Imines electrophilicity

Reactions of the allylic position of alkenes with carbonyl or imine electrophiles are known as Prins reactions and have been discussed in previous sections (3.2.9). More examples of similar Alder-ene-type reactions (the Prins reaction) will be discussed in Chapter 8. 

Among the nucleophilic monomers studied are 5,6-dihydro-4T/-l,3-oxazines, cyclic phosphites and phosphonites, iminodioxolanes, and imines electrophilic monomers include... 

The Pictet-Spengler reaction, the cyclization of an electron-rich aryl or heteroaryl group onto an imine electrophile, is the established method for the synthesis of tetrahydroisoquinoline and tetrahydro-/ -carboline ring systems. Catalytic asymmetric approaches to these synthetically important structures are mostly restricted to asymmetric hydrogenations of cyclic imines [77, 78]. In a noteworthy... 

Another catalytic application of chiral ketene enolates to [4 + 2]-type cydizations was the discovery of their use in the diastereoselective and enantioselective syntheses of disubstituted thiazinone. Nelson and coworkers described the cyclocondensations of acid chlorides and a-amido sulfones as effective surrogates for asymmetric Mannich addition reactions in the presence of catalytic system composed of O-TM S quinine lc or O-TMS quinidine Id (20mol%), LiC104, and DIPEA. These reactions provided chiral Mannich adducts masked as cis-4,5 -disubstituted thiazinone heterocycles S. It was noteworthy that the in situ formation of enolizable N-thioacyl imine electrophiles, which could be trapped by the nucleophilic ketene enolates, was crucial to the success of this reaction. As summarized in Table 10.2, the cinchona-catalyzed ketene-N-thioacyl-imine cycloadditions were generally effective for a variety of alkyl-substituted ketenes and aliphatic imine electrophiles (>95%ee, >95%cis trans) [12]. 

However, cycloaddition involving aryl a-amido sulfone afforded modestly attenuated yields due to competing formation of the P-lactam adducts, possessing the unanticipated trans diastereoselection that was not observed for alkyl imine electrophiles (Eq. (10.1)). 

Moreover, the reaction of methyl acrylate and N nosylbenzaldimine, which was promoted by DABCO in the absence of la, was homogeneous in CHCI3 and proved amenable to kinetic analysis. The reaction was monitored by GC analysis, and was found to display a first order kinetic dependence on both DABCO and methyl acrylate. In contrast to the MBH reaction, rate saturation with respect to the imine electrophile was observed. A prominent primary kinetic isotope effect was also observed ka/ko = 3.81) by comparison of initial reaction rate of methyl acrylate with separate reactions of a deuterio methyl acrylate, strongly suggesting that deprotona tion of the a H(D) was rate limiting. 

Chen and coworkers employed the cinchona alkaloid-derived catalyst 26 to direct Mannich additions of 3-methyloxindole 24 to the A-tosylimine 25 to afford the all-carbon quaternary center of oxindole 27 with good enantioselectivity (84% ee) [22]. The outcome of this Mannich reaction is notable in that it provided very good selectivity for the anti diastereomer (anti/syn 94 6). The mechanism of asymmetric induction has been suggested to involve a hydrogen bonding network between the cinchona alkaloid 26, the oxindole enolate of 24, and the imine electrophile 25 (Scheme 7). Asymmetric allylic alkylation of oxindoles with Morita-Baylis-Hillman carbonates has been reported by the same group [23]. 

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. 

The above in situ strategy was also applied to Schiff base substrates (in Ueu of aldehydes or ketones), affording azuidination products in fair yield, moderate dr, and outstanding enantioselectivity [44, 45]. The specific examples of benzyUdene transfer illustrated in Table 4 confirm that electron-poor (entry 1), electron-rich (entry 4), aliphatic (entry 2), and a,p-unsaturated groups are tolerated in the A-SES imine electrophiles. As shown in Scheme 17, the utility of the method was showcased in an unconventional preparation of paclitaxel side-chain 49 that ultimately begins with 3-furfural. The optically pure heterocyclic aziridine 48 was obtained as an inconsequential diastereomeric mixture by the trio of coordinated phase transfer, achiral rhodium, and chiral sulfide catalyses, albeit in the antipodal series (see ent-47) subsequent conversicm to the target amido ester was by way of standard manipulations [130]. 

Metal carbenes generated from the reaction of paUadium or ruthenium catalysts with a-diazo esters have also been found to be electrophilic enough to undergo electrophilic aromatic substitution with pyrrole. The Ru-catalyzed reaction leads to a 2-alkylated pyrrole upon rearomatization. In contrast, the Pd car-bene, in combination with a phosphoric acid cocatalysL generates an intermediate enolate, which subsequently combines with an imine electrophile to furnish a three-component adduct with good enantioselectivity and moderate S37i/a -selectivity (eq 6). 

In this respect, the imine electrophile and the nucleophile are fixed in a spatial orientation, which is necessary for the stereoselective C-C bond formation, making the addition of a chiral catalyst unnecessary. As an example, here we wish to highlight only the most recent examples of the incorporation of an intramolecular Mannich reaction in the enantiose-lective total synthesis of L-Lys-derived alkaloids, namely, (-)-hippodamine (267) and (-)-lyconadine C (256). The latter was accessible from the bicyclic intermediate 252 in a tandem ketal removal/Mannich reaction to furnish the tricyclic core structure 254 (Scheme 11.53) [160],... 

Substrate control is another approach for synthesis of anti-Mannich products. The proline-catalyzed Mannich reaction between aldehydes and pre-formed N-Boc-imines affords the syn-Mannich product with exceptionally high diastereoselectivi-ties and enantioselectivities [44]. In contrast, the reaction of aldehyde 83 with N-Boc-imines, generated in situ from the stable a-amido sulfone 84, catalyzed by the commercially available chiral secondary amine 85 provides antt-Mannich product 86 with 96% ee (Scheme 28.7a) [45]. Cyclic iminoglyoxylate 88, readily prepared from commercially available starting materials, is a useful alternative imine electrophile its configuration is locked in the (Z)-form. Because of the (Z)-configuration of imine 88, the anti-selective Mannich reaction proceeds (Scheme 28.7b) [46]. 

---