Primary amines, 31 Table acylation

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]. 

With nonacylated polyethylenimines (Table II) the rate constant is increased by a factor of about 4 over that of propylamine. This small enhancement may be due merely to the fact that a greater fraction of primary amine groups in the polymer are in the basic, NH2 state. With these polyethylenimines, as with propylamine, k drops with increasing length of the hydrocarbon chain of the acyl nitrophenyl ester. 

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). 

Support-bound alkenes substituted with at least one electron-withdrawing group can react with primary or secondary amines (Table 10.6). If acrylates are used as Michael acceptors, the products (fl-alanine derivatives) are generally stable and do not undergo [l-elimination either upon N-acylation or upon treatment with TFA (for a longer synthetic sequence with a support-bound 2-(l-piperazinyl)propionate, see [42]). Suitable solvents for the addition of amines to electron-poor alkenes are THF, NMP, and DMSO. DMF is less suitable because it often contains dimethylamine, which also adds to Michael acceptors [112],... 

Sulfonamides prepared from 9-(chlorosulfonyl)anthracene and polystyrene-bound primary amines can be converted into amides by N-acylation of the sulfonamide (carboxylic acid anhydride, DMAP, pyridine, THF, 24 h) followed by nucleophilic desulfo-nylation with neat 1,3-propanedithiol/DIPEA [213] (Entry 4, Table 10.13). An example of the use of sulfonamides as linkers for amines is given in Table 3.23. 

Isothiocyanates can be prepared from support-bound primary amines by treatment with thiophosgene [14] or synthetic analogs thereof (Entry 5, Table 14.2). In an alternative two-step procedure, the amine is first treated with CS2 and a tertiary amine to yield an ammonium dithiocarbamate, which is subsequently desulfurized with TsCl or a chloroformate (Entry 6, Table 14.2 Experimental Procedure 14.1). Highly reactive acyl isothiocyanates have been prepared from support-bound acyl chlorides and tetra-butylammonium thiocyanate (Entry 7, Table 14.2). These acyl isothiocyanates react with amines to give the corresponding 7V-acylthiourcas, which can be used to prepare guanidines on insoluble supports (Entry 6, Table 14.3). 

One type of oligoamide that can readily be prepared on supports without the need for any partially protected monomers (which are often tedious and expensive to synthesize) are N-substituted oligoglycines (Figure 16.21). These compounds are prepared by a sequence of acylation of a support-bound amine with bromoacetic acid, displacement of the bromide with a primary aliphatic or aromatic amine, and repeated acylation with bromoacetic acid. Because primary amines are cheap and available in large number, this approach enables the cost-efficient production of large, diverse compound libraries. Alternatively, protected N-substituted glycines can also be prepared in solution and then assembled on insoluble supports (Entry 5, Table 16.2). 

Regiochemical synthesis of 1-substituted imidazole-4-carboxylates can be achieved by treatment of a (Z)-)3-dimethylamino-of-isocyanoacrylate with an alkyl or acyl halide (see Section 2.1.1 and Scheme 2.1.8), by cyclization of 3-alkylamino-2-aminopropanoic acids with triethyl orthoformate followed by dehydrogenation of the initially formed imidazoline (see Section 3.1.1 and Scheme 3.1.2), by condensation of 3-arylamino-2-nitro-2-enones with ortho esters in the presence of reducing agents (see Section 3.1.1 and Scheme 3.1.4), by reaction of an alkyl A -cyanoalkylimidate with a primary amine (see Section 3.2 and Scheme 3.2.1), the poor-yielding acid-catalysed cyclization of a 2-azabutadiene with a primary amine (see Section 3.2 and Scheme 3.2.3), the cyclocondensation of an isothiourea with the enolate form of ethyl isocyanoacetate (see Section 4.2 and Scheme 4.2.5), and from the interaction of of-aminonitrile, primary tunine and triethyl orthoformate (see Chapter 5, Scheme 5.1.5, and Tables 5.1.1 and 5.1.2). 

