BREDERECK Imidazole synthesis

BREDERECK Imidazole synthesis Synthesis o( imidazoles Irom (ormamide (acetamide) and a-diketones, a-ketols, a-aminoketones, a-oziminoketones... 

BREDERECK Imidazole synthesis 48 BROOK Sitaketona rearrangement 49 BROWN Stereoselective reduction 50 BROWN Hydroboiation 51-52 Bnirmer 104... 

Similar enamine cyclization processes occur in several other successful heterocycle syntheses, e.g. in the Fischer indole synthesis. In this case, however, a labile N—N bond of a l-aryl-2-vinylhydrazine is cleaved in a [3,3]-sigmatropic rearrangement, followed by cyclization and elimination of ammonia to yield the indole (B. Robinson, 1963, 1969 R. J. Sundberg, 1970). Regioselectivity is only observed if R2 contains no enolizable hydrogen, otherwise two structurally isomeric indoles are obtained. Other related cyclization reactions are found in the Pechmann synthesis of triazoles (T.L. Gilchrist, 1974) and in G. Bredereck s (1939) imidazole synthesis (M.R. Grimmett, 1970). 

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. 

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. 

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. 

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). 

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>. 

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 first report of the use of cellulose beads as support for microwave-assisted SPOS was published in 2003 and described the generation of a library of pyrazoles and isoxazoles [49]. The synthesis was performed using commercially available amino cellulose (Perloza VT-100) containing aminoaryl ethyl sulfone groups in flexible chains (Scheme 16.27). Initially, the solid support was treated with excess formyl imidazole and the corresponding yS-keto compounds to generate cellulose-bound enaminones in a one-pot Bredereck-type condensation. The reaction was catalyzed by (+)-camphor-10-sulfonic acid (CSA) and performed under microwave-irradiation conditions in an open vessel to enable the methanol formed to be removed from the reaction equilibrium [49]. 

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