Unique Structural Properties of 2,4,6‐Tri‐tert‐butylanilide: Isomerization and Switching between Separable Amide Rotamers through the Reaction of Anilide Enolates

Herein, we report a unique structural property of 2,4,6‐tri‐tert‐butylanilide, which can be separated into its amide rotamers at room temperature. Interconversion between the rotamers of anilide enolates occurs readily at room temperature and their reaction with electrophiles gives mixtures of the rotamers in a ratio that depends on the reactivity of the corresponding electrophile. That is, the reaction of the 2,4,6‐tri‐tert‐butylacetanilide enolate with reactive electrophiles, such as allyl bromide or protic acids, gives mixtures of the anilide rotamers in which the E rotamer is the major component, whereas less‐reactive electrophiles, such as 1‐bromopropane and 2‐iodopropane, yield mixtures of the rotamers in which the Z rotamer is the major component. The rotameric ratio of the product is also strongly dependent on the reactivity of the anilide enolate. Switching between the anilide rotamers can be achieved through protonation of a less‐reactive enolate by a less‐reactive protic acid and thermal isomerization of the anilide.     

Highly enantioselective synthesis of atropisomeric anilide derivatives through catalytic asymmetric N-arylation: conformational analysis and application to asymmetric enolate chemistry

In the presence of (R)-DTBM-SEGPHOS-Pd(OAc)(2) catalyst, N-arylation (aromatic amination) of various o-tert-butylanilides with p-iodonitrobenzene proceeds with high enantioselectivity (88-96% ee) to give atropisomeric N-(p-nitrophenyl)anilides having an N-C chiral axis in good yields. Atropisomeric anilide products highly prefer to exist as the E-rotamer which has trans-disposed o-tert-butylphenyl group and carbonyl oxygen. The application of the present catalytic enantioselective N-arylation to an intramolecular version gives atropisomeric lactam derivatives with high optical purity (92-98% ee). The reaction of the lithium enolate prepared from the atropisomeric anilide and lactam products with various alkyl halides gives alpha-alkylated products with high diastereoselectivity (diastereomer ratio = 13:1 to 46:1).     

Computational strategies for evaluating barrier heights for gas-phase reactions of lithium enolates

Gas-phase activation energies were calculated for three lithium enolate reactions by using several different ab initio and density functional theory (DFT) methods to determine which levels of theory generate acceptable results. The reactions included an aldol-type addition of an enolate to an aldehyde, a proton transfer from an alcohol to a lithium enolate, and an S(N)2 reaction of an enolate with chloromethane. For each reaction, the calculations were performed for both the monomeric and dimeric forms of the lithium enolate. It was found that transition state geometry optimization with B3LYP followed by single point MP2 calculations generally provided acceptable results compared to higher level ab initio methods.     

Das 1,3‐Dimethylcyanurat‐Ion als ambidenter Ligand

The 1,3‐Dimethylcyanurate Ion as an Ambident Ligand 1,3‐Dimethyl‐2,4,6‐trioxo‐1,3,5‐triazin ( 7 ), (1,3‐dimethylcyanuric acid, DMCH), obtained from the thermolysis of methyl urea, is deprotonated with lithium ethylate. In the resulting dinuclear complex [(DMCLi)₂·4 H₂O] ( 8 ), the heterocyclic anions are linked to the lithium centres with oxygen atoms as its enolate form. In the corresponding silver complex [(DMCAg)₂·en] ( 10 ), (en = ethylendiamine), N‐coordination of the ligand is observed. The crystal structures of 7 , 8 , and 10 reveal the presence of intermolecular hydrogen bonds.     

Specific reactivity of 2,4,6-tri-tert-butylanilide anions and its application to benzylation reagent

The reaction of methyl iodide with an anilide anion prepared from 2,4,6-tri-tert-butylanilide and NaH in CH₃CN gave N-methyl anilide (N-alkylation product) as a major product, while in the reaction of benzyl bromide with the anilide anion in DMF, O-benzyl imidate (O-alkylation product) was obtained with almost complete selectivity. The treatment of O-benzyl imidate with alcohols and carboxylic acids in the presence of trifluoromethane sulfonic acid gave benzyl ethers and benzyl esters, respectively.     

