Hantzsch multicomponent

A -(l-Haloalkyl)pyridinium halides have been advantageously employed in the Hantzsch multicomponent synthesis, yielding alkyl 1,4-dihydropyri-dine-3,5-dicarboxylates, which are a well-known class of calcium channel modulators (81AGE762). Tire halides readily interact with an excess of an ethyl 3-aminobut-2-enoate 82 (R = H) in dichloromethane at room temperature to afford the heterocycles 83 (R = H) in good to excellent yields (65-95%) (92T1263). Tliis observation has been exploited to perform a quantitative study of the reactivity of the salts (93CB1251).Tlie results have... 

In a related example involving the use of the same instrument (Fig. 12.6) in the Hantzsch multicomponent condensation, the serial synthesis of 24 dihydropyridine... 

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 ... 

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. 

For example, it was reported in several independent articles that multicomponent treatment of 5-amino-3-methylpyrazles with 1,3-cyclohexandiones and aldehydes under refluxing in EtOH [82, 83], in DMF with methanol [84], or with application of continuous-flow microwave-assisted procedure in DMSO [85] yielded exclusively pyrazoloquinolinones 50 (Scheme 23). On the other hand, the treatment of 3-unsub-stituted 5-aminopyrazoles with cyclic p-diketones or ketosulfones gave mixtures of Hantzsch dihydropyridines 51 and Biginelly dihydropyrimidines 52 in different ratios [86]. 

Other efforts in the anticancer area have focused on the use of heterocyclic podophyllotoxin analogs 76 as antiproliferative and apoptosis inducing agents [43, 44] Libraries of analogs were prepared by a one-step multicomponent Hantzsch-type protocol employing aminopyrazoles (Scheme 18). Apoptosis... 

The same group has also repotted a multicomponent Hantzsch protocol which provided access to polycyclic indenoheterocycles 78 utilizing a variety of aromatic and heterocyclic amines (Scheme 19) [45]. Some of the compounds disclosed showed apoptosis-inducing activity in a human T-cell leukemia cell line similar to etoposide. One of the most potent analogs was compound 79 (Scheme 19) which showed greater than 30% induction of apoptosis at 25 pM, as assessed in a flow cytometric aimexin V/propidium iodide assay in Jurkat cells. 

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]. 

A one-pot synthetic method for pyridines on a multigram scale was achieved from a condensation between 2 moles of a jS-keto ester and 1 mole of aldehyde under MWI using bentonite clay as a support and ammonium nitrate as the source of ammonia and oxidant. However, good yields of C-4 substituted pyridines 155 could only be obtained when the aldehydes were aliphatic, but only 5% yield of 155 (R = Ph) and 75% yield of 156 were obtained when benzaldehyde was used. A number of 1,3-dicarbonyl compounds including jS-keto esters were used as building blocks for the multicomponent Hantzsch synthesis (95T6511) whereby symmetrical 155 and 157 and nonsymmetrical pyridines 158 were synthesized (Scheme 32) (98TL1117). 

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... 

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... 

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