Imino aldol

Similarly, the addition of an amine to the enone moiety can initiate a domino process leading to substituted diaminocyclohexanes [34]. In this transformation an imino aldol reaction occurs. The observed stereoselectivity was again >95 5, and the yield between 51 % and 69% in all cases. 

As expected, some sequences also occur where a domino anionic/pericyclic process is followed by another bond-forming reaction. An example of this is an anionic/per-icyclic/anionic sequence such as the domino iminium ion formation/aza-Cope/ imino aldol (Mannich) process, which has often been used in organic synthesis, especially to construct the pyrrolidine framework. The group of Brummond [450] has recently used this approach to synthesize the core structure 2-885 of the immunosuppressant FR 901483 (2-886) [451] (Scheme 2.197). The process is most likely initiated by the acid-catalyzed formation of the iminium ion 2-882. There follows an aza-Cope rearrangement to produce 2-883, which cyclizes under formation of the aldehyde 2-884. As this compound is rather unstable, it was transformed into the stable acetal 2-885. The proposed intermediate 2-880 is quite unusual as it does not obey Bredf s rule. Recently, this approach was used successfully for a formal total synthesis of FR 901483 2-886 [452]. 

Amberlyst 15 DRY, a sulfonic cation exchange resin with a large surface area, was found to catalyze the imino aldol reaction of imines with ketene silyl acetals to provide racemic y9-amino esters in yields up to 99% [104]. 

Kobayashi S, Akiyama R, Moriwaki M, Three-component or four-component coupling reactions leading to 6-lactams, Facile synthesis of y-acyl-6-lactams from silyl enolates, a, /l-unsaturated thioesters, and imines or amines and aldehydes via tandem Michael-imino aldol reactions, Tetrahedron Lett., 38 4819—4822, 1997. 

Kobayashi et al. also published experiments in which they applied polymer-bound rare earth metal triflates [9], The performance of Lewis acid-catalyzed imino-aldol reactions at the solid phase was realized by linking the silyl enolethers u5-(4 -chloromethylphenyl)pentylpolystyrene[10]. 

Lewis acid-catalyzed tandem Michael imino-aldol reactions enable the one-pot synthesis of 7-acyl-(5-lactams from a, j6-unsaturated thio-esters, silyl enolates and imines [15]. For the initial Michael addition, the combination of SbClj with Sn(OTf>3 (5 mol %) proved to be efficient. However, after the addition of the imino compound the iminoaldol product was isolated in moderate yield. For the enhancement of turnover and yield, Sc(OTf)3, once again proved to be the Lewis acid of choice (Scheme 4, 15 16 = 81 19, 94%). 

A novel type of polymer-supported Lewis acid, a microencapsulated Lewis acid catalyst was investigated by Kobayashi [117]. Sc(OTf)3 was immobilized on to polystyrene by microencapsulation—Sc(OTf)3 is physically enveloped by polystyrene and stabilized by the interaction between the jr-electrons of benzene rings and vacant orbitals of the Lewis acid. This microencapsulated catalyst was used successfully in several Lewis acid-catalyzed carbon-carbon bond-forming reactions (imino aldol, aza Diels-... 

Smith et al. described a study of the hydroxylation of enolates derived from 1,3-dioxin vinologous esters (127) with (63a) (88JOC4314). The regioselectivity depended on both the counterion and the ester substitution pattern, for example, the lithium enolate of (127 R = H) gave primarily the a-hydroxylated product (128) while the sodium enolate afforded mixtures of both (128) and (129). Particularly noteworthy is the fact that the sodium enolate of (127 R = Me) gave (129) while the lithium enolate gave (128) (Equation (28)). Moreover, imino-aldol products (18-26%) were isolated for the lithium enolates, but not with the sodium enolates. 

The potassium enolate of camphor (130) is oxidized with oxaziridine (63a) at — 78 °C to afford a-hydroxyketone (131) in 85% yield (Equation (29)) <84JOC324i>. As mentioned earlier lower yields were observed for the lithium enolate because of the imino-aldol side-reaction. The exclusive formation of the endo product is consistent with attack of the oxaziridine from the sterically least-hindered face of the enolate and is a general phenomena for these reagents. 

Yields for the hydroxylation of the lithium enolate of Y-r-butoxycarbonyl-L-pyroglutamate (146) to (147) with 2-(p-toluenesulfonyl)-3-phenyloxaziridine (63d) are reported to vary from 30% <92TL1509> and 61% <88TL329>. Considerable amounts of the imino-aldol product (148) were also isolated (Equation (35)) <92TL1509>. 

