Hantzsch synthesis dihydropyridines

Hansa Yellows, 1, 334 5, 299 Hantzsch synthesis, 2, 87-88 1,4-dihydropyridine, 2, 482 thiazoles, 6, 294-299 A -thiazolines, 6, 314 Hantzsch-Widman names parent names, 1, 35 stem suffixes, 1, 12 Hantzsch-Widman system nomenclature, 1, 11-12 Hardeners in photography... 

The immediate outcome of the Hantzsch synthesis is the dihydropyridine which requires a subsequent oxidation step to generate the pyridine core. Classically, this has been accomplished with nitric acid. Alternative reagents include oxygen, sodium nitrite, ferric nitrate/cupric nitrate, bromine/sodium acetate, chromium trioxide, sulfur, potassium permanganate, chloranil, DDQ, Pd/C and DBU. More recently, ceric ammonium nitrate (CAN) has been found to be an efficient reagent to carry out this transformation. When 100 was treated with 2 equivalents of CAN in aqueous acetone, the reaction to 101 was complete in 10 minutes at room temperature and in excellent yield. 

An obvious outcome of the Hantzsch synthesis is the symmetrical nature of the dihydropyridines produced. A double protection strategy has been developed to address this issue. The protected chalcone 103 was reacted with an orthogonally protected ketoester to generate dihydropyridine 104. Selective deprotection of the ester at C3 could be accomplished and the resultant acid coupled with the appropriate amine. Iteration of this sequence with the C5 ester substituent ultimately gave rise to the unsymmetrical 1,4-dihydropyridine 105. 

A modihed Hantzsch synthesis has been utilized for the preparation of 1,4-dihydropyridines (Scheme 66). Thus, condensation of formylfurazans 116 with an acetoacetic ester and aminocrotonic acid ester in isopropanol at reflux led to 1,4-dihydropyridine derivatives 117 in about 70% yield (92AE921). Both isomeric furoxan aldehydes reacted in a similar way. 

A general method for the construction of a pyridine ring is the Hantzsch synthesis. A condensation reaction of two equivalents of a /3-ketoester 1 with an aldehyde 2 and ammonia leads to a 1,4-dihydropyridine 3, which can be oxidized to the corresponding pyridine 4—for example by nitric acid ... 

Dihydropyridines not only are intermediates for the synthesis of pyridines, but also are themselves an important class of N-heterocycles an example is the coenzyme NADH. Studies on the function of NADH led to increased interest in the synthesis of dihydropyridines as model compounds. Aryl-substituted dihy-dropyridines have been shown to be physiologically active as calcium antagonists. Some derivatives have found application in the therapy of high blood pressure and angina pectoris. For that reason the synthesis of 1,4-dihydropyridines has been the subject of intensive research and industrial use. The Hantzsch synthesis has thus become an important reaction. 

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]. 

Sugar Based Low Melting Mixtures as Green Solvents in The Hantzsch Synthesis of Substituted 1,4-Dihydropyridines... 

Franke PT, Johansen RL, Bertelsen S, Jorgensen KA (2008) Organocatalytic enantioselective one-pot synthesis and application of substituted 1,4-dihydropyridines - Hantzsch ester analogues. Chem Asian J 3 216—224... 

The most used route to pyridines is called the Hantzsch synthesis. This uses a 1,3-dicarbonyl compound, frequently a 1,3-keto ester [ethyl ace-toacetate (ethyl 3-oxobutanoate)], and an aldehyde, which are heated together with ammonia (Scheme 2.18). At the end of the reaction the dihydropyridine is oxidized to the corresponding pyridine with nitric acid (or another oxidant such as Mn02). The normal Hantzsch procedure leads to symmetrical dihydropyridines. Two different 1,3-dicarbonyl compounds may not be used as two enoiate anions might form, giving mixed products when reacted with the aldehyde. The aldehyde itself should preferably be non-enolizable, otherwise the chance of aldoliza-tion exists, but with care this can be avoided. 

Hantzsch synthesis The reaction of 1,3-dicarbonyl compounds with aldehydes and NH3 provides a 1,4-dihydropyridine, which can be aromatized by oxidation with nitric acid or nitric oxide. Instead of NH3, primary amine can be used to give 1-substituted 1,4-dihydropyridines. 

The more usual cyclocondensations of two identical molecules of 1,3-dicarbonyl or other C-acidic components with a third different oxo compound (mostly an aldehyde) afford exclusively 4//-pyrans and resemble the well-known Hantzsch synthesis of 1,4-dihydropyridines. It usually proceeds... 

There are several significant ring syntheses for pyridines, of which the most important is the Hantzsch synthesis of dihydropyridines (Section 4.2.3.4.2). However, the majority of substituted pyridines are prepared from pyridine itself or from a simple alkyl derivative. 

