Acylation Schotten-Baumann

The Schotten-Baumann acylation of pyrroles and indoles is discussed in Section 3.05.1.2.6 and reactions of the heteroaryl anions with aldehydes and ketones are presented in Section... 

The first enantioselective total synthesis of (-)-tejedine was completed by P.E. Georghiou using a chiral auxiliary-assisted diastereoselective Bischler-Napieralsid cycHzation as one of the key steps.The chiral auxiliary was the commercially available (S)-a-methylbenzylamine, which was coupled to the substrate using the original Schotten-Baumann acylation conditions. The acid chloride was reacted with the chiral amine in a solvent mixture containing aqueous sodium hydroxide and dichloromethane and the desired amide was isolated in excellent yield. 

In spite of the routine nature of the chemistry involved in N-acylation (Equation (4.2)), Schotten-Baumann acylation requires an acid chloride as reagent, a compound that can react with the carboxy group as well. The mystification that the consequences of this caused at the time (1962) - since dipeptides and oligopeptides were being formed in this way - actually had a constructive outcome, since the mixed anhydride procedure of peptide-bond formation (Chapter 7) was developed by the workers who unravelled the course of events (Equation (4.2)). 

A similar acid/base washing strategy has been employed for the synthesis of an aryl piperazine hbrary [9]. The synthesis was based on a nucleophilic aromatic substitution of nitro-fluoro aromatic compounds with Boc-piperazine and subsequent Schotten-Baumann acylation with acid chlorides. The products were purified by extractive work-up after each step. 

This process is successful with both aromatic566 and aliphatic amines567 and for large batches of the latter is preferable to the Schotten-Baumann acylation described below.567 It can also be used for amino acids presented as internal salts.566,568... 

Salicylic acid, 11, 42 14, 48, 52 Schaeffer s acid, 16, 16 Schaeffer s salt, 16, 13 Schotten-Baumann acylation, 12, 41 ... 

Ester formation is a typical example of category 2. Although other methods such as the use of distillation column reactors (see Chapter 25) are preferred, layer separation can also be used by adding dichloromethane to remove the water. A well-known example of biphasing in organic synthesis belongs to this class, the Schotten-Baumann acylation reaction... 

This reaction was first reported by Schotten in 1884 and subsequently extended by Baumann in 1886. It is the acylation of alcohols and amines from acyl halide or anhydride in an aqueous alkaline solution (e.g., 1 M NaOH), and is generally known as the Schotten-Baumann reaction or Schotten-Baumann acylation. Occasionally, it is also referred to as the Schotten-Baumann method,or Schotten-Baumann esterification. Likewise, the formation of benzoyl ester under these conditions is called the Schotten-Baumann benzoylation." It is assumed that the reaction would perform well if carried out in a biphasic system of water and an immiscible organic solvent (e.g., CH2CI2), which has an important application in the acylation of amino acids.For example, p-nitrohippuric acid and dibenzoylornithine (ornithuric acid) all can be prepared under these conditions. 

Miscellaneous. In an interesting example of the enhanced reactivity of this reagent (in comparison with tosyl chloride), Fuchs reported the ring opening of thebaine with tosyl bromide under standard Schotten-Baumann acylation conditions (eq IS). ... 

Figure 11.5 The Schotten-Baumann acylation of amines and alcohols.

Georg, G.I., Boge, T.C., Cheruvallath, Z.S., Harriman, G.C.B., Hepperle, M. Park, H., et al., Schotten-Baumann acylation of N debenzoyltaxok an efficient route to N acyl taaal analogues and their biological evaluation, Bioorg. Med. Chem. Lett., 1994,4(2), 335 338. 

Acid catalysis has not been observed during the esterification reactions, and it has not yet been decided whether a base catalysis takes place during the reaction. Schotten-Baumann acylation could probably serve as an example of base catalysis. However, the reaction takes place in the heterogeneous phase and its kinetics have not been studied. 

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