Catalyzed amination reactions, protecting

Figure 14.23 Use of protecting groups in transaminase catalyzed amination reactions.

The -butylformamidine was used to protect and direct the course of metalation of secondary amines. It is formed from A, A-dimethyl-A -r-butylformamidine by an acid-catalyzed exchange reaction or from the A-r-butylimidate tetrafluorobo-rate salt and is cleaved with hydrazine. 

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

In the palladium-catalyzed allylic amination reaction, primary and secondary amines can be used as nucleophiles, whereas ammonia does not react. Therefore, many ammonia synthons have been developed, and a variety of protected primary allyl amines can now be prepared using azide, sulphonamide, phthalimide, di-f-butyl iminocarbonate ((Boc)2NLi), and dialkyl A-(rerr-butoxycarbonyl)phosphoramide anions as the nucleophile [20], An example of the use of ((Boc)2NLi) 30 as the amine nucleophile in the palladium-catalyzed allylic amination reaction is shown in Eq. (9). This reaction also illustrates the problem with the regioselectivity in the reaction as a mixture of the products 31-33 are obtained [21]. 

The use of a strong base in the palladium-catalyzed amination of aryl halides precludes the use of many substrates, such as those with aromatic nitro groups or enolizable hydrogens, esters other than tert-butyl esters, and many substrates with base-sensitive stereochemistry such as some protected amino acids and heterocyclic substrates [191]. Thus, conditions that employ milder bases are required. A solution that involves reaction temperatures as low as those used for reactions conducted with sodium tert-butoxide has not been developed. However, carbonate and phosphate bases can be used with certain catalysts at reaction temperatures comparable to those of reactions involving the first- and second-generation catalysts. 

Several 2 -deoxyadenosine-amine adducts that have been implicated in carcinogenesis were prepared via the Pd-catalyzed amine arylation reaction as reported by Lakshman and co-coworkers [135]. For example, the coupling of the protected 6-bromoadenosine derivative below was achieved in good yield using the 4/Pd-catalyst, Eq. (168). 

The asymmetric synthesis of indolizidine alkaloids is described utilizing a palladium-catalyzed amination process. Ionization of an allylic carbonate provides a symmetrical rr-allyl palladium complex, subsequent reaction with a protected homoallylamine gave the product in 93% yield and >99.5% ee (eq 5). ... 

Hi. Intermolecular reactions of carbamates. Carbamates possess a more electron-rich nitrogen atom than amides or sulfonamides, and thus participate more readily in palladium-catalyzed aminations of aryl halides. For example, f-butyl carbamate has been shown to react with aryl halides to form f-Boc protected anilines (equation 34)68. The catalyst... 

Aripiprazole is used for the treatment of schizophrenia. The key intermediate, phenylpiperazine 56, was prepared by conventional methodology via a ring closure reaction from 2,3-dichlorophenol in six steps with an overall yield of 9%. Alternatively, phenyl-piperazine 56 was prepared via a Pd-catalyzed amination of benzyl protected 4-bromo-2,3-dichlorophenol 54 with piperazine. The coupling reactions proceeded regio-selectively to provide excellent yield of phenyl piperazine [136-140]. 

Hbhne et al. reported a substrate protection strategy that enhanced both the rate and the enantioselectivity of transaminase catalyzed kinetic resolution reactions [32]. The co transaminase catalyzed resolution of the pharmaceutically important syn thons 3 amino pyrrolidine 53 and 3 aminopiperidine 54 was imp roved by the addition of protecting groups to the substrate amines. Reaction rates were improved by up to 50 fold, and product ee was improved from 86 to 99% (Figure 14.23). 

In 2008, Zhang, Ying, and co-workers reported an organocatalytic p-amination reaction of a,p-unsaturated aldehydes with nitrosobenzene catalyzed by an NHC. Specifically, the addition of NHC to a,p-unsaturated aldehyde generates a homoenolate intermediate that reacts with nitrosobenzene to afford Af-phenylisoxazolidin-5-ones, followed by an acid-catalyzed esterification and Bamberger-type rearrangement to produce Af-PMP-protected p-amino esters. A preliminary study on the enantioselective reaction of... 

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