Primary amines acyl derivatives

Salts of aromatic amines acyl derivatives of primary and secondary aromatic amines (often very slowly) high mol.wt. amino-acids hydrazine derivatives aryl ureas and aryl thioureas. 

Note. PRIMARY ALIPHATIC AMINES. The lower amines are gases or low-boiling liquids (b.ps. CHjNH, 7 CiHjNH, 17 CH,(CH2,>,NH 49 (CHg)jCHNHa, 34 ) but may be encountered in aqueous or alcoholic solution, or as their crystalline salts. They are best identified as their benzoyl, or toluene-/>-sulphonyl derivatives (c/. (C) above), and as their picrates when these are not too soluble. This applies also to benzylamine, CjHsCHjNH, b.p. 185 also to ethylenediamine, usually encountered as the hydrate, NHj (CHj)j NH2,HjO, b.p. 116 , for which a moderate excess of the reagent should be used to obtain the di-acyl derivative. (M.ps., pp. 55 55 )... 

The product of this reaction is an imide (Section 20 16) a diacyl derivative of an amine Either aqueous acid or aqueous base can be used to hydrolyze its two amide bonds and liberate the desired primary amine A more effective method of cleaving the two amide bonds is by acyl transfer to hydrazine... 

Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and tire Curtius rearrangement. Although the Hofmann rearrangement involves a primary-amide and the Curtius rearrangement involves an acyl azide, both proceed through similar mechanisms. 

Protection of primary amines. Primary amines are selectively converted into mono-t-BDPSi derivatives by reaction with /-butyldiphenylchlorosilane and N(C2H,)3 in CH,CN. These derivatives are stable to basic and hydrolytic reagents as well as alkylating and acylating reagents such as CH,I and a base. They are cleaved by 80% HOAc at 25° or by Py-HF at 25°. 

Primary and secondary amines are acylated by acid chlorides and anhydrides, in particular also by the chloride of benzene sulphonic add (p. 192). The preparation of acetanilide has already been described (pp. 125, 128). The acetyl- and benzoyl-derivatives of all the simpler primary amines of the benzene and naphthalene series are known, so that these derivatives can always serve for purposes of identification. 

The simplicity of the two-phase modification of the Gabriel synthesis of primary amines, via the N-alkylation of potassium phthalimide, makes the procedure considerably more convenient than the traditional method, which normally requires the use of anhydrous dipolar aprolic solvents. The reaction can be conducted under solid liquid conditions using potassium hydroxide in toluene [25], or with preformed potassium phthalimide [26, 27] (cf ref. 28). As is normal for acylation reactions, relatively mild conditions are required for the preparation of the A-ethoxycarbonyl derivative [29], whereas a reaction temperature of 100°C is generally used for N-alkylation (Table 5.16). The reaction time for the soliddiquid two-phase system can be reduced dramatically with retention of the high yields, when the reaction mixture is subjected to microwave irradiation [30]. 

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. 

This intermediate, like 6-APA, incorporates a primary amine that can be coupled with a host of side chains. The presence of an additional reactive function, the allylic acetate at the 3 position, provides an additional center that can be modified. The observation that both types of modifications provided unproved antibiotics has resulted in the synthesis of hundreds of analogues. The very few examples discussed below barely scratch the surface in this field. One of the earliest examples of a doubly derivatized 7-ACA derivative, cephalothin (19-1), is stUl widely used as an antibiotic. Acylation of (18-4) with 2-thiophenylacetyl chloride gives the corresponding amide (19-2). Heating that product with pyridine leads to the displacement of the allyl acetate by the basic nitrogen. The resulting product, cephalothin (19-3), is isolated as the internal betaine [23]. 

The ability of [18]crown-6 derivatives to complex primary alkylammonium ions has been elegantly exploited in the protection of primary amines (80CC300). In the presence of primary amines, secondary amines can be acylated selectively by adding [18]crown-6 and a proton source. This strategy has obvious advantages over normal amine protecting groups which require a deprotection step. 

The lower members of the homologous series of 1. Alcohols 2. Aldehydes 3. Ketones 4. Acids 5. Esters 6. Phenols 7. Anhydrides 8. Amines 9. Nitriles 10. Polyhydroxy phenols 1. Polybasic acids and hydro-oxy acids. 2. Glycols, poly-hydric alcohols, polyhydroxy aldehydes and ketones (sugars) 3. Some amides, ammo acids, di-and polyamino compounds, amino alcohols 4. Sulphonic acids 5. Sulphinic acids 6. Salts 1. Acids 2. Phenols 3. Imides 4. Some primary and secondary nitro compounds oximes 5. Mercaptans and thiophenols 6. Sulphonic acids, sulphinic acids, sulphuric acids, and sul-phonamides 7. Some diketones and (3-keto esters 1. Primary amines 2. Secondary aliphatic and aryl-alkyl amines 3. Aliphatic and some aryl-alkyl tertiary amines 4. Hydrazines 1. Unsaturated hydrocarbons 2. Some poly-alkylated aromatic hydrocarbons 3. Alcohols 4. Aldehydes 5. Ketones 6. Esters 7. Anhydrides 8. Ethers and acetals 9. Lactones 10. Acyl halides 1. Saturated aliphatic hydrocarbons Cyclic paraffin hydrocarbons 3. Aromatic hydrocarbons 4. Halogen derivatives of 1, 2 and 3 5. Diaryl ethers 1. Nitro compounds (tertiary) 2. Amides and derivatives of aldehydes and ketones 3. Nitriles 4. Negatively substituted amines 5. Nitroso, azo, hy-drazo, and other intermediate reduction products of nitro com-pounds 6. Sulphones, sul-phonamides of secondary amines, sulphides, sulphates and other Sulphur compounds... 

The clean conversion of support-bound, primary amines into sulfonamides by treatment with sulfonyl chlorides is more difficult to perform than the acylation of amines with carboxylic acid derivatives, probably because of the oxidizing properties of sulfonyl chlorides and because primary amines can be doubly sulfonylated. Weak bases (pyridine, 2,6-lutidine, NMM, collidine), short reaction times, and only a slight excess of sulfonyl chloride should therefore be used to convert primary amines into sulfonamides (Table 8.7). 

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