Hantzsch Michael reactions

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. 

Alkynes bearing electron-withdrawing substituents are more suitable for this reaction as was shown earlier by Bohlmann and Rahtz. Pyridines are formed from intermediate Michael adducts in the reaction of a-oxoalkynes having a j8-hydrogen and several primary enaminones in high yield. If, however, jS-substituted propargylaldehyde derivatives are used, a normal Hantzsch-type reaction without attack of the alkyne bond leads to 1,4-dihydropyridines (equation 79). This method was used later for converting cyclic enaminones to pyridine derivatives, however in low yield, and to quinolines in a better yield (equation 80). 

The aldol-type reaction occurs in some processes (i.e. Weiss-Cook and Hantzsch reactions), in tandem with the Michael reaction. Therefore, some significant applications of this last reaction in aqueous media will be illustrated. 

Aqueous solutions of hydrotropes (e.g. NaBMGS, sodium methylcello-solve sulfate) have been used in the Hantzsch dihydropyridine synthesis, a tandem Knoevenagel and Michael reaction, in which acetoacetic ester reacts with benzaldehydes and methyl aminocrotonate or aqueous ammonia at room temperature or heated with microwaves (MW) [16,17] ... 

To meet the needs of the advanced students, preparations have now been included to illustrate, for example, reduction by lithium aluminium hydride and by the Meerwein-Ponndorf-Verley method, oxidation by selenium dioxide and by periodate, the Michael, Hoesch, Leuckart and Doebner-Miller Reactions, the Knorr pyrrole and the Hantzsch collidine syntheses, various Free Radical reactions, the Pinacol-Pinacolone, Beckmann and Arbusov Rearrangements, and the Bart and the Meyer Reactions, together with many others. 

Many of the known chemical syntheses such as Wittig [29, 165], Knoevenagel [29], aldol [292], Ugi [29,293], Michael addition [29], Hantzsch [29,156,157], Diels-Alder [294], Azo coupling [136,182], Suzuki coupling [29,155] or enamine [29, 295] reactions (Table 1.8), to name but a few, have been carried out successfully in mi-... 

Keywords 1,3-Dicarbonyls, Biginelh reaction, Hantzsch reaction, Heterocyclic chemistry, Knoevenagel condensation, Mannich reaction, Michael addition, Multi-component reactions... 

An iron-catalyzed reaction of an a,P-unsaturated oxime such as 68 with a P-oxo ester also gave pyridine derivatives such as nicotinic acid 69 [99]. Under the reaction conditions (150-160 °C, without solvent) first Michael adducts such as intermediate 70 are presumably formed, which further condense via intermediate 71. This method is not restricted to a centric symmetry in the substitution pattern, which is an advantage compared with the Hantzsch synthesis. Moreover, the method starts with hydroxylamine being two oxidation stages above ammonia therefore, no oxidation in the final stage from dihydro- to pyridine is necessary (Scheme 8.31). 

Although the exact reaction mechanism for this three-component condensation reaction was not confirmed in [193, 194], the hypothesized mechanism is likely to involve the initial base-catalyzed formation of the Michael adduct, and its subsequent reaction with the aminopyrazole component to furnish the tricyclic intermediate (Scheme 3.63). Elimination of water from this intermediate leads to the formation of the classic Hantzsch-type dihydropyridine... 

MacMillan s catalysts 56a and 61 allowed also the combination of the domino 1,4-hydride addition followed by intramolecular Michael addition [44]. The reaction is chemoselective, as the hydride addition takes place first on the iminium-activated enal. The enamine-product of the reaction is trapped in a rapid intramolecular reaction by the enone, as depicted in Scheme 2.54. The intramolecular trapping is efficient, as no formation of the saturated aldehyde can be observed. The best results were obtained with MacMillan s imidazolidinium salt 61 and Hantzsch ester 62 as hydride source. As was the case in the cyclization reaction, the reaction affords the thermodynamic trans product in high selectivity. This transformation sequence is particularly important in demonstrating that the same catalyst may trigger different reactions via different mechanistic pathways, in the same reaction mixture. 

Hantzsch heterocyclization Henry reaction Knoevenagel condensation Michael addition enolate... 

Davis and coworkers have used an intramolecular asymmetric Michael addition to an optically pure a,(3-unsaturated sulfoxide as part of the synthesis of the dihydropyridine sulfone (132), a potent antihypertensive agent [108], The Hantzsch reaction (treatment with 3-aminocrotonate (130) in MeOH under reflux) of the a-acyl-a,P-unsaturated sulfoxide (129) gave the product (131) as a single diastereoisomer in 48% yield, resulting from an asymmetric Michael addition followed by dehydrative cyclization. The sulfoxide was then oxidized to the corresponding sulfone (132) (Scheme 5.44). 

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