Acetylating Amination

The quinaldine is separated from any unreacted aniline and from the alkyl-anilines by treatment with acetic anhydride, basified with sodium carbonate and steam distilled. Only the primary and secondary amines are acetylated the acetylated amines are now much less volatile so that separation from the steam-volatile quinaldine (a tertiary amine) is facile. 

Another effective way of preventing coupling reactions is to acetylate the primary amine as formed by carrying out the reduction in an anhydride solvent. This techniq ue is especially useful if the acetylated amine is the desired product 17,30,59,77). 

A related process reacts acetamide with amines and aluminum chloride to give the N-acetyl amine. ... 

It is frustrating that this result, and accordingly file enthalpy of formation of 54, is probably in error. After all, it is often assumed that acetylated amines are easier to purify than the parent amine—for example, we recall that samples of acetanilide are generally clean white solids while those of aniline are discolored liquids. 

Acetoxymethyl carbamates of primary amines behaved differently from the pathway depicted in Fig. 8.19, the predominant reaction being intramolecular acyl transfer to generate the A-acetylated amine as the major product [209]. This parasitic reaction was observed in buffer and proportionally less in plasma, disqualifying (acyloxy)methyl carbamates for use as prodrugs of primary amines. However, this type of derivative appears well suited for the preparation of prodrugs of secondary amines, as documented below. 

Scheme 4, (21), Nu = OCH3) are formed nearly exclusively. In acetic acid, the corresponding acetate is found and in acetonitrile an -acetyl amine via reaction of (18) with the nitrogen of acetonitrile is obtained [78, 79]. 

On deamination, 2-amino-l,5-anhydro-2-deoxy-l>mannitol gave l,5-anhydro-2-deoxy-D-eryf/iro-3-hexulose as the major product.54 The substitution product 1,5-anhydro-D-glucitol was formed to a small extent, and inversion again predominated, as with other axial amines (60, 72, and methyl 4-amino-4-deoxy-a-D-galactopyranoside) this is in accord with the predominant inversion of configuration reported for deamination, in water-rich media, of simple cyclohexyla-mines,154 and aminodecahydronaphthalenes39 in which the amino group is axial. As discussed previously (see p. 15), the extent of inversion can vary considerably with the nature of the solvent, and steric factors appear to be important in deaminations of per-O-acetyl amines (see pp. 37 and 49). 

Occasionally, a per-O-acetylated amine can be used in the synthesis of a partially acetylated compound. For example, 2-amino-2-deoxy-neo-inositol pentaacetate, which was prepared from hygromycin A, was converted by deamination into 1,2,3,4,6-penta-O-acetyl-myo-inositol.226... 

Many gas chromatographic methods for amphetamine have been developed since then, most of which include a recommended internal standard such as N,N-dimethylaniline, phenethylamine, and di-phenylamine. These methods also include the formation of derivatives such as the acetylated amines and the ketone derivative of amphetamine as a further check on identity. 

Fig.4.11. Separation of some acetylated amines (see text for details). Peaks 1 = unknown 2 = 0-phenyl-ethylamine 3 tyramine 4 - tryptamine 5 1 methoxytryptamine 6 = serotonin 7 = prednisone.

The HPLC separation of a number of acetylated amines of biological interest is shown in Fig.4.11. The separation was achieved on a 30-cm column of Spherosil XOA-400 (25 °C) with methylene chloride (prepared by shaking 11 of methylene chloride with 17 ml of water and 15 ml of absolute ethanol for 10 h, then discarding the polar aqueous phase) as the eluting solvent at a flow-rate of 1.3 ml/min (1S75 p.s.i.). The limits of detection of 11 amines carried through this system are given in Table 4.2. 

Deacetylation. Deacetylation occurs in a number of species, but there is a large difference between species, strains, and individuals in the extent to which the reaction occurs. Because acetylation and deacetylation are catalyzed by different enzymes, the levels of which vary independently in different species, the importance of deacetylation as a xenobiotic metabolizing mechanism also varies between species. This can be seen in a comparison of the rabbit and the dog. The rabbit, which has high acetyltransferase activity and low deacetylase, excretes significant amounts of acetylated amines. The dog, in which the opposite situation obtains, does not. 

THE PREPARATION OF UNSYMMETRICAL BIARYLS BY THE DIAZO REACTION AND THE NITRO SO ACETYL AMINE... 

The final ring closure again paralleled the olivacine synthesis passing through the intermediate jV-formyl rather than the V-acetyl, amine, to give 1,2-dihydroellipticine (CCXCIII) from which ellipticine was obtained by palladium dehydrogenation (160a). 

At Lonza [94] an alternative route was developed. Based on the acetylated amine a straightforward hydrolysis gave the desired amino alcohol (Scheme 6.28 B). The wrong enantiomer could not be recycled. Indeed, this is a problem with all the above-described kinetic resolutions half of the starting material is waste and needs to be recycled. 

N-Debenzylation.1 The P-D-glucopyranoside 1, when dissolved in DMSO containing KOC(CH3)3, is rapidly converted into the N-acetamide derivative 2 when air is passed into the stirred solution. This conversion of an N-benzylacetamido group into an acet-amido group is a general reaction. It can also be used to prepare acetylated amines. Thus... 

Nature employs nucleophilic aQ l aubstitntion reactioiLs in the biosynthesis of many molecules, using thiol eaters for the purpose. Acetyl coenzyme A lavotyl C oA> ia a complex thiol ester that i- employed in living sj stcms to acetylate amines and alcoliola. 

Symmetrical anhydrides are prepared according to reactions reviewed in Chapter 2.1 of this volume. Advantageously, in contrast to unsymmetric anhydrides nucleophilic attack on both possible carbonyls gives the correct product. The disadvantage is the waste of one equivalent of carboxylic acid (which will be recovered in the case of expensive protected amino acids). The most widely used is acetic anhydride, which acetylates amines under mild conditions. 

This family of enzymes is cytosolic and is widely distributed in a variety of mammalian tissues. There are also enzymes that hydrolyze N-substituted acetamides (i.e., amidases, as described previously) and the extent to which free versus acetylated amines are present in vivo depends on the relative rates of the acetylation and deacetylation reactions, on the physical and chemical properties of the two products, and whether or not the amine is metabolized by competing pathways. Some acetylated hydroxamic acids are chemically reactive and appear to be ultimate carcinogens. 

Initial studies indicated that these techniques were also amenable to monitoring the acetylation and deacetylation kinetics in mice, dogs and monkeys. These studies will be published in detail at a later date. It should be noted that dogs do not acetylate amines. In dogs administered deuterium labelled N-acetyl LY201116, no non-deuterated N-acetyl LY201116 was detected, further evidence that the deuterium was not exchanged in vivo CQ. 

Overall, we have established a convenient and cost-effective three-step reductive amination process for the manufacture of multifarious a-1-arylalkylamines. Importantly, the new procedure outlined here also allows the preparation of previously unavailable enamides. including a-alkyl-substituted derivatives. For instance, this method has been used to convert pinacolone into enamide 22, which upon hydrogenation with the (S,S)-Me-DuPHOS-Rh catalyst affords the corresponding A-acetyl amine 23 with very high enantiomeric excess (99% ee) (Scheme 11) [27]. 

Furthermore, secondary monophosphine ligand, (2S,5S) 2,5 diphenylphospho lane, was also used in the rhodium catalyzed asymmetric hydrogenation of P substituted enamide for the synthesis of chiral N acetyl amines, albeit with low enantioselectivity (<28% ee) [46]. 

---