Geminal Dialkylation Research Articles

Tert-Butoxide-Mediated Protodeformylative Decarbonylation of α-Quaternary Homobenzaldehydes

Abstract tert-Butoxide mediates the Haller–Bauer-type (protodeformylative) decarbonylation of readily accessed α-quaternary homobenzaldehydes and related compounds at room temperature, generating cumene products. Both geminal dialkyl and geminal diaryl substituents are tolerated. gem-Dimethyls are sufficient for decarbonylation of polycyclic arenyl substrates whereas monocyclic aromatic homobenzaldehydes require cyclic gem-dialkyls or gem-diaryls for significant decarbonylation.

Separation of the Thorpe−Ingold and Reactive Rotamer Effect by Using the Formation of Bicyclic Aziridinium Ions

AbstractThe geminal dialkyl effect is widely used in organic synthesis to promote cyclization reactions, although the exact origin of its rate enhancement remains unclear. In the present study, we demonstrate the applicability of this effect for the intramolecular formation of bicyclic aziridinium ions and assign it to angle contractions provided by introduction of sterically demanding substituents. Due to the cyclic structure of the examined 3‐chloropiperidines the acceleration of this ring closure cannot be explained by an increased population of reactive gauche rotamers and therefore agrees with the original Thorpe‐Ingold theory. Furthermore, introduction of strained aliphatic rings resulted in internal angle expansions and were accompanied by a preliminary decrease of rate constants for the investigated aziridinium ion formation. These results lead to a linear correlation between internal angle and relative reaction rate, supported by computational and X‐ray crystallographic structural data.

Palladium catalysis with sulfurated substrates under aerobic conditions: A direct oxidative carbonylation approach to thiophene-3-carboxylic esters

The first example of a palladium-catalyzed oxidative carbonylative S-cyclization process carried out under aerobic conditions is reported. The method is based on the use of the PdI2/KI catalytic system and an acetylenic substrate bearing a sulfurated group in suitable position for attacking the coordinated triple bond. To avoid the possible oxidation of a free thiol group, a methylthio group was used as sulfur nucleophile, since the methyl group on sulfur could be removed under the reaction conditions by reaction with the iodide anion to give methyl iodide. In particular, we have employed as substrates 1-(methylthio)-3-yn-2-ols, which, upon S-cyclization, demethylation, and alkoxycarbonylation, led to thiophene-3-carboxylic esters in one step, in alcohols as external nucleophile and solvents, and under 40 atm of a 4:1 mixture of CO-air (air being the source of oxygen, used as external oxidant). The Pd(0) species deriving from the alkoxycarbonylation process was reoxidized back to catalytically active PdI2 by the action of oxygen in combination with the hydrogen iodide ensuing from the alkoxycarbonylation step and from water attack to methyl iodide. This new synthetic transformation could be successfully applied to a variety of differently substituted 1-(methylthio)-3-yn-2-ols, including substrates bearing geminal dialkyl substituents.

Radical Cyclization Followed by the Fragmentation of Carbonyl Compounds: Effect of an α-Benzoyl Group.

To study a recently developed radical cyclization reaction followed by a fragmentation process in more detail, a series of α-benzoyl carbonyl compounds were prepared, including precursors with aldehyde and ketone moieties. Initiated by tributyltin hydride and AIBN, radical cyclization followed by fragmentation proceeded to give the desired carbonyl translocation products in 4-benzoyl-5-pentanal, 4-benzoyl-5-pentanone, 5-benzoyl-6-hexanal, and 5-benzoyl-6-hexanone radical systems. In comparison with early reports on radical cyclization reactions of α-oxy carbonyl compounds, neither a geminal dialkyl effect nor a conformationally rigid system was required to give the desired carbonyl translocation products. This effect clearly proves that a benzoyl group serves as a protecting group in these radical processes, which not only enhances cyclization efficiency but also increases the rate of the fragmentation step, eventually producing the desired carbonyl translocation products. These observations provide an alternative point of view in the field of radical cyclization reactions. Since the fragmentation step could be enhanced by appropriately positioning an α-benzoyl group, these four radical processes could be used to convert the naturally occurring d-sugars, such as d-pentoses and d-hexoses, into rare deoxy-l-sugars. Furthermore, a cascade radical process involving radical cyclization and fragmentation followed by addition to the allyltin reagent was developed and is reported herein.

