction: a formal synthesis of gephyrotoxin

The intramolecular capture of benzocyclobutyl, benzocyclopentyl, and benzocyclohexyl carbocations 7 by azides produces spirocyclic aminodiazonium ions 8, which undergo 1,2-C-to-N rearrangement with loss of dinitrogen to produce benzo-fused iminium ions resulting from either aryl (9) or alkyl (10) migration to the electron-deficient nitrogen atom. Reduction of the iminium ions affords regioisomeric benzo-fused 1-azabicyclo[m.n.0]alkanes, e.g., benzopyrrolizidines, benzoindolizidines, benzoquinolizidines, or perhydrobenzo[f]pyrrolo[1,2-a]azepines in two regioisomeric versions, anilines (e.g., 11-14) and benzylic amines (e.g., 15-18), the result of aryl and alkyl migrations, respectively. Generally, aryl migration is preferred, despite modeling that shows that the lowest energy aminodiazonium ions are those where the departing dinitrogen is preferentially antiperiplanar to the migrating alkyl group rather than the aryl group. The utility of this methodology was illustrated by a formal synthesis of the alkaloid gephyrotoxin 4. A dependence on the efficiency and regioselectivity of the Schmidt reaction upon subtle changes in the structure of the cation precursor was observed, necessitating the exploration of a variety of substrates. Fortunately, these materials were easily made. Ultimately, the azido-alkene 81 bearing a 2-bromoethyl side-chain was useful for the Schmidt reaction, producing the known benzo-fused indolizidine 49, which had been transformed by Ito et al. into gephyrotoxin 4. The synthesis of 49 required nine steps (five purifications) from commercially available 4-methoxy-1-indanone 60 and proceeded in 22% overall yield.     

Predicting Absolute Rate Constants for Huisgen Reactions of Unsaturated Iminium Ions with Diazoalkanes

The kinetics and stereochemistry of the reactions of iminium ions derived from cinnamaldehydes and MacMillan's imidazolidinones with diphenyldiazomethane and aryldiazomethanes were investigated experimentally and with DFT calculations. The reactions of diphenyldiazomethane with iminium ions derived from MacMillan's second‐generation catalysts gave 3‐aryl‐2,2‐diphenylcyclopropanecarbaldehydes with yields >90 % and enantiomeric ratios of ≥90:10. Predominantly 2:1 products were obtained from the corresponding reactions with monoaryldiazomethanes. The measured rate constants are in good agreement with the rate constants derived from the one‐center nucleophilicity parameters N and s_N of diazomethanes and the one‐center electrophilicity parameters E of iminium ions as well as with quantum chemically calculated activation energies.     

Intramolecular reactions of benzylic azides with ketones: competition between Schmidt and Mannich pathways.

The Lewis acid-promoted reactions of benzylic azides with ketones can proceed by two major pathways. The azido-Schmidt reaction involves simple addition of azide to the ketone followed by rearrangement and ring expansion. In addition, benzylic azides can undergo prior rearrangement to afford iminium ions that can subsequently participate in a Mannich reaction. A series of ketones containing an alpha CH2(CH2)nCH(N3)Ph substituent (n = 1-3) was prepared to investigate the dependence of products on ketone ring size and tether length. For all ketones examined, good yields of bicyclic lactams arising from intramolecular Schmidt reaction were obtained when a four-carbon linker was used (n = 1 in the above formulation), but Mannich products predominated for the longer tethers examined (n = 2, 3).     

Glycine enolates: the effect of formation of iminium ions to simple ketones on alpha-amino carbon acidity and a comparison with pyridoxal iminium ions

Equilibrium constants in D2O were determined by 1H NMR analyses for formation of imines/iminium ions from addition of glycine methyl ester to acetone and from addition of glycine to phenylglyoxylate. First-order rate constants, also determined by 1H NMR, are reported for deuterium exchange between solvent D2O and the alpha-amino carbon of glycine methyl ester and glycine in the presence of increasing concentrations of ketone and Br?nsted bases. These rate and equilibrium data were used to calculate second-order rate constants for deprotonation by DO- and by Br?nsted bases of the alpha-imino carbon of the ketone adducts. Formation of the iminium ion between acetone and glycine methyl ester and between phenylglyoxylate and glycine is estimated to cause 7 unit and 15 unit decreases, respectively, in the pKa's of 21 and 29 for deprotonation of the parent carbon acids. The effect of formation of iminium ions to phenylglyoxylate and to 5'-deoxypyridoxal (DPL) [Toth, K.; Richard, J. P. J. Am. Chem. Soc. 2007, 129, 3013-3021] on the carbon acidity of glycine is similar. However, DPL is a much better catalyst than phenylglyoxylate of deprotonation of glycine, because of the exceptionally large thermodynamic driving force for conversion of the amino acid and DPL to the reactive iminium ion.     

