Hantzsch procedure

Bohlmann and Rahtz, in 1957, reported the preparation of 2,3,6-trisubstituted pyridines. Their method employed the Michael addition of acetylenic ketones 35 with enamines 36. The 5-aminoketones 37 are typically isolated and subsequently heated at temperatures greater than 120°C to facilitate the cyclodehydration to afford 38. Again one can see the parallels in this mechanism with that for the Hantzsch protocol. However, in this case the pyridine is formed directly removing the need for the oxidation step in the Hantzsch procedure. 

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]... 

Thiazole and its derivatives are conventionally prepared from lachrymatory, a-halo-ketones and thioureas (or thioamides) by Hantzsch procedure [146]. In a marked improvement, Varma et al. have synthesized the title compounds by the simple reaction of in situ-generated a-tosyloxyketones, from arylmethyl ketones and [hydroxy(tosyl-oxy)iodo]benzene (HTIB), with thioamides in the presence of K 10 clay using micro-wave irradiation (Scheme 6.43) the process is solvent-free in both the steps [147]. 

The standard Hantzsch procedure does not involve the use of additive or reagent, but to improve reaction time and yield, the use of a large variety of catalysts has been developed, which makes possible to operate at room temperature in some cases. In the last few years, particular efforts have been devoted to the utilization of low cost, nontoxic, environmentally benign and reusable catalysts [22, 29 0]. 

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]. 

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. 

Hint a simple Hantzsch procedure cannot be used since mixed products would form (see Section 2.6.1, p. 28). 

Holzapfel-Meyers-Nicolaou Modified Hantzsch Procedure Stepl... 

Hantzsch procedure. In his initial work, Knoevenagel used Claisen s method (anhydrous HCl) for the synthesis of the alkylidine acetoacetates, and used sodium ethoxide to catalyze the Michael addition of the second equivalent of acetoacetate. 

The known but newer, more elaborate approach to 4//-thiopyrans by procedures A, B, and C (Scheme 1) resembles the Hantzsch-like syntheses of 4iT-pyrans (83AHC145, Section III,D). The results are summarized in Table I for 3,5-dicyano products 21. The chemistry of cyanothioacetamide as the key starting component has also been reviewed (86H2023 87H205). Cyclocondensations A to C usually proceed under mild conditions and afford 21 in satisfactory yields. 

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. 

A one pot procedure for the preparation of 1,3-sclenazoles has been reported. The method, a variation on the Hantzsch synthesis, involves the a-tosylation of ketones 90 with [hydroxy(tosyloxy)iodo]benzene followed by treatment with selenoamides to give 1,3-selenazoles 91 in moderate to high yields <00S1219>. 

List was the first to explore this possibility, examining the Hantzsch ester mediated reduction of a,P-unsaturated aldehydes [209], Using 20 mol% of the binaphthyl derived phosphonate salt of morpholine (153) in dioxane at 50 °C, a series of P-aryl a,P-unsaturated aldehydes underwent transfer hydrogenation with Hantzsch ester 154 with excellent levels of absolute stereocontrol (96-98% ee) (Scheme 63). The method was also applied to the aliphatic substrates ( )-citral and famesal to give the mono-reduced products in 90% and 92% ee, respectively. Significantly, in line with many of the chiral secondary amine catalysed transformations described above the reactions follow a simple and practical procedure without the need for exclusion of moisture and air. 

Subsequently, List reported that although the method described above was not applicable to the reduction of a,P-unsaturated ketones, use of a chiral amine in conjunction with a chiral anion provided an efficient and effective procedure for the reduction of these challenging substrates [210]. Transfer hydrogenation of a series of cyclic and acyclic a,P-unsaturated ketones with Hantzsch ester 119 could be achieved in the presence of 5 mol% of valine tert-butyl ester phosphonate salt 155 with outstanding levels of enantiomeric control (Scheme 64). A simple mechanistic model explains the sense of asymmetric induction within these transformations aUowing for reliable prediction of the reaction outcome. It should also be noted that matched chirality in the anion and amine is necessary to achieve high levels of asymmetric induction. 

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]. 

The modified element name sila indicates replacement in the carbon skeleton, and similar treatment can be applied to other element names. The parent hydride names of Table 5.2 may all be adapted in this way and used in the same fashion as in the oxa-aza nomenclature of organic chemistry. In inorganic chemistry, a major use is in names of cyclic derivatives that have heteroelement atoms replacing carbon atoms in structures. It may be possible to name such species by Hantzsch-Widman procedures (see p. 77), and these should always be used when applicable. 

Various more or less efficient methods have been reported for the synthesis of 2-(l-ami-noalkyl)thiazole-4-carboxylic acids and their suitably protected derivatives. 237,539,541,558-568 Optimal conditions must be selected in these syntheses to prevent racemization at the chiral aminoalkyl moiety, e.g. when applying a modified Hantzsch synthesis 559 racemization has been observed to occur at the level of the starting Na-protected amino acid thioamide as well as in the base-mediated dehydration step of the intermediate hydroxydihydrothiazoles. 558 The 2-(aminoalkyl)thiazole-4-carboxylic acids are incorporated into the linear precursors by standard procedures of peptide synthesis, 237,514,529,539,552,555,558,564,569 and cyclization is pref-... 

As might be expected, there are relatively few reactions for the preparation of heterocyclic systems which are useful on a laboratory scale and which involve the formation of four ring bonds. The Hantzsch pyridine synthesis (equation 148) (and a number of variations of the original procedure) is perhaps the classic example of this type of reaction, which is... 

Recently, we established that several proton acids catalyze the metal-free reduction of ketimines under hydrogen-transfer conditions with Hantzsch dihydropyridine as the hydrogen source.Additionally, we were able to demonstrate a catalytic enantioselective procedure of this new transformation by employing a chiral Br0nsted acid as catalyst.(see Chapter 4.1). 

We summarize here the rules of the so-called Hantzsch-Widman nomenclature system for heterocycles, which currently is the fashionable procedure, although relegated to second-class status by a recent, very practical approach to organic nomenclature.1... 

Ohberg, L. and Westman, J., An efficient and fast procedure for the Hantzsch dihydro pyridine synthesis under microwave conditions, Synlett, 2001, 8, 1296-1298. 

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. 

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). 

General Procedure for Transfer Hydrogenation of Enals Using Symmetric Hantzsch Ester [97] (pp. 110 and 394)... 

Cyano-5-(3,4-dimethoxyphenyl)-l-methylpyrazinium iodide (356) gave 6-(3,4-dimethoxyphenyl)-4-methyl-4,5-dihydro-2-pyrazinecarbonitrile (357) [ Hantzsch ester (diethyl 2,6-dimethyl-l,4-dihydro-3,5-pyridinedicar-boxylate) (1 mol), MeCN, 20°C, 3 h 80% or NaBH4, MeCN, 20°C, 30 min 83%], and thence 6-(3,4-dimethoxyphenyl)-4-methyl-l,4,5,6-tetrahydro-2-pyrazinocarbonitrile (357a) (repeat procedures for 24 and 3 h, respectively, both affording 72%).1262... 

With the chiral BINOL-phosphates in hand we started to examine the enantioselective transferhydrogenation of ketimines 1. After reaction optimization, including a survey of different solvents, temperatures, BINOL-phosphates, and Hantzsch dihydropyridines, we found that indeed enantioselectivities are observed and the best selectivities are obtained with Brpnsted acid 5a and Hantzsch ester 2a (Table 2). In general, for the first time, high enantioselectivities and good yields are observed in this newly developed metal-free reduction procedure (Rueping et al. 2005b Hofmann et al. 2005 Storer et al. 2006). 

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