Of a 1,4-diketone with ammonia

Substituted pyrroles are often prepared by treatment of a 1,4-diketone with ammonia. Suggest a mechanism. 

Paal-Knorr Synthesis. The condensation of a 1,4-diketone, for example, with ammonia or a primary amine generally gives good yields of pyrroles many syntheses have been reported (24). The lack of avaHabitity of the appropriate 1,4-diketone sometimes limits the usefiilness of the reaction. 

A useful and possibly more general alternative to the Lwowski synthesis- of 1,3-diphenylisoindoles involves condensation of a l,2-dibenzoyl-l,4-cyclohexadiene (e.g., 55) with ammonia or a primary amine. Cyclohexadiene derivatives of this type are easily prepared by Riels-Alder addition of a 1,3-diene to dibenzoylacetylene, and these adducts lead directly, and in high yield, to the corresponding isoindoles (56). The reaction is closely related to the well-known synthesis of pyrroles by condensation of 1,4-diketones with ammonia. 4,7-Dihydro- and 4,5,6,7-tetrahydroisoindoles (57 and 58) have been... 

This reaction consists of the condensation of two molecular equivalents of a 1,3 diketone (or a J3-keto-ester) with one equivalent of an aldehyde and one of ammonia. Thus the interaction of ethyl acetoacetate and acetaldehyde and ammonia affords the 1,4-dihy dro-pyridine derivative (1), which when boiled with dilute nitric acid readily undergoes dehydrogenation and aromatisation" to gb e the diethyl ester of collidine (or 2,4,6-trimethyl-pyridine-3,5 dicarboxylic acid (II)). For the initial condensation the solid aldehyde-ammonia can conveniently be used in place of the separate reagents. 

The Paal-Knorr pyrrole synthesis is the condensation of a primary amine 4 (or ammonia) with a 1,4-diketone 5 (or 1,4-dialdehyde) to give a pyrrole 6. ... 

According to the classical Hantzsch synthesis of pyridine derivatives, an a,(5-unsaturated carbonyl compound is first formed by Knoevenagel condensation of an aldehyde with a P-dicarbonyl compound. The next step is a Michael reaction with another equivalent of the P-dicarbonyl compound (or its enamine) to form a 1,5-diketone, which finally undergoes a cyclocondensation with ammonia to give a 1,4-dihydropyridine with specific symmetry in its substitution pattern. 

Pyrylium ions react with ammonia or primary amines to give pyridinium ions (see p. 498). Primary amines react with 1,4-diketones, with microwave irradiation, to give A -substituted pyrroles.Similar reactions in the presence of Montmorillo-nite KSF or by simply heating the components with tosic acid have been reported. 

Reaction of 1,4-diketones with liquid ammonia results in the formation of unstable 5-hydroxy-A -pyrrolenines which subsequently dehydrate to pyrroles <86X623, 88X3531>. Monoimines of the diketones are also observable by NMR <86X623,91JOC6924>, but they may simply be in equilibrium with the ketone, amine and carbinolamine and may not be on the cyclization path. The currently available information suggests a minimal reaction system depicted in Scheme 69. None of the existing evidence appears to exclude cyclization at the imine stage. 

The Paal-Knorr Synthesis of Pyrroies. The Paal-Knorr method makes use of a 1,4-di-carbonyl compound (aldehyde or ketone) in reaction with primary amines or ammonia. Many pyrroles have been made by this general process. Alkyl and some other substituents are allowed on the dicarbonyl chain. Diketones, dialdehydes, and ketoalde-hydes all serve as reactants. Primary amines give rise to 1-alkylpyrroles. Examples of the overall process are shown in Scheme 4.2. 

Paal and Knorr independently discovered the straightforward reaction of primary amines (or ammonia) with 1,4-diketones to give pyrroles following loss of water7 Like the Knorr pyrrole synthesis, the PK method is a powerful and widely used method of constructing pyrroles (vide infra). 

We can put this into practice immediately with the synthesis of pyrroles 16. Disconnection of both C-N bonds gives a very reasonable intermediate, the 1,4-diketone 17. This will need to be made by one of the methods from chapter 25 and treatment with ammonia gives 16. On the other hand, if the furan 18 is needed, no heteroatom needs to be added and treatment with acid cyclises the diketone 17 to the furan 18. 

What we need is an amine— ammonia in this case—and a diketone. If the two carbonyl groups have a 1,4 relationship we will get a pyrrole out of this reaction. So hexane-2)5-dione reacts with ammonia to give a high yield of 2,5-dimethyl pyrrole. 

The reaction of 3-thia-1,5-diketones with amines forms fully-conjugated 1,4-thiazines, as well as 1,4-thiazine S, A-dioxides for example, 1,4-thiazine 1,1-dioxides 452 are formed by the cyclodehydration of diacyl sulfones 451 and ammonia (Scheme 210) <19720S(52)135>. 

Examples of reactions which have used 1,2-diketones and ammonia with or without added aldehyde include the isolation of good yields of lophine (2,4,5-triphenylimidazole) from benzil and ammonia, a rather elegant synthesis of 4,5-di-t-butylimidazole (135), and the preparation of a series of 2-aryl-5-trifluoromethyl-4-phenylimidazoles (136) from 3,3,3-trifluoro-l-phenylpropane-l,2-dione monohydrate (Scheme 74). Additionally, the formation of 1-hydroxyimidazole 3-oxides (137) from a-diketones, hydroxylamine and aldehydes (74CI(L)38), and the preparations of 2,2 -bis- (138) and 2,2, 2"-tris-imidazolyls (139) from benzil, ammonia and polyformyl aromatics provide further examples of this versatile reaction (Scheme 74). There is yet some doubt about the pathway or pathways involved in these... 

Diketones are accessible via a number routes, for example by Michael addition of enolate to enone (or precursor Mannich base " ), by ozonolysis of a cyclopentene precursor, or by reaction of silyl enol ethers with 3-methoxyallylic alcohols. They react with ammonia, with loss of two mol equivalents of water to produce a cyclic bis-enamine, i.e. a 1,4-dihydropyridine, which is generally unstable but can be easily and efficiently dehydrogenated to the aromatic heterocycle. 

The first step in the Katritzky pyridine synthesis is believed to be the Michael addition of a a-benzotriazolyl ketone 2 to the a,p-unsaturated carbonyl compound 1 to generate a 1,5-diketone derivative 4. The 1,5-diketone is not typically isolated although its formation has been confirmed via preparation under typical Michael reaction conditions in the absence of ammonium acetate. 1,5-Diketone derivatives are known intermediates in the synthesis of pyridines and undergo condensation with ammonia or its equivalent followed by cyclization to form dihydropyridine 5. Elimination of benzotriazole completes the aromatization process and generates the pyridine ring. 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

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