Ethers, enol, addition Mannich reaction with

Besides the allylation reactions, imines can also undergo enol silyl ether addition as with carbonyl compounds. Carbon-carbon bond formation involving the addition of resonance-stabilized nucleophiles such as enols and enolates or enol ethers to iminium salt or imine can be referred to as a Mannich reaction, and this is one of the most important classes of reactions in organic synthesis.104... 

Since then, efficient catalytic asymmetric methods have been developed for the addition of silyl enol ethers or silyl ketene acetals to imines with chiral metal catalysts [29-34], Recently, direct catalytic asymmetric Mannich reactions which do not require preformation of enolate equivalents have appeared. 

The peptidic phosphine ligands that had been introduced by Hoveyda and co-workers271 for enantioselective copper-catalyzed Michael additions (see Section 9.12.2.2.1) were also employed successfully in silver-catalyzed asymmetric Mannich reactions.3 Thus, the aryl-substituted imines 372 reacted with various silyl enol ethers in the presence of stoichiometric amounts of isopropanol, as well as catalytic amounts of silver acetate and ligand 373 to... 

Use of trimethylsilyl triflate to bring about Piunmeier rearrangement requires the presence of a base such as a tertiary amine (vide supra equations 15 and 26). In some instances, involving attempts to alkylate Pummerer intermediates with silyl enol ethers under such conditions, the base has been found to compete as a nucleophile. In the absence of the silyl enol ether, amine addition can be very efficient. For example, treatment of methallyl phenyl sulfoxide with diisopropylethylamine and trimethylsilyl inflate in dichloromethane (equation 29) at 0 C yields the ammonium triflate indicated in 91% yield. Other tertiary amines which undergo this reaction include niethylamine and Af,Af-diethyltrimethylsiI-amine. In the latter case with allyl phenyl sulfoxide as the substrate and a mildly acidic wotk-up, the Mannich derivative shown in equation (30) can be obtained in 90% yield. ... 

Cationic Pd complexes can be applied to the asymmetric aldol reaction. Shibasaki and coworkers reported that (/ )-BINAP PdCP, generated from a 1 1 mixture of (i )-BINAP PdCl2 and AgOTf in wet DMF, is an effective chiral catalyst for asymmetric aldol addition of silyl enol ethers to aldehydes [63]. For instance, treatment of trimethylsi-lyl enol ether of acetophenone 49 with benzaldehyde under the influence of 5 mol % of this catalyst affords the trimethylsilyl ether of aldol adduct 113 (87 % yield, 71 % ee) and desilylated product 114 (9 % yield, 73 % ee) as shown in Sch. 31. They later prepared chiral palladium diaquo complexes 115 and 116 from (7 )-BINAP PdCl2 and (i )-p-Tol-BINAP PdCl2, respectively, by reaction with 2 equiv. AgBF4 in wet acetone [64]. These complexes are tolerant of air and moisture, and afford similar reactivity and enantioselec-tivity in the aldol condensation of 49 and benzaldehyde. Sodeoka and coworkers have recently developed enantioselective Mannich-type reactions of silyl enol ethers with imi-nes catalyzed by binuclear -hydroxo palladium(II) complexes 117 and 118 derived from the diaquo complexes 115 and 116 [65]. These reactions are believed to proceed via a chiral palladium(fl) enolate. 

Further extension of the reaction pool of Schilf bases 138 was achieved by their reaction with tran -l-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (Danishefsky s diene) to give 2-substituted 5,6-didehydro-piperidin-4-ones 164 [135,136] (Scheme 10.54). The reaction is considered to be a sequence of an initial Mannich reaction between the imine and the silyl enol ether, followed by an intramolecular Michael addition and subsequent elimination of methanol. If the reaction was terminated by dilute ammonium chloride solution, then the Mannich bases 163 could be isolated and further transformed to the dehydropiperidinones 164 by treatment with dilute hydrochloric acid. This result proved that the reaction pathway is not a concerted hetero Diels-Alder type process between the electron-rich diene and the activated imine. The use of hydrogen chloride as a terminating agent resulted in exclusive isolation of the piperidine derivatives 164 formed with... 

As mentioned in the previous sections, silyl enolates are excellent enolate components in the Mannich-type reactions with imines. Alternatively, it was found that vinyl ethers also reacted with imines smoothly in the presence of a catalytic amount of Ln(OTf)3 to afford the corresponding b-amino ketones. In addition, the reactions proceeded smoothly by the combination of aldehydes, amines, and vinyl ethers in aqueous media [55]. 

Related Mannich reactions have been reported by Holy and Wang. These chemists generated the silyl enol ethers under either thermodynamic or kinetic control, but cleaved the ether with methyllithium to the same lithium enolate and then added the Mannich salt. Product distributions demonstrated that the addition reaction is regiospecific. They also found that the reaction can be conducted by the trapping technique of conjugate addition of dimethylcopper-lithium to cyclohexenone followed by addition of the immonium salt (equation I.)... 

