Ammonium Ylides Research Articles

Rotational and Vibrational Signatures of Astrophyscially relevant Gas-Phase Stereo-isomeric Species of Proteinogenic Amino acid Leucine

The search for life-supporting molecules in outer space is an ever-growing endeavour. Towards this, the computational chemistry supporting the astronomical spectroscopic observations is becoming a valuable tool to unravel the complex chemical network in interstellar medium (ISM). In the present work, quantum-mechanical computations, accounting for anharmonic effects, are performed to obtain the rotational and vibrational line-data for the gas-phase conformers of proteinogenic amino acid Leucine and its isomeric species predicted to be involved in its stereoinversion under the extreme environment of ISM. These species exhibit diverse chemistry including branched skeleton and zwitterionic ammonium ylides. A few of the species have significantly high dipole moment, which can act as tracer for the conformers of Leucine having low dipole moment. Besides this, the species, which are terrestrially less stable, can be of significant importance to the astronomers. Notably, the spectral database generated in this work can assist in the detection of proteinogenic Leucine and its isomeric species in different regions of ISM.

Organocatalytic Asymmetric Cyclopropanation of 3-Acylcoumarins with 3-Halooxindoles: Access to Spirooxindole-cyclopropa[c]coumarin Compounds.

A highly diastereo- and enantioselective cyclopropanation reaction of 3-acylcoumarins with 3-halooxindoles catalyzed by an organocatalyst through a [2 + 1] Michael/intramolecular cyclization process was developed. This scenario provides a facile strategy to access spirooxindole-cyclopropa[c]coumarin compounds bearing three continuous stereocenters, including two vicinal quaternary all-carbon stereocenters with high to excellent diastereo- and enantioselectivities. The HRMS study revealed the vital importance of the ammonium ylide intermediate in the catalytic process.

Iron-promoted dealkylative carbene aminocyclization of δ-arylamino-α-diazoesters.

Herein, we report a novel methodology to access N-aryl proline derivatives using amino-tethered α-diazoesters and cheap, readily available iron salts. Mechanistically, the aminocyclization reaction involves the initial formation of an iron-carbene complex followed by a nucleophilic attack of the aniline nitrogen atom to give an ammonium ylide intermediate, which finally undergoes the iron-promoted dealkylation.

Enantioselective Construction of Chiral Cyclopropa[c]coumarins via Lewis Base-Catalyzed Cyclopropanation.

The first highly enantioselective construction of chiral cyclopropa[c]coumarins was described. Using commercially available (bis)cinchona alkaloid (DHQ)2PYR as the chiral Lewis base catalyst, together with Cs2CO3 as the achiral base, the reaction of a series of coumarin-3-carboxylate and 3-benzoyl coumarins with tert-butyl 2-bromoacetate could give rise to the corresponding cyclopropa[c]coumarins bearing three continuous chiral stereocenters in 83-93% ee and 90-97% ee, respectively. The reaction is proposed to proceed via an in situ generated ammonium ylide intermediate.

Unveiling the high reactivity of benzyne in the formal [3+2] cycloaddition reactions towards thioamides through the Molecular Electron Density Theory

AbstractThe domino reaction of benzyne with thioamide has been studied within the Molecular Electron Density Theory (MEDT) at the MPWB1K/6-311G(d) level. This domino reaction takes place through i) a formal [3 + 2] cycloaddition (32CA) reaction affording an ammonium ylide, and ii) an extrusion of ethylene from this species yielding a dihydrothiazole. Topological analysis of the electron density of benzyne shows its pseudodiradical structure, that is, without any energy cost, changes to a carbenoid one, allowing its participation as electrophile in polar reactions. As a consequence, the formal 32CA reaction does not have an activation enthalpy. Analysis of the changes of electron density along the domino reaction indicates that while the formal 32CA reaction takes place through a two-stage one-step mechanism, the extrusion of ethylene takes place through an intramolecular E2 elimination mechanism. The present MEDT study reveals the chameleonic structure/reactivity of benzyne, allowing its participation in both non-polar and polar reaction with an unappreciable activation enthalpy.

