The remarkable ability of lithium ion to reverse the stereoselectivity in the conjugate addition of Li[BuCuI] to a chiral N-crotonyl-2-oxazolidinone

[reaction: see text] The influence of lithium ions on the conjugate addition of the monoorganocuprate reagent, Li[BuCuI], to a chiral crotonate has been investigated. The results show that iodotrimethylsilane (TMSI) is crucial for the asymmetric conjugate addition of the copper reagent, but only in THF or when 12-crown-4 is used. The reaction is thought not to involve any halosilane in any critical steps in the organocopper mechanisms conducted in Et(2)O.     

Influence des interactions de torsion dans les reactions d'addition sur les cyclohexanones. interpretation generale du deroulement sterique des reactions des hydrures ou des organomagnesiens sur les cyclohexanones

The addition of allyl and butenyl Grignard reagents to 4-t-butylcyclohexanone affords a greater proportion of the equatorial alcohols than is formed from the corresponding saturated Grignard reagents (propyl and s-butyl). In the case of the allyl Grignard reagent, the equatorial alcohol is the major product. Lithium aluminium hydride reduction in ether at 0° of cis and trans 4-t-butyl-2-methyl-cyclohexanone and cis and trans 4-t-butyl-2-chlorocyclohexanone affords mixtures of epimeric alcohols in ratios of equatorial to axial OH 8.4:1, 20:1, 4.2:1, and >70:1 respectively. These results fit in well with the view that polar interactions and torsional strain are both important in determining the steric course of the reaction.     

Iron-catalyzed δ-selective conjugate addition of methyl and cyclopropyl Grignard reagents to α,β,γ,δ-unsaturated esters and amides

Iron-catalyzed δ-selective conjugate addition of methyl and cyclopropyl Grignard reagents to α,β,γ,δ-unsaturated esters and amides took place in good yields to give products exclusively with cis-β,γ-olefinic bond.     

Analyse conformationnelle de cétones cyclopropaniques par RMN à l'aide des déplacements paramagnétiques induits par Eu(dpm)3

The lanthanide induced shifts (LIS) of the lanthanide shift reagent Eu(dpm)₃ are reported for several cyclopropyl ketones. The conformational preference of the cyclopropanoyl group is determined via LIS by comparison with two compounds: dispiro-[2.1.2.2]nonane-4-one and 4,4,5-trimethyl bicyclo[3.1.0]hexane 2-one which are respectively in s-cis and s-trans conformation.     

Stereoselective synthesis of isoindolinones and tert-butyl sulfoxides

A reaction of Grignard reagents with an optically pure N-sulfinylimine derived from methyl 2-formylbenzoate yields enantioenriched isoindolinones and tert-butyl sulfoxides. The products are formed by the addition of the nucleophile to N-sulfinylimine followed by cyclization to form N-tert-butylsulfinylisoindolinone, which readily undergoes substitution with a second equivalent of Grignard reagent. The reaction can be carried out in dichloromethane at room temperature or at elevated temperatures without any loss of stereoselectivity. The use of nucleophiles other than Grignard reagents has also been investigated.     

Alkynenitriles: stereoselective chelation controlled conjugate addition-alkylations

Chelation-controlled conjugate addition of Grignard reagents to γ-hydroxyalkynenitriles stereoselectively generates tri- and tetra-substituted alkenenitriles. t-BuMgCl-initiated deprotonation of hydroxyalkynenitriles followed by addition of a second Grignard reagents triggers a facile conjugate addition leading to a cyclic magnesium chelate. Protonation of the chelate stereoselectively generates trisubstituted nitriles whereas the addition of t-BuLi causes conversion to an ‘ate’ complex that allows alkylation with aldehyde electrophiles. The chelation-controlled conjugate addition-alkylation generates tri- and tetra-substituted alkenenitriles that are otherwise difficult to synthesize.     

Preparation of cis-2-aminocyclopropanol: [2+1] cycloaddition reaction of bis(iodozincio)methane with α-ketoimine

A reaction of α-ketoimine with bis(iodozincio)methane gave a cis-2-aminocyclopropanol derivative via [2+1] cycloaddition. The reaction proceeded via a sequential nucleophilic attack of bis(iodozincio)methane to a couple of carbonyl groups in the substrate, which was fixed into s-cis conformation with a couple of zinc atoms in the reagent. The reaction proceeded with high diastereoselectivity.     

gamma-hydroxy unsaturated nitriles: chelation-controlled conjugate additions

[reaction--see text] Chelation between gamma-hydroxy unsaturated nitriles and Grignard reagents promotes an otherwise difficult anionic conjugate addition reaction. The intermediate chelate is readily generated by deprotonation with t-BuMgCl followed by the addition of a second Grignard reagent that triggers an intramolecular conjugate addition. Structurally diverse Grignard reagents add with equal efficiency, providing an intermediate anion that stereoselectively alkylates BnBr in an overall addition-alkylation reaction.     

