Hantzsch pyridine derivatives

Hantzsch pyridine derivatives 146 were prepared by the reaction of aldehydes and 3-dicarbonyls in the presence of ammonium chlorate at 80 C under solvent-free conditions. Ammonium chlorate was used both as ammonia source and as oxidizing agent source for the direct synthesis and oxidation of Hantzsch 1,4-dihydropyridines to pyridines. 

Hantzsch synthesis The formation of pyridine derivatives by the condensation of ethyl acetoacetate with ammonia and an aldehyde. Also applied to similar syntheses of pyrroles. 

Subsequent to Hantzsch s communication for the construction of pyridine derivatives, a number of other groups have reported their efforts towards the synthesis of the pyridine heterocyclic framework. Initially, the protocol was modified by Beyer and later by Knoevenagel to allow preparation of unsymmetrical 1,4-dihydropyridines by condensation of an alkylidene or arylidene P-dicarbonyl compound with a P-amino-a,P-unsaturated carbonyl compound. Following these initial reports, additional modifications were communicated and since these other methods fall under the condensation approach, they will be presented as variations, although each of them has attained the status of named reaction . 

The rapid synthesis of heteroaromatic Hantzsch pyridines can be achieved by aromatization of the corresponding 1,4-DHP derivative under microwave-assisted conditions [51]. However, the domino synthesis of these derivatives has been reported in a domestic microwave oven [58,59] using bentonite clay and ammoniiun nitrate, the latter serving as both the source of ammonia and the oxidant, hi spite of some contradictory findings [51,58,59], this approach has been employed in the automated high-throughput parallel synthesis of pyridine libraries in a 96-well plate [59]. In each well, a mixture of an aldehyde, ethyl acetoacetate and a second 1,3-dicarbonyl compound was irradiated for 5 min in the presence of bentonite/ammonium nitrate. For some reactions, depending upon the specific 1,3-dicarbonyl compound used. 

A variety of conditions (solution, dry media, solvent-free) has been used for microwave-assisted synthesis of Hantzsch 1,4-DHP only procedures involving solvent-free conditions under the action of irradiation led to the aromatized pyridine derivatives. 

In Hantzsch s synthesis the condensation product is a derivative of dihydropjndine and is only converted into a true pyridine derivative by dehydrogenation. It is only by the removal of the two hydrogen atoms in the 1 4-positions that the heterocyclic ring system analogous to benzene is produced. The corresponding conversion of ethyl A 2 5-dihydroterephthalate into ethyl terephthalate takes place much more readily. 

The Hantzsch reaction that allows the synthesis of pyridine derivatives, is a condensation involving two equivalents of a yS-ketoester or a yS-ketoamide, one equivalent of an aldehyde and ammonia. The Hantzsch reaction was used by Patel et al. for the synthesis of a 300 member dihydropyridine library (Scheme 3.27) [287]. 

Hantzsch 1,4-dihydropyridines were oxidized quantitatively to give the corresponding pyridine derivatives by irradiation in CCI4. A photo-induced electron-transfer mechanism is involved. The critical step in this mechanism is the fast dechlorination of CCI4 (Scheme A)P... 

The formation of azine derivatives by condensation of enamines and enamides with 1,3-dielectrophiles has been known for almost a century, and there are a number of reactions (e.g. the Hantzsch pyridine synthesis) which proceed by intermediate formation of such compounds. Examples are shown in equations (117)—(119). The transformations outlined in equations (120) and (121) are mechanistically related processes. 

Among the methods available for the synthesis of the pyridine system, Hantzsch synthesis is probably the most important and widely used synthetic route. However, the pyridine ring can be synthesized from the reaction between pentan-2,4-dione and ammonium acetate. Cyclization of 1,5-diketones is also considered as a convenient method for the synthesis of corresponding pyridine derivatives. Commercially, pyridine is obtained from distillation of coal tar. 

Various approaches can be used to synthesize pyridines and partially saturated pyridines on insoluble supports. Dihydropyridines can be readily prepared by cyclocondensation of amines with ketones and aldehydes (Hantzsch pyridine synthesis, Figure 15.12). This synthesis proceeds particularly smoothly when using a 3-keto carboxylic acid derivative as the ketone component. This cyclocondensation has been realized on... 