As is shown in Scheme 13.5, the authors found that treatment of enol ether 32 with TEA resulted in both the removal of the Boc group and hydration of the enol ether to give lactol 33. After removal of the DNs (2-(2,4-dinitrophenyl)ethoxycarbonyl) group with pyrrolidine, the hemiacetal moiety reacted with the prereleased secondary amine to produce the cyclic enamine 34. Subsequently, the Michael addition of the enamine to the unsaturated ester and Mannich reaction of the indole to the resultant iminium ion furnished the desired 35 as the sole isomer. Finally, a regioselective dehydration and stereoselective epoxidation, followed by a deprotection step, gave the desired lower segment (-)-taberhanine, which was used for the total synthesis of conophylline. 

Ferraris et al.108 demonstrated an asymmetric Mannich-type reaction using chiral late-transition metal phosphine complexes as the catalyst. As shown in Scheme 3-59, the enantioselective addition of enol silyl ether to a-imino esters proceeds at —80°C, providing the product with moderate yield but very high enantioselectivity (over 99%). 

This BINAP silver(I) complex was subsequently used by Lectka and coworkers as a catalyst for Mannich-type reactions [35]. Slow addition of silyl enol ether 49 to a solution of tosylated a-imino ester 80 under the influence of 10 mol % (i )-BINAP AgSbFg at -80 °C affords the corresponding amino acid derivative 81 in 95 % yield with 90 % ee (Sch. 20). They reported, however, that (R)-Tol-BINAP-CuC104-(CH3CN)2 was a more effective chiral Lewis acid for the reaction and gave the highest yield and ee at 0 °C. 

In recent years, catalytic asymmetric Mukaiyama aldol reactions have emerged as one of the most important C—C bond-forming reactions [35]. Among the various types of chiral Lewis acid catalysts used for the Mukaiyama aldol reactions, chirally modified boron derived from N-sulfonyl-fS)-tryptophan was effective for the reaction between aldehyde and silyl enol ether [36, 37]. By using polymer-supported N-sulfonyl-fS)-tryptophan synthesized by polymerization of the chiral monomer, the polymeric version of Yamamoto s oxazaborohdinone catalyst was prepared by treatment with 3,5-bis(trifluoromethyl)phenyl boron dichloride ]38]. The polymeric chiral Lewis acid catalyst 55 worked well in the asymmetric aldol reaction of benzaldehyde with silyl enol ether derived from acetophenone to give [i-hydroxyketone with up to 95% ee, as shown in Scheme 3.16. In addition to the Mukaiyama aldol reaction, a Mannich-type reaction and an allylation reaction of imine 58 were also asymmetrically catalyzed by the same polymeric catalyst ]38]. 

Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched P-amino ketones or esters [48a, 48b]. For the most part, these methods involve the use of chirally modified enolates or imines. Only a handful of examples has been reported on the reaction of imines with enolates of carboxylic acid derivatives or silyl ketene acetals in the presence of a stoichiometric amount of a chiral controller [49a, 49b, 49c]. Reports describing the use of a substoichiometric amount of the chiral agent are even more scarce. This section contains some of the most recent advances in the field of catalytic enantioselective additions of lithium enolates and silyl enol ethers of esters and ketones to imines. 

Diketones are accessible via a number routes, for example by Michael addition of enolate to enone (or precursor Mannich base " ), by ozonolysis of a cyclopentene precursor, or by reaction of silyl enol ethers with 3-methoxyallylic alcohols. They react with ammonia, with loss of two mol equivalents of water to produce a cyclic bis-enamine, i.e. a 1,4-dihydropyridine, which is generally unstable but can be easily and efficiently dehydrogenated to the aromatic heterocycle. 

Kobayashi and co-workers discovered catalytic enantioselective Mannich-type reactions of silyl enol ethers of thiol esters with aldimines using a novel zirconium catalyst. For example, in the presence of 10 mol% of catalyst 28, the silyl enol ether 20 was treated with aldimine 26 in CH2CI2 at -45 °C in the co-existence of N-methylimidazole (NMl) as an additive to afford the adduct 27 in 78% yield with 88% ee (Scheme 6) [36]. 

Based on Mannich-type reactions of N-acryliminoacetates with silyl enol ethers, a new method for the preparation of N-acylated amino acid derivatives via nucleophilic addition to N-acrylimino ester has been developed using a polymer-supported amine and scandium catalysts (Scheme 12.5) [9]. Ethyl N-benzoyl-2-bromoglycine was used as a substrate. It could be readily converted to reactive N-acrylimino ester in situ by treatment with a base. Immobilizations of the amine and the scandium species into polymeric supports prevented loss of activity of the catalyst. The method is simple and provides a convenient method for the preparation of N-acrylated amino acid derivatives. 

Carretero and coworkers have successfully employed a copper(I)-Fesulphos complex as a Lewis acid for enantioselective Mannich-type reactions of N-sulfonyl imines [43]. A combination of [151 CuBr]2 and AgCl04 does efficiently catalyze the addition of silyl enol ethers of ketones, esters, and thioesters (150) to N-(2-thienyl)sulfonyl aldimines (Scheme 17.30). The corresponding P-amino carbonyl derivatives (152) were isolated in good yields with generally good enan-tioselectivity. 

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