Influence of MgCl2 on Grignard reagent composition in tetrahydrofuran. III

Reaction of [MgCl₂(THF)₂] with [NBu₄][BF₄] yields the compounds [NBu₄][MgCl₄] (IV) and [Mg(THF)₆][BF₄]₂ (V). After addition of dioxane the reaction equilibrium shifts in the opposite direction. The formation of [MgCl₂(C₄H₈O₂)₂] in solution does not require the presence of MgCl₂. This compound may be formed in the reaction of dioxane with the ionic or molecular species formed by the magnesium atom in solution. The [NBu₄][BF₄] salt also reacts with the Grignard reagent to produce compound IV which confirms that there is a new equilibrium between [Mg(R)X(THF)_n] and [MgR₂(THF)₂], [MgCl₄]²⁻ and [Mg(THF)₆]²⁺. Bis(tetrahydrofuran)magnesium dichloride, because of its reactivity is only stable in Grignard reagent. For that reason the composition of the Grignard reagent in solution is best described as an equilibrium between [Mg(R)X(THF)_n] and [(THF)₄Mg(μ-Cl)₂MgR₂] and [RMg₂(μ-Cl)₃(THF)₅] rather than as a Schlenk equilibrium.     

Synthesis and Structural Characterization of Butadienylcalcium-based Heavy Grignard Reagents and a Ca4[O] Inverse Crown Ether Complex

The structure elucidation of heavy Grignard reagents (RAeX, Ae=Ca, Sr, and Ba, X=halides) has been greatly strived after, mainly because of their inaccessibility and remarkable instability. The synthesis of a series of butadienylcalcium compounds is presented, including 1-calcio-4-lithio-1,3-butadiene, 1,4-dicalcio-1,3-butadiene, and a Ca₄[O] inverse crown ether complex, via the reaction between 1,4-dilithio-1,3-butadienes and calcium iodide in THF. Single-crystal X-ray analysis of these unprecedented heavy Grignard reagents revealed unique structural characteristics and bonding modes. Preliminary reaction chemistry was investigated. This study provides a novel class of alkenyl heavy Grignard reagents and a useful synthetic strategy for otherwise unavailable reactive organometallic compounds.     

Application of paramagnetic shift reagents to the conformational analysis of isomeric dienones

Paramagnetic NMR shift reagents, Eu(fod)₃ and Pr(fod)₃, have been applied to study the one-ene conformations of isomeric dienones. The results obtained using various complex formation models are analysed. The preferred model suggests participation of both carbonyl oxygen Ione pairs in binding with the shift reagents. Criteria for the estimation of errors in the determination of the structure parameters of the substrate-paramagnetic reagent complexes are suggested. The data obtained using NMR shift reagents are consistent with the existence of dienone α,β-cis-isomers as s-cis-conformers only, with the carbonyl group lying out of the plane of all the other atoms of the molecule. Both s-cis and s-trans conformers occur in dienone α,β-trans-isomers.     

Total synthesis of (+)-cylindricine C

A stereoselective total synthesis of (+)-cylindricine C has been achieved starting with (S)-N-Boc-2-pyrrolidinone. The key elements of this synthesis involve the sequence of reactions including BF₃-mediated addition of the allyl Grignard reagent to the cyclic imine, spirocyclization via enamine formation, and intramolecular Michael addition to form the tricyclic core.     

Synthesis and Structural Characterization of Butadienylcalcium‐based Heavy Grignard Reagents and a Ca4[O] Inverse Crown Ether Complex

The structure elucidation of heavy Grignard reagents (RAeX, Ae=Ca, Sr, and Ba, X=halides) has been greatly strived after, mainly because of their inaccessibility and remarkable instability. The synthesis of a series of butadienylcalcium compounds is presented, including 1‐calcio‐4‐lithio‐1,3‐butadiene, 1,4‐dicalcio‐1,3‐butadiene, and a Ca₄[O] inverse crown ether complex, via the reaction between 1,4‐dilithio‐1,3‐butadienes and calcium iodide in THF. Single‐crystal X‐ray analysis of these unprecedented heavy Grignard reagents revealed unique structural characteristics and bonding modes. Preliminary reaction chemistry was investigated. This study provides a novel class of alkenyl heavy Grignard reagents and a useful synthetic strategy for otherwise unavailable reactive organometallic compounds.     

