Hantzsch MCR

The Hantzsch MCR is a well-established tool in the arsenal of contemporary synthetic organic and medicinal chemists and has, along with many of its variants, been a subject of past review articles [34]. The material of this chapter briefly summarizes past contributions and focuses on recent examples of the Hantzsch reaction in the synthesis of potential medicinal agents. In its original incarnation. 

Scheme 14.13 Unsymmetrical Hantzsch MCR for the synthesis of drug targets.

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

MCRs of Hantzsch and Biginelli-types with participation of aldehydes, aminoa-zoles, and cyclic CH-acids, first of all 1,3-diketones and Meldrum acid, as well as the treatments discussed in the previous sub-chapter, are in the focus of interest due to high biological activity of their products. However, on the other hand, in many cases these processes can give several final heterocycles with different position or regiodirection. Moreover, sometimes for the same reactions carried out under similar conditions contradictory facts were published with high level of credibility. 

A number of MCRs having enolate-derived nucleophilic components were subsequently discovered (Scheme 7.3), including the Hantzsch dihydropyridine synthesis [13], the Biginelli reaction [14, 15] and the Mannich reaction [16-20], An added complication in many of these MCRs is the potential irreversible addition of the nucleophile to the carbonyl component, leading to carbonyl addition products. Such MCRs, however, become feasible by the appropriate selection of components that do not favor such alternative transformations. For example, the use of formaldehyde is more effective in the Mannich reaction, because its greater reactivity towards the amine prevents its undesired reaction with the enolate component. 

The Hantzsch synthesis of dihydropyridines represents a classical example of MCR, generating an array of diversely substituted heterocycles in a one-pot reaction procedure. Given that the reaction requires elevated temperatures and extended reaction times to proceed, acceleration of the process by microwave irradiation could be envisioned. Indeed, dielectric heating of aldehyde (aliphatic or aromatic) and 5 equivalents of /i-keloesler in aqueous 25% NH4OH (used both as reagent and solvent) at 140-150 °C for merely 10-15 min furnished 4-aryl-l,4-dihydropyridines in 51-92% yield after purification on a silica gel column [100]. The Hantzsch synthesis under reflux conditions ( 100 °C) featured a remarkably longer time (12 hours) and lower yields (15- 72%). To demonstrate the suitability of the procedure for the needs of combinatorial chemistry, a 24-membered library of 1,4-dihydropyridines (DHP) was prepared (Scheme 36). 

The first important MCR was developed by Strecker in 1850 (Scheme 1) [20]. In this reaction ammonia, an aldehyde and hydrogen cyanide combine to form a-cyano amines 1, which upon hydrolysis form a-amino acids 2. Also, heterocyclic compounds were obtained using MCRs. An example of this is the Hantzsch reaction, discovered in 1882 [21]. This reaction is a condensation of an aldehyde with two equivalents of a (3-ketoester in the presence of ammonia resulting in the formation of dihydropyridines 3. A comparable reaction is the Biginelli reaction, founded in 1893 ([22] and see for review [23]). This reaction is a 3-component reaction (3CR) between an aldehyde, a (3-ketoester and urea to afford dihydropyrimidines 4. 

A series of 4-aryl-6-(l//-indol-3-yl)-2,2-bipyridine-5-carbonitriles 9 was synthesized by Perumal and co-workers [60] via a one-pot MCR of an aromatic aldehyde, a 3-(cyanoacetyl)indole, 2-acetyl pyridine and ammonium acetate by microwave irradiation under solvent-free conditions. The compounds were obtained in high yields and in a very short period of time as compared to conventional heating. Remarkably, when 2,4-dichlorobenzaldehyde was used in this reaction, only the Hantzsch 1,4-dihydropyridine was isolated which had to be separately dehydrogenated to get the targeted pyridine (Scheme 9). 

Cyclic 1,3 diketones could also participate in this MCR allowing for a four-component Hantzsch synthesis of unsymmetrically substituted 1, 4-dihydropyri-dines or pyridines depending upon reaction conditions [36, 37] (Scheme 14). 

The reaction mixture was irradiated in a domestic MW oven for 5 min on a surface of bentonite clay. Not only traditional j8-keto esters, but also, for example, cyclic 1,3-diketones can participate in this MCR, thus enabling a four-component Hantzsch-type synthesis of unsymmetrically substituted 1,4-pyridines 20 (Scheme 17.15) [29, 37]. 

Contrary to the general perception, MCR occupies an important position in the development of modern organic chemistry. Indeed, many important named reactions such as the Strecker amino nitrile synthesis (1850) [6], the Hantzsch dihydropyridine synthesis (1882) [7], the Biginelli dihydropyrimidine synthesis (1891) [8], the Mannich reaction (1912) [9], the isocyanide-based Passerini reaction (1921) [10], and the Ugi (1959) reaction [11], among others, are all multicomponent processes. In spite of the significant contribution of MCRs to the state of the art of modern organic chemistry and its demonstrated potential in the synthesis of... 

In the intensively studied field of multicomponent reactions (MCRs), one can highlight several interesting cascades involving successive C-N and C-C bond formations. It is important to note that, although the majority of these sequences such as the Hantzsch, the Biginelli, or the Mannich reactions are known for more than one century, their organocatalytic enantioselective versions have been disclosed only very recently. 

However, many MCRs result in a single type of scaffold structure, for example, the Biginelli reaction or the Hantzsch dihydropyridine synthesis, which clearly... 

The Hantzsch synthesis can be conducted directly to the pyridines 167 in one-pot procedures (i) by combining the MCR process with oxidative aromatization by Pd-C/montmorillonite K-10 [123] and (ii) by using [NH4]C103 as a source of NH3 [124]. (b) In a three-component domino process, a,p-unsaturated aldehydes (mainly cinnamaldehydes), aromatic primary amines, and P-ketoesters catalyzed by CAN [125] or L-proline [126] are cyclocondensed to give N-arylsubstituted-5,6-unsubstituted 1,4-dihydropyridines 173 ... 

Like many other MCRs, the Hantzsch protocol usually commences with a condensation reaction that produces an imine from the amine and aldehyde. In this case, however, the Knoevenagel adduct undergoes addition by the nucleophilic p-keto ester, which generates the intermediary dihydropyranol. Ammonium acetate addition then finally initiates the expected cyclocondensation to give the aminal. Although the... 

Many basic MCRs are name reactions, for example, Ugi [2], Passerini [3], van Leusen [4], Strecker [5], Hantzsch [6], Biginelli [7], or one of their many variations. Several descriptive tags are regularly attached to MCRs because they are atom economical, for example, the majority, if not all, of the atoms of the starting materials... 

Despite the chemical complexity of multicomponent reactions (MCRs), the dawn of MCRs was fairly early in the history of organic chemistry. The first MCR was the so-called Strecker reaction discovered in 1850 [1, 2], which generates amino acids via a three-component reactiOTi between amines, aldehydes (or ketones), and hydrogen cyanide (Scheme 1). Since then, organic chemists have devoted much effort to the discovery of additional MCRs. Thus, we now can find a number of MCRs, including the Biginelli reaction [3], the Gewald reaction [4], the van Leusen three-component reaction [5], the Hantzsch reaction [6], the Mannich reaction [7], the Kabachnik-Fields reaction [8, 9], the Passerini reaction [10], the Ugi reaction [11, 12] and numerous variations thereof [13]. 

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