Dihydropyridine formation Hantzsch

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]. 

The classical Hantzsch reaction, the formation of dihydropyridines from an aldehyde, a 5-keto ester and an amine, was first described in 18826. In the 1940s, the interest for this substance class increased due to its pharmacological activity, for example, 4-aryl-1,4-dihydropyrdines form an important class of calcium channel antagonists such as Nifedipin. 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

Although the exact reaction mechanism for this three-component condensation reaction was not confirmed in [193, 194], the hypothesized mechanism is likely to involve the initial base-catalyzed formation of the Michael adduct, and its subsequent reaction with the aminopyrazole component to furnish the tricyclic intermediate (Scheme 3.63). Elimination of water from this intermediate leads to the formation of the classic Hantzsch-type dihydropyridine... 

A major synthetic use of l,4-dihydropyridine-3,5-dicarboxylates is as reducing agents. In particular, the so-called Hantzsch dihydropyridine 123 is frequently used, and an interesting example is formation of cyclopropane 124 from bromomethylcinnamates 122 (Scheme 33) <2001JOC344>. It was found that the reaction of either (/. )-122 or (Z)-122 gave identical yields of only the (-E)-isomer of cyclopropane 124. The same conditions can also be used to form indanes 126 from benzylic bromides 125. 

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. 

This review deals with the formation of reduced pyridines and their benzo analogs from the parent heteroaromatic bases. Included are acridines, isoquinolines, pyridines and quinolines and their quaternary ammonium salts and N-oxides. The formation of the reduced species by other methods, e.g. Hantzsch dihydropyridine synthesis, is not addressed. 

The resulting achiral iminium cations, with chiral phosphate counteranion, were then enantioselectively reduced using an achiral Hantzsch ester (dihydropyridine) providing enantioenriched amines. During this imine reduction study, one example was shown in which acetophenone and p anisidine [16] were prestirred in the presence of toluene and 4 A molecular sieves [17] for 9h (imine formation), after which the temperature was raised to 35 °C, and the Hantzsch ester (1.4 equiv) and phosphoric acid (TRIP, 5 mol%) were added to give the amine product in 88% ee over an additional 45 h. This is an exciting observation and while not a reductive amination, it is an operational improvement over simple imine reduction which requires imine isolation. 

Formally, one can also propose the formation of the 2,5-dihydro isomer, but even if this isomer does form during the reaction, it is easily transformed to the thermodynamically more stable 1,2-dihydro compound. This reaction is nearly identical to the classical Hantzsch s synthesis of dihydropyridines, with only the molar ratio of starting materials being changed. However, in contrast to the widely investigated Hantzsch reaction, there are few examples in the literature, and it needs detailed study. 

Two unusual Hantzsch ester syntheses have been reported. One involved elimination of a 4-antipyiyl group during spontaneous aromatization of the 1,4-dihydropyridine intermediate (94H(37)815). Other reported formation of an oxygen-bridged tetrahydropyridine (34) (Scheme 14) <94JCR(S)106). 

Symmetric 1,4-Dihydropyridines The most common Hantzsch synthesis produces symmetrical 1,4-dihydropyridines by the use of two equivalents of the P-ketocarbonyl compound. For the solvent-free performance, the nitrogen sources are limited to sohd or high boiling ones, like ammonium acetate [220-224, 232, 235], ammonium chlorate [237], ammonium formate [238], or primary aryl amines (Scheme 13.131) [218b]. 

In this process - which is complementary to the classical Hantzsch synthesis - primarily a,P-unsaturated imines 174 are likely to be formed, which undergo Michael addition with the P-ketoester ( 175) followed by cyclizing enamine formation establishing the C-2/C-3 bond of the 1,4-dihydropyridine 173. 

The synthesis is initiated by the organocatalyzed cascade that activates a,p-unsaturated aldehyde 8 with the formation of an iminium ion (Scheme 14.2). In this way, the imidazolidinone catalyst allows hydride transfer from the Hantzsch dihydropyridine 9 onto the highly activated conjugated alkene 11, which creates the nucleophilic enamine intermediate 12. Because of the chirality of the organocatalyst, stereoselective Michael addition (97% ee) to the adjacent enone occurs, with minor preference for the cis diastereomer (2 1 dr). Fortunately, this undesired diastereomer slowly epimerizes to the required trans isomer, which produces (-l-)-ricciocarpin A when treated with samarium triisopropoxide. Besides the Cannizzaro-like redox disproportionation, which allows the lactone producing Evans-Tihchenko reaction to occur, samarium(III) also enhances the epimerization to the trans isomer and therefore produces the desired isomer in high selectivity. 

A one-pot Hantzsch reaction in aqueous medium without any solvent or catalyst is known for the synthesis of 1,4-dihydropyridines. Tamaddon and coworkers have reported the synthesis of 1,4-dihydropyridines 107 by the reaction of aldehydes 51 and methyl/ethyl acetoacetates 106 in aqueous ammonium carbonate at 55-60 °C (Scheme 35) [88]. Recently, a similar study has also been carried out by Yang and coworkers to obtain dihydro-pyridines [89]. Another example of dihydro pyridine ring formation in water employs methyl/ethyl acetoacetates and aromatic aldehydes with 6-amino-l,3-dimethyluracil in the presence of thiourea dioxide as the catalyst [90]. The utilization of water as a solvent and indium(III) chloride as a promoter for the formation of dihydropyridine ring is reported by Khurana and coworkers in the reaction of with 6-amino-l,3-dimethyluracil, aldehydes, and 1,3-diketones [91]. 

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