Benzopyranopyridine derivatives 3. Reaction of 1-azaxanthone with grignard reagents

Three different classes of compounds were isolated in the reaction of Grignard reagents with 5-H[1]benzopyrano[2,3-b]pyridin-5-one, commonly called 1-azaxanthone. The formation of (a) 4-substituted 1,4-dihydro-1-azaxanthones (II), (b) 5-substituted-5-hydroxy-1-azaxanthenes (III) or (c) 4,5-disubstituted-1-azaxanthenes (IV) is dependent on the solvent used in the preparation of the Griganrd reagent (i.e. ether or tetrahydrofuran), the steric properties of the reagent and on the temperature. The isolated compounds were characterized by chemical derivatives and/or spectroscopic analyses.     

A convenient preparation of furo[2,3-b]indoles by conjugated addition of organomagnesium reagents to 2-hydroxyindolylidenemalonates

The chelate-controlled conjugated addition of Grignard reagents to 2-hydroxyindolylidenemalonates was studied as a means of preparing 3a-alkyl-3-methoxycarbonyl-2-oxofuro[2,3-b]indoles in one or two steps. In addition to the alkylorganometallic group variation, the effects of substitution at the aromatic ring on the reaction outcome were established. The indolylidenemalonates were found to be less reactive than the analogous indolylidenecyanoacetates.     

Stereoselective generation of cis-2-lithio-3-CF3-oxirane via CF3-substituted β-oxido carbenoids. Highly stereoselective synthesis of CF3-substituted tri- and tetrasubstituted oxiranes and tetrasubstituted alkenes

Treatment of 2-substituted 3,3-dichloro-1,1,1-trifluoropropan-2-ols with organolithium reagents R²Li in THF at −98°C stereoselectively produces 2,3-disubstituted 2-lithio-3-trifluoromethyloxiranes with Li and CF₃cis. The reagents react with electrophiles El-X or organoboranes R³BR₂ to give CF₃-containing tri- and tetrasubstituted oxiranes or tetrasubstituted alkenes, respectively, with high diastereoselectivities.     

Diborylated Magnesium Anthracene as Precursor for B2H5−‐Bridged 9,10‐Dihydroanthracene

9,10‐(Bpin)₂‐anthracene ( 3 , HBpin=pinacolborane) was synthesized from 9,10‐dibromoanthracene in a stepwise lithiation/borylation sequence. The reaction of 3 with highly activated magnesium furnished the diborylated magnesium anthracene 4 , which was quenched in situ with ethereal HCl to yield cis‐9,10‐(Bpin)₂‐DHA (cis‐ 5 , DHA=9,10‐dihydroanthracene). Compound cis‐ 5 , in turn, can be reduced with Li[AlH₄] in THF to give its diborate Li₂[cis‐9,10‐(BH₃)₂‐DHA] (Li₂[cis‐ 6 ]). In the crystal lattice, the THF solvate Li₂[cis‐ 6 ] ? 3 THF establishes a dimeric structure with Li‐(μ‐H)‐B coordination modes. Hydride abstraction from Li₂[cis‐ 6 ] with Me₃SiCl yields the B?H?B‐bridged DHA Li[ 7 ]. This product can also be viewed as a unique cyclic B₂H₇^? derivative with a hydrocarbon backbone. Treatment of Li₂[cis‐ 6 ] with the stronger hydride abstracting agent Me₃SiOTf (HOTf=trifluoromethanesulfonic acid) in THF affords the THF diadduct of cis‐9,10‐(BH(OTf))₂‐DHA.     

Addition of grignard reagents to aryl acid chlorides: an efficient synthesis of aryl ketones

[chemical reaction: see text]. Direct addition of Grignard reagents to acid chlorides in the presence of bis[2-(N,N-dimethylamino)ethyl] ether proceeds selectively to provide aryl ketones in high yields. A possible tridentate interaction between Grignard reagents and bis[2-(N,N-dimethylamino)ethyl] ether moderates the reactivity of Grignard reagents, preventing the newly formed ketones from nucleophilic addition by Grignard reagents.     

Unexpected highly diastereoconvergent Grignard additions to d-xylofuranose-derived t-butanesulfinyl aldimines

Unexpected high levels of diastereoconvergence (dr >15:1) were observed in the addition of a series of Grignard reagents in THF to d-xylose-derived t-BS aldimines 2a,b affording (S_S,5R)- and (R_S,5R)-adducts. This anomaly was absent when using ethereal solutions of organometallic reagents, revealing the subtle solvent effects. This study illustrates the scope and limitations of N-t-BS imine chemistry in complex systems.     

Catalytic enantioselective conjugate addition en route to paxilline indoloterpenoids

Development of enantioselective synthesis of precursor en route to paxilline indoloterpenoids is described. Evaluation of 25 diphosphine-based ligands has led to identification of JosiPhos derivative that allows for asymmetric conjugate addition of homoprenyl Grignard reagent to 2-methylcyclopent-2-en-1-one in excellent yield and with appreciable levels of enantioinduction. Application to the conjugate addition of other Grignard reagents is demonstrated.