Khadilkar, B.M., Gaikar, V.G. and Chitnavis, A.A., Aqueous hydrotrope solution as a safer medium for microwave enhanced Hantzsch dihydropyridine ester synthesis, Tetrahedron Lett., 1995, 36, 8083-8083 Khadilkar, B.M. and Chitnavis, A.A., Rate enhancement in the synthesis of some 4-aryl- 1,4-dihydropyridines using methyl 3-aminocrotonate, under microwave irradiation, Indian J. Chem., Sect. B, 1995, 34, 652-653. 

Keywords aldehyde, /Tkctonic ester, urea, Hantzsch synthesis, microwave irradiation, 1,4-dihydropyridine... 

According to the classical Hantzsch synthesis of pyridine derivatives, an a,(5-unsaturated carbonyl compound is first formed by Knoevenagel condensation of an aldehyde with a P-dicarbonyl compound. The next step is a Michael reaction with another equivalent of the P-dicarbonyl compound (or its enamine) to form a 1,5-diketone, which finally undergoes a cyclocondensation with ammonia to give a 1,4-dihydropyridine with specific symmetry in its substitution pattern. 

In addition to procedures for pyridine ring closure based on the use of 3-amino-thiophene derivatives, there are alternative methods for the construction of thieno [3,2-Z>]pyridines. One approach made use of cyclic (3-keto sulfones, which proved to be convenient synthons for the modified Hantzsch synthesis of fused pyridines (1986KGS1563, 1990JHC1453, 2000MI1, 2002USP6191140). For example, the reactions of benzothiophene 1,1-dioxide 168 with enamines 169 or methylene-active compounds 170 in the presence of NH4OAc produced fused dihydropyridines 171 (1990JHC1453). 

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). 

As well as being intermediates for the synthesis of pyridines, these dihydropyridines are themselves an important class of heterocycles. For instance, dihydropyridine 5.14 is a drug for lowering blood pressure. In the synthesis of 5.14 note that carrying out the Hantzsch synthesis stepwise allows for the preparation of an unsymmetrical dihydropyridine, having both a methyl and an ethyl ester. 

The Hantzsch synthesis produces a reduced pyridine but there are many syntheses that go directly to pyridines. One of the simplest is to use hydroxylamine (NH2OH) instead of ammonia as the nucleophile. Reaction with a 1,5-diketone gives a dihydropyridine but then water is lost and no oxidation is needed. 

The Hantzsch pyridine synthesis affords 1,4-dihydropyridines 214, although spontaneous oxidation to pyridines often occurs. In its simplest form it involves the condensation of two molecules of a -keto ester with an aldehyde and ammonia (Scheme 119) . Compounds resulting from the condensation of ammonia with one of the carbonyl components can be used in the Hantzsch synthesis. Thus, -aminocrotonic ester 215 can replace the ammonia and one mole of acetoacetic ester in Scheme 119. The mechanism of the Hantzsch synthesis has been clarified by 13C and 1SN NMR spectroscopy <1987T5171>. 

A variation of the Hantzsch synthesis uses enaminones instead of / -dicarbonyl derivatives (for another variant, see Section II.A.l.e). Here the method consists of a condensation of two enaminone molecules and one molecule of aromatic or aliphatic aldehyde to give 1,4-dihydropyridines (equation 14). Various dihydropyridines have been synthesized by this method20-22. Enaminonitriles can be cyclocondensed in the same manner23 (equation 15). 

The same reaction was later carried out by Greenhill and coworkers240 using two equivalents of a cyclohexanedione derivative and 2-alkylaminoacroleins with the result of isolating unexpected acridinedione derivatives (equation 170). The reaction is explained by loss of the formyl group of aminoacrolein as a formic acid and is reminiscent of the Hantzsch synthesis of 1,4-dihydropyridines. 

The joint action of pyridine and thionyl chloride on aliphatic or aromatic aldehydes RCHO results in 1-chloromethylpyridinium chlorides 272, which react with ethyl jS-aminocrotonate to give 1,4-dihydropyridines 273 (equation 113). The reaction constitutes a modified Hantzsch synthesis it has the advantage over the latter that it proceeds under milder conditions and gives better yields138. The dihydropyridine 273 (R = H) is also readily obtained from ethyl / -aminocrotonate and formaldehyde in the presence of catalytic amounts of 4-(dimethylamino)pyridine139. 

The hydride-donating potential of 1,4-dihydropyridines has already been discussed in a mechanistic context in Section 1.3.2.3. Commonly available 1,4-dihydropyridines are the Hantzsch esters (7 X = OR), obtained from condensation of a -keto ester with ammonia and an aldehyde. By far the simplest syntheses of Hantzsch esters involve condensation of ammonia (substituted amines react in general poorly) and an aldehyde if a hydride equivalent at the 4-position is desired. The Hantzsch synthesis has been used in many guises, also to produce nonsymmetrical systems. The interest in these compounds as calcium antagonists has doubtless stimulated the extensive synthetic effort. ... 

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