Marckwald reaction

Furylcarbinols with protic acids (fluoroboric acid) may merely give car-benium (furylium) salts.171 Similar cations are accessible via 2-furyldiazo-methane derivatives,172 but in many cases ring opening and prototropic shifts ensue as in Marckwald reactions (Scheme 30).173 A recent development controls solution acidity by using magnesium or zinc ions instead of protons... 

Examples are available.287, 289, 290-292 The reaction is inherently analogous to the so-called Marckwald reaction. 

Bauman and Axendale [12] reported a new approach to synthesized functionalized thioimidazoles via three-component reaction using unprotected aldoses and ketoses. This sequential approach is based on the Marckwald reaction as illustrated in Scheme 6.8. 

The third approach is the main topic of this volume. According to the definition given above it involves enantiomerically pure starting materials which at some point must be provided by resolution or ex-chiral-pool synthesis. It is more or less equivalent to the term asymmetric synthesis defined by Marckwald in 19047 as follows Asymmetric syntheses are those reactions which produce optically active substances from symmetrically constituted compounds with the intermediate use of optically active materials but with the exclusion of all analytical processes . In today s language, this would mean that asymmetric syntheses are those reactions, or sequences of reactions, which produce chiral nonracemic substances from achiral compounds with the intermediate use of chiral nonracemic materials, but excluding a separation operation. 

In conclusion, the term asymmetric synthesis should be used, if at all, only in the modernized" Marckwald sense. The Morrison-Mosher generalization is much better covered by the term stereoselective reaction. 

Furan-2-methanols are cleaved to derivatives of levulinic ester by methanolic hydrogen chloride a mechanism involving the carbonium ion (375) has been proposed. Under similar conditions, a,(3- unsaturated carbonyl compounds of type (384) undergo a similar rearrangement, a reaction known as the Marckwald rearrangement, and afford keto esters of type (385), as shown in Scheme 105 in an example drawn from a synthesis of equilenin (70AJC547). 

The Marckwald synthesis116 employed the reaction of a-amino-ketones with cyanates, thiocyanates, and isothiocyanates to yield 3 -imidazol-2-ones or AH-imidazole-2-thiones which are readily converted into imidazoles. The chief limitation of this method, which has been discussed adequately in earlier reviews,1-3 is in the synthesis of the a-aminocarbonyl compounds. The most convenient procedure is by reduction with sodium amalgam of a-amino acids.117 Among recent applications of the method118 119 is the synthesis118 of 4,5-... 

The earliest method of this type, developed by Marckwald, employed the reaction of a-aminocarbonyl compounds (or their acetals) with cyanates, thiocyanates or isothiocyanates to give 3//-imidazoline-2-thiones. These compounds can be converted readily into imidazoles by oxidation or dehydrogenation. The major limitations of this synthetic procedure are the difficulty of synthesis of a wide variety of the a-aminocarbonyl compounds, and the limited range of 2-substituents which are introduced. The reduction of a-amino acids with aluminum amalgam provides one source of starting materials. The method has been applied to the preparation of 4,5-trimethyleneimidazole (83) from 2-bromocyclopentanone (70AHC(12)103), and to the synthesis of pilocarpine (84 Scheme 47) (80AHC(27)24l). If esters of a-amino acids react with cyanates or thiocyanates, the products are hydantoins and 2-thiohydantoins, respectively. 

In situ formation of a-aminoketones has been achieved from the reaction of a-hydroxy- or a-haloketones with amines. l,3-Dihydroxypropan-2-one has been used as a starting material in the Marckwald synthesis <1997JME3297>. Also, reaction of 4-chloro-Wmethyl-3-oxobutanamide 1274 with amines leads to cyclic (E)-N-methyl-5-(methylimino)-2,5-dihydrofuran-3-amines 1275, which behave as latent a-aminoketones. Treatment of 1275 with isothiocyanates in refluxing EtOH affords imidazole-2-thiones 1276 (Scheme 323) <2005JC0826>. 

Thioamides can serve as surrogates for isothiocyanates in the Marckwald synthesis. For example, reaction of a-amino acetals 1278 with thioamides 1277 in the presence of HgClz affords amidine intermediates, which cyclize to form imidazoles under acidic conditions. This method has been applied to synthesize a variety of sugar imidazoles (Scheme 324) <2005HCA10, 2004HCA3035, 2004HCA719, 2000TA435>. 

The last reaction, oxidation of 1,2,4-triazole-3-thiol to 1,2,4-triazole, requires comment. The replacement of the sulfhydryl group by hydrogen by oxidation with dilute nitric acid was discovered by Marckwald in the imidazole series ... 

