Marckwald synthesis

Treatment of the a-aminoaldehyde (125) with potassium thiocyanate gave 3//-imidazoIe-2-thione (126) (Marckwald synthesis), which produced the 5-acetyl derivative of (127) hydrolysis gave (127) itself (54JCS3283). 

The earliest method of this type was the old Marckwald synthesis (1] in which a suitable a-aminocarbonyl compound is cyclized with cyanate, thiocyanate or isothiocyanatc. More recent modifications have employed the acetals of the a-amino aldehyde or ketone or an a-amino acid ester. The two-carbon fragment can also be provided by cyanamide, a thioxamate, a carbodiimidc or an imidic ester. When cyanates, thiocyanates or isothiocyanates are used, the imidazolin-2-ones or -2-thiones (1) are formed initially, but they can be converted into 2-unsubstituted imidazoles quite readily by oxidative or dehydrogenative means (Scheme 4.1.1). The chief limitations of the method arc the difficulty of making some a-aminocarbonyls and the very limited range of 2 substituents which are possible in the eventual imidazole products. The method is nonetheless valuable and widely used, and typically condenses the hydrochloride of an a-amino aldehyde or ketone (or the acetals or ketals), or an a-amino-)6-ketoester with the salt of a cyanic or thiocyanic acid. Usually the aminocarbonyl hydrochloride is warmed in aqueous solution with one equivalent of sodium or potassium cyanate or thiocyanate. An alkyl or aryl isocyanate or isothiocyanate will give an A-substituted imidazole product (2), as will a substituted aminocarbonyl compound (Scheme 4.1.1) [2-4]. 

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>. 

An adaptation of the old Marckwald synthesis has allowed an improved preparation of pilocarpine (30) (see Scheme 8). 

The most common examples utilize the old Marckwald synthesis in which an a-aminocarbonyl species (or equivalent aminonitrile) reacts with cyanates, thiocyanates, cyanamide, etc. to give 2-imidazolones, 2-imidazolethiones, 2-aminoimidazoles, or reduced versions in cases where aro-matization is not favored. Often oxidation or dehydrogenation will accomplish the aromatization. 

This synthetic principle (Marckwald synthesis) can be applied in various ways cyanates yield imida-zole-2(3//)-ones, thiocyanates imidazole-2(37 /)"thiones and alkylisothiocyanates 1-alkylimidazole-2(3//)-thiones. 

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... 

Madelung synthesis (indole) 137 Marckwald cleavage, of furans 79 Marckwald synthesis (imidazole) 224 Meth-Cohn synthesis (quinoline) 402 Meyer s oxazoline method 183 Morin reaction 456 Mukaiyama reaction 380 Mukaiyama reagents 53, 380... 

Debus synthesis, Radiszewski synthesis, dehydrogenation of imidazolines, from a-halo ketones, Wallach synthesis, from aminonitrile and aldehyde and Marckwald synthesis [116]. There have been reports of several assisted syntheses of imidazoles from 1,2-diketones and aldehydes in the presence of a variety of catalysts [117]. 

The first successful attempt in asymmetric synthesis was made by Marckwald in 1904 who prepared an active (-) -valeric acid by heating the half brucine salt of ethyl methyl malonic acid at 170°C. 

The biological method thus only serves for the preparation of that isomer which does not occur in nature, since the mould or yeast or enzyme destroys the naturally occurring form, leaving the other isomer untouched, or according to Marckwald and Mackenzie, it acts upon the natural isomer more rapidly than upon the other. The method therefore does not lead to the synthesis of the naturally occurring amino acid. 

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. 

Many modified Marckwald procedures are available to prepare structurally diverse imidazoles most of them are focused on the preparation of an oe-aminoketone or its equivalents. For example, a regiospecific synthesis of trisubstituted imidazoles has been developed. Thus, treatment of BOC-protected a-amino acids 1265 with malonic monoester leads to a-aminoketones. After removal of the BOC protecting group, the resulted a-aminoketone salt 1266 will condense with isothiocyanates to form thioureas 1267. The intermediates 1285 undergo cyclodehydration under acidic conditions, yielding imidazole-2-thiones 1268 in good yields. Both reductive and oxidative desulfonation have been used to convert the imidazole-2-thiones 1268 into imidazoles (1269 or 1270) (Scheme 321) <2005TL7315>. 

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 most quoted definition of an asymmetric synthesis is that of Marckwald [29] ... 

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 ... 

Interestingly, the Marckwald definition is taken from a paper that was rebutting a criticism [33] of Marckwald s claim to have achieved an asymmetric synthesis by a group-selective decarboxylation of the bmcine salt of 2-ethyl-2-methylmalonic acid [34,35] ... 

Thus from the very beginning, the definition of what an asymmetric synthesis might encompass, or even if one was possible, has been a matter of debate. On the latter point, the idea that a chemist could synthesize something in optically active form from an achiral precursor was doubted in some circles, even in Marckwald s... 

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).)... 

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. ... 

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