Hantzsch reaction modified

Oxa-tetrahydropyridines are interesting intermediates for the preparation of pharmaceuticals and natural product based alkaloid systems. A modified Hantzsch reaction was developed under microwave irradiation for the preparation of 2-oxa-tetrahydropyridines 173 by reaction of Meldrum s acid, a /3-ketoester and an aldehyde, using NH4OAC as the source of ammonia (Scheme 62). Yields ranged from 81 to 91% at temperatures of 100-130 °C depending on the substrate (the aldehyde) employed. All the products obtained have the same structure except for the aromatic substituent in position 4 [109]. 

Scheme 62 A modified Hantzsch reaction for the preparation of 2-oxa-tetrahydropyridines...

Hofmann (1889LA(250)294) was the first to report the synthesis of selenazoles in a modified Hantzsch reaction in which derivatives of selenocarboxamides are allowed to react with a-chlorocarboxyl compounds. Other substituted selenazoles are prepared similary (Scheme 19). 

This reaction was first reported by Hantzsch and Weber in 1887. It is the formation of thiazole derivatives by means of condensation of a-haloketones (or aldehydes) and thioamides. Therefore, it is generally known as the Hantzsch thiazole synthesis. In addition, other names, including the Hantzsch synthesis, Hantzsch reaction, and Hantzsch thiazole reaction are also used from time to time. Besides thioamides, other thio-ketone derivatives such as thiourea, dithiocarbamates, and ketone thiosemicarbazone can also condense with a-halo ketones (or aldehydes) to form thiazoles. This reaction occurs because of the strong nucleophilicity of the sulfur atom in thioamides or thioureas, and normally gives excellent yields for simple thiazoles but low yields for some substituted thiazoles, as of dehalogenation. This reaction has been proven to be a multistep reaction, and the intermediates have been isolated at low temperatures, in which the dehydration of cyclic intermediates seems to be the slow step. It is found that a variety of reaction conditions might result in the racemized thiazoles that contain an enolizable proton at their chiral center, and it is the intermediate not the final product that is involved in the racemization. Therefore, some modifications have been made to reduce or even eliminate the epimeriza-tion upon thiazole formation. In addition, this reaction has been modified using a-tosyloxy ketones to replace a-haloketones. ... 

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 modified two component Hantzsch (Baeyer-Knoevenagel modification) was also examined. Shorter reactions times (2-3 h) were noted in this variation using 82 and 85 with slightly better yields (78-85%) being observed for the formation of 84. 

Faneti/ole (122) is a biological response modifier with significant immunosuppressant activity It can be synthesized by conversion of 2 phen> lethylamine (120) with ammonium thio cyanate to the corresponding thiourea analogue 121 The synthesis of faneli/ole (122) concludes by thiazole nng formation of 121 by reaction with phenacylbromide Thus its synthesis involves use of the classic Hantzsch procedure in which a bromoacetone analogue and an appropriate thio urea denvative are reacted 143]... 

A-Thiazolyl a-amino acids 56 have been prepared. The preferred route to these compounds would utilise the Hantzsch synthesis, however in this case the in situ formation of the required thiourea derivatives of a-aminoacids 52 failed. A variety of isothiocyanate reagents were tried, with the result being either no reaction, decomposition or the corresponding thiohydantoin 53. A modified version of the Hantzsch synthesis was developed. If the bromoketone 54 is initially treated with sodium thiocyanate an a-thiocyanatoketone 55 is formed, subsequent addition of the amino acid ester 51 yields A-thiazolyl a-amino acids 56 <00T3161>. 

In classical Hantzsch procedure, an enaminocarbonyl is formed in sim by condensation of ammonia source onto the 1,3-dicarbonyl substrate. But many groups have used a three-component modified-Hantzsch protocol in which the preformed enamine is introduced as a partner. Thus, utilization of cyclic or acyclic 1,3-dicarbonyl compounds, aldehydes, and acyclic or cyclic enamines has been reported, leading regioselectively to diversely substituted 1,4-DHP derivatives (Scheme 7). The sequence involving such starting materials was performed in numerous efficient systems, and more particularly in the following (1) microwave-assisted reaction in acetic acid [50], DMF [51], or an acetic acid/DMF system [52] (2) sonification in ethylene glycol [53] and (3) use of ionic liquids such as [bmim]BF4 [54]. 

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 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. 

Khadilkar and Madyar have developed a large scale continuous synthesis of Hantzsch l,4-dihydropyridine-3,5-dicarboxylates in aqueous hydrotope solution, using a modified domestic microwave oven [81]. The authors used novel reusable aqueous hydrotope solution as a safe alternative to inflammable organic solutions, in a microwave cavity, for synthesis of commercially important calcium blockers such as nifedipine, nitrendipine, and a variety of other 1,4-dihydropyridines (DHP) (Scheme 10.38). Nitrendipine (R = 3-N02, R = Me) has been obtained in 94% yield (50 g) after 24 min by microwave irradiation of the reaction mixture (final temperature 86 °C) at a flow rate of 100 mL min. The reaction mixture was circulated through the microwave cavity in four cycles of 6 min each a 2-min gap between each cycle was imposed to avoid excessive heating. 

The Hantzsch synthesis of thiazoles was presented in Chapter 4 as an example of a modified Paal-Knorr method. The reaction is reproduced here as Scheme 9.15. 

Shan and Knaus also used a chiral auxiliary in their modified Hantzsch approach to the synthesis of two new 1,4-dihydropyridine derivatives." Unfortunately, reaction of 3-aminocrotonate ester 249 with 2-trifluoromethylbenzadehyde 209 and 3-nitropropionate 250 gave 251 as a mixture of diastereomers in low yield (22%) with nearly equal mixtures of the R and desired S enantiomers (/ ,S,/ (10%) and 12%)). 

Lee used baker s yeast in his enzymatic approach to the synthesis of 1,4-dihydropyridines. The traditional Hantzsch synthesis was explored whereby 2 equiv of methyl acetoacetate 180 and ammonium acetate were treated with baker s yeast in a phosphate buffer to produce the corresponding dihydropyridine 179 in 67% yield. A modified Hantzsch was also employed in the synthesis of asymmetrical derivative 277. Treatment of 1 equiv of methyl acetoacetate 180 with 1 equiv of crotonitrile 217 gave the corresponding dihydropyridine derivative 277 in 46% yields. The traditional and modified approaches were also conducted using ethyl acetoacetate with similar yields for the reported reaction products. 

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