Cover Picture: Enantioselective Ammonium Ylide Mediated One‐Pot Synthesis of Highly Substituted γ‐Butyrolactones (Adv. Synth. Catal. 12/2020)

Cover Picture: Enantioselective Ammonium Ylide Mediated One‐Pot Synthesis of Highly Substituted <i>γ</i>‐Butyrolactones (Adv. Synth. Catal. 12/2020)

Enantioselective Ammonium Ylide Mediated One‐Pot Synthesis of Highly Substituted γ‐Butyrolactones

AbstractAn ammonium ylide mediated access towards trans‐β,γ‐disubstituted, all‐trans‐α,β,γ‐trisubstituted, and α,α,β,γ‐tetrasubstituted γ‐butyrolactones bearing a broad variety of functionalities was developed. Starting from widely accessible benzylidene Meldrum's acid derivatives and α‐bromo carbonyl compounds, γ‐butyrolactones were obtained in yields between 32–99% with up to excellent diastereoselectivities (&gt;95:5) via a DABCO‐mediated [2+1] annulation. Utilization of enantiomerically pure cinchona alkaloid derivatives enables the first asymmetric ammonium ylide mediated method to provide (3R, 4R)‐β,γ‐disubstituted and (2R, 3R, 4R)‐α,β,γ‐trisubstituted γ‐butyrolactones in moderate to good yields with up to very good enantiomeric ratios (97:3). The scalability of the transformation was proven while determining the absolute configuration.magnified image

DABCO-Catalyzed Michael/Alkylation Cascade Reactions Involving α-Substituted Ammonium Ylides for the Construction of Spirocyclopropyl Oxindoles: Access to the Powerful Chemical Leads against HIV-1

A novel Michael/alkylation cascade reaction of N-unprotected 3-bromooxindoles with α,β-unsaturated acyl phosphonates using DABCO as a robust catalyst followed by the derivatization of the acyl phosphonate intermediates in situ has been developed. This scenario enables rapid access to a diverse set of highly functionalized spirocyclopropyl oxindoles in moderate yields with good to excellent diastereoselectivities, which are analogues of a high active non-nucleoside reverse transcriptase inhibitor against HIV-1. The synthetic potential of this tactic has been highlighted by a gram-scale reaction and Suzuki cross-coupling reactions of the product. Moreover, the reaction mechanism has been tentatively elucidated by control experiments and dynamic high-resolution mass spectrometry studies, which indicates that the Michael/alkylation cascade reaction involves DABCO-derived α-substituted ammonium ylides.

Rotational and vibrational analysis of astrophysically relevant isomeric species of proteinogenic glutamic acid: A quantum-mechanical computational study

There has been growing curiosity in finding complex organic molecules such as proteinogenic amino acids in outer space. The life-supporting amino acids have been detected in the meteoritic samples with enantiomeric excess; however, their detection in the interstellar medium (ISM) has remained elusive so far. The spectral information received from ISM is often too complex to resolve for confirming the presence of a large-sized molecular species such as glutamic acid. The rotational and vibrational spectroscopy is the key to detection of such molecules in ISM. This work provides pure rotational and vibrational line data through quantum mechanical computations for glutamic acid and isomeric molecular species proposed along its gas-phase stereoinversion pathways under conditions akin to the ISM. The molecular species investigated in this work form a network of diverse molecules, which include zwitterionic ammonium ylide, di-carboxylic acid, gem-diol, vicinal-diol and imine. Notably, anharmonic calculations using vibrational second order perturbation theory have been performed to accurately predict the rotational and vibrational transitions, particularly in millimetre (mm), sub-mm, mid- and far-infrared regions, which can assist in the detection of glutamic acid in different regions of ISM.

Base-induced Sommelet–Hauser rearrangement of N-(α-(2-oxyethyl)branched)benzylic glycine ester-derived ammonium salts via a chelated intermediate

The base-induced Sommelet–Hauser (S–H) rearrangement of N-(α-branched)benzylic glycine ester-derived ammonium salts 1 was investigated. When the α-branched substituent was a simple alkyl, such as a methyl or butyl, desired S–H rearrangement product 2 was obtained in low yield with formation of the [1,2] Stevens rearranged 4 and Hofmann eliminated products 5 and 6. However, when the α-branched substituent had a 2-oxy moiety, such as 2-acetoxyethyl or 2-benzoyloxyethyl, the yields of 2 were improved. These results could be explained by formation of chelated intermediate C that stabilizes the carbanionic ylide, and the subsequent initial dearomative [2,3] sigmatropic rearrangement would be accelerated. The existence of C was supported by mechanistic experiments. This enhancement effect is not very strong or effective; however, it will expand the synthetic usefulness of ammonium ylide rearrangements.

Chiral N,N'-dioxide/Mg(OTf)2 complex-catalyzed asymmetric [2,3]-rearrangement of in situ generated ammonium salts.

