Hantzch synthesis

A convenient procedure for the solution phase preparation of a 2-aminothiazole combinatorial library has been reported. The Hantzch synthesis of 2-aminothiazoles has been adapted to allow the ready solution phase preparation of libraries of discrete 2-aminothiazoles <96BMC1409>. 

Synthesis of dihydropyridines through preliminary transformation of unsaturated ketones into 1,5-dicarbonyl compounds (Scheme 3.1, reaction a— variant of Hantzch synthesis)... 

Hantzch synthesis is a well-known pathway to dihydro derivatives of azines. In some of the variations of this synthesis, the electrophilic reagents can be unsaturated ketones (Scheme 3.1, reactions a and b). Hantzch syntheses, including reaction b in Scheme 3.1 in which enamines are formed in situ from ammonia and the corresponding carbonyls, are not a topic of this book. However, synthetic applications of such condensations were described in detail in some reviews [1,2]. 

As mentioned already, a reaction of enamines with a, 3-unsaturated ketones may be one of the stages of Hantzch synthesis. But in the literature there are a lot of examples of independent applications of a broad set of enamines in dihydropyrimidine syntheses. For example, in [3, 4], a reaction of 3-aminocy-clohex-2-enones 1 with an unsaturated ketone 2 was described which results in a dehydrogenation leading to the formation of a quinoline 3 (Scheme 3.2). 

The latter approach has been exemplified in a number of published cases. An indication of the development requirements of well-known reactions for successful employment in array synthesis is provided by the work ofWatson and co-workers [15] to prepare thiazole derivatives. Adaptation of the Hantzch synthesis of 2-aminothiazoles (Fig. 2) from a-haloketones and thioureas was used in the one-step preparation of discrete samples. Inclusion in the array of a compound of known biological activity provided a valuable internal control. 

The classical Hantzch dihydropyridine synthesis has been reported under microwave flash heating conditions45,46. More unusually, Hantzch products have also been obtained from Biginelli reaction under microwave flash heating conditions (Scheme 3.27)47. 

An approach similar to the synthesis of the Hantzch pyridine synthesis could be explored for its feasibility in the synthesis of these six-membered rings with one phosphorus atom in the ring. By proper choice of the phosphorus compound (with the right oxidation state) a simple approach may be feasible to synthesize various substituted (in all positions) phosphonines. 

A typical pyrilium salt synthesis is illustrated by the preparation of salt 9.12. The precursor to 9.12 is pyran 9.11, available by dehydration of 1,5-diketone 9.10. Note the similarity of this sequence to the Hantzch pyridine synthesis, Chapter 5. Also, the dehydrative cyclisation of a diketone to oxygen heterocycle 9.11 is reminiscent of furan synthesis, Chapter 2. 

The mechanism of this oxazole formation is identical to that of the Hantzch thiazole synthesis. However, because of the reduced nucleophilicity of a carbonyl group as compared to a thiocarbonyl (due to the higher electronegativity of oxygen), this synthesis only proceeds under vigorous conditions (high temperatures, amide component as solvent, etc). 

Quinolizidines 965 and 966, potentially useful intermediates for the synthesis of Nuphar alkaloids, have been prepared by reducing the quinolizinium salt precursor 967 with sodium cyanoborohydride in ethanol-acetic acid (616). Compound 967 was itself prepared by Hantzch condensation of ethyl (5-benzoyloxy-2-pyridyl)acetate with the ethyl enol ether of 3-furoylacetaldehyde. 

The Hantzch pyrrole synthesis is a variation of this reaction which is conducted as a three component synthesis from a j8-dicarbonyl compound, an a-haloketone or aldehyde and anunonia or an amine (Equation (38)). Yields for this procedure are typically 20-50% <7oaci689>. The regiochemistry is that resulting from N—C bond formation at the carbonyl carbon of the a-haloaldehyde. 

In a variant of the Hantzch ester synthesis for dihydropyridines <1882LA(215)1>, the suifone of (10), (31), can behave as a substitute for the normally used acetoacetic ester component (Equation (1)) <94JHC351>. 

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