N Boc protected imine

Given the rich chemical diversity accessible from aminohydrazones. Rueping investigated the imino-azaenamine reaction of N-Boc protected imines and... 

Glucosaminylurea derivahve 198 was also applied to catalyze the enantioselec-hve Mannich addition [72] of a silyl ketene acetal to the N-Boc-protected imine naphthalene-2-carbaldehyde resulting in the desired P-amino acid ester (Scheme... 

Scheme 7.13 Catal)4ic asymmetric cross-aza-benzoin reactions of aliphatic aldehydes with N-Boc-protected imines reported by Rovis.

Synthetically useful N-Boc-protected imines are also applicable to the amine-catalysed Mannich reaction. In 2008 List and coworkers reported the proline-catalysed asymmetric Mannich reaction of highly reactive acetaldehyde with N-Boc-protected imines (Scheme 17.9). With 20 mol% of l-proline the Mannich adducts were obtained with excellent enantioselectivity, albeit in low to moderate yields. On the other hand, the reaction using 2 mol% of (S)-3 gave the desired Mannich adducts in good yield with virtually perfect enantioselectivity. In the reaction catalysed by (S)-3, side reactions were completely suppressed and no byproducts were formed consequently, the turnover number of this reaction was significantly improved. 

N-Boc-protected imines were also applicable to the diastereo- and enan-tioselective Mannich reaction of aliphatic aldehydes other than acetaldehyde. The highly q n-selective asymmetric Mannich reaction catalysed by L-proline was reported by List and coworkers in 2007. In contrast, (5)-3 promoted the antz-selective asymmetric Mannich reaction between aliphatic aldehydes and iV-Boc-protected imines and the catalyst loading could be reduced to 1 mol% without loss of stereoselectivity. By using N-Cbz-protected aminoacetaldehyde instead of simple aliphatic aldehydes, both syn- and antz-vicinal diamines were synthesised by simply changing the catalyst through the above-mentioned amine-catalysed Mannich reactions, respectively. ... 

In almost the same period, Uraguchi and Terada reported the direct Mannich reaction of N-Boc-protected imines with acetyl acetone (Scheme 11.2) [5]. In their direct Mannich reaction, phosphoric acid also worked as a dual functional catalyst the Br0nsted acidic moiety of phosphoric acid catalyst Ic activated aldimines 5, and the Lewis basic site (phosphoryl oxygen) interacted with the O-H proton of the enol form of 6. As a result, the reaction proceeded under a chiral environment created by phosphoric acid 1, acetyl acetone, and aldimine through hydrogenbonding interactions to furnish optically active products 7. 

In 2010, Monge et al. reported a one-pot tandem reaction by combining bifunctional thiourea and Au complex [77], affording dihydropynole derivatives in moderate yields and high enantioselectivities. The reaction was based on a bifunctional thiourea-catalyzed Mannich-type reaction and a subsequent Au-catalyzed alkyne hydroamination and isomerization of propargylated malononitrile and N-Boc-protected imines (Scheme 9.72). Notably, acidic additive proved cracial to prevent deactivation of the gold catalyst and enhance the reactivity and selectivity. 

Very recently. Barber et al. reported a tandem reaction combining bifunctional urea and Au(I) salt for the asymmetric synthesis of valuable tetrahydropyridine derivatives [80]. This reaction consisted of a urea-promoted nitro-Mannich reaction of an alkyne-tethered secondary nitroalkane to N-Boc-protected imines and an Au(I) complex-catalyzed intramolecular hydroamination and isomerization (Scheme 9.75). Notably, since the inherent Lewis basic tertiary amine-tethered urea would deactivate the Au catalyst, the reaction system was acidified by additional DPP before addition of an Au catalyst to ensure the success of the overall process. 

An conceptually different approach using the chiral Bronsted acid catalyst 306 (Equation 33) was devised by Johnston [192]. This catalyst effected the stereoselective addition of nitroalkane 305 to N-Boc-protected imine 304 to provide the syn adduct 307 in 7 1 dr and 90 % ee. Interestingly, the pfC of 306 has been determined to be 5.8, thus indicating that this catalyst is not sufficiently acidic to protonate the imine 304 [193]. The inherent simplicity in the catalyst structure 306 is truly remarkable, given its ability to effect control over the stereochemical outcome of such addition reactions. 