The same anchor group is realized on a 5-(4 -chloromethylphenyl)-pentyl-PS/DVB (CMPP resin). R is introduced as R-COSK. Lewis acids can be used during synthesis without decomposition or deactivation (e.g. Sc(OTf)3-catalyzed imino aldol reaction) [322]... 

However, a catalyst made by microencapsulating scandium triflate in polystyrene was easy to recover and reuse with no loss in activity by filtration. In the imino aldol reaction (6.11), its activity was greater than that of the unencapsulated counterpart, maintaining activity (90% yields) after seven cycles 55 (Many Lewis acids do not work well in this reaction.)... 

Phosphoric acid immobilized on silica (H3P04/Si02) catalyst has been widely exploited over many years [128-130]. It has also been used as a reusable catalyst for solvent-free imino-aldol three-component coupling reaction in recent years [131]. 

Scheme 16. Imino aldol reaction (flow system)...

Aldol and imino-aldol reactions. A Yb complex prepared from YbfOTflj and a C -symmetric a,a -bistriflamidobibenzyl has been used in the Mukaiyama aldol reaction," resulting in moderate asymmetric induction. Imines are activated toward enol derivatives, such as ketene silyl ethers. iV-(a-aminoalkyl)benzotriazoles are suitable surrogates of imines. One-pot syntheses of p-amino esters and ketones can also be achieved. 

MPEG with proline PEG with proline =5,000" =4,600" =0.2" =0.4" DMF", DMSO", MeCN", CH2CI2", toluene", acetone" En an tios elective aldol and imino aldol condensations Precipitation (diethyl ether) (r) [140]... 

An imino aldol reaction catalyzed by a cation-exchange resin [31], and uncatalyzed aldol addition of enoxysilacyclobutanes to aldehydes [32] have also been reported. 

Imino aldol reaction of ketene silyl acetals with the chiral imine derived from tartaric acid 83 in the presence of a cation-exchange resin provided the corresponding /i-amino esters 84 in a good yield and high diastereose-lectivity [68]. The esters 84, thus obtained, were subjected to the Grignard reagent which promoted S-lactam formation. After a sequence of reactions compound 84 was transformed into the ester 85 [68] which in the past was... 

Lewis Acid Catalyzed Reactions. S amarium iodide catalyzes several transformations by presumably acting as a Lewis acid. For example, it is an efficient catalyst for the imino-Diels-Alder (eq 70) and for imino-aldol reactions. Tandem Mukaiyama-Michael-aldol (eq 71) and Michael imino-aldol processes have also been reported. ... 

Certain chemical reactions are common to the formation of many types of alkaloids (Geissman and Crout, 1969). Among these are decarboxylation, Schiff-base formation, Mannich-base condensation, and imino-aldol-type condensations. 

In 2010, two independent studies involving Michael-incorporated domino reaction for the synthesis of multifunctionaUzed piperidines were reported. First, 2,6-disubstituted piperidines 245 were prepared through a domino imino-aldol/aza-Michael reaction, which involved preparing the enolate of a-arylmethylidene-fS-keto ester 243 and reacting this with 2-aryl-N-sulfonylaldimines 244 (Scheme 7.53)... 

The memory of chirality concept has been employed in a strategy for the synthesis of chiral a,/ -diamino- and a-amino-/ -hydroxy ester derivatives via asymmetric imino-aldol and aldol reactions, starting from protected aminoesters. The route can 0 be extended to the enantioselective synthesis of aziridines. 

Activation of C=N Double Bonds. TBDMS triflate has been used to promote additions to, and for the isomerization of, a number of systems containing carbon-nitrogen double bonds. TBDMS triflate is the optimal silyl triflate to promote the Mukaiyama-type vinylogous imino-aldol (Mannich-type) addition of 2-[(f-butyldimethylsilyl)oxy]furan to the IV-benzyl imine derived from (25)-2,3-0-isopropylideneglyceraldehyde (eq 36). ... 

There are surprisingly few common approaches to the lupin indolizidines and their quinolizidine homologs despite their structural similarity. One such approach was recently reported by Cutter et al., who used imino—aldol reactions of phenyl 5-chlorovalerate (992) as the starting point for the synthesis of both (—)-tashiromine (ent-929) and (—)-epilupinine (ent-921) (Scheme 123). " The addition of the hthium enolate of 992 to the (S)-N-sulfinylimine (- -)-993 proved to be highly diastereoselective, giving a 78% yield of the adduct (- -)-994 and its (S,S)-isomer (+)-995 in a ratio of 16 1. The stereochemistry of 994 was confirmed by X-ray diffraction. 

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