Acylation, of amines

So far in this chapter, we have focused on ways of making amines. For the rest of the chapter, we will shift our focus. We will now explore reactions of amines. 

We wiU begin our survey with a reaction that we have actually already seen in a previous chapter. When we learned about carboxyhc acid derivatives (Chapter 6), we saw that you can convert an acid hahde into an amide. For example  

When we draw it this way (with the amine over the reaction arrow), the focus is on what happens to the acid halide (it is converted into an amide). But what if we choose to focus on the amine instead In other words, let s rewrite the same reaction a bit differently. Let s put the acid halide on top of the reaction arrow, hke this  

We have not changed the reaction at all. It is still the same reaction (an amine reacting with an acid halide). Bnt when we draw it like this, our attention focuses on converting the amine into an amide. The acid halide is just the reagent that we use to accomplish this conversion. 

Overall, we have placed an acyl group onto the amine  

The search for optimum methods and conditions in the production of chiral amines is nowadays considered as a key issue for the industrial sector [178]. Traditionally, hydrolases have played a major role in this area [179,180], although other classes of enzymes such as amine dehydrogenases, monoamine oxidases, phenyl amino-mutases, and transaminases have opened a myriad of possibilities in this field [181,182]. 

In this context, van Rantwijk and Sheldon reported in the last decade some remarkable examples of the potential of serine hydrolase for the enantioselective acylation of amines [183]. Here, more recent reactions will be discussed starting with KR of primary and secondary racemic amines and a few examples of the desymmetrization of diamines, a reaction that has scarcely been exploited. Acylation reactions are quite selective transformations for the formation of the desired final optically active amines and amides however, in some cases, a sister reaction such as the alkoxycarbonylation process using a carbonate instead of an ester will be mentioned in order to present some advantages, especially for the resolution of secondary cyclic amines. 

---

CgFgOAc, DMF, 25°, 1-12 h, 78-91% yield. These conditions allow selective acylation of amines in the presence of alcohols. If triethylamine is used in place of DMF, alcohols are also acylated (75-85% yield). 

Over the past years, interest in the preparation of chiral amines and amides by enzymatic ammonolysis or aminolysis reactions [4] has greatly increased for academic and industrial sectors. The role that the enzymatic acylation of amines or ammonia plays for the preparation of some pharmaceuticals is noteworthy [5]. 

Scheme 7.4 Enzymatic acylation of amines with carboxylic acids...

Although more studies have been devoted to the mechanism of the acylation of amines with carboxylic esters than with other reagents, the mechanistic details are not yet entirely clear.In its broad outlines, the mechanism appears to be essentially Bac2. ° Under the normal basic conditions, the reaction is general base... 

The method is not restricted to secondary aryl alcohols and very good results were also obtained for secondary diols [39], a- and S-hydroxyalkylphosphonates [40], 2-hydroxyalkyl sulfones [41], allylic alcohols [42], S-halo alcohols [43], aromatic chlorohydrins [44], functionalized y-hydroxy amides [45], 1,2-diarylethanols [46], and primary amines [47]. Recently, the synthetic potential of this method was expanded by application of an air-stable and recyclable racemization catalyst that is applicable to alcohol DKR at room temperature [48]. The catalyst type is not limited to organometallic ruthenium compounds. Recent report indicates that the in situ racemization of amines with thiyl radicals can also be combined with enzymatic acylation of amines [49]. It is clear that, in the future, other types of catalytic racemization processes will be used together with enzymatic processes. 

Drivers for Performing Acylations of Amines in Micro Reactors... 

Beneficial Micro Reactor Properties for Acylations of Amines... 

Acylations of Amines Investigated in Micro Reactors Organic synthesis 8 [OS 8] Acetic anhydride acylation of diverse amines... 

Aminodehydroxylation - Acylation of Amines by Acids (Peptide Synthesis)... 

Derivatives are prepared from the appropriate acid anhydride, or occasionally the acid chloride, usually in the presence of a base such as pyridine, triethylamine, or N,N-dimethyl-4-amlnopyridine at elevated temperatures [474-482]. Acylation of amines and phenols (not alcohols) in aqueous solution in the presence of potassium carbonate has been demonstrated (448,483,484), but does not constitute m l practice as reactions are generally performed under i Arous conditions. 

The intermediate N-acylpyridinium salt is highly stabilized by the electron donating ability of the dimethylamino group. The increased stability of the N-acylpyridinium ion has been postulated to lead to increased separation of the ion pair resulting in an easier attack by the nucleophile with general base catalysis provided by the loosely bound carboxylate anion. Dialkylamino-pyridines have been shown to be excellent catalysts for acylation (of amines, alcohols, phenols, enolates), tritylation, silylation, lactonization, phosphonylation, and carbomylation and as transfer agents of cyano, arylsulfonyl, and arylsulfinyl groups (lj-3 ). 

Since amides are often used as acyl donors in the enantioselective acylation of amines, a combination of a NHase and an amidase could, in principle, be used for the direct acylation of an amine by the nitrile precursor of the amide. An example of such a one-pot reaction is shown in Scheme 6.20. The (R)-enantiomer of phenylglycine nitrile undergoes NHase-catalyzed conversion to the corresponding (R)-amide and the latter reacts in situ with 7-aminodeacetoxycephalosporanic acid, in the presence of penidlhn amidase, to afford the cephalosporin antibiotic, cephalexin [39]. 

Although in recent years transesterification processes of racemic alcohols have received major attention, enzymatic acylation of amines for synthetic purposes is also being employed as a conventional tool for the synthesis of chiral amines and amides [31], using CALB as the biocatalyst in the majority of these reactions [31a]. The main difference between enzymatic acylation of alcohols and amines is the use of the corresponding acyl donor, because activated esters which are of utility... 

Quantitative stoichiometric gas-solid or solid-solid (these at 0 °C) acylations of amines with acid chlorides are varied (Scheme 32). However, for a clean reaction the liberated hydrochloric acid has to be neutralized by an additional gaseous or solid base that may also be a second mole of the amine. The reactions are performed in an evacuated flask or in a ball-mill, respectively. There are only minimal losses of the amides or sulfonamides upon removal of the stoichiometric coproduct with water [91]. The solid-solid reactions can be turned into sustainable 100% yield processes with optimal atom efficiency by milling stoichiometric 1 1 1 mixtures of acid chloride, aniline derivative, and K2CO3... 

---