To demonstrate the feasibility of organic synthesis using this support, the authors immobilized a N-Boc protected glycin (22) on the support (Scheme 7.5). After deprotection imine formation readily occurs with an excess of benzaldehyde. The product was then subjected to a Staudinger reaction with phenoxyacetylchlor-ide to yield the polymer supported / -lactam (26) which could be released to give the yS-lactam (27) with TEA in methanol. 

Scheme 6.182 Representative products obtained from the 222-catalyzed aza-Henry reaction of N-Boc-protected aromatic imines with nitromethane and nitroethane.

Scheme 6.184 Product range of the aza-Henry reaction of N-Boc-protected aiiphatic and aromatic imines catalyzed by N-suifinyi urea 227.

Imines are, preferably, used in the N-Boc-protected form less electrophilic N-allyl and N-benzyl imines gave unsuccessful results [36], The tert-butyldimethyl-silyl ketene acetals are the most suitable silyl ketene acetal substrates. It should be added that a low temperature is required to suppress an undesired uncatalyzed reaction that leads to racemates. 

In addition to chiral PTCs, cinchona-based thioureas have also been proved to serve as catalysts for nitro-Mannich reactions. In 2006, Ricci and coworkers first reported that the quinine-based thiourea 40 (20mol%) can catalyze the aza-Henry reaction between nitromethane and the N-protected imines 93 derived from aromatic aldehydes [40]. N-Boc-, N-Cbz-, and N-Fmoc protected imines gave the best results in terms of the chemical yields and enantioselectivities (up to 94% ee at —40°C) (Scheme 8.30). 

Alternatively, it is also possible to use in situ generated N Boc imines as electro philes [117]. When a carbamoyl sulfones are treated under the rhodium catalyzed addition of arylboronic acids, the imine is formed in situ, and the nucleophilic addition proceeds smoothly to generate the N Boc protected amine (Scheme 1.34). 

Aminals, compounds having two amino groups bound to the same carbon atom, are represented in many medicinal agents having versatile therapeutic action, such as proteinase inhibitors and neurotensins. Antilla and coworkers developed an en antioselective synthesis of protected aminals from the amidation reaction of N Boc imines with a series of sulfonamides catalyzed by chiral phosphoric acids (Scheme 3.54a) [111]. In this novel enantioselective transformation, phosphoric acid 9 exhibited excellent catalytic activity and enantioselectivity in addition to N Boc aromatic imines. The enantioenriched aminal products were stable upon storage neither decomposition nor racemization was observed in solution over several days. The same research group reported the enantioselective amidation reaction of N Boc aromatic imines with phthalimide or its derivatives (Scheme 3.54b) [112]. 

To facilitate the use of p-amino-aldehydes or -alcohols, obtained through asymmetric Mannich reactions, List et al. provided a procedure to use N-Boc-protected, preformed imines (21, 22) (Scheme 5.13a). While this method requires the formation of the imines, it provides products that can be deprotected under mild conditions, as compared to the widely used and robust PMB-protection in these reactions. Even acetaldehyde is applicable as aldehyde source (Scheme 5.13b). The p-amino-aldehydes (23, 24) obtained from this transformation are extremely valuable building blocks in organic synthesis, making this discovery one of the most useful applications of proline catalysis to date. 

N-acyl imines [144]. A slightly modified chiral Br0nsted acid 185 was found to catalytically induce addition of indoles to N-Boc-protected enecarbamates ISK) in high yields and enantioselectivities (Scheme 8.51) [145]. In a related study, Zhou demonstrated the use of a-aryl enamides to obtain optically enriched tertiary amine products [146]. 

Chiral two-center phase-transfer catalyst 202 possessing 2,6-disubstituted cyclohexane spiroacetal catalyzes the syn-selective Mannich-type reaction of glycine Schiff base 186 with N-Boc-protected aromatic imines as weU as enoUzable aUcyl imines (201) in high yields with moderate to good enantioselectivities (Scheme 28.24) [103],... 

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