Lewis bases enol formation

Lewis-Base Catalysis via Intermediate Formation of a Chiral Zwitterionic Enolate... 

Based on the same strategy, Denmark and coworkers developed a vinylogous aldol reaction using enolate activation with a catalyst derived from SiCl4 and dimeric phosphoramide 47 [24,25]. This strategy relies on the observation that not all Lewis acid - Lewis base interactions diminish the Lewis acidity [26-28]. Due to the formation of a pentacoordinated silicon cation (48), both the enolate and the substrate can be assembled in a closed transition state, giving rise to the observed high selectivities (Scheme 19) [29,30]. 

Fig. 12.5. Electrophilic side chain bromination of acetophenone (A). With catalytic amounts of AlCL, the acetophenone is transferred into the enol iso-A, while stoichiometric amounts of AlClj lead to the formation of acetophenone in the form of the Lewis acid/Lewis base complex D. So in the presence of catalytic amounts of AlCl the enol iso-A is brominated (- F, "phenacyl bromide") in the presence of stoichiometric amounts of AlCl3, however, bromination of the aromatic moiety of D takes place (-> meto-bromoaceto-phenone, cf. Section 5.2.1).

Recent developments in the field have also identified novel mechanistic pathways for the development of catalytic, asymmetric aldol processes. Thus in addition to Lewis acid catalysts that mediate the Mukaiyama aldol addition by electrophilic activation of the aldehyde reactant, metal complexes that lead to enolate activation by the formation of a metalloenolate have been documented. Additionally, a new class of Lewis-base-catalyzed addition reactions is now available for the asymmetric aldol addition reaction. 

Examination of electronic and thermodynamic factors in the aforementioned conventional enolate formation revealed that steric factors were of fundamental importance in fhe reaction. One alternative is to complex a carbonyl compound with a bulky Lewis acid (Fig. 6.13). Bulky aluminum reagents usually form relatively stable 1 1 complexes irreversibly wifh carbonyl compounds. We first hypothesized that even in the presence of a strong base (LDA or LTMP), a steric environment applied in the aluminum-carbonyl complex would kinetically adjust site-selective deprotonation of carbonyl compounds which offer multiple sites for enohzation and kinetically stabilize fhe resulting bulky enolates by retarding the rate of proton transfer or other undesirable side reactions. These fundamental considerations found particular application in fhe formation and reaction of novel aluminum enolates. 

France S, Shah MH, Weatherwax A, Wack H, Roth JP, Lectka T (2(X)5) Bifunctioneil Lewis acid-nucleophile-based asymmetric catalysis mechanistic evidence for imine activation working in tandem with chiral enolate formation in the synthesis of p-lacttuns. J Am Chem Soc 127 1206-1215... 

A second distinct process disclosed by Denmark involves the Lewis base-catalyzed addition of enol trichlorosilanes 36 to aldehydes (Eq. 3) [30b]. Remarkably, despite the fact that the imcatalyzed addition of such enol silanes to aldehydes is rapid at -78 C, the use of optically active phosphoramides substantially accelerates the addition reaction and leads to the formation of optically active products. As a consequence of stereochemical studies involving substituted enol trichlorosilanes, Denmark has proposed a hexacoordinated silicon atom as the organizational locus about which enolate and aldehyde are arranged in a cyclic array 37. 

In an important experiment, Mukaiyama and coworkers enolized carbonyl compounds under much milder conditions (low temperatures) with dialkylboryl triflate and a sterically hindered tertiary amine base such as 2,6-lutidine (2,6-dimethylpyridine) or diisopropylethylamine (DPEA).95-97 Less-hindered bases led to formation of a stable borane-amide complex (Lewis acid-Lewis base) and prevented the reaction with the carbonyl compound. Masamune et al,98 and Evans et a/.99100 carried out a study to investigate the reasons for the selective enolate formation. They showed that it depends on the boron ligand, base, solvent and the group attached to the carbonyl moiety. Ketones give (Z)-enolates with often excellent selectivity, whereas r-butyl thiolates give selectively the ( )-enolates (equations 32 and 33).100 101 Evans suggests that reactions with 9-BBN triflate are often under thermodynamic control.15 In equation... 

Conjugate addition reactions, including the Robinson annulation, which make use of reactive Michael acceptors such as methyl vinyl ketone, can suffer from low yields of the desired adduct. The basic conditions required for enolate formation can cause polymerization of the vinyl ketone. Further difficulties arise from the fact that the Michael adduct 42 and the original cyclohexanone have similar acidities and reactivities, such that competitive reaction of the product with the vinyl ketone can ensue. These problems can be minimized by the use of acidic conditions. Sulfuric acid is known to promote the conjugate addition and intramolecular aldol reaction of 2-methylcyclohexanone and methyl vinyl ketone in 55% yield. Alternatively, a silyl enol ether can be prepared from the ketone and treated with methyl vinyl ketone in the presence of a Lewis acid such as a lanthanide triflate" or boron tri fluoride etherate (BF3 OEt2) and a proton source to effect the conjugate addition (followed by base-promoted aldol closure). 

It should be clear that since the oxygen of the carbonyl is a Lewis base it can be protonated and keto-enol tautomerism is therefore also promoted by add Thus, as shown in Figure 5.47, protonation of the oxygen of the carbonyl and subsequent proton loss from the carbon a to the carbonyl results in enol formation (and, because this is an equilibrium process, vice versa). 

Methylenation of carboxylic acid derivatives The Tebbe reagent 3 is extremely valuable as a reagent for the methylenation of carboxylic acid derivatives, which is generally unsuccessful using phosphorus ylides. Esters and lactones are readily transformed into enol ethers (Table 4.3), especially when a Lewis base such as THE is present in the reaction mixture. In the methylenation of a,j8-unsaturated esters, the internal olefin is not involved in the reaction, and the configuration of the double bond is maintained (entry 4). When carbonyl compounds bearing a terminal double bond are subjected to the methylenation, significantly lower yields are observed (entries 6 and 11), which may be attributable to competitive formation of a titanacycle from titanocene-methylidene 4 and the terminal olefin. 

In addition to the range of asymmetric routes toward 13-lactone and (3-lactam scaffolds, Lewis bases have been used to access a variety of other important four-membered heterocyclic classes via formal [2+2] cycloadditions. In this section, the use of tertiary amines or NHCs to generate ammonium or azolium enolates, respectively from ketenes and their subsequent application toward the formation of other synthetically interesting heterocycles, will be discussed. A series of reports concerning the use of sulfenes, the sulfonyl equivalents of ketenes, in Lewis base-catalyzed asymmetric [2+2] cycloadditions will also be detailed. 

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