Stereochemical modification of geminal dialkyl substituents on pantothenamides alters antimicrobial activity

Pantothenamides are N-substituted pantothenate derivatives which are known to exert antimicrobial activity through interference with coenzyme A (CoA) biosynthesis or downstream CoA-utilizing proteins. A previous report has shown that replacement of the ProR methyl group of the benchmark N-pentylpantothenamide with an allyl group (R-anti configuration) yielded one of the most potent antibacterial pantothenamides reported so far (MIC of 3.2μM for both sensitive and resistant Staphylococcus aureus). We describe herein a synthetic route for accessing the corresponding R-syn diastereomer using a key diastereoselective reduction with Baker’s yeast, and report on the scope of this reaction for modified systems. Interestingly, whilst the R-anti diastereomer is the only one to show antibacterial activity, the R-syn isomer proved to be significantly more potent against the malaria parasite (IC50 of 2.4±0.2μM). Our research underlines the striking influence that stereochemistry has on the biological activity of pantothenamides, and may find utility in the study of various CoA-utilizing systems.

Insights into the Intermolecular C–H Activations of Hydrocarbons Initiated by Cp*W(NO)(η3-allyl)(CH2CMe3) Complexes

Thermolyses of 18e Cp*W(NO)(η3-allyl)(CH2CMe3) compounds (Cp* = η5-C5Me5) result in the intramolecular elimination of CMe4 and the formation of 16e η2-diene and/or η2-allene intermediate complexes that effect a variety of intermolecular C–H activations of hydrocarbons. The outcomes of the reactions of the Cp*W(NO)(η3-allyl)(CH2CMe3) compounds with both C(sp3)–H and C(sp2)–H bonds of hydrocarbons are dependent on the natures of the allyl ligands in ways that are not immediately obvious. In an effort to better understand the different selectivities of the various C–H activation processes, we have examined several of these transformations by DFT calculations. The results of these computational investigations have provided several interesting and useful insights into the mechanistic pathways involved. Specifically, they have established that geminal dialkyl substituents on the allyl ligands markedly stabilize the η2-allene intermediate complexes, whereas the absence of such substituents favors the formation o...

The Structural Characterization of Folded Peptides Containing the Conformationally Constrained β‐Amino Acid Residue β2,2Ac6c

AbstractBackbone alkylation has been shown to result in a dramatic reduction in the conformational space that is sterically accessible to α‐amino acid residues in peptides. By extension, the presence of geminal dialkyl substituents at backbone atoms also restricts available conformational space for β and γ residues. Five peptides containing the achiral β2,2‐disubstituted β‐amino acid residue, 1‐(aminomethyl)cyclohexanecarboxylic acid (β2,2Ac6c), have been structurally characterized in crystals by X‐ray diffraction. The tripeptide Boc‐Aib‐β2,2Ac6c‐Aib‐OMe (1) adopts a novel fold stabilized by two intramolecular H‐bonds (C11 and C9) of opposite directionality. The tetrapeptide Boc‐[Aib‐β2,2Ac6c]2‐OMe (2) and pentapeptide Boc‐[Aib‐β2,2Ac6c]2‐Aib‐OMe (3) form short stretches of a hybrid αβ C11 helix stabilized by two and three intramolecular H‐bonds, respectively. The structure of the dipeptide Boc‐Aib‐β2,2Ac6c‐OMe (5) does not reveal any intramolecular H‐bond. The aggregation pattern in the crystal provides an example of an extended conformation of the β2,2Ac6c residue, forming a ‘polar sheet’ like H‐bond. The protected derivative Ac‐β2,2Ac6c‐NHMe (4) adopts a locally folded gauche conformation about the CβCα bonds (θ=−55.7°). Of the seven examples of β2,2Ac6c residues reported here, six adopt gauche conformations, a feature which promotes local folding when incorporated into peptides. A comparison between the conformational properties of β2,2Ac6c and β3,3Ac6c residues, in peptides, is presented. Backbone torsional parameters of H‐bonded αβ/βα turns are derived from the structures presented in this study and earlier reports.

Geminal dialkyl derivatives of N-substituted pantothenamides: Synthesis and antibacterial activity

As a key precursor of coenzyme A (CoA) biosynthesis, pantothenic acid has proven to be a useful backbone to elaborate probes of this biosynthetic pathway, study CoA-utilizing systems, and design molecules with antimicrobial activity. The increasing prevalence of bacterial strains resistant to one or more antibiotics has prompted a renewed interest for molecules with a novel mode of antibacterial action such as N-substituted pantothenamides. Although numerous derivatives have been reported, most are varied at the terminal N-substituent, and fewer at the β-alanine moiety. Modifications at the pantoyl portion are limited to the addition of an ω-methyl group. We report a synthetic route to N-substituted pantothenamides with various alkyl substituents replacing the geminal dimethyl groups. Our methodology is also applicable to the synthesis of pantothenic acid, pantetheine and CoA derivatives. Here a small library of new N-substituted pantothenamides was synthesized. Most of these compounds display antibacterial activity against sensitive and resistant Staphylococcus aureus. Interestingly, replacement of the ProR methyl with an allyl group yielded a new N-substituted pantothenamide which is amongst the most potent reported so far.