Secondary amines do not react under these conditions. Thus, heating dibenzylamine with 1-hexanol under the experimental conditions resulted in a quantitative yield of hexyl hexanoate (entry 6, Table 1.8). The scope of this method was extended to the bis-acylation processes with diamines. Upon refluxing a slight excess of a primary alcohol and catalyst 1 with diamines (500 equivalent relative to 1) in toluene under argon, bis-amides were produced in high yields (Table 1.9). The high selectivity of the dehydrogenative amidation reaction to primary amine functionalities enabled the direct bis-acylation of diethylenetriamine with 1-hexanol to provide the bis-amide in 88% yield without the need to protect the secondary amine functionality [14]. 

The most typical type of hydrolase-catalyzed stereoselective reactions under continuous-flow conditions is KR. Continuous-flow KRs were performed on racemic acids by direct esterification with alcohols [100-102, 108, 109] or on racemic amines by acylation with esters (Figure 9.7 and Table 9.5) [110-114]. However, the most frequent so far is the continuous-flow KR of racemic primary... 

Reference should be made to Tables 4, 5, 29, for amides, anilides and p-toluidides of carboxylic and sulphonic acids Tables 14, 15, 16, for formyl, acetyl, benzoyl and p-toluenesulphonyl derivatives of primary and secondary amines Table 18 for acyl derivatives of amino-acids Table 7 for acyl derivatives of aminophenols. 

Backvall and coworkers have also developed a practical method for the chemo-enz3unatic DKR of primary amines using dibenzyl carbonate as acyl donor, combining the use of CAL-B and the ruthenium complex mentioned above in toluene at 90 °C for the production of enantioenriched (R)-carbamates (60-95% )deld, 90-99% ee Table 9.6) [243]. The main advantage of this method is that the benzyloxycarbonyl group (Cbz) can be easily removed by hydrogenolytic cleavage without any loss of the carbamate optical purity (compoimd in entry 1 of Table 9.6) [244]. 

Primary amine-catalyzed polymerization of NCAs in various solvents revealed that certain polar solvents themselves act as catalysts [3]. Characteristic for the catalytically active solvents is a relatively high nucleophihcity [4] (see left column in Table 15.1). This observation and the formation of cyclic polypeptides from the N-substituted sarcosine-NCA evidenced that a zwitterionic polymerization mechanism was catalyzed, which involves ROP and condensation steps (see Formula 15.2). Pyridine is known for many decades to activate carboxylic anhy-drdies by charge separation, i. e., formation of carboxylate anions plus N-acyl pyridinium ions Therefore, it is obvious that pyridine catalyzes the same zwitterionic mechanism as the nucleophilic polar solvents [5]. In the case of N-un-substitued NCAs the initiation step will be again a charge separation, but instead of... 

Various approaches have been used to prepare pyrroles on insoluble supports (Figure 15.1). These include the condensation of a-halo ketones or nitroalkenes with enamines (Hantzsch pyrrole synthesis) and the decarboxylative condensation of N-acyl a-amino acids with alkynes (Table 15.3). The enamines required for the Hanztsch pyrrole synthesis are obtained by treating support-bound acetoacetamides with primary aliphatic amines. Unfortunately, 3-keto amides other than acetoacetamides are not readily accessible this imposes some limitations on the range of substituents that may be incorporated into the products. Pyrroles have also been prepared by the treatment of polystyrene-bound vinylsulfones with isonitriles such as Tosmic [28] and by the reaction of resin-bound sulfonic esters of a-hydroxy ketones with enamines [29]. 

Under suitable conditions, amide formation can take place between an amine and a carboxylic acid, an acyl halide, or an acid anhydride. Along with ammonia, primary and secondary amines yield amides with carboxylic acids or derivatives. Table 33.2 relates the nitrogen base with the amide class (based on the number of alkyl or aryl groups on the nitrogen of the amide). 

Acylation is one of the most popular derivatization reactions for primary and secondary amines (Figure 11.1). The reagents listed in Table 11.5 easily react with amino groups under mild reaction conditions. In the reactions of amines with acid anhydrides and acyl chlorides, it is usually necessary to remove excess reagent and byproduct acid because these compounds damage the GC column. 

Similarly to acyl chlorides, arylsulphonyl chlorides react with primary and secondary amines. A number of arylsulphonyl chlorides have also been investigated by Clark and Wells [9]. The reaction and the conditions of derivatiz-ation used were similar to those for acyl chlorides. The spectrophotometric properties of some typical benzene-sulphonamides are given in Table 2. 

Table 5. iV-Acyl derivatives of primary and secondary amines. 

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