Hantzch reaction

Amlodipine 20 Calcium-channel (blocker) Analog of nifedipine Synthetic compound libraries derived from the Hantzch reaction Overcame short duration- Angina and hypertension Peripheral vasculature... 

The condensation of P-keto esters with hydroxylamine can occur in two directions to give either isoxazolin-3-ones [which exist predominately as 3-hydroxyisoxazoles (2)] or isoxazolin-5-ones (3). Early work by Claisen, Hantzch, and others showed that the products from 2-unsubstituted P-keto esters were isoxazolin-5-ones. In the early 1960 s, Katritzky found that 2-substituted analogues give 3-hydroxyisozaoles. Jacquier later showed that both types of products could be produced from both types of keto esters depending on the precise pH variation during the reaction workup. ... 

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. 

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 addition sequence may determine the primary reaction course or influence impurity formation. For example, condensation of diethyl 3-oxoglutarate 33 with chloroacetone and methylamine is expected to give the 5-methylpyrrole 34, the Hantzch pyrrole product (Figure 5.14). The isomeric 4-methylpyrrole 35 (a precursor to zomepirac sodium) was prepared in good yield by first treating 33 with methylamine, then adding chloroacetone [22]. The addition sequence was also important for the chlorination of the sulfinate anion 36 The dimer 37 was produced when N-chlorosuccinimide was added to the reaction, but when 36 was added slowly to excess Cl2, the desired sulfonyl chloride 38 was produced (Figure 5.14) [23], The course of these reactions may be predicted if one takes a mental snapshot of them. 

The Hantzch-Panek condensation of ethylpyruvate with acrylamide followed by treatment with trifluoroaceticanhydride (TFAA) provided 2-vinyloxazole-4-ethylcarboxylate 37 in good yield [57]. The Stille coupling of 2-chlorooxazole-4-ethylcarboxylate with vinyltrimetbylstannane also provided 2-vinyloxazole 37 [26]. The reactivity of 37 towards cycloaddition reactions with enone and coupling reactions with aryl halides were explored [57]. Heck reaction of vinyloxazole with p-iodoanisole gave the cinnamyl oxazole 97 in 71% yield [57]. 

A mixture of aldehyde 1 (0.5 mmol), malononitrile (0.5 mmol) and Hantzch 1,4-dihydropyridine 2 (0.51 mmol) was introduced, together with a stainless ball of 7.0 mm diameter, into a stainless steel jar (5 mL). The same mixture vessels were also introduced into a second, parallel jar. The two reaction vessels were closed and fixed on the vibration arms of a ball-milling apparatus (Retsch MM200 mixer mill, Retsch GmbH, Haan, Germany) and vibrated vigorously at a rate of 1800 rpm (30 Hz) at room temperature for 90 min. 

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. 

Pattenden and co-workers used an in situ Hantzch cyclization to convert the aminoketone 512 to the benzofuranyloxazole 513. Acetylation of 512 produced an intermediate 2-acylamino ketone (not shown) that cyclized to 513 under the reaction conditions (Scheme 1.138). This benzofuranyloxazole was a model for the quaternary center present in diazonamide A (see Section 1.5.5). 

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