Amines aldol-type reactions

Aldol-type reactions of nitrones (303) occur with electron-deficient ketones, such as a-keto esters, a, 3-diketones, and trifluoromethyl ketones. These reactions are catalyzed by secondary amines. The use of chiral cyclic amines A1-A7 leads to a-(2-hydroxyalkyl)nitrones (304) in moderate yields and rather high optical purity (Scheme 2.120) (381). The mechanism of the nitrone-aldol reaction of iV-methyl-C-ethyl nitrone with dimethyl ketomalonate in the absence and presence of L- proline has been studied by using density functional theory (DFT) (544). 

By 1989 Mukaiyama had already explored the behaviour of phosphonium salts as Lewis acid catalysts. It was possible to show that the aldol-type reaction of aldehydes or acetals with several nucleophiles and the Michael reaction of a,j3-unsatu-rated ketones or acetals with silyl nucleophiles gave the products in good yields with a phosphonium salt catalyst [116]. In addition, the same group applied bisphosphonium salts as shown in Scheme 45 in the synthesis of ]3-aminoesters [117]. High yields up to 98% were obtained in the reaction of A-benzylideneaniline and the ketene silyl acetal of methyl isobutyrate. Various analogues of the reaction parteers gave similar results. The bisphosphonium salt was found to be superior to Lewis acids like TiCl and SnCl, which are deactivated by the resulting amines. 

The synthesis pathway of quinolizidine alkaloids is based on lysine conversion by enzymatic activity to cadaverine in exactly the same way as in the case of piperidine alkaloids. Certainly, in the relatively rich literature which attempts to explain quinolizidine alkaloid synthesis °, there are different experimental variants of this conversion. According to new experimental data, the conversion is achieved by coenzyme PLP (pyridoxal phosphate) activity, when the lysine is CO2 reduced. From cadeverine, via the activity of the diamine oxidase, Schiff base formation and four minor reactions (Aldol-type reaction, hydrolysis of imine to aldehyde/amine, oxidative reaction and again Schiff base formation), the pathway is divided into two directions. The subway synthesizes (—)-lupinine by two reductive steps, and the main synthesis stream goes via the Schiff base formation and coupling to the compound substrate, from which again the synthetic pathway divides to form (+)-lupanine synthesis and (—)-sparteine synthesis. From (—)-sparteine, the route by conversion to (+)-cytisine synthesis is open (Figure 51). Cytisine is an alkaloid with the pyridone nucleus. 

Cyclizative condensations based on aldol-type reactions which conform to the llbd pattern have also been developed. Condensation of bis(alkoxycarbonylmethyl)amines or bis(cyanomethyl)amines with benzil affords 3,4-diarylpyrrole-2,5-dicarboxylic add esters or nitriles. These reactions frequently lead to partial hydrolysis of at least one of the alkoxycarbonyl substituents and if the 3,4-diarylpyrrole is the ultimate objective, work-up involving complete hydrolytic decarboxylation is appropriate (equation 119) (6lLA(639)l02, 65JOC859). 

The silatropic ene pathway, that is, direct silyl transfer from an silyl enol ether to an aldehyde, may be involved as a possible mechanism in the Mukaiyama aldol-type reaction. Indeed, ab initio calculations show that the silatropic ene pathway involving the cyclic (boat and chair) transition states for the BH3-promoted aldol reaction of the trihydrosilyl enol ether derived from acetaldehyde with formaldehyde is favored [60], Recently, we have reported the possible intervention of a silatropic ene pathway in the catalytic asymmetric aldol-type reaction of silyl enol ethers of thioesters [61 ]. Chlorine- and amine-containing products thus obtained are useful intermediates for the synthesis of carnitine and GABOB (Scheme 8C.26) [62],... 

Aldol-type reactions.1 In the presence of 1 or of 9-BBN triflate and a tertiary amine, acetonitriles and benzaldehydes react to form aldol products. 

This condensation is essentially an aldol-type reaction of an aldehyde with the methylene group of an anhydride. The sodium salt may be replaced by other basic catalysts such as potassium carbonate oi tertiary amines. If the acid residue in the anhydride is not the same as that in the sodium salt, an equilibrium between these substances may occur before condensation. Thus, a mixture of acetic anhydride and sodium butyrate or a mixture of butyric anhydride and sodium acetate gives cinnamic acid and a-ethylcinnamic acid in the same ratio. ... 

The Knoevenagel condensation is a base-catalyzed aldol-type reaction, and the exact mechanism depends on the substrates and the type of catalyst used. The first proposal for the mechanism was set forth by A.C.O. Hann and A. Lapworth Hann-Lapworth mechanism) In 1904." When tertiary amines are used as catalysts, the formation of a p-hydroxydlcarbonyl Intermediate is expected, which undergoes dehydration to afford the product. On the other hand, when secondary or primary amines are used as catalyst, the aldehyde and the amine condense to form an Imlnlum salt that then reacts with the enolate. Finally, a 1,2-ellmlnatlon gives rise to the desired a,p-unsaturated dicarbonyl or related compounds. The final product may undergo a Michael addition with the excess enolate to give a bis adduct. 

