1,3-diketones, reaction with ammonia

The application of acetic acid catalysis in reaction of 2-benzopyrylium salts with primary amines4, in contrast to the reaction with ammonia, does not lead to a simple result. Thus, if in 30 R3 is not Aik, excluding the alternative formation of a-naphthylamines of type 153, the use of acetic acid catalysis leads to isoquinolinium salts 152 in high yields (89KPS75), whereas without acetic acid, diketones 166 were the only products of interaction between 2-benzopyrylium salts 30 and primary amines. 

Trifluoroacetamidine (585) is most widely used for the principal synthesis of pyrimidines. Compound 585 can be prepared from ethyl trifluoroacetate by ammo-nolysis, followed by dehydration with P2O5 and reaction with ammonia (Scheme 124) [335,336]. Amidine 585 has been introduced into reaction with various p-dicarbonyl compounds and their synthetic equivalents (Table 27), including p-ketoesters (Entries 1-6), in particular p-ketopyruvates (Entry 3) and a-alkoxymethylene-p-ketoesters (Entries 4-6), p-enaminocarbonyl compounds (Entries 7-9), malonic acid derivatives (Entry 10), fluorinated p-diketones (Entry 11), vinamidinium salts (Entry 12), a,p-unsaturated nitriles with leaving group at p position (Entries 13-15) and other bis-electrophiles (Entries 16, 17). Usually, the reaction gives moderate yields of the target 2-CF3-pyrimidines (ca. 50 %). 

Reaction of MEK with ammonia and hydrogen produces j i -butylarnine, a fungistat and condensation with aUphatic esters under strongly alkaline conditions produces 1,3-diketones. 

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... 

A modification of this reaction by Orm et al. [16] included an a-diketone, an amine and an aldehyde that react with ammonia to afford a tetrasubstituted imidazole (Scheme 4). Microwave heating was used to substantially decrease the reaction time. 

Step, aldol condensation to form the benzylidene derivative (12-3). Conjugate addition of a second mole of acetoacetate would then afford the 1,5-diketone (12-4). Reaction of the carbonyl groups with ammonia will lead to the formation of the dihydropyridine ring. Alternatively, acetoacetate may go on to form the imine (12-5) reaction of this with the aldol product (13-3) will give the same dihydropyridine. The product, nifedipine (12-6) [13], has been used extensively for the treatment of angina and hypertension. 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

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. 

In this particular instance the correct oxidation level automatically results from the condensation reaction, giving pyrrole 2.16 directly. In other cases cyclisation does not afford the correct oxidation level and an unsaturated system has to be oxidised to achieve aromaticity. For instance, 1,5-diketones 1.27 react with ammonia to give dihydropyridines 1.28 which can be oxidised to pyridines 1.29. 

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 Hantzsch synthesis produces a reduced pyridine but there are many syntheses that go directly to pyridines. One of the simplest is to use hydroxylamine (NH2OH) instead of ammonia as the nucleophile. Reaction with a 1,5-diketone gives a dihydropyridine but then water is lost and no oxidation is needed. 

When a-diketones react with a mixture of formamide and formaldehyde at 180-200 °C it is not possible to detect a-hydroxy ketones during the reaction. It seems, therefore, that the formaldehyde cannot be acting as a reducing agent, and that imidazole formation must be a consequence of generation of ammonia from formamide, and subsequent reaction between the diketone, ammonia and formaldehyde. The major advantage here over earlier methods lies in the reduced decomposition of the a-diketone, which normally results in reduction in yields and mixtures of products. 

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. 

Reactions of 1,5-diketones with ammonia and its substituted derivatives 03KGS1283. 

Amino-enones or 3-amino-acrylates can be prepared by the straightforward reaction of ammonia with a 1,3-diketone or a 1,3-keto-ester. The simplest 1,3-dicarbonyl compound, malondialdehyde, is too unstable to be useful, but its acetal enol ether can be used instead, as shown below. ... 

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