Imines, dialkylzinc addition

The reactivity of /V-d i pheny 1 phosphi nyI imines toward dialkylzinc addition in the presence of a stoichiometric or catalytic amount of chiral ligand 165, 166, or 167 has also been meticulously investigated. The reaction in Scheme 3-57 gives good yield with up to 95% ee.106... 

Enantioselective Addition of Dialkylzincs to Imines. Enantioselective addition of dialkylzincs to N-diphenyl-phosphinoylimines in the presence of DBNE or its analog affords optically active phosphoramides. Subsequent hydrolysis affords optically active amines in up to 91% ee (eq 25). When the amount of DBNE is catalytic (10 mol %), the enantioselec-tivity is 75% ee. One of the advantages of this method over the alkyllithium method is the use of a lesser amount of chiral ligand. 

Dahmen S, Braese S. The asymmetric dialkylzinc addition to imines catalyzed by [2.2]paracyclophane-based A, 0-ligands. J. Am. Chem. Soc. 2002 124(21) 5940-5941. 

Asymmetric addition to ketimine in a reagent controlled manner has seldom been reported, even by 2008. When we investigated the potential for tbis asymmetric addition around 1992, there were no known examples. In 1990, Tomioka et al., reported the first asymmetric addition of alkyl lithium to N-p-methoxyphenyl aldo-imines in the presence ofa chiral (3-amino ether with 40-64% ee [8] (Scheme 1.11). In 1992, Katritzky reported the asymmetric addition of Et2Zn to in situ prepared N-acyl imine in the presence of a chiral (3-amino alcohol with 21-70% ee [15] (Scheme 1.12). In the same year, Soai et al., reported the asymmetric addition of dialkylzinc to diphenylphosphinoyl imines in the presence of chiral (3-amino alcohols with 85-87% ee [16] (Scheme 1.13). These three reports were, to the best of... 

Nitrones have a more reactive C=N bond toward nucleophilic addition compared to imines. In spite of this fact, there have been only a limited number of studies on the nucleophilic addition reactions of nitrones, particularly organometallic reagents.352-355 During the last decade, research related to reactions of nitrones with zinc-containing reagents was essentially focused on (i) dialkylzinc-assisted alkynylations356-358 and vinylations359 of nitrones, (ii) catalytic asymmetric nucleophilic additions to the C=N bond,360-364 and (iii) nitrone allylations by allylzinc halides.365,366... 

Chiral amines, ArCH(R)NH2, can be prepared by addition of a dialkylzinc to A-(diphenylphosphinoyl)imines, ArCH=N—P(=0)Ph2, using a suitable auxiliary, followed by acid hydrolysis to cleave the phosphorus moiety. A series of 2-azanorbornylmethanols (65) give ee% up to 92%, and they also induce some enantioselectivity in additions to benzaldehyde. A highly organized transition state with two zincs is proposed one coordinates the nitrogens of substrate and catalyst and the other coordinates the oxygens. 

These highly enantioselective Lewis-acid/Lewis-base-catalyzed dialkylzinc and phenylzinc addition reactions to imines give rise to arylalkylamides and diaryl-methylamides in excellent yields and enantioselectivities. Due to the simplicity of the process and the good availability of the imine precursors 23 from the corresponding aldehydes, wide applicability of the reported catalytic reaction can be expected. 

Nowadays, this chemistry includes a wide range of applications. The organozinc compounds employed in the enantioselective addition include dialkylzincs, dialkenylzincs, dialkynylzincs, diarylzincs and the related unsymmetrical diorganozincs. Electrophiles have been expanded to aldehydes, ketones and imines. Asymmetric amplification has been observed in the enantioselective addition of organozincs. Recently, asymmetric autocatalysis, i.e. automultiplication of chiral compounds, has been created in organozinc addition to aldehydes. 

High enantioselectivity has been achieved on addition of diethylzinc to benzaldehyde catalysed by a chiral diamine, (,S )-2-(A,A -disubstitutcd aminomethyl)pyrrolidine,116 and by chiral helical titanate complexes of tetradentate ligands.117 Enantioselective additions of dialkylzinc reagents to A,-(diphcnylphosphiiioyl)imines, promoted by aziridino alcohols,118 and to the carbon-nitrogen double bond of the nitrone 3,4-dihydroisoquinoline A-oxide, promoted by dicyclopentyl(R,R)-tartrate,119 have also been reported. 

