Synthesis of Benzoxazine

Topics: Imine, Nucleophilic acyl substitution, Amino acid Pages: 7 (1295 words) Published: March 6, 2013
Lady Jewellyn G.Diola*, Jennika Joy L. Casin, Andrian R. De Leon, Jan Rotsen Kyle A. Delos Santos

Department of Chemistry, College of Science

*Lady Jewellyn G. Diola;


Synthesis of 3,4-dihydro-3-(p-methylphenyl)-1,2-(2h)-benzoxazine involves the nucleophillic addition of the 1 °amine group upon the carbonyly group of the salicylaldehyde, the reduction of imine to amine and the addition of paraformaldehyde to proceed ring closure. The experiment prepared the product through Mannich reaction, a multicomponent condensation synthesis between ketone, aldehydes, enols and amines. Biosynthesis of benzoaxazines occur under reductive and nucleophilic reaction conditions. Formation of a Schiff base is necessary to perform first before reductive amination is performed. % yield of 3,4-dihydro-3-(p-methylphenyl)-1,2-(2h)-benzoxazinewas obtained from the reaction.

Keywords: Condensation Reactions, Mannich Reaction, Nucleophilic addition, Schiff Base, Reductive Amination.


Benzoxazines are a class of oxygen-nitrogen heterocyclic compounds bearing different biological activities. These activities include antimicrobial, antifungal, antiangiogenic, therapeutic agents, antiarrhythmic, neuropeptide, antagonists, neuroprotective agents, estrogen receptorβ, agonists, and antimycobacterial agents.Compounds which are enolic react with a mixture of an aldehyde and a primary or secondary amine in the presence of an acid to yield an aminomethyl derivative (Norman, R. 1993). The multi component condensation of an aldehyde with an amine is called Mannich reaction. Mannich reaction is primarily a complex condensation reaction where 2 moieties or molecules combine to form a larger molecule. For the experiment, a two step linear reaction was observed: 1) condensation reaction to yield the Schiff base and 2) ring closure reaction.

A Schiff base is obtained from amine and ketone or aldehyde reactions that produce C=N bonds. Generating this base proceeds through the nucleophilic attack of nitrogen to the carbonyl group. Intermolecular proton transfer comes next after the nucleophilic attack to form an amino alcohol. As protonation occurs, HOH or water is given off as a by-product. The iminium ion left is deprotonated to yield the imine or the Schiff base. In the experiment, this is the mechanism for the product salicylal-p-toluidine. Figure 1 shows the mechanism for imine formation.


Figure1: Mechanism of Schiff Base Formation

In between basification and ring closure, reductive amination was done to convert the imine to amine using a complex hydride NaBH₄. N-(2-hydroxybenzyl)-p-toluidine produced from the experiment was generated through indirect reductive amination. Figure 2 shows the basic mechanism of amine formation from imine reduction. [pic]

Figure 2: Indirect reductive amination
The last step of the experiment was the condensation reaction to combine N-(2-hydroxybenzyl)-p-toluidine with paraformaldehyde to gain ring closure thus yielding the final product 3,4-dihydro-3-(p-methylphenyl)-1,2-(2h)-benzoxazine. Figure 3 shows the general mechanism of mannich condensation reaction between amines, ketones and aldehydes.


Figure 3: Mannich reaction

The objective of the experiment is to conveniently prepare a bonzoxazine specifically ,4-dihydro-3-(p-methylphenyl)-1,2-(2h)-benzoxazine using Mannich reaction. It also aims to produce a high percentage yield as an experimental result.

Results and discussion

The synthesis of 3,4-dihydro-3-(p-methylphenyl)-1,2-(2h)-benzoxazine involved 2 linear steps. The synthesis yielded 3 products of which contain distinct characteristics different from one another.

Table 1.A shows all the observed changes and appearance of every reaction performed for the synthesis of Salicylal-p-toluidine.

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