Copper-catalyzed enantioselective conjugate addition of Grignard reagents to acyclic enones using monodentate phosphoramidite ligands

Herein, we report efficient catalysts based on phosphoramidites for the asymmetric copper-catalyzed conjugate addition of Grignard reagents to acyclic α,β-unsaturated ketones. A variety of Grignard reagents can be added to aliphatic and aromatic acyclic enones with good yields and moderate to good enantioselectivities.     

Michael addition of phosphorus derivatives on tetraethyl ethylidenediphosphonate

Nucleophilic phosphorus add to tetraethyl ethylidene diphosphonate in protic solvent to yield the product of the Michael reaction. This reaction appeared to be reversible at a temperature upper than 160 °C. To avoid this reverse reaction, alkylation in α position of the two phosphonate functions by activated elecrophile is reported.     

The retro Grignard addition reaction revisited: the reversible addition of benzyl reagents to ketones

The Grignard addition reaction is known to be a reversible process with allylic reagents, but so far the reversibility has not been demonstrated with other alkylmagnesium halides. By using crossover experiments it has been established that the benzyl addition reaction is also a reversible transformation. The retro benzyl reaction was shown by the addition of benzylmagnesium chloride to di-tert-butyl ketone followed by exchange of both the benzyl and the ketone moiety with another substrate. Similar experiments were performed with phenylmagnesium bromide and tert-butylmagnesium chloride, but in these two cases the Grignard addition reaction did not show any sign of a reverse transformation.     

Reactions of methylchlorodisilanes with Grignard reagents

Reactions of Cl₂MeSiSiMeCl₂ with RMgCl make it possible to obtain and isolate pure disilanes containing a smaller number of functional groups, namely, RMeClSiSiMeCl₂ (R = Ph), RMeClSiSiMeRCl (R = Prⁱ, Ph), and R₂MeSiSiMeRCl (R = Buⁱ). The reaction of Cl₂MeSiSiMeCl₂ with BuⁿMgCl is the least selective. The chlorides obtained were reduced with LiAlH₄ into the corresponding hydrides.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 954–957, May, 1995.     

Regioselective addition of Grignard reagents to 2,6-dicyanoanilines and cyclization to new quinazoline derivatives under thermal/microwave irradiation conditions

Two strategies have been developed for the synthesis of novel quinazoline derivatives. 2,6-Dicyanoanilines were reacted with Grignard reagents followed by cyclization to give two quinazoline regioisomers 2 and 3. Alternately 2,6-dicyanoanilines on reaction with Grignard reagents gave imine regioisomers 4 and 5. Each imine regioisomer was separated and independently cyclized to give new quinazoline derivatives 6, 7 and 8, 9, respectively, under different microwave irradiation conditions.     

Unusual reactions of Grignard reagents toward fluoroalkylated esters

Fluorine-containing esters were demonstrated to be convenient substrates for construction of the corresponding ketones by low temperature reaction with Grignard reagents followed by warming up to 0 °C, while heating the mixture up to 80 °C readily promoted the reduction of the ketones obtained by the generated magnesium alkoxides whose mechanism was speculated as Meerwein-Ponndorf-Verley type reduction by computational technique.     

Asymmetric Conjugate Addition of Grignard Reagents to 3‐Silyl Unsaturated Esters for the Facile Preparation of Enantioenriched β‐Silylcarbonyl Compounds and Allylic Silanes

A highly enantioselective conjugate addition of Grignard reagents to 3‐silyl unsaturated esters to deliver synthetically useful chiral β‐silylcarbonyl compounds was developed. The synthetic value of this methodology was further illustrated by the synthesis of enantioenriched β‐hydroxyl esters and the facile access granted to various α‐chiral allylic silanes. A plethora of diastereoselective transformations of β‐silylenolates were also investigated and afforded manifold organosilanes that contained contiguous stereogenic centers with excellent enantioselectivity.     

An efficient synthesis of 2-Aminoethylidene-1,1-Bisphosphonates derivatives via Michael addition reaction

A facile, rapid and cheap synthetic strategy towards a wide range of novel 2-aminoethylidene-1,1-bisphosphonate derivatives was developed through the Michael addition reaction of various aromatic amines, aromatic amides as well as nucleoside analogues with tetraethyl ethenylidene-1,1-bisphosphonate. All the newly obtained compounds were characterized by ¹H, ³¹P, ¹³C NMR spectroscopy, IR and HR MS.     

