Bredereck reaction

The other half starts with formation of the imidazole by the Bredereck reaction. The leaving group in 208 can be an acetate but more interestingly the nucleophile can be an excess of forma-mide HCONH2. The alcohol 205 reacts selectively in strongly acidic solution with the aminothiol to give 218 without protection. After isolation as the HBr salt, 203 is liberated and reacted with 217 to give the complete molecule. 

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. 

A similar reaction of a-substituted jS-dialkylaminoacroleins (18), developed by Bredereck et al., proved useful for the synthesis of 4-substituted isoxazoles (19). ... 

With sulfinyl chlorides the isolated product of their reaction with sulfinate ions is the sulfinyl sulfone (126) (Bredereck et al., 1960). However, whether this results because S-sulfinylation is kinetically preferred, or rather comes about because the sulfinic anhydride resulting from initial O-sulfinylation is readily converted by some of the remaining sulfinate ion to the thermodynamically more stable sulfinyl sulfone (126a), does not appear to have ever been definitely established. 

Addition of sulfinate ions to the carbonyl group of aldehydes to form c-hydroxy sulfones (Bredereck et al., 1954, Bredereck and Bader, 1954) is also known, as is the participation of sulfinic acids as the acid component in Mannich-type condensation reactions with aldehydes (129) (Rawson and Engberts, 1970 Engberts and Strating, 1964, 1965). 

Reaction of 434 with the Bredereck reagent gave the enamino ketone... 

The formation of a pyrimido[5,4-f][l,2]thiazine by annulation of a pyrimidine ring onto a benzoH[l,2]thiazin-4-one has been reported, involving condensation with dimethylformamide dimethyl acetal followed by Bredereck s reagent (Scheme 90), and reaction of the resultant vinylogous amide with guanidine <2005W02005/037843>. Essentially, the same approach has been used to prepare annulated forms of the isomeric pyrimido[4,5-< ][l,2]thiazines, as outlined in Scheme 91 <1998W098/28281>. 

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). 

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. 

According to Bredereck et al.,17,18 the reaction of carboxylic acid amides with dialkyl sulfates proceeds via the intermediate ambident cation such as (5). In the case of caprolactam, when excess dialkyl sulfate is taken, the A,(9-dialkyl derivative (6) is formed, which with base forms 3 (Scheme 1). 

Carboxylation. Bredereck s reagent has been used in a simple synthesis of L-y-carboxyglutamic acid (S), an unusual natural amino add present in prothrombin and believed to be involved in elotting. The starting material is the lactam 1 derived from L-glutamic acid and available commercially. It is converted by reaction with this reagent into the enamide 2. Reaction with 2,2,2-trichloroethoxycarbonyl chloride transforms 2 into the trichloroethyl ester 3 in moderate yield. The synthesis of 5 is completed by reaction with benzyl alcohol and triethylamine followed by hy drogenolysis. ... 

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>. 

It may be of advantage in certain reactions to protect individual hydroxyl groups by tritylation. For example, Bredereck found that the mutarotation of D-ribose proceeded in a different manner than that of its 5-trityl ether. With the latter, the mutarotation corresponded to an a-/3 transformation of the two furanose forms. In free ribose more than two forms participate in the mutarotation, probably the two pyranose forms in addition to the two furanose forms. The possible formation of a pyranose ring is excluded by tritylation in the 5-position. 

Bredereck " succeeded in preparing a hexaacetyltrehalosedieen (LX) from trehalose through ditrityltrehalose and 6,6 -diiodo-6,6 -didesoxy-trehalose hexaacetate. Since this compound does not reduce Fehling solution after deacetylation and does not give other carbonyl reactions, both components of trehalose contain pyranose rings. 

In 1933, Bredereck discovered that adenosine reacts with trityl chloride to give a raonotrityl-adenosine which, without direct experimental evidence, he assumed to be 5-trityl-adenosine. In support of this formulation he presented the observation that no reaction between trityl chloride and a mixture of a- and 8-methyl ribopyranosides (having no primary hydroxyl group) could be detected polarimetrically. 

Bolomey and Allen found that a non-specific phosphatase preparation (Bredereck ) containing a small amount of ribonuclease hydrolyzes ribosenucleic acid in such a manner that guanosine is liberated faster than adenosine, in the early stages of the hydrolysis the equivalent amount of free phosphoric acid is simultaneously formed. After hydrolysis of the purine nucleotide constituents has reached a maximum, hydrolysis of the pyrimidine nucleotides becomes appreciable. (If the ribosenucleic acid is subjected to the action of ribonuclease before treatment with the phosphatase, the reaction is much more rapid.) They therefore tentatively suggested that guanylic acid is the first mononucleotide liberated and adenylic acid the second. Hence, provided that... 

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. 

---