Intramolecular Carbolithiation Research Articles

“Back‐to‐Front” Indole and Carbazole Synthesis from N,N‐Bis‐(2‐bromoallyl)amines by Combining Carbolithiation Reactions with Gold‐Catalysis

AbstractThe combination of organolithium chemistry with gold catalysis has enabled the development of a synthetic strategy for accessing polysubstituted indoles and carbazoles from readily available starting materials. This method is based on a “back‐to‐front” approach from ketopyrroles, generated by intramolecular carbolithiation of N,N‐bis‐(2‐lithioallyl)amines that evolve into 3,4‐bis(lithiomethyl)dihydropyrrole intermediates capable of reacting with carboxylic esters and Weinreb amides. These ketopyrroles have demonstrated to be excellent precursors of mono or bis(alkynols)pyrroles that, under gold‐catalysis, experience a benzannulation reaction providing access to regioselectively substituted indoles or carbazoles.magnified image

Electrophile-Dependent Reactivity of Lithiated N-Benzylpyrene-1-Carboxamide.

In this paper, we describe the lithiation of N-benzylpyrene-1-carboxamide with RLi-TMEDA. We found that the reaction outcome strongly depends on the electrophile used in the quenching step. The electrophile can be introduced at either the benzylic position or at the C-2 position in the pyrene nucleus. Furthermore, when H+ was used as the quencher, the product of the intramolecular carbolithiation of the pyrene K-region was formed. Dehydrogenation of the obtained compound with DDQ allowed the synthesis of a novel nitrogen polycyclic compound with an aza-benzo[c,d]pyrene (azaolympicene) skeleton. Attempts to extend the reaction scope to the amides substituted in the phenyl ring 8a and 8b gave an unexpected result. The reaction of both compounds with BuLi gave 1-valerylpyrene (9) in good yield. Photophysical properties, including absorption spectra, emission spectra and quantum yields of the emission of selected products, were studied and discussed.

IntramolecularAnti‐Carbolithiation of Alkynes: Stereo‐Directing Effect of Lithium‐Coordinating Substituents

AbstractThis paper presents the results of our investigations on the stereochemical course of intramolecular carbolithiation of alkynes. It is shown that the presence of a lithium‐chelating propargylic substituent completely reverses the otherwise favoredsyn‐process towards ananti‐addition. The reaction was studied by both experiment and computation. Electrophile trapping and domino process led to the stereocontrolled preparation of tetrasubstituted alkylidene indenol derivatives. Additionally, preliminary results on challenging desymmetrizing carbolithiation mediated by an external chiral ligand of lithium are provided.

Computational Insight into 1,2-Diamine, -Diether, and -Amino Ether Chiral Ligand-Mediated Carbolithiation: A Case of Enantioinduction Reversal.

trans-1,2-Cyclohexanediamine, -diether, and -amino ether were compared as chiral inducers in the asymmetric intramolecular carbolithiation of olefinic aryllithiums. Switching from diamine to ethereal ligands inverts the sense of asymmetric induction. This reversal of stereoselectivity was investigated through density functional theory calculations. High enantioselectivities observed with diether and amino ether ligands arise from favorable weak interactions between the ligand and the substrate. The relative efficiency of the three ligands and sense of stereoinduction for the most efficient diether and amino ether ligands prove to be foreseeable by modeling the reaction with the parent achiral 1,2-bidentate additives and comparing the diastereomeric transition states stemming from the two half-chair conformations of their lithium chelate.

Lithium–Olefin π-Complexes and the Mechanism of Carbolithiation: Synthesis, Solution Behavior, and Crystal Structure of (2,2-Dimethylpent-4-en-1-yl)lithium

We describe the first crystallographically characterized example of a nonconjugated olefin bound in a simple dihapto fashion to a lithium center, as part of a study of two alkyllithium compounds that contain C═C double bonds at the alkyl chain terminus: (2,2-dimethylbut-3-en-1-yl)lithium (1) and the related pentenyl compound (2,2-dimethylpent-4-en-1-yl)lithium (2). The Li–olefin interactions in the crystal structure of 2 serve as a model for those proposed to be present in the [RLi···olefin] intermediate in olefin carbolithiation reactions. As seen in other systems, the Li–olefin interaction is correlated with deshielding of the 1H NMR resonances of the olefinic hydrogen atoms. DOSY and NOE measurements show that 1 and 2 remain tetrameric in cyclohexane and that the lithium–olefin interactions persist in solution. Addition of a Lewis base such as THF to these ω-alkenyllithium species has two effects: the THF displaces the lithium–olefin interactions while accelerating the rate of carbolithiation. A deuteration experiment shows that compound 2 undergoes reversible carbolithiation to the corresponding cyclobutylmethyllithium species in the presence of Lewis bases, but this transformation is thermodynamically uphill owing to ring strain. In comparison, the longer chain hexenyl species (2,2-dimethylhex-5-en-1-yl)lithium is thermodynamically unstable with respect to the intramolecular carbolithiation product [(3,3-dimethylcyclopentyl)methyl]lithium (3). We suggest that rate-determining step in carbolithiation reactions may not always be formation of the C–C bond, as is often assumed, but in some cases may be formation of the lithium–olefin complex; the coordination of the olefin to lithium may occur in a concerted fashion with disaggregation of lithium clusters. Finally, we point out that activation enthalpies can be obtained solely from NMR line shapes above the coalescence point.