Catalytic enantioselective [2,3]-rearrangements of in situ generated ammonium ylides from glycine pyrazoleamides and allyl bromides were achieved by employing a chiral N,N′-dioxide/MgII complex as the catalyst. This protocol provided a facile and efficient synthesis route to a series of anti-α-amino acid derivatives in good yields with high stereoselectivities. Moreover, a possible catalytic cycle was proposed to illustrate the reaction process and the origin of stereoselectivity.

Mechanism and kinetics of astrophysically relevant gas-phase stereoinversion in glutamic acid: A computational study

Enantiomeric excess of amino acids observed in the meteoritic samples of carbonaceous chondrites has incited many researchers to search for an extra-terrestrial origin of life on prebiotic Earth. However, in a non-catalytic environment, only racemic amino acids are synthesized. This computational quantum-mechanical study explores non-catalytic mechanistic pathways for stereoinversion in proteinogenic L-glutamic acid, which may be observable under gas-phase conditions of interstellar medium (ISM). The multi-step stereoinversion pathways proposed in this study are traced through a global reaction route mapping (GRRM) strategy utilizing density-functional and coupled-cluster theories. Notably, a few of the pathways are observed to proceed through simultaneous intramolecular hydrogen atom and proton transfer as well as through a proton-coupled electron transfer mechanism. The intermediates explored along the stereoinversion pathways resemble ammonium ylide and imine, the key ingredients in Strecker synthesis of amino acids. The thermodynamic and kinetic analysis of the stereoinversion pathways in different temperature regions of ISM are also carried out, predicting the streoinversion to proceed over any dissociation of intermediates and conformers of glutamic acid along the pathways. However, initial step of the pathways involves an unsurmountable energy barrier though the key step responsible for stereoinversion has a very low energy barrier and is predicted to proceeds with significant rates. The work suggests the possibility of observing stereoinversion of glutamic acid in the warmer regions of ISM.

Stereoselective aziridination of imines via ammonium ylides: A molecular electron density theory study

AbstractThe highly trans‐stereoselective reaction of ammonium salt (AS 2) toward (E)‐N‐benzylidene‐4‐methylbenzenesulfonamide (IM 4) in the presence of Na2CO3 leading to an aziridine derivative, trans‐Az 6, was theoretically studied using Molecular Electron Density Theory (MEDT) at the B3LYP/6‐31G(d) computational level to probe energy transformation, selectivities, and molecular mechanism. The reaction starts by a nucleophilic substitution reaction between 1,4‐diazabicyclo [2.2.2]octane (DABCO) and phenacyl bromide (PB) to form AS 2 which undergoes a proton abstraction by Na2CO3 to produce Ammonium Ylide (AY 3). Subsequently, nucleophilic addition of AY 3 to the double bond in IM 4 leads to form a betaine‐like intermediate, namely, IN‐Ta which named IN‐Ta. Finally, trans‐Az 6 is produced as a result of the nucleophilic attack of the negatively charged nitrogen atom on the carbon atom bearing DABCO in IN‐Ta. Analysis of the relative Gibbs free energies shows that the ring closure step is the rate‐determining step (RDS). By an investigation of the conceptual density functional theory, CDFT reactivity indices AY 3 and IM 4 are classified as a strong nucleophilic molecular system and as a strong electrophilic molecular system, respectively, which implies that the addition step of AY 3 to IM 4 has a high polar character. An analysis of the calculated electrophilic and nucleophilic Parr functions at the reactive sites of reagents clarifies the regioselectivity observed experimentally within the C1–C2 bond creation process.

Catalytic Enantioselective Syntheses of Functionalized 3,3-Spirocyclopropyl Oxindoles and Vinylcyclopropanes via Ammonium Ylides Generated from α-Bromoketones

Catalytic Enantioselective Syntheses of Functionalized 3,3-Spirocyclopropyl Oxindoles and Vinylcyclopropanes via Ammonium Ylides Generated from <i>α</i>-Bromoketones

Catalyst-Free [2,3]-Sigmatropic Rearrangement Reactions of Photochemically Generated Ammonium Ylides

The rearrangement reaction of ammonium ylides furnishes valuable α,α-disubstituted amino esters. In this work, we describe the visible-light photolysis reaction of aryldiazoacetates in the presence of tertiary amines that react via a free ammonium ylide in a sigmatropic rearrangement reaction to provide amino esters in moderate to very good yields (33 examples, up to 97% yield).