The enantioselective decarboxylative protonation, which is directly related to the venerable malonic add synthesis, has not shown the major advances in terms of selectivity that we could have expected for the oldest methodology used to carry out enantioselective protonations (Marckwald, 1904). The use of this reaction and, in particular, of its organocatalyzed version for the synthesis of compounds of biological significance is now emerging. This highlights the synthetic potential of this low-cost and operationally simple reaction, notably in the context of sustainable chemistry. However, this asymmetric reaction is not yet mature. Further investigations... 

The first use of a tosylamide in a cyclization reaction was reported nearly 100 years ago in German patents for the preparation of 1,4-ditosylpiperazine by Marckwald and Droste-Huelshoff (1898). Azetidine was also prepared by this process, as well as 1,5-diazacyclooctane using the appropriate halide and tosylamide (Bleier, 1899 Howard and Marckwald, 1899). A similar method was applied to macrocycles by Stetter and Roos (1954, 1955) when they reported the 2 2 cyclization reaction of an o ,(ij-dihalide with the dipotassium salt of an aromatic bis-sulfonamide as shown. Ring closure of an A-tosyl... 

In modem terminology, the core of Marckwald s definition is the conversion of an achiral substance into a chiral, nonracemic one by the action of a chiral reagent. By this criterion, the chiron approach falls outside the realm of asymmetric synthesis. Marckwald s point of reference of course, was biochemical processes, so it follows that modern enzymatic processes [30-32] are included by this definition. Marckwald also asserted that the nature of the reaction was irrelevant, so a self-immolative reaction or sequence such as an intermolecular chirality transfer in a Meerwein-Pondorf-Verley reaction would also be included ... 

A soln. of benzaldehyde and phenyl isoeyanide allowed to stand with (-)-menthoxyacetic acid at —5 for 4 days, and another 2 days after dilution with ether—> (-)-menthoxyacetylmandelic acid anilide. Crude Y 80% pure Y 56%.—The reaction is subject to asymmetric induction and yields one diastereomeric form in excess. It may be used, in the Marckwald sense, for the synthesis of optically active a-hvdroxy acids. (F. e. and limitations s. R. H. Baker and L. E. Linn, Am. Soc. 70, 3721 (1948).)... 

Under similar conditions, 2-furyl vinylcarbonyl systems (ketones, esters, acids) also produce keto esters. For example, 3-(2-furyl)acrylic acid 38, which is easily accessible from 2-furaldehyde by a decar-boxylating Knoevenagel reaction with malonic acid, yields the 3-oxoheptanedicarboxylic ester 39 (Marckwald cleavage) [9] ... 

This reaction was first reported by Marckwald in 1904. It is the synthesis of chiral L-valeric acid (a-methyl propanoic acid) from the pyrolysis of brucine salt of racemic o -methyl-o -ethylmalonic acid. Therefore, it is generally known as the Marckwald asymmetric synthesis. Occasionally, it is also referred to as the Marckwald method. In this reaction, the brucine salts of racemic a-methyl-a-ethylmalonic acid essentially exist as a pair of diastereomers that are separated by fractional crystallization the one with lower solubility is isolated. Upon pyrolysis of such crystalline salt at 170°C, the corresponding brucine salt of L-valeric acid forms upon decarboxylation, resulting in a 10% e.e. In addition, Marckwald defined the asymmetric synthesis as reactions that produce optically active molecules from symmetrically constituted compounds with the use of optically active materials and exclusion of any analytical processes, such as resolution. However, this work was challenged as not being a trae asymmetric synthesis because the procedure was similar to that of Pasteur. In fact, the If actional crystallization of the diastereomers is a resolution process. This process is used as base for many other preparations of chiral molecules, such as tartaric acid and under its influence, the kinetic resolution and tme asymmetric synthesis have been developed in modem organic synthesis. The asymmetric synthesis has been redefined by Morrison and Mosher as the reaction by which an achiral unit of the substrate is converted into a chiral unit in such a manner that the two resulting stereoisomers are produced in unequal amounts. ... 

The first discussions concerning the conditions for aeating optically active compounds in the laboratory may be traced to Pasteur and Le Bel. The first mention of the expression "asymmetric synthesis" can be found in the work of E. Fischer in 1894 concerning his stereochemical studies on sugars. He observed the formation of unequal amounts of cyanohydrins in the Kiliani reaction applied to aldehydic sugars. In 1904, Marckwald reported an asymmetric synthesis of 2-methyl-butanoic acid by decarboxylation of 2-ethyl 2-methyl-malonic acid in the presence of an alkaloid. The importance and the mechanism of this reaction were later the subject of much debate. However, this paper remains significant because Marckwald defined asymmetric synthesis, as follows "It is a reaction giving optically active products from symmetrical... 

The reaction principle manifested in the Marckwald synthesis is of considerable variability. Thus, cyanates or thiocyanates (via 40 43) yield imidazol-2-ones or -2-thiones... 

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