We developed a 1,3-dipolar cycloaddition reaction of azomethine imines with terminal alkynes catalyzed by group 11 metal amides to provide N,N-bicyclic pyrazolidinone derivatives. This reaction afforded the cycloadducts in a unique 5,7-disubstituted manner. Furthermore, we succeeded in applying this catalysis to asymmetric reactions, and the desired heterocycles were produced in high yields with exclusive regioselectivity and high enantioselectivity. Mechanistic studies elucidated a stepwise reaction pathway and critical features that determine the regioselectivity.
The synthesis of highly substituted pyrrolidine derivatives is very important in bioorganic and medicinal chemistry, because they are useful building blocks for biologically active molecules, and they sometimes show interesting biological activity.[1] The asymmetric [3+2] cycloaddition of a-amino ester Schiff bases with substituted olefins is one of the most efficient methods for pyrrolidine preparation in an optically pure form, [2] thus making it possible to introduce various substituents on the pyrrolidine skeleton stereoselectively. From the pioneering work of Grigg et al., [3] chiral catalyst systems based on a combination of chiral metal Lewis acids and tertiary amine bases have been reported, and high diastereo-and enantioselectivities have been attained in some cases. [4][5][6][7] However, there are some problems that have yet to be solved for this reaction: 1) addition of external amines is needed in most cases; 2) major products of the cycloaddition are endo, and there are few examples which provide exo adducts selectively; 3) applicable substrates for this method are still limited. In particular, successful examples using Schiff bases derived from aliphatic aldehydes are very rare (see below).In a previous paper, we described that silver bis(trimethylsilyl)amide (AgHMDS; HMDS = hexamethyldisilazide) when combined with a chiral ligand works well in the enanitioselective [3+2] cycloaddition of a-aminophosphonate Schiff bases, which have less-acidic hydrogen atoms at the a position, with substituted olefins.[8] High yields and diastereoselectivities were attained without addition of external bases. We thought that the key was the use of a basic silver reagent, AgHMDS, which was indeed employed for the first time in organic synthesis. In contrast, for the [3+2] cycloaddition of a-amino ester Schiff bases, which have moreacidic hydrogen atoms at the a position, we thought that AgHMDS might be too basic and thereby lead to low yields and selectivities because of some undesired side reactions. However, unexpectedly, a AgHMDS/chiral ligand complex was found to be a very efficient catalyst for enanitioselective [3+2] cycloaddition of a-amino ester Schiff bases with substituted olefins.First, we investigated a [3+2] cycloaddition reaction of the benzaldehyde Schiff base of glycine methyl ester (1 a) with methyl acrylate (2 a) in the presence of a chiral complex (10 mol %) prepared from AgHMDS and (R)-binap (L1) in toluene at 30 8C. The desired reaction proceeded in 82 % yield with moderate enantioselectivity (Table 1, entry 1). In this catalyst system, the endo adduct was obtained as the major diastereomer (endo/exo = 72:18). In contrast, we investigated other ligand structures and found that the use of segphos-type ligands afforded the exo adduct preferentially (entries 3 and 4); in particular (R)-DTBM-segphos (L4) showed high exo selectivity (endo/exo = 4:96) and good enantioselectivity (84 % ee, entry 4). Since typical chiral silver catalysts showed endo selectivity, it is remarkable that the exo product was ...
While Lewis acids and metal amides are among the most frequently used metal species, they are believed to be incompatible when combined. Here we describe a Lewis acid/metal amide hybrid, which contains electron-withdrawing groups and basic and bulky nitrogen functional groups in the same metal complex, as a novel catalyst. We have synthesized In(N(SiMe 3) 2) 2 Cl (In(HMDS) 2 Cl) and In(HMDS) 2 OTf as Lewis acid/metal amide hybrids, which showed excellent catalytic activity for the reaction of nitrones with terminal alkynes to give synthetically useful propargyl hydroxylamines. It is noted that neither the Lewis acids (InCl 3 , In(OTf) 3) nor the metal amides (In(HMDS) 3) have activity; only the hybrids worked well, and the catalytic activity of the hybrids was shown to be much higher than that of previously reported catalysts for this reaction. The concept of a Lewis acid/metal amide hybrid as a catalyst may be expanded to broad acid/base catalysis.