The mechanism of the Mannich reaction has been extensively investigated. The reaction can proceed under both acidic and basic conditions, but acidic conditions are more common. Under acidic conditions the first step is the reaction of the amine component with the protonated non-enolizable carbonyl compound to give a hemiaminal, which after proton transfer loses a molecule of water to give the electrophilic iminium ion.°° This iminium ion then reacts with the enolized carbonyl compound (nucleophile) at its a-carbon in an aldol-type reaction to give rise to the Mannich base. 

A possible origin of this ring-opened alkaloid is from the methyl chanofruticosinate (238) which on oxidation provides the iminium ion 360. Hydrolysis of this iminium ion gives the presumably unstable carbinol amine 361 which could then undergo a retro-aldol-type reaction... 

Although ketones are not generally considered to be reactive carbonyl partners in MBH reactions (except under high pressure), the enhanced reactivity of certain a-diketones towards aldol-type reactions make them suitable partners for reaction with MBH-type vinyl carbanion equivalents. Indeed, a-keto esters have been found to possess the requisite reactivity and are very reactive electrophiles for the MBH reaction of acrylate, methyl vinyl ketone, acrylonitrile and acrolein in the presence of a tertiary amine, such as DABCO (Scheme 1.66). " ... 

Interestingly, although Knoevenagel demonstrated the effectiveness of amine bases in promoting aldol-type reactions and though, as noted above, he was particularly interested in pyridine, he overlooked this material s potential application to aldol condensations. It was left to Verley (1899) and Doebner (1900) to introduce successful modifications of the condensation in which pyridine appears to play a number of roles as a solvent, as a base, and assisting in the decarboxylation. 

Ru has been used frequently for obtaining chiral amine units, in asymmetric transfer hydrogenations of imine substrates [40], aldol-type reactions with imine electrophiles [41], and C-H bond arylation (see Chapter 4) [42]. There are very few reports in the literature on the use of ruthenium cattilysts for imine arylation. 

P-Pyranone is not a stable end product of the maltose degradation, but reacts in the presence or absence of amines to give a wide range of advanced products (8). In aqueous solution P-pyranone isomerizes to a certain extent to cyclopentenone (2) (Figure 5). The reversible transformation represents an intramolecular aldol type reaction. 

Aldol-type Reactions. In 1993, Kobayashi et al. first introduced Sc(OTf)3 as an effective catalyst in aldol reactions of silyl enol ethers with aldehydes in aqueous media. Since then, other rare earth metal triflates [RE(OTf)3] have been shown to be useful for the aldol reaction, including Y(OTf)3. In general, Y(OTf)3 is less active than Sc(OTf)3 for the aldol reaction. However, good yields of the direct aldol reaction can be obtained at room temperature when stoichiometric amounts of Y(OTf)3 and a tertiary amine are used (eq 1). ... 

The Knoevenagel reaction is a base-catalyzed aldol-type reaction that can occur through two possible mechanisms, depending on the type of base used. When Emil Knoevenagel made his initial discovery of this reaction, it was already known that benzaldehyde could condense with two equivalents of piperidine to provide the benzylidine bispiperidine aminal 1 Therefore, he proposed the intermediacy of an aminal (or imine) in the condensation. 

The Lewis acid-promoted reaction of acetals with trimethylsilyl (TMS) enolates is valuable for the synthesis of p-alkoxy carbonyl compounds, that is, O-alkylated aldols [44]. This aldol-type reaction is effectively catalyzed by (la) [7d, 43], trimethylsilyl iodide (MesSil) [45] and trimethylsilyl bis(fluorosulfonyl)amide (Me3SiN(S02P)2) [46]. Recently, bis (trifluoromethanesulfonyl) amine (HNTf2) has been found to catalyze the aldol-type reaction. A comparison of HNTf2 with Me3SiNTf2 (lb) in catalytic activity suggests that an initial protodesilylation of TMS enolates with HNTf2 forms (lb) as the actual catalyst [47] (Scheme 9.8). 

The potential of 9 as a chiral Lewis base catalyst was further demonstrated by application to the aldol reaction of trichlorosilyl enol ethers of ketones with aldehydes, which proceeded with high diastereo- and enantioselectivity [32], The observed stereospecificity suggested the intervention of a six-membered cyclic transition state (Scheme 7.17). Notably, enoHzation of cyclohexanone derivatives and aliphatic aldehydes appeared feasible by SiCLt with the assistance of amine base and 9, leading to the estabhshment of a new protocol for direct aldol-type reactions between ketones and aldehydes or two aldehydes (Scheme 7.18) [33]. 

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

Their previous screening of catalysts for of aldol reactions and Robinson annu-lations suggested the possibility that chiral amines might also be able to catalyze the Mannich reaction [30, 31]. Thus, screening of catalysts for Mannich-type reactions between N-OMP-protected aldimines and acetone revealed that chiral diamine salt 10, L-proline 11, and 5,5-dimethylthiazolidine-4-carboxylic acid (DMTC) 12 are catalysts of Mannich-type reactions affording Mannich adducts in moderate yields with 60-88 % ee. To extend the Mannich-type reactions to aliphatic imines, the DMTC 12-catalyzed reactions are performed as one-pot three-component procedures. The o-anisidine component has to be exchanged with p-anisidine for the one-pot reactions to occur. The DMTC 12-catalyzed one-pot three-component direct asymmetric Mannich reactions provide Mannich adducts in moderate yield with 50-86 % ee. 

---