Lecture 9. Synthesis o f Six-membered Rings with Two Heteroatom.pptx

Synthesis o f Six-membered Rings with Two Heteroatom

1. Synthesis of Heterocyclic Six- membered Rings with Two Nitrogen Atoms ( Pyridazine , Pyrimidine , and Pyrazine ) The three diazines , pyridazine , pyrimidine , and pyrazine are stable, colourless compounds that are soluble in water. The three parent heterocycles , unlike pyridine, are expensive and not readily available and so are seldom used as starting materials for the synthesis of their derivatives. Organic Chem II Lecture 9 Dr. Mohamed Babiker Lecture 9

2. One striking aspect of the physical properties of the diazine trio is the high boiling point of pyridazine (207°C), 80 – 90°C higher than that of pyrimidine (123°C), pyrazine (118°C). The high boiling point of pyridazine is attributed to the polarisability of the N–N unit, which results in extensive dipolar association in the liquid. Diazines are weaker bases compared to pyridine due to inductive and electron withdrawing effect of second nitrogen atom. Two heteroatoms withdraw electron density from the ring carbons even more than one in pyridine. 2

3. Diazines compounds belong to the category of π-deficient ring systems similar to pyridine. Diazines are aromatic in nature and lone pair on sp2 hybridized nitrogen are not involved in aromatic sextet. Routes for the ring synthesis of the isomeric diazines are, as one would expect, quite different one from the other, and must therefore be dealt with separately. 3

4. 1. Methods of Synthesis of Pyridazines A) From a 1,4-Dicarbonyl Compound and a Hydrazine A common method for the synthesis of pyridazines involves a 1,4-dicarbonyl compound reacting with hydrazine; unless the four-carbon component is unsaturated, a final oxidative step is needed to give an aromatic pyridazine . The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone , which can be easily dehydrogenated to the fully aromatic heterocycle , often by C- bromination then dehydrobromination . 4

5. B) By Cycloaddition of a 1,2,4,5 - Tetrazine with an Alkyne Cycloaddition of a 1,2,4,5-tetrazine with an alkyne (or its equivalent), with elimination of nitrogen gives pyridazines . A wide range of substituents can be incorporated via the acetylene, including nitro and trimethylsilyl , the means to access other substituted pyridazines . The preparation of a boronic ester is another example. 5

6. A) From a 1,3-Dicarbonyl Compound and an N–C–N Fragment The most general pyrimidine ring synthesis involves the combination of a 1,3-dicarbonyl component with an N–C–N fragment such as a urea, an amidine or a guanidine. 2. Methods of Synthesis of Pyrimidines 6

7. The choice of N–C–N component ( amidine , guanidine, or a urea) governs the substitution at C-2 in the product heterocycle . 7

8. B) By Cycloadditions Cycloaddition of a 1,3,5 - triazine with an alkyne (or its equivalent) gives pyrimidines after loss of hydrogen cyanide. The formation of pyrimidines via aza - Diels–Alder reactions is similar to the preparation of pyridazines from tetrazines 8

9. C) From 3-Ethoxyacryloyl Isocyanate and Primary Amines Primary amines add to the isocyanate group in a 3-alkoxyacryloyl isocyanate ; ring closure then gives pyrimidines via intramolecular displacement of the alkoxy -group. 9

10. D) From an Aldehyde , a 1,3-Dicarbonyl-Compound and a Urea The Biginelli Synthesis This very old synthesis of 1,4-dihydropyrimidin-2- ones, is much used, particularly for library synthesis. The products are important in their own right, but can also be dehydrogenated to give pyrimidin - 2-ones. If guanidine is used instead of the urea component, 2-amino-1,4-dihydropyrimidines result. 10

11. E) From Ketones Condensation of ketones with two mole equivalents of a nitrile in the presence of trifl uoromethanesulfonic acid anhydride is a useful method for the production of a limited range of pyrimidines , where the substituents at C-2 and C-4 are identical. 11

12. Pyrazine is not easily made in the laboratory. Commercially, the high temperature cyclodehydrogenation of precursors such as N-hydroxyethylethane-1,2-diamine is used. A) From the Self-Condensation of a 2-Amino-Ketone Symmetrical pyrazines result from the spontaneous self condensation of two mole equivalents of a 2-amino-ketone, or 2-amino-aldehyde, followed by an oxidation. 3. Methods of Synthesis of Pyrazines 12

13. B) From 1,2-Dicarbonyl Compounds and 1,2-Diamines 1,2-Dicarbonyl compounds undergo double condensation with 1,2-diamines; an oxidation is then required. This method is well suited to the formation of symmetrical pyrazines , but if both diketone and diamine are unsymmetrical, two isomeric pyrazines are formed. The dihydro-pyrazines can be dehydrogenated and they will also react with aldehydes and ketones , with introduction of another alkyl group at the same time as achieving the aromatic oxidation level. 13

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