Diastereoselective [2,3]-Sigmatropic Rearrangement of N-Allyl Ammonium Ylides

A rapid and diastereoselective method was developed for the [2,3]-sigmatropic rearrangement of N-allyl ammonium ylides, affording products in up to 95% isolated yields and up to 97:3 dr; most of the desired products were formed within 1 minute. For the asymmetric reaction, a chiral auxiliary was introduced to the starting compound, affording the rearrangement product with high diastereoselectivities.

Gold(I)-catalyzed [4 + 1]/[4 + 3] annulations of diazo esters with hexahydro-1,3,5-triazines: Theoretical study of mechanism and regioselectivity

Hexahydro-1,3,5-triazines are often used as formaldimine precursors. The recent success of Sun et al. (Angew. Chem. Int. Ed., 2016, 55, 11867) in achieving gold-catalyzed [4 + 1]/[4 + 3] annulations of hexahydro-1,3,5-triazines with diazo esters, in which the hexahydro-1,3,5-triazine is directly used as the 1,4-dipole in the annulation, represents a breakthrough in mechanistic studies. In the present work, density functional theory (DFT) calculations were used for detailed investigation of possible catalytic mechanisms. The proposed catalytic cycle involves five major stages: dinitrogen elimination to form a gold–carbene intermediate; diazoacetate–hexahydro-1,3,5-triazine C–C coupling to give an ammonium ylide; ring opening of the hexahydro-1,3,5-triazine via C–N single-bond cleavage; a second C–N single-bond cleavage; and C–C-bond-forming reductive elimination. The regioselectivities of the cycloaddition of hexahydro-1,3,5-triazines with enol diazoacetates differ from those of cycloadditions with vinyl diazoacetates. The calculations also clarified the origins of the substrate-controlled regioselectivity.

An Empirical Model for Stereochemical Control in the Cyclization of Cyclopropanetricarboxylic Acid Esters

Abstract Here, we report an empirical model for diastereoselective cyclopropanation of fumarate/maleate diesters with chloroacetate, sulfonium ylide, or ammonium ylide. With symmetrical fumarate/maleate diesters, cyclopropanation was found to proceed with a high level of diastereoselectivity in favor of the chiral isomer. In contrast, production of the meso isomer was observed in 38–48% diastereoselectivity when unsymmetrical fumarate/maleate was employed. An improved synthesis of (N-desmethy)dysibetaine CPa in both racemic and enantiomerically pure forms was furthermore achieved. Configurational analysis by experimental and calculated 13C NMR data is also reported.

Computational rotational–vibrational spectroscopic analysis of isomeric species in the interstellar gas-phase stereoinversion of amino acid threonine

The gas-phase stereoinversion of amino acid threonine under the condition of interstellar medium (ISM) has been predicted to proceed through isomeric species with diverse chemistry. These species including ammonium ylides, epoxides, contain a variety of functional groups such as geminal-diol, triol besides alkenyl, carboxy, keto, hydroxy, and amino groups. The detection of these species in ISM can help in unravelling the enantiomeric excess observed in meteoritic samples. Towards this, the present work reports rotational and vibrational spectroscopic data computed for the conformers and isomeric intermediates predicted along the stereoinversion pathways of proteinogenic threonine under conditions akin to ISM. The rotational parameters are computed using quantum mechanical methods employing Møller–Plesset perturbation theory whereas for the vibrational analysis, density functional computations are performed using dispersion corrected exchange-correlation functionals. The anharmonic corrections are also computed using vibrational second-order perturbation theory, which, however, fails to account for the hydrogen bonded interactions in the species investigated. The rotational and vibrational transitions predicted for the conformers of threonine are observed to be in good agreement with the available experimental data. The gas-phase spectroscopic data computed for other isomeric species of threonine is quite reliable and can be used to search threonine or other amino acids in ISM by resolving the astrophysical data observed in the microwave and mid-infrared regions.

Rh(I)/Sc(OTf)3-co-catalyzed Michael addition of ammonium ylide to (E)-1,4-enediones: synthesis of functionalized 1,4-diketones.

A Rh(I)/Sc(III) co-catalyzed synthesis of highly valuable functionalized 1,4-diketone derivatives in good yields and with an excellent diastereoselectivity. The established method provides a rapid approach to structurally diverse 1,4-diketone scaffold in a very mild and rapid fashion from simple starting materials. Moreover, the protocol could be easily scaled up to gram-scale synthesis. An attempt to develop an asymmetric version of the Rh(I)/guanidine system was also explored, resulting in a moderate enantioselectivity (71% ee).