Bredereck methods

The isolated yields of the Bredereck method are satifactory for the synthesis of di-substituted compounds (figure 5) but are generally lower for 4(5)-mono-substituted imidazoles. 

Figure 5. Synthesis of histamine H) -agonists via the Bredereck method...

Such synthetic approaches can only be valid if the other heterocycles are readily available, or if their transformations lead to imidazoles difficult to make by other means. It is certainly important to be able to aromatize imidazolines since a number of ring-synthetic procedures lead to reduced imidazoles. 4-Aminoisoxazoles are sources of a-acylaminoenaminones which cyciize with bases to give 4-acylimidazoles. Oxazole-imidazole conversion has largely historical importance, but it is also implicated in some ring-synthetic procedures (e.g. the Bredereck method, see Chapter 5). Transformations of benzofuroxans into 2-substituted benzimidazole iV-oxides have some synthetic importance. Few, if any, ring contractions appear to have major application. 

Bredereck, Hennig, and Pfleiderer 6 describe a method for the formation of diaminouracil from uric acid which involves acetylation and subsequent hydrolysis of the acetyl derivative. This preparation was attempted on a large scale by the submitters without success (even when the acetylation step was carried out twice on the same material). 

Die Bredereck-Synthese (s.a. Bd. VII/2c, S. 2239 Bd. XI/1, S. 659) ist eine einfache und breit anwendbare Methode zur Herstellung von in 2-Stellung unsubstituierten Imidazolen aus -Hydroxy- oder a-Halogen-ketonen durch Umsetzung mit Formamid44. 

Diketone 12 must be condensed with a third, doubly functionalized octahydroacridine unit in the last step of the torand synthesis (cf Scheme 6.1). The following protocols (8-10) describe the three-step synthesis of torand precursor 15 from octahydroacridine 5. The reagents involved in these three steps are shown in Scheme 6.11. According to Protocol 8, octahydroacridine is condensed with benzaldehyde in the presence of acetic anhydride,24 as in the second stage of Protocol 2 (cf Scheme 6.3). The crystalline product 13 precipitates from the reaction mixture in high yield and purity. Ozonolysis of 13 (Protocol 9) is conducted by the method described in Protocol 7 for conversion of 11 to diketone 12 (cf. Scheme 6.10) and the same precautions apply. The product diketone 1425 requires no further purification after removal of benzaldehyde by trituration with diethyl ether. The third octahydroacridine unit is then readied for torand cyclization in Protocol 10 by condensing diketone 14 with Bredereck s reagent, r-butoxybis(dimethylamino)methane,26 which is commercially available. The bis[p-(dimethylamino)]enone product 15 is easily purified by precipitation from ether/dichloromethane. 

It becomes apparent when one is faced with a synthetic problem in imidazole chemistry that there is no single, widely applicable synthetic procedure. Even the methods devised by Bredereck (Section II, A) and the reaction of a-aminoketones with cyanates or thiocyanates (Section II, F) have limitations. 

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). 

H. Bredereck, R. Gompper, H. G. V. Schiih and G. Theilig in Newer Methods of Preparative Organic Chemistry, ed. W. Foerst Academic, New York, 1964,... 

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. 

Up to this time, little attention had been paid to the possibility of phosphoamide links because, in 1910, Levene and Jacobs had shown that the (three) primary amino groups (of the purines and the cytosine) are presumably not substituted in the nucleic acid since they can be determined by van Slyke s method. However, in 1936, Bredereck hydrolyzed ribosenucleic acid (Boehringer) by boiling an aqueous solution of the substance, and isolated a very small amount of material which was described as amorphous, monobasic, and readily hydrolyzed to guanine and uridylic acid. He therefore decided it was a guanine-uridylic acid and assigned it the following structure. 

Method (ii).—A method which seemed more promising for the specific synthesis of 6,6 -diesters of trehalose was then first studied with synthetic mycolic acids of lower molecular weight. This method consists in heating the potassium salt of an acid with 2,3,4,2, 3, 4 -hexa-0-acetyl-6,6 -di-0-p-tolylsulfonyltrehalose (10), a compound already described by Bredereck. "... 

In the method of Bredereck for permethylation of carbohydrates, partially methylated material is dissolved in ether, sodium wire is added followed by dimethyl sulfate diluted with ether. The reaction is complete in about one hour. 

Since simpler methods were available for the reduction of azo and nitro compounds, over half a century elapsed before practical use was made of these early flndings. Then Bredereck and von Schuh " encountered difficulty in the reduction of the nitro groups of a series of polynitroamido esters of formula (1). The compounds are insoluble in water and in aqueous acid. Hydrogenation in acetic acid... 

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%). 

This method is not suited to the preparation of 2-unsubstituted oxazoles the main difficulty is the preparation of the acyloin formates themselves. Bredereck and Gompper94 introduced a new method of synthesizing the acyloin formates (54) by the treatment of acyloins in formic acid solution in the cold with either phosphorus trichloride or thionyl chloride. The yields in the three reported cases are 61-91%. These a-formyloxy ketones on boiling with formamide in formic acid afford the corresponding oxazoles. unsubstituted in the 2-position, in 61-75% yields.94... 

Japan, pat. 732C86) (to Ajinomoto), C.A. 51, 3870b (1957). Structure Levene, Bess, op. ctt.. pp 187-192 Bredereck, Ber. 66, 198 (1933) Levene, Tipson, J. Biol. Chem. Ill, 3t3 (1935). Also prepd from muscle by enzymatic deamination of muscle adenylic acid Ostem, Biochem. Z. 254, 63 (1932) by hydrolysis of inosine triphosphate Kleinzeller, Biochem. J. 36, 729 (1942). Studies on the enzymatic synthesis Greenberg, J. Biol. Chem. 198, 611 (1951) Korn et al, ibid 217, 875 (1955). Microbial fermentation method using mutant strains of Micrococcus glutamicus Kinoshita el al. U.S. pat. 3,232,844 (1966 to Kyowa). 

Wasserman et al. have published details of their studies on the synthesis of a-keto-derivatives of ketones, lactones, esters, lactams and amides, by an approach which involves the cleavage of enamino carbonyl systems by reaction with singlet oxygen [equation (39)]. Several methods for the preparation of the enamino compounds are described with different reagents being preferred for different substrates. Thus, with ketones Bredereck s reagent [Bu OCH(NMe2)2 used, but esters and... 

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