Asymmetric [3+2] cycloaddition of α-aminoester Schiff bases with substituted olefins is one of the most efficient methods for the preparation of chiral pyrrolidine derivatives in optically pure form. In spite of its potential utility, applicable substrates for this method have been limited to Schiff bases that bear relatively acidic α-hydrogen atoms. Here we report a chiral silver amide complex for asymmetric [3+2] cycloaddition reactions. A silver complex prepared from silver bis(trimethylsilyl)amide (AgHMDS) and (R)-DTBM-SEGPHOS worked well in asymmetric [3+2] cycloaddition reactions of α-aminoester Schiff bases with several olefins to afford the corresponding pyrrolidine derivatives in high yields with remarkable exo- and enantioselectivities. Furthermore, α-aminophosphonate Schiff bases, which have less acidic α-hydrogen atoms, also reacted with olefins with high exo- and enantioselectivities. The stereoselectivities of the [3+2] cycloadditions with maleate and fumarate suggested that the reaction proceeded by means of a concerted mechanism. An NMR spectroscopic study indicated that complexation of AgHMDS with the bisphosphine ligand was not complete, and that free AgHMDS, which did not show any significant catalytic activity, existed in the catalyst solution. This means that significant ligand acceleration occurred in the current reaction system.
The synthesis of highly substituted pyrrolidine derivatives is very important in bioorganic and medicinal chemistry, because they are useful building blocks for biologically active molecules, and they sometimes show interesting biological activity. [1] The asymmetric [3+2] cycloaddition of a-amino ester Schiff bases with substituted olefins is one of the most efficient methods for pyrrolidine preparation in an optically pure form, [2] thus making it possible to introduce various substituents on the pyrrolidine skeleton stereoselectively. From the pioneering work of Grigg et al., [3] chiral catalyst systems based on a combination of chiral metal Lewis acids and tertiary amine bases have been reported, and high diastereo-and enantioselectivities have been attained in some cases. [4][5][6][7] However, there are some problems that have yet to be solved for this reaction: 1) addition of external amines is needed in most cases; 2) major products of the cycloaddition are endo, and there are few examples which provide exo adducts selectively; 3) applicable substrates for this method are still limited. In particular, successful examples using Schiff bases derived from aliphatic aldehydes are very rare (see below).In a previous paper, we described that silver bis(trimethylsilyl)amide (AgHMDS; HMDS = hexamethyldisilazide) when combined with a chiral ligand works well in the enanitioselective [3+2] cycloaddition of a-aminophosphonate Schiff bases, which have less-acidic hydrogen atoms at the a position, with substituted olefins. [8] High yields and diastereoselectivities were attained without addition of external bases. We thought that the key was the use of a basic silver reagent, AgHMDS, which was indeed employed for the first time in organic synthesis. In contrast, for the [3+2] cycloaddition of a-amino ester Schiff bases, which have moreacidic hydrogen atoms at the a position, we thought that AgHMDS might be too basic and thereby lead to low yields and selectivities because of some undesired side reactions. However, unexpectedly, a AgHMDS/chiral ligand complex was found to be a very efficient catalyst for enanitioselective [3+2] cycloaddition of a-amino ester Schiff bases with substituted olefins.First, we investigated a [3+2] cycloaddition reaction of the benzaldehyde Schiff base of glycine methyl ester (1 a) with methyl acrylate (2 a) in the presence of a chiral complex (10 mol %) prepared from AgHMDS and (R)-binap (L1) in toluene at 30 8C. The desired reaction proceeded in 82 % yield with moderate enantioselectivity (Table 1, entry 1). In this catalyst system, the endo adduct was obtained as the major diastereomer (endo/exo = 72:18). In contrast, we investigated other ligand structures and found that the use of segphos-type ligands afforded the exo adduct preferentially (entries 3 and 4); in particular (R)-DTBM-segphos (L4) showed high exo selectivity (endo/exo = 4:96) and good enantioselectivity (84 % ee, entry 4). Since typical chiral silver catalysts showed endo selectivity, it is remarkable that the exo product wa...
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