Hantzsch multicomponent reaction

Dondoni, A., Mass , A. Decoration of dihydropyrimidine and dihydropyridine scaffolds with sugars via Biginelli and Hantzsch multicomponent reactions An efficient entry to a collection of artificial nucleosides. Mol. Divers. 2003, 6, 261 -270. 

In Scheme 1.8.5.4, three versions of the Hantzsch multicomponent one-pot reaction are shown leading to thiazoles, pyrroles and dihydropyridines.3 ... 

Dihydropyridines can be prepared via the three-eomponent coupling of cinnamaldehyde, aniline and p-keto esters under solvent-free conditions by means again of L-Pro as catalyst in the transformation. The three-component reaction of 1,3-indanedione, isatins and enamines as the nucleophiles is also possible in the presence of L-Pro for the one-pot synthesis of highly functionalised spirooxindoles derivatives. While only some examples are highlighted here, ° ° the possibilities of L-Pro in multicomponent reactions are tremendous. It has also shown good catalytie activity in classic multicomponent reactions such as Biginelli reactions and Hantzsch dihydropyridine synthesis. 

Ramachary and Reddy developed one of these sequences using an amino acid-catalyzed three-component reductive alkylation (TCRA) as the first reaction of their MCC. This multicomponent reaction involved an aldehyde 21, a malonate 22, and the Hantzsch ester 24 under amino acid catalysis starting with a Knoevenagel condensation, which was followed by hydrogenation of the formed olefin 23 to form... 

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. 

Hantzsch s reaction is a multicomponent organic reaction between an aldehyde, a P-keto ester, and a nitrogen donor such as ammonium acetate or ammonia. It provides rapid access to dihydropyridine and polyhydroquinoline derivatives, which constitute an important class of calcium channel blockers. Zinc oxide nanoparticles have been used for one-pot four-component synthesis of Hantzsch s polyhydroquinolines (7) and 1,4-dihydropyridines (5) in higher yields and short reaction times by the condensation of aldehydes (1), dimedone (2), active methylene compounds (4,6), and ammonium acetate (3) under solvent-free conditions at room temperature (Kassaee et al. 2010) (Scheme 9.1). 

H. Banitaba, S. D. KhalUi, J. Mol. Catal. A Chem. 2011, 335, 46-50. Cellulose sulfuric acid catalyzed multicomponent reaction for efficient synthesis of 1,4-dihydropyridines via unsymmetrical Hantzsch reaction in aqueous media. 

H. Masrouri, F. Movahedi, Monatsh. Chem. 2010, 141, 317-322. ZnO-nanoparticle-promoted synthesis of poly hydroquinoline derivatives via multicomponent Hantzsch reaction, (d) F. K. Behbahani, H. S. Alaei, J. Chem. Sci. 2013,125, 623-626. L-Proline-catalysed synthesis of functionalized unsymmetrical dihydro-lH-indeno[l,2-b]pyri-dines. (e) S. K. Singh, K. N. Singh, J. Heterocycl. Chem. 2010, 47, 194—198. Glycine-catalyzed easy and efficient one-pot synthesis of polyhydroquinolines through hantzsch multicomponent condensation under controlled microwave. 

Even though the history of multicomponent reactions dates baek to the second half of the 19th century with the reactions of Strecker, Hantzsch, and Biginelli, it was only in recent decades with the work of Ugi that the concept of the multicomponent reaction has emerged as a powerful tool in synthetic... 

Note that the classical syntheses of dihydropyridines (eg, Hantzsch synthesis) employ de novo construction of the rings by multicomponent reactions rather than starting from pyridines, and that some of the pyridine reduction processes are actually reductions of pyridinium cations (eg, Fowler s sodium borohydride reduction of the N-acylpyridinium salts produced in situ by the reaction of pyridines with chloroformate esters). 

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]. 

In 1882, Hantzsch achieved the synthesis of symmetrically substituted dihydropyridines (DHPs) by reacting ammonia, aldehydes, and two equivalents of yS-ketoest-ers [27]. Since then, interest in these types of compound has grown, because of their pharmacological activity [28]. The Hantzsch reaction has successfully been used for synthesis of a wide range of DHPs and is still a popular tool for the construction of members of this class of heterocycles [29]. The classical multicomponent synthesis may require extended reaction times and yields can be low if sterically hindered aldehydes are used [30]. 

Pyrroles are the core unit of a wide variety of natural products [76]. Although many methods are available for the synthesis of these species, most are multi-step procedures resulting in low yields [77, 78]. However, Hantzsch made another important contribution to the progress of multicomponent chemistry. In his procedure pyrroles were successfully prepared from primary amines, j8-ketoesters, and a-halo-genated j5-ketoesters [79]. Only a few other one-step procedures have been reported for pyrroles but, because of to long reaction times and insufficient scope of substitution at the ring, these are not very satisfactory [80, 81]. 

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... 

Kassaee, M.Z., Masrouri, H. and Movahedi, F. 2010. ZnO-nanoparticle-promoted synthesis of polyhydroquinoline derivatives via multicomponent Hantzsch reaction. Chem. Month. 141 317-322. 

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