Diastereoselective Intramolecular Carbolithiations of Stereodefined Secondary Alkyllithiums Bearing a Remote Alkynylsilane.

Various secondary alkyl iodides bearing a remote alkynylsilane underwent intramolecular carbolithiations triggered by an I/Li-exchange performed at -100 °C using t-BuLi (2.5 equiv). The resulting alkenyllithiums were stereoselectively converted to tetrasubstituted cyclopentane exo-alkylidenes. After Pd-catalyzed hydrogenation, cyclopentanes and cis-bicyclo[4.3.0]nonanes were obtained with stereocontrol of four contiguous centers.

Readily Accessible 1,2-Amino Ether Ligands for Enantioselective Intramolecular Carbolithiation

A new class of chiral 1,2-amino ether ligands, readily accessible from naturally occurring α-amino- or α-hydroxy acids, was found to provide high levels of both conversion and stereocontrol (up to 95:5 er) in intramolecular carbolithiation reactions, outperforming the benchmark ligand (-)-sparteine. The ligand could be used in a substoichiometric amount (0.25 equiv) without significant loss of enantioselectivity.

Stereoselective Synthesis of Secondary Alkyllithiums and Their Application to Stereoselective Cuprations or Intramolecular Carbolithiations for the Stereoselective Synthesis of Alkylidene­cyclobutanes

Secondary alkyllithium reagents were prepared stereoselectively via an iodo–lithium exchange by using tert-butyllithium. The resulting secondary alkyllithiums were converted directly into the corresponding alkylcopper reagents by transmetalation with copper(I) bromide–triethyl phosphite [CuBr·P(OEt)3] with retention of configuration and without significant loss of stereoselectivity. The resulting alkylcopper reagents were used for carbocupration or acylation reactions. In addition, a new intramolecular carbolithiation of secondary alkyllithium reagents possessing a remote alkyne moiety was also investigated, allowing the stereoselective production of alkylidenecylobutane derivatives with very high stereocontrol.

Access to Apoerysopine and Pratosine Skeletons via Intramolecular Carbolithiation and Palladium-Catalyzed Alkenylation Reactions

Access to Apoerysopine and Pratosine Skeletons via Intramolecular Carbolithiation and Palladium-Catalyzed Alkenylation Reactions

A Computational Study of the Intramolec­ular Carbolithiation of Aryllithiums: Solvent and Substituent Effects

The intramolecular carbolithiation of olefinic aryllithiums provides an interesting route to functionalized carbo- and heterocyclic systems. We have computed mechanistic energy profiles (DFT) by varying the nature of the solvent and aryllithium. Our calculations suggest that the solvent mainly impacts the aggregation state of the aryllithium intermediates rather than activates the reactive species themselves. Further investigations revealed that substitution of the terminal position of the double bond and the N-allyl side-chain strongly influence the energy barriers, in good agreement with experimental data.

α-Lithiated Aryl Benzyl Ethers: Inhibition of [1,2]-Wittig Rearrangement and Application to the Synthesis of Benzo[b]furan Derivatives.

The use of t-BuLi at low temperature selectively leads to α-lithiation of benzyl phenyl ether generating a stable organolithium, which can be efficiently trapped with a variety of selected electrophiles prior to suffering the expected [1,2]-Wittig rearrangement. In the case of (o-alkynyl)phenyl benzyl ethers, the intermediate α-aryloxyorganolithium undergoes an unexpected anti intramolecular carbolithiation reaction leading to functionalized benzo[b]furan derivatives.

Intramolecular Carbolithiation of 3-Lithioxy-5-alkenyllithiums as a Platform for Cyclopentanols and Cyclopentanones

Intramolecular carbolithiation of 3-lithioxy-5-hexenyllithiums was studied. Unlike the case of 5-hexenyllithium, the cyclization of 3-lithioxy-5-hexenyllithium was very sluggish. Acceleration was observed when lithium chloride was added, suggesting that intramolecular lithioxy coordination would hinder the cyclization. Introduction of a silyl or thiophenyl group at the olefin terminus caused smooth cyclization. The resulting dianions having a cyclopentane framework are subjected to C–C bond-forming reaction with electrophiles to give 3-substituted cyclopentanols. Coupled with the Swern oxidation, the overall protocol served as a platform for 3-substituted cyclopentanones.

Intramolecular carbolithiation of heterosubstituted alkynes: an experimental and theoretical study.

