Keto-esters, reaction with ammonia

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 hydrogenolyaia of cyclopropane rings (C—C bond cleavage) has been described on p, 105. In syntheses of complex molecules reductive cleavage of alcohols, epoxides, and enol ethers of 5-keto esters are the most important examples, and some selectivity rules will be given. Primary alcohols are converted into tosylates much faster than secondary alcohols. The tosylate group is substituted by hydrogen upon treatment with LiAlH (W. Zorbach, 1961). Epoxides are also easily opened by LiAlH. The hydride ion attacks the less hindered carbon atom of the epoxide (H.B. Henhest, 1956). The reduction of sterically hindered enol ethers of 9-keto esters with lithium in ammonia leads to the a,/S-unsaturated ester and subsequently to the saturated ester in reasonable yields (R.M. Coates, 1970). Tributyltin hydride reduces halides to hydrocarbons stereoselectively in a free-radical chain reaction (L.W. Menapace, 1964) and reacts only slowly with C 0 and C—C double bonds (W.T. Brady, 1970 H.G. Kuivila, 1968). 

In the case of mono-ester substituted pyrroles (e.g., 68) wherein relatively unstable dianions likely to deprotonate ammonia might be produced, the authors instead utilized an excess of (MeOCH2CH2)2NH as a substitute for ammonia. It was felt that upon in situ formation of (MeOCH2CH2)2NLi, this base would be unable to protonate the dianion <00TL1331>. Remarkably, quenching the reduction reactions with benzoyl chloride affords P-keto esters (e.g., 69, R = COPh), a reaction that does not occur when conducted in liquid ammonia. 

The most used route to pyridines is called the Hantzsch synthesis. This uses a 1,3-dicarbonyl compound, frequently a 1,3-keto ester [ethyl ace-toacetate (ethyl 3-oxobutanoate)], and an aldehyde, which are heated together with ammonia (Scheme 2.18). At the end of the reaction the dihydropyridine is oxidized to the corresponding pyridine with nitric acid (or another oxidant such as Mn02). The normal Hantzsch procedure leads to symmetrical dihydropyridines. Two different 1,3-dicarbonyl compounds may not be used as two enoiate anions might form, giving mixed products when reacted with the aldehyde. The aldehyde itself should preferably be non-enolizable, otherwise the chance of aldoliza-tion exists, but with care this can be avoided. 

Pyrrolinones are best obtained by cyclizative condensation of y-keto esters with ammonia or a primary amine (reaction 195). Alternatively, the 2-pyrrolinones may be obtained by cyclization of preformed a-keto amides as shown in reaction (196) (71CC346). Preexisting lactones (2H- or 5H-furanones) also react with amines to give pyrrolinones (reaction 197). Jones and Bean give references to specific examples of these methods as well as to more specialized examples (B-77MI30610). 

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. 

This adduct is in equilibrium with the stable enolate from the keto-ester and elimination now gives an unsaturated carbonyl compound. Such chemistry is associated with the aldol reactions we discussed in Chapter 27. The new enone has two carbonyl groups at one end of the double bond and is therefore a very good Michael acceptor (Chapter 29). A second molecule of enolate does a conjugate addition to complete the carbon skeleton of the molecule. Now the ammonia attacks either of... 

The Chemistry of the Tetracyclic Diterpenoids.—The reaction of cnt-kaur-16-ene with thallium(lli) nitrate affords cnt-kaur-16-en-15j8-ol nitrate which undergoes a ready [3,3] sigmatropic rearrangement to cnt-kaur-15-en-17-ol nitrate. The reactions of phyllocladene and of labda-8(17)-en-13-ol with sodium azide and iodine chloride have been examined. ° The synthesis of 13-hydroxylated cnt-kaur-16-ene derivatives such as steviol using an acyloin-like cyclization of keto-esters has been developed. A detailed analysis was made of the products arising from the use of sodium in liquid ammonia in this reaction. 

Reaction of a keto ester with ammonia (to form the keto-amide in situ) leads, on further heating, to cyciization and the formation of a pyridin-2-one ring [2040]. The same ring is produced under Dean and Stark conditions from the... 

Keto and carboxylic ester groups in side-chains are annulated by reaction with ammonia. In this example, the reactants are heated in molten ammonium acetate. 

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. ... 

A great variety of methods is available for the ring synthesis of pyridines the most obvious approach is to construct a 1,5-dicarbonyl compound, preferably also having further unsaturation and allow it to react with ammonia, addition of which at each carbonyl group, with losses of water, producing the pyridine. 1,4-Dihydropyridines, which can easily be dehydrogenated to the fully aromatic system, result from the interaction of aldehydes with two mol equivalents of 1,3-diketones (or 1,3-keto-esters, etc.) and ammonia aldol and Michael reactions and addition of ammonia at the termini, produces the heterocycle. 

The same group successfully obtained symmetrical DHPs (3, Scheme 17.5) by using a similar reaction but exchanging the methyl yS-aminocrotonate for ammonium acetate [31b]. Later, Ohnberg et al. [31c] performed a similar reaction in a monomode closed-vessel MW synthesizer. In their approach, an aldehyde, a j8-keto ester, and aqueous ammonia were reacted in a one-pot condensation to form a small library of DHPs 3 (Scheme 17.5). The reaction mixture was irradiated with MW for 10-15 min at 140-150 °C and the desired DHPs 3 were obtained in 51-92% yield. Under conventional heating conditions the reaction mixture was heated under reflux for 12 h with yields ranging from 15-72% [30]. 

This reaction was first reported by Hantzsch in 1890. It is the preparation of 2,5-dialkyl or 2,4,5-trialkylpyrrole derivatives from the condensation of of-halo-ketones, )0-ketoesters and ammonia or amines. Therefore, it is often known as the Hantzsch pyrrole synthesis or simply the Hantzsch synthesis. During this synthesis, ammonia or amine reacts quickly with y0-keto esters to form enamine esters or 3-amino crotonates that cyclize with of-halo-ketones to form pyrrole derivatives upon heating, and the regioselectivity strongly depends on the substituents on the starting materials. Thus, this reaction can directly start from 3-amino crotonates or enamines of 0-keto esters. Further extension of this reaction from aromatic amines results in the formation of indole derivatives, or carbazole derivatives if cyclized with a-halo-cyclohexanones. The synthesized pyrroles have wide application in medicinal chemistry, conducting polymers, molecular optics, sensors,etc. 

The Davidson oxazole synthesis describes the preparation of substituted oxazoles 2 from the condensation of / -keto-esters 1 with ammonia or ammonium acetate. A general reaction scheme is depicted below. 

The reaction of P-keto acid derivatives and ammonia or amines relies on initial reaction with an aldehyde or ketone moiety. The carbonyl must be P- to the carboxyl group, however, in order to obtain the enamino acid or enamino-ester derivative (an enamine is a "vinyl amine," first used synthetically by Stork, and they are well known). These enamino derivatives are actually 3-aminopropenoic... 

The reactions of p-keto-esters just described are variations of a very old procedure. The treatment of 1.118 with ammonia was reported in 1887 and gave 1.119. 1 This approach has remained virtually unchanged for over a century and a wide range... 

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