Bredereck, formamide synthesis

It is convenient to combine these two synthetic approaches because they are formally similar. Both condense an a-functionalized ketone or aldehyde (C-4-C-5 synthon) with an amine or ammonia (N-1, N-3) and an aldehyde (C-2). "Die alternative Bredereck modification uses formamide as the source of the C-2-N-3 bond and of N-1. The older (Radziszewski or Weidenhagen) methods give 4-mono-, 4,5-di- and 2,4,5-trialkyl or -triaryl imidazoles the Bredereck formamide synthesis is largely restricted to the preparation of imidazoles with no 2 substituent. 

BREDERECK Imidazole synthesis Synthesis at imidazoles Irom formamide (acetamide) and a-diketones, o-ketols, o amnnketones, a-oximinoketones... 

Bredereck s [456] reagent, dime- pyrazole thyl formamide synthesis dimethyl acetal (solvent 50 mh for 5 g resin)... 

These reactions are typified by Bredereck s formamide synthesis . This has been applied to the synthesis of 4,5-dimethylimidazole (as its formic acid complex) from acetoin and formamide <91JHC1819>. A similar reaction leads to 5-methylhistamine (243) <8lJHC83l>. 1-Hydroxyimidazoles are accessible in high yield from reaction of nitrosonium fluoroborate with acetonitrile and appropriate alkenes (Scheme 177) <84TL1319>. 

Probably the most valuable advance in the field of oxazole syntheses has come from the methods developed by Bredereck and his co-workers.92-94 The so-called formamide synthesis of Bredereck et al. involves, especially in this case, the interaction of a-halo ketones with formamide and usually results in high yields of oxazoles (50-70%). 

The Bredereck-type synthesis, which is well known as a conventional preparation of pyrimidine derivatives, generally requires a reaction temperature of more than 160 °C, and the product yield is moderate. A simple, high-yielding synthesis of pyrimidines from ketones in the presence of HMDS and formamide is reported. Under microwave irradiation, heteroaromatic, aryl, aliphatic, and cyclic ketones cyclized to give pyrimidines in good yields. 

Whereas a-amino ketones readily form imidazoles with formamide, they are often not easy to prepare. Accordingly, they can be replaced by precursors, a-oximino ketones, which can be reduced either by dithionite or using catalytic mehods in formamide at 70-100 °C. Ring closure can then be achieved by raising the temperature (Scheme 80). When a-ketol esters are used it appears that the imidazole formation may in this instance proceed by way of the oxazole. A further special case is the formation of 4,5-disubstituted imidazoles from 1-chloro-l,2-epoxides and formamide. One recent example of an application of Bredereck s method is the synthesis of the imidazolepropanol (144) from 3-bromo-2-methoxytetra-hydropyran (Scheme 81) (80AHC(27)241). 

Some of the 4,5-dialkylimidazoIes made by Bredereck [48] are thought to be complexes with formic acid, i.e. the reaction of acetoin with formamide gives a 1 1 hydrogen-bonded adduct of formic acid and 4,5-dimethylimidazole rather than the formate salt, and so an alternative synthesis of 4,5-dimethylimidazole has been proposed using the sequence 4-hydroxymethyI-5-methylimidazole 4-chloromethyl-5-methylimidazole 4,5-dimethylimidazole (80-90%) as the free base [56],... 

Scheme 359 illustrates this classification. Bredereck s formamide cyclization continues to be one of the choices for the synthesis of 4,5-disubstituted or 4(5)-monosubstituted imidazoles <2005JME6632, 2005H(65)2783, 1997S347>. Typically, the reaction proceeds at high temperature with formamides and a-haloketones as the starting materials. For instance, monosubstituted imidazole 1389 is prepared from compound 1388 in 25% yield. 4,5-Disubstituted imidazole 1391 with a hindered side-chain is obtained from 1390 in 48% yield (Scheme 360) <2000JOC8402>. 

The Bredereck modification which uses an a-halo- (or otherwise functionalized) carbonyl compound with formamide has not received the attention that might have been expected. The synthesis of the imidazolepropanol 3 from 3-bromo-2-methoxytetrahydropyran provides one of the only examples (Eq. 2). 

An alternative imidazole synthesis supplies both nitrogen atoms as formamide HCONHj, and uses an a-halo ketone (100) for the rest. This is the Bredereck reaction another testimony to the ease of heterocyclic synthesis. 

Aminoimidazoles are obtained from guanidine, whereas urea or thiourea yield imidazole-2(3//)-one or -thione, respectively. Imidazoles 5 unsubstituted in the 2-position are obtained from a-hydroxy ketones and formamide Bredereck synthesis) ... 

The formamides 16 are intermediates. Formamide (Bredereck variant of the Traube synthesis [149]), formamidine, orthoformic ester, diethoxymethyl acetate, Vilsmeier reagent (fi om DMF and POCI3) and dithioformic acid are used as formic acid derivatives. 4,5-Diaminopyrimidines can be obtained from 4-aminopyrimidines 17 by nitrosation with HNO2 followed by reduction of the nitroso compounds 18 ... 

StUl noteworthy is the elegant two-stage synthesis of caffeine, which Hellmut Bredereck (1904-1981) published in 1950. [521] Thereby, uric acid - as a matter of choice, the excrement of snakes may be used as weU - is heated to reflux in formamide. The precipitated xanthine is dissolved in aqueous sodium hydroxide, purified with activated charcoal, and fmaUy methylated with dimethyl sulfate. With pure uric acid, the overall yield of caffeine is 60 %, and in the case of... 

Pyrimidine, mp 22.5 °C, bp 124°C, is a water-soluble, weak base that forms a sparingly soluble complex with HgCl2. Pyrimidine is prepared by condensation of 1,1,3,3-tetraethoxypropane with formamide over montmorillonite (Bredereck synthesis) at 210 °C in the gas phase [271] ... 

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