ChemInform Abstract: Transition Metal Promoted Reactions. Part 38. NiCl2(dppe)-Catalyzed Geminal Dialkylation of Dithioacetals and Trimethylation of Ortho Thioesters.

ChemInform Abstract: Transition Metal Promoted Reactions. Part 38. NiCl2(dppe)-Catalyzed Geminal Dialkylation of Dithioacetals and Trimethylation of Ortho Thioesters.

Rhodium‐Catalyzed Asymmetric Intramolecular Hydroamination of Unactivated Alkenes

Rhodium‐Catalyzed Asymmetric Intramolecular Hydroamination of Unactivated Alkenes

Rhodium‐Catalyzed Asymmetric Intramolecular Hydroamination of Unactivated Alkenes

Rhodium‐Catalyzed Asymmetric Intramolecular Hydroamination of Unactivated Alkenes

Ruthenium-Diphosphine-Catalyzed Allylation of Phenols: A gem-Dialkyl-Type Effect Induces High Selectivity toward O-Allylation

The catalytic performance of a series of novel cationic ruthenium(II) complexes with cyclopentadienyl and bidentate phosphine ligands was explored to establish a catalyst structure−performance relationship and gain mechanistic insight in the selective O-allylation of a phenol with allyl alcohol. It appears that catalysts containing bidentate phosphine ligands having geminal dialkyl substituents at the central atom of a C3-bridging group of the phosphine ligand are highly selective for O-allylation; apparently the presence of the substituents efficiently blocks the competitive and thermodynamically more favorable pathway to C-allylation. It appears that the electronic and structural properties of the Ru(II) precursor complexes in the solid state do not differ significantly from those of complexes containing unsubstituted analogous ligands, while the resulting catalysts show a vastly different catalytic performance. The complex [RuCp(dppp)](OTs), with the unsubstituted ligand, after six hours yields 70% conversion of phenol with a selectivity for O-allylation of only 27%, whereas the complex [RuCp(dppdmp)](OTs), with the dimethyl-substituted ligand, after six hours gives 60% conversion of phenol with 82% selectivity for O-allylation. The results suggest that the geminal dialkyl substitution at the central carbon of the C3 bridge of the ligand primarily leads to an increased kinetic stability of the bidentate chelate under reaction conditions, such as in the proposed intermediate [Ru(IV)(Cp)(diphosphine)(allyl)]2+ complexes. This implies that the high kinetic stability of the diphosphine chelate bound to Ru blocks the pathway to the thermodynamically favored C-allylation product. The results provide an interesting example in which the application of the geminal dialkyl substitution in the bridge of a bidentate ligand serves as a diagnostic tool to probe the nature of the selectivity-determining step in a catalytic pathway in homogeneous catalysis.

Mechanism of esterification of 1,3-dimethylamino alcohols by N-acetylimidazole in acetonitrile and the influence of alkyl and geminal dialkyl substitution upon the rate

3-(Dimethylamino)propan-1-ol and seven derivatives with alkyl substituents at the 2-position have been prepared by conventional methods, and second-order rate constants for their esterification by N-acetylimidazole in acetonitrile have been measured under pseudo-first-order conditions both by 1H NMR spectroscopy at a single temperature (23 °C) and by a UV spectroscopic method over the temperature range 25–65 °C. Evidence is presented that the intermolecular esterifications proceed via an initial rate-determining intramolecular general base catalysed formation of a cyclic tetrahedral intermediate. Effective molarities compared with the third-order reactions of simpler alcohols with acetylimidazole catalysed by triethylamine are estimated to be 13–14 mol dm–3, but alkyl substitution at the 2-position of the amino alcohol has only a modest effect upon reaction rates. All reactions have substantial negative entropies of activation and only modest enthalpies of activation as expected for concerted bimolecular reactions with highly ordered transition structures. Three structurally related carbocyclic amino alcohols constitute a short isokinetic series with the isokinetic temperature very close to the experimental range. Along this series, decreasing enthalpies of activation are almost exactly balanced in their contributions to the overall free energy of activation near room temperature by increasingly negative entropies of activation.