A series of heterosubstitued alkynes was successfully submitted to the intramolecular carbolithiation of their triple bond. We show that the addition is stereoselective because of the control exerted by the terminal substituent X on the geometry of the transition state. A complementary DFT study suggests that the addition is anti when a strong Li-X interaction occurs.

ChemInform Abstract: Carbolithiation of Chloro‐Substituted Alkynes: A New Access to Vinyl Carbenoids.

AbstractIntramolecular carbolithiation of chloro‐substituted alkynes such as (I), (III), and (V) provides access to exocyclic alkylidene carbonoids.

Matrix trace operators: from spectral moments of molecular graphs and complex networks to perturbations in synthetic reactions, micelle nanoparticles, and drug ADME processes.

The study of quantitative structure-property relationships (QSPR) is important to study complex networks of chemical reactions in drug synthesis or metabolism or drug-target interaction networks. A difficult but possible goal is the prediction of drug absorption, distribution, metabolism, and excretion (ADME) process with a single QSPR model. For this QSPR modelers need to use flexible structural parameters useful for the description of many different systems at different structural scales (multi-scale parameters). Also they need to use powerful analytical methods able to link in a single multi-scale hypothesis structural parameters of different target systems (multi-target modeling) with different experimental properties of these systems (multi-output models). In this sense, the QSPR study of complex bio-molecular systems may benefit substantially from the combined application of spectral moments of graph representations of complex systems with perturbation theory methods. On one hand, spectral moments are almost universal parameters that can be calculated to many different matrices used to represent the structure of the states of different systems. On the other hand, perturbation methods can be used to add "small" variation terms to parameters of a known state of a given system in order to approach to a solution of another state of the same or similar system with unknown properties. Here we present one state-of-art review about the different applications of spectral moments to describe complex bio-molecular systems. Next, we give some general ideas and formulate plausible linear models for a general-purpose perturbation theory of QSPR problems of complex systems. Last, we develop three new QSPR-Perturbation theory models based on spectral moments for three different problems with multiple in-out boundary conditions that are relevant to biomolecular sciences. The three models developed correctly classify more than pairs 115,600; 48,000; 134,900 cases of the effects of in-out perturbations in intra-molecular carbolithiations, drug ADME process, or self-aggregation of micelle nanoparticles of drugs or surfactants. The Accuracy (Ac), Sensitivity (Sn), and Specificity (Sp) of these models were >90% in all cases. The first model predicts variations in the yield or enantiomeric excess due to structural variations or changes in the solvent, temperature, temperature of addition, or time of reaction. The second model predicts changes in >18 parameters of biological effects for >3000 assays of ADME properties and/or interactions between 31,723 drugs and 100 targets (metabolizing enzymes, drug transporters, or organisms). The third model predicts perturbations due to changes in temperature, solvent, salt concentration, and/or structure of anions or cations in the self-aggregation of micelle nanoparticles of drugs and surfactants.

Carbolithiation of Chloro‐Substituted Alkynes: A New Access to Vinyl Carbenoids

The intramolecular carbolithiation of a series of chloro-substituted alkynes leads to exocyclic alkylidene carbenoids of which both nucleophilic and electrophilic characters can be drove. A sole stereoselective 5-exo-dig addition takes place, probably because of a strong and persisting Li-Cl interaction arising before the transition state.

ChemInform Abstract: Synthesis of Substituted Benzofurans by the Tandem One‐Pot Intramolecular Carbolithiation—Cyclization—Substitution Sequence.

AbstractA variety of 3‐substituted‐2,3‐dihydrobenzofurans are conveniently obtained by tandem intramolecular carbolithiation‐cyclization of 2‐bromophenyl‐3‐phenylprop‐2‐enyl ether, followed by in situ trapping of the lithiated intermediate by suitable electrophiles.

Synthesis of Substituted Benzofurans by the Tandem One-Pot Intramolecular Carbolithiation–Cyclization–Substitution Sequence

A convenient methodology for the synthesis of 3-sustituted-2,3-dihydrobenzofurans was developed based on the tandem intramolecular carbolithiation–cyclization of 2-bromophenyl-3-phenylprop-2-enyl ether, followed by trapping of the new lithiated intermediate by suitable electrophiles. Several electrophiles were tested, affording good to excellent yields. Alkyl bromides show better results than chlorides and when doubly halogenated alkyl chains are used as electrophiles only one position reacts, affording substituted benzofurans conveniently functionalized to undergo further reactions. The performance of both butyl and phenyllithium as lithiating agents was examined. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]

Progress of Asymmetric Carbolithiation Reactions in the Presence of (-)-Sparteine

Inter- and intra-molecular enantioselective carbolithiation reactions in the presence of (-)-sparteine provide access to construct new highly regio- and stereo-selective carbon-carbon bonds. The recent results of the (-)-sparteine mediated asymmetric carbolithiation reactions in organic synthesis are summarized.

Synthesis of Tetrahydroquinolines through Intramolecular Carbolithiation Reactions

Synthesis of Tetrahydroquinolines through Intramolecular Carbolithiation Reactions