In this reaction, phthalimide, which has an N-H acid group, reacts with the base to provide a nitrogen-containing anion, which, as a nucleophile, undergoes substitution with alkyl halides. Potassium phthalimide makes nucleophilic substitution with -haloacetate and the resulting product in the presence of base undergoes rearrangement to provide isoquinoline derivatives (Scheme 3). Metal nitrites can react with alkyl halides in both nitrogen and oxygen to give nitro and nitrite compounds, respectively, the proportions of which depend on the structure of the reactants and the reaction conditions.
For example, silver nitrite suspended in ether reacts with alkyl halides to form a mixture of nitro compounds and nitrites, the proportions of which depend on the nature of the alkyl halides (Scheme 4). Azides react with halides to form alkyl azides, which can be reduced to primary amines (Scheme 5). This is because the introduction of the first alkyl group increases the nucleophilicity of the alkylated nitrogen so that it tends to undergo further alkylation.
The fate of the adduct depends on the structure of the aldehydes, the amine and the reaction conditions. This strategy has been used to construct stereoregular chiral backbone polymers from optically active diamines and dialdehydes in excellent yields, which are otherwise difficult to access by other methods (Scheme 7). The formation of the product probably occurs in the reaction between a carboxylic acid, an isocyanide, and an imine formed from an aldehyde or ketone and ammonia or a primary amine.
The use of N-protected amino acids allows the reaction to be used for peptide synthesis.
Carbon-Nitrogen Bonds Formation II
- Robinson-Schopf Reaction
- The Strecker Synthesis
- Stork Enamine Synthesis
- Gabriel-Cromwell Reaction
- Schweizer Allyl Amine Synthesis
- Borche Reduction
- Doebner Reaction (Beyer Synthesis)
Condensation of an aldehyde with an amine yields an imine that can react with the cyanide ion in situ to form an -aminonitrile, which on hydrolysis yields an -amino acid. The mechanism shows how they react with an alkylating agent to form a new carbon-carbon bond. Aldehydes and ketones react with amines to give imines, which can be reduced using MCNBH3 (M= Li, Na) to amines.
The success of this method rests on the much greater reactivity of the imine salt compared to the carbonyl group of aldehydes and ketone to the reducing agent. Arylamine reacts with aldehydes and enolizable carbonyl compounds via condensation followed by aromatic electrophilic substitution and autoxidation to give quinolines.
Carbon-Nitrogen Bonds Formation III
Substitution by Nuclophilic Nitrogen at Unsaturated Carbon
- Reactions of Ammonia and Amines
- Reactions of other Nitrogen Nucleophiles
Cyclic imides can be easily prepared (practical method) by heating a mixture of acid anhydride and amine. The reaction of amines with ethyl chloroform and carbonyl chloride gives urethanes and ureas, respectively. The reaction of acid chloride with sodium azide gives acid azide which is the substrate precursor for the Curtius rearrangement.
Reactions of Electrophilic Nitrogen
- Nitrosation
- Nitration
- Imine Formation
In the second, enolates react with the nitrite in a manner similar to the Claisen condensation. First, various heterocyclic syntheses are carried out by reducing -keto oximes in the presence of compounds with which the products can proceed to react to give cyclized products such as pyrroles. Compounds that can generate enolates react with aromatic nitroso compounds to give imine which on hydrolysis gives carbonyl groups.
- The Synthesis of -Amino Acids
- From -Halo acids
- The Strecker Synthesis
- Bucherer-Bergs Reaction
- The Synthesis of Peptides
Below are some of the common methods used for the synthesis of -amino acids. The simplest method consists in converting the carboxylic acid into its -bromo- derivative which can react with ammonia to give the -amino acid. It involves treating the acid with bromine in the presence of a small amount of phosphorus to give acid bromine which undergoes (electrophilic) bromination at
The resulting product is exchanged with more acid to provide -bromo acid along with more bromo acid for further bromination. The amino group can also be introduced by the Gabriel procedure (4.2.2) which gives better yield than that of the reaction described above with ammonia as an aminating agent. The amino group can also be introduced via nitrosation (4.5.1) followed by reduction and hydrolysis processes.
The condensation of aldehydes with amine gives imine which can react in situ with cyanide ions to give a -aminonitrile which on hydrolysis gives -amino acid. Ketones react with ammonium carbonate in the presence of cyanide ions to yield hydantoin which can be hydrolyzed to β-amino acid. In the synthesis of peptides, one amino acid is protected at its amino terminus with a group Y and the second amino acid is protected at its carboxyl terminus with a group Z. The condensation of these protected amino acid derivatives is then performed using a dehydrating agent such as DCC to generate peptide bond .
Now, according to the requirement, one of the protecting groups is removed and a third protected amino acid is introduced in the second peptide bond. The carboxyl group is normally protected by converting it to its t-butyl ester using isobutylene in the presence of sulfuric acid. The protecting group was also easily removed by mild acid hydrolysis via the formation of a t-butyl carbocation.
9-Fluorenyl)methyoxycarbonyl group (Fmoc) is commonly used as a protecting group for the protection of amino group of amino acid which can be facilitated using Na2CO3 in a mixture of DME and water. The important feature of this protecting group is that it can be easily removed by treatment with an amine base such as piperidine. Coupling of Fmocglycine to the free amino group of t-butyl protected alanine could be accomplished by the reagent 1,3-dicyclohexylcarbodiimide (DCC) in the presence of N-hyroxysuccinimide (NHS).
The resulting protected dipeptide could be deprotected using piperine and coupled to Fmoc-phenylalanine to give the protected tripeptide Fmoc-Phe-Gly-Ala-tBu. The protecting groups could be deprotected using weak base (Fmoc) and mild acid (tBu) to provide the target peptide, Phe-Gly-Ala.
