Schotten-Baumann acylation, reaction

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... 

Syntheses of 2- and 3-substituted chromones normally start from 2-hydroxyphenyl ketones. In the first of two examples, a route to flavone is shown in Scheme 5,10 using 2-hydroxyacetophenone (2-hydrox-yphenylethanone) and benzoyl chloride as starting materials. Initially, the phenolic group of the acetophenone is O-acylated by benzoyl chloride, using pyridine as a base (a Schotten-Baumann-type reaction). 

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... 

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. 

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. 

Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) -> (67) or type (70)->(71) or (72). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. When two isomeric products could result, only the thermodynamically stable one is usually obtained because the acylation reactions are reversible and the products interconvert readily. Thus benzotriazole forms 1-acyl derivatives (99) which preserve the Kekule resonance of the benzene ring and are therefore more stable than the isomeric 2-acyl derivatives. Acylation of pyrazoles also usually gives the more stable isomer as the sole product (66AHCi6)347). The imidazole-catalyzed hydrolysis of esters can be classified as an electrophilic attack on the multiply bonded imidazole nitrogen. 

The reaction between acyl halides and alcohols or phenols is the best general method for the preparation of carboxylic esters. It is believed to proceed by a 8 2 mechanism. As with 10-8, the mechanism can be S l or tetrahedral. Pyridine catalyzes the reaction by the nucleophilic catalysis route (see 10-9). The reaction is of wide scope, and many functional groups do not interfere. A base is frequently added to combine with the HX formed. When aqueous alkali is used, this is called the Schotten-Baumann procedure, but pyridine is also frequently used. Both R and R may be primary, secondary, or tertiary alkyl or aryl. Enolic esters can also be prepared by this method, though C-acylation competes in these cases. In difficult cases, especially with hindered acids or tertiary R, the alkoxide can be used instead of the alcohol. Activated alumina has also been used as a catalyst, for tertiary R. Thallium salts of phenols give very high yields of phenolic esters. Phase-transfer catalysis has been used for hindered phenols. Zinc has been used to couple... 

Because the reaction of an amine with an acyl chloride is much faster than the hydrolysis of the acyl chloride, the reaction can usually be carried out in an aqueous alkali solution. This is well known as the Schotten-Baumann procedure.6 For example, a number of N-acyl taxol analogs have been prepared under Schotten-Baumann conditions by the reaction of A-debenzoyltaxol with various acid chlorides (Eq. 9.4).7 Highly purified /V-long-chain-acyl neutral amino acids such as potassium AMauroyTy-aminobutyrate, useful as surfactants for detergent... 

The reaction of acyl chlorides 150 led to the corresponding ketenes 108 while the allylamines 103 were deactivated as ammonium salts 103-HCl (Schotten-Baumann conditions). 

Schotten-Baumann reaction org chem An acylation reaction that uses an add chloride in the presence of dilute alkali to acylate the hydroxyl and amino group of organic compounds. shat-an bau.man re.ak tan )... 

No resolvable separation of the signals of the diastereomers formed from reaction of the amino acid with (5)-2-bromopropionyl chloride or Mosher s acid chloride are observed. However, with common amino acids, the latter reagent can be successfully used under similar Schotten -Baumann conditions for the detection of differences in 19F spectra57. The a-alkylated amino acids are particularly challenging. However, by proper choice of solvent and signal, sufficient peak separation can be obtained. No measurable amount of kinetic resolution occurs during acylation of the acids. 

Esters of the phenolic hydroxyl are obtained easily by the Schotten-Baumann reaction. The reaction in many cases involves an acid chloride as the acylating agent. However, acylation is achieved more commonly by reaction with an acid anhydride. The single most important commercial reaction of this type is the acetylation of salicylic acid with acetic anhydride to produce acetylsalicylic acid [50-78-2] (aspirin). 

Azoles containing a free NH group react comparatively readily with acyl halides. yV-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (75) — (76) or type (79)—>(80) or (81). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. 

Oxazolin-5-ones have also proven to be important intermediates in the homologation of carboxylic acids (71AG(E)655). The IV-acyl-DL-valine derivative (402), prepared from the acid chloride of the carboxylic acid and DL-valine by the Schotten-Baumann procedure, was treated with excess acetic anhydride to afford (403). Reaction of (403) with acrylonitrile and triethylamine led to (404) in good yield. Hydrolysis of (404) with dilute alkali or acid gave the y-keto nitrile or y-keto acid (Scheme 89). 

Acylation with acetic anhydride or under Schotten-Baumann conditions generally occurs on the 1-amino group and, as with the reactions of the bifunctional aldehydes and ketones,... 

The 2H-and 3//-pyrroles and -indoles are considerably more basic than the corresponding H-isomers and they readily undergo alkylation to give the quaternary salts, which are then highly susceptible to nucleophilic attack. Thus, for example, methylation of the trialkyl-3//-indole (507), followed by reaction with aqueous base, yields the indolin-2-ol (508). A similar reaction sequence results from the acylation of (507) under Schotten-Baumann conditions to give (509 X = OH). When the benzoylation is conducted in benzene in the absence of the base, the 2-chloroindoline (509 X = C1) is formed and acylation of (507) with a carboxylic acid anhydride produces the ester (509 X = OCOR) (79HC(25-3)l). 

Carbamates are by far the most common type of amine protection used in solid-phase synthesis. Various types of carbamate have been developed that can be cleaved under mild reaction conditions on solid phase. Less well developed, however, are techniques that enable the protection of support-bound amines as carbamates. Protection of amino acids as carbamates (Boc or Fmoc) is usually performed in solution using aqueous base (Schotten-Baumann conditions). These conditions enable the selective protection of amines without simultaneous formation of imides or acylation of hydroxyl groups. Unfortunately, however, Schotten-Baumann conditions are not compatible with insoluble, hydrophobic supports. Other bases and solvents have to be used in order to prepare carbamates on, for example, cross-linked polystyrene, and more side reactions are generally observed than in aqueous solution. 

SCHOTTEN-BAUMANN REACTION. Acylation of alcohols with acyl halides in aqueous alkaline solution. 

With aromatic acyl chlorides the reaction is not so rapid, but it can be greatly facilitated by the presence of caustic soda or caustic potash in dilute aqueous solution (Schotten-Baumann). 

The hydrolysis of an IV-acylated amino acid by an enzyme provides a resolution method to amino acids. Because the starting materials are readily available in the racemic series by the Schotten-Baumann reaction, the method can be cost effective (Scheme 2.21).68-71 The L-amino acid product can be separated by crystallization, whereas the D-amino acid, which is still /V-acylated, can be recycled by being resubjected to the Schotten-Baumann conditions used for the next batch. Tanabe has developed a process with an immobilized enzyme,72 73 whereas Degussa uses the method in a membrane reactor.69 74 The process is used to make L-methionine. 

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