Another important reaction of diketene derivatives is the Hantzsch pyridine synthesis (101). This synthesis is the preparation of 1,4-dihydropyridines (14) starting either from two acetoacetic esters, which react with an aldehyde and ammonia or a primary amine or from 3-aminocrotonates and 2-alkylidene acetoacetic esters, both diketene derivatives. Several such dihydropyridines such as nifedipine [21829-25-4] (102), nimodipine [66085-59-4], and nicardipine [55985-32-5] exhibit interesting pharmaceutical activity as vasodilators (blood vessel dilation) and antihypertensives (see Cardiovascularagents). 

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. 

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. 

An iron-catalyzed reaction of an a,P-unsaturated oxime such as 68 with a P-oxo ester also gave pyridine derivatives such as nicotinic acid 69 [99]. Under the reaction conditions (150-160 °C, without solvent) first Michael adducts such as intermediate 70 are presumably formed, which further condense via intermediate 71. This method is not restricted to a centric symmetry in the substitution pattern, which is an advantage compared with the Hantzsch synthesis. Moreover, the method starts with hydroxylamine being two oxidation stages above ammonia therefore, no oxidation in the final stage from dihydro- to pyridine is necessary (Scheme 8.31). 

The study of the enamine structure may be associated, to a certain degree, with the problem of the so-called pseudobases an instructive, but somewhat specialized, review of these compounds was contributed by the late Professor Beke 47 to the first volume of this series. The name pseudobases was given by Hantzsch,48 towards the end of the last century, to those a-aminocarbinols which undergo a structural change during salt formation and yield salts with the loss of one molecule of water. The liberation of pseudobases from their salts is accompanied by rehydration. This behavior has been observed with a,/3-unsaturated heterocyclic compounds and, to a certain degree, with aromatic heterocyclic pyridine derivatives. As formulated by Gadamer,49 the pseudobases represent a potential tautomeric system of three components, the quaternary hydroxide A, the carbinolamine B, and the open-chain amino-carbonyl derivative C, in which all three components exist in a mobile equilibrium ... 

The Hantzsch pyridine synthesis gives initially a dihydropyridine from the cyclization reaction. Adaptation of this reaction to the use of a 2-methylenethiazolidine yields the fused tetrahydro derivative (502) (77LA1888). Perhydro derivatives are simply prepared from 2-substituted thiazolidines by cycloalkylation as for (503) (80S387). The thiazolidine may also be generated in situ as in the reaction between y-benzoylbutyric acid and 2-mercaptoethylamines under azeotropic conditions to yield (504) (65JOC1506). 

There are numerous variations in the Hantzsch protocol deriving from variations in the aldehydes, ammonia derivatives and active methylene compounds employed. The final products are 1,4-dihydropyridine and pyridine derivatives as well as pyrroles. 

The above equation represents the classical pyridine synthesis of Hantzsch, the starting materials being an aldehyde, a /S-keto ester, and ammonia. The over-all yield of 3,5-dicarbethoxy-2,6-dimethylpyridine from formaldehyde, acetoacetic ester, and ammonia is 4S>-58%. A study of substituted aromatic aldehydes in this synthesis has been made. This is one of many condensations of aliphatic compounds that leads to pyridine derivatives. Although these condensations have been subdivided in various ways for purpose of discussion, the lines of de-... 

Hantzsch, A. Synthesis of pyridine derivatives from acetoacetic ester and aldehydeammoniak. Liebigs Ann. Chem. 1882, 215,1-82. 

In this transfer hydrogenation, aromatization of the dihydropyridine (Hantzsch ester) to form a pyridine derivative is essential for it to act as the hydride source. 

Alkynes bearing electron-withdrawing substituents are more suitable for this reaction as was shown earlier by Bohlmann and Rahtz. Pyridines are formed from intermediate Michael adducts in the reaction of a-oxoalkynes having a j8-hydrogen and several primary enaminones in high yield. If, however, jS-substituted propargylaldehyde derivatives are used, a normal Hantzsch-type reaction without attack of the alkyne bond leads to 1,4-dihydropyridines (equation 79). This method was used later for converting cyclic enaminones to pyridine derivatives, however in low yield, and to quinolines in a better yield (equation 80). 