Silberioneninduzierte Reaktion von 3-Chlor-2-pyrrolidinocyclohexen mit 1,3-Dienen. Vorläufige Mitteilung

3-Chloro-2-pyrrolidinocyclohexene ( 3 ) in the presence of silver tetrafluoroborate in methylene chloride at ?60° underwent cycloadditions with various 1,3-dienes; the resulting iminium tetrafluoroborate salts 4a–8a were hydrolysed to give the bicyclic and tricyclic ketones 4b–8b . The addition reactions can be regarded as [3+4]-cycloadditions of an intermediate 2-aminoallyl cation.     

Nucleophilicity parameters of enamides and their implications for organocatalytic transformations

The kinetics of the reactions of eleven substituted enamides with benzhydrylium ions (diarylcarbenium ions) were determined in acetonitrile solution. The second-order rate constants follow the correlation log k(2) (20 °C)=s(N)(E+N), which allowed us to derive reactivity parameters N and s(N). With 4.6相似文献   

Umlagerung von Vinyl-Cyclopropan-Carbaminalen

Rearrangement of Vinyl-Cyclopropane-Carbaminals Both (c-2, t-3-diphenyl-r-1-cyclopropyl)methylene-dipyrrolidine ( 4 ) and its (t-2, t-3)-isomer 10 underwent a thermal rearrangement to (E)-N-2-benzylidene-1-indanyl-pyrrolidine ( 5 ). Under the conditions of the rearrangement, 5 was partially converted into 2-benzyl-1-indanone ( 6 ) in a base catalysed reaction. The structures of 5 and 6 were derived from spectroscopic data and from degradation reactions.- N,N′-(t-2-Vinyl-r-1-cyclopropyl)methylene-dipyrrolidine ( 11 ) rearranged thermally to N-(2-methylidene-3-cyclopenten-1-yl)pyrrolidine ( 12 ), the structure of which was established from spectroscopic evidence and from a hydrogenation to N-(2-methylcyclopentyl)pyrrolidine ( 13 , cis/trans mixture 3:2). The aminal 4 was reduced with formic acid to give N-(c-2, t-3-diphenyl-r-1-cyclopropyl)methyl-pyrrolidine ( 14 ). If perdeuterio formic acid was used, the mixture product 14-d/14-d ₂ was obtained which contained exactly one deuterium atom in its methylene group and about half a deuterium atom on C(1). This labeling pattern is mechanistically explained with the existence of a fast equilibrium between the iminium ion 19 and the enamine 18 , so that 18 and 19 are considered to be plausible reactive intermediates in the above mentioned thermal rearrangement. - Based on this, several mechanisms for the rearrangements 4 → 5, 10 → 5 and 11 → 12 were considered: A Pictet-Spengler- or Mannich-type reaction, which starts from the iminium ion 23 and is followed by a cyclopropylmethyl-homoallylic rearrangement and by deprotonation (path a, Scheme 5), was judged to be improbable because the postulated intermediates could lead more easily to other stable products than the observed ones. If the reaction is formulated as a [3,3]-sigmatropic shift occurring on exclusively the (E)-isomer 5 suggests a concerted process whose steric course is predominantly controlled by strain factors. Alternatively, the reaction could be formulated via a dipolar ( 27 ) or a diradical ( 26 ) species derived from the enamine 22 (paths c and d, Scheme 5); attempts to trap such species by a number of agents were unsuccessful. - The previously unknown aminals 10 and 11 were synthesized by standard methods.     

