Palladium, benzyl catalyst acylation

In order to obtain a commercially viable process it is necessary to racemize the unwanted amine enantiomer, preferably in situ in a so-called DKR. The paUadium-on-charcoal-catalyzed racemization of amines was first reported by Murahashi et al. [23] and was later combined with Upase-catalyzed acylation, to afford a DKR, by Reetz [24] and others [25]. We were able to achieve a DKR of a-methyl benzyl-amine by performing the hpase-catalyzed acylation in the presence of a palladium nanoparticle catalyst (Scheme 6.10). 

The complete transformation of a racemic mixture into a single enantiomer is one of the challenging goals in asymmetric synthesis. We have developed metal-enzyme combinations for the dynamic kinetic resolution (DKR) of racemic primary amines. This procedure employs a heterogeneous palladium catalyst, Pd/A10(0H), as the racemization catalyst, Candida antarctica lipase B immobilized on acrylic resin (CAL-B) as the resolution catalyst and ethyl acetate or methoxymethylacetate as the acyl donor. Benzylic and aliphatic primary amines and one amino acid amide have been efficiently resolved with good yields (85—99 %) and high optical purities (97—99 %). The racemization catalyst was recyclable and could be reused for the DKR without activity loss at least 10 times. 

The second way differs little from the previous, and consists of the initial formation of 4-hydroxy-3-acetoxybromoacetophenone (11.1.27) by acylation of methyl ester salicylic acid using bromoacetyl chloride. This is also reacted with iV-benzyl-tcrt-buty-lamine, and the resulting product (11.1.28) is completely hydrolyzed by lithium aluminum hydride into the (V-benzyl substituted albuterol (11.1.29), the benzyl group of which is removed by hydrogen over a palladium catalyst to give the desired albuterol (11.1.26) [31]. 

Carbenicillin Carbenicillin, [25 -(2a,5a,6j3)]-3,3-dimethyl-7-oxo-6-(2-carboxy-2-phenylacetamido)-4-thia-l-azabicyclo[3.2.0]-heptan-2-carboxylic acid (32.1.1.32), is synthesized by direct acylation of 6-APA in the presence of sodium bicarbonate by phenylmalonic acid monobenzyl ester chloride, which forms the benzyl ester of carbenicillin (32.1.1.31), the hydrogenolysis of which using palladium on carbon or calcium carbonate as catalyst gives the desired product (32.1.1.32) [51-58]. 

The added advantage of the C (1 )-stannylated glycals is their abUity to participate in palladium-catalyzed coupling reactions with organic halides, a process independently reported by Beau [75] and Friesen [81]. Vinyl stannane 237 can be benzylated, allylated or acylated provided that appropriate catalysts are used [75,77] and representative examples are given in Scheme 59. The C-arylation of... 

Aryl halides can be dehalogenated with triethylsilane in the presence of a palladium catalyst. The method is versatile and can also be used for the reduction of acyl chlorides to aldehydes, or benzylicbromides to the corresponding hydrocarbons. If different types of halides are present in the molecule, selective dehalogenation takes place. Thus, an aryl iodide can be reduced in the presence of a chloride, and benzylic bromide is reduced more easily than an aryl bromide. Finally, the method is even able to distinguish between two aryl bromides in the same molecule (Scheme 4.41)67. 

Other olefinic ketones have been reduced selectively at room temperature and atmospheric pressure over a platinum or palladium catalyst to give good yields of the ketones, namely, 5-methyl->heptanone (94%), diisobutyl ketone (100%), and a-benzylacetophenone (81-95%). Selective hydrogenations of some 3-alkyl-2-cyclohexenones have been carried out over palladinized charcoal in essentially quantitative yields. Preparation of platinum catalyst has been described. Many olefinic ketones prepared by the aldol condensation or by acylation of olefins have been hydrogenated however, the yields are not always stated. Benzalacetone, CgHsCHasCHCOCHj, is selectively reduced to benzyl-acetone in a 63% yield by the action of sodium amalgam in acetic acid-alcohol solution. ... 

The homo-Reformatsky reagent derived from the benzyl ester of N-Boc protected P-iodoalanine (Ch. 5, p. 204) reacts under sonication with various electrophiles. With acyl chlorides in the presence of a palladium catalyst, protected y-keto a-amino acids are obtained without racemization (Fig. 28).i An experiment is described in Chapter 9 (p. 348). 

The benzyl ester of N-Boc protected p-iodoalanine reacts under sonication with the zinc-copper couple in benzene containing small amounts of dimethyl acetamide, to give a homo-Reformatsky reagent (Eq. 37, see p. 358). The relatively stable organometallic reacts with acyl chlorides in the presence of a palladium catalyst to give protected y-keto-a-amino acids without racemization. This step is also improved by sonication. 

Ethers are relatively unreactive and will not react in an acyl addition reaction or with the reactions of enolate anions. However, when a benzyl ether is treated with hydrogen gas and a palladium catalyst, hydrogenolysis leads to 2-butanol and toluene (see Chapter 19, Sections 19.3.4,19.3.5, and Chapter 21, Section 21.6, for hydrogenolysis). The benzyl ether is a good projecting group for an alcohol and a few other ethers may also be used. 

In the same way that an aromatic ring activates a neighboring (benzylic) C H toward oxidation, it also activates a benzylic carbonyl group toward reduction. Thus, an aryl alkyl ketone prepared by Friedel-Crafts acylation of an aromatic ring can be converted into an alkylbenzene by catalytic hydrogenation over a palladium catalyst. Propiophenone, for instance, is reduced to propylbenzene by catalytic hydrogenation. Since the net effect of Friedel-Crafts acylation followed by reduction is the preparation of a primary alkylbenzene, this two-step sequence of reactions makes it possible to circumvent the carbocation... 

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