Enantioselective conjugate addition of a lithium ester enolate catalyzed by chiral lithium amides

Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on alpha,beta-unsaturated esters. Michael adducts were obtained in ee's up to 76% combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction was found to be determined by both the relative configuration of the stereogenic centers borne by the amide and the solvent in which the reaction was conducted. [reaction: see text]     

Chiral ligand-controlled asymmetric conjugate addition of alpha-trimethylsilanylacetate to acyclic and cyclic enones

The reaction of lithium ester enolate with enones provides a challenge for chemoselectivity, that is, discrimination between a conjugate addition and a 1,2-addition. Asymmetric conjugate addition of a lithium enolate of alpha-trimethylsilanylacetate to acyclic and cyclic alpha,beta-unsaturated ketones was mediated by an external chiral ligand to give the corresponding 1,4-adducts in good enantioselectivity of 74% and good chemoselectivity.     

Studies towards complex bridged alkaloids: regio- and stereocontrolled enolate chemistry of 2,5-diketopiperazines

The substitution of symmetrical N-protected diketopiperazines (DKPs) via enolate intermediates has been studied. The enolate reactions were highly diastereocontrolled, leading to enantiopure DKP products if chiral amino acid precursors were employed, and giving racemic products, starting with centrosymmetric DKPs, even when a chiral lithium amide base was used to generate the lithium enolate. With unsymmetrical DKPs derived from proline and either alanine, phenylalanine or valine, the enolate substitution occurred with high regio- and stereoselectivity on the proline residue. This enabled the synthesis of substituted DKPs that could be cyclised via cationic processes to give the bicyclo[2.2.2]diazaoctane core structure present in paraherquamide and stephacidin natural products.     

Characterization of a chiral enolate aggregate and observation of 6Li-1H scalar coupling

A chiral enolate aggregate 1 containing a lithium enolate and a chiral lithium amide was systematically investigated by various NMR techniques. (1)H and (13)C DOSY at 25 and -78 degrees C provide its solution structure, aggregation number, and formula weight. Multiple 2D (6)Li NMR techniques, such as (6)Li-(6)Li EXSY, (6)Li-(1)H HOESY, were utilized to investigate its stereochemical structure. The configuration of the enolate in complex 1 was confirmed by (6)Li-(1)H HOESY and trapping with TMS-Cl. A unique (6)Li-(1)H coupling through the Li-N-C-H network was observed. This scalar coupling was corroborated by (6)Li-(1)H HMQC, deuterium labeling experiments, and selective (1)H decoupling (6)Li NMR. The stereostructure of 1 provides a model for the origin of enantioselectivity of chiral lithium amide-induced enolate addition reactions.     

Why is alkylation of an enolate accompanied by so much polyalkylation?

[reaction: see text] The lithium enolate 1-Li of 6-phenyl-alpha-tetralone forms a monomer-tetramer equilibrium in THF at 25 degrees C with K(1,4) = 4.7E+10 M(-3). The lithium enolate 2-Li, however, forms a monomer-dimer equilibrium with K(1,2) = 3800 M(-1). In both cases reaction with benzyl bromide is dominantly with the monomer. The results support an earlier conjecture of House that alkylation of an enolate is frequently accompanied by extensive polyalkylation because the less substituted enolates are more aggregated.     

Unusual transformations of lithium enolate of ethyl 4,4,4-trifluoro-3-oxobutanoate

The present paper describes unusual reactions of lithium enolate of ethyl 4,4,4-trifluoro-3-oxobutanoate with ammonium acetate and 1-aminonaphthalene. These reactions produce 4-amino-2,6-bis(trifluoromethyl)pyridine and 4-trifluoromethyl-2-[(Z)-1,1,1-trifluoroprop-1-en-2-ol-1-yl]benzo[h]quinoline, respectively. The reaction of 1,1,7,7,7-hexafluoroheptane-2,4,6-trione hydrate with 1-naphthylamine gives a mixture of 4-trifluoromethyl-2-[(Z)-1,1,1-trifluoroprop-1-en-2-ol-1-yl]benzo[h]quinoline and N,N??-bis(naphth-1-yl)-2,6-bis(trifluoromethyl)pyridine-4(1H)-imine, respectively.     

