Secondary amines acylation

Primary or secondary amine Acyl chloride Tetrahedral intermediate Amide... 

When MA reacts with ammonia, a primary or a secondary amine, acylation occurs resulting in formation of an amide derivative. This half-amide derivative is called maleamic acid 108. When one of the R groups in 108 is aryl, often the product is referred to as a maleanilic acid. 

Primary and secondary amines can also act as very weak acids ( 10 ). They react with acyl haUdes, anhydrides, and esters with rates depending on... 

Treatment of acyl pyrroles with primary and secondary amines affords amides. ... 

AC2O, 18-crown-6, Et3N, 98% yield. The crown ether forms a complex with a primary amine, thus allowing selective acylation of a secondary amine. 

These Br nsted-type plots often seem to be scatter diagrams until the points are collated into groups related by specific structural features. Thus, p-nitrophenyl acetate gives four separate, but parallel, lines for reactions with pyridines, anilines, imidazoles, and oxygen nucleophiles.Figure 7-4 shows such a plot for the reaction of trans-cmmm c anhydride with primary and secondary aliphatic amines to give substituted cinnamamides.All of the primary amines without substituents on the a carbon (R-CHi-NHi) fall on a line of slope 0.62 cyclopentylamine also lies on this line. If this line is characteristic of normal behavior, most of the deviations become qualitatively explicable. The line drawn through the secondary amines (slope 1.98) connects amines with the structure R-CHi-NH-CHi-R. The different steric requirements in the acylation reaction and in the model process... 

While enamines can usually be obtained directly from ketones and secondary amines their formation by an indirect route may bo advantageous. The previously mentioned condensation of rnethyl ketones during azeotropic enamine formation has prompted the alklyation (J) or acylation and reduction (59) of Schiff s bases. A parallel method uses the formation and desulfurization of N-acylthiazolines followed by hydride reduetion (60,61). 

In an analogous sequence, reductive alkylation of aminoalcohol, 46, with cyclohexanone affords the secondary amine (47). Acylation with benzoyl chloride affords hexylcaine (48) in a reaction that may again involve acyl migration. 

Demethylation of the tricyclic antihistamine 9, with cyanogen bromide gives the secondary amine 10 acylation of that intermediate with ethyl chloroformate affords the nonsedating H-1 antihistaminic agent loratidine (11) [3], It is of interest that this compound does not contain the zwitterionic funcrion which is thought to prevent passage through the blood-brain barrier, characteristic of this class of compounds. 

We ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide (Sections 21.4 and 21.5). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine. 

Thermolysis of the 3-acyl-3/f-azepine 32 in Decalin at 250°C also gives the phenacylpyridine but in much reduced yield (6%). In a similar manner, 4-chloro-yV,/V-diethyl-3-phenacylpyridin-2-amine (53 % bp 160 C/0.18 Torr) is produced by the photolysis or thermolysis of 3-benzoyl-5-chloro-Ar,Ar-diethyl-3/f-azepin-2-amine.246 However, if the 3ff-azepine bears a secondary amine residue at the 2-position, e.g. 36, then photolysis or thermolysis yields a pyrrolo[2,3-/>]pyridine by intramolecular cyclization of the 3-phenacylpyridin-2-amine intermediate. 

A very elegant approach has been developed by Kanerva et al. DKR of N-hetrocyclic a-amino esters is achieved using CAL-A [54]. Racemization occurs when acetaldehyde is released in situ from the acyl donor. In this case aldehyde-catalyzed racemization of the product cannot occur (Figure 4.28). This is one of the few examples reported for DKR of secondary amines (For a recent example see the above text and Ref. [38]). 

An efficient chemoenzymatic route for the synthesis of optically active substituted indolines has been recently developed (Scheme 7.27), and also the alkoxycarbonyla-tion process is more efficient than the acylation reaction. Different lipases have been tested in the alkoxycarbonylation of these secondary amines, GALA being found to be the best biocatalyst for 2-substituted-indolines, and CALB for 3-methylindoline. The combination of lipases with a variety of allyl carbonates and TBME as solvent has allowed the isolation of the carbamate and amine derivatives in a high level of enantiopurity [51]. 

The treatment of acyl halides with ammonia or amines is a very general reaction for the preparation of amides.The reaction is highly exothermic and must be carefully controlled, usually by cooling or dilution. Ammonia gives unsubstituted amides, primary amines give A-substituted amides, and secondary amines give N,N-disubstituted amides. Arylamines can be similarly acylated. In some cases aqueous... 

This reaction, similar in scope and mechanism to 10-55, can be carried out with ammonia or primary or secondary amines. Amino acids can be N-acylated using... 

Even though formic anhydride is not a stable compound (see p. 714), amines can be formylated with the mixed anhydride of acetic and formic acids (HCOO-COMe) °°° or with a mixture of formic acid and acetic anhydride. Acetamides are not formed with these reagents. Secondary amines can be acylated in the presence of a primary amine by conversion to their salts and addition of 18-crown-6. ° The crown ether complexes the primary ammonium salt, preventing its acylation, while the secondary ammonium salts, which do not fit easily into the cavity, are free to be acylated. 

In the first step, a resin-bound secondary amine is acylated with bromoacetic acid, in the presence of N,N-diisopropylcarbodiimide. Acylation of secondary amines is difficult, especially when coupHng an amino acid with a bulky side chain. The sub-monomer method, on the other hand, is facilitated by the use of bromoacetic acid, which is a very reactive acylating agent Activated bromoacetic acid is bis-reactive, in that it acylates by reacting with a nucleophile at the carbonyl carbon, or it can alkylate by reacting with a nucleophile at the neighboring ah-phatic carbon. Because acylation is approximately 1000 times faster than alkylation, acylation is exclusively observed. 

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