Silyl enol ethers Mannich reactions

Scheme 2.12 shows some representative Mannich reactions. Entries 1 and 2 show the preparation of typical Mannich bases from a ketone, formaldehyde, and a dialkylamine following the classical procedure. Alternatively, formaldehyde equivalents may be used, such as l>is-(di methyl ami no)methane in Entry 3. On treatment with trifluoroacetic acid, this aminal generates the iminium trifluoroacetate as a reactive electrophile. lV,A-(Dimethyl)methylene ammonium iodide is commercially available and is known as Eschenmoser s salt.192 This compound is sufficiently electrophilic to react directly with silyl enol ethers in neutral solution.183 The reagent can be added to a solution of an enolate or enolate precursor, which permits the reaction to be carried out under nonacidic conditions. Entries 4 and 5 illustrate the preparation of Mannich bases using Eschenmoser s salt in reactions with preformed enolates. 

More recently, asymmetric Mannich-type reactions have been studied in aqueous conditions. Barbas and co-worker reported a direct amino acid catalyzed asymmetric aldol and Mannich-type reactions that can tolerate small amounts of water (<4 vol%).53 Kobayashi found that a diastereo- and enantioselective Mannich-type reaction of a hydrazono ester with silyl enol ethers in aqueous media has been successfully achieved with ZnF2, a chiral diamine ligand, and trifluoromethanesul-fonic acid (Eq. 11.31).54 The diastereoselective Mannich-type reaction... 

Several examples of Bi(0Tf)34H20-catalyzed Mannich-type reactions of various A-benzyloxycarbonylamino sulfones 1 with silyl enol ethers are summarized in Table 5. A-Benzyloxycarbonylamino sulfones 1 derived from differently substituted benzaldehydes were reacted with trimethyl(l-phenylvinyloxy)silane in dichloromethane at room temperature. The corresponding (3-amino ketones 24 were smoothly obtained (Table 5, entries 1-6). The reaction was efficient using electron-deficient benzaldehyde-derived sulfones, and the corresponding (3-amino ketones 24... 

Table 5 Bi(0Tf)3-4H20-catalyzed Mannich-type reactions with various N-benzyloxycarbo-nylamino sulfones and silyl enol ethers...

In order to obtain further insight into the mechanism of the Mannich-type reaction, sulfone IP and silyl enol ether derived from acetophenone were reacted in the presence HOTf or TMSOTf, which could be produced in the reaction medium when using Bi(0Tf)3-4H20 as catalyst. It appeared that these two compounds efficiently catalyze the Mannich-type reaction (Table 7, entries 2 and 3). The reaction does not occur in the presence of 2,6-di-/<7V-buty I-4-methyl-pyridine [DTBMP] (1.0 equiv. of lp, 1.3 equiv. of silyl enol ether, 0.5 mol% of Bi(0Tf)34H20, 1.5 mol% of 2,6-di-/c/V-buty l-4-methy I-pyridine, 22 °C, 20 h, 99% recovery of lp), which indicates that triflic acid is involved in the mechanism (Table 7, entry 4). 

Several examples of Bi(OTf)3-catalyzed Mannich-type reactions with various silyl enol ethers are summarized in Table 12. Silyl enol ethers derived from aromatic and aliphatic ketones were reacted with an equimolar mixture of aldehyde and aniline (Scheme 10). The corresponding (3-amino ketones 27 were obtained in good yields (Table 12, entries 1M-) from aromatic-derived silyl enol ethers, except for the more hindered isobutyrophenone derivative. Silyl enol ethers derived from cyclopentanone or cyclohexanone afforded the (3-amino ketones in good yields (Table 12, entries 5 and 6). 

Table 12 Mannich-type reaction with silyl enol ethers derived from ketones...

Keywords Catalyst, Alkylation, Allylation, Arylation, Mannich reaction, Carbon-nitrogen double bond, Imine, Nitrone, Aldimine, Organozinc reagents, Silyl ketene acetal, Silyl enol ether, Amine, (3-Amino acid... 

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. 

In 1998, a new type of Pd(II) binuclear complex was reported which was effective for Mannich reactions of an imine derived from glyoxylate and anisidine with silicon enolates [38,39]. In these reactions, use of solvents including a small amount of water was essential. It was shown that water played an important role in this system water not only activated the Pd(II) complex to generate a cation complex, but also cleaved the N-Pd bond of the intermediate to regenerate the chiral catalyst. This reaction reportedly proceeded via an optically active palladium enolate on the basis of NMR and ESIMS analyses. A unique binuclear palladium-sandwiched enolate was obtained in the reaction of the p-hydroxo palladium complex with the silyl enol ether [(Eq. (9)]. 

The imines 12 (X = 4-CH3-QH4-SO2 (Ts), Ar, C02R, COR, etc.) preformed or generated in situ from N,0- or N,N-acetals or hemiacetals are another important class of Mannich reagents frequently used for diastereo- and/or enantioselective aminoalkylation reactions catalyzed by chiral Lewis acids (usually copper or palladium BINAP complexes such as 13). Among other things excellent results were obtained in the aminoalkylation of silyl enol ethers or ketene acetals [24], A typical example is the synthesis of Mannich bases 14 depicted in Scheme 5 [24b], Because of their comparatively high electrophilicity imines 12 could even be used successfully for the asymmetric aminoalkylation of unactivated alkenes 15 (ene reactions, see Scheme 5) [24h, 25], and the diastereo- and/or enantioselective aminoalkyla-... 