A survey of microwave activation in the chemistry of Hantzsch 1,4-dihydropyridines (1,4-DHP) was reported in 2003 [195]. The experimental method proposed more than a century ago remains the most widely used for synthesis of these heterocycles. Since 1992 the process has been adapted to microwave irradiation under a variety of conditions to reduce the reaction time and enhance the yield. Among these experiments, Zhang reported a solvent-free process starting from 3-aminocrotonate (20 mmol), methyl acetoacetate (20 mmol), and aromatic aldehydes (20 mmol) in a domestic oven [196]. Yields from 59 to 77% were reported for 10-min reaction. A variety of conditions (solution, dry media, solvent-free) has been used for microwave-assisted synthesis of Hantzsch 1,4-DHP. Only procedures involving solvent-free conditions under the action of microwave irradiation led to the aromatized pyridine derivatives. 

A new approach to stereoselective transfer hydrogenation of imines was the application of chiral phosphoric acid esters as organocatalysts [50-52]. The mechanism is based on the assumption that the imine is protonated by a chiral Bronsted acid, which acts as the catalyst. The resulting diastereomeric iminium ion pairs, which may be stabilized by hydrogen bonding, react with the Hantzsch dihydropyridine at different rates to give an enantiomerically enriched amine and a pyridine derivative [50-52]. The exact mechanism is still under discussion however computational density functional theory (DFT) studies ]53, 54] suggest a three-point contact model. ... 

Hantzsch s first important research was the synthesis of pyridine from acetoacetic ester and aldehyde ammonia, a general method of synthesis of pyridine derivatives. Coumarone, discovered by Fittig and Ebert (see p. 768), was (with some derivatives) synthesised by Hantzsch, who called it the fur-furane of the naphthalene series . He synthesised thiazole, and benzene, pyridine, and thiophen derivatives from derivatives of pentamethylene, and pyrrole, investigated tetrazoles, and perthiocyanic acid C2N2S3H2 (discovered by Wohler), giving it a cyclic structure." ... 

The Hantzsch synthesis has been used to generate pyrroles, thiazoles and dihydropyridine derivatives. Pyrroles (3) are generated from the reaction of P-ketoesters with ammonia, ammonia derivatives or primary amines, and a-haloketones (path A). Thiazoles (5) are generated from the reaction between a-haloketones and thiourea or thioamide derivatives (path B). Dihydropyridines (7) are generated from the reaction of aldehydes with p-ketoesters and ammonia or ammonia derivatives, or enamines derived from the reaction of ketones or P-ketoesters with amines (path C). Dihydropyridines can be readily converted to the corresponding pyridine derivatives and so this reaction is often termed the Hantzsch pyridine synthesis. 

In carbon-14 chemistry, Knoevenagel-Michael sequences with alkyl acetoacetates have found widest application in the synthesis of labeled 1,4-dihydropyridines (Hantzsch dihydropyridine synthesis). 4-Aryl-l,4-dihydro[ C]pyridine derivatives constitute a class of calcium antagonists and calcium channel blockers that play an important role in the treatment of cardiovascular diseases. The basic sequence, depicted in Figure 6.90, involves first the Knoevenagel condensation of an aromatic aldehyde with an alkyl... 

Probably first obtained by Hantzsch and Arapides (105) by condensation of a,/3-dichlorether with barium thiocyanate, and identified by its pyridine-like odor, thiazole was first prepared in 1889 by G. Popp (104) with a yield of 10% by the reduction in boiling ethanol of thiazol-2-yldiazonium sulfate resulting from the diazotization of 2-aminothiazole. prepared the year before by Traumann (103). The unique cyclization reaction affording directly the thiazole molecule was described in 1914 by Gabriel and Bachstez (106). They applied the method of cyclization, developed by Gabriel (107, 108), to the diethylacetal of 2-formylamino-ethanal and obtained thiazole with a yield of 62% - Thiazole was also formed in the course of a study on the ease of decarboxylation of the three possible monocarboxylic acids derived from it (109). On the other... 

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. 

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