ChemInform Abstract: Geminal Dialkylation, Alkylative Reduction and Olefination of Aliphatic Aldehydes. Reaction of gem‐Bistriflates with Higher Order Dialkylcyanocuprates

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.

Geminal Dialkyl Substitution, Intramolecular Reactions, and Enzyme Efficiency

Geminal Dialkyl Substitution, Intramolecular Reactions, and Enzyme Efficiency

ChemInform Abstract: Geminal Dialkylation and Alkylative Reduction of Aliphatic Aldehydes.

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.

Geminal dialkylation, alkylative reduction and olefination of aliphatic aldehydes. Reaction of gem-bistriflates with higher order dialkylcyanocuprates.

gem-Dialkylation or alkylative reduction of α-unbranched aliphatic aldehydes 1 is advantageously achieved by reaction of the corresponding gem-bistriflates 2 with di- n-alkylcyanocuprates or di- sec- and di- tert-alkylcyanocuprates respectively. The reaction of α-branched gem-bistriflates 2 with dialkylcyanocuprates in the presence of boron trifluoride affords the olefins 6 in good yield.

Preparation of spirocyclic cyclopropyl ketones through condensation of epoxides with .beta.-keto phosphonates

The β-keto phosphonate derivatives of several cyclic ketones have been shown to undergo condensation with epoxides upon treatment with base, affording spirocyclic cyclopropyl ketones. Moderate to resonable yields were obtained under sealed tube conditions with ethylene oxide, propylene oxide, and styrene oxide, and the substituted epoxides gave a single diastereomer in each case. The process can be viewed as an example of regiospecific geminal dialkylation, and cleavage of the cyclopropyl ring allows access to additional α,α-dialkylated ketones

Herstellung von α‐verzweigten Phenylalaninen und von 1,1‐disubstituierten Ethylendiaminen über chirale Imidazolidinone und Oxazolidinone aus Glycin – präparative und mechanistische Aspekte

Preparation of α‐Branched Phenylalanines and of 1,1‐Disubstituted Ethylenediamines via Chiral Imidazolidinones and Oxazolidinones of Glycine – Preparative and Mechanistic AspectsTo test the structural prerequisites for a new carbanionoid rearrangement of 3‐methyl‐2‐pivaloyl‐1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid to N‐(t‐butoxycarbonyl)‐1‐amino‐2‐methylindan‐2‐carboxylic acid (A → B), various α‐branched phenylalanines (C) were required. Geminal dialkylation of the chiral glycine building block Boc‐BMI (1) occurs in excellent yields and selectivities and can be carried out in a one‐pot procedure (products 2–10). However, phenylalanines with methoxy groups on the benzene ring and α‐branching by substituents larger than methyl cannot be set free by hydrolysis of the corresponding imidazolidinones, which, on the other hand can be reduced through N‐methyl amino acid amides (13–15) to geminally disubstituted N‐methyl‐ethylenediamines (16–18). A series of 2‐t‐butyl‐5‐oxo‐1,3‐oxazolidin‐3‐carboxylates (19–27) was prepared and could be resolved on ChiraSphere, Chiralcel OD, and Pirkle columns (Table 1). Alkylation (Me, Et, Bu), allylation, and benzylation of the rac‐oxazolidinones lead to trans‐disubstituted products (29–43) which were alkylated a second time (products 44–51); yields and selectivities are satisfactory (Table 2). Hydrolysis of 4,4‐dibenzyl‐substituted oxazolidinones to the amino acid derivatives is possible (examples 52–54). – Comparison of the methylation selectivities of seven 2‐t‐butyl‐1,3‐oxazolidin‐5‐one Li‐enolates bearing different N‐acyl groups (Figure 1) and an X‐ray crystal structure analysis of a phenol carbamate (26, Figure 2 and Table 3) show that our previous mechanistic model obtains: t‐butyl in the COR group gives the poorest selectivity (3:1), O‐phenyl the highest (>50:1). This is compatible with the view that the acylgroups (on pyramidalized nitrogens!) in these heterocyclic acetals occupy one face of the average plane of the rings, and the substituents on the acetal center (here t‐Bu) the other one (Figure 1).

Geminal Dialkylation and Alkylative Reduction of Aliphatic Aldehydes

gem-Dialkylation or alkylative reduction of α-unbranched aliphatic aldehydes is easily carried out by replacing the carbonyl oxygen with the gem-dihalide functionality followed by substitution of each halogen (bromine or iodine) by two n-alkyl groups or one sec- or tert-alkyl group and one hydrogen atom using higher-order dialkyllithium cyanocuprates.