The best catalyst for this transformation was AgSbFg (10 mol%), and (3-ketoesters, malonates, and silyl enol ethers have been used for the nucleophilic addition on the pyridinium intermediate DD. The dihydroisoquinolines 48 have been further used in several reactions in order to assemble the framework of various alkaloids. One example is given in the formation of dihydroisoquinoline 49, bearing a pendent a, 3-unsaturated ketone. Compound 49 can rearrange to the tetracycle 50 (related to the core structure of karachine, Scheme 5.23), using TMSOTf, via a tandem Michael addition-Mannich reaction process (intermediates EE and FF). 

Moreover, Hoveyda and coworkers have demonstrated that Mannich reactions between silyl enol ethers and aldimines are promoted by the chiral complex that was generated from AgOAc and an wo-Leu-derived phosphine ligand.26 When the reaction was conducted with trimethylsilyl enol ether and aldimine in the presence of AgOAc, /.so-Leu-derived phosphine ligand and 2-PrOH, the (3-aminoketone was obtained with high enantioselectivity (Schemes 9.15 and 9.16). 

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. ... 

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. 

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. 

Another type of pre-formed reagent (28) has been used to carry out diastereose-lective Mannich reactions. The lithium salts 27 are treated with TiCU to give 28, which is then treated with the enolate of a ketone." ° The palladium catalyzed Mannich reaction of enol ethers to imines is also known." ° The reaction of silyl enol ethers and imines is catalyzed by HBF4 in aqueous methanol." ° Similarly, silyl enol ethers react with aldehydes and aniline in the presence of InCla to give the p-amino ketone." ° Imines react on Montmorillonite KIO clay and microwave irra-... 

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... 

Utilization of preprepai ed A,A-dimethylmethyleneammonium iodide (Eschenmoser salt) or chloride gives higher yields of (3-amino ketones than does the classical Mannich reaction. Silyl enol ethers also react with the Eschenmoser salt to give Mannich bases, as exemplified below. 

Trimethylsilyl enol ethers continue to be useful synthons for various aldol typeis,lb and Michael1 18 reactions. Their utility in part is due to their ease of regiospecific preparation, ease of cleavage and high reactivity. Danishefsky and coworkers have shown that silyl enol ethers react with dimethyl(methylene)ammonium iodide yielding Mannich bases.19 Otherwise inaccessible Mannich bases are accessible via the series below. 

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. 

This catalytic asymmetric Mannich-type reaction of silyl enol ethers with a-im-ino esters is notable because it proceeds under neutral conditions. 

Although enol ethers have received moderate notice as nucleophiles to quench intramolecular iminium ions, silyl enol ethers have been given scant attention. The first report of a silyl enol ether participating in an intramolecular Mannich reaction is found in Oppolzer and coworkers synthesis of ( )-vincamine (Scheme 14). 2 Dihydro-3-carboline (25) and silyl enol ether (26) were mixed in DMF, then warmed to 70 C for 64 h in the presence of diisopropylethylamine to provide a 1 1 mixture of cis and trans tetracyclic aldehydes (27) in 74% yield. 

Mannich reaction. This reagent and similar rr-acids on polymer support effect chemoselective condensation between silyl enol ethers and imines in refluxing MeCN aldehydes do not participate in the reaction. 

Mannich-type reaction. Carbinolamines formally derived from amines and CFaCHO condense with silyl enol ethers when catalyzed by GaCl,. 

Mannich reactionsJ The reaction of methoxymethyl(dibenzyl)amine with silyl enol ethers proceeds at low temperatures in the presence of BFj-OEt A bulky silyl group at the a -position of the enol ether can serve as a stereocontrol element. 

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]. 

Scandium triflate-catalyzed aldol reactions of silyl enol ethers with aldehyde were successfully carried out in micellar systems and encapsulating systems. While the reactions proceeded sluggishly in water alone, strong enhancement of the reactivity was observed in the presence of a small amount of a surfactant. The effect of surfactant was attributed to the stabiMzation of enol silyl ether by it. Versatile carbon-carbon bondforming reactions proceeded in water without using any organic solvents. Cross-linked Sc-containing dendrimers were also found to be effective and the catalyst can be readily recycled without any appreciable loss of catalytic activity.Aldol reaction of 1-phenyl-l-(trimethylsilyloxy) ethylene and benzaldehyde was also conducted in a gel medium of fluoroalkyl end-capped 2-acrylamido-2-methylpropanesulfonic acid polymer. A nanostmctured, polymer-supported Sc(III) catalyst (NP-Sc) functions in water at ambient temperature and can be efficiently recycled. It also affords stereoselectivities different from isotropic solution and solid-state scandium catalysts in Mukaiyama aldol and Mannich-type reactions. 

In contrast, Sodeoka and coworkers reported Pd-catalyzed asymmetric Mannich-type reactions (Scheme 47) [189-191]. In this case, the Pd(II)/tol-BI-NAP hydroxo complex 68 did not act as a Lewis acid, but formed the chiral Pd enolate generated from the silyl enol ether 65 through transmetalation to give the product 67b in high enantioselectivity (90% ee). The Pd(II)/tol-BINAP hydroxo complex 65a is effective to suppress the generation of strong protic acid HBF4 that catalyzed the racemic reaction. 

---