Formation of iminium ions by fragmentation of a2 ions

Tandem mass spectrometric experiments have been carried out on the protonated amides H-Gly-Ala-NH2, H-Ala-Gly-NH2, H-Ala-Val-NH2, H-Val-Ala-pNA, H-Leu-Phe-NH2, H-Phe-Leu-NH2, H-Phe-Tyr-NH2 and H-Tyr-Phe-NH2 with particular emphasis on the fragmentation of the isomeric a2 ions derived therefrom. Primary fragmentation reactions of the protonated amides involve formation of the y1" and b2 ions with further fragmentation of the b2 ion to form the a2 ion which fragments to form iminium ions. Collision-induced dissociation studies of the mass-selected a2 ions were carried out. For the Gly-Ala, Ala-Gly and Val-Ala a2 ions, weak signals were observed corresponding to loss of CO from the a2 ion. With the exception of the Gly-Ala, Ala-Gly and Val-Ala a2 ions, both possible iminium ions (a1 and the internal iminium ion) are observed with the most abundant being that formed by proton attachment to the imine of higher proton affinity. The results provide strong support for the recently proposed (El Aribi et al. J. Am. Chem. Soc. 2003; 125: 9229) mechanism of fragmentation of a2 ions which involves elimination of CO from the a2 ion to form a proton-bound complex of two imines. Based on this mechanism ab initio calculations of the total energies of the a2 ions and the transition states for fragmentation have been carried out giving the energy barrier for fragmentation of each a2 ion. The experimental results are interpreted in terms of these energetics data, unimolecular rate constants calculated by using the RRKM theory, and the imine proton affinities.     

Kinetic resolution in the oxidation of iminium ion to lactam catalysed by aldehyde oxidase

A rabbit liver enzyme preparation oxidised racemic iminium ions 1 and 2 to optically active lactams 3 and 4 with enantiomer ratios ER/S = 5.5 and 0.14, respectively.     

Cascade iminium ion reactions for the facile synthesis of quinolizidines. Concise syntheses of (+/-)-epilupinine and (-)-epimyrtine

Several novel cascade processes have been designed and developed that involve sequential reactions of imines and iminium ions to form substituted quinolizidine ring systems in a single step from simple and readily available starting materials. The utility and promise of these cascade reactions is evident from their application to extraordinarily concise syntheses of the representative quinolizidine alkaloids (+/-)-epilupinine and (-)-epimyrtine.     

Reactive collisions in quadrupole cells. Part I. Reaction of [CH3NH2]+˙ with the isomeric butenes and pentenes

The reactions of mass-selected [CH₃NH₂]⁺˙ ions with the isomeric butenes and pentenes were studied at low collision energies in the radiofrequency-only quadrupole collision cell of a hybrid BEqQ tandem mass spectrometer. Characteristic iminium ions arising by addition of the methylamine to the olefin followed by fragmentation are observed for but-1-ene pent-1-ene and 3-methylbut-1-ene. However, for but-2-ene pent-2-ene 2-methylpropene 2-methylbut-1-ene and 2-methylbut-2-ene the major reaction channel of [CH₃NH₂]⁺˙ is charge exchange to form the olefinic molecular ion. The isomeric olefins are characterized to a considerable extent by the characteristic ion–molecule reactions that these molecular ions undergo with the neutral olefin.     

Aza Diels-Alder reactions in water: Cyclocondensation of C-acyl iminium ions with cyclopentadiene

C-Acyl-N-alkyl iminium ions as well as C-acyl N-unsubstituted iminium ions react with cyclopentadiene in water at ambient temperature giving rise to aza Diels-Alder adducts.     

Synthèse de 3,5-divinylidènepipéridines N-substituées à partir du 1,7-bis(triméthylsilyl)hepta-2,5-diyne et applications

The 1,7-bis(trimethylsilyl)hepta-2,5-diyne reacts with iminium ions generated in situ from primary alkyl- or primary functional amines by a double aminomethylation–desilylation process leading to N-substituted 3,5-divinylidenepiperidines.

Résumé

Le 1,7-bis(triméthylsilyl)hepta-2,5-diyne réagit avec les ions iminium générés in situ à partir d'alkylamines primaires ou d'amines primaires fonctionnelles pour conduire à des 3,5-divinylidènepipéridines N-substituées via un double processus d'aminométhylation–désilylation.     

Generation of α,β-Unsaturated Iminium Ions by Laser Flash Photolysis

Two at a time: α,β-Unsaturated iminium ions can be generated by laser flash photolysis of enaminophosphonium ions. The rate constants of their reactions with nucleophiles provide the first direct comparison of the electrophilicities of iminium ions derived from MacMillan's first- and second-generation catalysts.