Sequential addition reaction of lithium acetylides and Grignard reagents to thioiminium salts from thiolactams leading to 2,2-disubstituted cyclic amines

The reaction of thioiminium salts derived from γ- and δ-thiolactams with lithium acetylides and Grignard reagents proceeded sequentially to give 2,2-disubstituted pyrrolidines and piperidines in moderate to high yields. In the initial step of the reaction, 2-(methylthio)pyrrolidines and -piperidines may be formed. The use of lithium (trimethylsilyl)acetylide gave the products most effectively. Aryl-, alkyl-, and allylmagnesium halides were used as Grignard reagents. Silylcarbocyclization of N-allyl 2-ethynyl cyclic amines with HSiMe₂Ph in the presence of a catalytic amount of Rh₄(CO)₁₂ was carried out to give trisubstituted hexahydro-1H-pyrrolizines and octahydroindolizines.     

Copper-Catalyzed Addition of Grignard Reagents to in situ Generated Indole-Derived Vinylogous Imines

Chiral indole derivatives are ubiquitous motifs in pharmaceuticals and alkaloids. Herein, the first protocol for catalytic asymmetric conjugate addition of Grignard reagents to various sulfonyl indoles, offering a straightforward approach for the synthesis of chiral 3-sec-alkyl-substituted indoles in high yields and enantiomeric ratios is presented. This methodology makes use of a chiral catalyst based on copper phosphoramidite complexes and in situ formation of vinylogous imine intermediates.     

Reactions of Grignard reagents with 1,3-dicyanoadamantane

Reactions of Grignard reagents RMgX (R = Me, Et, Pr, Bu; X = Br, I) with 1,3-dicyanoadamantane (1) were studied. Optimum conditions for the synthesis of monoaddition products of Grignard reagents to compound 1 were established. The first stage of the reaction of cyanoadamantane 1 with MeMgBr was studied by the MNDO-PM3 method. According to calculations, the more preferable reaction mechanism involves formation of a six-membered cyclic intermediate containing two Mg atoms, two C atoms, and one Br and one N atom.     

Bromodifluoromethylation of aromatic Grignard reagents with CF2Br2

The bromodifluoromethylation of aromatic Grignard reagents having electron-withdrawing groups with dibromodifluoromethane (CF₂Br₂) was developed. The reaction proceeded to give the corresponding (bromodifluoromethyl)benzene derivatives via a difluorocarbene-mediated mechanism.     

The first nucleophilic aromatic substitution of suitably activated 2-methoxyfurans with Grignard reagents

The reaction of 2-methoxyfuroates 1 with Grignard reagents 2 leads to tertiary alcohols or S_NAr products depending on the position of the alkoxycarbonyl group. OMe-Displacement occurs only for 3-substituted derivatives. It takes place even for 3-acetyl-2-methoxyfuran while the presence of a further ester function at 4 position induces the formation of the sole 4-tertiary alcohol. The OMe-substitution has been verified for a wide range of furans and Grignard reagents and low yields have been found only in the reactions with the benzylic and allylic reagents which are delocalized anions. A mechanistic interpretation is given.     

A brief survey on the copper‐catalyzed allylation of alkylzinc and Grignard reagents under Barbier conditions

The same regioselectivity can be obtained in the CuI catalyzed allylic coupling of n‐butylzinc reagents prepared by either pre‐transmetallation or in situ transmetallation of Grignard reagents in the presence of allylic partner and catalyst. n‐Butylzinc bromide and di‐n‐butylzinc undergo γ‐selective allylation whereas tri‐n‐butylzincate gives preferential α‐selectivity. The regioselectivity obtained in the reaction of n‐butyl bromide and E‐crotyl chloride in the presence of Mg and CuCN is parallel to the coupling of preformed n‐butylmagnesium bromide. It is remarkable that the regiochemical outcome of copper catalyzed alkyl‐allyl coupling can be controlled by using Grignard reagents prepared under Barbier conditions and alkylzincs prepared by in situ transmetallation. Copyright © 2006 John Wiley & Sons, Ltd.