Addition of organometallic reagents to imines is not limited to allylmetal derivatives. Hoveyda and Snapper have demonstrated that dialkylzinc reagents can add to imines in a one-pot procedure. Using a zirconium complex as metal catalyst and a chiral peptide, diverse enantioenriched aryl, aliphatic and alkynyl amines 142 have been obtained with high levels of enantioselectivity (Scheme 8.60) [136],... 

Enantioselective addition of dialkylzincs to imines using chiral ligands asymmetric synthesis of optically active amines... 

Both Me-DuPHOS (483) and Me-DuPHOS monoxide (484) have been successfully used as chiral ligands in the copper catalysed highly enantio-selective addition of dialkylzinc to N-phosphinoyl imines (485). A simple deprotection of N-protecting group from (486) provided a-chiral amines (Figure 91). ... 

Asymmetric Addition of Dialkylzincs to Aldehydes and Imine Derivatives... 

Although the level of enantioselectivity observed in this study was modest, this contribution has documented for the first time the use of a dialkylzinc reagent for the stereoselective addition of a carbon nucleophile to the imine function. 

As part of an ongoing research program directed toward the use of chiral aziridines in asymmetric synthesis [36], Andersson, Tanner and co-workers have recently reported the detailed results of their own findings in the field of catalytic asymmetric dialkylzinc alkylation of imines [37dj. Tanner et al. had previously communicated their success in the catalytic asymmetric addition of organolith-ium reagents to imines with C2-symmetric bis(aziridines) [37a, 37b]. This was followed by a preliminary report on the use of aziridino alcohols as well as simple aziridines for the addition of diethylzinc to M-diphenylphosphinoylimines [37c]. The most recent report is an extension of this study, and includes the detailed preparation of the ligands [37d]. 

Chiral amines, ArCH(R)NH2, can be prepared by addition of a dialkylzinc to A-(diphenylphosphinoyl)imines, ArCH=N—P(=0)Ph2, using a suitable auxiliary, followed by acid hydrolysis to cleave the phosphorus moiety. A series of... 

Even the very efficient enantioselective catalysts used in organozinc addition reactions to carbonyl compounds failed to catalyze the corresponding addition reactions to nonactivated imines such as N-silyl-, N-phenyl-, or A-benzyl-imines. However, enantioselective additions of dialkylzinc compounds to more activated imines, like A7-acyl- or N-phosphinoyl-imines, in the presence of catalytic or stoichiometric amounts of chiral see Chiral) aminoalcohols, have been recently reported. For example, in presence of 1 equiv of (N,N-dibutylnorephedrine) (DBNE) diethylzinc reacts with masked N-acyl imines like A7-(amidobenzyl)benzotriazoles, to give chiral N- -phenylpropyl) amides with up to 76% e.e. (equation 68). 

The 1,2-addition of dialkylzinc reagents, in particular Et2Zn, to aryl imines is stereocontrolled by a ligated form of copper bearing a hemi-labile, monophosphine oxide (Me-DUPHOS(O), Nonracemic secondary carbon centers bearing a... 

Pyridyl)sulfonyl imines of chalcones also serve as substrates for enantioselective conjugate additions of dialkylzinc reagents catalyzed by CuTC (eq 26). ... 

Addition to Imines. CuOTf-catalyzed alkylation of N- acii-vated)imines also proceeds with dialkylzinc reagents. Use of a chiral amidophosphine leads to the asymmetric alkylation of N-(p-toluenesulfonyl)imines with dimethyl-, diethyl-, and di-E propylzinc in good yields and high enantioselectivities. CuOTf is the most active catalyst but efficiency is optimal with Cu(OTf)2 (eq 117). Chiral binaphthylthiophosphoramides give slightly lower selectivities. ... 

Combined use of ZnCh, EtaN, and MeaSiCl promotes a direct addition of terminal alkynes to imines to give propargylamines [140]. MeaSiCl activates imines to accelerate the addition of zinc acetylides generated from the alkynes. Dialkylzincs also adds efficiently to imines with the aid of Mea SiCl [141]. 

---