Lithium amide assisted asymmetric Mannich-type reactions of menthyl acetate with PMP-aldimines

A lithium enolate of menthyl acetate added to PMP-imines, in the presence of an equimolar amount of lithium diisopropylamide, affords the Mannich-type addition products in high stereoselectivity. [reaction--see text]     

Diastereo- and enantioselective aldol reaction of granatanone (pseudopelletierine)

Granatanone (granatan-3-one, 9-methyl-9-azabicyclo[3.3.1]nonan-3-one, pseudopelletierine or pseudopelletrierin) undergoes deprotonation with lithium amides giving a lithium enolate, which reacts with aldehydes diastereoselectively giving exclusively exo isomers and anti/syn selectivity up to 98:2. Granatanone can be enantioselectively lithiated by chiral lithium amides and the resulting non-racemic enolate can be reacted with aldehydes giving aldols with enantiomeric excess up to 93% (99% ee after recrystallization). The absolute and relative configuration of the aldol products was determined by NMR spectroscopy and X-ray analysis.Granatanone; aldol reaction; asymmetric synthesis; enantioselective deprotonation; chiral lithium amide.     

Generation and reactions of the lithium enolate of the iron acetyl complex Cp(CO)2FeCOCH3

The title acetyl complex of the Cp(CO)₂Fe system undergoes reaction with lithium hexamethyldisilazide to give the corresponding lithium enolate which reacts with a variety of electrophilic reagents.     

Li- and P NMR spectra of cyclopentanone lithium enolate in ethereal solvents: identification of the HMPA-coordinated aggregate structures

The structures of cyclopentanone lithium enolate under HMPA titration in 0.04-0.8 M diethyl ether and dimethyl ether solvents have been investigated using the low-temperature ⁷Li, ³¹P, and ¹³C NMR. The progressive solvation by HMPA occurs for the tetra- and dimeric enolates, and upon addition of >2 equiv. of HMPA, the lithium enolate has been converged on a mixture of tetra-HMPA coordinated tetramer and bis-HMPA coordinated dimer with the ratio of 5:95 and <1:99 in diethyl ether and dimethyl ether, respectively. Neither monomeric nor trimeric enolate is detectable under such HMPA titration.     

A ternary complex reagent for an asymmetric Michael reaction of lithium ester enolates with enoates

A lithium ester enolate was activated by both a chiral etheral ligand and a lithium amide to form a ternary complex reagent that reacted with enoates giving the corresponding Michael addition products in reasonably high enantioselectivity of up to 97% ee.     

The structure of some methyl and benzyl malonate derivatives of pyrimidine

Reaction of 2,4,6-trichloropyrimidine with sodium dibenzylmalonate in p-dioxane gave 4,6-dichloro-2-(dibenzylmalonyl)pyrimidine, while reaction of 2,4,6-trichloropyrimidine with sodium dimethylmalonate yielded both 4,6-dichloro-2-(dimethylmalonyl)pyrimidine and 2,2-bis-(4,6-dichloropyrimidin-2-yl)dimethylmalonate. Structural studies using nmr, ir and uv spectroscopy indicate that for the former two compounds in basic solvent, an equilibrium exists between the keto forms and resonance-stabilized enolate ions.     

A telluride-triggered nucleophilic ring opening of monoactivated cyclopropanes

[reaction: see text] Acylcyclopropanemethanol tosylates undergo rapid ring opening at room temperature by the action of lithium telluride to produce the enolate of a homoallylic ketone. The enolate can be protonated to yield the corresponding ketone or treated with benzaldehyde to give the aldol product with good syn or anti diastereoselectivity depending on the conditions.     

Catalytic enantioselective protonation of lithium enolates with chiral imides

The catalytic enantioselective protonation of simple enolates was achieved using a catalytic amount of chiral imides and stoichiometric amount of achiral proton sources. Among the achiral proton sources examined in the protonation of the lithium enolate of 2,2,6-trimethylcyclohexanone catalyzed by (S,S)-imide 1, 2, 6-di-tert-butyl-p-cresol (BHT) and its derivatives gave the highest enantiomeric excess. For example, 90% ee of (R)-enriched ketone was obtained when (S,S)-imide 1 (0.1 equiv) and BHT (1 equiv) were used. Use of 0.01 equiv of the chiral catalyst still caused a high level of asymmetric induction. For catalytic protonation of the lithium enolate of 2-methylcyclohexanone, chiral imide 6 possessing a chiral amide portion was superior to (S,S)-imide 1 as a chiral proton source and the enolate was effectively protonated with up to 82% ee.     

Regiospecific α-dialkoxymethylation of preformed enolates

Reaction of a preformed lithium enolate and trimethyl orthoformate with added boron trifluoride leads to the corresponding α-dimethoxymethyl ketone.