Amidocarbonylation

Amidocarbonylation is the only transition metal-catal) ed multi-component reaction, by which the amino acid framework is constructed directly from simple building blocks. [73] In the early 1970s, Hachiro Wakamatsu at Ajinomoto discovered by chance the cobalt-catalysed amidocarbonylation during investigation of the Oxo process with acrylonitrile, where he also found traces of -aminobutyric add. To determine the mechanism of this side-reaction, he 

Industrial applications of this reaction, which have in part been tested already on a pilot plant scale, are for example the synthesis of phenylalanine for Aspartame and of long-chain N-acyl derivatives of sarcosine (N-methylglycine) for anionic surfactants. 

In the classical sarcosinate procedure, the appropriate alkanoyl chloride is treated with sodium sarcosinate (worldwide capacity amounts to more than 10,000 tonnes annually). In contrast, amidocarbonylation offers the advantage that no salt is formed as a by-product. 

In 1987, while searching for patent-free catalysts for amidocarbonylation, Erhard Jagers at Hoechst AG found that palladium complexes are efficient catalysts for this reaction as well. These are commonly around 10-100 times more active than the corresponding cobalt systems. Also the reaction pressure and temperature are lower. An even broader industrial application of transition metal-catalysed amidocarbonylations can be expected overtime. 

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Another elegant example of a highly atom efficient process is the use of palladium-cataly.sed amidocarbonylation for the one-step synthesis of amino acid derivatives from an aldehyde, CO, and an amide (Eqn. (10)) (Beller et al., 1997, 1999). 

In a process developed by Hoffmann La Roche (Roessler, 1996) for the anti-Parkinsonian drug, lazabemide, palladium-catalysed amidocarbonylation of 2,5-dichloropyridine replaced an original synthesis that involved eight steps, starting from 2-methyl-5-ethylpyridine, and had an overall yield of 8%. The amidocarbonylation route affords lazabemide hydrochloride in 65% yield in one step, with 100% atom efficiency (Fig. 2.22). 

A very common combination in Pd-catalyzed domino reactions is the insertion of CO as the last step (this was discussed previously). However, there is also the possibility that CO is inserted as the first step after oxidative addition. This process, as well as the amidocarbonylation, the animation, the arylation of ketones, the isomerization of epoxides, and the reaction with isonitriles will be discussed in this section. 

Scheme 6/1.85. Palladium-catalyzed amidocarbonylation of aromatic aldehydes.

Amidocarbonylation converts aldehydes into amido-substituted amino acids, which have many important industrial applications ranging from pharmaceuticals to detergents and metal-chelating agents.588 Two catalyst systems have been developed, a cobalt-based system and, more recently a palladium-based system. In the cobalt system, alkenes can be used as the starting material, thus conducting alkene-hydroformylation, formation of hemi-amidal and carbonylation in one pot as... 

Iridium, rhodium, and ruthenium complexes were found to be active for amidocarbonylation under similar conditions as palladium.609... 

Amidocarbonylation is derived from the findings by Wakamatsu. It has been extensively reviewed and many mechanistic studies were reported by Ojima.610,611... 

Lin, I. I. Knifton, I. F. Amidocarbonylation. Catalyst Reaction Scope, and Industrial Application, In Advances in Chemistry Series 230 American Chemical Society Washington, DC, 1992, 235-247. 

Drauz,. K. Burkhardt, O. Beller, M. Eckert, M. (Degussa-Huels A.-G., Germany). Amidocarbonylation procedure and catalysts for the production of N-acylaminoacids from the reaction of carbon monoxide with aldehydes and amides or nitriles. Ger. Offen. 2000 DE 10012251. Chem. Abstr. 2000, 134, 56964. 

The amidocarbonylation of aldehydes provides highly efficient access to N-acyl a-amino acid derivatives by the reaction of the ubiquitous and cheap starting materials aldehyde, amide, and carbon monoxide under transition metal-catalysis [1,2]. Wakamatsu serendipitously discovered this reaction when observing the formation of amino acid derivatives as by-products in the cobalt-catalyzed oxo reaction of acrylonitrile [3-5]. The reaction was further elaborated to an efficient cobalt- or palladium-catalyzed one-step synthesis of racemic N-acyl a-amino acids [6-8] (Scheme 1). Besides the range of direct applications, such as pharmaceuticals and detergents, racemic N-acetyl a-amino acids are important intermediates in the synthesis of enantiomeri-cally pure a-amino acids via enzymatic hydrolysis [9]. 

Scheme 1 a Amidocarbonylation of aldehydes b Applications of N-acylamino acids... 

Scheme 2 Proposed mechanism for the cobalt-catalyzed amidocarbonylation...

Amidocarbonylation methodology can also be applied to the synthesis of N-acclyl- (D,L)-phenylalanine, a key intermediate for aspartame (1-aspartyl-l-phenylalanine methylester), from styrene oxide (via isomerization to phenac-etaldehyde) [24] or benzyl chloride [25] in good yields. 

Scheme 5 Domino isomerization-amidocarbonylation of allylic alcohols...

The relevance of the palladium-catalyzed amidocarbonylation for natural product synthesis has been demonstrated with the multi gram-scale preparation of the central amino acid of chloropeptin I ((S)-3,5-dichloro-4-hydroxyphenylglycine) as well as methionine and p-chlorophenyl alanine via the combination of amidocarbonylation and enzymatic hydrolysis (Table 4) [44]. 

Similarly, acylamino acids can be prepared with 100% atom utilization via palladium-catalyzed amidocarbonylation. " The method was used for the synthesis of a surfactant from sarcosine (Figure 9.8). 

Figure 9.8 Acylamino acids via palladium-catalyzed amidocarbonylation.

Because the compared protective groups in phenylalanine also differ in their electron acceptor activity, one can expect that anion-radical generation would result in the selective removal of amine protection. This assumption is supported by the ESR studies of some peptide cation-radicals (Lin et al. 1998). For instance, neat histone (a protein from cell nuclei) gives an anion-radical in which the unpaired electron is localized at the amidocarbonyl function. 

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